Significance of change in serum bilirubin in predicting left ventricular reverse remodeling and outcomes in heart failure patients with cardiac resynchronization therapy.

PubMed

Hosoda, Junya; Ishikawa, Toshiyuki; Matsumoto, Katsumi; Iguchi, Kohei; Matsushita, Hirooki; Ogino, Yutaka; Taguchi, Yuka; Sugano, Teruyasu; Ishigami, Tomoaki; Kimura, Kazuo; Tamura, Kouichi

2017-11-01

Research on the correlation of serum bilirubin level with cardiac function as well as outcomes in heart failure patients with cardiac resynchronization therapy (CRT) has not yet been reported. The aim of this study was to analyze the relationship between change in serum bilirubin level and left ventricular reverse remodeling, and also to clarify the impact of bilirubin change on clinical outcomes in CRT patients. We evaluated 105 consecutive patients who underwent CRT. Patients who had no serum total-bilirubin data at both baseline and 3-9 months' follow-up or had died less than 3 months after CRT implantation were excluded. Accordingly, a total of 69 patients were included in the present analysis. The patients were divided into two groups: decreased bilirubin group (serum total-bilirubin level at follow-up≤that at baseline; n=48) and increased bilirubin group (serum total-bilirubin level at follow-up>that at baseline; n=21). Mean follow-up period was 39.3 months. In the decreased bilirubin group, mean left ventricular end-systolic diameter decreased from 54.5mm to 50.2mm (p=0.001) and mean left ventricular ejection fraction increased significantly from 29.8% to 37.0% (p=0.001). In the increased bilirubin group, there was no significant change in echocardiographic parameters from baseline to follow-up. In Kaplan-Meyer analysis, cardiac mortality combined with heart failure hospitalization in the increased bilirubin group was significantly higher than that in the decreased bilirubin group (log-rank p=0.018). Multivariate Cox regression analysis revealed that increased bilirubin was an independent predictor of cardiac mortality combined with heart failure hospitalization (OR=2.66, p=0.023). The change in serum bilirubin is useful for assessment of left ventricular reverse remodeling and prediction of outcomes in heart failure patients with CRT. Copyright © 2017 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Effect of L-Carnitine Supplementation on Reverse Remodeling in Patients with Ischemic Heart Disease Undergoing Coronary Artery Bypass Grafting: A Randomized, Placebo-Controlled Trial.

PubMed

da Silva Guimarães, Sheila; de Souza Cruz, Wanise; da Silva, Licinio; Maciel, Gabrielle; Huguenin, Ana Beatriz; de Carvalho, Monicque; Costa, Bárbara; da Silva, Geisiane; da Costa, Carlos; D'Ippolito, João Alvaro; Colafranceschi, Alexandre; Scalco, Fernanda; Boaventura, Gilson

2017-01-01

During cardiac failure, cardiomyocytes have difficulty in using the substrates to produce energy. L-carnitine is a necessary nutrient for the transport of fatty acids that are required for generating energy. Coronary artery graft surgery reduces the plasma levels of L-carnitine and increases the oxidative stress. This study demonstrates the effect of L-carnitine supplementation on the reverse remodeling of patients undergoing coronary artery bypass graft. Patients with ischemic heart failure who underwent coronary graft surgery were randomized to group A - supplemented with L-carnitine or group B controls. Left ventricular ejection fraction, left ventricular systolic and diastolic diameters were assessed preoperatively, 60 and 180 days after surgery. Our study included 28 patients (26 [93.0%] males) with a mean age ± SD of 58.1 ± 10.5 years. The parameters for the evaluation of reverse remodeling did not improve after 60 and 180 days of coronary artery bypass grafting in comparison between groups (p > 0.05). Evaluation within the L-carnitine group showed a 37.1% increase in left ventricle ejection fraction (p = 0.002) and 14.3% (p = 0.006) and 3.3% (p > 0.05) reduction in systolic and diastolic diameters, respectively. L-carnitine supplementation at a dose of 50 mg/kg combined with artery bypass surgery did not demonstrate any additional benefit in reverse remodeling. However, evaluation within the L-carnitine group may indicate a clinical benefit of L-carnitine supplementation. © 2017 S. Karger AG, Basel.

Myocardial scar location as detected by cardiac magnetic resonance is associated with the outcome in heart failure patients undergoing surgical ventricular reconstruction.

PubMed

Castelvecchio, Serenella; Careri, Giulia; Ambrogi, Federico; Camporeale, Antonia; Menicanti, Lorenzo; Secchi, Francesco; Lombardi, Massimo

2018-01-01

Post-infarction myocardial scar causes adverse left ventricular remodelling and negatively affects the prognosis. We sought to investigate whether scar extent and location obtained by cardiac magnetic resonance may affect the reverse remodelling and survival of heart failure patients undergoing surgical ventricular reconstruction. From January 2011 to December 2015, 151 consecutive patients with previous myocardial infarction and left ventricular remodelling underwent surgical ventricular reconstruction at our Institution, of which 88 (58%) patients had a preoperative protocol-standardized late gadolinium enhancement (LGE)-cardiac magnetic resonance examination during the week before surgery. We excluded 40 patients with devices (26%), 15 patients with irregular heart rhythm (permanent atrial fibrillation, 10% not included in the device group) or mixed contraindications (severe claustrophobia or presence of material magnetic resonance not compatible). Among the 145 survivors, 11 patients received an implantable cardioverter defibrillator after surgery (mostly for persistent low ejection fraction) and were excluded as well, yielding a total of 59 patients (48 men, aged 65 ± 9 years) who repeated a protocol-standardized LGE-cardiac magnetic resonance examination even 6 months postoperatively and therefore represent the study population. Patients were grouped according to the presence of LGE in the antero-basal left ventricular segments (Group A) or the absence of LGE in the same segments (Group B). The postoperative left ventricular end-systolic volume index was considered the primary end-point. After surgery, left ventricular end-systolic volume index and end-diastolic volume index significantly decreased (P < 0.001, for both), while diastolic sphericity index and ejection fraction significantly increased (P = 0.015 and P < 0.001, respectively). The presence of LGE in the antero-basal left ventricular segments (10 patients, Group A) was the only independent predictor of outcome (P = 0.02) at multivariate analysis, being the postoperative left ventricular end-systolic volume index significantly higher compared to that of patients of Group B (49 patients) (78 ± 26 ml/m2 vs 55 ± 20 ml/m2, P = 0.003). Furthermore, patients with a postoperative left ventricular end-systolic volume index >60 ml/m2 showed a higher risk of cardiac events (hazard ratio = 3.67, P = 0.02). In patients undergoing surgical ventricular reconstruction, LGE scar location affects the left ventricular reverse remodelling, which in turn might limit the survival benefit. © The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Interlead distance and left ventricular lead electrical delay predict reverse remodeling during cardiac resynchronization therapy.

PubMed

Merchant, Faisal M; Heist, E Kevin; Nandigam, K Veena; Mulligan, Lawrence J; Blendea, Dan; Riedl, Lindsay; McCarty, David; Orencole, Mary; Picard, Michael H; Ruskin, Jeremy N; Singh, Jagmeet P

2010-05-01

Both anatomic interlead separation and left ventricle lead electrical delay (LVLED) have been associated with outcomes following cardiac resynchronization therapy (CRT). However, the relationship between interlead distance and electrical delay in predicting CRT outcomes has not been defined. We studied 61 consecutive patients undergoing CRT for standard clinical indications. All patients underwent intraprocedural measurement of LVLED. Interlead distances in the horizontal (HD), vertical (VD), and direct (DD) dimensions were measured from postprocedure chest radiographs (CXR). Remodeling indices [percent change in left ventricle (LV) ejection fraction, end-diastolic, end-systolic dimensions] were assessed by transthoracic echocardiogram. There was a positive correlation between corrected LVLED and HD on lateral CXR (r = 0.361, P = 0.004) and a negative correlation between LVLED and VD on posteroanterior (PA) CXR (r =-0.281, P = 0.028). To account for this inverse relationship, we developed a composite anatomic distance (defined as: lateral HD-PA VD), which correlated most closely with LVLED (r = 0.404, P = 0.001). Follow-up was available for 48 patients. At a mean of 4.1 +/- 3.2 months, patients with optimal values for both corrected LVLED (>or=75%) and composite anatomic distance (>or=15 cm) demonstrated greater reverse LV remodeling than patients with either one or neither of these optimized values. We identified a significant correlation between LV-right ventricular interlead distance and LVLED; additionally, both parameters act synergistically in predicting LV anatomic reverse remodeling. Efforts to optimize both interlead distance and electrical delay may improve CRT outcomes.

Surgical treatment of tricuspid valve insufficiency promotes early reverse remodeling in patients with axial-flow left ventricular assist devices.

PubMed

Maltais, Simon; Topilsky, Yan; Tchantchaleishvili, Vakhtang; McKellar, Stephen H; Durham, Lucian A; Joyce, Lyle D; Daly, Richard C; Park, Soon J

2012-06-01

The HeartMate II (Thoratec Corp, Pleasanton, Calif) continuous-flow left ventricular assist device has emerged as the standard of care for patients with advanced heart failure. The objective of this study was to assess the safety and early effectiveness of concomitant tricuspid valve procedures in patients undergoing implantation of a HeartMate II device. From February 2007 to April 2010, 83 patients underwent HeartMate II left ventricular assist device implantation. Of these, 37 patients had concomitant tricuspid valve procedures (32 repairs, 5 replacements) for severe tricuspid regurgitation. The effects of a tricuspid valve procedure on tricuspid regurgitation and right ventricular remodeling were assessed comparing echocardiographic findings at baseline and 30 days after left ventricular assist device implantation. Overall survival was also compared. Patients undergoing a concomitant tricuspid valve procedure had more tricuspid regurgitation (vena contracta, 5.6 ± 2.1 mm vs 2.9 ± 2.0 mm; P < .001), worse right ventricular dysfunction (right ventricular end-diastolic area, 33.6 ± 6.2 mm vs 31.6 ± 8.5 mm; P = .05), higher mean right atrial pressure (17.4 ± 7.1 mm Hg vs 14.9 ± 5.1 mm Hg; P = .03), and a higher Kormos score (2.6 ± 2.1 vs 1.2 ± 1.4; P = .0008) preoperatively. One month after surgery, tricuspid regurgitation was worse in patients who underwent left ventricular assist device implantation alone (+18.6%), whereas it improved significantly in patients undergoing a concomitant tricuspid valve procedure (-50.2%) (P = .005). A corresponding significant reduction in right ventricular end-diastolic area (33.6% ± 6.2% vs 30.1% ± 9.7%; P = .03) and a trend toward better right ventricular function (55.5% ± 79.7% vs 35.7% ± 60.5%; P = .28) were noted in patients undergoing a concomitant tricuspid valve procedure. Survival was comparable between the 2 groups. In patients with severe tricuspid regurgitation undergoing left ventricular assist device implantation, a concomitant tricuspid valve procedure effectively reduces tricuspid regurgitation and promotes reverse remodeling of the right ventricle. Copyright © 2012 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Size, shape, and stamina: the impact of left ventricular geometry on exercise capacity.

PubMed

Lam, Carolyn S P; Grewal, Jasmine; Borlaug, Barry A; Ommen, Steve R; Kane, Garvan C; McCully, Robert B; Pellikka, Patricia A

2010-05-01

Although several studies have examined the cardiac functional determinants of exercise capacity, few have investigated the effects of structural remodeling. The current study evaluated the association between cardiac geometry and exercise capacity. Subjects with ejection fraction > or = 50% and no valvular disease, myocardial ischemia, or arrhythmias were identified from a large prospective exercise echocardiography database. Left ventricular mass index and relative wall thickness were used to classify geometry into normal, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. All of the subjects underwent symptom-limited treadmill exercise according to standard Bruce protocol. Maximal exercise tolerance was measured in metabolic equivalents. Of 366 (60+/-14 years; 57% male) subjects, 166 (45%) had normal geometry, 106 (29%) had concentric remodeling, 40 (11%) had eccentric hypertrophy, and 54 (15%) had concentric hypertrophy. Geometry was related to exercise capacity: in descending order, the maximum achieved metabolic equivalents were 9.9+/-2.8 in normal, 8.9+/-2.6 in concentric remodeling, 8.6+/-3.1 in eccentric hypertrophy, and 8.0+/-2.7 in concentric hypertrophy (all P<0.02 versus normal). Left ventricular mass index and relative wall thickness were negatively correlated with exercise tolerance in metabolic equivalents (r=-0.14; P=0.009 and r=-0.21; P<0.001, respectively). Augmentation of heart rate and ejection fraction with exercise were blunted in concentric hypertrophy compared with normal, even after adjusting for medications. In conclusion, the pattern of ventricular remodeling is related to exercise capacity among low-risk adults. Subjects with concentric hypertrophy display the greatest limitation, and this is related to reduced systolic and chronotropic reserve. Reverse remodeling strategies may prevent or treat functional decline in patients with structural heart disease.

Size, Shape and Stamina: The Impact of Left Ventricular Geometry on Exercise Capacity

PubMed Central

Lam, Carolyn S.P.; Grewal, Jasmine; Borlaug, Barry A.; Ommen, Steve R.; Kane, Garvan C.; McCully, Robert B.; Pellikka, Patricia A.

2010-01-01

While several studies have examined the cardiac functional determinants of exercise capacity, few have investigated the effects of structural remodeling. The current study evaluated the association between cardiac geometry and exercise capacity. Subjects with ejection fraction ≥ 50% and no valvular disease, myocardial ischemia or arrhythmias were identified from a large prospective exercise echocardiography database. Left ventricular mass index and relative wall thickness were used to classify geometry into normal, concentric remodeling, eccentric hypertrophy and concentric hypertrophy. All subjects underwent symptom-limited treadmill exercise according to standard Bruce protocol. Maximal exercise tolerance was measured in metabolic equivalents. Of 366 (60±14 years; 57% male) subjects, 166(45%) had normal geometry, 106(29%) had concentric remodeling, 40(11%) had eccentric hypertrophy and 54(15%) had concentric hypertrophy. Geometry was related to exercise capacity: in descending order, the maximum achieved metabolic equivalents was 9.9±2.8 in normal, 8.9±2.6 in concentric remodeling, 8.6±3.1 in eccentric hypertrophy and 8.0±2.7 in concentric hypertrophy (all p<0.02 vs normal). Left ventricular mass index and relative wall thickness were negatively correlated with exercise tolerance in metabolic equivalents (r= -0.14; p=0.009 and r= -0.21; p<0.001, respectively). Augmentation of heart rate and ejection fraction with exercise were blunted in concentric hypertrophy compared to normal, even after adjusting for medications. In conclusion, the pattern of ventricular remodeling is related to exercise capacity among low-risk adults. Subjects with concentric hypertrophy display the greatest limitation and this is related to reduced systolic and chronotropic reserve. Reverse remodeling strategies may prevent or treat functional decline in patients with structural heart disease. PMID:20215563

A novel hydrodynamic approach of drag-reducing polymers to improve left ventricular hypertrophy and aortic remodeling in spontaneously hypertensive rats.

PubMed

Zhang, Xinlu; Wang, Xu; Hu, Feng; Zhou, Boda; Chen, Hai-Bin; Zha, Daogang; Liu, Yili; Guo, Yansong; Zheng, Lemin; Xiu, Jiancheng

Drag-reducing polymers (DRPs), when added in minute concentrations, have been shown to decrease peripheral vascular resistance. In this study, the effect of DRPs on the hypertension-induced left ventricular hypertrophy and aortic remodeling was evaluated in spontaneously hypertensive rats (SHR). Male SHR and age-matched Wistar rats were divided into four groups and received intravenous injection of normal saline (NS) or DRPs. Body weight (BW), heart rate (HR) and systolic blood pressure (SBP) were measured. Echocardiography was used to evaluate the changes in left ventricle (LV) function and global wall motion. The LV and aorta were stained by hematoxylin and eosin. Cell size of cardiomyocytes and aortic medial thickness were evaluated for each section. The expression of endothelin-1 (ET-1) of LV and aorta was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. There was no significant difference in the increase of SBP among SHR + NS, SHR + 10DRP and SHR + 20DRP groups. SHR + NS group had markedly smaller left ventricular end-systolic diameter and left ventricular end-diastolic diameter but bigger anterior and posterior systolic wall thicknesses, while there was no significant difference in fractional shortening and ejection fraction. The cross-sectional areas (CSAs) of cardiomyocytes and the medial thickness of the aorta in SHR + 10 (ppm) DRP and SHR + 20 (ppm) DRP groups were significantly reduced compared with SHR + NS group. The expression of ET-1 in SHR + 10DRP and SHR + 20DRP groups was significantly attenuated. These results suggest that chronic treatment with DRPs can protect against left ventricular hypertrophy and aortic remodeling. DRPs may offer a new approach to the treatment of left ventricular hypertrophy and aortic remodeling caused by hypertension.

A novel hydrodynamic approach of drag-reducing polymers to improve left ventricular hypertrophy and aortic remodeling in spontaneously hypertensive rats

PubMed Central

Zhang, Xinlu; Wang, Xu; Hu, Feng; Zhou, Boda; Chen, Hai-Bin; Zha, Daogang; Liu, Yili; Guo, Yansong; Zheng, Lemin; Xiu, Jiancheng

2016-01-01

Drag-reducing polymers (DRPs), when added in minute concentrations, have been shown to decrease peripheral vascular resistance. In this study, the effect of DRPs on the hypertension-induced left ventricular hypertrophy and aortic remodeling was evaluated in spontaneously hypertensive rats (SHR). Male SHR and age-matched Wistar rats were divided into four groups and received intravenous injection of normal saline (NS) or DRPs. Body weight (BW), heart rate (HR) and systolic blood pressure (SBP) were measured. Echocardiography was used to evaluate the changes in left ventricle (LV) function and global wall motion. The LV and aorta were stained by hematoxylin and eosin. Cell size of cardiomyocytes and aortic medial thickness were evaluated for each section. The expression of endothelin-1 (ET-1) of LV and aorta was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and immunohistochemistry. There was no significant difference in the increase of SBP among SHR + NS, SHR + 10DRP and SHR + 20DRP groups. SHR + NS group had markedly smaller left ventricular end-systolic diameter and left ventricular end-diastolic diameter but bigger anterior and posterior systolic wall thicknesses, while there was no significant difference in fractional shortening and ejection fraction. The cross-sectional areas (CSAs) of cardiomyocytes and the medial thickness of the aorta in SHR + 10 (ppm) DRP and SHR + 20 (ppm) DRP groups were significantly reduced compared with SHR + NS group. The expression of ET-1 in SHR + 10DRP and SHR + 20DRP groups was significantly attenuated. These results suggest that chronic treatment with DRPs can protect against left ventricular hypertrophy and aortic remodeling. DRPs may offer a new approach to the treatment of left ventricular hypertrophy and aortic remodeling caused by hypertension. PMID:28008249

Prediction of Reverse Remodeling at Cardiac MR Imaging Soon after First ST-Segment-Elevation Myocardial Infarction: Results of a Large Prospective Registry.

PubMed

Bodi, Vicente; Monmeneu, Jose V; Ortiz-Perez, Jose T; Lopez-Lereu, Maria P; Bonanad, Clara; Husser, Oliver; Minana, Gemma; Gomez, Cristina; Nunez, Julio; Forteza, Maria J; Hervas, Arantxa; de Dios, Elena; Moratal, David; Bosch, Xavier; Chorro, Francisco J

2016-01-01

To assess predictors of reverse remodeling by using cardiac magnetic resonance (MR) imaging soon after ST-segment-elevation myocardial infarction (STEMI). Written informed consent was obtained from all patients, and the study protocol was approved by the institutional committee on human research, ensuring that it conformed to the ethical guidelines of the 1975 Declaration of Helsinki. Five hundred seven patients (mean age, 58 years; age range, 24-89 years) with a first STEMI were prospectively studied. Infarct size and microvascular obstruction (MVO) were quantified at late gadolinium-enhanced imaging. Reverse remodeling was defined as a decrease in left ventricular (LV) end-systolic volume index (LVESVI) of more than 10% from 1 week to 6 months after STEMI. For statistical analysis, a simple (from a clinical perspective) multiple regression model preanalyzing infarct size and MVO were applied via univariate receiver operating characteristic techniques. Patients with reverse remodeling (n = 211, 42%) had a lesser extent (percentage of LV mass) of 1-week infarct size (mean ± standard deviation: 18% ± 13 vs 23% ± 14) and MVO (median, 0% vs 0%; interquartile range, 0%-1% vs 0%-4%) than those without reverse remodeling (n = 296, 58%) (P < .001 in pairwise comparisons). The independent predictors of reverse remodeling were infarct size (odds ratio, 0.98; 95% confidence interval [CI]: 0.97, 0.99; P = .04) and MVO (odds ratio, 0.92; 95% CI: 0.86, 0.99; P = .03). Once infarct size and MVO were dichotomized by using univariate receiver operating characteristic techniques, the only independent predictor of reverse remodeling was the presence of simultaneous nonextensive infarct-size MVO (infarct size < 30% of LV mass and MVO < 2.5% of LV mass) (odds ratio, 3.2; 95% CI: 1.8, 5.7; P < .001). Assessment of infarct size and MVO with cardiac MR imaging soon after STEMI enables one to make a decision in the prediction of reverse remodeling. © RSNA, 2015

Refining success of cardiac resynchronization therapy using a simple score predicting the amount of reverse ventricular remodelling: results from the Markers and Response to CRT (MARC) study.

PubMed

Maass, Alexander H; Vernooy, Kevin; Wijers, Sofieke C; van 't Sant, Jetske; Cramer, Maarten J; Meine, Mathias; Allaart, Cornelis P; De Lange, Frederik J; Prinzen, Frits W; Gerritse, Bart; Erdtsieck, Erna; Scheerder, Coert O S; Hill, Michael R S; Scholten, Marcoen; Kloosterman, Mariëlle; Ter Horst, Iris A H; Voors, Adriaan A; Vos, Marc A; Rienstra, Michiel; Van Gelder, Isabelle C

2018-02-01

Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in systolic heart failure patients with ventricular conduction delay. Variability of individual response to CRT warrants improved patient selection. The Markers and Response to CRT (MARC) study was designed to investigate markers related to response to CRT. We prospectively studied the ability of 11 clinical, 11 electrocardiographic, 4 echocardiographic, and 16 blood biomarkers to predict CRT response in 240 patients. Response was measured by the reduction of indexed left ventricular end-systolic volume (LVESVi) at 6 months follow-up. Biomarkers were related to LVESVi change using log-linear regression on continuous scale. Covariates that were significant univariately were included in a multivariable model. The final model was utilized to compose a response score. Age was 67 ± 10 years, 63% were male, 46% had ischaemic aetiology, LV ejection fraction was 26 ± 8%, LVESVi was 75 ± 31 mL/m2, and QRS was 178 ± 23 ms. At 6 months LVESVi was reduced to 58 ± 31 mL/m2 (relative reduction of 22 ± 24%), 130 patients (61%) showed ≥ 15% LVESVi reduction. In univariate analysis 17 parameters were significantly associated with LVESVi change. In the final model age, QRSAREA (using vectorcardiography) and two echocardiographic markers (interventricular mechanical delay and apical rocking) remained significantly associated with the amount of reverse ventricular remodelling. This CAVIAR (CRT-Age-Vectorcardiographic QRSAREA -Interventricular Mechanical delay-Apical Rocking) response score also predicted clinical outcome assessed by heart failure hospitalizations and all-cause mortality. The CAVIAR response score predicts the amount of reverse remodelling after CRT and may be used to improve patient selection. Clinical Trials: NCT01519908. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling.

PubMed

Li, Y Y; McTiernan, C F; Feldman, A M

2000-05-01

Myocardial fibrosis due to maladaptive extracellular matrix remodeling contributes to dysfunction of the failing heart. Further elucidation of the mechanism by which myocardial fibrosis and dilatation can be prevented or even reversed remains of great interest as a potential means to limit myocardial remodeling and dysfunction. Matrix metalloproteinases (MMPs) are the driving force behind extracellular matrix degradation during remodeling and are increased in the failing human heart. MMPs are regulated by a variety of growth factors, cytokines, and matrix fragments such as matrikines. In the present report, we discuss the regulation of MMPs, the role of MMPs in the development of cardiac fibrosis, and the modulation of MMP activity using gene transfer and knockout technologies. We also present recent findings from our laboratory on the regulation of the extracellular MMP inducer (EMMPRIN), MMPs, and transforming growth factor-beta(1) in the failing human heart before and after left ventricular assist device support, as well as the possibility of preventing ventricular fibrosis using different anti-MMP strategies. Several studies suggest that such modulation of MMP activity can alter ventricular remodeling, myocardial dysfunction, and the progression of heart failure. It is therefore suggested that the interplay of MMPs and their regulators is important in the development of the heart failure phenotype, and myocardial fibrosis in heart failure may be modified by modulating MMP activity.

The impact of trans-catheter aortic valve replacement induced left-bundle branch block on cardiac reverse remodeling.

PubMed

Dobson, Laura E; Musa, Tarique A; Uddin, Akhlaque; Fairbairn, Timothy A; Bebb, Owen J; Swoboda, Peter P; Haaf, Philip; Foley, James; Garg, Pankaj; Fent, Graham J; Malkin, Christopher J; Blackman, Daniel J; Plein, Sven; Greenwood, John P

2017-02-22

Left bundle branch block (LBBB) is common following trans-catheter aortic valve replacement (TAVR) and has been linked to increased mortality, although whether this is related to less favourable cardiac reverse remodeling is unclear. The aim of the study was to investigate the impact of TAVR induced LBBB on cardiac reverse remodeling. 48 patients undergoing TAVR for severe aortic stenosis were evaluated. 24 patients with new LBBB (LBBB-T) following TAVR were matched with 24 patients with a narrow post-procedure QRS (nQRS). Patients underwent cardiovascular magnetic resonance (CMR) prior to and 6 m post-TAVR. Measured cardiac reverse remodeling parameters included left ventricular (LV) size, ejection fraction (LVEF) and global longitudinal strain (GLS). Inter- and intra-ventricular dyssynchrony were determined using time to peak radial strain derived from CMR Feature Tracking. In the LBBB-T group there was an increase in QRS duration from 96 ± 14 to 151 ± 12 ms (P < 0.001) leading to inter- and intra-ventricular dyssynchrony (inter: LBBB-T 130 ± 73 vs nQRS 23 ± 86 ms, p < 0.001; intra: LBBB-T 118 ± 103 vs. nQRS 13 ± 106 ms, p = 0.001). Change in indexed LV end-systolic volume (LVESVi), LVEF and GLS was significantly different between the two groups (LVESVi: nQRS -7.9 ± 14.0 vs. LBBB-T -0.6 ± 10.2 ml/m 2 , p = 0.02, LVEF: nQRS +4.6 ± 7.8 vs LBBB-T -2.1 ± 6.9%, p = 0.002; GLS: nQRS -2.1 ± 3.6 vs. LBBB-T +0.2 ± 3.2%, p = 0.024). There was a significant correlation between change in QRS and change in LVEF (r = -0.434, p = 0.002) and between change in QRS and change in GLS (r = 0.462, p = 0.001). Post-procedure QRS duration was an independent predictor of change in LVEF and GLS at 6 months. TAVR-induced LBBB is associated with less favourable cardiac reverse remodeling at medium term follow up. In view of this, every effort should be made to prevent TAVR-induced LBBB, especially as TAVR is now being extended to a younger, lower risk population.

Comparison of right ventricular septal pacing and right ventricular apical pacing in patients receiving cardiac resynchronization therapy defibrillators: the SEPTAL CRT Study

PubMed Central

Leclercq, Christophe; Sadoul, Nicolas; Mont, Lluis; Defaye, Pascal; Osca, Joaquim; Mouton, Elisabeth; Isnard, Richard; Habib, Gilbert; Zamorano, Jose; Derumeaux, Genevieve; Fernandez-Lozano, Ignacio; Dupuis, Jean-Marc; Rouleau, Frédéric; Tassin, Aude; Bordachar, Pierre; Clémenty, Jacques; Lafitte, Stephane; Ploux, Sylvan; Reant, Patricia; Ritter, Philippe; Defaye, Pascal; Jacon, Peggy; Mondesert, Blandine; Saunier, Carole; Vautrin, Estelle; Kacet, Salem; Guedon-Moreau, Laurence; Klug, Didier; Kouakam, Claude; Marechaux, Sylvestre; Marquie, Christelle; Polge, Anne Sophie; Richardson, Marjorie; Chevallier, Philippe; De Breyne, Brigitte; Lotek, Marcin M.; Nonin, Emilie; Pineau, Julien; Deharo, Jean-Claude; Bastard, Emilie; Franceschi, Frédéric; Habib, Gilbert; Jego, Christophe; Peyrouse, Eric; Prevot, Sebastien; Saint-Joseph, Hôpital; Bremondy, Michel; Faure, Jacques; Ferracci, Ange; Lefevre, Jean; Pisapia, Andre; Davy, Jean-Marc; Cransac, Frederic; Cung, Tien Tri; Georger, Frederic; Pasquie, Jean-Luc; Raczka, Franck; Sportouch-Dukhan, Catherine; Sadoul, Nicolas; Blangy, Hugues; Bruntz, Jean-François; Freysz, Luc; Groben, Laurent; Huttin, Olivier; Bammert, Antoine; Burban, Marc; Cebron, Jean-Pierre; Gras, Daniel; Frank, Robert; Duthoit, Guillaume; Hidden-Lucet, Françoise; Himbert, Caroline; Isnard, Richard; Lacotte, Jérôme; Pousset, Françoise; Zerah, Thierry; Leclercq, Christophe; Bellouin, Annaïk; Crocq, Christophe; Deplace, Christian; Donal, Erwan; Hamon, Cécile; Mabo, Philippe; Romain, Olivier; Solnon, Aude; Frederic, Anselme; Bauer, Fabrice; Bernard, Mathieu; Godin, Benedicte; Kurtz, Baptiste; Savoure, Arnaud; Copie, Xavier; Lascault, Gilles; Paziaud, Olivier; Piot, Olivier; Touche, Thierry; Delay, Toulouse Marc; Chilon, Talia; Detis, Nicolas; Duparc, Alexandre; Hebrard, Aurélien; Massabuau, Pierre; Maury, Philippe; Mondoly, Pierre; Rumeau, Philippe; Pasteur, Clinique; Boveda, Serge; Adrover, Laurence; Combes, Nicolas; Deplagne, Antoine; Marco-Baertich, Isabelle; Fondard, Olivier; Martínez, Juan Gabriel; Ibañez Criado, José Luis; Ortuño, Diego; Mont, Lluis; Berruezo, Antonio; Eduard, Belu; Martín, Ana; Merschon, Franco M.; Sitges, Marta; Tolosana, José María; Vidal, Bárbara; Hebron, H. Valle; i Mitjans, Angel Moya; Rodriguez, Oscar Alcalde; Rodriguez Palomares, José Fernando; Rivas, Nuria; Teixidó, Gisela; de Hierro, H. Puerta; Lozano, Ignacio Fernández; Ruiz Bautista, Maria Lorena; Castro, Victor; Cavero, Miguel Angel; Gutierrez, Carlos; Ros, Natalia; de la Victoria, H. Virgen; Alzueta Rodriguez, Francisco Javier; Cabrera, Fernando; Cordero, Alberto Barrera; Peña, José Luis; de Valme Sevilla, H.; Gonzáles, Juan Lealdel Ojo; Garcia Medina, Mª Dolores; Jiménez, Ricardo Pavón; Villagomez, David; de la Salud Toledo, H. Virgen; Castellanos Martinez, Eduardo; Alcalá, Juan; Maicas, Carolina; Arias Palomares, Miguel Angel; Puchol, Alberto; Valencia, H. La Fé; OscaAsensi, Joaquim; Carmona, Anastasio Quesada; De Carranza, Mª José Sancho-Tello; De Ros, José Olagüe; Pareja, Enrique Castro; Pérez, Oscar Cano; Saez, Ana Osa; Hortega, H. Rio; Guilarte, Benito Herreros; Muñoz San Jose, Juan Francisco; Pérez Sanz, Teresa Myriam; Logeart, Damien; Gil, Maria Lopez; Leclercq, Christophe; Lozano, Ignacio Fernandez; de Hierro, H. Puerta; Derumeaux, Genevieve

2016-01-01

Abstract Aims Cardiac resynchronization therapy (CRT) is a recommended treatment of heart failure (HF) patients with depressed left ventricular ejection fraction and wide QRS. The optimal right ventricular (RV) lead position being a matter of debate, we sought to examine whether RV septal (RVS) pacing was not inferior to RV apical (RVA) pacing on left ventricular reverse remodelling in patients receiving a CRT-defibrillator. Methods and results Patients (n = 263, age = 63.4 ± 9.5 years) were randomly assigned in a 1:1 ratio to RVS (n = 131) vs. RVA (n = 132) pacing. Left ventricular end-systolic volume (LVESV) reduction between baseline and 6 months was not different between the two groups (−25.3 ± 39.4 mL in RVS group vs. −29.3 ± 44.5 mL in RVA group, P = 0.79). Right ventricular septal pacing was not non-inferior (primary endpoint) to RVA pacing with regard to LVESV reduction (average difference = −4.06 mL; P = 0.006 with a −20 mL non-inferiority margin). The percentage of ‘echo-responders’ defined by LVESV reduction >15% between baseline and 6 months was similar in both groups (50%) with no difference in the time to first HF hospitalization or death (P = 0.532). Procedural or device-related serious adverse events occurred in 68 patients (RVS = 37) with no difference between the two groups (P = 0.401). Conclusion This study demonstrates that septal RV pacing in CRT is non-inferior to apical RV pacing for LV reverse remodelling at 6 months with no difference in the clinical outcome. No recommendation for optimal RV lead position can hence be drawn from this study. ClinicalTrials. gov number NCT 00833352. PMID:26374852

Comparison of right ventricular septal pacing and right ventricular apical pacing in patients receiving cardiac resynchronization therapy defibrillators: the SEPTAL CRT Study.

PubMed

Leclercq, Christophe; Sadoul, Nicolas; Mont, Lluis; Defaye, Pascal; Osca, Joaquim; Mouton, Elisabeth; Isnard, Richard; Habib, Gilbert; Zamorano, Jose; Derumeaux, Genevieve; Fernandez-Lozano, Ignacio

2016-02-01

Cardiac resynchronization therapy (CRT) is a recommended treatment of heart failure (HF) patients with depressed left ventricular ejection fraction and wide QRS. The optimal right ventricular (RV) lead position being a matter of debate, we sought to examine whether RV septal (RVS) pacing was not inferior to RV apical (RVA) pacing on left ventricular reverse remodelling in patients receiving a CRT-defibrillator. Patients (n = 263, age = 63.4 ± 9.5 years) were randomly assigned in a 1:1 ratio to RVS (n = 131) vs. RVA (n = 132) pacing. Left ventricular end-systolic volume (LVESV) reduction between baseline and 6 months was not different between the two groups (-25.3 ± 39.4 mL in RVS group vs. -29.3 ± 44.5 mL in RVA group, P = 0.79). Right ventricular septal pacing was not non-inferior (primary endpoint) to RVA pacing with regard to LVESV reduction (average difference = -4.06 mL; P = 0.006 with a -20 mL non-inferiority margin). The percentage of 'echo-responders' defined by LVESV reduction >15% between baseline and 6 months was similar in both groups (50%) with no difference in the time to first HF hospitalization or death (P = 0.532). Procedural or device-related serious adverse events occurred in 68 patients (RVS = 37) with no difference between the two groups (P = 0.401). This study demonstrates that septal RV pacing in CRT is non-inferior to apical RV pacing for LV reverse remodelling at 6 months with no difference in the clinical outcome. No recommendation for optimal RV lead position can hence be drawn from this study. NCT 00833352. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Changes in Left Ventricular Morphology and Function After Mitral Valve Surgery

PubMed Central

Shafii, Alexis E.; Gillinov, A. Marc; Mihaljevic, Tomislav; Stewart, William; Batizy, Lillian H.; Blackstone, Eugene H.

2015-01-01

Degenerative mitral valve disease is the leading cause of mitral regurgitation in North America. Surgical intervention has hinged on symptoms and ventricular changes that develop as compensatory ventricular remodeling takes place. In this study, we sought to characterize the temporal response of left ventricular (LV) morphology and function to mitral valve surgery for degenerative disease, and identify preoperative factors that influence reverse remodeling. From 1986–2007, 2,778 patients with isolated degenerative mitral valve disease underwent valve repair (n=2,607/94%) or replacement (n=171/6%) and had at least 1 postoperative transthoracic echocardiogram (TTE); 5,336 TTEs were available for analysis. Multivariable longitudinal repeated-measures analysis was performed to identify factors associated with reverse remodeling. LV dimensions decreased in the first year after surgery (end-diastolic from 5.7±0.80 to 4.9±1.4 cm; end-systolic from 3.4±0.71 to 3.1±1.4 cm). LV mass index decreased from 139±44 to 112±73 g·m−2. Reduction of LV hypertrophy was less pronounced in patients with greater preoperative left heart enlargement (P<.0001) and greater preoperative LV mass (P<.0001). Postoperative LV ejection fraction initially decreased from 58±7.0 to 53±20, increased slightly over the first postoperative year, and was negatively influenced by preoperative heart failure symptoms (P<.0001) and lower preoperative LV ejection fraction (P<.0001). Risk-adjusted response of LV morphology and function to valve repair and replacement was similar (P>.2). In conclusion, a positive response toward normalization of LV morphology and function after mitral valve surgery is greatest in the first year. The best response occurs when surgery is performed before left heart dilatation, LV hypertrophy, or LV dysfunction develop. PMID:22534055

Thyroid-stimulating hormone and adverse left ventricular remodeling following ST-segment elevation myocardial infarction.

PubMed

Reindl, Martin; Feistritzer, Hans-Josef; Reinstadler, Sebastian Johannes; Mueller, Lukas; Tiller, Christina; Brenner, Christoph; Mayr, Agnes; Henninger, Benjamin; Mair, Johannes; Klug, Gert; Metzler, Bernhard

2018-04-01

Adverse left ventricular remodeling is one of the major determinants of heart failure and mortality in patients surviving ST-segment elevation myocardial infarction (STEMI). The hypothalamic-pituitary-thyroid axis is a key cardiovascular regulator; however, the relationship between hypothalamic-pituitary-thyroid status and post-STEMI left ventricular remodeling is unclear. We aimed to investigate the association between thyroid-stimulating hormone concentrations and the development of left ventricular remodeling following reperfused STEMI. In this prospective observational study of 102 consecutive STEMI patients, thyroid-stimulating hormone levels were measured at the first day after infarction and 4 months thereafter. Cardiac magnetic resonance scans were performed within the first week as well as at 4 months follow-up to determine infarct characteristics, myocardial function and as primary endpoint left ventricular remodeling, defined as a 20% or greater increase in left ventricular end-diastolic volume. Patients with left ventricular remodeling ( n=15, 15%) showed significantly lower concentrations of baseline (1.20 [0.92-1.91] vs. 1.73 [1.30-2.60] mU/l; P=0.02) and follow-up (1.11 [0.86-1.28] vs. 1.51 [1.15-2.02] mU/l; P=0.002) thyroid-stimulating hormone. The association between baseline thyroid-stimulating hormone and left ventricular remodeling remained significant after adjustment for major clinical (peak high-sensitivity cardiac troponin T and C-reactive protein, heart rate; odds ratio (OR) 5.33, 95% confidence interval (CI) 1.52-18.63; P=0.01) and cardiac magnetic resonance predictors of left ventricular remodeling (infarct size, microvascular obstruction, ejection fraction; OR 4.59, 95% CI 1.36-15.55; P=0.01). Furthermore, chronic thyroid-stimulating hormone was related to left ventricular remodeling independently of chronic left ventricular remodeling correlates (infarct size, ejection fraction, left ventricular end-diastolic volume, left ventricular end-systolic volume; OR 9.22, 95% CI 1.69-50.22; P=0.01). Baseline and chronic thyroid-stimulating hormone concentrations following STEMI were independently associated with left ventricular remodeling, proposing a novel pathophysiological axis in the development of post-STEMI left ventricular remodeling.

The reverse remodeling response to sacubitril/valsartan therapy in heart failure with reduced ejection fraction.

PubMed

Martens, Pieter; Beliën, Hanne; Dupont, Matthias; Vandervoort, Pieter; Mullens, Wilfried

2018-05-17

Major classes of medical therapy for heart failure with reduced ejection fraction (HFrEF) induce reverse remodeling. The revere remodeling response to sacubitril/valsartan remains unstudied. We performed a single-center, prospective assessor-blinded study to determine the reverse remodeling response of sacubitril/valsartan therapy in HFrEF patients with a class I indication (New York heart Association [NYHA]-class II-IV, Left ventricular ejection fraction [LVEF] < 35%, optimal dose with Renin-Angiotensin-System-Blocker [RAS-blocker]). Doses of sacubitril/valsartan were optimized to individual tolerance. Echocardiographic images were assessed offline by 2 investigators blinded to both the clinical data and timing of echocardiograms. One-hundred-twenty-five HFrEF patients (66 ± 10 years) were prospectively included. The amount of RAS-blocker before and after switch to sacubitril/valsartan was similar(P = .290), indicating individual optimal dosing of sacubitril/valsartan. Over a median(IQR) follow-up of 118(77-160) days after initiation of sacubitril/valsartan, LVEF improved (29.6 ± 6% vs 34.8 ± 6%; P < .001) and Left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) decreased (LVESV; 147 ± 57 mL vs 129 ± 55 mL; P < .001 and LVEDV; 206 ± 71 mL vs197 ± 72 mL; P = .027). Volumetric remodeling was associated with a reduction in the degree of mitral regurgitation (1.59 ± 1.0 vs 1.11 ± 0.8; P < .001; [scale from 0-4]). Metrics of diastolic function improved; including a drop in the E/A-wave ratio (1.75 ± 1.13 vs 1.38 ± 0.88; P = .002) and diastolic filling time (% of cycle length) prolonged (48 ± 9% vs 52 ± 1%; P = .005). The percent of patients with a restrictive mitral filling pattern dropped from 47% to 23% (P = .004). A dose-dependent effect was noted for changes in LVEF (P < .001) and LVESV (P = .031), with higher doses of sacubitril/valsartan leading to more reverse remodeling. Switching therapy in eligible HFrEF patients from a RAS-blocker to sacubitril/valsartan induces beneficial reverse remodeling of both metrics of systolic as diastolic function. © 2018 John Wiley & Sons Ltd.

Effect of Neurohormonal Blockade Drug Therapy on Outcomes and Left Ventricular Function and Structure After Left Ventricular Assist Device Implantation.

PubMed

Grupper, Avishay; Zhao, Yanjun M; Sajgalik, Pavol; Joyce, Lyle D; Park, Soon J; Pereira, Naveen L; Stulak, John M; Burnett, John C; Edwards, Brooks S; Daly, Richard C; Kushwaha, Sudhir S; Schirger, John A

2016-06-01

Neurohormonal blockade drug therapy (NHBDT) is the cornerstone therapy in heart failure (HF) management for promoting reverse cardiac remodeling and improving outcomes. It's utility in left ventricular assist device (LVAD) supported patients remains undefined. Sixty-four patients who received continuous flow LVAD at our institution were retrospectively reviewed and divided into 2 groups: no-NHBDT group (n = 33) received LVAD support only and NHBDT group (n = 31) received concurrent NHBDT based on the clinical judgment of the attending physicians. Cardiac remodeling (echocardiographic parameters and biomarkers) and clinical outcome (functional status, HF-related hospital readmissions, and mortality) data were collected. A statistically significant increase in ejection fraction, decrease in LV end-diastolic diameter index and LV mass index, and a sustained reduction in N-terminal pro B-type natriuretic peptide (NTproBNP) were observed in the NHBDT group at 6 months after LVAD implant (p <0.05). NHBDT-treated patients experienced significantly greater improvement in New York Heart Association functional classification and 6-minute-walk distance throughout the study. The combined end point of cardiovascular death or HF hospitalization was significantly reduced in patients receiving NHBDT (p = 0.013) associated primarily with a 12.1% absolute reduction in HF-related hospitalizations (p = 0.046). In conclusion, NHBDT in LVAD-supported patients is associated with a significant reversal in adverse cardiac remodeling and a reduction in morbidity and mortality compared with LVAD support alone. Copyright © 2016 Elsevier Inc. All rights reserved.

Bridge to Removal: A Paradigm Shift for Left Ventricular Assist Device Therapy

PubMed Central

Selzman, Craig H.; Madden, Jesse L.; Healy, Aaron H.; McKellar, Stephen H.; Koliopoulou, Antigone; Stehlik, Josef; Drakos, Stavros G.

2014-01-01

Ventricular assist devices have become standard therapy for patients with advanced heart failure either as a bridge to transplantation or destination therapy. Despite the functional and biologic evidence of reverse cardiac remodeling, few patients actually proceed to myocardial recovery, and even fewer to the point of having their device explanted. An enhanced understanding of the biology and care of the mechanically supported patient has redirected focus on the possibility of using ventricular assist devices as a bridge to myocardial recovery and removal. Herein, we review the current issues and approaches to transforming myocardial recovery to a practical reality. PMID:25442985

A state of reversible compensated ventricular dysfunction precedes pathological remodelling in response to cardiomyocyte-specific activity of angiotensin II type-1 receptor in mice.

PubMed

Frentzou, Georgia A; Drinkhill, Mark J; Turner, Neil A; Ball, Stephen G; Ainscough, Justin F X

2015-08-01

Cardiac dysfunction is commonly associated with high-blood-pressure-induced cardiomyocyte hypertrophy, in response to aberrant renin-angiotensin system (RAS) activity. Ensuing pathological remodelling promotes cardiomyocyte death and cardiac fibroblast activation, leading to cardiac fibrosis. The initiating cellular mechanisms that underlie this progressive disease are poorly understood. We previously reported a conditional mouse model in which a human angiotensin II type-I receptor transgene (HART) was expressed in differentiated cardiomyocytes after they had fully matured, but not during development. Twelve-month-old HART mice exhibited ventricular dysfunction and cardiomyocyte hypertrophy with interstitial fibrosis following full receptor stimulation, without affecting blood pressure. Here, we show that chronic HART activity in young adult mice causes ventricular dysfunction without hypertrophy, fibrosis or cardiomyocyte death. Dysfunction correlated with reduced expression of pro-hypertrophy markers and increased expression of pro-angiogenic markers in the cardiomyocytes experiencing increased receptor load. This stimulates responsive changes in closely associated non-myocyte cells, including the downregulation of pro-angiogenic genes, a dampened inflammatory response and upregulation of Tgfβ. Importantly, this state of compensated dysfunction was reversible. Furthermore, increased stimulation of the receptors on the cardiomyocytes caused a switch in the secondary response from the non-myocyte cells. Progressive cardiac remodelling was stimulated through hypertrophy and death of individual cardiomyocytes, with infiltration, proliferation and activation of fibroblast and inflammatory cells, leading to increased angiogenic and inflammatory signalling. Together, these data demonstrate that a state of pre-hypertrophic compensated dysfunction can exist in affected individuals before common markers of heart disease are detectable. The data also suggest that there is an initial response from the housekeeping cells of the heart to signals emanating from distressed neighbouring cardiomyocytes to suppress those changes most commonly associated with progressive heart disease. We suggest that the reversible nature of this state of compensated dysfunction presents an ideal window of opportunity for personalised therapeutic intervention. © 2015. Published by The Company of Biologists Ltd.

Apocynin improving cardiac remodeling in chronic renal failure disease is associated with up-regulation of epoxyeicosatrienoic acids.

PubMed

Zhang, Kun; Liu, Yu; Liu, Xiaoqiang; Chen, Jie; Cai, Qingqing; Wang, Jingfeng; Huang, Hui

2015-09-22

Cardiac remodeling is one of the most common cardiac abnormalities and associated with a high mortality in chronic renal failure (CRF) patients. Apocynin, a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been showed cardio-protective effects. However, whether apocynin can improve cardiac remodeling in CRF and what is the underlying mechanism are unclear. In the present study, we enrolled 94 participants. In addition, we used 5/6 nephrectomized rats to mimic cardiac remodeling in CRF. Serum levels of epoxyeicosatrienoic acids (EETs) and its mainly metabolic enzyme-soluble epoxide hydrolase (sEH) were measured. The results showed that the serum levels of EETs were significantly decreased in renocardiac syndrome participants (P < 0.05). In 5/6 nephrectomized CRF model, the ratio of left ventricular weight / body weight, left ventricular posterior wall thickness, and cardiac interstitial fibrosis were significantly increased while ejection fraction significantly decreased (P < 0.05). All these effects could partly be reversed by apocynin. Meanwhile, we found during the process of cardiac remodeling in CRF, apocynin significantly increased the reduced serum levels of EETs and decreased the mRNA and protein expressions of sEH in the heart (P < 0.05). Our findings indicated that the protective effect of apocynin on cardiac remodeling in CRF was associated with the up-regulation of EETs. EETs may be a new mediator for the injury of kidney-heart interactions.

Apocynin improving cardiac remodeling in chronic renal failure disease is associated with up-regulation of epoxyeicosatrienoic acids

PubMed Central

Chen, Jie; Cai, Qingqing; Wang, Jingfeng; Huang, Hui

2015-01-01

Cardiac remodeling is one of the most common cardiac abnormalities and associated with a high mortality in chronic renal failure (CRF) patients. Apocynin, a nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase inhibitor, has been showed cardio-protective effects. However, whether apocynin can improve cardiac remodeling in CRF and what is the underlying mechanism are unclear. In the present study, we enrolled 94 participants. In addition, we used 5/6 nephrectomized rats to mimic cardiac remodeling in CRF. Serum levels of epoxyeicosatrienoic acids (EETs) and its mainly metabolic enzyme-soluble epoxide hydrolase (sEH) were measured. The results showed that the serum levels of EETs were significantly decreased in renocardiac syndrome participants (P < 0.05). In 5/6 nephrectomized CRF model, the ratio of left ventricular weight /body weight, left ventricular posterior wall thickness, and cardiac interstitial fibrosis were significantly increased while ejection fraction significantly decreased (P < 0.05). All these effects could partly be reversed by apocynin. Meanwhile, we found during the process of cardiac remodeling in CRF, apocynin significantly increased the reduced serum levels of EETs and decreased the mRNA and protein expressions of sEH in the heart (P < 0.05). Our findings indicated that the protective effect of apocynin on cardiac remodeling in CRF was associated with the up-regulation of EETs. EETs may be a new mediator for the injury of kidney-heart interactions. PMID:26322503

Mitochondrial ROS Drive Sudden Cardiac Death and Chronic Proteome Remodeling in Heart Failure.

PubMed

Dey, Swati; DeMazumder, Deeptankar; Sidor, Agnieszka; Foster, D B; O'Rourke, Brian

2018-06-13

Rationale: Despite increasing prevalence and incidence of heart failure (HF), therapeutic options remain limited. In early stages of HF, sudden cardiac death (SCD) from ventricular arrhythmias claims many lives. Reactive oxygen species (ROS) have been implicated in both arrhythmias and contractile dysfunction. However, little is known about how ROS in specific subcellular compartments contribute to HF or SCD pathophysiology. The role of ROS in chronic proteome remodeling has not been explored. Objective: We will test the hypothesis that elevated mitochondrial ROS (mROS) is a principal source of oxidative stress in HF and in vivo reduction of mROS mitigates SCD. Methods and Results: Using a unique guinea pig model of non-ischemic HF that recapitulates important features of human HF, including prolonged QT interval and high incidence of spontaneous arrhythmic SCD. Compartment-specific ROS sensors revealed increased mROS in resting and contracting left ventricular (LV) myocytes in failing hearts. Importantly, mitochondrially-targeted antioxidant (MitoTEMPO) normalized global cellular ROS. Further, in vivo MitoTEMPO treatment of HF animals prevented and reversed HF; eliminated SCD by decreasing dispersion of repolarization and ventricular arrhythmias; suppressed chronic HF-induced remodeling of the expression proteome; and prevented specific phosphoproteome alterations. Pathway analysis of mROS-sensitive networks indicated that increased mROS in HF disrupts the normal coupling between cytosolic signals and nuclear gene programs driving mitochondrial function, antioxidant enzymes, Ca2+ handling and action potential repolarization, suggesting new targets for therapeutic intervention. Conclusions: mROS drive both acute emergent events, such as electrical instability responsibly for SCD, and those that mediate chronic HF remodeling, characterized by suppression or altered phosphorylation of metabolic, antioxidant and ion transport protein networks. In vivo reduction of mROS prevents and reverses electrical instability, SCD and HF. Our findings support the feasibility of targeting the mitochondria as a potential new therapy for HF and SCD while identifying new mROS-sensitive protein modifications.

Increased de novo ceramide synthesis and accumulation in failing myocardium

PubMed Central

Ji, Ruiping; Akashi, Hirokazu; Drosatos, Konstantinos; Liao, Xianghai; Jiang, Hongfeng; Kennel, Peter J.; Brunjes, Danielle L.; Castillero, Estibaliz; Zhang, Xiaokan; Deng, Lily Y.; Homma, Shunichi; George, Isaac J.; Takayama, Hiroo; Naka, Yoshifumi; Goldberg, Ira J.

2017-01-01

Abnormal lipid metabolism may contribute to myocardial injury and remodeling. To determine whether accumulation of very long–chain ceramides occurs in human failing myocardium, we analyzed myocardial tissue and serum from patients with severe heart failure (HF) undergoing placement of left ventricular assist devices and controls. Lipidomic analysis revealed increased total and very long–chain ceramides in myocardium and serum of patients with advanced HF. After unloading, these changes showed partial reversibility. Following myocardial infarction (MI), serine palmitoyl transferase (SPT), the rate-limiting enzyme of the de novo pathway of ceramide synthesis, and ceramides were found increased. Blockade of SPT by the specific inhibitor myriocin reduced ceramide accumulation in ischemic cardiomyopathy and decreased C16, C24:1, and C24 ceramides. SPT inhibition also reduced ventricular remodeling, fibrosis, and macrophage content following MI. Further, genetic deletion of the SPTLC2 gene preserved cardiac function following MI. Finally, in vitro studies revealed that changes in ceramide synthesis are linked to hypoxia and inflammation. In conclusion, cardiac ceramides accumulate in the failing myocardium, and increased levels are detectable in circulation. Inhibition of de novo ceramide synthesis reduces cardiac remodeling. Thus, increased de novo ceramide synthesis contributes to progressive pathologic cardiac remodeling and dysfunction. PMID:28469091

Preoperative left ventricular ejection fraction and left atrium reverse remodeling after mitral regurgitation surgery.

PubMed

Machado, Lucia R; Meneghelo, Zilda M; Le Bihan, David C S; Barretto, Rodrigo B M; Carvalho, Antonio C; Moises, Valdir A

2014-11-06

Left atrium enlargement has been associated with cardiac events in patients with mitral regurgitation (MR). Left atrium reverse remodeling (LARR) occur after surgical correction of MR, but the preoperative predictors of this phenomenon are not well known. It is therefore important to identify preoperative predictors for postoperative LARR. We enrolled 62 patients with chronic severe MR (prolapse or flail leaflet) who underwent successful mitral valve surgery (repair or replacement); all with pre- and postoperative echocardiography. LARR was defined as a reduction in left atrium volume index (LAVI) of ≥ 25%. Stepwise multiple regression analysis was used to identify independent predictors of LARR. LARR occurred in 46 patients (74.2%), with the mean LAVI decreasing from 85.5 mL/m2 to 49.7 mL/m2 (p <0.001). These patients had a smaller preoperative left ventricular systolic volume (p =0.022) and a higher left ventricular ejection fraction (LVEF) (p =0.034). LVEF was identified as the only preoperative variable significantly associated with LARR (odds ratio, 1.086; 95% confidence interval, 1.002-1.178). A LVEF cutoff value of 63.5% identified patients with LARR of ≥ 25% with a sensitivity of 71.7% and a specificity of 56.3%. LARR occurs frequently after mitral valve surgery and is associated with preoperative LVEF higher than 63.5%.

Patterns of left ventricular remodeling among patients with essential and secondary hypertension.

PubMed

Radulescu, Dan; Stoicescu, Laurentiu; Buzdugan, Elena; Donca, Valer

2013-12-01

High blood pressure causes left ventricular hypertrophy, which is a negative prognostic factor among hypertensive patients. To assess left ventricular geometric remodeling patterns in patients with essential hypertension or with hypertension secondary to parenchymal renal disease. We analyzed data from echocardiograms performed in 250 patients with essential hypertension (150 females) and 100 patients with secondary hypertension (60 females). The interventricular septum and the left ventricular posterior wall thickness were measured in the parasternal long-axis. Left ventricular mass was calculated using the Devereaux formula. The most common remodeling type in females and males with essential hypertension were eccentric and concentric left ventricular hypertrophy (cLVH), respectively. Among patients with secondary arterial hypertension, cLVH was most commonly observed in both genders. The prevalence of left ventricular hypertrophy was higher among patients with secondary hypertension. The left ventricular mass index and the relative left ventricular wall thickness were higher in males and also in the secondary hypertension group. Age, blood pressure values and the duration of hypertension, influenced remodeling patterns. We documented a higher prevalence of LVH among patients with secondary hypertension. The type of ventricular remodeling depends on gender, age, type of hypertension, blood pressure values and the duration of hypertension.

Polymer Injection Therapy to Reverse Remodel the Papillary Muscles: Efficacy in Reducing Mitral Regurgitation in a Chronic Ischemic Model

PubMed Central

Solis, Jorge; Levine, Robert A.; Johnson, Benjamin; Guerrero, J. Luis; Handschumacher, Mark D.; Suzanne, Suzanne; Lam, Kaitlyn; Berlin, Jason; Braithwaite, Gavin J.C.; Muratoglu, Orhun K.; Vlahakes, Gus J.; Hung, Judy

2010-01-01

Ischemic mitral regurgitation (IMR) results from displacement of the papillary muscles due to ischemic ventricular distortion. Recurrent IMR is frequent after annuloplasty, particularly when left ventricular remodeling continues to progress. Our hypothesis is that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) hydrogel polymer into the myocardium in chronic MR despite advanced left ventricular remodeling. Methods Nine sheep underwent ligation of circumflex branches to produce chronic ischemic MR over eight weeks. Once MR developed, PVA was injected into the myocardium underlying the infarcted PM. 2D and 3D echocardiograms and hemodynamic data were obtained pre infarct (baseline), pre PVA (Chronic MR) and post PVA. Results One animal died early, one did not develop MR, and the remaining 7 developed moderate MR. PVA injection significantly decreased the MR from moderate to trace. This was associated with a decrease in infarcted papillary muscle-to-mitral annulus tethering distance (32.6 ± 4.4 to 27.6 ± 4.2 mm, P<0.05), tenting volume (2.1±0.3 to 1.6 ± 0.3 mm2 P<0.05) and leaflet closure area (9.3 ± 0.8 to 8.2 ± 0.7 mm2, P<0.04). PVA was not associated with significant decreases in LVEF (42 ± 3 % vs 40 ± 2 %, p=ns) or end-systolic elastance. Measures of left ventricular diastolic function, tau (99 ± 55 ms to 87 ± 36;) and left ventricular stiffness coefficient (0.04 ± 0.03 to 0.05 ± 0.03) did not increase post PVA. Conclusions PVA hydrogel injections improve coaptation and reduce remodeling in chronic MR without impairing LV systolic and diastolic function. This new approach offers a potential alternative for relieving ischemic mitral regurgitation by correcting papillary muscle position, thus relieving tethering that causes ischemic mitral regurgitation. PMID:20736444

Renin-Angiotensin-Aldosterone Genotype Influences Ventricular Remodeling in Infants with Single Ventricle

PubMed Central

Mital, Seema; Chung, Wendy K.; Colan, Steven D.; Sleeper, Lynn A.; Manlhiot, Cedric; Arrington, Cammon B.; Cnota, James F.; Graham, Eric M.; Mitchell, Michael E.; Goldmuntz, Elizabeth; Li, Jennifer S.; Levine, Jami C.; Lee, Teresa M.; Margossian, Renee; Hsu, Daphne T.

2011-01-01

Background We investigated the effect of polymorphisms in the renin-angiotensin-aldosterone system (RAAS) genes on ventricular remodeling, growth, renal function and response to enalapril in infants with single ventricle. Methods and Results Single ventricle infants enrolled in a randomized trial of enalapril were genotyped for polymorphisms in 5 genes: angiotensinogen, angiotensin-converting enzyme, angiotensin II type 1 receptor, aldosterone synthase, and chymase. Alleles associated with RAAS upregulation were classified as risk alleles. Ventricular mass, volume, somatic growth, renal function using estimated glomerular filtration rate (eGFR), and response to enalapril were compared between patients with ≥2 homozygous risk genotypes (high-risk), and those with <2 homozygous risk genotypes (low-risk) at two time points - before the superior-cavopulmonary-connection (pre-SCPC) and at age 14 months. Of 230 trial subjects, 154 were genotyped: 38 were high-risk, 116 were low-risk. Ventricular mass and volume were elevated in both groups pre-SCPC. Ventricular mass and volume decreased and eGFR increased after SCPC in the low-risk (p<0.05) but not the high-risk group. These responses were independent of enalapril treatment. Weight and height z-scores were lower at baseline and height remained lower in the high-risk group at 14 months especially in those receiving enalapril (p<0.05). Conclusions RAAS-upregulation genotypes were associated with failure of reverse remodeling after SCPC surgery, less improvement in renal function, and impaired somatic growth, the latter especially in patients receiving enalapril. RAAS genotype may identify a high-risk subgroup of single ventricle patients who fail to fully benefit from volume unloading surgery. Follow-up is warranted to assess longterm impact. Clinical Trial Registration Clinical Trials.gov Identifier NCT00113087 PMID:21576655

Cardiovascular response to prescribed detraining among recreational athletes.

PubMed

Pedlar, Charles R; Brown, Marcel G; Shave, Robert E; Otto, James M; Drane, Aimee; Michaud-Finch, Jennifer; Contursi, Miranda; Wasfy, Meagan M; Hutter, Adolph; Picard, Michael H; Lewis, Gregory D; Baggish, Aaron L

2018-04-01

Exercise-induced cardiac remodeling (EICR) and the attendant myocardial adaptations characteristic of the athlete's heart may regress during periods of exercise reduction or abstinence. The time course and mechanisms underlying this reverse remodeling, specifically the impact of concomitant plasma volume (PV) contraction on cardiac chamber size, remain incompletely understood. We therefore studied recreational runners ( n = 21, age 34 ± 7 yr; 48% male) who completed an 18-wk training program (~7 h/wk) culminating in the 2016 Boston Marathon after which total exercise exposure was confined to <2 h/wk (no single session >1 h) for 8 wk. Cardiac structure and function, exercise capacity, and PV were assessed at peak fitness (10-14 days before) and at 4 wk and 8 wk postmarathon. Mixed linear modeling adjusting for age, sex, V̇o 2peak , and marathon finish time was used to compare data across time points. Physiological detraining was evidenced by serial reductions in treadmill performance. Two distinct phases of myocardial remodeling and hematological adaptation were observed. After 4 wk of detraining, there were significant reductions in PV (Δ -6.0%, P < 0.01), left ventricular (LV) wall thickness (Δ -8.1%, <0.05), LV mass (Δ -10.3%, P < 0.001), and right atrial area (Δ -8.2%, P < 0.001). After 8 wk of detraining, there was a significant reduction in right ventricle chamber size (end-diastolic area Δ = -8.0%, P < 0.05) without further concomitant reductions in PV or LV wall thickness. Abrupt reductions in exercise training stimulus result in a structure-specific time course of reverse cardiac remodeling that occurs largely independently of PV contraction. NEW & NOTEWORTHY Significant reverse cardiac remodeling, previously documented among competitive athletes, extends to recreational runners and occurs with a distinct time course. Initial reductions in plasma volume and left ventricular (LV) mass, driven by reductions in wall thickness, are followed by contraction of the right ventricle. Consistent with data from competitive athletes, LV chamber volumes appear less responsive to detraining and may be a more permanent adaptation to sport.

Effect of cardiac resynchronization therapy on beat-to-beat T-wave amplitude variability.

PubMed

Žižek, David; Cvijić, Marta; Tasič, Jerneja; Jan, Matevž; Frljak, Sabina; Zupan, Igor

2012-11-01

T-wave amplitude variability (TAV) is a promising non-invasive predictor of arrhythmic events in patients with dilated cardiomyopathy. We aimed to evaluate the effect of cardiac resynchronization therapy (CRT) on native TAV, its relation with left ventricular (LV) reverse remodelling and the occurrence of ventricular tachyarrhythmias (VTs). In this prospective study, we included 40 heart failure patients with left bundle branch block in sinus rhythm (25 male; 16 with ischaemic aetiology; aged 62.7 ± 9.5 years; New York Heart Association class II-IV). Echocardiographic parameters and TAV were evaluated at baseline and 6 months after implantation of CRT device combined with an implantable cardioverter-defibrillator. T-wave amplitude variability was determined by a 20-min high-resolution electrocardiogram Holter recording during native conduction. After TAV assessment, patients were monitored for 15.7 ± 5.2 months for the occurrence of VTs. Decrease in median TAV [from 40.45 μV (24.75-56.00) to 28.15 μV (20.93-37.95), P = 0.004] was observed after 6 months of CRT. However, decrease of median TAV was only noticed in patients with LV reverse remodelling [46.9 μV (27.5-70.0) to 25.8 μV (20.2-32.4), P < 0.001] and in patients without VTs [40.5 μV (27.5-55.9) to 24.4 μV (17.1-31.5), P < 0.001]. Native median TAV > 35.4 µV after 6 months of CRT had an 83% sensitivity and 93% specificity for predicting the occurrence of VTs. Decrease of TAV after CRT is associated with LV reverse remodelling and indicates a reduction of the intrinsic arrhythmogenic substrate. Median TAV after CRT had a good predicting value for VT occurrence in long-term follow-up.

Is the epicardial left ventricular lead implantation an alternative approach to percutaneous attempt in patients with Steinert disease? A case report

PubMed Central

PAPA, ANDREA ANTONIO; RAGO, ANNA; PETILLO, ROBERTA; D’AMBROSIO, PAOLA; SCUTIFERO, MARIANNA; FEO, MARISA DE; MAIELLO, CIRO; PALLADINO, ALBERTO

2017-01-01

Steinert’s disease or Myotonic Dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder characterized by myotonia, muscle and facial weakness, cataracts, cognitive, endocrine and gastrointestinal involvement, and cardiac conduction abnormalities. Although mild myocardial dysfunction may be detected in this syndrome with age, overt myocardial dysfunction with heart failure is not frequent. Cardiac resynchronization therapy is an effective treatment to improve morbidity and reduce mortality in patients with DM1 showing intra-ventricular conduction delay and/or congestive heart failure. We report the case of a patient with Steinert disease showing an early onset ventricular dysfunction due to chronic right ventricular apical pacing, in which an epicardial left ventricular lead implantation was performed following the failure of the percutaneous attempt. As no relief in symptoms of heart failure, nor an improvement of left ventricular ejection fraction and reverse remodelling was observed six months later, the patient was addressed to the heart transplantation.

Reverse remodeling is associated with changes in extracellular matrix proteases and tissue inhibitors after mesenchymal stem cell (MSC) treatment of pressure overload hypertrophy.

PubMed

Molina, Ezequiel J; Palma, Jon; Gupta, Dipin; Torres, Denise; Gaughan, John P; Houser, Steven; Macha, Mahender

2009-02-01

Changes in ventricular extracellular matrix (ECM) composition of pressure overload hypertrophy determine clinical outcomes. The effects of mesenchymal stem cell (MSC) transplantation upon determinants of ECM composition in pressure overload hypertrophy have not been studied. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After an absolute decrease in fractional shortening of 25% from baseline, 1 x 10(6) MSC (n = 28) or PBS (n = 20) was randomly injected intracoronarily. LV protein analysis, including matrix metalloproteinases (MMP-2, MMP-3, MMP-6, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3), was performed after sacrifice on postoperative day 7, 14, 21 or 28. Left ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 were demonstrated to be decreased in the MSC group compared with controls after 28 days. Expression of MMP-2 and TIMP-2 remained relatively stable in both groups. Successful MSCs delivery was confirmed by histological analysis and visualization of labelled MSCs. In this model of pressure overload hypertrophy, intracoronary delivery of MSCs during heart failure was associated with specific changes in determinants of ECM composition. LV reverse remodeling was associated with decreased ventricular levels of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3, which were upregulated in the control group as heart failure progressed. These effects were most significant at 28 days following injection. (c) 2008 John Wiley & Sons, Ltd.

Understanding nonresponders of cardiac resynchronization therapy--current and future perspectives.

PubMed

Yu, Cheuk-Man; Wing-Hong Fung, Jeffrey; Zhang, Qing; Sanderson, John E

2005-10-01

Cardiac resynchronization therapy (CRT) is now an established nonpharmacologic therapy for advanced heart failure with electromechanical delay. Despite compelling evidence of the benefits of CRT, one troubling issue is the lack of a favorable response in about one-third of patients. Currently, there is no unifying definition of responders, and published data were based on acute hemodynamic changes, chronic left ventricular reverse remodeling, as well as the intermediate or long-term clinical response. The lack of improvement with CRT can be due to many factors including the placement of the left ventricular pacing lead in an inappropriate location, the absence of electrical conduction delay or mechanical dyssynchrony despite wide QRS complexes, and possibly failure to optimize the CRT settings after device implantation. In acute hemodynamic studies, placing the left ventricular leads at the free wall region has been suggested to generate the best pulse pressure and positive dp/dt. The degree of mechanical dyssynchrony has recently been assessed noninvasively in CRT patients by echocardiography and in particular by tissue Doppler imaging. These studies suggested that responders of left ventricular reverse remodeling or systolic function had more severe systolic dyssynchrony. However, further studies are needed to examine the clinical utility of these parameters when applied to the standardized anatomic or functional endpoints. Optimization of atrioventricular and interventricular pacing intervals may also reduce the number of nonresponders, though newer methods, especially interventricular pacing intervals, are still under clinical investigation. With the adjunctive use of imaging technology, physicians are able to characterize the response to CRT objectively, and cardiac imaging is an important clinical tool for determining more precisely the presence and degree of mechanical dyssynchrony.

Ejection fraction improvement and reverse remodeling achieved with Sacubitril/Valsartan in heart failure with reduced ejection fraction patients.

PubMed

Almufleh, Aws; Marbach, Jeffrey; Chih, Sharon; Stadnick, Ellamae; Davies, Ross; Liu, Peter; Mielniczuk, Lisa

2017-01-01

Sacubitril/Valsartan has been shown to improve mortality and reduce hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF). The effect of Sacubitril/Valsartan on ejection fraction (EF) and reverse remodeling parameters have not been previously described. We performed a single-center, retrospective, cohort study of HFrEF patients (n=48) who were treated with Sacubitril/Valsartan for a median duration of 3 months (Interquartile range 2-6 months). Clinical and echocardiographic parameters were reviewed at three time points (pre-baseline which was median of 18 months before starting Sacubitril/Valsartan, baseline before treatment started, and post-Sacubitril/Valsartan). Paired sample t-test and one-way repeated measures ANOVA were used for normally distributed data, while Wilcoxon Signed Rank test for non-normally distributed data. Sacubitril/Valsartan use was associated with an average 5% (±1.2) increase in EF, from a mean baseline of 25.33% to 30.14% (p<0.001) with a median duration of treatment 3 months. There was no significant change in mean LVEF over a median duration of 11 months (IQR 5.5-15.5) between pre-baseline and baseline time points prior to treatment (p=1.0). The mean increase in ejection fraction tended to be marginally greater in the medium/high dose cohort as compared to the low dose cohort, with a mean increase of 5.09% (±1.36) and 4.03% (±3.17), respectively (p=0.184). There was a 3.36 mm reduction in left ventricular end-systolic diameter (p=0.04), a 2.64 mm reduction in left ventricular end-diastolic diameter (p=0.02), and a 14.4 g/m 2 reduction in left ventricular mass index (p<0.01). Sacubitril/Valsartan was found to improve EF and multiple measures of reverse remodeling beyond the effects of concomitant optimal medical therapy. Though these results are encouraging, our small sample, observational study requires confirmation in larger cohorts with longer follow-up periods.

Serelaxin treatment reverses vascular dysfunction and left ventricular hypertrophy in a mouse model of Type 1 diabetes

PubMed Central

Ng, Hooi Hooi; Leo, Chen Huei; Prakoso, Darnel; Qin, Chengxue; Ritchie, Rebecca H.; Parry, Laura J.

2017-01-01

Serelaxin prevents endothelial dysfunction in the mouse aorta ex vivo and inhibits apoptosis in cardiomyocytes under acute hyperglycaemia. Less is known about the effects of serelaxin in an in vivo mouse model of diabetes. Therefore, we tested the hypothesis in streptozotocin (STZ)-treated mice that serelaxin is able to reverse diabetes-induced vascular dysfunction and cardiac remodelling. Mice were divided into citrate buffer + placebo, STZ + placebo and STZ + serelaxin (0.5 mg/kg/d, 2 weeks) groups. After 12 weeks of diabetes, sensitivity to the endothelium-dependent agonist acetylcholine (ACh) was reduced in the mesenteric artery. This was accompanied by an enhanced vasoconstrictor prostanoid contribution and a decrease in endothelium-derived hyperpolarisation (EDH)-mediated relaxation. Serelaxin restored endothelial function by increasing nitric oxide (NO)-mediated relaxation but not EDH. It also normalised the contribution of vasoconstrictor prostanoids to endothelial dysfunction and suppressed diabetes-induced hyper-responsiveness of the mesenteric artery to angiotensin II. Similarly, diabetes reduced ACh-evoked NO-mediated relaxation in the aorta which was reversed by serelaxin. In the left ventricle, diabetes promoted apoptosis, hypertrophy and fibrosis; serelaxin treatment reversed this ventricular apoptosis and hypertrophy, but had no effect on fibrosis. In summary, serelaxin reversed diabetes-induced endothelial dysfunction by enhancing NO-mediated relaxation in the mouse vasculature and attenuating left ventricular hypertrophy and apoptosis. PMID:28067255

Regression of left ventricular hypertrophy and aortic remodelling in NO-deficient hypertensive rats: effect of L-arginine and spironolactone.

PubMed

Paulis, L; Matuskova, J; Adamcova, M; Pelouch, V; Simko, J; Krajcirovicova, K; Potacova, A; Hulin, I; Janega, P; Pechanova, O; Simko, F

2008-09-01

We investigated, whether the substrate for nitric oxide (NO) formation -L-arginine - and the aldosterone receptor antagonist - spironolactone - are able to reverse alterations of the left ventricle (LV) and aorta in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Six groups of male adult Wistar rats were investigated: controls after 4 and 7 weeks of experiment, rats treated with L-NAME for 4 weeks and three recovery groups: spontaneous-reversion (4 weeks L-NAME + 3 weeks placebo), spironolactone-induced reversion (4 weeks L-NAME + 3 weeks spironolactone) and L-arginine-induced reversion (4 weeks L-NAME+ 3 weeks L-arginine). Blood pressure was measured by tail-cuff plethysmography. Relative weight of the LV, myocardial fibrosis (based upon histomorphometry and hydroxyproline determination) and conjugated dienes in the LV and aortic cross-sectional area, inner diameter and wall thickness were determined. NO-synthase activity was investigated in the LV and aorta. L-NAME administration induced hypertension, left ventricular hypertrophy (LVH), LV fibrosis, aortic thickening and diminution of NO-synthase activity in the LV and aorta. Reduction in blood pressure and regression of LVH were observed in all recovery groups, yet reduction in LV fibrosis and aortic thickening were not. NO-synthase activity was restored only in the L-arginine and spironolactone group. In our study, the reversion of hypertension and LVH was not dependent on the restoration of NO-synthase activity. Moreover, LV fibrosis and aortic remodelling seem to be more resistant to conditions resulting in regression of LVH. Preserved level of fibrosis in the initial period of LVH regression might result in loss of structural homogeneity and possible functional alterations of the LV.

Dyssynchronous Ventricular Activation in Asymptomatic Wolff-Parkinson-White Syndrome: A Risk Factor for Development of Dilated Cardiomyopathy

PubMed Central

Udink ten Cate, Floris EA; Wiesner, Nathalie; Trieschmann, Uwe; Khalil, Markus; Sreeram, Narayanswami

2010-01-01

A subset of children and adults with Wolff-Parkinson-White (WPW) syndrome develop dilated cardiomyopathy (DCM). Although DCM may occur in symptomatic WPW patients with sustained tachyarrhythmias, emerging evidence suggests that significant left ventricular dysfunction may arise in WPW in the absence of incessant tachyarrhythmias. An invariable electrophysiological feature in this non-tachyarrhythmia type of DCM is the presence of a right-sided septal or paraseptal accessory pathway. It is thought that premature ventricular activation over these accessory pathways induces septal wall motion abnormalities and ventricular dyssynchrony. LV dyssynchrony induces cellular and structural ventricular remodelling, which may have detrimental effects on cardiac performance. This review summarizes recent evidence for development of DCM in asymptomatic patients with WPW, discusses its pathogenesis, clinical presentation, management and treatment. The prognosis of accessory pathway-induced DCM is excellent. LV dysfunction reverses following catheter ablation of the accessory pathway, suggesting an association between DCM and ventricular preexcitation. Accessory pathway-induced DCM should be suspected in all patients presenting with heart failure and overt ventricular preexcitation, in whom no cause for their DCM can be found. PMID:20552060

Overexpressed connective tissue growth factor in cardiomyocytes attenuates left ventricular remodeling induced by angiotensin II perfusion.

PubMed

Zhang, Ying; Yan, Hua; Guang, Gong-Chang; Deng, Zheng-Rong

2017-01-01

To evaluate the improving effects of specifically overexpressed connective tissue growth factor (CTGF) in cardiomyocytes on mice with hypertension induced by angiotensin II (AngII) perfusion, 24 transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) were divided into two equal groups that were perfused with acetic acid and AngII, respectively, for 7 days. Another 24 cage-control wild-type C57BL/6 mice (NLC) were divided and treated identically. Blood pressure was detected by caudal artery cannulation. Cardiac structural and functional changes were observed by echocardiography. Cardiac fibrosis was detected by Masson staining. After AngII perfusion, blood pressures of NLC and Tg-CTGF mice, especially those of the formers, significantly increased. Compared with NLC + AngII group, Tg-CTGF + AngII group had significantly lower left ventricular posterior wall thickness at end-diastole and left ventricular posterior wall thickness at end-systole as well as significantly higher left ventricular end-systolic diameter and left ventricular end-diastolic diameter (P < 0.05). Reverse transcription-polymerase chain reaction (RT-PCR) showed that Tg-CTGF + AngII group had significantly lower collagen I, α-SMA, and TGF-β mRNA expressions in cardiac tissues (P < 0.05). Tg-CTGF can protect AngII-induced cardiac remodeling of mice with hypertension by mitigating inflammatory response. CTGF may be a therapy target for hypertension-induced myocardial fibrosis, but the detailed mechanism still needs in-depth studies.

Ablation of biglycan attenuates cardiac hypertrophy and fibrosis after left ventricular pressure overload.

PubMed

Beetz, Nadine; Rommel, Carolin; Schnick, Tilman; Neumann, Elena; Lother, Achim; Monroy-Ordonez, Elsa Beatriz; Zeeb, Martin; Preissl, Sebastian; Gilsbach, Ralf; Melchior-Becker, Ariane; Rylski, Bartosz; Stoll, Monika; Schaefer, Liliana; Beyersdorf, Friedhelm; Stiller, Brigitte; Hein, Lutz

2016-12-01

Biglycan, a small leucine-rich proteoglycan, has been shown to play an important role in stabilizing fibrotic scars after experimental myocardial infarction. However, the role of biglycan in the development and regression of cardiomyocyte hypertrophy and fibrosis during cardiac pressure overload and unloading remains elusive. Thus, the aim of the present study was to assess the effect of biglycan on cardiac remodeling in a mouse model of left ventricular pressure overload and unloading. Left ventricular pressure overload induced by transverse aortic constriction (TAC) in mice resulted in left ventricular dysfunction, fibrosis and increased biglycan expression. Fluorescence- and magnetic-assisted sorting of cardiac cell types revealed upregulation of biglycan in the fibroblast population, but not in cardiomyocytes, endothelial cells or leukocytes after TAC. Removal of the aortic constriction (rTAC) after short-term pressure overload (3weeks) improved cardiac contractility and reversed ventricular hypertrophy but not fibrosis in wild-type (WT) mice. Biglycan ablation (KO) enhanced functional recovery but did not resolve cardiac fibrosis. After long-term TAC for 9weeks, ablation of biglycan attenuated the development of cardiac hypertrophy and fibrosis. In vitro, biglycan induced hypertrophy of neonatal rat cardiomyocytes and led to activation of a hypertrophic gene program. Putative downstream mediators of biglycan signaling include Rcan1, Abra and Tnfrsf12a. These genes were concordantly induced by TAC in WT but not in biglycan KO mice. Left ventricular pressure overload induces biglycan expression in cardiac fibroblasts. Ablation of biglycan improves cardiac function and attenuates left ventricular hypertrophy and fibrosis after long-term pressure overload. In vitro biglycan induces hypertrophy of cardiomyocytes, suggesting that biglycan may act as a signaling molecule between cell types to modulate cardiac remodeling. Copyright © 2016 Elsevier Ltd. All rights reserved.

Plasma bilirubin values on admission and ventricular remodeling after a first anterior ST-segment elevation acute myocardial infarction.

PubMed

Miranda, Berta; Barrabés, José A; Figueras, Jaume; Pineda, Victor; Rodríguez-Palomares, José; Lidón, Rosa-Maria; Sambola, Antonia; Bañeras, Jordi; Otaegui, Imanol; García-Dorado, David

2016-01-01

Bilirubin may elicit cardiovascular protection and heme oxygenase-1 overexpression attenuated post-infarction ventricular remodeling in experimental animals, but the association between bilirubin levels and post-infarction remodeling is unknown. In 145 patients with a first anterior ST-segment elevation acute myocardial infarction (STEMI), we assessed whether plasma bilirubin on admission predicted adverse remodeling (left ventricular end-diastolic volume [LVEDV] increase ≥20% between discharge and 6 months, estimated by magnetic resonance imaging). Patients' baseline characteristics and management were comparable among bilirubin tertiles. LVEDV increased at 6 months (P < 0.001) with respect to the initial exam, but the magnitude of this increase was similar across increasing bilirubin tertiles (10.8 [30.2], 10.1 [22.9], and 12.7 [24.3]%, P = 0.500). Median (25-75 percentile) bilirubin values in patients with and without adverse remodeling were 0.75 (0.60-0.93) and 0.73 (0.60-0.92) mg/dL (P = 0.693). Absence of final TIMI flow grade 3 (odds ratio 3.92, 95% CI 1.12-13.66) and a history of hypertension (2.04, 0.93-4.50), but not admission bilirubin, were independently associated with adverse remodeling. Bilirubin also did not predict the increase in ejection fraction at 6 months. Admission bilirubin values are not related to LVEDV or ejection fraction progression after a first anterior STEMI and do not predict adverse ventricular remodeling. Key messages Bilirubin levels are inversely related to cardiovascular disease, and overexpression of heme oxygenase-1 (the enzyme that determines bilirubin production) has prevented post-infarction ventricular remodeling in experimental animals, but the association between bilirubin levels and the progression of ventricular volumes and function in patients with acute myocardial infarction remained unexplored. In this cohort of patients with a first acute anterior ST-segment elevation myocardial infarction receiving contemporary management, bilirubin levels on admission were not predictive of the changes in left ventricular volumes or ejection fraction at 6 months measured by serial cardiac magnetic resonance imaging. The data are contrary to a significant protective effect of bilirubin against post-infarction ventricular remodeling.

Baduanjin Exercise Prevents post-Myocardial Infarction Left Ventricular Remodeling (BE-PREMIER trial): Design and Rationale of a Pragmatic Randomized Controlled Trial.

PubMed

Mao, Shuai; Zhang, Xiaoxuan; Shao, Biying; Hu, Xiyan; Hu, Yanan; Li, Winny; Guo, Liheng; Zhang, Minzhou

2016-06-01

Left ventricular (LV) remodeling following myocardial infarction (MI) is an established prognostic factor for adverse cardiovascular events and the leading cause of heart failure. Empirical observations have suggested that Baduanjin exercise, an important component of traditional Chinese Qigong, may exert potential benefits on cardiopulmonary function. However, the impact of a Baduanjin exercise-based cardiac rehabilitation program for patients recovering from a recent MI has yet to be assessed. The aim of this trial is to evaluate the potential role of Baduanjin exercise in preventing the maladaptive progression to adverse LV remodeling in patients post-MI. A total of 110 clinically stable patients following an MI after undergoing successful infarct-related artery reperfusion will be randomly assigned to the Baduanjin exercise group or usual exercise control group. In addition to usual physical activity, participants in the Baduanjin exercise group will participate in a 45 min Baduanjin exercise training session twice a week, for a total of 12 weeks. The primary endpoint will be the percentage change in LV end-diastolic volume index (LVEDVi) assessed using echocardiography from baseline to 6 months. The results of this study may provide novel evidence on the efficacy of Baduanjin exercise therapy in post-MI patients in reversing adverse LV remodeling and improving clinical outcome. Clinical Trials.gov: NCT02693795.

Echocardiographic phase imaging to predict reverse remodeling after cardiac resynchronization therapy.

PubMed

Buss, Sebastian J; Humpert, Per M; Bekeredjian, Raffi; Hardt, Stefan E; Zugck, Christian; Schellberg, Dieter; Bauer, Alexander; Filusch, Arthur; Kuecherer, Helmut; Katus, Hugo A; Korosoglou, Grigorios

2009-05-01

The aim of our study was to investigate whether echocardiographic phase imaging (EPI) can predict response in patients who are considered for cardiac resynchronization therapy (CRT). CRT improves quality of life, exercise capacity, and outcome in patients with bundle-branch block and advanced heart failure. Previous studies used QRS duration to select patients for CRT; the accuracy of this parameter to predict functional recovery, however, is controversial. We examined 42 patients with advanced heart failure (New York Heart Association [NYHA] functional class III to IV, QRS duration >130 ms, and ejection fraction <35%) before and 6 to 8 months after CRT. Left ventricular (LV) dyssynchrony was estimated by calculating the SD of time to peak velocities (Ts-SD) by conventional tissue Doppler imaging (TDI), and the mean phase index (mean EPI-Index) was calculated by EPI in 12 mid-ventricular and basal segments. Patients who were alive and had significant relative decrease in end-systolic LV volume of Delta ESV >or=15% at 6 to 8 months of follow-up were defined as responders. All others were classified as nonresponders. The Ts-SD and the mean EPI-Index were related to Delta ESV (r = 0.43 for Ts-SD and r = 0.67 for mean EPI-Index, p < 0.01 for both), and both parameters yielded similar accuracy for the prediction of LV remodeling (area under the curve of 0.87 for TDI vs. 0.90 for EPI, difference between areas = 0.03, p = NS) and ejection fraction (EF) improvement (area under the curve of 0.87 for TDI vs. 0.93 for EPI, difference between areas = 0.06, p = NS). Furthermore, patients classified as responders by EPI (mean EPI-Index

Post-transcriptional regulation of α-1-antichymotrypsin by microRNA-137 in chronic heart failure and mechanical support.

PubMed

Lok, Sjoukje I; van Mil, Alain; Bovenschen, Niels; van der Weide, Petra; van Kuik, Joyce; van Wichen, Dick; Peeters, Ton; Siera, Erica; Winkens, Bjorn; Sluijter, Joost P G; Doevendans, Pieter A; da Costa Martins, Paula A; de Jonge, Nicolaas; de Weger, Roel A

2013-07-01

Better understanding of the molecular mechanisms of remodeling has become a major objective of heart failure (HF) research to stop or reverse its progression. Left ventricular assist devices (LVADs) are being used in patients with HF, leading to partial reverse remodeling. In the present study, proteomics identified significant changes in α-1-antichymotrypsin (ACT) levels during LVAD support. Moreover, the potential role of ACT in reverse remodeling was studied in detail. Expression of ACT mRNA (quantitative-polymerase chain reaction) decreased significantly in post-LVAD myocardial tissue compared with pre-LVAD tissue (n=15; P<0.01). Immunohistochemistry revealed that ACT expression and localization changed during LVAD support. Circulating ACT levels were elevated in HF patients (n=18) as compared with healthy controls (n=6; P=0.001) and normalized by 6 months of LVAD support. Because increasing evidence implicates that microRNAs (miRs) are involved in myocardial disease processes, we also investigated whether ACT is post-transcriptionally regulated by miRs. Bioinformatics analysis pointed miR-137 as a potential regulator of ACT. The miR-137 expression is inversely correlated with ACT mRNA in myocardial tissue. Luciferase activity assays confirmed ACT as a direct target for miR-137, and in situ hybridization indicated that ACT and miR-137 were mainly localized in cardiomyocytes and stromal cells. High ACT plasma levels in HF normalized during LVAD support, which coincides with decreased ACT mRNA in heart tissue, whereas miR-137 levels increased. MiR-137 directly targeted ACT, thereby indicating that ACT and miR-137 play a role in the pathophysiology of HF and reverse remodeling during mechanical support.

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers.

PubMed

Sydykov, Akylbek; Mamazhakypov, Argen; Petrovic, Aleksandar; Kosanovic, Djuro; Sarybaev, Akpay S; Weissmann, Norbert; Ghofrani, Hossein A; Schermuly, Ralph T

2018-01-01

Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function.

Inflammatory Mediators Drive Adverse Right Ventricular Remodeling and Dysfunction and Serve as Potential Biomarkers

PubMed Central

Sydykov, Akylbek; Mamazhakypov, Argen; Petrovic, Aleksandar; Kosanovic, Djuro; Sarybaev, Akpay S.; Weissmann, Norbert; Ghofrani, Hossein A.; Schermuly, Ralph T.

2018-01-01

Adverse right ventricular (RV) remodeling leads to ventricular dysfunction and failure that represents an important determinant of outcome in patients with pulmonary hypertension (PH). Recent evidence indicates that inflammatory activation contributes to the pathogenesis of adverse RV remodeling and dysfunction. It has been shown that accumulation of inflammatory cells such as macrophages and mast cells in the right ventricle is associated with maladaptive RV remodeling. In addition, inhibition of inflammation in animal models of RV failure ameliorated RV structural and functional impairment. Furthermore, a number of circulating inflammatory mediators have been demonstrated to be associated with RV performance. This work reviews the role of inflammation in RV remodeling and dysfunction and discusses anti-inflammatory strategies that may attenuate adverse structural alterations while promoting improvement of RV function. PMID:29875701

Worsening of left ventricular end-systolic volume and mitral regurgitation without increase in left ventricular dyssynchrony on acute interruption of cardiac resynchronization therapy.

PubMed

Kuppahally, Suman S; Fowler, Michael B; Vagelos, Randall; Wang, Paul; Al-Ahmad, Amin; Paloma, Allan; Liang, David

2009-08-01

Responders to cardiac resynchronization therapy (CRT) have greater left ventricular (LV) dyssynchrony than nonresponders prior to CRT. We conducted this study to see whether the long term responders have more worsening of LV dyssynchrony and LV function on acute interruption of CRT. We identified 22 responders and 13 nonresponders who received CRT as per standard criteria for 23.73 +/- 7.9 months (median 24.5 months). We assessed the acute change in LV function, mitral regurgitation (MR) and compared LV dyssynchrony in CRT on and off modes. On turning off CRT, there was no significant worsening of LV dyssynchrony in both responders and nonresponders. The dyssynchrony measurements by SPWMD, TDI and 3D echocardiography did not correlate significantly. LVESV increased (p = 0.02) and MR (p = 0.01) worsened in CRT-off mode in responders only without significant change in LVEF or LV dimensions. In long-term responders to CRT, there is alteration in the function of remodeled LV with acute interruption of CRT, without significant worsening of LV dyssynchrony. The role of different echocardiographic parameters in the assessment of LV dyssynchrony remains controversial. Even after long-term CRT reversely remodels the LV, the therapy needs to be continued uninterrupted for sustained benefits.

Left ventricular torsion assessed by two-dimensional echocardiography speckle tracking as a predictor of left ventricular remodeling and short-term outcome following primary percutaneous coronary intervention for acute myocardial infarction: A single-center experience.

PubMed

Awadalla, Hany; Saleh, Mohamed Ayman; Abdel Kader, Mohamed; Mansour, Amr

2017-08-01

Left ventricular (LV) torsion is a novel method to assess systolic LV function. This study aimed at exploring the utility of 2D speckle tracking-based assessment of left ventricular torsion in patients with acute myocardial infarction (AMI) undertaking primary percutaneous intervention (pPCI) in predicting left ventricular remodeling. The study included 115 patients (mean±SD, age 52.2±9.67, males 84.3%) who underwent pPCI for AMI. Echocardiographic assessment of LV torsion by two-dimensional speckle tracking was performed early after the index pPCI. Patients underwent repeat echocardiography at 6 months to detect remodeling. LV torsion in the acute setting was significantly lower in those who demonstrated LV remodeling at follow-up compared to those without remodeling (7.56±1.95 vs 15.16±4.65; P<.005). Multivariate analysis identified peak CK & CK-MB elevation (β=-0.767 and -0.725; P<.001), SWMA index (β=-0.843; P<.001), and Simpson's derived LV ejection fraction (LVEF; β=0.802; P<.001) as independent predictors of baseline LV torsion. It also identified peak LV torsion (β: 0.27; 95% CI: 0.15-0.5, P=.001) and SWMA index (β: 1.07, 95% CI: 1.03-1.12, P=.005) as independent predictors of LV remodeling. Baseline Killip's grades II and higher (β: 48.6; 95% CI 5.5-428, P<.001) and diabetes mellitus (β: 29.7; 95% CI 1.1-763, P<.05) were independent predictors of mortality. Left ventricular torsion in acute MI setting is impaired and predicts subsequent LV remodeling at 6-month follow-up. © 2017, Wiley Periodicals, Inc.

Targeted deletion of apoptosis signal-regulating kinase 1 attenuates left ventricular remodeling

PubMed Central

Yamaguchi, Osamu; Higuchi, Yoshiharu; Hirotani, Shinichi; Kashiwase, Kazunori; Nakayama, Hiroyuki; Hikoso, Shungo; Takeda, Toshihiro; Watanabe, Tetsuya; Asahi, Michio; Taniike, Masayuki; Matsumura, Yasushi; Tsujimoto, Ikuko; Hongo, Kenichi; Kusakari, Yoichiro; Kurihara, Satoshi; Nishida, Kazuhiko; Ichijo, Hidenori; Hori, Masatsugu; Otsu, Kinya

2003-01-01

Left ventricular remodeling that occurs after myocardial infarction (MI) and pressure overload is generally accepted as a determinant of the clinical course of heart failure. The molecular mechanism of this process, however, remains to be elucidated. Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase that plays an important role in stress-induced apoptosis. We used ASK1 knockout mice (ASK-/-) to test the hypothesis that ASK1 is involved in development of left ventricular remodeling. ASK-/- hearts showed no morphological or histological defects. Echocardiography and cardiac catheterization revealed normal global structure and function. Left ventricular structural and functional remodeling were determined 4 weeks after coronary artery ligation or thoracic transverse aortic constriction (TAC). ASK-/- had significantly smaller increases in left ventricular end-diastolic and end-systolic ventricular dimensions and smaller decreases in fractional shortening in both experimental models compared with WT mice. The number of terminal deoxynucleotidyl transferase biotin-dUDP nick end-labeling-positive myocytes after MI or TAC was decreased in ASK-/- compared with that in WT mice. Overexpression of a constitutively active mutant of ASK1 induced apoptosis in isolated rat neonatal cardiomyocytes, whereas neonatal ASK-/- cardiomyocytes were resistant to H2O2-induced apoptosis. An in vitro kinase assay showed increased ASK1 activity in heart after MI or TAC in WT mice. Thus, ASK1 plays an important role in regulating left ventricular remodeling by promoting apoptosis. PMID:14665690

Reverse remodeling and the mechanism of mitral regurgitation improvement in patients with dilated cardiomyopathy.

PubMed

Kuperstein, Rafael; Blechman, Ido; Ben Zekry, Sagit; Klempfner, Robert; Freimark, Dov; Arad, Michael

2015-01-01

Functional mitral regurgitation (MR) is a common finding in dilated cardiomyopathy. Left ventricular (LV) reverse remodeling with LV size reduction and improvement in LV function is a well recognized phenomenon. We aimed to evaluate the impact of LV remodeling on the mechanism leading to functional MR. Among 188 patients with non-ischemic dilated cardiomyopathy, 10 patients significantly improved their LV function, reduced LV size and MR severity during follow-up (RRMR). A comparison was made between their baseline and follow-up echocardiographic examinations and to a matched-control group of patients who did not improve (no RRMR). LV and left atrium (LA) dimensions and volumes, LV mass (LVM), LV ejection fraction (LVEF) (Simpsons), sphericity index (SI), mitral valve tenting area (TA) coaptation distance (CD), effective regurgitant orifice (ERO), and regurgitant volume were calculated. Multivariable analysis was performed in order to evaluate which echocardiographic parameters related to MR improvement in reverse remodeling. LV and LA dimensions and volumes, LVM, SI, TA, CD, ERO and right ventricle, in the RRMR group significantly decreased at follow-up (p < 0.04 for all). When compared to no RRMR, despite a similar ERO (0.2 ± 0.05 vs. 0.2 ± 0.08, p = 0.13) and a larger regurgitant volume (38 ± 9 vs. 29 ± 8 mL, p = 0.05) and despite similar clinical characteristics and medical treatment we found significantly higher LVEF, smaller LV dimensions and volumes, smaller LVM and SI in the RRMR group (p < 0.05 for all). On multivariable analysis the SI was the sole predictor of RRMR (p = 0.04, OR = 0.76, CI 0.58-0.99). Reverse remodeling characterized by improvement in LV function, reduction in LV size and an associated reduction in MR severity is related to LV SI at baseline.

Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

PubMed

Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

2012-03-01

Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

Internal associations and dynamic expression of c-kit and nanog genes in ventricular remodelling induced by adriamycin.

PubMed

Liu, Zhen; Li, Shuo; Liu, Lingling; Guo, Zhikun; Wang, Pengfei

2016-09-01

The present study aimed to investigate the dynamic expression of the c-kit and nanog genes in rats with left ventricular remodelling induced by adriamycin (ADR), and explore its internal association and mechanism of action. Sprague-Dawley male rats were randomly divided into a normal control group and a heart failure model group. Heart failure was induced by a single intraperitoneal injection of ADR (4 mg/kg) weekly for six weeks. The normal control group was given the same amount of saline. At the eighth week, rat cardiac function was examined to demonstrate the formation of heart failure. The rat hearts were harvested frozen and sectioned, and the expression levels of the nanog and c-kit genes in the myocardial tissue samples were detected using immunohistochemistry, immunofluorescence and reverse transcription-polymerase chain reaction (RT-PCR). Hematoxylin and eosin staining demonstrated various pathological changes in the myocardial cells in the heart failure model group, whereas myocardial infarction was not observed in the normal control group. Immunohistochemistry and immunofluorescence demonstrated that nanog-positive cells were predominantly expressed in the vascular endothelium, with a few myocardial cells and stem cells in normal myocardium. The expression levels of c-kit and nanog in the myocardium of the rats with heart failure decreased significantly. c-kit-positive cells clustered together in the epicardium and its vicinity, and c-kit expression significantly decreased in the myocardium of rats with heart failure, as compared with normal rats. In both groups, some cells co-expressed both the c-kit and nanog genes. The RT-PCR results demonstrated that the expression levels of the two genes in the heart failure model group were significantly lower compared with those in the normal control group (P<0.05). In conclusion, the c-kit- and nanog-positive stem cells decreased in the myocardium of the rats with left ventricular remodelling induced by ADR. Their abnormal expression was significantly correlated with left ventricular remodelling, thereby indicating an internal association (influences of two indexes in the experimental group and control group) between them.

Effects of Frequent Hemodialysis on Ventricular Volumes and Left Ventricular Remodeling

PubMed Central

Greene, Tom; Chertow, Glenn M.; Kliger, Alan S.; Stokes, John B.; Beck, Gerald J.; Daugirdas, John T.; Kotanko, Peter; Larive, Brett; Levin, Nathan W.; Mehta, Ravindra L.; Rocco, Michael; Sanz, Javier; Yang, Phillip C.; Rajagopalan, Sanjay

2013-01-01

Summary Background and objectives Higher left ventricular volume is associated with death in patients with ESRD. This work investigated the effects of frequent hemodialysis on ventricular volumes and left ventricular remodeling. Design, setting, participants, & measurements The Frequent Hemodialysis Network daily trial randomized 245 patients to 12 months of six times per week versus three times per week in-center hemodialysis; the Frequent Hemodialysis Network nocturnal trial randomized 87 patients to 12 months of six times per week nocturnal hemodialysis versus three times per week predominantly home-based hemodialysis. Left and right ventricular end systolic and diastolic volumes, left ventricular mass, and ejection fraction at baseline and end of the study were ascertained by cardiac magnetic resonance imaging. The ratio of left ventricular mass/left ventricular end diastolic volume was used as a surrogate marker of left ventricular remodeling. In each trial, the effect of frequent dialysis on left or right ventricular end diastolic volume was tested between predefined subgroups. Results In the daily trial, frequent hemodialysis resulted in significant reductions in left ventricular end diastolic volume (−11.0% [95% confidence interval, −16.1% to −5.5%]), left ventricular end systolic volume (−14.8% [−22.7% to −6.2%]), right ventricular end diastolic volume (−11.6% [−19.0% to −3.6%]), and a trend for right ventricular end systolic volume (−11.3% [−21.4% to 0.1%]) compared with conventional therapy. The magnitude of reduction in left and right ventricular end diastolic volumes with frequent hemodialysis was accentuated among patients with residual urine output<100 ml/d (P value [interaction]=0.02). In the nocturnal trial, there were no significant changes in left or right ventricular volumes. The frequent dialysis interventions had no substantial effect on the ratio of left ventricular mass/left ventricular end diastolic volume in either trial. Conclusions Frequent in-center hemodialysis reduces left and right ventricular end systolic and diastolic ventricular volumes as well as left ventricular mass, but it does not affect left ventricular remodeling. PMID:23970131

Chronic hypoxia decreases arterial and venous compliance in isolated perfused rat lungs: an effect that is reversed by exogenous l-arginine

PubMed Central

Jin, Yi; Chen, Bernadette; Calvert, Thomas J.; Chicoine, Louis G.; Liu, Yusen

2013-01-01

Chronic hypoxia (CH)-induced pulmonary hypertension is characterized by vasoconstriction and vascular remodeling, leading to right ventricular dysfunction. Given the role of arterial compliance (Ca) in right ventricular work, a decrease in Ca would add to right ventricular work. Nitric oxide (NO) is a potent vasodilator made by NO synthases from l-arginine (l-Arg). However, little is known of the effect of l-Arg on vascular compliance (Cv) in the lung. We hypothesized that exposure to CH would decrease Ca and that this effect would be reversed by exogenous l-Arg. Sprague-Dawley rats were exposed to either normoxia or CH for 14 days; the lungs were then isolated and perfused. Vascular occlusions were performed and modeled using a three-compliance, two-resistor model. Pressure-flow curves were generated, and a distensible vessel model was used to estimate distensibility and a vascular resistance parameter (R0). Hypoxia resulted in the expected increase in arterial resistance (Ra) as well as a decrease in both Ca and Cv. l-Arg had little effect on Ra, Ca, or Cv in isolated lungs from normoxic animals. l-Arg decreased Ra in lungs from CH rats and redistributed compliance to approximately that found in normoxic lungs. CH increased R0, and l-Arg reversed this increase in R0. l-Arg increased exhaled NO, and inhibition of l-Arg uptake attenuated the l-Arg-induced increase in exhaled NO. These data demonstrate that the CH-induced decrease in Ca was reversed by l-Arg, suggesting that l-Arg may improve CH-induced right ventricular dysfunction. PMID:23103497

Left ventricular reverse remodeling is not related to biopsy-detected extracellular matrix fibrosis and serum markers of fibrosis in dilated cardiomyopathy, regardless of the definition used for LVRR.

PubMed

Rubiś, Paweł; Wiśniowska-Śmiałek, Sylwia; Biernacka-Fijałkowska, Barbara; Rudnicka-Sosin, Lucyna; Wypasek, Ewa; Kozanecki, Artur; Dziewięcka, Ewa; Faltyn, Patrycja; Karabinowska, Aleksandra; Khachatryan, Lusine; Hlawaty, Marta; Leśniak-Sobelga, Agata; Kostkiewicz, Magdalena; Płazak, Wojciech; Podolec, Piotr

2017-06-01

Left ventricular reverse remodeling (LVRR) is reported in dilated cardiomyopathy (DCM) patients (pts). However, numerous definitions of LVRR exist. Measurements of serum markers of fibrosis provide insight into myocardial fibrosis. The relationship between LVRR and fibrosis is poorly understood. From July 2014 until October 2015, we included 63 consecutive DCM pts (48 ± 12.1 years, EF 24.4 ± 7.4%) with completed baseline and 3-month follow-up echocardiograms. LVRR was assessed on the basis of four differing definitions. Procollagens type I and III carboxy- and amino-terminal peptides (PICP, PINP, PIIICP, and PIIINP), collagen 1, ostepontin, tumor growth factor beta-1, connective tissue growth factor, and matrix metalloproteinases (MMP-2, MMP-9), and their tissue inhibitor (TIMP-1) were measured in serum. In addition, all pts underwent right ventricular endomyocardial biopsy. Depending on the definition chosen, LVRR could be diagnosed in between 14.3 and 50.8% pts. Regardless of the LVRR definition used, the frequency of LVRR was similar in fibrosis negative and positive DCM. Minor differences of markers of fibrosis were detected between pts with and without LVRR. For every LVRR definition, adjusted and unadjusted models were constructed to evaluate the predictive value of serum fibrosis parameters. Only an increase of TIMP-1 by 1 ng/ml was found to independently increase the probability of LVRR by 0.016%. The choice of a particular definition of LVRR determines the final diagnosis, and this has a profound impact on subsequent management. LVRR is unrelated to biopsy-detected ECM fibrosis. Serum markers of fibrosis are only weakly related to LVRR, and are not of use in the prediction of LVRR.

Cardiac fibrosis detected by magnetic resonance imaging on predicting time course diversity of left ventricular reverse remodeling in patients with idiopathic dilated cardiomyopathy.

PubMed

Ikeda, Yuki; Inomata, Takayuki; Fujita, Teppei; Iida, Yuichiro; Nabeta, Takeru; Ishii, Shunsuke; Maekawa, Emi; Yanagisawa, Tomoyoshi; Mizutani, Tomohiro; Naruke, Takashi; Koitabashi, Toshimi; Takeuchi, Ichiro; Ako, Junya

2016-11-01

This study aimed to identify the association between the time course of left ventricular reverse remodeling (LVRR) and late gadolinium enhancement in cardiac magnetic resonance imaging (LGE-cMRI) in patients with idiopathic dilated cardiomyopathy (IDCM). We identified 214 IDCM patients treated by optimal pharmacotherapies. LVRR was defined as ≥10 % increment in LV ejection fraction along with ≥10 % reduction in LV end-diastolic dimension. Findings of LGE-cMRI focusing on presence and extent of LGE were evaluated at baseline. Echocardiographic evaluation for detecting LVRR was performed in all patients for 3 years. The primary endpoint was defined as composite events (CEs) including readmission for heart failure, detection of major ventricular arrhythmia, and all-cause mortality. LVRR was found at <1 year in 59 patients (28 %, early responder), ≥1 year in 56 patients (26 %, late responder), and was absent in 99 patients (46 %, non-responder). Multivariate Cox-proportional hazards analysis revealed that both early responders (P = 0.02) and late responders (P < 0.001) had lower incidence of CEs than non-responders. Among 66 subjects (23 %) with complete cMRI evaluation, LGE was detected more often in late and non- than early responders (65, 83 vs. 23 % P < 0.001, respectively), whereas the LGE area was smaller in both early and late than non-responders (2 ± 3, 4 ± 3 vs. 12 ± 10 %, P < 0.001, respectively). In conclusion, evaluating the presence and the extent of LGE is useful for predicting the clinical differences of LVRR time course and subsequent long-term outcomes.

Left ventricular assist device and drug therapy for the reversal of heart failure.

PubMed

Birks, Emma J; Tansley, Patrick D; Hardy, James; George, Robert S; Bowles, Christopher T; Burke, Margaret; Banner, Nicholas R; Khaghani, Asghar; Yacoub, Magdi H

2006-11-02

In patients with severe heart failure, prolonged unloading of the myocardium with the use of a left ventricular assist device has been reported to lead to myocardial recovery in small numbers of patients for varying periods of time. Increasing the frequency and durability of myocardial recovery could reduce or postpone the need for subsequent heart transplantation. We enrolled 15 patients with severe heart failure due to nonischemic cardiomyopathy and with no histologic evidence of active myocarditis. All had markedly reduced cardiac output and were receiving inotropes. The patients underwent implantation of left ventricular assist devices and were treated with lisinopril, carvedilol, spironolactone, and losartan to enhance reverse remodeling. Once regression of left ventricular enlargement had been achieved, the beta2-adrenergic-receptor agonist clenbuterol was administered to prevent myocardial atrophy. Eleven of the 15 patients had sufficient myocardial recovery to undergo explantation of the left ventricular assist device a mean (+/-SD) of 320+/-186 days after implantation of the device. One patient died of intractable arrhythmias 24 hours after explantation; another died of carcinoma of the lung 27 months after explantation. The cumulative rate of freedom from recurrent heart failure among the surviving patients was 100% and 88.9% 1 and 4 years after explantation, respectively. The quality of life as assessed by the Minnesota Living with Heart Failure Questionnaire score at 3 years was nearly normal. Fifty-nine months after explantation, the mean left ventricular ejection fraction was 64+/-12%, the mean left ventricular end-diastolic diameter was 59.4+/-12.1 mm, the mean left ventricular end-systolic diameter was 42.5+/-13.2 mm, and the mean maximal oxygen uptake with exercise was 26.3+/-6.0 ml per kilogram of body weight per minute. In this single-center study, we found that sustained reversal of severe heart failure secondary to nonischemic cardiomyopathy could be achieved in selected patients with the use of a left ventricular assist device and a specific pharmacologic regimen. Copyright 2006 Massachusetts Medical Society.

Orthogonal decomposition of left ventricular remodeling in myocardial infarction

PubMed Central

Zhang, Xingyu; Medrano-Gracia, Pau; Ambale-Venkatesh, Bharath; Bluemke, David A.; Cowan, Brett R; Finn, J. Paul; Kadish, Alan H.; Lee, Daniel C.; Lima, Joao A. C.; Young, Alistair A.; Suinesiaputra, Avan

2017-01-01

Abstract Left ventricular size and shape are important for quantifying cardiac remodeling in response to cardiovascular disease. Geometric remodeling indices have been shown to have prognostic value in predicting adverse events in the clinical literature, but these often describe interrelated shape changes. We developed a novel method for deriving orthogonal remodeling components directly from any (moderately independent) set of clinical remodeling indices. Results: Six clinical remodeling indices (end-diastolic volume index, sphericity, relative wall thickness, ejection fraction, apical conicity, and longitudinal shortening) were evaluated using cardiac magnetic resonance images of 300 patients with myocardial infarction, and 1991 asymptomatic subjects, obtained from the Cardiac Atlas Project. Partial least squares (PLS) regression of left ventricular shape models resulted in remodeling components that were optimally associated with each remodeling index. A Gram–Schmidt orthogonalization process, by which remodeling components were successively removed from the shape space in the order of shape variance explained, resulted in a set of orthonormal remodeling components. Remodeling scores could then be calculated that quantify the amount of each remodeling component present in each case. A one-factor PLS regression led to more decoupling between scores from the different remodeling components across the entire cohort, and zero correlation between clinical indices and subsequent scores. Conclusions: The PLS orthogonal remodeling components had similar power to describe differences between myocardial infarction patients and asymptomatic subjects as principal component analysis, but were better associated with well-understood clinical indices of cardiac remodeling. The data and analyses are available from www.cardiacatlas.org. PMID:28327972

Diabetes Mellitus Associates with Increased Right Ventricular Afterload and Remodeling in Pulmonary Arterial Hypertension.

PubMed

Whitaker, Morgan E; Nair, Vineet; Sinari, Shripad; Dherange, Parinita A; Natarajan, Balaji; Trutter, Lindsey; Brittain, Evan L; Hemnes, Anna R; Austin, Eric D; Patel, Kumar; Black, Stephen M; Garcia, Joe G N; Yuan Md PhD, Jason X; Vanderpool, Rebecca R; Rischard, Franz; Makino, Ayako; Bedrick, Edward J; Desai, Ankit A

2018-06-01

Diabetes mellitus is associated with left ventricular hypertrophy and dysfunction. Parallel studies have also reported associations between diabetes mellitus and right ventricular dysfunction and reduced survival in patients with pulmonary arterial hypertension. However, the impact of diabetes mellitus on the pulmonary vasculature has not been well characterized. We hypothesized that diabetes mellitus and hyperglycemia could specifically influence right ventricular afterload and remodeling in patients with Group I pulmonary arterial hypertension, providing a link to their known susceptibility to right ventricular dysfunction. Using an adjusted model for age, sex, pulmonary vascular resistance, and medication use, associations of fasting blood glucose, glycated hemoglobin, and the presence of diabetes mellitus were evaluated with markers of disease severity in 162 patients with pulmonary arterial hypertension. A surrogate measure of increased pulmonary artery stiffness, elevated pulmonary arterial elastance (P = .012), along with reduced log(pulmonary artery capacitance) (P = .006) were significantly associated with the presence of diabetes mellitus in patients with pulmonary arterial hypertension in a fully adjusted model. Similar associations between pulmonary arterial elastance and capacitance were noted with both fasting blood glucose and glycated hemoglobin. Furthermore, right ventricular wall thickness on echocardiography was greater in pulmonary arterial hypertension patients with diabetes, supporting the link between right ventricular remodeling and diabetes. Cumulatively, these data demonstrate that an increase in right ventricular afterload, beyond pulmonary vascular resistance alone, may influence right ventricular remodeling and provide a mechanistic link between the susceptibility to right ventricular dysfunction in patients with both diabetes mellitus and pulmonary arterial hypertension. Copyright © 2018 Elsevier Inc. All rights reserved.

Orthogonal decomposition of left ventricular remodeling in myocardial infarction.

PubMed

Zhang, Xingyu; Medrano-Gracia, Pau; Ambale-Venkatesh, Bharath; Bluemke, David A; Cowan, Brett R; Finn, J Paul; Kadish, Alan H; Lee, Daniel C; Lima, Joao A C; Young, Alistair A; Suinesiaputra, Avan

2017-03-01

Left ventricular size and shape are important for quantifying cardiac remodeling in response to cardiovascular disease. Geometric remodeling indices have been shown to have prognostic value in predicting adverse events in the clinical literature, but these often describe interrelated shape changes. We developed a novel method for deriving orthogonal remodeling components directly from any (moderately independent) set of clinical remodeling indices. Six clinical remodeling indices (end-diastolic volume index, sphericity, relative wall thickness, ejection fraction, apical conicity, and longitudinal shortening) were evaluated using cardiac magnetic resonance images of 300 patients with myocardial infarction, and 1991 asymptomatic subjects, obtained from the Cardiac Atlas Project. Partial least squares (PLS) regression of left ventricular shape models resulted in remodeling components that were optimally associated with each remodeling index. A Gram-Schmidt orthogonalization process, by which remodeling components were successively removed from the shape space in the order of shape variance explained, resulted in a set of orthonormal remodeling components. Remodeling scores could then be calculated that quantify the amount of each remodeling component present in each case. A one-factor PLS regression led to more decoupling between scores from the different remodeling components across the entire cohort, and zero correlation between clinical indices and subsequent scores. The PLS orthogonal remodeling components had similar power to describe differences between myocardial infarction patients and asymptomatic subjects as principal component analysis, but were better associated with well-understood clinical indices of cardiac remodeling. The data and analyses are available from www.cardiacatlas.org. © The Author 2017. Published by Oxford University Press.

3-Bromopyruvate reverses hypoxia-induced pulmonary arterial hypertension through inhibiting glycolysis: In vitro and in vivo studies.

PubMed

Chen, Fangzheng; Wang, Heng; Lai, Jiadan; Cai, Shujing; Yuan, Linbo

2018-05-04

Pulmonary arterial smooth muscle cell (PASMC) proliferation is vital to pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) pathogenesis, and inhibiting PASMC metabolism could serve as a new possible therapy to reverse the process. 3-Bromopyruvate (3-BrPA) is an effective glycolysis inhibitor with its effect in PAH remains unclear. Our study aims to assess the therapeutic effect of 3-BrPA in PAH rats and investigate the possible mechanism of 3-BrPA in PASMC proliferation and apoptosis. 27 healthy SD rats were grouped and treated with hypoxia/normoxia and administration of 3-BrPA/physiological saline. Mean pulmonary artery pressure (mPAP) and cardiac output (CO) were measured and pulmonary vascular resistance (PVR) was calculated. Right ventricular hypertrophy index (RVHI) was calculated to evaluate the right ventricular hypertrophy degree. The percentage of medial wall area (WA%) and medial wall thickness (WT%) were measured by image analysis. PASMCs groups received hypoxia/normoxia treatments and 3-BrPA/physiological saline. PASMC proliferation and migration were respectively detected by CCK-8 and cell wound scratch assay. Hexokinase II (HK-2) expression and lactate level were respectively measured by Western Blotting and lactate test kit to detect glycolysis. mPAP, PVR, PVHI, WA% and WT% in rats increased after the hypoxia treatment, but were lower compared to rats received 3-BrPA in hypoxia environment. HK-2 expression, lactate concentration, OD value and scratch areas in PASMCs increased after the hypoxia treatment, but were decreased after the administration of 3-BrPA. 3-BrPA can inhibit PASMC proliferation and migration by inhibiting glycolysis, and is effective in reversing the vascular remodeling in hypoxia-induced PAH rats. Copyright © 2017. Published by Elsevier B.V.

Effects of chronic treatment with the new ultra-long-acting β2 -adrenoceptor agonist indacaterol alone or in combination with the β1 -adrenoceptor blocker metoprolol on cardiac remodelling.

PubMed

Rinaldi, Barbara; Donniacuo, Maria; Sodano, Loredana; Gritti, Giulia; Martuscelli, Eugenio; Orlandi, Augusto; Rafaniello, Concetta; Rossi, Francesco; Calzetta, Luigino; Capuano, Annalisa; Matera, Maria Gabriella

2015-07-01

The ability of a chronic treatment with indacaterol, a new ultra-long-acting β2 -adrenoceptor agonist, to reverse cardiac remodelling and its effects in combination with metoprolol, a selective β1 -adrenoceptor antagonist, were investigated on myocardial infarction in a rat model of heart failure (HF). We investigated the effects of indacaterol and metoprolol, administered alone or in combination, on myocardial histology, β-adrenoceptor-mediated pathways, markers of remodelling and haemodynamic parameters in a rat model of HF. Five groups of rats were assessed: sham-operated rats; HF rats; HF + indacaterol 0.3 mg·kg(-1) ·day(-1) ; HF + metoprolol 100 mg·kg(-1) ·day(-1) ; HF + metoprolol + indacaterol. All pharmacological treatments continued for 15 weeks. Treatment with either indacaterol or metoprolol significantly reduced the infarct size in HF rats. However, the combination of indacaterol and metoprolol reduced the infarct size even further, reduced both BP and heart rate, reversed the decrease in ejection fraction, normalized left ventricular systolic and diastolic internal diameters, normalized the decreased β1 adrenoceptor mRNA expression as well as cardiac cAMP levels and reduced cardiac GPCR kinase 2 expression, compared with the untreated HF group. The results of our study demonstrated an additive interaction between indacaterol and metoprolol in normalizing and reversing cardiac remodelling in our experimental model of HF. The translation of these findings to clinical practice might be of interest, as this combination of drugs could be safer and more effective in patients suffering from HF and COPD. © 2015 The British Pharmacological Society.

Impact of Iron Deficiency on Response to and Remodeling After Cardiac Resynchronization Therapy.

PubMed

Martens, Pieter; Verbrugge, Frederik; Nijst, Petra; Dupont, Matthias; Tang, W H Wilson; Mullens, Wilfried

2017-01-01

Iron deficiency is prevalent in heart failure with reduced ejection fraction and relates to symptomatic status, readmission, and all-cause mortality. The relation between iron status and response to cardiac resynchronization therapy (CRT) remains insufficiently elucidated. This study assesses the impact of iron deficiency on clinical response and reverse cardiac remodeling and outcome after CRT. Baseline characteristics, change in New York Heart Association functional class, reverse cardiac remodeling on echocardiography, and clinical outcome (i.e., all-cause mortality and heart failure readmissions) were retrospectively evaluated in consecutive CRT patients who had full iron status and complete blood count available at implantation, implanted at a single tertiary care center with identical dedicated multidisciplinary CRT follow-up from October 2008 to August 2015. A total of 541 patients were included with mean follow-up of 38 ± 22 months. Prevalence of iron deficiency was 56% at implantation. Patients with iron deficiency exhibited less symptomatic improvement 6 months after implantation (p value <0.001). In addition, both the decrease in left ventricular end-diastolic diameter (-3.1 vs -6.2 mm; p value = 0.011) and improvement in ejection fraction (+11% vs +15%, p value = 0.001) were significantly lower in patients with iron deficiency. Iron deficiency was significantly associated with an increased risk for heart failure admission or all-cause mortality (adjusted hazard ratio 1.718, 95% confidence interval 1.178 to 2.506), irrespectively of the presence of anemia (Hemoglobin <12 g/dl in women and <13 g/dl in men). In conclusion, iron deficiency is prevalent and affects both clinical response and reverse cardiac remodeling after CRT implantation. Moreover, it is a powerful predictor of adverse clinical outcomes in CRT. Copyright © 2016 Elsevier Inc. All rights reserved.

Three-dimensional echocardiographic measurements using automated quantification software for big data processing.

PubMed

Feng, Cheng; Chen, Lixin; Li, Jian; Wang, Jiangtao; Dong, Fajin; Xu, Jinfeng

2017-01-01

To compare a full-automated software to quantify 3D transthoracic echocardiography namely, 3DE-HM (three-dimensional echocardiography HeartModel, Philips Healthcare) with the traditional manual quantitative method (3DE-manual) for assessing volumes of left atrial and ventricular volumes, and left ventricular ejection fraction (LVEF). 3D full volume images acquired from 156 subjects were collected and divided into 3 groups, which include 70 normal control cases (Group A), 17 patients with left ventricular remodeling after acute myocardial infarction (AMI) (Group B), and 69 patients with left atrial remodeling secondary to hypertension (Group C). The 3DE-HM method was used to quantify left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), left atrial end-systolic volume (LAESV), and left ventricular ejection fraction (LVEF), respectively. The results were compared with those obtained with the 3DE-manual method for correlation and consistency analyses. The reproducibility of the 3DE-HM method was also evaluated. There was a high correlation between LVEDV, LVESV, LAESV and LVEF values obtained with the 3DE-HM method and those obtained using the 3DE-manual method (r = 0.72 to 0.97). The correlation was strongest for Group B, patients with left ventricular remodeling post-AMI also demonstrated the greatest degree of morphologic changes. There was a significant difference in all parameters measured with the 3DE-HM method in different groups (P < 0.05). The difference in the measurements of LVEDV and LVESV between the two methods was greatest in patients in Group B compared with patients with hypertension-induced left ventricular remodeling (Group C) and in normal controls (Group A) (P < 0.05). Lastly, the difference in the measurement of LAESV between the two methods was greater in patients with hypertension-induced left ventricular remodeling (Group C) than that in the control group (Group A) (P < 0.05). The post-processing time of the 3DE-HM data was significantly shorter than that using the 3DE-manual method (P < 0.05). There was no significant variability in repeated measurements at different time points using the 3DE-HM method either between subjects in different groups or within the same subject. 3DE-HM is a quick and feasible method for left ventricular quantification and is clinically applicable for evaluating patients with left atrial and left ventricular remodeling.

Left ventricular remodelling in chronic primary mitral regurgitation: implications for medical therapy.

PubMed

McCutcheon, Keir; Manga, Pravin

Surgical repair or replacement of the mitral valve is currently the only recommended therapy for severe primary mitral regurgitation. The chronic elevation of wall stress caused by the resulting volume overload leads to structural remodelling of the muscular, vascular and extracellular matrix components of the myocardium. These changes are initially compensatory but in the long term have detrimental effects, which ultimately result in heart failure. Understanding the changes that occur in the myocardium due to volume overload at the molecular and cellular level may lead to medical interventions, which potentially could delay or prevent the adverse left ventricular remodelling associated with primary mitral regurgitation. The pathophysiological changes involved in left ventricular remodelling in response to chronic primary mitral regurgitation and the evidence for potential medical therapy, in particular beta-adrenergic blockers, are the focus of this review.

Flexible band versus rigid ring annuloplasty for functional tricuspid regurgitation: two different patterns of right heart reverse remodelling

PubMed Central

Gatti, Giuseppe; Dell'Angela, Luca; Morosin, Marco; Maschietto, Luca; Pinamonti, Bruno; Benussi, Bernardo; Forti, Gabriella; Nicolosi, Gian Luigi; Sinagra, Gianfranco; Pappalardo, Aniello

2016-01-01

OBJECTIVES Annuloplasty bands and rings are widely used to treat functional tricuspid regurgitation (TR). However, the question as to which is the ideal annuloplasty device remains open. Early and late outcomes of tricuspid valve annuloplasty with flexible band (B-TVA) or rigid ring (R-TVA) are compared in the present study. METHODS Between 1999 and 2014, 462 consecutive patients (mean age, 69.2 ± 9.5 years) with grade ≥1+ functional TR (graded from 0 to 3+) underwent either B-TVA (n = 345; mean EuroSCORE II 9.2 ± 10.8%) or R-TVA (n = 117; mean EuroSCORE II 12 ± 13.4%) in addition to other cardiac procedures at the authors' institution. RESULTS One-to-one propensity score-matched analysis resulted in 98 pairs with similar baseline characteristics and operative risk. Hospital mortality was 7.5% after B-TVA and 12% after R-TVA (P = 0.14). R-TVA was associated with higher rates of low cardiac output (10.1 vs 17.9%, P = 0.025) and transient complete atrioventricular block (10.3 vs 17.2%, P = 0.046). Among the matched pairs, there were no significant differences in hospital mortality (5.1 vs 9.2%, P = 0.27) and perioperative complications. Both in overall series and matched pairs, between B-TVA and R-TVA patients, there were no significant differences in freedom from all-cause death (P = 0.29 and 0.91), cardiac and cerebrovascular deaths (P = 0.63 and 0.87) and grade ≥2+ TR (P = 0.68 and 0.77). Right atrial and tricuspid valve reverse remodelling combined with right ventricular reverse remodelling occurred after R-TVA but not after B-TVA. CONCLUSIONS B-TVA and R-TVA are equally effective in the treatment of functional TR. However, R-TVA causes over time a more complete right heart reverse remodelling. PMID:26993479

The Biological Role of Nestin(+)-Cells in Physiological and Pathological Cardiovascular Remodeling

PubMed Central

Calderone, Angelino

2018-01-01

The intermediate filament protein nestin was identified in diverse populations of cells implicated in cardiovascular remodeling. Cardiac resident neural progenitor/stem cells constitutively express nestin and following an ischemic insult migrate to the infarct region and participate in angiogenesis and neurogenesis. A modest number of normal adult ventricular fibroblasts express nestin and the intermediate filament protein is upregulated during the progression of reparative and reactive fibrosis. Nestin depletion attenuates cell cycle re-entry suggesting that increased expression of the intermediate filament protein in ventricular fibroblasts may represent an activated phenotype accelerating the biological impact during fibrosis. Nestin immunoreactivity is absent in normal adult rodent ventricular cardiomyocytes. Following ischemic damage, the intermediate filament protein is induced in a modest population of pre-existing adult ventricular cardiomyocytes bordering the peri-infarct/infarct region and nestin(+)-ventricular cardiomyocytes were identified in the infarcted human heart. The appearance of nestin(+)-ventricular cardiomyocytes post-myocardial infarction (MI) recapitulates an embryonic phenotype and depletion of the intermediate filament protein inhibits cell cycle re-entry. Recruitment of the serine/threonine kinase p38 MAPK secondary to an overt inflammatory response after an ischemic insult may represent a seminal event limiting the appearance of nestin(+)-ventricular cardiomyocytes and concomitantly suppressing cell cycle re-entry. Endothelial and vascular smooth muscle cells (VSMCs) express nestin and upregulation of the intermediate filament protein may directly contribute to vascular remodeling. This review will highlight the biological role of nestin(+)-cells during physiological and pathological remodeling of the heart and vasculature and discuss the phenotypic advantage attributed to the intermediate filament protein. PMID:29492403

Timing and Targeting of Treatment in Left Ventricular Hypertrophy.

PubMed

Nam, Deokhwa; Reineke, Erin L

2017-01-01

In most clinical cases, left ventricular hypertrophy (LVH) occurs over time from persistent cardiac stress. At the molecular level, this results in both transient and long-term changes to metabolic, sarcomeric, ion handling, and stress signaling pathways. Although this is initially an adaptive change, the mechanisms underlying LVH eventually lead to maladaptive changes including fibrosis, decreased cardiac function, and failure. Understanding the regulators of long-term changes, which are largely driven by transcriptional remodeling, is a crucial step in identifying novel therapeutic targets for preventing the downstream negative effects of LVH and treatments that could reverse or prevent it. The development of effective therapeutics, however, will require a critical understanding of what to target, how to modify important pathways, and how to identify the stage of pathology in which a specific treatment should be used.

Long-term outcome in dogs with patent ductus arteriosus: 520 cases (1994-2009).

PubMed

Saunders, A B; Gordon, S G; Boggess, M M; Miller, M W

2014-01-01

Published information regarding survival and long-term cardiac remodeling after patent ductus arteriosus (PDA) closure in dogs is limited. To report outcome and identify prognostic variables in dogs with PDA, and to identify risk factors for persistent remodeling in dogs with a minimum of 12 months of follow-up after closure. Five hundred and twenty client-owned dogs. Retrospective review of medical records of 520 dogs with PDA. Outcome was determined by contacting owners and veterinarians. Dogs with PDA closure and ≥ 12 months of follow-up were asked to return for a re-evaluation. In multivariable analysis of 506 dogs not euthanized at the time of diagnosis, not having a PDA closure procedure negatively affected survival (HzR = 16.9, P < .001). In 444 dogs undergoing successful PDA closure, clinical signs at presentation (HzR = 17, P = .02), concurrent congenital heart disease (HD) (HzR = 4.8, P = .038), and severe mitral regurgitation (MR) documented within 24 hours of closure (HzR = 4.5, P = .028) negatively affected survival. Seventy-one dogs with ≥ 12 months follow-up demonstrated a significant reduction in radiographic and echocardiographic measures of heart size (P = 0) and increased incidence of acquired HD (P = .001) at re-evaluation. Dogs with increased left ventricular size and low fractional shortening at baseline were more likely to have persistent remodeling at re-evaluation. Patent ductus arteriosus closure confers important survival benefits and results in long-term reverse remodeling in most dogs. Clinical signs at presentation, concurrent congenital HD, and severe MR negatively affect survival. Increased left ventricular systolic dimensions and systolic dysfunction at baseline correlated significantly with persistent remodeling. Copyright © 2013 by the American College of Veterinary Internal Medicine.

Determinants of Reverse Remodeling of the Left Atrium Following Transaortic Myectomy.

PubMed

Nguyen, Anita; Schaff, Hartzell V; Nishimura, Rick A; Dearani, Joseph A; Geske, Jeffrey B; Lahr, Brian D; Ommen, Steve R

2018-04-18

In patients with hypertrophic cardiomyopathy (HCM), enlargement of the left atrium (LA) is associated with increased morbidity and mortality due to risk of atrial fibrillation (AF), stroke, and heart failure. In this study, we investigated whether LA reverse remodeling occurs following septal myectomy. Between March 2007 and July 2015, 656 patients underwent myectomy at our institution and had pre- and postoperative transthoracic echocardiographic (TTE) recording of LA volume index (LAVI). We reviewed clinical and echocardiographic data of these patients, and assessed for changes over time by comparing pre- and postoperative measurements. The median age was 56 (46, 65) years, and 370 (56%) were male. New York Heart Association Class III/IV dyspnea was present in 581 (89%). Preoperative TTE showed LAVI of 48 (38, 60) mL/m 2 . In patients with history of AF, preoperative LAVI was 57 (45, 68) mL/m 2 , and in those without AF, LAVI measured 45 (37, 57) mL/m 2 (p < 0.001). All patients underwent transaortic septal myectomy. Early postoperative TTE (4 [3, 5] days) demonstrated LAVI of 43 (36, 52) mL/m 2 (p < 0.001), and late postoperative TTE (2.0 [1.1, 4.1] years) showed LAVI of 38 (29, 47) mL/m 2 (p < 0.001). Preoperative LAVI was associated with late development of AF (p = 0.002). Left atrial volume decreases significantly following surgical relief of left ventricular outflow tract obstruction. Early changes likely reflect lower LA pressure due to gradient relief and abolishment of mitral regurgitation, and late reduction suggests continued reverse remodeling. Copyright © 2018. Published by Elsevier Inc.

Effect of Shenxinning decoction on ventricular remodeling in AT1 receptor-knockout mice with chronic renal insufficiency.

PubMed

Yang, Xuejun; Zhou, Hua; Qu, Huiyan; Liu, Weifang; Huang, Xiaojin; Shun, Yating; He, Liqun

2014-01-01

To observe the efficacy of Shenxinning Decoction (SXND) in ventricular remodeling in AT1 receptor-knockout (AT1-KO) mice with chronic renal insufficiency (CRI). AT1-KO mice modeled with subtotal (5/6) nephrectomy were intervened with SXND for 12 weeks. Subsequently, blood urea nitrogen (BUN), serum creatinine (SCr), brain natriuretic peptide (BNP), echocardiography (left ventricular end-diastolic diameter, LVDD; left ventricular end-systolic diameter, LVDS; fractional shortening, FS; and ejection fraction, EF), collagen types I and III in the heart and kidney, myocardial mitochondria, and cardiac transforming growth factor-β1 (TGF-β1) of the AT1-KO mice were compared with the same model with nephrectomy only and untreated with SXND. AT1-KO mice did not affect the process of CRI but it could significantly affect cardiac remodeling process. SXND decreased to some extent the AT1-KO mice's BUN, SCr, BNP, and cardiac LVDD, LVDS, and BNP, improved FS and EF, lowered the expression of collagen type I and III in heart and kidney, increased the quantity of mitochondria and ameliorated their structure, and down-regulated the expression of TGF-β1. SXND may antagonize the renin-angiotensin system (RAS) and decrease uremia toxins, thereby ameliorating ventricular remodeling in CRI. Furthermore, SXND has a mechanism correlated with the improvement of myocardial energy metabolism and the down-regulation of TGF-β1.

Serum phosphorus is related to left ventricular remodeling independent of renal function in hospitalized patients with chronic kidney disease.

PubMed

Zou, Jun; Yu, Yi; Wu, Ping; Lin, Fu-Jun; Yao, Yao; Xie, Yun; Jiang, Geng-Ru

2016-10-15

Increasing evidence indicated that phosphorus emerged as an important cardiovascular risk factor in patients with chronic kidney disease (CKD). The fact that serum phosphorus was closely linked to vascular and valvar calcification may account for one important reason. However, left ventricular remodeling may also serve as another potential mechanism of the cardiac toxicity of phosphorus. In the present study, we evaluated the association of serum phosphorus with left ventricular remodeling. We investigated consecutive hospitalized patients with pre-dialysis CKD, who did not have symptomatic heart failure or take any phosphorus binder or calcitriol medications. Transthoracic echocardiography was applied to assess their left ventricular remodeling indices, both structural and functional. The 296 study subjects (mean age 56.4years) included 169 (57.1%) men, 203 (68.6%) hypertensive patients. In addition to gender, systolic blood pressure, and estimated glomerular filtration rate, serum phosphorus was an independent determinant of left ventricular mass index (LVMI, P=0.001). Similarly, serum phosphorus was also a determinant of left ventricular end diastolic dimension (P=0.0003), but not of relative wall thickness. In multivariate logistic analyses, serum phosphorus was significantly and independently associated with the prevalence of left ventricular hypertrophy (LVH, odds ratio [OR] 2.38 for each 1mmol/L increase, 95% CI 1.20-4.75, P=0.01). Moreover, the association was only confirmatory in eccentric LVH (OR 3.01, 95% CI 1.43-6.32, P=0.003) but not in concentric LVH (1.38, 95% CI, 0.54-3.49, P=0.50). Serum phosphorus was significantly and independently associated with LVMI and the prevalence of eccentric LVH in hospitalized patients with CKD. Copyright © 2016. Published by Elsevier Ireland Ltd.

Matrix modulation and heart failure: new concepts question old beliefs.

PubMed

Deschamps, Anne M; Spinale, Francis G

2005-05-01

Myocardial remodeling is a complex process involving several molecular and cellular factors. Extracellular matrix has been implicated in the remodeling process. Historically, the myocardial extracellular matrix was thought to serve solely as a means to align cells and provide structure to the tissue. Although this is one of its important functions, evidence suggests that the extracellular matrix plays a complex and divergent role in influencing cell behavior. This paper characterizes some of the notable studies on this dynamic entity and on adverse myocardial remodeling that have been published over the past year, which further question the belief that the extracellular matrix is a static structure. Progress has been made in understanding how the extracellular matrix is operative in the three major conditions (myocardial infarction, left ventricular hypertrophy due to overload, and dilated cardiomyopathy) that involve myocardial remodeling. Several studies have examined plasma profiles of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases following myocardial infarction and during left ventricular hypertrophy as surrogate markers of remodeling/remodeled myocardium. It has been demonstrated that bioactive signaling molecules and growth factors, proteases, and structural proteins influence cell-matrix interactions in the context of left ventricular hypertrophy. Finally, studies that either removed or added tissue inhibitor of metalloproteinases species in the myocardium demonstrated the importance of this regulatory protein in the remodeling process. Understanding the cellular and molecular triggers that in turn give rise to changes in the extracellular matrix could provide opportunities to modify the remodeling process.

QRS Width as a Predictor of Right Ventricular Remodeling After Percutaneous Pulmonary Valve Implantation.

PubMed

Paech, C; Dähnert, I; Riede, F T; Wagner, R; Kister, T; Nieschke, K; Wagner, F; Gebauer, R A

2017-08-01

Recent data showed a right ventricular dyssynchrony in patients with tetralogy of Fallot (TOF). Percutaneous pulmonary valve implantation (PPVI) has become an important procedure to treat a pulmonary stenosis and/or regurgitation of the right ventricular outflow tract in these patients. Despite providing good results, there is still a considerable number of nonresponders to PPVI. The authors speculated that electrical dysfunction of the right ventricle plays an underestimated role in the outcome of patients after PPVI. This study aimed to investigate the influence of right ventricular electrical dysfunction, i.e., right bundle branch block (RBBB) on the RV remodeling after PPVI. The study included consecutive patients after correction of TOF with or without RBBB, who had received a PPVI previously at the Heart Center of the University of Leipzig, Germany during the period from 2012 to 2015. 24 patients were included. Patients without RBBB, i.e., with narrow QRS complexes pre-intervention, had significantly better RV function and had smaller right ventricular volumes. Patients with pre-interventionally QRS width below 150 ms showed a post-interventional remodeling of the right ventricle with the decreasing RV volumes (p = 0.001). The parameters of LV function and volume as well as RV ejection fraction remained unaffected by RBBB. The presented data indicate that the QRS width seems to be a valuable parameter in the prediction of right ventricular remodeling after PPVI, as it represents both electrical and mechanical functions of the right ventricle and may serve as an additional parameter for optimal timing of a PPVI.

Pulmonary arterial stiffening in COPD and its implications for right ventricular remodelling.

PubMed

Weir-McCall, Jonathan R; Liu-Shiu-Cheong, Patrick Sk; Struthers, Allan D; Lipworth, Brian J; Houston, J Graeme

2018-02-27

Pulmonary pulse wave velocity (PWV) allows the non-invasive measurement of pulmonary arterial stiffening, but has not previously been assessed in COPD. The aim of the current study was to assess PWV in COPD and its association with right ventricular (RV) remodelling. Fifty-eight participants with COPD underwent pulmonary function tests, 6-min walk test and cardiac MRI, while 21 healthy controls (HCs) underwent cardiac MRI. Thirty-two COPD patients underwent a follow-up MRI to assess for longitudinal changes in RV metrics. Cardiac MRI was used to quantify RV mass, volumes and PWV. Differences in continuous variables between the COPD and HC groups was tested using an independent t-test, and associations between PWV and right ventricular parameters was examined using Pearson's correlation coefficient. Those with COPD had reduced pulsatility (COPD (mean±SD):24.88±8.84% vs. HC:30.55±11.28%, p=0.021), pulmonary acceleration time (COPD:104.0±22.9ms vs. HC: 128.1±32.2ms, p<0.001), higher PWV (COPD:2.62±1.29ms -1 vs. HC:1.78±0.72ms -1 , p=0.001), lower RV end diastolic volume (COPD:53.6±11.1ml vs. HC:59.9±13.0ml, p=0.037) and RV stroke volume (COPD:31.9±6.9ml/m 2 vs. HC:37.1±6.2ml/m 2 , p=0.003) with no difference in mass (p=0.53). PWV was not associated with right ventricular parameters. While pulmonary vascular remodelling is present in COPD, cardiac remodelling favours reduced filling rather than increased afterload. Treatment of obstructive lung disease may have greater effect on cardiac function than treatment of pulmonary vascular disease in most COPD patients KEY POINTS: • Pulmonary pulse wave velocity (PWV) is elevated in COPD. • Pulmonary PWV is not associated with right ventricular remodelling. • Right ventricular remodelling is more in keeping with that of reduced filling.

Rationale and design of the Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research Trial (MANTICORE 101--Breast): a randomized, placebo-controlled trial to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer using cardiac MRI.

PubMed

Pituskin, Edith; Haykowsky, Mark; Mackey, John R; Thompson, Richard B; Ezekowitz, Justin; Koshman, Sheri; Oudit, Gavin; Chow, Kelvin; Pagano, Joseph J; Paterson, Ian

2011-07-27

MANTICORE 101 - Breast (Multidisciplinary Approach to Novel Therapies in Cardiology Oncology Research) is a randomized trial to determine if conventional heart failure pharmacotherapy (angiotensin converting enzyme inhibitor or beta-blocker) can prevent trastuzumab-mediated left ventricular remodeling, measured with cardiac MRI, among patients with HER2+ early breast cancer. One hundred and fifty-nine patients with histologically confirmed HER2+ breast cancer will be enrolled in a parallel 3-arm, randomized, placebo controlled, double-blind design. After baseline assessments, participants will be randomized in a 1:1:1 ratio to an angiotensin-converting enzyme inhibitor (perindopril), beta-blocker (bisoprolol), or placebo. Participants will receive drug or placebo for 1 year beginning 7 days before trastuzumab therapy. Dosages for all groups will be systematically up-titrated, as tolerated, at 1 week intervals for a total of 3 weeks. The primary objective of this randomized clinical trial is to determine if conventional heart failure pharmacotherapy can prevent trastuzumab-mediated left ventricular remodeling among patients with HER2+ early breast cancer, as measured by 12 month change in left ventricular end-diastolic volume using cardiac MRI. Secondary objectives include 1) determine the evolution of left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer, 2) understand the mechanism of trastuzumab mediated cardiac toxicity by assessing for the presence of myocardial injury and apoptosis on serum biomarkers and cardiac MRI, and 3) correlate cardiac biomarkers of myocyte injury and extra-cellular matrix remodeling with left ventricular remodeling on cardiac MRI in patients with HER2+ early breast cancer. Cardiac toxicity as a result of cancer therapies is now recognized as a significant health problem of increasing prevalence. To our knowledge, MANTICORE will be the first randomized trial testing proven heart failure pharmacotherapy in the prevention of trastuzumab-mediated cardiotoxicity. We expect the findings of this trial to provide important evidence in the development of guidelines for preventive therapy. ClinicalTrials.gov: NCT01016886.

The Parathyroid Gland and Heart Disease.

PubMed

Brown, Spandana J; Ruppe, Mary D; Tabatabai, Laila S

2017-01-01

The parathyroid glands are critical to maintaining calcium homeostasis through actions of parathyroid hormone (PTH). Recent clinical and molecular research has shown that direct and indirect actions of PTH also affect the heart and vasculature through downstream actions of G protein-coupled receptors in the myocardium and endothelial cells. Patients with disorders of the parathyroid gland have higher incidences of hypertension, arrhythmias, left ventricular hypertrophy, heart failure, and calcific disease which translate into increased cardiac morbidity and mortality. Importantly, clinical research also suggests that early treatment of parathyroid disorders through medical or surgical management may reverse cardiovascular remodeling and mitigate cardiac risk factors.

Advantages, Disadvantages, and Trend of Integrative Medicine in the Treatment of Heart Failure.

PubMed

Zhang, PeiYing

2015-06-01

Integrative medicine therapy using traditional Chinese medicine (TCM) combined with western medicine has shown some advantages in treating heart failure (HF), such as holistic concept; multi-target treatment; dialectical logic; personalized therapy; formulae compatibility; and reduction of side effects of western medicine. However, problems still exist in TCM treatment of HF, including non-uniformed categorization of TCM, lack of standardized syndrome differentiation and lack of an evidence base. The future of treatment of HF seems to be focused on reversing ventricular remodeling, improving cardiac rehabilitation, and accelerating experimental research and drug discovery in TCM.

Electrocardiographic measures of repolarization dispersion and their relationships with echocardiographic indices of ventricular remodeling and premature ventricular beats in hypertension

PubMed Central

Ciobanu, Ana; Tse, Gary; Liu, Tong; Deaconu, Maria V; Gheorghe, Gabriela S; Ilieşiu, Adriana M; Nanea, Ioan T

2017-01-01

Objective To examine the relationship between Tpeak- Tend interval (Tpe) and Tpe/QT ratio with occurrence of ventricular premature beats (VPBs) and left ventricular remodeling in hypertension. Methods A total of 52 patients with mild to moderate essential hypertension were included, undergoing echocardiography and 24-hours Holter monitoring. Ventricular remodeling was assessed by left ventricular mass index (LVMI) using the Devereux formula and diastolic function by transmitral E and A wave velocities and E/A ratio. Tpe was measured in the precordial leads. The end of the T wave was set by the method of the tangent to the steepest descending slope of the T wave. Results Tpe and Tpe/QT in leads V2 (r = 0.33, P = 0.01; r = 0.27, P = 0.04 respectively) and V3 (r = 0.40, P = 0.002; r = 0.40, P = 0.003, respectively) correlated significantly with LVMI. A significant inverse relationship was observed between E/A ratio and QT (r = −0.33, P = 0.01), Tpe in V3 (r = −0.39, P = 0.003) and Tpe/QT in V3 (r = −0.31, P = 0.02). Tpe in V3, V5, mean Tpe and maximum Tpe with cut-off values of 60 ms, 59 ms, 62 ms and 71 ms, respectively, associated with the occurrence of ventricular premature beats. Conclusions The repolarization parameters Tpe interval and Tpe/QT ratio correlate with LVMI and indices of left ventricular diastolic function and show better predictive values than traditional parameters such as QT interval and QT dispersion. Lead V3 is the best lead for measuring Tpe and Tpe/QT. These ECG indices can therefore be used in clinical practice to monitor LV remodeling and predict occurrence of VPBs. PMID:29581710

Noninvasive evaluation of reverse atrial remodeling after catheter ablation of atrial fibrillation by P wave dispersion.

PubMed

Fujimoto, Yuhi; Yodogawa, Kenji; Takahashi, Kenta; Tsuboi, Ippei; Hayashi, Hiroshi; Uetake, Shunsuke; Iwasaki, Yu-Ki; Hayashi, Meiso; Miyauchi, Yasushi; Shimizu, Wataru

2017-11-01

Atrial fibrillation (AF) itself creates structural and electrophysiological changes such as atrial enlargement, shortening of refractory period and decrease in conduction velocity, called "atrial remodeling", promoting its persistence. Although the remodeling process is considered to be reversible, it has not been elucidated in detail. The aim of this study was to assess the feasibility of P wave dispersion in the assessment of reverse atrial remodeling following catheter ablation of AF. Consecutive 126 patients (88 males, age 63.0 ± 10.4 years) who underwent catheter ablation for paroxysmal AF were investigated. P wave dispersion was calculated from the 12 lead ECG before, 1 day, 1 month, 3 months and 6 months after the procedure. Left atrial diameter (LAD), left atrial volume index (LAVI), left ventricular ejection fraction (LVEF), transmitral flow velocity waveform (E/A), and tissue Doppler (E/e') on echocardiography, plasma B-type natriuretic peptide (BNP) concentrations, serum creatinine, and estimated glomerular filtration rate (eGFR) were also measured. Of all patients, 103 subjects remained free of AF for 1 year follow-up. In these patients, P wave dispersion was not changed 1 day and 1 month after the procedure. However, it was significantly decreased at 3 and 6 months (50.1 ± 14.8 to 45.4 ± 14.4 ms, p < 0.05, 45.2 ± 9.9 ms, p < 0.05, respectively). Plasma BNP concentrations, LAD and LAVI were decreased (81.1 ± 103.8 to 44.8 ± 38.3 pg/mL, p < 0.05, 38.2 ± 5.7 to 35.9 ± 5.6 mm, p < 0.05, 33.3 ± 14.2 to 29.3 ± 12.3 mL/m 2 , p < 0.05) at 6 months after the procedure. There were no significant changes in LVEF, E/A, E/e', serum creatinine, and eGFR during the follow up period. P wave dispersion was decreased at 3 and 6 months after catheter ablation in patients without recurrence of AF. P wave dispersion is useful for assessment of reverse remodeling after catheter ablation of AF.

Race differences in ventricular remodeling and function among college football players.

PubMed

Haddad, Francois; Peter, Shanon; Hulme, Olivia; Liang, David; Schnittger, Ingela; Puryear, Josephine; Gomari, Fatemeh A; Finocchiaro, Gherardo; Myers, Jonathan; Froelicher, Victor; Garza, Daniel; Ashley, Euan A

2013-07-01

Athletic training is associated with increases in ventricular mass and volume. Recent studies have shown that left ventricular mass increases proportionally in white athletes with a mass/volume ratio approaching unity. The objective of this study was to compare the proportionality in ventricular remodeling and ventricular function in black versus white National Collegiate Athletic Association Division I football players. From 2008 to 2011, football players at Stanford University underwent cardiovascular screening with a 12-point history and physical examination, electrocardiography, and focused echocardiography. Compared with white players, black players had on average higher left ventricular mass indexes (77 ± 11 vs 71 ± 11 g/m(2), p = 0.009), higher mass/volume ratios (1.18 ± 0.16 vs 1.06 ± 0.09 g/ml, p <0.001), and higher QRS vector magnitudes (3.2 ± 0.7 vs 2.7 ± 0.8, p = 0.002). Black race had an odds ratio of 14 (95% confidence interval 5 to 42, p <0.001) for a mass/volume ratio >1.2. Mass/volume ratio was inversely related to early diastolic tissue Doppler velocity e' (r = -0.50, p <0.001) but not to QRS vector magnitude (r = 0.065, p = 0.034). With regard to systolic indexes, there was no significant difference in the left ventricular ejection fraction, velocity of circumferential shortening, and isovolumic acceleration. In conclusion, black college football players exhibit more concentric ventricular remodeling, lower early diastolic annular velocities, and increased ventricular voltage compared with white players. Ventricular mass increases proportionally to volume in white players but not in black players. Copyright © 2013 Elsevier Inc. All rights reserved.

Functional Capacity of Patients with Pacemaker Due to Isolated Congenital Atrioventricular Block

PubMed Central

de Oliveira Júnior, Roberto Márcio; da Silva, Kátia Regina; Kawauchi, Tatiana Satie; Alves, Lucas Bassolli de Oliveira; Crevelari, Elizabeth Sartori; Martinelli, Martino; Costa, Roberto

2015-01-01

Background Isolated congenital atrioventricular block (CAVB) is a rare condition with multiple clinical outcomes. Ventricular remodeling can occur in approximately 10% of the patients after pacemaker (PM) implantation. Objectives To assess the functional capacity of children and young adults with isolated CAVB and chronic pacing of the right ventricle (RV) and evaluate its correlation with predictors of ventricular remodeling. Methods This cross-sectional study used a cohort of patients with isolated CAVB and RV pacing for over a year. The subjects underwent clinical and echocardiographic evaluation. Functional capacity was assessed using the six-minute walk test. Chi-square test, Fisher's exact test, and Pearson correlation coefficient were used, considering a significance level of 5%. Results A total of 61 individuals were evaluated between March 2010 and December 2013, of which 67.2% were women, aged between 7 and 41 years, who were using PMs for 13.5 ± 6.3 years. The percentage of ventricular pacing was 97.9 ± 4.1%, and the duration of the paced QRS complex was 153.7 ± 19.1 ms. Majority of the subjects (95.1%) were asymptomatic and did not use any medication. The mean distance walked was 546.9 ± 76.2 meters and was strongly correlated with the predicted distance (r = 0.907, p = 0.001) but not with risk factors for ventricular remodeling. Conclusions The functional capacity of isolated CAVB patients with chronic RV pacing was satisfactory but did not correlate with risk factors for ventricular remodeling. PMID:25387405

Effect of Shenxinning decoction on ventricular remodeling in AT1 receptor-knockout mice with chronic renal insufficiency

PubMed Central

Yang, Xuejun; Zhou, Hua; Qu, Huiyan; Liu, Weifang; Huang, Xiaojin; Shun, Yating; He, Liqun

2014-01-01

Objective: To observe the efficacy of Shenxinning Decoction (SXND) in ventricular remodeling in AT1 receptor-knockout (AT1-KO) mice with chronic renal insufficiency (CRI). Materials and Methods: AT1-KO mice modeled with subtotal (5/6) nephrectomy were intervened with SXND for 12 weeks. Subsequently, blood urea nitrogen (BUN), serum creatinine (SCr), brain natriuretic peptide (BNP), echocardiography (left ventricular end-diastolic diameter, LVDD; left ventricular end-systolic diameter, LVDS; fractional shortening, FS; and ejection fraction, EF), collagen types I and III in the heart and kidney, myocardial mitochondria, and cardiac transforming growth factor-β1 (TGF-β1) of the AT1-KO mice were compared with the same model with nephrectomy only and untreated with SXND. Results: AT1-KO mice did not affect the process of CRI but it could significantly affect cardiac remodeling process. SXND decreased to some extent the AT1-KO mice's BUN, SCr, BNP, and cardiac LVDD, LVDS, and BNP, improved FS and EF, lowered the expression of collagen type I and III in heart and kidney, increased the quantity of mitochondria and ameliorated their structure, and down-regulated the expression of TGF-β1. Conclusion: SXND may antagonize the renin–angiotensin system (RAS) and decrease uremia toxins, thereby ameliorating ventricular remodeling in CRI. Furthermore, SXND has a mechanism correlated with the improvement of myocardial energy metabolism and the down-regulation of TGF-β1. PMID:25097276

The potential of multi-slice computed tomography based volumetry for demonstrating reverse remodeling induced by cardiac resynchronization therapy.

PubMed

Langer, Christoph; Schroeder, Janina; Peterschroeder, Andreas; Vaske, Bernhard; Faber, Lothar; Welge, Dirk; Niethammer, Matthias; Lamp, Barbara; Butz, Thomas; Bitter, Thomas; Oldenburg, Olaf; Horstkotte, Dieter

2010-07-01

Multi-slice computed tomography (MSCT) was proved to provide precise cardiac volumetric assessment. Cardiac resynchronization therapy (CRT) is an effective treatment for selected patients with heart failure and reduced ejection fraction (HFREF). In HFREF patients we investigated the potential of MSCT based wall motion analysis in order to demonstrate CRT-induced reversed remodeling. Besides six patients with normal cardiac pump function serving as control group seven HFREF patients underwent contrast enhanced MSCT before and after CRT. Short cardiac axis views of the left ventricle (LV) in end-diastole (ED) and end-systole (ES) served for planimetry. Pre- and post-CRT MSCT based volumetry was compared with 2D echo. To demonstrate CRT-induced reverse remodeling, MSCT based multi-segment color-coded polar maps were introduced. With regard to the HFREF patients pre-CRT MSCT based volumetry correlated with 2D echo data for LV-EDV (MSCT 278.3+/-75.0mL vs. echo 274.4+/-85.6mL) r=0.380, p=0.401, LV-ESV (MSCT 226.7+/-75.4mL vs. echo 220.1+/-74.0mL) r=0.323, p=0.479 and LV-EF (MSCT 20.2+/-8.8% vs. echo 20.0+/-11.9%) r=0.617, p=0.143. Post-CRT MSCT correlated well with 2D echo: LV-EDV (MSCT 218.9+/-106.4mL vs. echo 188.7+/-93.1mL) r=0.87, p=0.011, LV-ESV (MSCT 145+/-71.5mL vs. echo 125.6+/-78mL) r=0.84, p=0.018 and LV-EF (MSCT 29.6+/-11.3mL vs. echo 38.6+/-14.6mL) r=0.89, p=0.007. There was a significant increase of the mid-ventricular septum in terms of absolute LV wall thickening of the responders (pre 0.9+/-2.1mm vs. post 3.3+/-2.2mm; p<0.0005). MSCT based volumetry involving multi-segment color-coded polar maps offers wall motion analysis to demonstrate CRT-induced reverse remodeling which needs to be further validated. 2010 Elsevier Ltd. All rights reserved.

Restrictive annuloplasty to treat functional mitral regurgitation: optimize the restriction to improve the results?

PubMed

Totaro, Pasquale; Adragna, Nicola; Argano, Vincenzo

2008-03-01

Today, the 'gold standard' treatment of functional mitral regurgitation (MR) is the subject of much discussion. Although restrictive annuloplasty is currently considered the most reproducible technique, the means by which the degree of annular restriction is optimized remains problematic. The study was designed in order to identify whether the degree of restriction of the mitral annulus could influence early and midterm results following the treatment of functional MR using restrictive annuloplasty. A total of 32 consecutive patients with functional MR grade > or = 3+ was enrolled, among whom the mean anterior-posterior (AP) mitral annulus diameter was 39 +/- 3 mm. Restrictive mitral annuloplasty (combined with coronary artery bypass grafting) was performed in all patients using a Carpentier-Edwards Classic or Physio ring (size 26 or 28). The degree of AP annular restriction was calculated for each patient, and correlated with early and mid-term residual MR and left ventricular (LV) reverse remodeling (in terms of LV end-diastolic diameter (LVEDD) and LV end-diastolic volume (LVEDV) reduction). All surviving patients were examined at a one-year follow up. The mean AP mitral annulus restriction achieved was 48 +/- 4%. Intraoperatively, transesophageal echocardiography showed no residual MR in any patient. Before discharge from hospital, transthoracic echocardiography confirmed an absence of residual MR and showed significant LV reverse remodeling (LVEDV from 121 +/- 25 ml to 97 +/- 26 ml; LVEDD from 55 +/- 6 mm to 47 +/- 8 mm). A significant correlation (r = 0.57, p < 0.001) was identified between the degree of AP annulus restriction and LVEDV reduction. A cut-off of annular restriction of 40% (based on AP annulus measurement) correlated with a more significant reverse remodeling. The early postoperative data, with no recurrence of significant MR, was confirmed at a one-year follow up examination. A marked restriction of the AP mitral annulus diameter (> 40% of preoperative) appears to have a favorable influence on early postoperative LV reverse remodeling, and also allows for complete resolution of functional MR. In addition, 'no tolerance' of early residual MR seems to have a favorable influence on mid-term results, leading to a reduction in the one-year recurrence of significant MR.

Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction

PubMed Central

Gavioli, Mariana; Lara, Aline; Almeida, Pedro W. M.; Lima, Augusto Martins; Damasceno, Denis D.; Rocha-Resende, Cibele; Ladeira, Marina; Resende, Rodrigo R.; Martinelli, Patricia M.; Melo, Marcos Barrouin; Brum, Patricia C.; Fontes, Marco Antonio Peliky; Souza Santos, Robson A.; Prado, Marco A. M.; Guatimosim, Silvia

2014-01-01

Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease. PMID:24992197

Intermedin improves cardiac function and sympathetic neural remodeling in a rat model of post myocardial infarction heart failure

PubMed Central

Xu, Bin; Xu, Hao; Cao, Heng; Liu, Xiaoxiao; Qin, Chunhuan; Zhao, Yanzhou; Han, Xiaolin; Li, Hongli

2017-01-01

Emerging evidence has suggested that intermedin (IMD), a novel member of the calcitonin gene-related peptide (CGRP) family, has a wide range of cardioprotective effects. The present study investigated the effects of long-term administration of IMD on cardiac function and sympathetic neural remodeling in heart failure (HF) rats, and studied potential underlying mechanism. HF was induced in rats by myocardial infarction (MI). Male Sprague Dawley rats were randomly assigned to either saline or IMD (0.6 µg/kg/h) treatment groups for 4 weeks post-MI. Another group of sham-operated rats served as controls. Cardiac function was assessed by echocardiography, cardiac catheterization and plasma level of B-type natriuretic peptide (BNP). Cardiac sympathetic neural remodeling was assessed by immunohistochemistical study of tyrosine hydroxylase (TH) and growth associated protein 43 (GAP43) immunoreactive nerve fibers. The protein expression levels of nerve growth factor (NGF), TH and GAP43 in the ventricular myocardium were studied by western blotting. Ventricular fibrillation threshold (VFT) was determined to evaluate the incidence of ventricular arrhythmia. Oxidative stress was assessed by detecting the activity of superoxide dismutase and the level of malondialdehyde. Compared with rats administrated with saline, IMD significantly improved cardiac function, decreased the plasma BNP level, attenuated sympathetic neural remodeling, increased VFT and suppressed oxidative stress. In conclusion, these results indicated that IMD prevents ventricle remodeling and improves the performance of a failing heart. In addition, IMD attenuated sympathetic neural remodeling and reduced the incidence of ventricular arrhythmia, which may contribute to its anti-oxidative property. These results implicate IMD as a potential therapeutic agent for the treatment of HF. PMID:28627670

Quality of life measured with EuroQol-five dimensions questionnaire predicts long-term mortality, response, and reverse remodelling in cardiac resynchronization therapy patients.

PubMed

Nagy, Klaudia Vivien; Széplaki, Gábor; Perge, Péter; Boros, András Mihály; Kosztin, Annamária; Apor, Astrid; Molnár, Levente; Szilágyi, Szabolcs; Tahin, Tamás; Zima, Endre; Kutyifa, Valentina; Gellér, László; Merkely, Béla

2017-11-22

There are previous studies on quality of life (QoL) in cardiac resynchronization therapy (CRT) patients; however, there are no data with the short EuroQol-five dimensions (EQ-5D) questionnaire predicting outcomes. We aimed to assess the predictive role of baseline QoL and QoL change at 6 months after CRT with EQ-5D on 5-year mortality and response. In our prospective follow-up study, 130 heart failure (HF) patients undergoing CRT were enrolled. Clinical evaluation, echocardiography, and EQ-5D were performed at baseline and at 6 months of follow-up, continued to 5 years. Primary endpoint was all-cause mortality at 5 years. Secondary endpoints were (i) clinical response with at least one class improvement in New York Heart Association without HF hospitalization and (ii) reverse remodelling with 15% reduction in left ventricular end-systolic volume at 6 months. Fifty-four (41.5%) patients died during 5 years, 85 (65.3%) clinical responders were identified, and 63 patients (48.5%) had reverse remodelling. Baseline issues with mobility were associated with lower response [odds ratio (OR) 0.36, 95% confidence interval (CI) 0.16-0.84; P = 0.018]. Lack of reverse remodelling correlated with self-care issues at baseline (OR 0.10, 95% CI 0.01-0.94; P = 0.04). Furthermore, self-care difficulties [hazard ratio (HR) 2.39, 95% CI 1.17-4.86; P = 0.01) or more anxiety (HR 1.51, 95% CI 1.00-2.26; P = 0.04) predicted worse long-term survival. At 6 months, mobility (HR 3.95, 95% CI 1.89-8.20; P < 0.001), self-care (HR 7.69, 95% CI 2.23-25.9; P = 0.001), or ≥ 10% visual analogue scale (VAS) (HR 2.24, 95% CI 1.27-3.94; P = 0.005) improvement anticipated better survival at 5 years. EuroQol-five dimension is a simple method assessing QoL in CRT population. Mobility issues at baseline are associated with lower clinical response, whereas self-care issues predict lack of reverse remodelling. Problems with mobility or anxiety before CRT and persistent issues with mobility, self-care, and VAS scale at 6 months predict adverse outcome. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology

Left ventricular remodeling leads to heart failure in mice with cardiac-specific overexpression of VEGF-B167: echocardiography and magnetic resonance imaging study.

PubMed

Lottonen-Raikaslehto, Line; Rissanen, Riina; Gurzeler, Erika; Merentie, Mari; Huusko, Jenni; Schneider, Jurgen E; Liimatainen, Timo; Ylä-Herttuala, Seppo

2017-03-01

Cardiac-specific overexpression of vascular endothelial growth factor (VEGF)-B 167 is known to induce left ventricular hypertrophy due to altered lipid metabolism, in which ceramides accumulate to the heart and cause mitochondrial damage. The aim of this study was to evaluate and compare different imaging methods to find the most sensitive way to diagnose at early stage the progressive left ventricular remodeling leading to heart failure. Echocardiography and cardiovascular magnetic resonance imaging were compared for imaging the hearts of transgenic mice with cardiac-specific overexpression of VEGF-B 167 and wild-type mice from 5 to 14 months of age at several time points. Disease progression was verified by molecular biology methods and histology. We showed that left ventricular remodeling is already ongoing at the age of 5 months in transgenic mice leading to heart failure by the age of 14 months. Measurements from echocardiography and cardiovascular magnetic resonance imaging revealed similar changes in cardiac structure and function in the transgenic mice. Changes in histology, gene expressions, and electrocardiography supported the progression of left ventricular hypertrophy. Longitudinal relaxation time in rotating frame (T 1 ρ ) in cardiovascular magnetic resonance imaging could be suitable for detecting severe fibrosis in the heart. We conclude that cardiac-specific overexpression of VEGF-B 167 leads to left ventricular remodeling at early age and is a suitable model to study heart failure development with different imaging methods. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Atorvastatin Improves Ventricular Remodeling after Myocardial Infarction by Interfering with Collagen Metabolism

PubMed Central

Reichert, Karla; Pereira do Carmo, Helison Rafael; Galluce Torina, Anali; Diógenes de Carvalho, Daniela; Carvalho Sposito, Andrei; de Souza Vilarinho, Karlos Alexandre; da Mota Silveira-Filho, Lindemberg; Martins de Oliveira, Pedro Paulo

2016-01-01

Purpose Therapeutic strategies that modulate ventricular remodeling can be useful after acute myocardial infarction (MI). In particular, statins may exert effects on molecular pathways involved in collagen metabolism. The aim of this study was to determine whether treatment with atorvastatin for 4 weeks would lead to changes in collagen metabolism and ventricular remodeling in a rat model of MI. Methods Male Wistar rats were used in this study. MI was induced in rats by ligation of the left anterior descending coronary artery (LAD). Animals were randomized into three groups, according to treatment: sham surgery without LAD ligation (sham group, n = 14), LAD ligation followed by 10mg atorvastatin/kg/day for 4 weeks (atorvastatin group, n = 24), or LAD ligation followed by saline solution for 4 weeks (control group, n = 27). After 4 weeks, hemodynamic characteristics were obtained by a pressure-volume catheter. Hearts were removed, and the left ventricles were subjected to histologic analysis of the extents of fibrosis and collagen deposition, as well as the myocyte cross-sectional area. Expression levels of mediators involved in collagen metabolism and inflammation were also assessed. Results End-diastolic volume, fibrotic content, and myocyte cross-sectional area were significantly reduced in the atorvastatin compared to the control group. Atorvastatin modulated expression levels of proteins related to collagen metabolism, including MMP1, TIMP1, COL I, PCPE, and SPARC, in remote infarct regions. Atorvastatin had anti-inflammatory effects, as indicated by lower expression levels of TLR4, IL-1, and NF-kB p50. Conclusion Treatment with atorvastatin for 4 weeks was able to attenuate ventricular dysfunction, fibrosis, and left ventricular hypertrophy after MI in rats, perhaps in part through effects on collagen metabolism and inflammation. Atorvastatin may be useful for limiting ventricular remodeling after myocardial ischemic events. PMID:27880844

The Prognostic Impact of the Evolution of RV Function in Idiopathic DCM.

PubMed

Merlo, Marco; Gobbo, Marco; Stolfo, Davide; Losurdo, Pasquale; Ramani, Federica; Barbati, Giulia; Pivetta, Alberto; Di Lenarda, Andrea; Anzini, Marco; Gigli, Marta; Pinamonti, Bruno; Sinagra, Gianfranco

2016-09-01

In this study, the authors analyzed the prognostic role of right ventricular systolic function (RVF) longitudinal trends in a large cohort of patients affected by dilated cardiomyopathy (DCM). RVF is a known prognostic predictor in DCM; however, whether RVF changes over time to better predict the long-term disease progression has not been investigated. From 1993 to 2008, we analyzed 512 patients with DCM (46 years of age [36 to 55 years of age], left ventricular ejection fraction 32% [25% to 41%]) with a potential follow-up of ≥72 months and available data at baseline and at least 1 pre-specified follow-up evaluation (i.e., 6, 24, 48, or 72 months). RV dysfunction was defined as RV fractional area change <35% at 2-dimensional echocardiography. The primary outcome measure was a composite of death or heart transplantation. At enrollment, 103 (20%) patients had RV dysfunction. During follow-up, 89 of them (86%, 17% of the overall cohort) normalized RVF at a median time of 6 months, whereas 38 of the remaining 409 patients with normal baseline RVF (9%; 7% of the overall population) exhibited a new-onset RV dysfunction (median time: 36 months). RVF normalization was significantly associated with subsequent left ventricular reverse remodeling that was observed at a median time of 24 months (odds ratio: 2.49; 95% confidence interval [CI]: 1.17 to 5.3; p = 0.018). At baseline multivariate analysis, RV dysfunction was independently associated with the primary outcome measure (hazard ratio: 1.71; 95% CI: 1.02 to 2.85; p = 0.0413). At time-dependent model, RVF revaluation over time maintained an independent predictive value (hazard ratio: 2.83; 95% CI: 1.57 to 5.11; p = 0.0006). Patients with DCM frequently present RV dysfunction at first evaluation. However, a complete RVF recovery is largely observed early after optimization of medical therapy and predates subsequent left ventricular reverse remodeling. Systematic revaluation of patients including RVF throughout regular follow-up conferred additive long-term prognostic value to the baseline evaluation. Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Right ventricular effects of intracoronary delivery of mesenchymal stem cells (MSC) in an animal model of pressure overload heart failure.

PubMed

Molina, Ezequiel J; Palma, Jon; Gupta, Dipin; Gaughan, John P; Houser, Steven; Macha, Mahender

2009-12-01

In a rat model of left ventricular pressure overload hypertrophy with biventricular failure, we studied the effects of intracoronary delivery of mesenchymal stem cells (MCS) upon right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling. Sprague-Dawley rats underwent aortic banding and were followed by echocardiography. After a decrease in left ventricular fractional shortening of 25% from the baseline (relative 50% reduction), animals were randomized to an intracoronary injection of MSC (n=28) or PBS (n=20). Right ventricular hemodynamic assessment and measurement of local inflammatory markers, proapoptotic factors, and determinants of extracellular matrix remodeling were performed on post-transplantation day 7, 14, 21 or 28. MSC injection improved right ventricular systolic function in the MSC group compared to the control group (mean+/-SD, max dP/dt 772+/-272 mm Hg/s vs. 392+/-132 at 28 days, P<0.01). Diastolic function was similarly improved (mean+/-SD, max -dP/dt -558+/-171 mm Hg/s vs. -327+/-131 at 28 days, P<0.05). Right ventricular levels of IL-1, IL-6, TNF-alpha, bax, bak and p38 were significantly decreased in the MSC treated animals. Expression of MMP-3, MMP-6, MMP-9, TIMP-1 and TIMP-3 declined in the MSC group compared with controls after 28 days. In this model of left ventricular pressure overload hypertrophy and biventricular failure, intracoronary delivery of MSC was associated with an improvement in the right ventricular hemodynamic performance, profiles of local inflammation and apoptosis, and determinants of extracellular matrix remodeling.

The 4th Report of the Working Group on ECG diagnosis of Left Ventricular Hypertrophy.

PubMed

Bacharova, Ljuba; Estes, Harvey E; Schocken, Douglas D; Ugander, Martin; Soliman, Elsayed Z; Hill, Joseph A; Bang, Lia E; Schlegel, Todd T

The 4th Report provides a brief review of publications focused on the electrocardiographic diagnosis of left ventricular hypertrophy published during the period of 2010 to 2016 by the members of the Working Group on ECG diagnosis of Left Ventricular Hypertrophy. The Working Group recommended that ECG research and clinical attention be redirected from the estimation of LVM to the identification of electrical remodeling, to better understanding the sequence of events connecting electrical remodeling to outcomes. The need for a re-definition of terms and for a new paradigm is also stressed. Copyright © 2016 Elsevier Inc. All rights reserved.

Resveratrol Reverses Monocrotaline-Induced Pulmonary Vascular and Cardiac Dysfunction: A Potential Role for Atrogin-1 in Smooth Muscle

PubMed Central

Paffett, Michael L.; Lucas, Selita N.; Campen, Matthew J.

2011-01-01

Arterial remodeling contributes to the elevated pulmonary artery (PA) pressures and right ventricular hypertrophy seen in pulmonary hypertension (PH). Resveratrol, a sirtuin-1 (SIRT1) pathway activator, can prevent the development of PH in a commonly used animal model, but it is unclear whether it can reverse established PH pathophysiology. Furthermore, atrophic ubiquitin ligases, such as atrogin-1 and MuRF-1, are known to be induced by SIRT1 activators but have not been characterized in hypertrophic vascular disease. Therefore, we hypothesized that monocrotaline (MCT)-induced PH would attenuate atrophy pathways in the PA while, conversely, SIRT1 activation (resveratrol) would reverse indices of PH and restore atrophic gene expression. Thus, we injected Sprague-Dawley rats with MCT (50 mg/kg i.p.) or saline at Day 0, and then treated with oral resveratrol or sildenafil from days 28–42 post-MCT injection. Oral resveratrol attenuated established MCT-induced PH indices, including right ventricular systolic pressure, right ventricular hypertrophy, and medial thickening of intrapulmonary arteries. Resveratrol also normalized PA atrogin-1 mRNA expression, which was significantly reduced by MCT. In cultured human PA smooth muscle cells (hPASMC), resveratrol significantly inhibited PDGF-stimulated proliferation and cellular hypertrophy, which was also associated with improvements in atrogin-1 levels. In addition, SIRT1 inhibition augmented hPASMC proliferation, as assessed by DNA mass, and suppressed atrogin mRNA expression. These findings demonstrate an inverse relationship between indices of PH and PA atrogin expression that is SIRT1 dependent and may reflect a novel role for SIRT1 in PASMCs opposing cellular hypertrophy and proliferation. PMID:22146233

Hypercholesterolaemia exacerbates ventricular remodelling after myocardial infarction in the rat: role of angiotensin II type 1 receptors

PubMed Central

Mączewski, M; Mączewska, J; Duda, M

2008-01-01

Background and purpose: Diet-induced hypercholesterolaemia exacerbates post-myocardial infarction (MI) ventricular remodelling and heart failure, but the mechanism of this phenomenon remains unknown. This study examined whether worsening of post-MI ventricular remodelling induced by dietary hypercholesterolaemia was related to upregulation of angiotensin II type 1 (AT1) receptor in the rat heart. Experimental approach: MI was induced surgically in rats fed normal or high cholesterol diet. Both groups of rats were then assigned to control, atorvastatin, losartan or atorvastatin+losartan-treated subgroups and followed for 8 weeks. Left ventricular (LV) function was assessed with echocardiography. In isolated hearts, LV pressures were measured with a latex balloon and a tip catheter. AT1-receptor density was assessed in LV membranes with radioligand-binding assays. Key results: High cholesterol diet exacerbated LV dilation and dysfunction in post-MI hearts. Atorvastatin or losartan prevented these hypercholesterolaemia-induced effects, whereas their combination was not more effective than each drug alone. AT1 receptors were upregulated 8 weeks after MI, this was further increased by hypercholesterolaemia and restored to baseline levels by atorvastatin. Conclusions and implications: Hypercholesterolaemia exacerbated LV remodelling and dysfunction in post-MI rat hearts and upregulated cardiac AT1 receptors. All these effects were effectively prevented by atorvastatin. Thus, the pleiotropic statin effects may include interference with the renin-angiotensin system through downregulation of AT1 receptors. PMID:18536757

Right ventricular remodelling after transcatheter pulmonary valve implantation.

PubMed

Pagourelias, Efstathios D; Daraban, Ana M; Mada, Razvan O; Duchenne, Jürgen; Mirea, Oana; Cools, Bjorn; Heying, Ruth; Boshoff, Derize; Bogaert, Jan; Budts, Werner; Gewillig, Marc; Voigt, Jens-Uwe

2017-09-01

To define the optimal timing for percutaneous pulmonary valve implantation (PPVI) in patients with severe pulmonary regurgitation (PR) after Fallot's Tetralogy (ToF) correction. PPVI among the aforementioned patients is mainly driven by symptoms or by severe right ventricular (RV) dilatation/dysfunction. The optimal timing for PPVI is still disputed. Twenty patients [age 13.9 ± 9.2 years, (range 4.3-44.9), male 70%] with severe PR (≥3 grade) secondary to previous correction of ToF, underwent Melody valve (Medtronic, Minneapolis, MN) implantation, after a pre-stent placement. Full echocardiographic assessment (traditional and deformation analysis) and cardiovascular magnetic resonance evaluation were performed before and at 3 months after the intervention. 'Favorable remodelling' was considered the upper quartile of RV size decrease (>20% in 3 months). After PPVI, indexed RV effective stroke volume increased from 38.4 ± 9.5 to 51.4 ± 10.7 mL/m 2 , (P = 0.005), while RV end-diastolic volume and strain indices decreased (123.1 ± 24.1-101.5 ± 18.3 mL/m 2 , P = 0.005 and -23.5 ± 2.5 to -21 ± 2.5%, P = 0.002, respectively). After inserting pre-PPVI clinical, RV volumetric and deformation parameters in a multiple regression model, only time after last surgical correction causing PR remained as significant regressor of RV remodelling [R 2  = 0.60, beta = 0.387, 95%CI(0.07-0.7), P = 0.019]. Volume reduction and functional improvement were more pronounced in patients treated with PPVI earlier than 7 years after last RV outflow tract (RVOT) correction, reaching close-to-normal values. Early PPVI (<7 years after last RVOT operation) is associated with a more favorable RV reverse remodelling toward normal range and should be considered, before symptoms or RV damage become apparent. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice

PubMed Central

2012-01-01

Background Obesity is an important cardiovascular risk factor. This study tested the effect of obesity reduction on preserving left ventricular ejection fraction (LVEF) and attenuating inflammation, oxidative stress and LV remodeling in obese mice. Methods and results Eight-week-old C57BL/6 J mice (n=24) were equally divided into control (fed a control diet for 22 weeks), obesity (high-fat diet, 22 weeks), and obese reduction (OR) (high-fat diet, 14 weeks; then control diet, 8 weeks). Animals were sacrificed at post 22-week high-fat diet and the LV myocardium collected. Heart weight, body weight, abdominal-fat weight, total cholesterol level and fasting blood glucose were higher in obesity than in control and OR (all p<0.001). Inflammation measured by mRNA expressions of IL-6, MMP-9, PAI-1 and leptin and protein expression of NF-κB was higher, whereas anti-inflammation measured by mRNA expressions of adiponectin and INF-γ was lower in obesity than in control and OR (all p<0.003). Oxidative protein expressions of NOX-1, NOX-2 and oxidized protein were higher, whereas expression of anti-oxidant markers HO-1 and NQO-1 were lower (all p<0.01); and apoptosis measured by Bax and caspase 3 was higher, whereas anti-apoptotic Bcl-2 was lower in obesity as compared with control and OR (all p<0.001). The expressions of fibrotic markers phosphorylated Smad3 and TGF-β were higher, whereas expression of anti-fibrotic phosphorylated Smad1/5 and BMP-2 were lower (all p<0.02); and LVEF was lower, whereas the LV remodeling was higher in obesity than in control and OR (all p<0.001). Conclusion Impaired LVEF, enhanced LV remodeling, inflammation, fibrosis, oxidative stress and apoptosis were reversed by reduction in mouse obesity. PMID:22784636

Polymer injection therapy to reverse remodel the papillary muscles: efficacy in reducing mitral regurgitation in a chronic ischemic model.

PubMed

Solis, Jorge; Levine, Robert A; Johnson, Benjamin; Guerrero, J Luis; Handschumacher, Mark D; Sullivan, Suzanne; Lam, Kaitlyn; Berlin, Jason; Braithwaite, Gavin J C; Muratoglu, Orhun K; Vlahakes, Gus J; Hung, Judy

2010-10-01

Ischemic mitral regurgitation (MR) results from displacement of the papillary muscles caused by ischemic ventricular distortion. Progressive left ventricular (LV) remodeling has challenged therapy. Our hypothesis is that repositioning of the papillary muscles can be achieved by injection of polyvinyl-alcohol (PVA) hydrogel polymer into the myocardium in chronic MR despite advanced LV remodeling. Ten sheep underwent ligation of the circumflex branches to produce chronic ischemic MR over 8 weeks. PVA was injected into the myocardium underlying the infarcted papillary muscle. Two-dimensional and 3D echocardiograms and hemodynamic data were obtained before infarct (baseline), before PVA (chronic MR), and after PVA. PVA injection significantly decreased MR from moderate to severe to trace (MR vena contracta, 5.8±1.2 to1.8±1.3 mm; chronic MR to post-PVA stage; P=0.0003). This was associated with a decrease in infarcted papillary muscle-to-mitral annulus tethering distance (30.3±5.7 to 25.9±4.6 mm, P=0.02), tenting volume (1.8±0.7 to 1.4±0.5 mL, P=0.01), and leaflet closure area (8.8±1.3 cm(2)to 7.6±1.3 cm(2), P=0.004) from chronic MR to post-PVA stages. PVA was not associated with significant decreases in LV ejection fraction (41±3% versus 40±3%, P=NS), end-systolic elastance, τ (82±36 ms to 72±26, P=NS), or LV stiffness coefficient (0.05±0.04 to 0.03±0.01). PVA hydrogel injections improve coaptation and reduce remodeling in chronic MR without impairing LV systolic and diastolic function. This new approach offers a potential alternative for relieving tethering and ischemic MR by correcting papillary muscle position.

Postoperative Reverse Remodeling and Symptomatic Improvement in Normal-Flow Low-Gradient Aortic Stenosis After Aortic Valve Replacement.

PubMed

Carter-Storch, Rasmus; Møller, Jacob E; Christensen, Nicolaj L; Irmukhadenov, Akhmadjon; Rasmussen, Lars M; Pecini, Redi; Øvrehus, Kristian A; Søndergård, Eva V; Marcussen, Niels; Dahl, Jordi S

2017-12-01

Severe aortic stenosis (AS) most often presents with reduced aortic valve area (<1 cm 2 ), normal stroke volume index (≥35 mL/m 2 ), and either high mean gradient (≥40 mm Hg; normal-flow high-gradient AS) or low mean gradient (normal-flow low-gradient [NFLG] AS). The benefit of aortic valve replacement (AVR) among NFLG patients is controversial. We compared the impact of NFLG condition on preoperative left ventricular (LV) remodeling and myocardial fibrosis and postoperative remodeling and symptomatic benefit. Eighty-seven consecutive patients with reduced aortic valve area and normal stroke volume index undergoing AVR underwent echocardiography, magnetic resonance imaging, a 6-minute walk test, and measurement of natriuretic peptides before and 1 year after AVR. Myocardial fibrosis was assessed from magnetic resonance imaging. Patients were stratified as NFLG or normal-flow high-gradient. In total, 33 patients (38%) had NFLG. Before AVR, they were characterized by similar symptom burden but less severe AS measured by aortic valve area index (0.50±0.09 versus 0.40±0.08 cm 2 /m 2 ; P <0.0001), lower LV mass index (74±18 versus 90±26 g/m 2 ; P =0.01), but the same degree of myocardial fibrosis. After AVR, NFLG had a smaller reduction in LV mass index (-3±10 versus -±18 g/m 2 ; P <0.0001) and a smaller reduction in natriuretic peptides. Both groups experienced similar symptomatic improvement. Normal-flow high-gradient condition independently predicted change in LV mass index. Patients with NFLG had less severe AS and LV remodeling than patients with normal-flow high-gradient. Furthermore, NFLG patients experienced less reverse remodeling but the same symptomatic benefit. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02316587. © 2017 American Heart Association, Inc.

The effect of disease on human cardiac protein expression profiles in paired samples from right and left ventricles

PubMed Central

2014-01-01

Background Cardiac diseases (e.g. coronary and valve) are associated with ventricular cellular remodeling. However, ventricular biopsies from left and right ventricles from patients with different pathologies are rare and thus little is known about disease-induced cellular remodeling in both sides of the heart and between different diseases. We hypothesized that the protein expression profiles between right and left ventricles of patients with aortic valve stenosis (AVS) and patients with coronary artery disease (CAD) are different and that the protein profile is different between the two diseases. Left and right ventricular biopsies were collected from patients with either CAD or AVS. The biopsies were processed for proteomic analysis using isobaric tandem mass tagging and analyzed by reverse phase nano-LC-MS/MS. Western blot for selected proteins showed strong correlation with proteomic analysis. Results Proteomic analysis between ventricles of the same disease (intra-disease) and between ventricles of different diseases (inter-disease) identified more than 500 proteins detected in all relevant ventricular biopsies. Comparison between ventricles and disease state was focused on proteins with relatively high fold (±1.2 fold difference) and significant (P < 0.05) differences. Intra-disease protein expression differences between left and right ventricles were largely structural for AVS patients and largely signaling/metabolism for CAD. Proteins commonly associated with hypertrophy were also different in the AVS group but with lower fold difference. Inter-disease differences between left ventricles of AVS and CAD were detected in 9 proteins. However, inter-disease differences between the right ventricles of CAD and AVS patients were associated with differences in 73 proteins. The majority of proteins which had a significant difference in one ventricle compared to the other pathology also had a similar trend in the adjacent ventricle. Conclusions This work demonstrates for the first time that left and right ventricles have a different proteome and that the difference is dependent on the type of disease. Inter-disease differential expression was more prominent for right ventricles. The finding that a protein change in one ventricle was often associated with a similar trend in the adjacent ventricle for a large number of proteins suggests cross-talk proteome remodeling between adjacent ventricles. PMID:25249829

Coronary artery bypass surgery with or without mitral valve annuloplasty in moderate functional ischemic mitral regurgitation: final results of the Randomized Ischemic Mitral Evaluation (RIME) trial.

PubMed

Chan, K M John; Punjabi, Prakash P; Flather, Marcus; Wage, Riccardo; Symmonds, Karen; Roussin, Isabelle; Rahman-Haley, Shelley; Pennell, Dudley J; Kilner, Philip J; Dreyfus, Gilles D; Pepper, John R

2012-11-20

The role of mitral valve repair (MVR) during coronary artery bypass grafting (CABG) in patients with moderate ischemic mitral regurgitation (MR) is uncertain. We conducted a randomized, controlled trial to determine whether repairing the mitral valve during CABG may improve functional capacity and left ventricular reverse remodeling compared with CABG alone. Seventy-three patients referred for CABG with moderate ischemic MR and an ejection fraction >30% were randomized to receive CABG plus MVR (34 patients) or CABG only (39 patients). The study was stopped early after review of interim data. At 1 year, there was a greater improvement in the primary end point of peak oxygen consumption in the CABG plus MVR group compared with the CABG group (3.3 mL/kg/min versus 0.8 mL/kg/min; P<0.001). There was also a greater improvement in the secondary end points in the CABG plus MVR group compared with the CABG group: left ventricular end-systolic volume index, MR volume, and plasma B-type natriuretic peptide reduction of 22.2 mL/m(2), 28.2 mL/beat, and 557.4 pg/mL, respectively versus 4.4 mL/m(2) (P=0.002), 9.2 mL/beat (P=0.001), and 394.7 pg/mL (P=0.003), respectively. Operation duration, blood transfusion, intubation duration, and hospital stay duration were greater in the CABG plus MVR group. Deaths at 30 days and 1 year were similar in both groups: 3% and 9%, respectively in the CABG plus MVR group, versus 3% (P=1.00) and 5% (P=0.66), respectively in the CABG group. Adding mitral annuloplasty to CABG in patients with moderate ischemic MR may improve functional capacity, left ventricular reverse remodeling, MR severity, and B-type natriuretic peptide levels, compared with CABG alone. The impact of these benefits on longer term clinical outcomes remains to be defined.

Effect of trimetazidine treatment on the transient outward potassium current of the left ventricular myocytes of rats with streptozotocin-induced type 1 diabetes mellitus.

PubMed

Xiang, Yu-luan; He, Li; Xiao, Jun; Xia, Shuang; Deng, Song-bai; Xiu, Yun; She, Qiang

2012-03-01

Cardiovascular complications are a leading cause of mortality in patients with diabetes mellitus (DM). The present study was designed to investigate the effects of trimetazidine (TMZ), an anti-angina drug, on transient outward potassium current (Ito) remodeling in ventricular myocytes and the plasma contents of free fatty acid (FFA) and glucose in DM. Sprague-Dawley rats, 8 weeks old and weighing 200-250 g, were randomly divided into three groups of 20 animals each. The control group was injected with vehicle (1 mM citrate buffer), the DM group was injected with 65 mg/kg streptozotocin (STZ) for induction of type 1 DM, and the DM + TMZ group was injected with the same dose of STZ followed by a 4-week treatment with TMZ (60 mg·kg-1·day-1). All animals were then euthanized and their hearts excised and subjected to electrophysiological measurements or gene expression analyses. TMZ exposure significantly reversed the increased plasma FFA level in diabetic rats, but failed to change the plasma glucose level. The amplitude of Ito was significantly decreased in left ventricular myocytes from diabetic rats relative to control animals (6.25 ± 1.45 vs 20.72 ± 2.93 pA/pF at +40 mV). The DM-associated Ito reduction was attenuated by TMZ. Moreover, TMZ treatment reversed the increased expression of the channel-forming alpha subunit Kv1.4 and the decreased expression of Kv4.2 and Kv4.3 in diabetic rat hearts. These data demonstrate that TMZ can normalize, or partially normalize, the increased plasma FFA content, the reduced Ito of ventricular myocytes, and the altered expression Kv1.4, Kv4.2, and Kv4.3 in type 1 DM.

Severity of structural and functional right ventricular remodeling depends on training load in an experimental model of endurance exercise.

PubMed

Sanz-de la Garza, Maria; Rubies, Cira; Batlle, Montserrat; Bijnens, Bart H; Mont, Lluis; Sitges, Marta; Guasch, Eduard

2017-09-01

Arrhythmogenic right ventricular (RV) remodeling has been reported in response to regular training, but it remains unclear how exercise intensity affects the presence and extent of such remodeling. We aimed to assess the relationship between RV remodeling and exercise load in a long-term endurance training model. Wistar rats were conditioned to run at moderate (MOD; 45 min, 30 cm/s) or intense (INT; 60 min, 60 cm/s) workloads for 16 wk; sedentary rats served as controls. Cardiac remodeling was assessed with standard echocardiographic and tissue Doppler techniques, sensor-tip pressure catheters, and pressure-volume loop analyses. After MOD training, both ventricles similarly dilated (~16%); the RV apical segment deformation, but not the basal segment deformation, was increased [apical strain rate (SR): -2.9 ± 0.5 vs. -3.3 ± 0.6 s -1 , SED vs. MOD]. INT training prompted marked RV dilatation (~26%) but did not further dilate the left ventricle (LV). A reduction in both RV segments' deformation in INT rats (apical SR: -3.3 ± 0.6 vs. -3.0 ± 0.4 s -1 and basal SR: -3.3 ± 0.7 vs. -2.7 ± 0.6 s -1 , MOD vs. INT) led to decreased global contractile function (maximal rate of rise of LV pressure: 2.53 ± 0.15 vs. 2.17 ± 0.116 mmHg/ms, MOD vs. INT). Echocardiography and hemodynamics consistently pointed to impaired RV diastolic function in INT rats. LV systolic and diastolic functions remained unchanged in all groups. In conclusion, we showed a biphasic, unbalanced RV remodeling response with increasing doses of exercise: physiological adaptation after MOD training turns adverse with INT training, involving disproportionate RV dilatation, decreased contractility, and impaired diastolic function. Our findings support the existence of an exercise load threshold beyond which cardiac remodeling becomes maladaptive. NEW & NOTEWORTHY Exercise promotes left ventricular eccentric hypertrophy with no changes in systolic or diastolic function in healthy rats. Conversely, right ventricular adaptation to physical activity follows a biphasic, dose-dependent, and segmentary pattern. Moderate exercise promotes a mild systolic function enhancement at the right ventricular apex and more intense exercise impairs systolic and diastolic function. Copyright © 2017 the American Physiological Society.

Racial/Ethnic Differences in Left Ventricular Structure and Function in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort.

PubMed

Ahmad, Faraz S; Cai, Xuan; Kunkel, Katherine; Ricardo, Ana C; Lash, James P; Raj, Dominic S; He, Jiang; Anderson, Amanda H; Budoff, Matthew J; Wright Nunes, Julie A; Roy, Jason; Wright, Jackson T; Go, Alan S; St John Sutton, Martin G; Kusek, John W; Isakova, Tamara; Wolf, Myles; Keane, Martin G

2017-08-01

Chronic kidney disease (CKD) is associated with increased risk of cardiovascular disease (CVD) and it is especially common among Blacks. Left ventricular hypertrophy (LVH) is an important subclinical marker of CVD, but there are limited data on racial variation in left ventricular structure and function among persons with CKD. In a cross-sectional analysis of the Chronic Renal Insufficiency Cohort Study, we compared the prevalence of different types of left ventricular remodeling (concentric hypertrophy, eccentric hypertrophy, and concentric remodeling) by race/ethnicity. We used multinomial logistic regression to test whether race/ethnicity associated with different types of left ventricular remodeling independently of potential confounding factors. We identified 1,164 non-Hispanic Black and 1,155 non-Hispanic White participants who completed Year 1 visits with echocardiograms that had sufficient data to categorize left ventricular geometry type. Compared to non-Hispanic Whites, non-Hispanic Blacks had higher mean left ventricular mass index (54.7 ± 14.6 vs. 47.4 ± 12.2 g/m2.7; P < 0.0001) and prevalence of concentric LVH (45.8% vs. 24.9%). In addition to higher systolic blood pressure and treatment with >3 antihypertensive medications, Black race/ethnicity was independently associated with higher odds of concentric LVH compared to White race/ethnicity (odds ratio: 2.73; 95% confidence interval: 2.02, 3.69). In a large, diverse cohort with CKD, we found significant differences in left ventricular mass and hypertrophic morphology between non-Hispanic Blacks and Whites. Future studies will evaluate whether higher prevalence of LVH contribute to racial/ethnic disparities in cardiovascular outcomes among CKD patients. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Serum Bilirubin Concentration is Associated with Left Ventricular Remodeling in Patients with Type 2 Diabetes Mellitus: A Cohort Study.

PubMed

Inoue, Tomoaki; Sonoda, Noriyuki; Hiramatsu, Shinsuke; Kimura, Shinichiro; Ogawa, Yoshihiro; Inoguchi, Toyoshi

2018-02-01

Previous studies have shown that serum bilirubin concentration is inversely associated with the risk of cardiovascular disease. The relationship between serum bilirubin concentration and left ventricular geometry, however, has not been investigated in patients with diabetes mellitus. In this cohort study, 158 asymptomatic patients with type 2 diabetes mellitus without overt heart disease were enrolled. Left ventricular structure and function were assessed using echocardiography. Serum bilirubin concentration, glycemic control, lipid profile, and other clinical characteristics were evaluated, and their association with left ventricular geometry was determined. Patients with New York Heart Association Functional Classification greater than I, left ventricular ejection fraction less than 50%, history of coronary artery disease, severe valvulopathy, chronic atrial fibrillation, or creatinine clearance less than 30 ml/min, and those receiving insulin treatment, were excluded. Univariate analyses showed that relative wall thickness (RWT) was significantly correlated with diastolic blood pressure (P = 0.003), HbA1c (P = 0.024), total cholesterol (P = 0.043), urinary albumin (P = 0.023), and serum bilirubin concentration (P = 0.009). There was no association between left ventricular mass index and serum bilirubin concentration. Multivariate linear regression analysis showed that log RWT was positively correlated with diastolic blood pressure (P = 0.010) and that log RWT was inversely correlated with log bilirubin (P = 0.003). In addition, the patients with bilirubin less than 0.8 mg/dl had a higher prevalence of concentric left ventricular remodeling compared with those with bilirubin 0.8 mg/dl or more. Our study shows that the serum bilirubin concentration may be associated with the progression of concentric left ventricular remodeling in patients with type 2 diabetes mellitus.

Atrioventricular node functional remodeling induced by atrial fibrillation.

PubMed

Zhang, Youhua; Mazgalev, Todor N

2012-09-01

The atrioventricular node (AVN) plays a vital role in determining the ventricular rate during atrial fibrillation (AF). AF results in profound electrophysiological and structural remodeling in the atria as well as the sinus node. However, it is unknown whether AVN undergoes remodeling during AF. To determine whether AVN undergoes functional remodeling during AF. AVN conduction properties were studied in vitro in 9 rabbits with AF and 10 normal controls. A previously validated index of AVN dual-pathway electrophysiology, His-electrogram alternans, was used to monitor fast-pathway or slow-pathway (SP) AVN conduction in these experiments. AVN conduction properties were further studied in vivo in 7 dogs with chronic AF and 8 controls. Compared with the control rabbits, the rabbits with AF had a longer AVN conduction time (83 ± 16 ms vs 68 ± 7 ms; P <.01), longer AVN effective refractory period (141 ± 27 ms vs 100 ± 9 ms; P <.01), an earlier transition from fast-pathway to SP conduction (at a longer prematurity, 249 ± 60 ms vs 171 ± 24 ms; P <.01), and a slower ventricular rate during simulated AF (RR interval 249 ± 42 ms vs 202 ± 12 ms; P <.01). Notably, a larger proportion of conducted beats utilized the SP in AF preparations (92% ± 12% vs 63% ± 32%; P <.05). Long-term AF in dogs resulted in a longer atrioventricular conduction time and AVN effective refractory period and a slower ventricular rate during AF compared with the controls. Pronounced AVN functional electrophysiological remodeling occurs after long-term AF, which could lead to a spontaneous slowing of the ventricular rate. Furthermore, the SP dominance during AF underscores the effectiveness of its modification by ablation for ventricular rate control during AF. Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Simulated Microgravity and Recovery-Induced Remodeling of the Left and Right Ventricle

PubMed Central

Zhong, Guohui; Li, Yuheng; Li, Hongxing; Sun, Weijia; Cao, Dengchao; Li, Jianwei; Zhao, Dingsheng; Song, Jinping; Jin, Xiaoyan; Song, Hailin; Yuan, Xinxin; Wu, Xiaorui; Li, Qi; Xu, Qing; Kan, Guanghan; Cao, Hongqing; Ling, Shukuan; Li, Yingxian

2016-01-01

Physiological adaptations to microgravity involve alterations in cardiovascular systems. These adaptations result in cardiac remodeling and orthostatic hypotension. However, the response of the left ventricle (LV) and right ventricle (RV) following hindlimb unloading (HU) and hindlimb reloading (HR) is not clear and the underlying mechanism remains to be understood. In this study, three groups of mice were subjected to HU by tail suspension for 28 days. Following this, two groups were allowed to recover for 7 or 14 days. The control group was treated equally, with the exception of tail suspension. Echocardiography was performed to detect the structure and function changes of heart. Compared with the control, the HU group of mice showed reduced LV-EF (ejection fraction), and LV-FS (fractional shortening). However, mice that were allowed to recover for 7 days after HU (HR-7d) showed increased LVIDs (systolic LV internal diameter) and LV Vols (systolic LV volume). Mice that recovered for 14 days (HR-14d) returned to the normal state. In comparison, RV-EF and RV-FS didn't recover to the normal conditions till being reloaded for 14 days. Compared with the control, RVIDd (diastolic RV internal diameter), and RV Vold (diastolic RV volume) were reduced in HU group and recovered to the normal conditions in HR-7d and HR-14d groups, in which groups RVIDs (systolic RV internal diameter) and RV Vols (systolic RV volume) were increased. Histological analysis and cardiac remodeling gene expression results indicated that HU induces left and right ventricular remodeling. Western blot demonstrated that the phosphorylation of HDAC4 and ERK1/2 and the ratio of LC3-II / LC3-I, were increased following HU and recovered following HR in both LV and RV, and the phosphorylation of AMPK was inhibited in both LV and RV following HU, but only restored in LV following HR for 14 days. These results indicate that simulated microgravity leads to cardiac remodeling, and the remodeling changes can be reversed. Furthermore, in the early stages of recovery, cardiac remodeling may be intensified. Finally, compared with the LV, the RV is not as easily reversed. Cardiac remodeling pathways, such as, HDAC4, ERK1/2, LC3-II, and AMPK were involved in the process. PMID:27445861

Long-term cardiovascular changes following creation of arteriovenous fistula in patients with end stage renal disease.

PubMed

Reddy, Yogesh N V; Obokata, Masaru; Dean, Patrick G; Melenovsky, Vojtech; Nath, Karl A; Borlaug, Barry A

2017-06-21

Short-term studies have reported left ventricular (LV) dilatation following surgical creation of arteriovenous fistulas (AVF) or arteriovenous grafts (AVGs), but chronic cardiac structural and functional changes have not been examined or related to clinical outcomes following AVF/AVG. We sought to characterize the long-term changes in cardiac structure and function in patients undergoing shunt creation for haemodialysis. A retrospective analysis was performed of patients undergoing echocardiography before and after surgical AVF/AVG creation for the initiation of haemodialysis. 137 patients underwent echocardiographic examinations prior to AVF and 2.6 years (median) after AVF creation. Following AVF and dialysis initiation, there were reductions in blood pressure, body weight and estimated plasma volume coupled with modest reverse LV remodelling. In contrast, AVF/AVG creation was associated with significant right ventricular (RV) dilatation and deterioration in RV function. Incident heart failure (HF) developed in 43% of patients in tandem with greater RV remodeling. The development of RV dilation following surgical AVF/AVG was independently associated with increased risk of death [HR 3.9, 95% CI (1.7-9.2), P = 0.001]. In long-term follow-up, RV remodelling and dysfunction develop following AVF/AVG creation and dialysis initiation, despite improved control of LV pressure load through dialysis. Deleterious effects on right heart structure and function are coupled with development of incident HF and increased risk of death. Further study is required to identify patients at greatest risk for detrimental AVF/AVG changes who may benefit from alternate forms of dialysis or potentially ligation of existing AVF. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Maternal PUFA omega-3 supplementation prevents hyperoxia-induced pulmonary hypertension in the offspring.

PubMed

Zhong, Ying; Catheline, Daniel; Houeijeh, Ali; Sharma, Dyuti; Du, Li-Zhong; Besengez, Capucine; Deruelle, Philippe; Legrand, Philippe; Storme, Laurent

2018-03-29

Pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) affect 16-25% of premature infants with bronchopulmonary dysplasia (BPD), contributing significantly to perinatal morbidity and mortality. Polyunsaturated fatty acids ω-3 (PUFA ω-3) can improve vascular remodeling, angiogenesis, and inflammation under pathophysiological conditions. However, the effects of PUFA ω-3 supplementation in BPD-associated PH are unknown. The present study aimed to evaluate the effects of PUFA ω-3 on pulmonary vascular remodeling, angiogenesis, and inflammatory response in a hyperoxia-induced rat model of PH. From embryonic day 15, pregnant Spague-Dawley rats were supplemented daily with PUFA ω-3, PUFA ω-6, or normal saline (0.2 ml/day). After birth, pups were pooled, assigned as 12 per litter, and randomly to either in air or continuous oxygen exposure (FiO2 = 85%) for 20 days, then sacrificed for pulmonary hemodynamic and morphometric analysis. We found that PUFA ω-3 supplementation improved survival, decreased right ventricular systolic pressure and RVH caused by hyperoxia, and significantly improved alveolarization, vascular remodeling, and vascular density. PUFA ω-3 supplementation produced a higher level of total ω-3 in lung tissue and breast milk, and was found reversing the reduced levels of VEGFA, VEGFR-2, ANGPT-1, TIE-2, eNOS, and NO concentrations in lung tissue, and the increased ANGPT-2 levels in hyperoxia-exposed rats. The beneficial effects of PUFA ω-3 in improving lung injuries were also associated with an inhibition of leukocyte infiltration, and reduced expression of proinflammatory cytokines IL-1β, IL-6 and TNF-α. These data indicated that maternal PUFA ω-3 supplementation strategies could effectively protect against infant PH induced by hyperoxia.

Comparison of the effects of candesartan cilexetil and enalapril maleate on right ventricular myocardial remodeling in dogs with experimentally induced pulmonary stenosis.

PubMed

Yamane, Tsuyoshi; Fujii, Yoko; Orito, Kensuke; Osamura, Kaori; Kanai, Takao; Wakao, Yoshito

2008-12-01

To compare the effects of candesartan cilexetil and enalapril maleate on right ventricular myocardial remodeling in dogs with experimentally induced pulmonary stenosis. 24 Beagles. 18 dogs underwent pulmonary arterial banding (PAB) to induce right ventricular pressure overload, and 6 healthy dogs underwent sham operations (thoracotomy only [sham-operated group]). Dogs that underwent PAB were allocated to receive 1 of 3 treatments (6 dogs/group): candesartan (1 mg/kg, PO, q 24 h [PABC group]), enalapril (0.5 mg/kg, PO, q 24 h [PABE group]), or no treatment (PABNT group). Administration of treatments was commenced the day prior to surgery; control dogs received no cardiac medications. Sixty days after surgery, right ventricular wall thickness was assessed echocardiographically and plasma renin activity, angiotensin-converting enzyme activity, and angiotensin I and II concentrations were assessed; all dogs were euthanatized, and collagenous fiber area, cardiomyocyte diameter, and tissue angiotensin-converting enzyme and chymase-like activities in the right ventricle were evaluated. After 60 days of treatment, right ventricular wall thickness, cardiomyocyte diameter, and collagenous fiber area in the PABNT and PABE groups were significantly increased, compared with values in the PABC and sham-operated groups. Chymase-like activity was markedly greater in the PABE group than in other groups. Results indicated that treatment with candesartan but not enalapril effectively prevented myocardial remodeling in dogs with experimentally induced subacute right ventricular pressure overload.

Targeted ablation of cardiac sympathetic neurons improves ventricular electrical remodelling in a canine model of chronic myocardial infarction.

PubMed

Xiong, Liang; Liu, Yu; Zhou, Mingmin; Wang, Guangji; Quan, Dajun; Shen, Caijie; Shuai, Wei; Kong, Bin; Huang, Congxin; Huang, He

2018-05-31

The purpose of this study was to evaluate the cardiac electrophysiologic effects of targeted ablation of cardiac sympathetic neurons (TACSN) in a canine model of chronic myocardial infarction (MI). Thirty-eight anaesthetized dogs were randomly assigned into the sham-operated, MI, and MI-TACSN groups, respectively. Myocardial infarction-targeted ablation of cardiac sympathetic neuron was induced by injecting cholera toxin B subunit-saporin compound in the left stellate ganglion (LSG). Five weeks after surgery, the cardiac function, heart rate variability (HRV), ventricular electrophysiological parameters, LSG function and neural activity, serum norepinephrine (NE), nerve growth factor (NGF), and brain natriuretic peptide (BNP) levels were measured. Cardiac sympathetic innervation was determined with immunofluorescence staining of growth associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Compared with MI group, TACSN significantly improved HRV, attenuated LSG function and activity, prolonged corrected QT interval, decreased Tpeak-Tend interval, prolonged ventricular effective refractory period (ERP), and action potential duration (APD), decreased the slopes of APD restitution curves, suppressed the APD alternans, increased ventricular fibrillation threshold, and reduced serum NE, NGF, and BNP levels. Moreover, the densities of GAP43 and TH-positive nerve fibres in the infarcted border zone in the MI-TACSN group were lower than those in the MI group. Targeted ablation of cardiac sympathetic neuron attenuates sympathetic remodelling and improves ventricular electrical remodelling in the chronic phase of MI. These data suggest that TACSN may be a novel approach to treating ventricular arrhythmias.

High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction

PubMed Central

Halle, Martin; Conraads, Viviane; Støylen, Asbjørn; Dalen, Håvard; Delagardelle, Charles; Larsen, Alf-Inge; Hole, Torstein; Mezzani, Alessandro; Van Craenenbroeck, Emeline M.; Videm, Vibeke; Beckers, Paul; Christle, Jeffrey W.; Winzer, Ephraim; Mangner, Norman; Woitek, Felix; Höllriegel, Robert; Pressler, Axel; Monk-Hansen, Tea; Snoer, Martin; Feiereisen, Patrick; Valborgland, Torstein; Kjekshus, John; Hambrecht, Rainer; Gielen, Stephan; Karlsen, Trine; Prescott, Eva; Linke, Axel

2017-01-01

Background: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). Methods: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. Results: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were −2.8 mm (−5.2 to −0.4 mm; P=0.02) in HIIT and −1.2 mm (−3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. Conclusions: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046. PMID:28082387

High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction.

PubMed

Ellingsen, Øyvind; Halle, Martin; Conraads, Viviane; Støylen, Asbjørn; Dalen, Håvard; Delagardelle, Charles; Larsen, Alf-Inge; Hole, Torstein; Mezzani, Alessandro; Van Craenenbroeck, Emeline M; Videm, Vibeke; Beckers, Paul; Christle, Jeffrey W; Winzer, Ephraim; Mangner, Norman; Woitek, Felix; Höllriegel, Robert; Pressler, Axel; Monk-Hansen, Tea; Snoer, Martin; Feiereisen, Patrick; Valborgland, Torstein; Kjekshus, John; Hambrecht, Rainer; Gielen, Stephan; Karlsen, Trine; Prescott, Eva; Linke, Axel

2017-02-28

Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT ( P =0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P =0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P =0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake ( P =0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P =0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046. © 2017 The Authors.

Renal sympathetic denervation alleviates myocardial fibrosis following isoproterenol-induced heart failure.

PubMed

Wang, Neng; Zheng, Xiaoxin; Qian, Jin; Yao, Wei; Bai, Lu; Hou, Guo; Qiu, Xuan; Li, Xiaoyan; Jiang, Xuejun

2017-10-01

The aim of the present study was to determine if renal sympathetic denervation (RSD) may alleviate isoproterenol-induced left ventricle remodeling, and to identify the underlying mechanism. A total of 70 rats were randomly divided into control (n=15), sham operation (n=15), heart failure (HF) with sham operation (HF + sham; n=20) and HF with treatment (HF + RSD; n=20) groups. The HF model was established by subcutaneous injection of isoproterenol; six weeks later, 1eft ventricular internal diameter at end‑systole (LVIDs), left ventricular systolic posterior wall thickness (LVPWs), 1eft ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured. Plasma norepinephrine (NE), angiotensin II (Ang II) and aldosterone (ALD) levels were measured by ELISA. Myocardial collagen volume fraction (CVF) was determined by Masson's staining. Reverse transcription‑quantitative polymerase chain reaction was used to determine the mRNA expression levels of ventricular transforming growth factor‑β (TGF‑β), connective tissue growth factor (CTGF) and microRNAs (miRs), including miR‑29b, miR‑30c and miR‑133a. The results demonstrated that LVIDs and LVPWs in the HF + RSD group were significantly decreased compared with the HF + sham group. By contrast, LVFS and LVEF in the HF + RSD group were significantly increased compared with the HF + sham group. RSD significantly reduced the levels of plasma NE, Ang II and ALD. CVF in the HF + RSD group was reduced by 38.1% compared with the HF + sham group. Expression levels of TGF‑β and CTGF were decreased, whereas those of miR‑29b, miR‑30c and miR‑133a were increased, in the HF + RSD group compared with the HF + sham group. These results indicated that RSD alleviates isoproterenol‑induced left ventricle remodeling potentially via downregulation of TGF‑β/CTGF and upregulation of miR‑29b, miR‑30c and miR‑133a. RSD may therefore be an effective non‑drug therapy for the treatment of heart failure.

Renal sympathetic denervation alleviates myocardial fibrosis following isoproterenol-induced heart failure

PubMed Central

Wang, Neng; Zheng, Xiaoxin; Qian, Jin; Yao, Wei; Bai, Lu; Hou, Guo; Qiu, Xuan; Li, Xiaoyan; Jiang, Xuejun

2017-01-01

The aim of the present study was to determine if renal sympathetic denervation (RSD) may alleviate isoproterenol-induced left ventricle remodeling, and to identify the underlying mechanism. A total of 70 rats were randomly divided into control (n=15), sham operation (n=15), heart failure (HF) with sham operation (HF + sham; n=20) and HF with treatment (HF + RSD; n=20) groups. The HF model was established by subcutaneous injection of isoproterenol; six weeks later, 1eft ventricular internal diameter at end-systole (LVIDs), left ventricular systolic posterior wall thickness (LVPWs), 1eft ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) were measured. Plasma norepinephrine (NE), angiotensin II (Ang II) and aldosterone (ALD) levels were measured by ELISA. Myocardial collagen volume fraction (CVF) was determined by Masson's staining. Reverse transcription-quantitative polymerase chain reaction was used to determine the mRNA expression levels of ventricular transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF) and microRNAs (miRs), including miR-29b, miR-30c and miR-133a. The results demonstrated that LVIDs and LVPWs in the HF + RSD group were significantly decreased compared with the HF + sham group. By contrast, LVFS and LVEF in the HF + RSD group were significantly increased compared with the HF + sham group. RSD significantly reduced the levels of plasma NE, Ang II and ALD. CVF in the HF + RSD group was reduced by 38.1% compared with the HF + sham group. Expression levels of TGF-β and CTGF were decreased, whereas those of miR-29b, miR-30c and miR-133a were increased, in the HF + RSD group compared with the HF + sham group. These results indicated that RSD alleviates isoproterenol-induced left ventricle remodeling potentially via downregulation of TGF-β/CTGF and upregulation of miR-29b, miR-30c and miR-133a. RSD may therefore be an effective non-drug therapy for the treatment of heart failure. PMID:28849013

Valve sparing aortic replacement - root remodeling.

PubMed

Lausberg, Henning F; Schäfers, Hans-Joachim

2006-01-01

Aortic root remodeling restores aortic root geometry and improves valve competence. We have used this technique whenever aorto-ventricular diameter is preserved. The operative technique is detained in this presentation. As a result of our 10-year experience with root remodeling we propose this operation as a reproducible option for patients with dilatation of the aortic root.

Identification of genetic markers for treatment success in heart failure patients: insight from cardiac resynchronization therapy.

PubMed

Schmitz, Boris; De Maria, Renata; Gatsios, Dimitris; Chrysanthakopoulou, Theodora; Landolina, Maurizio; Gasparini, Maurizio; Campolo, Jonica; Parolini, Marina; Sanzo, Antonio; Galimberti, Paola; Bianchi, Michele; Lenders, Malte; Brand, Eva; Parodi, Oberdan; Lunati, Maurizio; Brand, Stefan-Martin

2014-12-01

Cardiac resynchronization therapy (CRT) can improve ventricular size, shape, and mass and reduce mitral regurgitation by reverse remodeling of the failing ventricle. About 30% of patients do not respond to this therapy for unknown reasons. In this study, we aimed at the identification and classification of CRT responder by the use of genetic variants and clinical parameters. Of 1421 CRT patients, 207 subjects were consecutively selected, and CRT responder and nonresponder were matched for their baseline parameters before CRT. Treatment success of CRT was defined as a decrease in left ventricular end-systolic volume >15% at follow-up echocardiography compared with left ventricular end-systolic volume at baseline. All other changes classified the patient as CRT nonresponder. A genetic association study was performed, which identified 4 genetic variants to be associated with the CRT responder phenotype at the allelic (P<0.035) and genotypic (P<0.031) level: rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11). Machine learning algorithms were used for the classification of CRT patients into responder and nonresponder status, including combinations of the identified genetic variants and clinical parameters. We demonstrated that rule induction algorithms can successfully be applied for the classification of heart failure patients in CRT responder and nonresponder status using clinical and genetic parameters. Our analysis included information on alleles and genotypes of 4 genetic loci, rs3766031 (ATPIB1), rs5443 (GNB3), rs5522 (NR3C2), and rs7325635 (TNFSF11), pathophysiologically associated with remodeling of the failing ventricle. © 2014 American Heart Association, Inc.

Quinapril decreases myocardial accumulation of extracellular matrix components in spontaneously hypertensive rats.

PubMed

Panizo, A; Pardo, J; Hernández, M; Galindo, M F; Cenarruzabeitia, E; Díez, J

1995-08-01

In genetic and acquired hypertension, a structural remodeling of the nonmyocyte compartment of myocardium, including the accumulation of fibrillar collagen and other components of the extracellular matrix (ECM) within the interstitium, represents a determinant of pathologic hypertrophy that leads to ventricular dysfunction. Therefore, to evaluate the potential benefit of the angiotensin converting enzyme (ACE) inhibitor quinapril in reversing the interstitial remodeling in spontaneously hypertensive rats (SHR) with established left ventricular hypertrophy (LVH), we treated 16-week-old male SHR with oral quinapril (average dose, 10 mg/kg body weight/day) for 20 weeks. Interstitial fibrosis was determined morphometrically using an automatic image analyzer. The amount of collagen was evaluated by measuring myocardial hydroxyproline concentration. Myocardial deposition of collagen molecules (types I, III, and IV) and other ECM components (fibronectin, laminin) was analyzed by immunohistochemical techniques using specific monoclonal antibodies. The activity of ACE was measured in left ventricular tissue by a fluorometric assay. In quinapril-treated SHR compared with 36-week-old untreated SHR and age- and sex-matched Wistar-Kyoto (WKY) controls, we found 1) a lesser degree of LVH and a lesser level of blood pressure, 2) a lesser degree of interstitial fibrosis, represented by less interstitial collagen volume fraction (5.73 +/- 0.45% v 3.42 +/- 0.28%, P < .05; WKY, 3.44 +/- 0.66%), 3) a lower hydroxyproline concentration (1.09 +/- 0.05 mumol/L/g dry weight/100 g body weight to 0.81 +/- 0.05 mumol/L/g dry weight/100 g body weight, P < .05; WKY, 0.96 +/- 0.06 mumol/L/g dry weight/100 g body weight), 4) a lesser presence of collagen fibers, and 5) a lesser presence of collagen IV, fibronectin, and laminin.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac fibroblast GSK-3β regulates ventricular remodeling and dysfunction in ischemic heart

PubMed Central

Lal, Hind; Ahmad, Firdos; Zhou, Jibin; Yu, Justine E.; Vagnozzi, Ronald J.; Guo, Yuanjun; Yu, Daohai; Tsai, Emily J.; Woodgett, James; Gao, Erhe; Force, Thomas

2014-01-01

Background Myocardial infarction-induced remodeling includes chamber dilatation, contractile dysfunction, and fibrosis. Of these, fibrosis is the least understood. Following MI, activated cardiac fibroblasts (CFs) deposit extracellular matrix. Current therapies to prevent fibrosis are inadequate and new molecular targets are needed. Methods and Results Herein we report that GSK-3β is phosphorylated (inhibited) in fibrotic tissues from ischemic human and mouse heart. Using two fibroblast-specific GSK-3β knockout mouse models, we show that deletion of GSK-3β in CFs leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Deletion of GSK-3β induces a pro-fibrotic myofibroblast phenotype in isolated CFs, in post-MI hearts, and in MEFs deleted for GSK-3β. Mechanistically, GSK-3β inhibits pro-fibrotic TGF-β1-SMAD-3 signaling via interactions with SMAD-3. Moreover, deletion of GSK-3β resulted in the suppression of SMAD-3 transcriptional activity. This pathway is central to the pathology since a small molecule inhibitor of SMAD-3 largely prevented fibrosis and limited LV remodeling. Conclusion These studies support targeting GSK-3β in myocardial fibrotic disorders and establish critical roles of CFs in remodeling and ventricular dysfunction. PMID:24899689

Epicardial catheter-based ventricular reconstruction: a novel therapy for ischaemic heart failure with anteroapical aneurysm†

PubMed Central

Cheng, Yanping; Aboodi, Michael S.; Wechsler, Andrew S.; Kaluza, Greg L.; Granada, Juan F.; Van Bladel, Kevin; Annest, Lon S.; Yi, Geng-Hua

2013-01-01

OBJECTIVES Surgical ventricular reconstruction has been used to treat ischaemic cardiomyopathy with large akinetic or dyskinetic areas. However, application of this approach requires a sternotomy, cardiopulmonary bypass and a left ventriculotomy. This study assessed the feasibility and efficacy of minimally invasive, off-pump, epicardial catheter-based ventricular reconstruction (ECVR) in an anteroapical aneurysm ovine model. METHODS Left ventricular (LV) anteroapical myocardial infarction was induced percutaneously by coil embolization of the left anterior descending coronary artery. Eight weeks after infarction, via mini left thoracotomy and without cardiopulmonary bypass, ECVR was performed in six sheep. The scar was excluded by placing anchor pairs on the LV epicardial anterior wall and the right ventricular side of the interventricular septum under fluoroscopic guidance. LV performance was evaluated before, immediately after device implantation and after 6 weeks by echocardiography. Terminal histopathology was performed. RESULTS ECVR was completed expeditiously in all animals without complications. Parameters obtained 6 weeks after device implantation were compared with baseline (pre-device). End-systolic volume was decreased by 38% (25.6 ± 6.1 ml vs baseline 41.2 ± 7.2 ml, P = 0.02) with preservation of stroke volume. Ejection fraction was significantly increased by 13% (48.5 ± 7% vs baseline 35.8 ± 7%, P = 0.02). The circumferential strain in the anterior septum (−7.67 ± 5.12% vs baseline −0.96 ± 2.22%, P = 0.03) and anterior wall (−9.01 ± 3.51% vs baseline −4.15 ± 1.36%, P = 0.01) were significantly improved. The longitudinal strain in apex was reversed (−3.08 ± 1.53% vs baseline 3.09 ± 3.39%, P = 0.01). Histopathology showed full endocardial healing over the anchors with appreciable reduction of the chronic infarct in the LV. CONCLUSIONS ECVR without cardiopulmonary bypass is a less invasive alternative to current standard therapies, reverses LV remodelling and improves cardiac performance in an ovine model of anteroapical aneurysm. PMID:23985410

Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling.

PubMed

Li, Yulin; Li, Zhenya; Zhang, Congcong; Li, Ping; Wu, Yina; Wang, Chunxiao; Bond Lau, Wayne; Ma, Xin-Liang; Du, Jie

2017-05-23

Hypertensive ventricular remodeling is a common cause of heart failure. However, the molecular mechanisms regulating ventricular remodeling remain poorly understood. We used a discovery-driven/nonbiased approach to identify increased activating transcription factor 3 (ATF3) expression in hypertensive heart. We used loss/gain of function approaches to understand the role of ATF3 in heart failure. We also examined the mechanisms through transcriptome, chromatin immunoprecipitation sequencing analysis, and in vivo and in vitro experiments. ATF3 expression increased in murine hypertensive heart and human hypertrophic heart. Cardiac fibroblast cells are the primary cell type expressing high ATF3 levels in response to hypertensive stimuli. ATF3 knockout (ATF3KO) markedly exaggerated hypertensive ventricular remodeling, a state rescued by lentivirus-mediated/miRNA-aided cardiac fibroblast-selective ATF3 overexpression. Conversely, conditional cardiac fibroblast cell-specific ATF3 transgenic overexpression significantly ameliorated ventricular remodeling and heart failure. We identified Map2K3 as a novel ATF3 target. ATF3 binds with the Map2K3 promoter, recruiting HDAC1, resulting in Map2K3 gene-associated histone deacetylation, thereby inhibiting Map2K3 expression. Genetic Map2K3 knockdown rescued the profibrotic/hypertrophic phenotype in ATF3KO cells. Last, we demonstrated that p38 is the downstream molecule of Map2K3 mediating the profibrotic/hypertrophic effects in ATF3KO animals. Inhibition of p38 signaling reduced transforming growth factor-β signaling-related profibrotic and hypertrophic gene expression, and blocked exaggerated cardiac remodeling in ATF3KO cells. Our study provides the first evidence that ATF3 upregulation in cardiac fibroblasts in response to hypertensive stimuli protects the heart by suppressing Map2K3 expression and subsequent p38-transforming growth factor-β signaling. These results suggest that positive modulation of cardiac fibroblast ATF3 may represent a novel therapeutic approach against hypertensive cardiac remodeling. © 2017 American Heart Association, Inc.

Anti-hypertensive and cardioprotective effects of a novel apitherapy formulation via upregulation of peroxisome proliferator-activated receptor-α and -γ in spontaneous hypertensive rats.

PubMed

Sun, Yanru; Han, Mingfeng; Shen, Zhenhuang; Huang, Haibo; Miao, Xiaoqing

2018-02-01

Ventricular remodeling is associated with many heart diseases, and ventricular remodeling induced by hypertension can be fatal independent of hypertension. In this study, we prepared a novel apitherapy formulation, designated Bao-Yuan-Ling (BYL), which contained propolis, royal jelly, and bee venom, to treat spontaneous hypertensive rats (SHRs). We then evaluated the pharmacology of BYL and the potential mechanisms through which BYL affects hypertension and ventricular remodeling. We found that BYL treatment could reduce blood pressure in SHRs. Thereafter, we found that BYL treatment reduced serum levels of angiotensin II, endothelin 1, and transforming growth factor-β and improved the myocardial structure. Moreover, the results of quantitative real-time polymerase chain reaction indicated that BYL treatment could upregulate the mRNA expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ. Thus, we could conclude that BYL had hypotensive and cardioprotective effects in SHRs, potentially through improvement of myocardial energy metabolism.

Incidence and predictors of left ventricular remodeling among elderly Asian women: a community-based cohort study.

PubMed

Wu, Jing; Wu, Caiqin; Fan, Wenjing; Zhou, Jie; Xu, Ling

2017-01-14

Left ventricular (LV) remodeling is closely linked to the progression of heart failure. There are limited data on the epidemiology of new onset LV remodeling among elderly women, which requires further investigation. We examined data from a community-based cohort of women aged > 65 years, who had received > 2 echocardiography scans from 2009 to 2014. Exclusion criteria for patients included prior echocardiographic evidence of left ventricular enlargement (LVE) or hypertrophy (LVH). LVE was defined as the index of left ventricular internal diameter at end-diastole to height, and LVH was defined as the left ventricular mass and thickness index which indicate hypertrophy. Of the 474 subjects (age 71.85 ± 6.47 years), 49 (10.3%) developed LVH, while 55 (11.6%) developed LVE during the mean follow-up period of 5 years. Independent predictors of LVH included: central blood pressure (CBP, per 10 mmHg) [HR 1.094, 95% CI 1.011-1.202], BMI˃25(kg/m 2 )[HR 1.306, 95% CI 1.175-1.434], B-type natriuretic peptide (BNP) ≥ 100 (pg/mL) [HR 1.635, 95% CI 1.107-3.311] and brachial-ankle pulse wave velocity (baPWV) ≥16 m/s [HR 1.605, 95% CI 1.474-2.039]. Predictors of LVE were CBP (per 10 mmHg) [HR 1.121, 95% CI 1.027-1.238], BMI˃25(kg/m 2 )[HR 1.302, 95% CI 1.173-1.444], Low-density lipoprotein cholesterol (LDL-C) [HR 1.193, 95%CI 1.013-1.405] and E/e' ratio [HR 1.077, 95% CI 1.017-1.140]. CBP and BMI were demonstrated to be independent and robust predictors of left ventricular remodeling among elderly women, including both LVE and LVH. BNP and baPWV were specifically related to the development of LVH, whereas LDL-C and E/e' ratio were related to LVE.

Using impedance cardiography with postural change to stratify patients with hypertension.

PubMed

DeMarzo, Arthur P

2011-06-01

Early detection of cardiovascular disease in patients with hypertension could initiate appropriate treatment to control blood pressure and prevent the progression of cardiovascular disease. The goal of this study was to show how impedance cardiography waveform analysis with postural change can be used to detect subclinical cardiovascular disease in patients with high blood pressure. Patients with high blood pressure had impedance cardiography data obtained in two positions, standing upright and supine. In 50 adults, impedance cardiography indicated that all patients had abnormal data, with 44 (88%) having multiple abnormalities. Impedance cardiography showed 32 (64%) had ventricular dysfunction, 48 (96%) had vascular load abnormalities, 34 (68%) had hemodynamic abnormalities, 2 (4%) had hypovolemia, and 3 (6%) had hypervolemia. Hypertensive patients have diverse cardiovascular abnormalities that can be quantified by impedance cardiography. By stratifying patients with ventricular, vascular, and hemodynamic abnormalities, treatment could be customized based on the abnormal underlying mechanisms with the potential to rapidly control blood pressure, prevent progression of cardiovascular disease, and possibly reverse remodeling.

Dyssynchronous ventricular contraction in Wolff-Parkinson-White syndrome: a risk factor for the development of dilated cardiomyopathy.

PubMed

Dai, Chen-Cheng; Guo, Bao-Jing; Li, Wen-Xiu; Xiao, Yan-Yan; Jin, Mei; Han, Lin; Sun, Jing-Ping; Yu, Cheuk-Man; Dong, Jian-Zeng

2013-11-01

Emerging evidence suggests that significant left ventricular dysfunction may arise in right-sided septal or paraseptal accessory pathways (APs) with Wolff-Parkinson-White syndrome, even in the absence of recurrent or incessant tachycardia. During 1 year and 9 months, we identified four consecutive female children with median age of 8 years diagnosed as having dilated cardiomyopathy (DCM) combined with overt right-sided APs several years ago. Incessant or recurrent tachycardia as the cause of DCM could be excluded. Anti-heart failure chemotherapy did not produce satisfactory effects. The patients underwent radiofrequency ablations (RFCAs). This report describes the clinical and echocardiographic characteristics of the cases before and after the ablation. Dyssynchronous ventricular contraction was observed in all patients. The locations of the APs were the right-sided anteroseptum and the free wall (n = 2 each). All patients received successful RFCAs. Their physical activities and growth improved greatly, and the echocardiographic data demonstrated that their left ventricular (LV) contraction recovered to synchrony shortly after the ablation and that their LV function recovered to normal gradually during the follow-up. A causal relationship between overt ventricular preexcitation and the development of DCM is supported by the complete recovery of LV function and reversed LV remodeling after the loss of ventricular preexcitation. Preexcitation-related dyssynchrony was probably the crucial mechanism. Not only right-sided septal or paraseptal but also free wall overt APs may induce LV dysfunction and even DCM. AP-induced DCM is an indication for ablation with a good prognosis.

Masked hypertension and cardiac remodeling in middle-aged endurance athletes.

PubMed

Trachsel, Lukas D; Carlen, Frederik; Brugger, Nicolas; Seiler, Christian; Wilhelm, Matthias

2015-06-01

Extensive endurance training and arterial hypertension are established risk factors for atrial fibrillation. We aimed to assess the proportion of masked hypertension in endurance athletes and the impact on cardiac remodeling, mechanics, and supraventricular tachycardias (SVT). Male participants of a 10-mile race were recruited and included if office blood pressure was normal (<140/90 mmHg). Athletes were stratified into a masked hypertension and normotension group by ambulatory blood pressure. Primary endpoint was diastolic function, expressed as peak early diastolic mitral annulus velocity (E'). Left ventricular global strain, left ventricular mass/volume ratio, left atrial volume index, signal-averaged P-wave duration (SAPWD), and SVT during 24-h Holter monitoring were recorded. From 108 runners recruited, 87 were included in the final analysis. Thirty-three (38%) had masked hypertension. The mean age was 42 ± 8 years. Groups did not differ with respect to age, body composition, cumulative training hours, and 10-mile race time. Athletes with masked hypertension had a lower E' and a higher left ventricular mass/volume ratio. Left ventricular global strain, left atrial volume index, SAPWD, and SVT showed no significant differences between the groups. In multiple linear regression analysis, masked hypertension was independently associated with E' (beta = -0.270, P = 0.004) and left ventricular mass/volume ratio (beta = 0.206, P = 0.049). Cumulative training hours was the only independent predictor for left atrial volume index (beta = 0.474, P < 0.001) and SAPWD (beta = 0.481, P < 0.001). In our study, a relevant proportion of middle-aged athletes had masked hypertension, associated with a lower diastolic function and a higher left ventricular mass/volume ratio, but unrelated to left ventricular systolic function, atrial remodeling, or SVT.

Paeoniflorin improves cardiac function and decreases adverse postinfarction left ventricular remodeling in a rat model of acute myocardial infarction.

PubMed

Chen, Hengwen; Dong, Yan; He, Xuanhui; Li, Jun; Wang, Jie

2018-01-01

Paeoniflorin (PF) is the active component of Paeonia lactiflora Pall. or Paeonia veitchii Lynch. This study was, therefore, aimed to evaluate the improvement and mechanism of the PF on ventricular remodeling in rats with acute myocardial infarction (AMI). In this study, AMI model was established by ligating the anterior descending coronary artery in Wistar rats. After 4 weeks gavage of PF, the apparent signs and the left ventricle weight index of Wistar rats were observed. The left ventricular ejection fraction (LVEF) was evaluated by Doppler ultrasonography. Changes in cardiac morphology were observed by pathologic examination, and apoptosis was observed by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. In addition, enzyme-linked immunosorbent assay was used to detect the expression of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) interleukin-10 (IL-10) and brain natriuretic peptide (BNP). Immunohistochemistry and Western blot method were applied to detect Caspase-3 and Caspase-9. Compared with the model control, the survival conditions of rats in all treatment groups were generally improved after PF treatment. LVEF was significantly increased, and both left ventricular end-diastolic inner diameter and left ventricular end-systolic inner diameter were significantly reduced. Moreover, pathologic examination showed that the myocardium degeneration of the rats treated with PF was decreased, including neater arrangement, more complete myofilament, more uniform gap and less interstitial collagen fibers. Furthermore, the mitochondrial structure of cardiomyocytes was significantly improved. The ultrastructure was clear, and the arrangement of myofilament was more regular. Also, the expression of Caspase-3 and Caspase-9 was inhibited, and apoptosis was obviously reduced in the PF treatment groups. BNP, TNF-α and IL-6 were also decreased and IL-10 was increased in the treated rats. PF could significantly improve the LVEF of rats. It decreased adverse left ventricular remodeling after myocardial infarction in rat models. The potential mechanism could be that PF decreased and inhibited BNP, TNF-α and IL-6, increased IL-10 and further inhibited the expression of Caspase-3 and Caspase-9, thus promoting ventricular remodeling.

Identification of a New Modulator of the Intercalated Disc in a Zebrafish Model of Arrhythmogenic Cardiomyopathy

PubMed Central

Asimaki, Angeliki; Kapoor, Sudhir; Plovie, Eva; Arndt, Anne Karin; Adams, Edward; Liu, ZhenZhen; James, Cynthia A.; Judge, Daniel P.; Calkins, Hugh; Churko, Jared; Wu, Joseph C.; MacRae, Calum A.; Kléber, André G.; Saffitz, Jeffrey E.

2015-01-01

Arrhythmogenic cardiomyopathy (ACM) is characterized by frequent cardiac arrhythmias. To elucidate the underlying mechanisms and discover potential chemical modifiers, we created a zebrafish model of ACM with cardiac myocyte–specific expression of the human 2057del2 mutation in the gene encoding plakoglobin. A high-throughput screen identified SB216763 as a suppressor of the disease phenotype. Early SB216763 therapy prevented heart failure and reduced mortality in the fish model. Zebrafish ventricular myocytes that expressed 2057del2 plakoglobin exhibited 70 to 80% reductions in INa and IK1 current densities, which were normalized by SB216763. Neonatal rat ventricular myocytes that expressed 2057del2 plakoglobin recapitulated pathobiological features seen in patients with ACM, all of which were reversed or prevented by SB216763. The reverse remodeling observed with SB216763 involved marked subcellular redistribution of plakoglobin, connexin 43, and Nav1.5, but without changes in their total cellular content, implicating a defect in protein trafficking to intercalated discs. In further support of this mechanism, we observed SB216763-reversible, abnormal subcellular distribution of SAP97 (a protein known to mediate forward trafficking of Nav1.5 and Kir2.1) in rat cardiac myocytes expressing 2057del2 plakoglobin and in cardiac myocytes derived from induced pluripotent stem cells from two ACM probands with plakophilin-2 mutations. These observations pinpoint aberrant trafficking of intercalated disc proteins as a central mechanism in ACM myocyte injury and electrical abnormalities. PMID:24920660

Combined atorvastatin and coenzyme Q10 improve the left ventricular function in isoproterenol-induced heart failure in rat.

PubMed

Garjani, Alireza; Andalib, Sina; Biabani, Sajjad; Soraya, Hamid; Doustar, Yousef; Garjani, Afagh; Maleki-Dizaji, Nasrin

2011-09-01

The effect of atorvastatin on cardiac remodeling, function, and homodynamic parameters in isoproterenol-induced heart failure was evaluated in the present study. A subcutaneous injection of isoproterenol (5mg/kg/day) for 10 days was used for the induction of heart failure. Isoproterenol administration produced intensive myocardial necrosis and fibrosis with a significant decrease in the arterial pressure indices, heart rate, contractility (LVdP/dt(max)) and relaxation (LVdP/dt(min)), but an increase in the left ventricular end-diastolic pressure. Rats were randomly assigned to control, treatment with only atorvastatin, and treatment with atorvastatin plus coenzyme Q10. Histopathological analysis showed a marked attenuation of myocyte necrosis and interstitial fibrosis in all atorvastatin treated groups (P<0.001). A low dose of atorvastatin (5mg/kg/day) significantly improved the left ventricular systolic pressure, contractility and relaxation (P<0.01). On the contrary, a high dose of atorvastatin (20mg/kg/day) worsened the isoproterenol-induced left ventricular dysfunction by a further reduction of LVdP/dt(max) from +2780 ± 94 to +1588 ± 248 (mmHg/s; P<0.01) and LVdP/dt(min) from -2007 ± 190 to -2939 ± 291 (mmHg/s; P<0.05). Co-administration of coenzyme Q10 with atorvastatin reversed the hemodynamic depression and the left ventricular dysfunction to a high level (P<0.001). There was a lower level of LVEDPs in the atorvastatin+coenzyme Q10 treated groups (3 ± 1 and 4 ± 1.4 versus 8 ± 3.5 and 14 ± 3.6 mmHg, respectively), thereby suggesting improvement in the myocardial stiffness by the combined coenzyme Q10 and atorvastatin treatment. The atorvastatin therapy attenuated myocardial necrosis and fibrosis in isoproterenol-induced heart failure. However, a high dose of the drug considerably worsened the left ventricular dysfunction and hemodynamic depression, which was reversed by coenzyme Q10 co-administration. Copyright © 2011 Elsevier B.V. All rights reserved.

Perinatal outcomes associated with abnormal cardiac remodeling in women with treated chronic hypertension.

PubMed

Ambia, Anne M; Morgan, Jamie L; Wells, C Edward; Roberts, Scott W; Sanghavi, Monika; Nelson, David B; Cunningham, F Gary

2018-05-01

Adverse maternal outcomes associated with chronic hypertension include accelerated hypertension and resultant target organ damage. One example is long-standing hypertension leading to maternal cardiac dysfunction. Our group has previously identified that features of such injury manifest as cardiac remodeling with left ventricular hypertrophy. Moreover, these features of cardiac remodeling identified in women with chronic hypertension during pregnancy were associated with adverse perinatal outcomes. Recent definitions of maternal cardiac remodeling using echocardiography have been expanded to include measurements of wall thickness. We hypothesized that these new features characterizing cardiac remodeling in women with chronic hypertension may also be associated with adverse perinatal outcomes. There were 3 aims in this study of women with treated chronic hypertension during pregnancy: to (1) apply the updated definitions of maternal cardiac remodeling; (2) elucidate whether these features of cardiac remodeling were associated with adverse perinatal outcomes; and (3) determine which, if any, of the newly defined cardiac remodeling strata were most damaging when compared to women with normal cardiac geometry. This was a retrospective study of women with treated chronic hypertension during pregnancy delivered from January 2009 through January 2016. Cardiac remodeling was categorized by left ventricular mass index and relative wall thickness into 4 groups determined using the 2015 American Society of Echocardiography guidelines: normal geometry, concentric remodeling, eccentric hypertrophy, and concentric hypertrophy. Perinatal outcomes were analyzed according to each category of cardiac remodeling compared with outcomes in women with normal geometry. A total of 314 women with treated chronic hypertension underwent echocardiography at a mean gestational age of 17.9 weeks. There were no differences between maternal age (P = .896), habitus (P = .36), or duration of chronic hypertension (P = .212) among the 4 groups. Abnormal cardiac remodeling was found in 51% and was significantly associated with increased rates of superimposed preeclampsia (P = .015), preterm birth (P < .001), and neonatal intensive care admission (P = .003). These outcomes reached the greatest significance when comparisons were made between eccentric hypertrophy and normal geometry. Using current American Society of Echocardiography guidelines, 51% of women with treated chronic hypertension during pregnancy have some degree of abnormal cardiac remodeling. Any suggestion of maternal cardiac remodeling, regardless of subtype, was associated with increased risks for superimposed preeclampsia and preterm birth with its resultant perinatal sequelae. Eccentric ventricular hypertrophy, previously thought to mimic exercise physiology, appears to be the most associated with adverse perinatal outcomes. Despite evidence of cardiac remodeling, ejection fraction was preserved. Copyright © 2018 Elsevier Inc. All rights reserved.

[Role of cyclic adenosine monophosphate response element binding protein in ventricular pacing induced cardiac electrical remodeling in a canine model].

PubMed

Chen, Xuesi; Chen, Xingxing; Cheng, Junhua; Hong, Jun; Zheng, Cheng; Zhao, Jinglin; Li, Jin; Lin, Jiafeng

2015-04-01

This project is designed to explore the potential role of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) in cardiac electrical remodeling induced by pacing at different ventricular positions in dogs. An animal model by implanting the pacemakers in beagles was established. According to the different pacing positions, the animals were divided into 4 groups:conditional control group (n=6), left ventricle pacing group (n=6), right ventricle pacing group (n=6) and bi-ventricle pacing group (n=6). Cardiac and electrical remodeling were observed by echocardiography, electrocardiogram and plasma BNP. Myocardial pathology and protein expression of extracellular regulated protein kinases1/2 (ERK1/2), P38 mitogen activated protein kinases (P38 MAPK) and CREB were examined at 4 weeks post pacing. Cardiac structure and plasma BNP level were similar among 4 groups (all P>0.05). Electrocardiogram derived Tp-Te interval was significantly prolonged post pacing (92±11, 91±10, and 79±13 ms vs. 60±12 ms), and the Tp-Te interval in bi-ventricle pacing group was shorter than in left or right ventricle pacing group (P < 0.05). Western blot results showed that the expression of p-ERK1/2 in left ventricular myocardium of left ventricle pacing group, right ventricular myocardium of right ventricle pacing group and bi-ventricular myocardium of bi-ventricle pacing group was 2.7±0.4, 2.4±0.2, 1.7±0.1 and 1.9±0.2, respectively, the expression of p-P38 MAPK was 1.9±0.3, 1.7±0.2, 0.8±0.1 and 1.1±0.1, respectively, and the expression of p-CREB was 2.1±0.2, 2.0±0.2, 2.7±0.4 and 2.6±0.3, respectively. The p-ERK1/2 and p-P38 MAPK expression of bi-ventricle pacing group was lower,but the p-CREB expression was higher compared to the other pacing groups (P < 0.05). Ventricular pacing could induce electrical remodeling evidenced by prolonged Tp-Te interval and increased phosphorylation of ERK1/2 and p38 MAPK and reduced phosphorylation of CREB. Compared with single ventricle pacing, bi-ventricle pacing could attenuate electrical remodeling in this model.

Evaluation of right ventricular remodeling using cardiac magnetic resonance imaging in co-existent chronic obstructive pulmonary disease and obstructive sleep apnea.

PubMed

Sharma, Bhavneesh; Neilan, Tomas G; Kwong, Raymond Y; Mandry, Damien; Owens, Robert L; McSharry, David; Bakker, Jessie P; Malhotra, Atul

2013-02-01

Untreated chronic obstructive pulmonary disease (COPD) co-existing with obstructive sleep apnea (OSA), also known as overlap syndrome, has higher cardiovascular mortality than COPD alone but its underlying mechanism remains unclear. We hypothesize that the presence of overlap syndrome is associated with more extensive right ventricular (RV) remodeling compared to patients with COPD alone. Adult COPD patients (GOLD stage 2 or higher) with at least 10 pack-years of smoking history were included. Overnight laboratory-based polysomnography was performed to test for OSA. Subjects with an apnea-hypopnea index (AHI) >10/h were classified as having overlap syndrome (n = 7), else classified as having COPD-only (n = 11). A cardiac MRI was performed to assess right and left cardiac chambers sizes, ventricular masses, and cine function. RV mass index (RVMI) was markedly higher in the overlap group than the COPD-only group (19 ± 6 versus 11 ± 6; p = 0.02). Overlap syndrome subjects had a reduced RV remodeling index (defined as the ratio between RVMI and RV end-diastolic volume index) compared to the COPD-only group (0.27 ± 0.06 versus 0.18 ± 0.08; p = 0.02). In the overlap syndrome subjects, the extent of RV remodeling was associated with severity of oxygen desaturation (R(2) = 0.65, p = 0.03). Our pilot results suggest that untreated overlap syndrome may cause more extensive RV remodeling than COPD alone.

Muscle remodeling in relation to blood supply: implications for seasonal changes in mitochondrial enzymes.

PubMed

McClelland, G B; Dalziel, A C; Fragoso, N M; Moyes, C D

2005-02-01

We investigated if seasonal changes in rainbow trout muscle energetics arise in response to seasonal changes in erythrocyte properties. We assessed if skeletal muscle mitochondrial enzymes changed (1) acutely in response to changes in erythrocyte abundance, or (2) seasonally when we altered the age profile of erythrocytes. Rainbow trout were treated with pheynylhydrazine, causing a 75% reduction in hematocrit within 4 days. After erythropoiesis had returned hematocrit to normal, treated and control fish were subjected to a seasonal cold acclimation regime to assess the impact of erythrocyte age on skeletal muscle remodeling. Anemia (i.e. phenylhydrazine treatment) did not alter the specific activities (U g(-1) tissue) of mitochondrial enzymes in white or red muscle. Anemic pretreatment did not alter the normal pattern of cold-induced mitochondrial proliferation in skeletal muscle, suggesting erythrocyte age was not an important influence on seasonal remodeling of muscle. Anemia and cold acclimation both induced a 25-30% increase in relative ventricular mass. The increase in relative ventricular mass with phenylhydrazine treatment was accompanied by a 35% increase in DNA content (mg DNA per ventricle), suggesting an increase in number of cells. In contrast, the increase in ventricular mass with cold temperature acclimation occurred without a change in DNA content (mg DNA per ventricle), suggesting an increase in cell size. Despite the major increases in relative ventricular mass, neither anemia nor seasonal acclimation had a major influence on the specific activities of a suite of mitochondrial enzymes in heart. Collectively, these studies argue against a role for erythrocyte dynamics in seasonal adaptive remodeling of skeletal muscle energetics.

Cellular Plasticity in the Diabetic Myocardium

DTIC Science & Technology

2017-09-01

demonstrated that obese diabetic db/db mice in a C57Bl6J background exhibit cardiac remodeling, associated with modest ventricular dilation...HFpEF, the cellular basis for fibrotic remodeling of the ventricle is poorly understood. Metabolic diseases (such as obesity and diabetes) are

Dilation and Hypertrophy: A Cell-Based Continuum Mechanics Approach Towards Ventricular Growth and Remodeling

NASA Astrophysics Data System (ADS)

Ulerich, J.; Göktepe, S.; Kuhl, E.

This manuscript presents a continuum approach towards cardiac growth and remodeling that is capable to predict chronic maladaptation of the heart in response to changes in mechanical loading. It is based on the multiplicative decomposition of the deformation gradient into and elastic and a growth part. Motivated by morphological changes in cardiomyocyte geometry, we introduce an anisotropic growth tensor that can capture both hypertrophic wall thickening and ventricular dilation within one generic concept. In agreement with clinical observations, we propose wall thickening to be a stress-driven phenomenon whereas dilation is introduced as a strain-driven process. The features of the proposed approach are illustrated in terms of the adaptation of thin heart slices and in terms overload-induced dilation in a generic bi-ventricular heart model.

Biomechanics of Cardiac Function

PubMed Central

Voorhees, Andrew P.; Han, Hai-Chao

2015-01-01

The heart pumps blood to maintain circulation and ensure the delivery of oxygenated blood to all the organs of the body. Mechanics play a critical role in governing and regulating heart function under both normal and pathological conditions. Biological processes and mechanical stress are coupled together in regulating myocyte function and extracellular matrix structure thus controlling heart function. Here we offer a brief introduction to the biomechanics of left ventricular function and then summarize recent progress in the study of the effects of mechanical stress on ventricular wall remodeling and cardiac function as well as the effects of wall mechanical properties on cardiac function in normal and dysfunctional hearts. Various mechanical models to determine wall stress and cardiac function in normal and diseased hearts with both systolic and diastolic dysfunction are discussed. The results of these studies have enhanced our understanding of the biomechanical mechanism in the development and remodeling of normal and dysfunctional hearts. Biomechanics provide a tool to understand the mechanism of left ventricular remodeling in diastolic and systolic dysfunction and guidance in designing and developing new treatments. PMID:26426462

Rationale and methods of the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF).

PubMed

Januzzi, James L; Butler, Javed; Fombu, Emmanuel; Maisel, Alan; McCague, Kevin; Piña, Ileana L; Prescott, Margaret F; Riebman, Jerome B; Solomon, Scott

2018-05-01

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor indicated for the treatment of patients with chronic heart failure (HF) with reduced ejection fraction; however, its mechanism of benefit remains unclear. Biomarkers that are linked to ventricular remodeling, myocardial injury, and fibrosis may provide mechanistic insight and important clinical guidance regarding sacubitril/valsartan use. This 52-week, multicenter, open-label, single-arm study is designed to (1) correlate biomarker changes with cardiac remodeling parameters, cardiovascular outcomes, and patient-reported outcome data and (2) determine short- and long-term changes in concentrations of biomarkers related to potential mechanisms of action and effects of sacubitril/valsartan therapy. Approximately 830 patients with HF with reduced ejection fraction will be initiated and titrated on sacubitril/valsartan according to United States prescribing information. Primary efficacy end points include the changes in N-terminal pro-B-type natriuretic peptide concentrations and cardiac remodeling from baseline to 1 year. Secondary end points include changes in concentrations of N-terminal pro-B-type natriuretic peptide and remodeling to 6 months, and changes in patient-reported outcomes using the Kansas City Cardiomyopathy Questionnaire-23 from baseline to 1 year. In addition, several other relevant biomarkers will be measured. Biomarker changes relative to the number of cardiovascular events in 12 months will also be assessed as exploratory end points. Results from the Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure (PROVE-HF) will help establish a mechanistic understanding of angiotensin receptor-neprilysin inhibitor therapeutic benefits and provide clinicians with clarity on how to interpret information on biomarkers during treatment (PROVE-HF ClinicalTrials.gov identifier: NCT02887183). Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Impact of aerobic interval training and continuous training on left ventricular geometry and function: a SAINTEX-CAD substudy.

PubMed

Van De Heyning, Caroline M; De Maeyer, Catherine; Pattyn, Nele; Beckers, Paul J; Cornelissen, Véronique A; Goetschalckx, Kaatje; Possemiers, Nadine; Van Craenenbroeck, Emeline M; Voigt, Jens-Uwe; Vanhees, Luc; Shivalkar, Bharati

2018-04-15

Increase of exercise capacity (peak VO 2 ) after cardiac rehabilitation improves outcome in patients with coronary artery disease (CAD). Systolic and diastolic function have been associated with peak VO 2 , but their role towards improvement of exercise capacity remains unclear. It is unknown which exercise intensity has the most beneficial impact on left ventricular (LV) geometry and function in CAD patients without heart failure. 200 stable CAD patients without heart failure were randomized to 3months of aerobic interval training (AIT) or aerobic continuous training (ACT). Cardiopulmonary exercise test and transthoracic echocardiography were scheduled before and after 3months of training. At baseline, a higher peak VO 2 correlated with lower LV posterior wall thickness (p=0.002), higher LV ejection fraction (p=0.008), better LV global longitudinal strain (p=0.043) and lower E/e' (0=0.001). After multivariate stepwise regression analysis only E/é remained an independent predictor of peak VO 2 (p=0.042). Improvement of peak VO 2 after 3months of training correlated with reverse remodeling of the interventricular septum (p=0.005), enlargement of LV diastolic volume (p=0.007) and increase of LV stroke volume (p=0.018) but not with other indices of systolic or diastolic function. Significant reduction of the interventricular septum thickness after cardiac rehabilitation was observed (p=0.012), with a trend towards more reverse remodeling after ACT compared to AIT (p=0.054). In contrast, there were no changes in other parameters of LV geometry, diastolic or systolic function. Systolic and diastolic function are determinants of baseline exercise capacity in CAD patients without heart failure, but do not seem to mediate improvement of peak VO 2 after either AIT or ACT. Copyright © 2017 Elsevier B.V. All rights reserved.

Systems Biology and Biomechanical Model of Heart Failure

PubMed Central

Louridas, George E; Lourida, Katerina G

2012-01-01

Heart failure is seen as a complex disease caused by a combination of a mechanical disorder, cardiac remodeling and neurohormonal activation. To define heart failure the systems biology approach integrates genes and molecules, interprets the relationship of the molecular networks with modular functional units, and explains the interaction between mechanical dysfunction and cardiac remodeling. The biomechanical model of heart failure explains satisfactorily the progression of myocardial dysfunction and the development of clinical phenotypes. The earliest mechanical changes and stresses applied in myocardial cells and/or myocardial loss or dysfunction activate left ventricular cavity remodeling and other neurohormonal regulatory mechanisms such as early release of natriuretic peptides followed by SAS and RAAS mobilization. Eventually the neurohormonal activation and the left ventricular remodeling process are leading to clinical deterioration of heart failure towards a multi-organic damage. It is hypothesized that approaching heart failure with the methodology of systems biology we promote the elucidation of its complex pathophysiology and most probably we can invent new therapeutic strategies. PMID:22935019

Improved pulmonary vascular reactivity and decreased hypertrophic remodeling during nonhypercapnic acidosis in experimental pulmonary hypertension

PubMed Central

Christou, Helen; Reslan, Ossama M.; Mam, Virak; Tanbe, Alain F.; Vitali, Sally H.; Touma, Marlin; Arons, Elena; Mitsialis, S. Alex; Kourembanas, Stella

2012-01-01

Pulmonary hypertension (PH) is characterized by pulmonary arteriolar remodeling with excessive pulmonary vascular smooth muscle cell (VSMC) proliferation. This results in decreased responsiveness of pulmonary circulation to vasodilator therapies. We have shown that extracellular acidosis inhibits VSMC proliferation and migration in vitro. Here we tested whether induction of nonhypercapnic acidosis in vivo ameliorates PH and the underlying pulmonary vascular remodeling and dysfunction. Adult male Sprague-Dawley rats were exposed to hypoxia (8.5% O2) for 2 wk, or injected subcutaneously with monocrotaline (MCT, 60 mg/kg) to develop PH. Acidosis was induced with NH4Cl (1.5%) in the drinking water 5 days prior to and during the 2 wk of hypoxic exposure (prevention protocol), or after MCT injection from day 21 to 28 (reversal protocol). Right ventricular systolic pressure (RVSP) and Fulton's index were measured, and pulmonary arteriolar remodeling was analyzed. Pulmonary and mesenteric artery contraction to phenylephrine (Phe) and high KCl, and relaxation to acetylcholine (ACh) and sodium nitroprusside (SNP) were examined ex vivo. Hypoxic and MCT-treated rats demonstrated increased RVSP, Fulton's index, and pulmonary arteriolar thickening. In pulmonary arteries of hypoxic and MCT rats there was reduced contraction to Phe and KCl and reduced vasodilation to ACh and SNP. Acidosis prevented hypoxia-induced PH, reversed MCT-induced PH, and resulted in reduction in all indexes of PH including RVSP, Fulton's index, and pulmonary arteriolar remodeling. Pulmonary artery contraction to Phe and KCl was preserved or improved, and relaxation to ACh and SNP was enhanced in NH4Cl-treated PH animals. Acidosis alone did not affect the hemodynamics or pulmonary vascular function. Phe and KCl contraction and ACh and SNP relaxation were not different in mesenteric arteries of all groups. Thus nonhypercapnic acidosis ameliorates experimental PH, attenuates pulmonary arteriolar thickening, and enhances pulmonary vascular responsiveness to vasoconstrictor and vasodilator stimuli. Together with our finding that acidosis decreases VSMC proliferation, the results are consistent with the possibility that nonhypercapnic acidosis promotes differentiation of pulmonary VSMCs to a more contractile phenotype, which may enhance the effectiveness of vasodilator therapies in PH. PMID:22287610

Possible mechanism by which renal sympathetic denervation improves left ventricular remodelling after myocardial infarction.

PubMed

Zheng, Xiao-Xin; Li, Xiao-Yan; Lyu, Yong-Nan; He, Yi-Yu; Wan, Wei-Guo; Zhu, Hong-Ling; Jiang, Xue-Jun

2016-02-01

What is the central question of this study? The enzyme system that is responsible for extracellular matrix (ECM) turnover is the matrix metalloproteinases (MMPs), which can be blocked by the tissue inhibitors of MMPs (TIMPs). Whether renal sympathetic denervation (RSD) is able to ameliorate post-myocardial infarction left ventricular remodelling through attenuation of ECM via regulation of MMP activity and/or the MMP-TIMP complex remains unknown. What is the main finding and its importance? Renal sympathetic denervation has therapeutic effects on post-myocardial infarction left ventricular remodelling, probably by attenuating the ECM through regulation of the MMP9-TIMP1 complex in the transforming growth factor-β1 (a profibrotic cytokine that accelerates ECM remodelling after ischaemia) signalling pathway. Whether renal sympathetic denervation (RSD) is able to ameliorate post-myocardial infarction (post-MI) left ventricular (LV) remodelling by attenuation of the extracellular matrix via regulation of matrix metalloproteinase (MMP) activity and/or the MMP-tissue inhibitor of matrix metalloproteinase (TIMP) complex remains unknown. Sixty-five Sprague-Dawley rats were randomly divided into the following four groups: normal (N, n = 15), RSD (RSD, n = 15), myocardial infarction (MI, n = 15) and RSD 3 days after MI (MI3d+RSD, n = 20). The bilateral renal nerves were surgically denervated 3 days after MI had been induced by coronary artery ligation. Left ventricular function was assessed using echocardiography and a Millar catheter at 6 weeks post-MI. Plasma noradrenaline, angiotensin II and aldosterone, collagen volume fraction, transforming growth factor-β1 (TGF-β1), MMP2, MMP9 and TIMP1 in heart tissue were measured 6 weeks after MI. In rats with MI3d+RSD compared with MI rats, RSD improved systolic and diastolic function, resulting in an improvement in ejection fraction (P < 0.05), fractional shortening (P < 0.05) and LV internal dimension in systole (P < 0.05) and diastole (P < 0.05). Additionally, RSD treatment decreased left ventricular end-diastolic pressure (P < 0.05) and increased LV systolic pressure (P < 0.05) and maximal and minimal rate of LV pressure (both P < 0.05). Meanwhile, RSD reduced collagen content (P < 0.01). TIMP1 was upregulated (P < 0.05), whereas MMP2, MMP9 and TGF-β1 were downregulated in the LV of RSD-treated animals (P < 0.05). Renal sympathetic denervation has therapeutic effects on post-MI LV remodelling, probably owing to effects on the extracellular matrix by regulation of the MMP9-TIMP1 balance in the TGF-β1 signalling pathway. Renal sympathetic denervation may be considered as a non-pharmacological approach for the improvement of post-MI cardiac dysfunction. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Fibroblasts and the extracellular matrix in right ventricular disease.

PubMed

Frangogiannis, Nikolaos G

2017-10-01

Right ventricular failure predicts adverse outcome in patients with pulmonary hypertension (PH), and in subjects with left ventricular heart failure and is associated with interstitial fibrosis. This review manuscript discusses the cellular effectors and molecular mechanisms implicated in right ventricular fibrosis. The right ventricular interstitium contains vascular cells, fibroblasts, and immune cells, enmeshed in a collagen-based matrix. Right ventricular pressure overload in PH is associated with the expansion of the fibroblast population, myofibroblast activation, and secretion of extracellular matrix proteins. Mechanosensitive transduction of adrenergic signalling and stimulation of the renin-angiotensin-aldosterone cascade trigger the activation of right ventricular fibroblasts. Inflammatory cytokines and chemokines may contribute to expansion and activation of macrophages that may serve as a source of fibrogenic growth factors, such as transforming growth factor (TGF)-β. Endothelin-1, TGF-βs, and matricellular proteins co-operate to activate cardiac myofibroblasts, and promote synthesis of matrix proteins. In comparison with the left ventricle, the RV tolerates well volume overload and ischemia; whether the right ventricular interstitial cells and matrix are implicated in these favourable responses remains unknown. Expansion of fibroblasts and extracellular matrix protein deposition are prominent features of arrhythmogenic right ventricular cardiomyopathies and may be implicated in the pathogenesis of arrhythmic events. Prevailing conceptual paradigms on right ventricular remodelling are based on extrapolation of findings in models of left ventricular injury. Considering the unique embryologic, morphological, and physiologic properties of the RV and the clinical significance of right ventricular failure, there is a need further to dissect RV-specific mechanisms of fibrosis and interstitial remodelling. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Impact of cardiac support device combined with slow-release prostacyclin agonist in a canine ischemic cardiomyopathy model.

PubMed

Kubota, Yasuhiko; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Watabe, Hiroshi; Daimon, Takashi; Sakai, Yoshiki; Akita, Toshiaki; Sawa, Yoshiki

2014-03-01

The cardiac support device supports the heart and mechanically reduces left ventricular (LV) diastolic wall stress. Although it has been shown to halt LV remodeling in dilated cardiomyopathy, its therapeutic efficacy is limited by its lack of biological effects. In contrast, the slow-release synthetic prostacyclin agonist ONO-1301 enhances reversal of LV remodeling through biological mechanisms such as angiogenesis and attenuation of fibrosis. We therefore hypothesized that ONO-1301 plus a cardiac support device might be beneficial for the treatment of ischemic cardiomyopathy. Twenty-four dogs with induced anterior wall infarction were assigned randomly to 1 of 4 groups at 1 week postinfarction as follows: cardiac support device alone, cardiac support device plus ONO-1301 (hybrid therapy), ONO-1301 alone, or sham control. At 8 weeks post-infarction, LV wall stress was reduced significantly in the hybrid therapy group compared with the other groups. Myocardial blood flow, measured by positron emission tomography, and vascular density were significantly higher in the hybrid therapy group compared with the cardiac support device alone and sham groups. The hybrid therapy group also showed the least interstitial fibrosis, the greatest recovery of LV systolic and diastolic functions, assessed by multidetector computed tomography and cardiac catheterization, and the lowest plasma N-terminal pro-B-type natriuretic peptide levels (P < .05). The combination of a cardiac support device and the prostacyclin agonist ONO-1301 elicited a greater reversal of LV remodeling than either treatment alone, suggesting the potential of this hybrid therapy for the clinical treatment of ischemia-induced heart failure. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Age-associated Pro-inflammatory Remodeling and Functional Phenotype in the Heart and Large Arteries

PubMed Central

Wang, Mingyi; Shah, Ajay M

2015-01-01

The aging population is increasing dramatically. Aging–associated stress simultaneously drives proinflammatory remodeling, involving angiotensin II and other factors, in both the heart and large arteries. The structural remodeling and functional changes that occur with aging include cardiac and vascular wall stiffening, systolic hypertension and suboptimal ventricular-arterial coupling, features that are often clinically silent and thus termed a silent syndrome. These age-related effects are the result of responses initiated by cardiovascular proinflammatory cells. Local proinflammatory signals are coupled between the heart and arteries due to common mechanical and humoral messengers within a closed circulating system. Thus, targeting proinflammatory signaling molecules would be a promising approach to improve age-associated suboptimal ventricular-arterial coupling, a major predisposing factor for the pathogenesis of clinical cardiovascular events such as heart failure. PMID:25665458

Left ventricular remodeling in the post-infarction heart: a review of cellular, molecular mechanisms, and therapeutic modalities.

PubMed

Gajarsa, Jason J; Kloner, Robert A

2011-01-01

As more patients survive myocardial infarctions, the incidence of heart failure increases. After an infarction, the human heart undergoes a series of structural changes, which are governed by cellular and molecular mechanisms in a pathological metamorphosis termed "remodeling." This review will discuss the current developments in our understanding of these molecular and cellular events in remodeling and the various pharmacological, cellular and device therapies used to treat, and potentially retard, this condition. Specifically, this paper will examine the neurohormonal activity of the renin-angiotensin-aldosterone axis and its molecular effects on the heart. The emerging understanding of the extra-cellular matrix and the various active molecules within it, such as the matrix metalloproteinases, elicits new appreciation for their role in cardiac remodeling and as possible future therapeutic targets. Cell therapy with stem cells is another recent therapy with great potential in improving post-infarcted hearts. Lastly, the cellular and molecular effects of left ventricular assist devices on remodeling will be reviewed. Our increasing knowledge of the cellular and molecular mechanisms underlying cardiac remodeling enables us not only to better understand how our more successful therapies, like angiotensin-converting enzyme inhibitors, work, but also to explore new therapies of the future.

Rapamycin nanoparticles localize in diseased lung vasculature and prevent pulmonary arterial hypertension.

PubMed

Segura-Ibarra, Victor; Amione-Guerra, Javier; Cruz-Solbes, Ana S; Cara, Francisca E; Iruegas-Nunez, David A; Wu, Suhong; Youker, Keith A; Bhimaraj, Arvind; Torre-Amione, Guillermo; Ferrari, Mauro; Karmouty-Quintana, Harry; Guha, Ashrith; Blanco, Elvin

2017-05-30

Vascular remodeling resulting from pulmonary arterial hypertension (PAH) leads to endothelial fenestrations. This feature can be exploited by nanoparticles (NP), allowing them to extravasate from circulation and accumulate in remodeled pulmonary vessels. Hyperactivation of the mTOR pathway in PAH drives pulmonary arterial smooth muscle cell proliferation. We hypothesized that rapamycin (RAP)-loaded NPs, an mTOR inhibitor, would accumulate in diseased lungs, selectively targeting vascular mTOR and preventing PAH progression. RAP poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-PCL) NPs were fabricated. NP accumulation and efficacy were examined in a rat monocrotaline model of PAH. Following intravenous (IV) administration, NP accumulation in diseased lungs was verified via LC/MS analysis and confocal imaging. Pulmonary arteriole thickness, right ventricular systolic pressures, and ventricular remodeling were determined to assess the therapeutic potential of RAP NPs. Monocrotaline-exposed rats showed increased NP accumulation within lungs compared to healthy controls, with NPs present to a high extent within pulmonary perivascular regions. RAP, in both free and NP form, attenuated PAH development, with histological analysis revealing minimal changes in pulmonary arteriole thickness and no ventricular remodeling. Importantly, NP-treated rats showed reduced systemic side effects compared to free RAP. This study demonstrates the potential for nanoparticles to significantly impact PAH through site-specific delivery of therapeutics. Copyright © 2017 Elsevier B.V. All rights reserved.

Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation.

PubMed

Stembridge, Mike; Ainslie, Philip N; Hughes, Michael G; Stöhr, Eric J; Cotter, James D; Nio, Amanda Q X; Shave, Rob

2014-08-01

Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function. Copyright © 2014 the American Physiological Society.

Ventricular structure, function, and mechanics at high altitude: chronic remodeling in Sherpa vs. short-term lowlander adaptation

PubMed Central

Ainslie, Philip N.; Hughes, Michael G.; Stöhr, Eric J.; Cotter, James D.; Nio, Amanda Q. X.; Shave, Rob

2014-01-01

Short-term, high-altitude (HA) exposure raises pulmonary artery systolic pressure (PASP) and decreases left-ventricular (LV) volumes. However, relatively little is known of the long-term cardiac consequences of prolonged exposure in Sherpa, a highly adapted HA population. To investigate short-term adaptation and potential long-term cardiac remodeling, we studied ventricular structure and function in Sherpa at 5,050 m (n = 11; 31 ± 13 yr; mass 68 ± 10 kg; height 169 ± 6 cm) and lowlanders at sea level (SL) and following 10 ± 3 days at 5,050 m (n = 9; 34 ± 7 yr; mass 82 ± 10 kg; height 177 ± 6 cm) using conventional and speckle-tracking echocardiography. At HA, PASP was higher in Sherpa and lowlanders compared with lowlanders at SL (both P < 0.05). Sherpa had smaller right-ventricular (RV) and LV stroke volumes than lowlanders at SL with lower RV systolic strain (P < 0.05) but similar LV systolic mechanics. In contrast to LV systolic mechanics, LV diastolic, untwisting velocity was significantly lower in Sherpa compared with lowlanders at both SL and HA. After partial acclimatization, lowlanders demonstrated no change in the RV end-diastolic area; however, both RV strain and LV end-diastolic volume were reduced. In conclusion, short-term hypoxia induced a reduction in RV systolic function that was also evident in Sherpa following chronic exposure. We propose that this was consequent to a persistently higher PASP. In contrast to the RV, remodeling of LV volumes and normalization of systolic mechanics indicate structural and functional adaptation to HA. However, altered LV diastolic relaxation after chronic hypoxic exposure may reflect differential remodeling of systolic and diastolic LV function. PMID:24876358

Remote Zone Extracellular Volume and Left Ventricular Remodeling in Survivors of ST-Elevation Myocardial Infarction.

PubMed

Carberry, Jaclyn; Carrick, David; Haig, Caroline; Rauhalammi, Samuli M; Ahmed, Nadeem; Mordi, Ify; McEntegart, Margaret; Petrie, Mark C; Eteiba, Hany; Hood, Stuart; Watkins, Stuart; Lindsay, Mitchell; Davie, Andrew; Mahrous, Ahmed; Ford, Ian; Sattar, Naveed; Welsh, Paul; Radjenovic, Aleksandra; Oldroyd, Keith G; Berry, Colin

2016-08-01

The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10-2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling. URL: https://www.clinicaltrials.gov. Unique identifier: NCT02072850. © 2016 The Authors.

Remote Zone Extracellular Volume and Left Ventricular Remodeling in Survivors of ST-Elevation Myocardial Infarction

PubMed Central

Carberry, Jaclyn; Carrick, David; Haig, Caroline; Rauhalammi, Samuli M.; Ahmed, Nadeem; Mordi, Ify; McEntegart, Margaret; Petrie, Mark C.; Eteiba, Hany; Hood, Stuart; Watkins, Stuart; Lindsay, Mitchell; Davie, Andrew; Mahrous, Ahmed; Ford, Ian; Sattar, Naveed; Welsh, Paul; Radjenovic, Aleksandra; Oldroyd, Keith G.

2016-01-01

The natural history and pathophysiological significance of tissue remodeling in the myocardial remote zone after acute ST-elevation myocardial infarction (STEMI) is incompletely understood. Extracellular volume (ECV) in myocardial regions of interest can now be measured with cardiac magnetic resonance imaging. Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI [British Heart Foundation Magnetic Resonance Imaging in Acute ST-Segment Elevation Myocardial Infarction study]). Cardiac magnetic resonance was performed at 1.5 Tesla at 2 days and 6 months post STEMI. T1 modified Look-Locker inversion recovery mapping was performed before and 15 minutes after contrast (0.15 mmol/kg gadoterate meglumine) in 140 patients at 2 days post STEMI (mean age: 59 years, 76% male) and in 131 patients at 6 months post STEMI. Remote zone ECV was lower than infarct zone ECV (25.6±2.8% versus 51.4±8.9%; P<0.001). In multivariable regression, left ventricular ejection fraction was inversely associated with remote zone ECV (P<0.001), and diabetes mellitus was positively associated with remote zone ECV (P=0.010). No ST-segment resolution (P=0.034) and extent of ischemic area at risk (P<0.001) were multivariable associates of the change in remote zone ECV at 6 months (ΔECV). ΔECV was a multivariable associate of the change in left ventricular end-diastolic volume at 6 months (regression coefficient [95% confidence interval]: 1.43 (0.10–2.76); P=0.036). ΔECV is implicated in the pathophysiology of left ventricular remodeling post STEMI, but because the effect size is small, ΔECV has limited use as a clinical biomarker of remodeling. Clinical Trial Registration— URL: https://www.clinicaltrials.gov. Unique identifier: NCT02072850. PMID:27354423

Microdomain-Specific Modulation of L-Type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure

PubMed Central

Sanchez-Alonso, Jose L.; Bhargava, Anamika; O’Hara, Thomas; Glukhov, Alexey V.; Schobesberger, Sophie; Bhogal, Navneet; Sikkel, Markus B.; Mansfield, Catherine; Korchev, Yuri E.; Lyon, Alexander R.; Punjabi, Prakash P.; Nikolaev, Viacheslav O.; Trayanova, Natalia A.

2016-01-01

Rationale: Disruption in subcellular targeting of Ca2+ signaling complexes secondary to changes in cardiac myocyte structure may contribute to the pathophysiology of a variety of cardiac diseases, including heart failure (HF) and certain arrhythmias. Objective: To explore microdomain-targeted remodeling of ventricular L-type Ca2+ channels (LTCCs) in HF. Methods and Results: Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore the distribution of single LTCCs in different membrane microdomains of nonfailing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to the redistribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability was dramatically increased (0.034±0.011 versus 0.154±0.027, P<0.001). High open probability was linked to enhance calcium–calmodulin kinase II–mediated phosphorylation in non-native microdomains and resulted in an elevated ICa,L window current, which contributed to the development of early afterdepolarizations. A novel model of LTCC function in HF was developed; after its validation with experimental data, the model was used to ascertain how HF-induced T-tubule loss led to altered LTCC function and early afterdepolarizations. The HF myocyte model was then implemented in a 3-dimensional left ventricle model, demonstrating that such early afterdepolarizations can propagate and initiate reentrant arrhythmias. Conclusions: Microdomain-targeted remodeling of LTCC properties is an important event in pathways that may contribute to ventricular arrhythmogenesis in the settings of HF-associated remodeling. This extends beyond the classical concept of electric remodeling in HF and adds a new dimension to cardiovascular disease. PMID:27572487

Effects of Baicalin on Blood Pressure and Left Ventricular Remodeling in Rats with Renovascular Hypertension

PubMed Central

Dai, Hualei; Zhang, Xinjin; Yang, Zhigang; Li, Jianmei; Zheng, Jialin

2017-01-01

Background This study aimed to explore the effect of baicalin, which is a kind of bioactive flavonoid, on blood pressure and left ventricular remodeling in rats with renovascular hypertension. Material/Methods A total of 40 male Wistar rats were randomly assigned into sham-operation (n=10) and renal hypertension model groups (2-kidney-1 clip; 2K-1C, n=30). The rats in the renal hypertension model group were randomly subdivided into 2K-1C (n=13) and 2K-1C/Baicalin groups (n=14). The cardiac function indexes were determined after 4 weeks. The morphological changes in the myocardial tissue were observed using hematoxylin and eosin and Masson staining. The myocardial apoptosis was detected using the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling method, and the expression of C/EBP homologous protein and caspase-3 was monitored by Western blot. The expression of GRP78 and GRP94 in myocardial cells of rats was detected by qPCR and Western blot technology. Results No significant change in blood pressure was observed in the 2K-1C/Baicalin group compared with the 2K-1C group, but the indexes of left ventricular remodeling significantly improved. Pathological myocardial fibrosis and expression of fibrosis-related factors significantly decreased in the 2K-1C/Baicalin group compared with the 2K-1C group. The expression of glucose-regulated protein (GRP)78, GRP94, CHOP, and caspase-3, and apoptosis of cardiomyocytes also decreased in the 2K-1C/Baicalin group. Conclusions Baicalin has no significant antihypertensive effect, but reduced pathological changes in the myocardium, alleviated endoplasmic reticulum stress, and reduced myocardial apoptosis, reverting left ventricular remodeling in rats with renovascular hypertension. PMID:28622281

Cannabinoid-induced actomyosin contractility shapes neuronal morphology and growth

PubMed Central

Roland, Alexandre B; Ricobaraza, Ana; Carrel, Damien; Jordan, Benjamin M; Rico, Felix; Simon, Anne; Humbert-Claude, Marie; Ferrier, Jeremy; McFadden, Maureen H; Scheuring, Simon; Lenkei, Zsolt

2014-01-01

Endocannabinoids are recently recognized regulators of brain development, but molecular effectors downstream of type-1 cannabinoid receptor (CB1R)-activation remain incompletely understood. We report atypical coupling of neuronal CB1Rs, after activation by endo- or exocannabinoids such as the marijuana component ∆9-tetrahydrocannabinol, to heterotrimeric G12/G13 proteins that triggers rapid and reversible non-muscle myosin II (NM II) dependent contraction of the actomyosin cytoskeleton, through a Rho-GTPase and Rho-associated kinase (ROCK). This induces rapid neuronal remodeling, such as retraction of neurites and axonal growth cones, elevated neuronal rigidity, and reshaping of somatodendritic morphology. Chronic pharmacological inhibition of NM II prevents cannabinoid-induced reduction of dendritic development in vitro and leads, similarly to blockade of endocannabinoid action, to excessive growth of corticofugal axons into the sub-ventricular zone in vivo. Our results suggest that CB1R can rapidly transform the neuronal cytoskeleton through actomyosin contractility, resulting in cellular remodeling events ultimately able to affect the brain architecture and wiring. DOI: http://dx.doi.org/10.7554/eLife.03159.001 PMID:25225054

Attenuation of cardiac fibrosis by pirfenidone and amiloride in DOCA-salt hypertensive rats

PubMed Central

Mirkovic, Stevo; Seymour, Anne-Marie L; Fenning, Andrew; Strachan, Anna; Margolin, Solomon B; Taylor, Stephen M; Brown, Lindsay

2002-01-01

This study has administered pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) or amiloride to attenuate the remodelling and associated functional changes, especially an increased cardiac stiffness, in DOCA-salt hypertensive rats. In control rats, the elimination half-life of pirfenidone following a single intravenous dose of 200 mg kg−1 was 37 min while oral bioavailability at this dose was 25.7%. Plasma pirfenidone concentrations in control rats averaged 1.9±0.1 μg ml−1 over 24 h after 14 days' administration as a 0.4% mixture in food. Pirfenidone (approximately 250 – 300 mg kg−1 day−1 as 0.4% in food) and amiloride (1 mg kg−1 day−1 sc) were administered for 2 weeks starting 2 weeks post-surgery. Pirfenidone but not amiloride attenuated ventricular hypertrophy (2.69±0.09, UNX 2.01±0.05. DOCA-salt 3.11±0.09 mg kg−1 body wt) without lowering systolic blood pressure. Collagen deposition was significantly increased in the interstitium after 2 weeks and further increased with scarring of the left ventricle after 4 weeks; pirfenidone and amiloride reversed the increases and prevented further increases. This accumulation of collagen was accompanied by an increase in diastolic stiffness constant; both amiloride and pirfenidone reversed this increase. Noradrenaline potency (positive chronotropy) was decreased in right atria (neg log EC50: control 6.92±0.06; DOCA-salt 6.64±0.08); pirfenidone but not amiloride reversed this change. Noradrenaline was a more potent vasoconstrictor in thoracic aortic rings (neg log EC50: control 6.91±0.10; DOCA-salt 7.90±0.07); pirfenidone treatment did not change noradrenaline potency. Thus, pirfenidone and amiloride reverse and prevent cardiac remodelling and the increased cardiac stiffness without reversing the increased vascular responses to noradrenaline. PMID:11861324

Prolonged intra-aortic balloon pump support in biventricular heart failure induces right ventricular reverse remodeling.

PubMed

Ntalianis, Argyrios; Kapelios, Chris J; Kanakakis, John; Repasos, Evangelos; Pantsios, Christos; Nana, Emmeleia; Kontogiannis, Christos; Malliaras, Konstantinos; Tsamatsoulis, Michael; Kaldara, Elisabeth; Charitos, Christos; Nanas, John N

2015-08-01

Right ventricular dysfunction is associated with high morbidity and mortality in candidates for left ventricular assist device (LVAD) implantation or cardiac transplantation. We examined the effects of prolonged intra-aortic balloon pump (IABP) support on right ventricular, renal and hepatic functions in patients presenting with end-stage heart failure. Between March 2008 and June 2013, fifteen patients (mean age = 49.5 years; 14 men) with end-stage systolic heart failure (HF), contraindications for any life saving procedure (conventional cardiac surgery, heart transplantation, LVAD implantation) and right ventricular dysfunction were supported with the IABP. The patients remained on IABP support for a mean of 73 ± 50 days (median 72, range of 13-155). We measured the echocardiographic and hemodynamic changes in right ventricular function, and the changes in serum creatinine and bilirubin concentrations before and during IABP support. Mean right atrial pressure decreased from 12.7 ± 6.5 to 3.8 ± 3.3 (P < 0.001) and pulmonary artery pressure decreased from 35.7 ± 10.6 to 25 ± 8.4 mmHg (P = 0.001), while cardiac index increased from 1.5 ± 0.4 to 2.2 ± 0.7 l/m(2)/min (P = 0.003) and right ventricular stroke work index from 485 ± 228 to 688 ± 237 mmHg × ml/m(2) (P = 0.043). Right ventricular end-diastolic diameter decreased from 34.0 ± 6.5 mm to 27.8 ± 6.2 mm (P < 0.001) and tricuspid annular systolic tissue Doppler velocity increased from 9.6 ± 2.4 cm/s to 11.1 ± 2.3 cm/s (P = 0.029). Serum creatinine and bilirubin decreased from 2.1 ± 1.3 to 1.4 ± 0.6 mg/dl and 2.0 ± 1.0 to 0.9 ± 0.5 mg/dl, respectively (P = 0.002 and P < 0.001, respectively). Prolonged IABP support of patients presenting with end-stage heart failure and right ventricular dysfunction induced significant improvement in right ventricular and peripheral organ function. Copyright © 2015. Published by Elsevier Ireland Ltd.

SOCS3

PubMed Central

Yasukawa, Hideo; Nagata, Takanobu; Oba, Toyoharu; Imaizumi, Tsutomu

2012-01-01

The suppressors of cytokine signaling (SOCS) family of proteins are cytokine-inducible inhibitors of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT) signaling pathways. Among the family, SOCS1 and SOCS3 potently suppress cytokine actions by inhibiting JAK kinase activities. The generation of mice lacking individual SOCS genes has been instrumental in defining the role of individual SOCS proteins in specific cytokine pathways in vivo; SOCS1 is an essential negative regulator of interferon-γ (IFNγ) and SOCS3 is an essential negative regulator of leukemia inhibitory factor (LIF). JAK-STAT3 activating cytokines have exhibited cardioprotective roles in the heart. The cardiac-specific deletion of SOCS3 enhances the activation of cardioprotective signaling pathways, inhibits myocardial apoptosis and fibrosis and results in the inhibition of left ventricular remodeling after myocardial infarction (MI). We propose that myocardial SOCS3 is a key determinant of left ventricular remodeling after MI, and SOCS3 may serve as a novel therapeutic target to prevent left ventricular remodeling after MI. In this review, we discuss the signaling pathways mediated by JAK-STAT and SOCS proteins and their roles in the development of myocardial injury under stress (e.g., pressure overload, viral infection and ischemia). PMID:24058778

Favorable Changes in Cardiac Geometry and Function Following Gastric Bypass Surgery

PubMed Central

Owan, Theophilus; Avelar, Erick; Morley, Kimberly; Jiji, Ronny; Hall, Nathaniel; Krezowski, Joseph; Gallagher, James; Williams, Zachary; Preece, Kevin; Gundersen, Nancy; Strong, Michael B.; Pendleton, Robert C.; Segerson, Nathan; Cloward, Tom V.; Walker, James M.; Farney, Robert J.; Gress, Richard E.; Adams, Ted D.; Hunt, Steven C.; Litwin, Sheldon E.

2013-01-01

Objectives The objective of this study was to test the hypothesis that gastric bypass surgery (GBS) would favorably impact cardiac remodeling and function. Background GBS is increasingly used to treat severe obesity, but there are limited outcome data. Methods We prospectively studied 423 severely obese patients undergoing GBS and a reference group of severely obese subjects that did not have surgery (n = 733). Results At a 2-year follow up, GBS subjects had a large reduction in body mass index compared with the reference group (−15.4 ± 7.2 kg/m2 vs. −0.03 ± 4.0 kg/m2; p < 0.0001), as well as significant reductions in waist circumference, systolic blood pressure, heart rate, triglycerides, low-density lipoprotein cholesterol, and insulin resistance. High-density lipoprotein cholesterol increased. The GBS group had reductions in left ventricular (LV) mass index and right ventricular (RV) cavity area. Left atrial volume did not change in GBS but increased in reference subjects. In conjunction with reduced chamber sizes, GBS subjects also had increased LV midwall fractional shortening and RV fractional area change. In multivariable analysis, age, change in body mass index, severity of nocturnal hypoxemia, E/E', and sex were independently associated with LV mass index, whereas surgical status, change in waist circumference, and change in insulin resistance were not. Conclusions Marked weight loss in patients undergoing GBS was associated with reverse cardiac remodeling and improved LV and RV function. These data support the use of bariatric surgery to prevent cardiovascular complications in severe obesity. PMID:21292133

Atlas-Based Ventricular Shape Analysis for Understanding Congenital Heart Disease.

PubMed

Farrar, Genevieve; Suinesiaputra, Avan; Gilbert, Kathleen; Perry, James C; Hegde, Sanjeet; Marsden, Alison; Young, Alistair A; Omens, Jeffrey H; McCulloch, Andrew D

2016-12-01

Congenital heart disease is associated with abnormal ventricular shape that can affect wall mechanics and may be predictive of long-term adverse outcomes. Atlas-based parametric shape analysis was used to analyze ventricular geometries of eight adolescent or adult single-ventricle CHD patients with tricuspid atresia and Fontans. These patients were compared with an "atlas" of non-congenital asymptomatic volunteers, resulting in a set of z-scores which quantify deviations from the control population distribution on a patient-by-patient basis. We examined the potential of these scores to: (1) quantify abnormalities of ventricular geometry in single ventricle physiologies relative to the normal population; (2) comprehensively quantify wall motion in CHD patients; and (3) identify possible relationships between ventricular shape and wall motion that may reflect underlying functional defects or remodeling in CHD patients. CHD ventricular geometries at end-diastole and end-systole were individually compared with statistical shape properties of an asymptomatic population from the Cardiac Atlas Project. Shape analysis-derived model properties, and myocardial wall motions between end-diastole and end-systole, were compared with physician observations of clinical functional parameters. Relationships between altered shape and altered function were evaluated via correlations between atlas-based shape and wall motion scores. Atlas-based shape analysis identified a diverse set of specific quantifiable abnormalities in ventricular geometry or myocardial wall motion in all subjects. Moreover, this initial cohort displayed significant relationships between specific shape abnormalities such as increased ventricular sphericity and functional defects in myocardial deformation, such as decreased long-axis wall motion. These findings suggest that atlas-based ventricular shape analysis may be a useful new tool in the management of patients with CHD who are at risk of impaired ventricular wall mechanics and chamber remodeling.

Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach.

PubMed

Iborra-Egea, Oriol; Gálvez-Montón, Carolina; Roura, Santiago; Perea-Gil, Isaac; Prat-Vidal, Cristina; Soler-Botija, Carolina; Bayes-Genis, Antoni

2017-01-01

Sacubitril/Valsartan, proved superiority over other conventional heart failure management treatments, but its mechanisms of action remains obscure. In this study, we sought to explore the mechanistic details for Sacubitril/Valsartan in heart failure and post-myocardial infarction remodeling, using an in silico, systems biology approach. Myocardial transcriptome obtained in response to myocardial infarction in swine was analyzed to address post-infarction ventricular remodeling. Swine transcriptome hits were mapped to their human equivalents using Reciprocal Best (blast) Hits, Gene Name Correspondence, and InParanoid database. Heart failure remodeling was studied using public data available in gene expression omnibus (accession GSE57345, subseries GSE57338), processed using the GEO2R tool. Using the Therapeutic Performance Mapping System technology, dedicated mathematical models trained to fit a set of molecular criteria, defining both pathologies and including all the information available on Sacubitril/Valsartan, were generated. All relationships incorporated into the biological network were drawn from public resources (including KEGG, REACTOME, INTACT, BIOGRID, and MINT). An artificial neural network analysis revealed that Sacubitril/Valsartan acts synergistically against cardiomyocyte cell death and left ventricular extracellular matrix remodeling via eight principal synergistic nodes. When studying each pathway independently, Valsartan was found to improve cardiac remodeling by inhibiting members of the guanine nucleotide-binding protein family, while Sacubitril attenuated cardiomyocyte cell death, hypertrophy, and impaired myocyte contractility by inhibiting PTEN. The complex molecular mechanisms of action of Sacubitril/Valsartan upon post-myocardial infarction and heart failure cardiac remodeling were delineated using a systems biology approach. Further, this dataset provides pathophysiological rationale for the use of Sacubitril/Valsartan to prevent post-infarct remodeling.

Relationship among LRP1 expression, Pyk2 phosphorylation and MMP-9 activation in left ventricular remodelling after myocardial infarction.

PubMed

Revuelta-López, Elena; Soler-Botija, Carol; Nasarre, Laura; Benitez-Amaro, Aleyda; de Gonzalo-Calvo, David; Bayes-Genis, Antoni; Llorente-Cortés, Vicenta

2017-09-01

Left ventricular (LV) remodelling after myocardial infarction (MI) is a crucial determinant of the clinical course of heart failure. Matrix metalloproteinase (MMP) activation is strongly associated with LV remodelling after MI. Elucidation of plasma membrane receptors related to the activation of specific MMPs is fundamental for treating adverse cardiac remodelling after MI. The aim of current investigation was to explore the potential association between the low-density lipoprotein receptor-related protein 1 (LRP1) and MMP-9 and MMP-2 spatiotemporal expression after MI. Real-time PCR and Western blot analyses showed that LRP1 mRNA and protein expression levels, respectively, were significantly increased in peri-infarct and infarct zones at 10 and 21 days after MI. Confocal microscopy demonstrated high colocalization between LRP1 and the fibroblast marker vimentin, indicating that LRP1 is mostly expressed by cardiac fibroblasts in peri-infarct and infarct areas. LRP1 also colocalized with proline-rich tyrosine kinase 2 (pPyk2) and MMP-9 in cardiac fibroblasts in ischaemic areas at 10 and 21 days after MI. Cell culture experiments revealed that hypoxia increases LRP1, pPyk2 protein levels and MMP-9 activity in fibroblasts, without significant changes in MMP-2 activity. MMP-9 activation by hypoxia requires LRP1 and Pyk2 phosphorylation in fibroblasts. Collectively, our in vivo and in vitro data support a major role of cardiac fibroblast LRP1 levels on MMP-9 up-regulation associated with ventricular remodelling after MI. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Association between atrial fibrillation, atrial enlargement, and left ventricular geometric remodeling.

PubMed

Seko, Yuta; Kato, Takao; Haruna, Tetsuya; Izumi, Toshiaki; Miyamoto, Shoichi; Nakane, Eisaku; Inoko, Moriaki

2018-04-23

This study investigated the relationship between atrial fibrillation (AF) and left ventricular (LV) geometric patterns in a hospital-based population in Japan. We retrospectively analyzed 4444 patients who had undergone simultaneous scheduled transthoracic echocardiography (TTE) and electrocardiography during 2013. A total of 430 patients who had findings of previous myocardial infarctions (n = 419) and without the data on body surface area (n = 11) were excluded from the study. We calculated the LV mass index (LVMI) and relative wall (RWT) and categorized 4014 patients into four groups as follows: normal geometry (n = 3046); concentric remodeling (normal LVMI and high RWT, n = 437); concentric hypertrophy (high LVMI and high RWT, n = 149); and eccentric remodeling (high LVMI and normal RWT, n = 382). The mean left atrial volume indices (LAVI) were 22.5, 23.8, 33.3, and 37.0 mm/m 2 in patients with normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, respectively. The mean LV ejection fractions (LVEF) were 62.7, 62.6, 60.8, and 53.8%, respectively, whereas the prevalence of AF was 10.4%, 10.5%, 14.8%, and 16.8% in patients with normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy, respectively. In conclusion, the prevalence of AF was increasing according to LV geometric remodeling patterns in association with LA size and LVEF.

[EFFICACY OF STANDARD TWO-YEAR COMPREHENSIVE THERAPY TO ACHIEVE TARGET BLOOD PRESSURE AND REGRESSION DEGREES OF REMODELING OF THE LEFT VENTRICULAR HYPERTROPHY IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION WITH COMORBID HYPERTENSION].

PubMed

Denesiuk, E V

2015-01-01

The study involved 23 men after acute myocardial infarction (AMI) with comorbid arterial hypertension (AH). Mean age of patients was 56.7 years. Recurrent myocardial infarction was determined in 38.4%, cardiac failure I-III functional classes--100% of the cases. All patients underwent clinical examination, electrocardiography and echocardiography, blood lipid profile. Standard comprehensive treatment for two years included an perindopril 5-10 mg/day, beta-blocker bisoprolol--5-10 mg/day, antisclerotic drug atorvastatin--20 mg/day and aspirin--75 mg/day. The patients after treatment was determined by a gradual increase towards the target of AT at 3, 6 and 12 to 24 months. Concentric left ventricular hypertrophy (LVH) before treatment was determined in 47.8%, eccentric--in 52.2% of patients. In the study of degrees of LVH I (initial) the extent to treatment was determined by 4.3%, II (moderate)--26.1%, III (large)--at 69.6%, indicating the development of cardiac remodeling. After the treatment was determined by marked reduction III (large) degree and transfer it in the II (moderate) and I (small) degree of left ventricular hypertrophy due to more or less pronounced changes remodeling left ventricular. The obtained data allow a more detailed and adequately assess the structural and functional outcome variables and determine the regression of myocardial hypertrophy in the background to achieve target blood pressure, which is important in practical cardiology.

Diabetes mellitus is associated with adverse structural and functional cardiac remodelling in chronic heart failure with reduced ejection fraction.

PubMed

Walker, Andrew Mn; Patel, Peysh A; Rajwani, Adil; Groves, David; Denby, Christine; Kearney, Lorraine; Sapsford, Robert J; Witte, Klaus K; Kearney, Mark T; Cubbon, Richard M

2016-09-01

Diabetes mellitus is associated with an increased risk of death and hospitalisation in patients with chronic heart failure. Better understanding of potential underlying mechanisms may aid the development of diabetes mellitus-specific chronic heart failure therapeutic strategies. Prospective observational cohort study of 628 patients with chronic heart failure associated with left ventricular systolic dysfunction receiving contemporary evidence-based therapy. Indices of cardiac structure and function, along with symptoms and biochemical parameters, were compared in patients with and without diabetes mellitus at study recruitment and 1 year later. Patients with diabetes mellitus (24.2%) experienced higher rates of all-cause [hazard ratio, 2.3 (95% confidence interval, 1.8-3.0)] and chronic heart failure-specific mortality and hospitalisation despite comparable pharmacological and device-based therapies. At study recruitment, patients with diabetes mellitus were more symptomatic, required greater diuretic doses and more frequently had radiologic evidence of pulmonary oedema, despite higher left ventricular ejection fraction. They also exhibited echocardiographic evidence of increased left ventricular wall thickness and pulmonary arterial pressure. Diabetes mellitus was associated with reduced indices of heart rate variability and increased heart rate turbulence. During follow-up, patients with diabetes mellitus experienced less beneficial left ventricular remodelling and greater deterioration in renal function. Diabetes mellitus is associated with features of adverse structural and functional cardiac remodelling in patients with chronic heart failure. © The Author(s) 2016.

Role of chymase in cigarette smoke-induced pulmonary artery remodeling and pulmonary hypertension in hamsters.

PubMed

Wang, Tao; Han, Su-Xia; Zhang, Shang-Fu; Ning, Yun-Ye; Chen, Lei; Chen, Ya-Juan; He, Guang-Ming; Xu, Dan; An, Jin; Yang, Ting; Zhang, Xiao-Hong; Wen, Fu-Qiang

2010-03-31

Cigarette smoking is an important risk factor for pulmonary arterial hypertension (PAH) in chronic obstructive pulmonary disease (COPD). Chymase has been shown to function in the enzymatic production of angiotensin II (AngII) and the activation of transforming growth factor (TGF)-beta1 in the cardiovascular system. The aim of this study was to determine the potential role of chymase in cigarette smoke-induced pulmonary artery remodeling and PAH. Hamsters were exposed to cigarette smoke; after 4 months, lung morphology and tissue biochemical changes were examined using immunohistochemistry, Western blotting, radioimmunoassay and reverse-transcription polymerase chain reaction. Our results show that chronic cigarette smoke exposure significantly induced elevation of right ventricular systolic pressures (RVSP) and medial hypertrophy of pulmonary arterioles in hamsters, concurrent with an increase of chymase activity and synthesis in the lung. Elevated Ang II levels and enhanced TGF-beta1/Smad signaling activation were also observed in smoke-exposed lungs. Chymase inhibition with chymostatin reduced the cigarette smoke-induced increase in chymase activity and Ang II concentration in the lung, and attenuated the RVSP elevation and the remodeling of pulmonary arterioles. Chymostatin did not affect angiotensin converting enzyme (ACE) activity in hamster lungs. These results suggest that chronic cigarette smoke exposure can increase chymase activity and expression in hamster lungs. The capability of activated chymase to induce Ang II formation and TGF-beta1 signaling may be part of the mechanism for smoking-induced pulmonary vascular remodeling. Thus, our study implies that blockade of chymase might provide benefits to PAH smokers.

Ca2+ handling remodeling and STIM1L/Orai1/TRPC1/TRPC4 upregulation in monocrotaline-induced right ventricular hypertrophy.

PubMed

Jessica, Sabourin; Angèle, Boet; Catherine, Rucker-Martin; Mélanie, Lambert; Ana-Maria, Gomez; Jean-Pierre, Benitah; Frédéric, Perros; Marc, Humbert; Fabrice, Antigny

2018-05-01

Right ventricular (RV) function is the most important prognostic factor for pulmonary arterial hypertension (PAH) patients. The progressive increase of pulmonary vascular resistance induces RV hypertrophy (RVH) and at term RV failure (RVF). However, the molecular mechanisms of RVH and RVF remain understudied. In this study, we gained insights into cytosolic Ca 2+ signaling remodeling in ventricular cardiomyocytes during the pathogenesis of severe pulmonary hypertension (PH) induced in rats by monocrotaline (MCT) exposure, and we further identified molecular candidates responsible for this Ca 2+ remodeling. After PH induction, hypertrophied RV myocytes presented longer action potential duration, higher and faster [Ca 2+ ] i transients and increased sarcoplasmic reticulum (SR) Ca 2+ content, whereas no changes in these parameters were detected in left ventricular (LV) myocytes. These modifications were associated with increased P-Ser 16 -phospholamban pentamer expression without altering SERCA2a (Sarco/Endoplasmic Reticulum Ca 2+ -ATPase) pump abundance. Moreover, after PH induction, Ca 2+ sparks frequency were higher in hypertrophied RV cells, while total RyR2 (Ryanodine Receptor) expression and phosphorylation were unaffected. Together with cellular hypertrophy, the T-tubules network was disorganized. Hypertrophied RV cardiomyocytes from MCT-exposed rats showed decreased expression of classical STIM1 (Stromal Interaction molecule) associated with increased expression of muscle-specific STIM1 Long isoform, glycosylated-Orai1 channel form, and TRPC1 and TRPC4 channels, which was correlated with an enhanced Ca 2+ -release-activated Ca 2+ (CRAC)-like current. Pharmacological inhibition of TRPCs/Orai1 channels in hypertrophied RV cardiomyocytes normalized [Ca 2+ ] i transients amplitude, the SR Ca 2+ content and cell contractility to control levels. Finally, we showed that most of these changes did not appear in LV cardiomyocytes. These new findings demonstrate RV-specific cellular Ca 2+ cycling remodeling in PH rats with maladaptive RVH and that the STIM1L/Orai1/TRPC1/C4-dependent Ca 2+ current participates in this Ca 2+ remodeling in RVH secondary to PH. Copyright © 2018 Elsevier Ltd. All rights reserved.

Renal sympathetic denervation attenuates hypertension and vascular remodeling in renovascular hypertensive rats.

PubMed

Li, Peng; Huang, Pei-Pei; Yang, Yun; Liu, Chi; Lu, Yan; Wang, Fang; Sun, Wei; Kong, Xiang-Qing

2017-01-01

Li P, Huang P, Yang Y, Liu C, Lu Y, Wang F, Sun W, Kong X. Renal sympathetic denervation attenuates hypertension and vascular remodeling in renovascular hypertensive rats. J Appl Physiol 122: 121-129, 2017. First published October 14, 2016; doi:10.1152/japplphysiol.01019.2015-Sympathetic activity is enhanced in patients with essential or secondary hypertension, as well as in various hypertensive animal models. Therapeutic targeting of sympathetic activation is considered an effective antihypertensive strategy. We hypothesized that renal sympathetic denervation (RSD) attenuates hypertension and improves vascular remodeling and renal disease in the 2-kidney, 1-clip (2K1C) rat model. Rats underwent 2K1C modeling or sham surgery; then rats underwent RSD or sham surgery 4 wk later, thus resulting in four groups (normotensive-sham, normotensive-RSD, 2K1C-sham, and 2K1C-RSD). Norepinephrine was measured by ELISA. Echocardiography was used to assess heart function. Fibrosis and apoptosis were assessed by Masson and TUNEL staining. Changes in mean arterial blood pressure in response to hexamethonium and plasma norepinephrine levels were used to evaluate basal sympathetic nerve activity. The 2K1C modeling success rate was 86.8%. RSD reversed the elevated systolic blood pressure induced by 2K1C, but had no effect on body weight. Compared with rats in the 2K1C-sham group, rats in the 2K1C-RSD group showed lower left ventricular mass/body weight ratio, interventricular septal thickness in diastole, left ventricular end-systolic diameter, and left ventricular posterior wall thickness in systole, whereas fractional shortening and ejection fraction were higher. Right kidney apoptosis and left kidney hypertrophy were not changed by RSD. Arterial fibrosis was lower in animals in the 2K1C-RSD group compared with those in the 2K1C-sham group. RSD reduced plasma norepinephrine and basal sympathetic activity in rats in the 2K1C-RSD group compared with rats in the 2K1C-sham group. These results suggest a possible clinical efficacy of RSD for renovascular hypertension. The effects of renal sympathetic denervation (RSD) on hypertension, cardiac function, vascular fibrosis, and renal apoptosis were studied in the 2K1C rat model. Results showed that RSD attenuated hypertension, improved vascular remodeling, and reduced vascular fibrosis through decreased sympathetic activity in the 2K1C rat model, but it did not change the kidney size, renal apoptosis, or renal caspase-3 expression. These results could suggest possible clinical efficacy of RSD for renovascular hypertension. Copyright © 2017 the American Physiological Society.

Obese subjects show sex-specific differences in right ventricular hypertrophy.

PubMed

Rider, Oliver J; Lewis, Andrew J M; Lewandowski, Adam J; Ntusi, Ntobeko; Nethononda, Richard; Petersen, Steffen E; Francis, Jane M; Pitcher, Alex; Banerjee, Rajarshi; Leeson, Paul; Neubauer, Stefan

2015-01-01

As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy. Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3-59.2 kg/m2) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P<0.001). Whereas women exhibited RV cavity dilatation (RV end-diastolic volume, +1.0 mL per BMI point increase; P<0.001), BMI was not correlated with RV end-diastolic volume in men (R=0.04; P=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R=0.41; women, R=0.51; both P<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men, R=-0.43; women, R=-0.44; both P<0.001) and RV mass/volume ratio (men, R=-0.37; women, R=-0.35; both P<0.001). A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling. © 2014 American Heart Association, Inc.

Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis.

PubMed

Ismahil, Mohamed Ameen; Hamid, Tariq; Bansal, Shyam S; Patel, Bindiya; Kingery, Justin R; Prabhu, Sumanth D

2014-01-17

The role of mononuclear phagocytes in chronic heart failure (HF) is unknown. Our aim was to delineate monocyte, macrophage, and dendritic cell trafficking in HF and define the contribution of the spleen to cardiac remodeling. We evaluated C57Bl/6 mice with chronic HF 8 weeks after coronary ligation. As compared with sham-operated controls, HF mice exhibited: (1) increased proinflammatory CD11b+ F4/80+ CD206- macrophages and CD11b+ F4/80+ Gr-1(hi) monocytes in the heart and peripheral blood, respectively, and reduced CD11b+ F4/80+ Gr-1(hi) monocytes in the spleen; (2) significantly increased CD11c+ B220- classical dendritic cells and CD11c+ low)B220+ plasmacytoid dendritic cells in both the heart and spleen, and increased classic dendritic cells and plasmacytoid dendritic cells in peripheral blood and bone marrow, respectively; (3) increased CD4+ helper and CD8+ cytotoxic T-cells in the spleen; and (4) profound splenic remodeling with abundant white pulp follicles, markedly increased size of the marginal zone and germinal centers, and increased expression of alarmins. Splenectomy in mice with established HF reversed pathological cardiac remodeling and inflammation. Splenocytes adoptively transferred from mice with HF, but not from sham-operated mice, homed to the heart and induced long-term left ventricular dilatation, dysfunction, and fibrosis in naive recipients. Recipient mice also exhibited monocyte activation and splenic remodeling similar to HF mice. Activation of mononuclear phagocytes is central to the progression of cardiac remodeling in HF, and heightened antigen processing in the spleen plays a critical role in this process. Splenocytes (presumably splenic monocytes and dendritic cells) promote immune-mediated injurious responses in the failing heart and retain this memory on adoptive transfer.

Multidetector computed tomography shows reverse cardiac remodeling after double lung transplantation for pulmonary hypertension.

PubMed

Mandich Crovetto, D; Alonso Charterina, S; Jiménez López-Guarch, C; Pont Vilalta, M; Pérez Núñez, M; de Pablo Gafas, A; Escribano Subías, P

2016-01-01

To use multidetector computed tomography (MDCT) to evaluate the structural changes in the right heart and pulmonary arteries that occur in patients with severe pulmonary hypertension treated by double lung transplantation. This was a retrospective study of 21 consecutive patients diagnosed with severe pulmonary hypertension who underwent double lung transplantation at our center between 2010 and 2014. We analyzed the last MDCT study done before lung transplantation and the first MDCT study done after lung transplantation. We recorded the following variables: diameter of the pulmonary artery trunk, ratio of the diameter of the pulmonary artery trunk to the diameter of the ascending aorta, diameter of the right ventricle, ratio of the diameter of the left ventricle to the diameter of the right ventricle, and eccentricity index. Statistical analysis consisted of the comparison of the means of the variables recorded. In all cases analyzed, the MDCT study done a mean of 24±14 days after double lung transplantation showed a significant reduction in the size of the right heart chambers, with improved indices of ventricular interdependency index, and reduction in the size of the pulmonary artery trunk (p<0.001 for all the variables analyzed). Patients with pulmonary hypertension treated by double lung transplantation present early reverse remodeling of the changes in the structures of the right heart and pulmonary arterial tree. MDCT is useful for detecting these changes. Copyright © 2016 SERAM. Publicado por Elsevier España, S.L.U. All rights reserved.

Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs.

PubMed

Xie, Chaoqin; Biary, Nora; Tocchetti, Carlo G; Aon, Miguel A; Paolocci, Nazareno; Kauffman, Justin; Akar, Fadi G

2013-04-01

Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P = 0.004) and STZ + Ins (P = 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P = 0.045) and STZ + Ins (P = 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P = 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression.

Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs

PubMed Central

Xie, Chaoqin; Biary, Nora; Tocchetti, Carlo G.; Aon, Miguel A.; Paolocci, Nazareno; Kauffman, Justin

2013-01-01

Chronic hyperglycemia in type-1 diabetes mellitus is associated with oxidative stress (OS) and sudden death. Mechanistic links remain unclear. We investigated changes in electrophysiological (EP) properties in a model of chronic hyperglycemia before and after challenge with OS by GSH oxidation and tested reversibility of EP remodeling by insulin. Guinea pigs survived for 1 mo following streptozotocin (STZ) or saline (sham) injection. A treatment group received daily insulin for 2 wk to reverse STZ-induced hyperglycemia (STZ + Ins). EP properties were measured using high-resolution optical action potential mapping before and after challenge of hearts with diamide. Despite elevation of glucose levels in STZ compared with sham-operated (P = 0.004) and STZ + Ins (P = 0.002) animals, average action potential duration (APD) and arrhythmia propensity were not altered at baseline. Diamide promoted early (<10 min) formation of arrhythmic triggers reflected by a higher arrhythmia scoring index in STZ (P = 0.045) and STZ + Ins (P = 0.033) hearts compared with sham-operated hearts. APD heterogeneity underwent a more pronounced increase in response to diamide in STZ and STZ + Ins hearts compared with sham-operated hearts. Within 30 min, diamide resulted in spontaneous incidence of ventricular tachycardia and ventricular fibrillation (VT/VF) in 3/6, 2/5, 1/5, and 0/4 STZ, STZ + Ins, sham-operated, and normal hearts, respectively. Hearts prone to VT/VF exhibited greater APD heterogeneity (P = 0.010) compared with their VT/VF-free counterparts. Finally, altered EP properties in STZ were not rescued by insulin. In conclusion, GSH oxidation enhances APD heterogeneity and increases arrhythmia scoring index in a guinea pig model of chronic hyperglycemia. Despite normalization of glycemic levels by insulin, these proarrhythmic properties are not reversed, suggesting the importance of targeting antioxidant defenses for arrhythmia suppression. PMID:23376824

Maternal obesity, gestational weight gain and childhood cardiac outcomes: role of childhood body mass index.

PubMed

Toemen, L; Gishti, O; van Osch-Gevers, L; Steegers, E A P; Helbing, W A; Felix, J F; Reiss, I K M; Duijts, L; Gaillard, R; Jaddoe, V W V

2016-07-01

Maternal obesity may affect cardiovascular outcomes in the offspring. We examined the associations of maternal prepregnancy body mass index and gestational weight gain with childhood cardiac outcomes and explored whether these associations were explained by parental characteristics, infant characteristics or childhood body mass index. In a population-based prospective cohort study among 4852 parents and their children, we obtained maternal weight before pregnancy and in early, mid- and late pregnancy. At age 6 years, we measured aortic root diameter (cm) and left ventricular dimensions. We calculated left ventricular mass (g), left ventricular mass index (g m(-2.7)), relative wall thickness ((2 × left ventricular posterior wall thickness)/left ventricular diameter), fractional shorting (%), eccentric left ventricular hypertrophy and concentric remodeling. A one standard deviation score (SDS) higher maternal prepregnancy body mass index was associated with higher left ventricular mass (0.10 SDS (95% confidence interval (CI) 0.08, 0.13)), left ventricular mass index (0.06 SDS (95% CI 0.03, 0.09)) and aortic root diameter (0.09 SDS (95% CI 0.06, 0.12)), but not with relative wall thickness or fractional shortening. A one SDS higher maternal prepregnancy body mass index was associated with an increased risk of eccentric left ventricular hypertrophy (odds ratio 1.21 (95% CI 1.03, 1.41)), but not of concentric remodeling. When analyzing the effects of maternal weight in different periods simultaneously, only maternal prepregnancy weight and early pregnancy weight were associated with left ventricular mass, left ventricular mass index and aortic root diameter (P-values<0.05), independent of weight in other pregnancy periods. All observed associations were independent of parental and infant characteristics, but attenuated to non-significance after adjustment for childhood body mass index. Maternal prepregnancy body mass index and weight gain in early pregnancy are both associated with offspring cardiac structure in childhood, but these associations seem to be fully explained by childhood body mass index.

Longstanding Hyperthyroidism Is Associated with Normal or Enhanced Intrinsic Cardiomyocyte Function despite Decline in Global Cardiac Function

PubMed Central

Redetzke, Rebecca A.; Gerdes, A. Martin

2012-01-01

Thyroid hormones (THs) play a pivotal role in cardiac homeostasis. TH imbalances alter cardiac performance and ultimately cause cardiac dysfunction. Although short-term hyperthyroidism typically leads to heightened left ventricular (LV) contractility and improved hemodynamic parameters, chronic hyperthyroidism is associated with deleterious cardiac consequences including increased risk of arrhythmia, impaired cardiac reserve and exercise capacity, myocardial remodeling, and occasionally heart failure. To evaluate the long-term consequences of chronic hyperthyroidism on LV remodeling and function, we examined LV isolated myocyte function, chamber function, and whole tissue remodeling in a hamster model. Three-month-old F1b hamsters were randomized to control or 10 months TH treatment (0.1% grade I desiccated TH). LV chamber remodeling and function was assessed by echocardiography at 1, 2, 4, 6, 8, and 10 months of treatment. After 10 months, terminal cardiac function was assessed by echocardiography and LV hemodynamics. Hyperthyroid hamsters exhibited significant cardiac hypertrophy and deleterious cardiac remodeling characterized by myocyte lengthening, chamber dilatation, decreased relative wall thickness, increased wall stress, and increased LV interstitial fibrotic deposition. Importantly, hyperthyroid hamsters demonstrated significant LV systolic and diastolic dysfunction. Despite the aforementioned remodeling and global cardiac decline, individual isolated cardiac myocytes from chronically hyperthyroid hamsters had enhanced function when compared with myocytes from untreated age-matched controls. Thus, it appears that long-term hyperthyroidism may impair global LV function, at least in part by increasing interstitial ventricular fibrosis, in spite of normal or enhanced intrinsic cardiomyocyte function. PMID:23056390

Mitral regurgitation: anatomy is destiny.

PubMed

Athanasuleas, Constantine L; Stanley, Alfred W H; Buckberg, Gerald D

2018-04-26

Mitral regurgitation (MR) occurs when any of the valve and ventricular mitral apparatus components are disturbed. As MR progresses, left ventricular remodelling occurs, ultimately causing heart failure when the enlarging left ventricle (LV) loses its conical shape and becomes globular. Heart failure and lethal ventricular arrhythmias may develop if the left ventricular end-systolic volume index exceeds 55 ml/m2. These adverse changes persist despite satisfactory correction of the annular component of MR. Our goal was to describe this process and summarize evolving interventions that reduce the volume of the left ventricle and rebuild its elliptical shape. This 'valve/ventricle' approach addresses the spherical ventricular culprit and offsets the limits of treating MR by correcting only its annular component.

Impact of Atrial Fibrillation Ablation on Left Ventricular Filling Pressure and Left Atrial Remodeling

PubMed Central

dos Santos, Simone Nascimento; Henz, Benhur Davi; Zanatta, André Rodrigues; Barreto, José Roberto; Loureiro, Kelly Bianca; Novakoski, Clarissa; dos Santos, Marcus Vinícius Nascimento; Giuseppin, Fabio F.; Oliveira, Edna Maria; Leite, Luiz Roberto

2014-01-01

Background Left ventricular (LV) diastolic dysfunction is associated with new-onset atrial fibrillation (AF), and the estimation of elevated LV filling pressures by E/e' ratio is related to worse outcomes in patients with AF. However, it is unknown if restoring sinus rhythm reverses this process. Objective To evaluate the impact of AF ablation on estimated LV filling pressure. Methods A total of 141 patients underwent radiofrequency (RF) ablation to treat drug-refractory AF. Transthoracic echocardiography was performed 30 days before and 12 months after ablation. LV functional parameters, left atrial volume index (LAVind), and transmitral pulsed and mitral annulus tissue Doppler (e' and E/e') were assessed. Paroxysmal AF was present in 18 patients, persistent AF was present in 102 patients, and long-standing persistent AF in 21 patients. Follow-up included electrocardiographic examination and 24-h Holter monitoring at 3, 6, and 12 months after ablation. Results One hundred seventeen patients (82.9%) were free of AF during the follow-up (average, 18 ± 5 months). LAVind reduced in the successful group (30.2 mL/m2 ± 10.6 mL/m2 to 22.6 mL/m2 ± 1.1 mL/m2, p < 0.001) compared to the non-successful group (37.7 mL/m2 ± 14.3 mL/m2 to 37.5 mL/m2 ± 14.5 mL/m2, p = ns). Improvement of LV filling pressure assessed by a reduction in the E/e' ratio was observed only after successful ablation (11.5 ± 4.5 vs. 7.1 ± 3.7, p < 0.001) but not in patients with recurrent AF (12.7 ± 4.4 vs. 12 ± 3.3, p = ns). The success rate was lower in the long-standing persistent AF patient group (57% vs. 87%, p = 0.001). Conclusion Successful AF ablation is associated with LA reverse remodeling and an improvement in LV filling pressure. PMID:25590928

The role of echocardiography in the evaluation of cardiac re-modelling and differentiation between physiological and pathological hypertrophy in teenagers engaged in competitive amateur sports.

PubMed

Sulovic, Ljiljana S; Mahmutovic, Meho; Lazic, Snezana; Sulovic, Nenad

2017-05-01

Aims "Athlete's heart" is a cardiac adaptation to long-term intensive training. The aims of this study were to show the prevalence of left ventricular hypertrophy in teenagers who participate in sports, to define the different types of cardiac re-modelling, and to differentiate between physiological and pathological hypertrophy. Echocardiographic measurements were obtained by M-mode, two dimensional, and Doppler techniques of participants from sports and control groups. The echocardiographic examinations included 100 healthy teenagers taking part in dynamic sports such as football and basketball and 100 healthy teenagers taking part in static sports such as karate and judo. The control group (n=100) included healthy, sedentary teenagers. Sports participants had significantly higher left ventricular mass when compared with the control group, (p0.05). Respondents from both groups had E/A ratios (transmitral flow velocity ratio)>1, preserved diastolic function, and statistically they did not differ from the control group. Echocardiographic parameters show that physiological hypertrophy and cardiac re-modelling are present in teenagers who play sports. Unexpectedly, the prevalence of concentric and eccentric types of re-modelling is equally possible in the group of static sports participants.

Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions.

PubMed

Roy, Ashbeel; Dakroub, Mouhamed; Tezini, Geisa C S V; Liu, Yin; Guatimosim, Silvia; Feng, Qingping; Salgado, Helio C; Prado, Vania F; Prado, Marco A M; Gros, Robert

2016-02-01

Autonomic dysfunction is a characteristic of cardiac disease and decreased vagal activity is observed in heart failure. Rodent cardiomyocytes produce de novo ACh, which is critical in maintaining cardiac homeostasis. We report that this nonneuronal cholinergic system is also found in human cardiomyocytes, which expressed choline acetyltransferase (ChAT) and the vesicular acetylcholine transporter (VAChT). Furthermore, VAChT expression was increased 3- and 1.5-fold at the mRNA and protein level, respectively, in ventricular tissue from patients with heart failure, suggesting increased ACh secretion in disease. We used mice with genetic deletion of cardiomyocyte-specific VAChT or ChAT and mice overexpressing VAChT to test the functional significance of cholinergic signaling. Mice deficient for VAChT displayed an 8% decrease in fractional shortening and 13% decrease in ejection fraction compared with angiotensin II (Ang II)-treated control animals, suggesting enhanced ventricular dysfunction and pathologic remodeling in response to Ang II. Similar results were observed in ChAT-deficient mice. Conversely, no decline in ventricular function was observed in Ang II-treated VAChT overexpressors. Furthermore, the fibrotic area was significantly greater (P < 0.05) in Ang II-treated VAChT-deficient mice (3.61 ± 0.64%) compared with wild-type animals (2.24 ± 0.11%). In contrast, VAChT overexpressing mice did not display an increase in collagen deposition. Our results provide new insight into cholinergic regulation of cardiac function, suggesting that a compensatory increase in cardiomyocyte VAChT levels may help offset cardiac remodeling in heart failure. © FASEB.

Endoplasmic reticulum stress sensor protein kinase R-like endoplasmic reticulum kinase (PERK) protects against pressure overload-induced heart failure and lung remodeling.

PubMed

Liu, Xiaoyu; Kwak, Dongmin; Lu, Zhongbing; Xu, Xin; Fassett, John; Wang, Huan; Wei, Yidong; Cavener, Douglas R; Hu, Xinli; Hall, Jennifer; Bache, Robert J; Chen, Yingjie

2014-10-01

Studies have reported that development of congestive heart failure is associated with increased endoplasmic reticulum stress. Double stranded RNA-activated protein kinase R-like endoplasmic reticulum kinase (PERK) is a major transducer of the endoplasmic reticulum stress response and directly phosphorylates eukaryotic initiation factor 2α, resulting in translational attenuation. However, the physiological effect of PERK on congestive heart failure development is unknown. To study the effect of PERK on ventricular structure and function, we generated inducible cardiac-specific PERK knockout mice. Under unstressed conditions, cardiac PERK knockout had no effect on left ventricular mass, or its ratio to body weight, cardiomyocyte size, fibrosis, or left ventricular function. However, in response to chronic transverse aortic constriction, PERK knockout mice exhibited decreased ejection fraction, increased left ventricular fibrosis, enhanced cardiomyocyte apoptosis, and exacerbated lung remodeling in comparison with wild-type mice. PERK knockout also dramatically attenuated cardiac sarcoplasmic reticulum Ca(2+)-ATPase expression in response to aortic constriction. Our findings suggest that PERK is required to protect the heart from pressure overload-induced congestive heart failure. © 2014 American Heart Association, Inc.

Manipulation of sarcoplasmic reticulum Ca2+ release in heart failure through mechanical intervention

PubMed Central

Ibrahim, Michael; Nader, Anas; Yacoub, Magdi H; Terracciano, Cesare

2015-01-01

Left ventricular assist devices (LVADs) were developed as a means of temporary circulatory support, but the mechanical unloading they offer also results in significant reverse remodelling. In selected patients, these improvements are sufficient to allow ultimate device explantation without requiring transplantation; this represents a fundamental shift in our understanding of heart failure. Like heart failure itself, LVADs influence multiple biological systems. The transverse tubules are a system of membrane invaginations in ventricular cardiomyocytes which allow rapid propagation of the action potential throughout the cell. Through their dense concentration of L-type Ca2+ channels in close proximity to intracellular ryanodine receptors, the t-tubules enable synchronous Ca2+ release throughout the cell. The t-tubules’ structure appears to be specifically regulated by mechanical load, such that either the overload of heart failure (or the spontaneously hypertensive rat model) or the profound unloading in a chronically unloaded heart result in impaired t-tubule structure, with ineffective Ca2+ release. While there are multiple molecular pathways which underpin t-tubule regulation, Telethonin (Tcap) appears to be important in regulating the effect of altered loading on the t-tubule system. PMID:25922157

Spironolactone differently influences remodeling of the left ventricle and aorta in L-NAME-induced hypertension.

PubMed

Simko, F; Matúsková, J; Lupták, I; Pincíková, T; Krajcírovicová, K; Stvrtina, S; Pomsár, J; Pelouch, V; Paulis, L; Pechánová, O

2007-01-01

Aldosterone receptor antagonist, spironolactone, has been shown to prevent remodeling of the heart in several models of left ventricular hypertrophy. The aim of the present study was to determine whether the treatment with spironolactone can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) and aortic remodeling in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Four groups of rats were investigated: control, spironolactone (200 mg/kg), L-NAME (40 mg/kg) and L-NAME + spironolactone (in corresponding dosage). Animals were studied after 5 weeks of treatment. The decrease of NO-synthase activity in the LV and kidney was associated with the development of hypertension and LV hypertrophy, with increased DNA concentration in the LV, and remodeling of the aorta in the L-NAME group. Spironolactone prevented the inhibition of NO-synthase activity in the LV and kidney and partially attenuated hypertension and LVH development and the increase in DNA concentration. However, remodeling of the aorta was not prevented by spironolactone treatment. We conclude that the aldosterone receptor antagonist spironolactone improved nitric oxide production and partially prevented hypertension and LVH development without preventing hypertrophy of the aorta in NO-deficient hypertension. The reactive growth of the heart and aorta seems to be controlled by different mechanisms in L-NAME-induced hypertension.

Left ventricular remodeling and hypertrophy in patients with aortic stenosis: insights from cardiovascular magnetic resonance

PubMed Central

2012-01-01

Background Cardiovascular magnetic resonance (CMR) is the gold standard non-invasive method for determining left ventricular (LV) mass and volume but has not been used previously to characterise the LV remodeling response in aortic stenosis. We sought to investigate the degree and patterns of hypertrophy in aortic stenosis using CMR. Methods Patients with moderate or severe aortic stenosis, normal coronary arteries and no other significant valve lesions or cardiomyopathy were scanned by CMR with valve severity assessed by planimetry and velocity mapping. The extent and patterns of hypertrophy were investigated using measurements of the LV mass index, indexed LV volumes and the LV mass/volume ratio. Asymmetric forms of remodeling and hypertrophy were defined by a regional wall thickening ≥13 mm and >1.5-fold the thickness of the opposing myocardial segment. Results Ninety-one patients (61±21 years; 57 male) with aortic stenosis (aortic valve area 0.93±0.32cm2) were recruited. The severity of aortic stenosis was unrelated to the degree (r2=0.012, P=0.43) and pattern (P=0.22) of hypertrophy. By univariate analysis, only male sex demonstrated an association with LV mass index (P=0.02). Six patterns of LV adaption were observed: normal ventricular geometry (n=11), concentric remodeling (n=11), asymmetric remodeling (n=11), concentric hypertrophy (n=34), asymmetric hypertrophy (n=14) and LV decompensation (n=10). Asymmetric patterns displayed considerable overlap in appearances (wall thickness 17±2mm) with hypertrophic cardiomyopathy. Conclusions We have demonstrated that in patients with moderate and severe aortic stenosis, the pattern of LV adaption and degree of hypertrophy do not closely correlate with the severity of valve narrowing and that asymmetric patterns of wall thickening are common. Trial registration ClinicalTrials.gov Reference Number: NCT00930735 PMID:22839417

Specific α7 nicotinic acetylcholine receptor agonist ameliorates isoproterenol-induced cardiac remodelling in mice through TGF-β1/Smad3 pathway.

PubMed

Yang, Yong-Hua; Fang, Huan-Le; Zhao, Ming; Wei, Xiang-Lan; Zhang, Ning; Wang, Shun; Lu, Yi; Yu, Xiao-Jiang; Sun, Lei; He, Xi; Li, Dong-Ling; Liu, Jin-Jun; Zang, Wei-Jin

2017-12-01

It is well-accepted that inflammation plays an important role in the development of cardiac remodelling and that therapeutic approaches targeting inflammation can inhibit cardiac remodelling. Although a large amount of evidence indicates that activation of α7 nicotinic acetylcholine receptor (α7nAChR) causes an anti-inflammatory effect, the role of α7nAChR in cardiac remodelling and the underlying mechanism have not been established. To investigate the effect of the specific α7nAChR agonist, PNU282987, on cardiac remodelling induced by isoproterenol (ISO 60 mg/kg per day) in mice, the cardiomyocyte cross-sectional area (CSA) and collagen volume fraction were evaluated by hematoxylin and eosin (HE) and Masson staining, respectively. Cardiac function and ventricular wall thickness were measured by echocardiography. The protein expressions of collagen I, matrix metalloproteinase 9 (MMP-9), transforming growth factor β1 (TGF-β1), and Smad3 were analyzed by Western blot. ISO-induced cardiac hypertrophy, characterized by an increase in the heart weight/body weight ratio, CSA and ventricular wall thickness. Moreover, cardiac fibrosis indices, such as collagen volume fraction, MMP-9 and collagen I protein expression, were also increased by ISO. PNU282987 not only attenuated cardiac hypertrophy but also decreased the cardiac fibrosis induced by ISO. Furthermore, PNU282987 suppressed TGF-β1 protein expression and the phosphorylation of Smad3 induced by ISO. In conclusion, PNU282987 ameliorated the cardiac remodelling induced by ISO, which may be related to the TGF-β1/Smad3 pathway. These data imply that the α7nAChR may represent a novel therapeutic target for cardiac remodelling in many cardiovascular diseases. © 2017 John Wiley & Sons Australia, Ltd.

Short-term adaptation and chronic cardiac remodelling to high altitude in lowlander natives and Himalayan Sherpa.

PubMed

Stembridge, Mike; Ainslie, Philip N; Shave, Rob

2015-11-01

What is the topic of this review? At high altitude, the cardiovascular system must adapt in order to meet the metabolic demand for oxygen. This review summarizes recent findings relating to short-term and life-long cardiac adaptation to high altitude in the context of exercise capacity. What advances does it highlight? Both Sherpa and lowlanders exhibit smaller left ventricular volumes at high altitude; however, myocardial relaxation, as evidenced by diastolic untwist, is reduced only in Sherpa, indicating that short-term hypoxia does not impair diastolic relaxation. Potential remodelling of systolic function, as evidenced by lower left ventricular systolic twist in Sherpa, may facilitate the requisite sea-level mechanical reserve required during exercise, although this remains to be confirmed. Both short-term and life-long high-altitude exposure challenge the cardiovascular system to meet the metabolic demand for O2 in a hypoxic environment. As the demand for O2 delivery increases during exercise, the circulatory component of oxygen transport is placed under additional stress. Acute adaptation and chronic remodelling of cardiac structure and function may occur to facilitate O2 delivery in lowlanders during sojourn to high altitude and in permanent highland residents. However, our understanding of cardiac structural and functional adaption in Sherpa remains confined to a higher maximal heart rate, lower pulmonary vascular resistance and no differences in resting cardiac output. Ventricular form and function are intrinsically linked through the left ventricular (LV) mechanics that facilitate efficient ejection, minimize myofibre stress during contraction and aid diastolic recoil. Recent examination of LV mechanics has allowed detailed insight into fundamental cardiac adaptation in high-altitude Sherpa. In this symposium report, we review recent advances in our understanding of LV function in both lowlanders and Sherpa at rest and discuss the potential consequences for exercise capacity. Collectively, data indicate chronic structural ventricular adaptation, with adult Sherpa having smaller absolute and relative LV size. Consistent with structural remodelling, cardiac mechanics also differ in Sherpa when compared with lowlanders at high altitude. These differences are characterized by a reduction in resting systolic deformation and slower diastolic untwisting, a surrogate of relaxation. These changes may reflect a functional cardiac adaptation that affords Sherpa the same mechanical reserve seen in lowlanders at sea level, which is absent when they ascend to high altitude. © 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.

A new shape for an old function: lasting effect of a physiologic surgical restoration of the left ventricle

PubMed Central

Cirillo, Marco; Amaducci, Andrea; Villa, Emmanuel; Tomba, Margherita Dalla; Brunelli, Federico; Mhagna, Zen; Troise, Giovanni; Quaini, Eugenio

2006-01-01

Background Long-term morphofunctional outcome may vary widely in surgical anterior left ventricular wall restoration, suggesting variability in post-surgical remodeling similar to that observed following acute myocardial infarction. The aim of this pilot study was to demonstrate that surgical restoration obtained with a particular shape of endoventricular patch leads to steady morphofunctional ventricular improvement when geometry, volume and residual akinesia can be restored as normal as possible. Methods This study involved 12 consecutive patients with previous anterior myocardial infarction, dilated cardiomyopathy and no mitral procedures, who underwent left ventricular reconstruction and coronary revascularization between May 2002 and May 2003 using a small, narrow, oval patch aiming at a volume ≤ 45 mL/m2 with elliptical shape. Eleven geometric parameters were examined preoperatively and at least 3, 12 and 24 months after the operation by serial echocardiographic studies and evaluated by paired t test taking the time of surgery as a starting point for remodeling. Results All patients were in NYHA class 1 at follow-up. Patch geometry obtained a conical shape of the ventricle with new apex, physiologic rearrangement of functioning myocardial wall and small residual akinesia. Ventricular changes at the four time-points showed that all parameters improved significantly compared to preoperative values (end-diastolic volume = 184.2 ± 23.9 vs 139.9 ± 22.0, p = 0.001; vs 151.0 ± 33.8, p = 0.06; vs 144.9 ± 34.0, p = 0.38; end-systolic volume = 125.7 ± 20.6 vs 75.2 ± 14.1, p = 0.001; vs 82.1 ± 23.9, p = 0,18; vs 77.1 ± 19.4, p = 0.41) without further changes during follow-up except for wall motion score index (2.0 ± 0.2 to 1.7 ± 0.2, to 1.4 ± 0.2, to 1.3 ± 0.2) and percentage of akinesia (30.4 ± 7.5 to 29.3 ± 4.2, to 19.8 ± 11.6, to 14.5 ± 7.2) which slowly and significantly improved suggesting a positive post-surgery remodeling. Conclusion Ventricular reconstruction caring of physiological shape, volume, revascularization and residual akinesia obtained a steady geometry. Positive remodeling and equalization of geometrical outcome may persistently prevent long-term redilation. PMID:17083734

Reduction of N terminal-pro-brain (B-type) natriuretic peptide levels with exercise-based cardiac rehabilitation in patients with left ventricular dysfunction after myocardial infarction.

PubMed

Giallauria, Francesco; De Lorenzo, Anna; Pilerci, Francesco; Manakos, Athanasio; Lucci, Rosa; Psaroudaki, Marianna; D'Agostino, Mariantonietta; Del Forno, Domenico; Vigorito, Carlo

2006-08-01

N-terminal-pro-brain (B-type) natriuretic peptide (NT-pro-BNP) is a peptide hormone released from ventricles in response to myocyte stretch. The aim of the study was to investigate the influence of exercise training on plasma NT-pro-BNP to verify if this parameter could be used as a biological marker of left ventricular remodelling in myocardial infarction patients undergoing an exercise training programme. Forty-four patients after myocardial infarction were enrolled into a cardiac rehabilitation programme, and were randomized in two groups of 22 patients each. Group A patients followed a 3-month exercise training programme, while group B patients received only routine recommendations. All patients underwent NT-pro-BNP assay, and cardiopulmonary exercise test before hospital discharge and after 3 months. In Group A, exercise training reduced NT-pro-BNP levels (from 1498+/-438 to 470+/-375 pg/ml, P=0.0026), increased maximal (VO2peak+4.3+/-2.9 ml/kg per min, P<0.001; Powermax+38+/-7, P<0.001) exercise parameters and work efficiency (Powermax/VO2peak+1.3+/-0.4 Power/ml per kg per min, P<0.001); there was also an inverse correlation between changes in NT-pro-BNP levels and in VO2peak (r=-0.72, P<0.001), E-wave (r=-0.51, P<0.001) and E/A ratio (r=0.59, P<0.001). In group B, at 3 months, no changes were observed in NT-pro-BNP levels, exercise and echocardiographic parameters. Three months exercise training in patients with moderate left ventricular systolic dysfunction after myocardial infarction induced a reduction in NT-pro-BNP levels, an improvement of exercise capacity and early left ventricular diastolic filling, without negative left ventricular remodelling. Whether the reduction of NT-pro-BNP levels could be useful as a surrogate marker of favourable left ventricular remodelling at a later follow-up remains to be further explored.

Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease

PubMed Central

Hunt, James M.; Bethea, Brian; Liu, Xiang; Gandjeva, Aneta; Mammen, Pradeep P. A.; Stacher, Elvira; Gandjeva, Marina R.; Parish, Elisabeth; Perez, Mario; Smith, Lynelle; Graham, Brian B.; Kuebler, Wolfgang M.

2013-01-01

Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins. In addition, we addressed the expression pattern of a candidate molecular marker and analyzed the structural pattern of vascular remodeling of pulmonary veins in a rodent model of PH-LHD and in lung tissue of patients with PH-LHD obtained at time of placement on a left ventricular assist device. We detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs. Expression of uPAR remained elevated in pulmonary veins of rats with PH-LHD; however, we also detected induction of uPAR expression in remodeled pulmonary arteries. These findings were validated in lungs of patients with PH-LHD. In selected patients with sequential lung biopsy at the time of removal of the left ventricular assist device, we present early data suggesting improvement in pulmonary hemodynamics and venous remodeling, indicating potential regression of venous remodeling in response to assist device treatment. Our data indicate that remodeling of pulmonary veins is an integral part of PH-LHD and that pulmonary veins share some key features present in remodeled yet not normotensive pulmonary arteries. PMID:24039255

Action of the Metalloproteinases in Gonadal Remodeling during Sex Reversal in the Sequential Hermaphroditism of the Teleostei Fish Synbranchus marmoratus (Synbranchiformes: Synbranchidae)

PubMed Central

Mazzoni, Talita Sarah; Lo Nostro, Fabiana Laura; Antoneli, Fernanda Natália; Quagio-Grassiotto, Irani

2018-01-01

Teleostei present great plasticity regarding sex change. During sex reversal, the whole gonad including the germinal epithelium undergoes significant changes, remodeling, and neoformation. However, there is no information on the changes that occur within the interstitial compartment. Considering the lack of information, especially on the role played by metalloproteinases (MMPs) in fish gonadal remodeling, the aim of this study was to evaluate the action of MMPs on gonads of sex reversed females of Synbranchus marmoratus, a fresh water protogynic diandric fish. Gonads were processed for light microscopy and blood samples were used for the determination of plasma sex steroid levels. During sex reversal, degeneration of the ovaries occurred and were gradually replaced by the germinal tissue of the male. The action of the MMPs induces significant changes in the interstitial compartment, allowing the reorganization of germinal epithelium. Leydig cells also showed an important role in female to male reversion. The gonadal transition coincides with changes in circulating sex steroid levels throughout sex reversion. The action of the MMPs, in the gonadal remodeling, especially on the basement membrane, is essential for the establishment of a new functional germinal epithelium. PMID:29695033

Systems approach to the study of stretch and arrhythmias in right ventricular failure induced in rats by monocrotaline

PubMed Central

Benoist, David; Stones, Rachel; Benson, Alan P.; Fowler, Ewan D.; Drinkhill, Mark J.; Hardy, Matthew E.L.; Saint, David A.; Cazorla, Olivier; Bernus, Olivier; White, Ed

2014-01-01

We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats. We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate. Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations. PMID:25016242

Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension

PubMed Central

Naik, Jay S.; Weise-Cross, Laura; Detweiler, Neil D.; Herbert, Lindsay M.; Yellowhair, Tracylyn R.; Resta, Thomas C.

2017-01-01

Pulmonary arterial hypertension is associated with a decreased antioxidant capacity. However, neither the contribution of reactive oxygen species to pulmonary vasoconstrictor sensitivity, nor the therapeutic efficacy of antioxidant strategies in this setting are known. We hypothesized that reactive oxygen species play a central role in mediating both vasoconstrictor and arterial remodeling components of severe pulmonary arterial hypertension. We examined the effect of the chemical antioxidant, TEMPOL, on right ventricular systolic pressure, vascular remodeling, and enhanced vasoconstrictor reactivity in both chronic hypoxia and hypoxia/SU5416 rat models of pulmonary hypertension. SU5416 is a vascular endothelial growth factor receptor antagonist and the combination of chronic hypoxia/SU5416 produces a model of severe pulmonary arterial hypertension with vascular plexiform lesions/fibrosis that is not present with chronic hypoxia alone. The major findings from this study are: 1) compared to hypoxia alone, hypoxia/SU5416 exposure caused more severe pulmonary hypertension, right ventricular hypertrophy, adventitial lesion formation, and greater vasoconstrictor sensitivity through a superoxide and Rho kinase-dependent Ca2+ sensitization mechanism. 2) Chronic hypoxia increased medial muscularization and superoxide levels, however there was no effect of SU5416 to augment these responses. 3) Treatment with TEMPOL decreased right ventricular systolic pressure in both hypoxia and hypoxia/SU5416 groups. 4) This effect of TEMPOL was associated with normalization of vasoconstrictor responses, but not arterial remodeling. Rather, medial hypertrophy and adventitial fibrotic lesion formation were more pronounced following chronic TEMPOL treatment in hypoxia/SU5416 rats. Our findings support a major role for reactive oxygen species in mediating enhanced vasoconstrictor reactivity and pulmonary hypertension in both chronic hypoxia and hypoxia/SU5416 rat models, despite a paradoxical effect of antioxidant therapy to exacerbate arterial remodeling in animals with severe pulmonary arterial hypertension in the hypoxia/SU5416 model. PMID:28666030

Prolonged administration of a dithiol antioxidant protects against ventricular remodeling due to ischemia-reperfusion in mice.

PubMed

Ambler, S Kelly; Hodges, Yvonne K; Jones, Gayle M; Long, Carlin S; Horwitz, Lawrence D

2008-09-01

The prolonged production of reactive oxygen species due to ischemia-reperfusion (I/R) is a potential cause of the pathological remodeling that frequently precedes heart failure. We tested the ability of a potent dithiol antioxidant, bucillamine, to protect against the long-term consequences of I/R injury in a murine model of myocardial infarction. After transiently occluding the left anterior descending coronary artery for 30 min, saline or bucillamine (10 microg/g body wt) was injected intravenously as a bolus within the first 5 min of reperfusion. The antioxidant treatment continued with daily subcutaneous injections for 4 wk. There were no differences in infarct sizes between bucillamine- and saline-treated animals. After 4 wk of reperfusion, cardiac hypertrophy was decreased by bucillamine treatment (ventricular weight-to-body weight ratios: I/R + saline, 4.5 +/- 0.2 mg/g vs. I/R + bucillamine, 4.2 +/- 0.1 mg/g; means +/- SE; P < 0.05). Additionally, the hearts of bucillamine-treated mice had improved contractile function (echocardiographic measurement of fractional shortening) relative to saline controls: I/R + saline, 32 +/- 3%, versus I/R + bucillamine, 41 +/- 4% (P < 0.05). Finally, I/R-induced injury in the saline-treated mice was accompanied by a fetal pattern of gene expression determined by ribonuclease protection assay that was consistent with pathological cardiac hypertrophy and remodeling [increased atrial natriuretic peptide, beta-myosin heavy chain (MHC), skeletal alpha-actin; decreased sarco(endo)plasmic reticulum Ca2+ ATPase 2a, and alpha-MHC-to-beta-MHC ratio]. These changes in gene expression were significantly attenuated by bucillamine. Therefore, treatment with a dithiol antioxidant for 4 wk after I/R preserved ventricular function and prevented the abnormal pattern of gene expression associated with pathological cardiac remodeling.

Independent influences of excessive body weight and elevated blood pressure from childhood on left ventricular geometric remodeling in adulthood.

PubMed

Yan, Yinkun; Liu, Junting; Wang, Liang; Hou, Dongqing; Zhao, Xiaoyuan; Cheng, Hong; Mi, Jie

2017-09-15

Obesity and hypertension are two risk factors of left ventricular hypertrophy (LVH) in adults. We aimed to examine the impacts of body weight and blood pressure (BP) from childhood on adult LV geometric remodeling. The study cohort consisted of 1256 adults aged 27-42years who had 2-10 measurements of body mass index (BMI) and BP from childhood in 1987 to adulthood in 2010. We calculated the cumulative and incremental values of BMI and BP from childhood to adulthood. In adulthood, four LV geometric patterns were defined based on the values of left ventricular mass index (g/m 2.7 ) and relative wall thickness: normal geometry, concentric remodeling (CR), eccentric hypertrophy (EH) and concentric hypertrophy (CH). The prevalence of abnormal LV geometric patterns in adults was 26.4% for CR, 2.0% for EH and 2.5% for CH. For childhood values, systolic BP (Odds Ratio [OR]=1.26, 95% confidence interval [CI]=1.08-1.47) but not BMI (OR=1.06, 95%CI=0.93-1.18) was associated with adult CR, whereas BMI (OR=3.53, 95%CI=2.09-5.98) but not systolic BP (OR=1.04, 95%CI=0.65-1.66) was associated with adult EH. Both childhood BMI (OR=2.69, 95%CI=1.77-4.09) and systolic BP (OR=1.64, 95%CI=1.07-2.51) were independently associated with adult CH. For adulthood, cumulative and incremental values, BMI and systolic BP were independently associated with adult CR, EH and CH. Excessive body weight and elevated BP from childhood have independent influences on the development of adult LV geometric remodeling. Copyright © 2017 Elsevier B.V. All rights reserved.

Tricuspid regurgitation progression and regression in pulmonary arterial hypertension: implications for right ventricular and tricuspid valve apparatus geometry and patients outcome.

PubMed

Medvedofsky, Diego; Aronson, Doron; Gomberg-Maitland, Mardi; Thomeas, Vasiliki; Rich, Stuart; Spencer, Kirk; Mor-Avi, Victor; Addetia, Karima; Lang, Roberto M; Shiran, Avinoam

2017-01-01

The aim of this study was to determine the mechanism of tricuspid regurgitation (TR) progression in pulmonary arterial hypertension (PAH) and its effect on survival. We studied 88 patients with PAH and functional TR (mean pulmonary artery pressure 49 ± 14 mmHg; 43% idiopathic PAH) who had serial echocardiograms. TR progression (n = 35) was defined as ≤mild TR on Echo 1 and ≥moderate TR on Echo 2. TR regression (n = 17) was defined as ≥moderate TR on Echo 1 and ≤mild TR on Echo 2. Stable TR (n = 36) was defined as ≤mild TR on both echoes. TR progression was associated with an increase in pulmonary artery systolic pressure (PASP, 62 ± 22-92 ± 23 mmHg, P < 0.0001), right ventricular (RV) enlargement, mainly at mid-ventricular level, increased RV sphericity (6.1 ± 1.7-6.9 ± 1.8, P = 0.004), tricuspid annular (TA) dilatation (4.0 ± 0.7-4.6 ± 0.7 cm, P < 0.0001), and increased tricuspid valve (TV) tenting area (2.0 ± 0.7-2.5 ± 1.0 cm 2 , P = 0.0003). TR regression was associated with a reduction in PASP (84 ± 15-55 ± 18 mmHg, P < 0.0001), reverse RV remodelling with a reduction in RV sphericity (6.3 ± 1.4-5.5 ± 1.0, P = 0.02), and a reduction in TA size (4.1 ± 0.7-3.6 ± 0.7 cm, P = 0.02) and TV tenting (2.1 ± 0.7-1.3 ± 0.5 cm 2 , P = 0.0002). TR progression was associated with all-cause mortality (log-rank P = 0.0007). In PAH, TR progression was associated with worsening pulmonary hypertension and adverse RV and TV apparatus remodelling. TR progression is associated with poor outcome in PAH. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Impact of hypertension with or without diabetes on left ventricular remodeling in rural Chinese population: a cross-sectional study.

PubMed

Li, Tan; Chen, Shuang; Guo, Xiaofan; Yang, Jun; Sun, Yingxian

2017-07-27

The aim of this study was to assess the impact of hypertension with or without diabetes on left ventricular (LV) remodeling in rural Chinese population. A total of 10,270 participants were classified into control group, hypertension without diabetes (HT) group, and hypertension with diabetes (HT + DM) group. We compared clinical characteristics and echocardiographic parameters, and used multivariable logistic regression analysis to assess the associations of interest. HT + DM group had higher interventricular septal thickness (IVSd), posterior wall thickness (PWTd), left ventricular mass (LVM), LVM index (LVMI), relative wall thickness (RWT), left atrial diameter (LAD), A wave and lower E wave than HT group (all P < 0.05). The prevalence rates of left ventricular hypertrophy (LVH) and abnormal geometry were statistically different among three groups (P < 0.001) and eccentric hypertrophy was the highest proportion of geometry abnormality. Logistic regression analysis suggested that subjects in HT and HT + DM groups had odds ratio (OR) values of 2.81, 4.41, 2.24 and 3.94, 7.20, 2.38 for LVH, concentric hypertrophy and eccentric hypertrophy in the total population, respectively, compared to control group. When compared with HT group, those in HT + DM group had approximately 1.40-, 1.61- and 1.38-, 1.71-fold increased risk for LVH and concentric hypertrophy in the total and female population separately, but no association of HT + DM with LVH and abnormal geometrical patterns was found in men. This study demonstrated that, to varying degrees, hypertension was associated with LV remodeling in rural Chinese population, and this risk association was obviously increased for LVH and concentric hypertrophy when accompanied by diabetes, especially for women.

Continuous light and L-NAME-induced left ventricular remodelling: different protection with melatonin and captopril.

PubMed

Simko, Fedor; Pechanova, Olga; Pelouch, Vaclav; Krajcirovicova, Kristina; Celec, Peter; Palffy, Roland; Bednarova, Kristina; Vrankova, Stanislava; Adamcova, Michaela; Paulis, Ludovit

2010-09-01

Blood pressure enhancement induced by continuous light exposure represents an attractive but rarely investigated model of experimental hypertension. The aim of this study was to show whether the combination of continuous light (24 h/day) exposure and chronic N-nitro-L-arginine-methyl ester (L-NAME) treatment induces remodelling of the left ventricle and whether captopril or melatonin can modify these potential alterations. Six groups of 3-month-old Wistar rats (nine per group) were treated for 6 weeks: control (untreated), L-NAME (40 mg/kg per day), exposed to continuous light, L-NAME treated and exposed to continuous light (L24), L24 rats treated with either captopril 100 mg/kg per day, or melatonin (10 mg/kg/24 h). Systolic blood pressure (SBP), relative weights of the left ventricle, endothelial nitric oxide synthase (eNOS) and angiotensin-converting enzyme (ACE) expression in tissues, malondialdehyde and advanced oxidation protein product concentrations in the plasma and hydroxyproline levels in collagenous protein fractions were measured. The continuous light and L-NAME treatment led to hypertension, left ventricular hypertrophy (LVH) and fibrosis. An increase in SBP was completely prevented by captopril and partly by melatonin in the L24 group. Both drugs reduced oxidative damage and attenuated enhanced expression of ACE in the myocardium. Neither of the drugs prevented the attenuation of eNOS expression in the combined hypertensive model. Only captopril reduced LVH development in L24, whereas captopril and melatonin reduced left ventricular hydroxyproline concentrations in soluble and insoluble collagen, respectively. The total hydroxyproline concentration was reduced only by melatonin. In hypertension induced by a combination of continuous light and L-NAME treatment, melatonin and captopril protect the heart against pathological left ventricular remodelling differently.

Effects of exercise training on pulmonary vessel muscularization and right ventricular function in an animal model of COPD.

PubMed

Hassel, Erlend; Berre, Anne Marie; Skjulsvik, Anne Jarstein; Steinshamn, Sigurd

2014-09-28

Right ventricular dysfunction in COPD is common, even in the absence of pulmonary hypertension. The aim of the present study was to examine the effects of high intensity interval training (HIIT) on right ventricular (RV) function, as well as pulmonary blood vessel remodeling in a mouse model of COPD. 42 female A/JOlaHsd mice were randomized to exposure to either cigarette smoke or air for 6 hours/day, 5 days/week for 14 weeks. Mice from both groups were further randomized to sedentariness or HIIT for 4 weeks. Cardiac function was evaluated by echocardiography and muscularization of pulmonary vessel walls by immunohistochemistry. Smoke exposure induced RV systolic dysfunction demonstrated by reduced tricuspid annular plane systolic excursion. HIIT in smoke-exposed mice reversed RV dysfunction. There were no significant effects on the left ventricle of neither smoke exposure nor HIIT. Muscularization of the pulmonary vessels was reduced after exercise intervention, but no significant effects on muscularization were observed from smoke exposure. RV function was reduced in mice exposed to cigarette smoke. No Increase in pulmonary vessel muscularization was observed in these mice, implying that other mechanisms caused the RV dysfunction. HIIT attenuated the RV dysfunction in the smoke exposed mice. Reduced muscularization of the pulmonary vessels due to HIIT suggests that exercise training not only affects the heart muscle, but also has important effects on the pulmonary vasculature.

Cardiac resynchronization therapy for patients with cardiac sarcoidosis.

PubMed

Sairaku, Akinori; Yoshida, Yukihiko; Nakano, Yukiko; Hirayama, Haruo; Maeda, Mayuho; Hashimoto, Haruki; Kihara, Yasuki

2017-05-01

Sarcoidosis with cardiac involvement is a rare pathological condition, and therefore cardiac resynchronization therapy (CRT) for patients with cardiac sarcoidosis is even further rare. We aimed to clarify the clinical features of patients with cardiac sarcoidosis who received CRT. We retrospectively reviewed the clinical data on CRT at three cardiovascular centres to detect cardiac sarcoidosis patients. We identified 18 (8.9%) patients with cardiac sarcoidosis who met the inclusion criteria out of 202 with systolic heart failure who received CRT based on the guidelines. The majority of the patients were female [15 (83.3%)] and underwent an upgrade from a pacemaker or implantable cardioverter defibrillator [13 (72.2%)]. We found 1 (5.6%) cardiovascular death during the follow-up period (mean ± SD, 4.7 ± 3.0 years). Seven (38.9%) patients had a composite outcome of cardiovascular death or hospitalization from worsening heart failure within 5 years after the CRT. Twelve (66.7%) patients had a history of sustained ventricular arrhythmias or those occurring after the CRT. Among the overall patients, no significant improvement was found in either the end-systolic volume or left ventricular ejection fraction (LVEF) 6 months after the CRT. A worsening LVEF was, however, more likely to be seen in 5 (27.8%) patients with ventricular arrhythmias after the CRT than in those without (P = 0.04). An improved clinical composite score was seen in 10 (55.6%) patients. Cardiac sarcoidosis patients receiving CRT may have poor LV reverse remodelling and a high incidence of ventricular arrhythmias. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions please email: journals.permissions@oup.com.

Correlation between cardiac remodelling, function, and myocardial contractility in rat hearts 5 weeks after myocardial infarction.

PubMed

Gosselin, H; Qi, X; Rouleau, J L

1998-01-01

Early after infarction, ventricular dysfunction occurs as a result of loss of myocardial tissue. Although papillary muscle studies suggest that reduced myocardial contractility contributes to this ventricular dysfunction, in vivo studies indicate that at rest, cardiac output is normal or near normal, suggesting that contractility of the remaining viable myocardium of the ventricular wall is preserved. However, this has never been verified. To explore this further, 100 rats with various-sized myocardial infarctions had ventricular function assessed by Langendorff preparation or by isolated papillary muscle studies 5 weeks after infarction. Morphologic studies were also done. Rats with large infarctions (54%) had marked ventricular dilatation (dilatation index from 0.23 to 0.75, p < 0.01) and papillary muscle dysfunction (total tension from 6.7 to 3.2 g/mm2, p < 0.01) but only moderate left ventricular dysfunction (maximum developed tension from 206 to 151 mmHg (1 mmHg = 133.3 Pa), p < 0.01), a decrease less than one would expect with an infarct size of 54%. The contractility of the remaining viable myocardium of the ventricle was also moderately depressed (peak systolic midwall stress 91 to 60 mmHg, p < 0.01). Rats with moderate infarctions (32%) had less marked but still moderate ventricular dilatation (dilatation index 0.37, p < 0.001) and moderate papillary muscle dysfunction (total tension 4.2 g/mm2, p < 0.01). However, their decrease in ventricular function was only mild (maximum developed pressure 178 mmHg, p < 0.01) and less than one would expect with an infarct size of 32%. The remaining viable myocardium of the ventricular wall appeared to have normal contractility (peak systolic midwall stress = 86 mmHg, ns). We conclude that in this postinfarction model, in large myocardial infarctions, a loss of contractility of the remaining viable myocardium of the ventricular wall occurs as early as 5 weeks after infarction and that papillary muscle studies slightly overestimate the degree of ventricular dysfunction. In moderate infarctions, the remaining viable myocardium of the ventricular wall has preserved contractility while papillary muscle function is depressed. In this relatively early postinfarction phase, ventricular remodelling appears to help maintain left ventricular function in both moderate and large infarctions.

Pacing-induced chronic atrial fibrillation impairs sinus node function in dogs. Electrophysiological remodeling.

PubMed

Elvan, A; Wylie, K; Zipes, D P

1996-12-01

We assessed the effects of pacing-induced chronic atrial fibrillation (AF) on sinus node function, intra-atrial conduction, and atrial refractoriness. In 15 mongrel dogs (20 to 30 kg), AV nodal block was produced by radiofrequency catheter ablation, and a ventricular-inhibited (VVI) pacemaker (Minix 8330, Medtronic) was implanted and programmed to pace at 80 pulses per minute. In 11 of these dogs, right atrial endocardial pacing leads were connected to a pulse generator (Itrel 7432, Medtronic) and set at a rate of 20 Hz to induce AF. Corrected sinus node recovery time, P-wave duration, 24-hour Holter ECG to assess AF duration, maximal heart rate in response to isoproterenol (10 micrograms/min), intrinsic heart rate after administration of atropine (0.04 mg/kg) and propranolol (0.1 mg/kg), and atrial effective refractory periods (ERPs) were obtained at baseline (EPS-1) and after 2 to 6 weeks (EPS-2) of VVI pacing alone (n = 4) or VVI pacing and rapid atrial pacing (n = 11). At EPS-2, corrected sinus node recovery time and P-wave duration were prolonged, maximal heart rate and intrinsic heart rate were decreased, atrial ERPs were shortened, and the duration of AF was increased significantly compared with EPS-1. These changes partially reversed toward baseline 1 week after conversion to sinus rhythm. Sinus node function and AF inducibility observed in the control dogs that underwent ventricular pacing alone (n = 4) did not change. Pacing-induced chronic AF induces sinus node dysfunction, prolongs intra-atrial conduction time, shortens atrial refractoriness, and perpetuates AF, changes that reverse gradually after termination of AF.

Predictors of Left Ventricular Remodeling After Myocardial Infarction in Patients With a Patent Infarct Related Coronary Artery After Percutaneous Coronary Intervention (from the Post-Myocardial Infarction Remodeling Prevention Therapy [PRomPT] Trial).

PubMed

Garber, Leonid; McAndrew, Thomas C; Chung, Eugene S; Stancak, Branislav; Svendsen, Jesper H; Monteiro, Joao; Fischer, Trent M; Kueffer, Fred; Ryan, Thomas; Bax, Jeroen; Leon, Angel R; Stone, Gregg W

2018-06-01

Left ventricular (LV) remodeling after myocardial infarction (MI) is a strong predictor of heart failure and mortality. The predictors of long-term remodeling after MI have been incompletely studied. We therefore examined the correlates of LV remodeling in patients with large ST-segment elevation myocardial infarction and a patent infarct artery after percutaneous 2coronary intervention (PCI) from the randomized Post-Myocardial Infarction Remodeling Prevention Therapy trial. Peri-infarct pacing had a neutral effect on long-term remodeling in patients with large first MI. The present analysis includes 109 patients in whom an open artery was restored after PCI, and in whom LV end-diastolic volume (LVEDV) at baseline and 18 months was assessed by transthoracic echocardiography. Multivariable models were fit to identify the independent predictors of LVEDV at baseline and 18 months. By multivariable analysis, male sex (p = 0.004) and anterior MI location (p = 0.03) were independently associated with baseline LVEDV. The following variables were independent predictors of increased LVEDV at 18 months: younger age (p = 0.01), male sex (p = 0.03), peak creatine phosphokinase (p = 0.03), shorter time from MI to baseline transthoracic echocardiography (p = 0.04), baseline LVEDV (p < 0.0001), and lack of statin use (p = 0.03). In conclusion, patients with large MI and an open infarct artery after PCI, anterior MI location, and male sex were associated with greater baseline LVEDV, but MI location was not associated with 18-month LVEDV. In contrast, younger age, peak creatine phosphokinase, male sex, baseline LVEDV, and lack of statin use were associated with long-term LV remodeling. Copyright © 2018 Elsevier Inc. All rights reserved.

Advanced mitral-tricuspid disease with severe right ventricular dysfunction: the double-staged approach.

PubMed

Jouan, Jérôme; Achouh, Paul; Besson, Laila; Carpentier, Alain; Fabiani, Jean-Noël

2012-09-01

Tricuspid valve surgery in the presence of severe right ventricular dysfunction and pulmonary hypertension secondary to mitral valve stenosis is associated with poor early outcomes. We report the case of a young patient, presenting with severe chronic mitral-tricuspid disease responsible for long-lasting pulmonary hypertension and altered right ventricular function, who initially underwent mitral valve replacement and 7 days later the correction of her tricuspid insufficiency. This 2-staged approach permitted progressive reduction of pulmonary pressure and partial right ventricular remodeling before closing the systolic release valve of the right ventricle represented by tricuspid regurgitation. Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

MicroRNAs in right ventricular remodelling.

PubMed

Batkai, Sandor; Bär, Christian; Thum, Thomas

2017-10-01

Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

SERIAL ULTRASOUND EVALUATION OF INTRAMYOCARDIAL STRAIN AFTER REPERFUSED MYOCARDIAL INFARCTION REVEALS THAT REMOTE ZONE DYSSYNCHRONY DEVELOPS IN CONCERT WITH LEFT VENTRICULAR REMODELING

PubMed Central

Li, Yinbo; Garson, Christopher D.; Xu, Yaqin; Helm, Patrick A.; Hossack, John A.; French, Brent A.

2011-01-01

This study noninvasively evaluated the development of left ventricular (LV) dyssynchrony following reperfused myocardial infarction (MI) in mice using an ultrasonic speckle-tracking method. Eight C57BL/6J mice were assessed by high-resolution echocardiography at baseline and at eight time-points following MI. Images were acquired at 1mm elevational intervals encompassing the entire LV to determine chamber volumes and radial strain. Receiver-operating characteristic (ROC) analysis of regional radial strain was used to segment the three-dimensional (3-D) LV into infarct, adjacent and remote zones. This in vivo segmentation was correlated to histologic infarct size (R = 0.89, p < 0.01) in a short-axis, slice-by-slice comparison. The onset of dyssynchrony during LV remodeling was assessed by standard deviation of time to peak radial strain in the infarct, adjacent and remote zones. It was discovered that the form of LV dyssynchrony that develops in the remote zone late after MI does so in concert with the progression of LV remodeling (R = 0.70, p < 0.05). PMID:21640480

Association of dietary iron restriction with left ventricular remodeling after myocardial infarction in mice.

PubMed

Eguchi, Akiyo; Naito, Yoshiro; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Sawada, Hisashi; Nishimura, Koichi; Oboshi, Makiko; Fujii, Kenichi; Mano, Toshiaki; Masuyama, Tohru; Hirotani, Shinichi

2016-02-01

Several epidemiologic studies have reported that body iron status and dietary iron intake are related to an increased risk of acute myocardial infarction (MI). However, it is completely unknown whether dietary iron reduction impacts the development of left ventricular (LV) remodeling after MI. Here, we investigate the effect of dietary iron restriction on the development of LV remodeling after MI in an experimental model. MI was induced in C57BL/6 J mice (9-11 weeks of age) by the permanent ligation of the left anterior descending coronary artery (LAD). At 2 weeks after LAD ligation, mice were randomly divided into two groups and were given a normal diet or an iron-restricted diet for 4 weeks. Sham operation without LAD ligation was also performed as controls. MI mice exhibited increased LV dilatation and impaired LV systolic function that was associated with cardiomyocyte hypertrophy and interstitial fibrosis in the remote area, as compared with the controls at 6 weeks after MI. In contrast, dietary iron restriction attenuated LV dilatation and impaired LV systolic function coupled to cardiomyocyte hypertrophy and interstitial fibrosis in the remote area. Importantly, cardiac expression of cellular iron transport proteins, transferrin receptor 1 and divalent metal transporter 1 was increased in the remote area of MI mice compared with the controls. Dietary iron restriction attenuated the development of LV remodeling after MI in mice. Cellular iron transport might play a role in the pathophysiological mechanism of LV remodeling after MI.

Left ventricular structural and functional characteristics in Cushing's syndrome.

PubMed

Muiesan, Maria Lorenza; Lupia, Mario; Salvetti, Massimo; Grigoletto, Consuelo; Sonino, Nicoletta; Boscaro, Marco; Rosei, Enrico Agabiti; Mantero, Franco; Fallo, Francesco

2003-06-18

This study was designed to evaluate left ventricular (LV) anatomy and function in patients with Cushing's syndrome. A high prevalence of LV hypertrophy and concentric remodeling has been reported in Cushing's syndrome, although no data have been reported on LV systolic and diastolic function. Forty-two consecutive patients with Cushing's syndrome and 42 control subjects, matched for age, gender, and blood pressure, were studied. Left ventricular mass index (LVMI) and relative wall thickness (RWT) were measured by echocardiography, endocardial and midwall fractional shortening (FS) were assessed, and diastolic filling was measured by Doppler transmitral flow. The RWT was significantly greater in Cushing patients than in controls. Left ventricular hypertrophy and concentric remodeling were observed in 10 and 26 patients with Cushing's syndrome, respectively. In Cushing patients, midwall FS was significantly reduced compared with controls (16.2 +/- 3% vs. 21 +/- 4.5%, p = 0.01). The ratio of transmitral E and A flow velocities was reduced and E deceleration time was prolonged in Cushing patients compared with controls (p = 0.03 and p < 0.001, respectively). In patients with Cushing's syndrome, cardiac structural changes are associated with reduced midwall systolic performance and with diastolic dysfunction that may contribute to the high risk of cardiovascular events observed in these patients.

Prolonged intra-myocardial growth hormone administration ameliorates post-infarction electrophysiologic remodeling in rats.

PubMed

Kontonika, Marianthi; Barka, Eleonora; Roumpi, Maria; La Rocca, Vassilios; Lekkas, Panagiotis; Daskalopoulos, Evangelos P; Vilaeti, Agapi D; Baltogiannis, Giannis G; Vlahos, Antonios P; Agathopoulos, Simeon; Kolettis, Theofilos M

2017-02-01

Experimental studies indicate improved ventricular function after treatment with growth hormone (GH) post-myocardial infarction, but its effect on arrhythmogenesis is unknown. Here, we assessed the medium-term electrophysiologic remodeling after intra-myocardial GH administration in (n = 33) rats. GH was released from an alginate scaffold, injected around the ischemic myocardium after coronary ligation. Two weeks thereafter, ventricular tachyarrhythmias were induced by programmed electrical stimulation. Monophasic action potentials were recorded from the infarct border, coupled with evaluation of electrical conduction and repolarization from a multi-electrode array. The arrhythmia score was lower in GH-treated rats than in alginate-treated rats or controls. The shape and the duration of the action potential at the infarct border were preserved, and repolarization-dispersion was attenuated after GH; moreover, voltage rise was higher and activation delay was shorter. GH normalized also right ventricular parameters. Intra-myocardial GH preserved electrical conduction and repolarization-dispersion at the infarct border and decreased the incidence of induced tachyarrhythmias in rats post-ligation. The long-term antiarrhythmic potential of GH merits further study.

Novel pathogenetic mechanisms and structural adaptations in ischemic mitral regurgitation.

PubMed

Silbiger, Jeffrey J

2013-10-01

Ischemic mitral regurgitation (MR) is a common complication of myocardial infarction thought to result from leaflet tethering caused by displacement of the papillary muscles that occurs as the left ventricle remodels. The author explores the possibility that left atrial remodeling may also play a role in the pathogenesis of ischemic MR, through a novel mechanism: atriogenic leaflet tethering. When ischemic MR is hemodynamically significant, the left ventricle compensates by dilating to preserve forward output using the Starling mechanism. Left ventricular dilatation, however, worsens MR by increasing the mitral valve regurgitant orifice, leading to a vicious cycle in which MR begets more MR. The author proposes that several structural adaptations play a role in reducing ischemic MR. In contrast to the compensatory effects of left ventricular enlargement, these may reduce, rather than increase, its severity. The suggested adaptations involve the mitral valve leaflets, the papillary muscles, the mitral annulus, and the left ventricular false tendons. This review describes the potential role each may play in reducing ischemic MR. Therapies that exploit these adaptations are also discussed. Copyright © 2013 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.

Structural and Functional Phenotyping of the Failing Heart: Is the Left Ventricular Ejection Fraction Obsolete?

PubMed

Bristow, Michael R; Kao, David P; Breathett, Khadijah K; Altman, Natasha L; Gorcsan, John; Gill, Edward A; Lowes, Brian D; Gilbert, Edward M; Quaife, Robert A; Mann, Douglas L

2017-11-01

Diagnosis, prognosis, treatment, and development of new therapies for diseases or syndromes depend on a reliable means of identifying phenotypes associated with distinct predictive probabilities for these various objectives. Left ventricular ejection fraction (LVEF) provides the current basis for combined functional and structural phenotyping in heart failure by classifying patients as those with heart failure with reduced ejection fraction (HFrEF) and those with heart failure with preserved ejection fraction (HFpEF). Recently the utility of LVEF as the major phenotypic determinant of heart failure has been challenged based on its load dependency and measurement variability. We review the history of the development and adoption of LVEF as a critical measurement of LV function and structure and demonstrate that, in chronic heart failure, load dependency is not an important practical issue, and we provide hemodynamic and molecular biomarker evidence that LVEF is superior or equal to more unwieldy methods of identifying phenotypes of ventricular remodeling. We conclude that, because it reliably measures both left ventricular function and structure, LVEF remains the best current method of assessing pathologic remodeling in heart failure in both individual clinical and multicenter group settings. Because of the present and future importance of left ventricular phenotyping in heart failure, LVEF should be measured by using the most accurate technology and methodologic refinements available, and improved characterization methods should continue to be sought. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

"Reversibility of Cardiovascular Injury With CPAP Use: Mechanisms Involved"

ClinicalTrials.gov

2015-09-29

Sleep Apnea, Obstructive; Hypoxia; Hypercapnia; Sleep Disorders; Obesity; Hypertension; Coronary Artery Vasospasm; Right Ventricular Overload; Left Ventricular Function Systolic Dysfunction; Ventricular Hypertrophy

Electrophysiological and Structural Remodeling in Heart Failure Modulate Arrhythmogenesis. 2D Simulation Study

PubMed Central

Gomez, Juan F.; Cardona, Karen; Martinez, Laura; Saiz, Javier; Trenor, Beatriz

2014-01-01

Background Heart failure is operationally defined as the inability of the heart to maintain blood flow to meet the needs of the body and it is the final common pathway of various cardiac pathologies. Electrophysiological remodeling, intercellular uncoupling and a pro-fibrotic response have been identified as major arrhythmogenic factors in heart failure. Objective In this study we investigate vulnerability to reentry under heart failure conditions by incorporating established electrophysiological and anatomical remodeling using computer simulations. Methods The electrical activity of human transmural ventricular tissue (5 cm×5 cm) was simulated using the human ventricular action potential model Grandi et al. under control and heart failure conditions. The MacCannell et al. model was used to model fibroblast electrical activity, and their electrotonic interactions with myocytes. Selected degrees of diffuse fibrosis and variations in intercellular coupling were considered and the vulnerable window (VW) for reentry was evaluated following cross-field stimulation. Results No reentry was observed in normal conditions or in the presence of HF ionic remodeling. However, defined amount of fibrosis and/or cellular uncoupling were sufficient to elicit reentrant activity. Under conditions where reentry was generated, HF electrophysiological remodeling did not alter the width of the VW. However, intermediate fibrosis and cellular uncoupling significantly widened the VW. In addition, biphasic behavior was observed, as very high fibrotic content or very low tissue conductivity hampered the development of reentry. Detailed phase analysis of reentry dynamics revealed an increase of phase singularities with progressive fibrotic components. Conclusion Structural remodeling is a key factor in the genesis of vulnerability to reentry. A range of intermediate levels of fibrosis and intercellular uncoupling can combine to favor reentrant activity. PMID:25054335

Protease-Activated Receptor 1 Inhibition by SCH79797 Attenuates Left Ventricular Remodeling and Profibrotic Activities of Cardiac Fibroblasts

PubMed Central

Sonin, Dmitry L.; Wakatsuki, Tetsuro; Routhu, Kasi V.; Harmann, Leanne M.; Petersen, Matthew; Meyer, Jennifer; Strande, Jennifer L.

2013-01-01

Purpose Fibroblast activity promotes adverse left ventricular (LV) remodeling that underlies the development of ischemic cardiomyopathy. Transforming growth factor-β (TGF-β) is a potent stimulus for fibrosis, and the extracellular signal-regulated kinases(ERK) 1/2 pathway also contributes to the fibrotic response. The thrombin receptor, protease-activated receptor 1 (PAR1), has been shown to play an important role in the excessive fibrosis in different tissues. The aim of this study was to investigate the influence of a PAR1 inhibitor, SCH79797, on cardiac fibrosis, tissue stiffness and postinfarction remodeling, and effects of PAR1 inhibition on thrombin-induced TGF-β and (ERK) 1/2 activities in cardiac fibroblasts. Methods We used a rat model of myocardial ischemia–reperfusion injury, isolated cardiac fibroblasts, and 3-dimensional (3D) cardiac tissue models fabricated to ascertain the contribution of PAR1 activation on cardiac fibrosis and LV remodeling. Results The PAR1 inhibitor attenuated LV dilation and improved LV systolic function of the reperfused myocardium at 28 days. This improvement was associated with a nonsignificant decrease in scar size (%LV) from 23 ± % in the control group (n = 10) to 16% ± 5.5% in the treated group (n = 9; P = .052). In the short term, the PAR1 inhibitor did not rescue infarct size or LV systolic function after 3 days. The PAR1 inhibition abolished thrombin-mediated ERK1/2 phosphorylation, TGF-β and type I procollagen production, matrix metalloproteinase-2/9 activation, myofibroblasts transformation in vitro, and abrogated the remodeling of 3D tissues induced by chronic thrombin treatment. Conclusion These studies suggest PAR1 inhibition initiated after ischemic injury attenuates adverse LV remodeling through late-stage antifibrotic events. PMID:23598708

Post-infarct treatment with [Pyr1]apelin-13 exerts anti-remodelling and anti-apoptotic effects in rats' hearts.

PubMed

Azizi, Yaser; Imani, Alireza; Fanaei, Hamed; Khamse, Safoura; Parvizi, Mohammad Reza; Faghihi, Mahdieh

2017-01-01

Ischaemic heart disease is the main cause of mortality in the world. After myocardial infarction (MI) cardiomyocytes apoptosis and ventricular remodelling have occurred. Apelin is a peptide that has been shown to exert cardioprotective effects. The aim of this study was to investigate the anti-apoptotic and anti-remodelling effects of [Pyr¹]apelin-13 in the rat model of post-MI. Thirty-six male Wistar rats were randomly divided into three groups: (1) sham, (2) MI, and (3) MI treated with [Pyr¹] apelin-13 (MI+Apel). MI animals were subjected to 30-min ligation of the left anterior descending coronary artery (LAD) and 14 days of reperfusion. Twenty-four hours after LAD ligation, [Pyr¹]apelin-13 (10 nmol/kg/day, i.p.) was administered for five consecutive days. Hypertrophic parameters, left ventricular (LV) remodelling, and gene expression of Apel, apelin receptor (Apelr), Bax, caspase-3 (Casp-3), and Bcl-2 by real-time polymerase chain reaction and cardiomyocytes apoptosis by TUNEL immunostaining were assessed on day 14 post-MI. Post-infarct treatment with [Pyr¹]apelin-13 improved myocardial hypertrophic and LV remodelling parameters and led to a significant increase in the expression of Apel, Apelr, and Bcl-2, and a decrease in the expression of Bax and Casp-3. Furthermore, treatment with [Pyr¹]apelin-13 decreased cardiomyocyte apoptosis. [Pyr¹]apelin-13 has anti-hypertrophic, anti-remodelling, and anti-apoptotic effects via overexpression of Apel, Apelr, and Bcl-2 and reduces gene expression of Bax and Casp-3 in the infarcted myocardium, which can in turn lead to repair myocardium.

Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept.

PubMed

Klein, Franziska J; Bell, Stephen; Runte, K Elisabeth; Lobel, Robert; Ashikaga, Takamuru; Lerman, Lilach O; LeWinter, Martin M; Meyer, Markus

2016-10-01

Lowering the heart rate is considered to be beneficial in heart failure (HF) with reduced ejection fraction (HFrEF). In a dilated left ventricle (LV), pharmacological heart rate lowering is associated with a reduction in LV chamber size. In patients with HFrEF, this structural change is associated with better survival. HF with preserved ejection fraction (HFpEF) is increasingly prevalent but, so far, without any evidence-based treatment. HFpEF is typically associated with LV concentric remodeling and hypertrophy. The effects of heart rate on this structural phenotype are not known. Analogous with the benefits of a low heart rate on a dilated heart, we hypothesized that increased heart rates could lead to potentially beneficial remodeling of a concentrically hypertrophied LV. This was explored in an established porcine model of concentric LV hypertrophy and fibrosis. Our results suggest that a moderate increase in heart rate can be used to reduce wall thickness, normalize LV chamber volumes, decrease myocardial fibrosis, and improve LV compliance. Our results also indicate that the effects of heart rate can be titrated, are reversible, and do not induce HF. These findings may provide the rationale for a novel therapeutic approach for HFpEF and its antecedent disease substrate. Copyright © 2016 the American Physiological Society.

Design of the heart failure endpoint evaluation of AII-antagonist losartan (HEAAL) study in patients intolerant to ACE-inhibitor.

PubMed

Konstam, Marvin A; Poole-Wilson, Philip A; Dickstein, Kenneth; Drexler, Helmut; Justice, Steven J; Komajda, Michel; Malbecq, William; Martinez, Felipe A; Neaton, James D; Riegger, Gunter A J; Guptha, Soneil

2008-09-01

In patients with heart failure and reduced left ventricular ejection fraction, angiotensin receptor blockers have been found to reduce mortality and morbidity and to prevent or reverse left ventricular remodelling, compared to optimized background treatment. In light of these data, The Heart failure Endpoint evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was developed to determine whether losartan 150 mg is superior to losartan 50 mg (antihypertensive dose) in reducing morbidity and mortality among patients with symptomatic heart failure who are intolerant of angiotensin-converting enzyme (ACE)-inhibitors. To compare the effect of high and moderate doses of losartan on the primary endpoint of all-cause mortality and hospitalisation due to heart failure in patients (n = 3834) with symptomatic heart failure and an ejection fraction < or = 40% who are intolerant of ACE-inhibitor treatment. This paper presents the rationale, trial design, and baseline characteristics of the study population. The study, which completed recruitment on 31 March 2005, is event-driven and is estimated to accrue the target of 1710 adjudicated primary events during the latter half of 2008. The results of HEAAL should facilitate selection of an optimal dosing regimen for losartan in patients with symptomatic heart failure who are intolerant of ACE-inhibitors.

Usefulness of cardiac resynchronization therapy in the management of Doxorubicin-induced cardiomyopathy.

PubMed

Ajijola, Olujimi A; Nandigam, K Veena; Chabner, Bruce A; Orencole, Mary; Dec, G William; Ruskin, Jeremy N; Singh, Jagmeet P

2008-05-01

Doxorubicin is a widely used antineoplastic agent that may cause irreversible dilated cardiomyopathy. Doxorubicin-induced cardiomyopathy (DIC) can occur several years after exposure and carries a poor prognosis. Although cardiac resynchronization therapy (CRT) is a useful intervention in end-stage heart failure unresponsive to optimal medical therapies, its efficacy in DIC remains unknown. Four consecutive patients receiving CRT for DIC were evaluated before and after CRT. CRT resulted in improvements in the mean left ventricular ejection fraction at 1 month from 21+/-4.7% to 34+/-5% (p=0.03) and at 6 months (to 46+/-7.5%, p=0.01). CRT-induced reverse remodeling was observed, with a mean reduction in left ventricular internal diameter at end-diastole from 54.75+/-3.7 to 52.5+/-1.9 mm at 1 month (p=0.06) and further to 47+/-2.3 mm at 6 months (p=0.03). All patients experienced reductions in heart failure symptoms and improvements in New York Heart Association functional class (p<0.05). The impact of CRT was sustained over a follow-up of 18.5+/-3.5 months. In conclusion, this study suggests that patients with DIC, refractory to optimal pharmacologic therapy and meeting criteria for resynchronization device implantation, may achieve sustained benefit from CRT.

Beta-erythropoietin effects on ventricular remodeling, left and right systolic function, pulmonary pressure, and hospitalizations in patients affected with heart failure and anemia.

PubMed

Palazzuoli, Alberto; Silverberg, Donald S; Calabrò, Anna; Spinelli, Tommaso; Quatrini, Ilaria; Campagna, Maria S; Franci, Beatrice; Nuti, Ranuccio

2009-06-01

Anemia in heart failure is related to advanced New York Heart Association classes, severe systolic dysfunction, and reduced exercise tolerance. Although anemia is frequently found in congestive heart failure (CHF), little is known about the effect of its' correction with erythropoietin (EPO) on cardiac structure and function. The present study examines, in patients with advanced CHF and anemia, the effects of beta-EPO on left ventricular volumes, left ventricular ejection fraction (LVEF), left and right longitudinal function mitral anular plane systolic excursion (MAPSE), tricuspid anular plane excursion (TAPSE), and pulmonary artery pressures in 58 patients during 1-year follow-up in a double-blind controlled study of correction of anemia with subcutaneous beta-EPO. Echocardiographic evaluation, B-Type natriuretic peptide (BNP) levels, and hematological parameters are reported at 4 and 12 months. The patients in group A after 4 months of follow-up period demonstrated an increase in LVEF and MAPSE (P < 0.05 and P < 0.01, respectively) with left ventricular systolic volume reduction (P < 0.02) with respect to baseline and controls. After 12 months, results regarding left ventricular systolic volume LVEF and MAPSE persisted (P < 0.001). In addition, TAPSE increased and pulmonary artery pressures fell significantly in group A (P < 0.01). All these changes occurred together with a significant BNP reduction and significant hemoglobin increase in the treated group. Therefore, we revealed a reduced hospitalization rate in treated patients with respect to the controls (25% in treated vs. 54% in controls). In patients with anemia and CHF, correction of anemia with beta-EPO and oral iron over 1 year leads to an improvement in left and right ventricular systolic function by reducing cardiac remodeling, BNP levels, and hospitalization rate.

Effect of Sleep Apnea and Continuous Positive Airway Pressure on Cardiac Structure and Recurrence of Atrial Fibrillation

PubMed Central

Neilan, Tomas G.; Farhad, Hoshang; Dodson, John A.; Shah, Ravi V.; Abbasi, Siddique A.; Bakker, Jessie P.; Michaud, Gregory F.; van der Geest, Rob; Blankstein, Ron; Steigner, Michael; John, Roy M.; Jerosch‐Herold, Michael; Malhotra, Atul; Kwong, Raymond Y.

2013-01-01

Background Sleep apnea (SA) is associated with an increased risk of atrial fibrillation (AF). We sought to determine the effect of SA on cardiac structure in patients with AF, whether therapy for SA was associated with beneficial cardiac structural remodelling, and whether beneficial cardiac structural remodelling translated into a reduced risk of recurrence of AF after pulmonary venous isolation (PVI). Methods and Results A consecutive group of 720 patients underwent a cardiac magnetic resonance study before PVI. Patients with SA (n=142, 20%) were more likely to be male, diabetic, and hypertensive and have an increased pulmonary artery pressure, right ventricular volume, atrial dimensions, and left ventricular mass. Treated SA was defined as duration of continuous positive airway pressure therapy of >4 hours per night. Treated SA patients (n=71, 50%) were more likely to have paroxysmal AF, a lower blood pressure, lower ventricular mass, and smaller left atrium. During a follow‐up of 42 months, AF recurred in 245 patients. The cumulative incidence of AF recurrence was 51% in patients with SA, 30% in patients without SA, 68% in patients with untreated SA, and 35% in patients with treated SA. In a multivariable model, the presence of SA (hazard ratio 2.79, CI 1.97 to 3.94, P<0.0001) and untreated SA (hazard ratio 1.61, CI 1.35 to 1.92, P<0.0001) were highly associated with AF recurrence. Conclusions Patients with SA have an increased blood pressure, pulmonary artery pressure, right ventricular volume, left atrial size, and left ventricular mass. Therapy with continuous positive airway pressure is associated with lower blood pressure, atrial size, and ventricular mass, and a lower risk of AF recurrence after PVI. PMID:24275628

Prognostic heterogeneity of diastolic abnormalities along left ventricular remodeling continuum according to survival rates and laser polarimetry of blood

NASA Astrophysics Data System (ADS)

Boychuk, T. M.; Ivashchuk, O. I.; Kolomoiets, M. Y.; Mikhaliev, K. O.; Chursina, T. Y.

2011-09-01

The results of examination of 35 arterial hypertension and coronary heart disease patients are presented. The clinical, paraclinical and echocardiographic examinations were performed, and the parameters of prognosis (survival) according to Seattle Heart Failure Model, as well as the optical (polarimetric) properties of erythrocytic suspension were determined. The group of patients under examination was stratified by patterns of remodeling of left ventricle (LV). It was determined that increasing of anisotropy of erythrocytic suspension along LV remodeling patterns continuum correlates with aggravation of structural and functional state of LV and is associated with unfavorable prognosis.

Prognosis parameters and polarimetric properties of erythrocytes of the patients suffering from arterial hypertension and coronary heart disease at various patterns of left ventricular remodeling

NASA Astrophysics Data System (ADS)

Ivaschuk, Oleg I.; Kolomoiets, M. Y.; Mikhaliev, K. O.; Chursina, T. Ya.

2011-09-01

The results of examination of 35 arterial hypertension and coronary heart disease patients are presented. The clinical, paraclinical and echocardiographic examinations were performed, and the parameters of prognosis (survival) according to Seattle Heart Failure Model, as well as the optical (polarimetric) properties of erythrocytic suspension were determined. The group of patients under examination was stratified by patterns of remodeling of left ventricle (LV). It was determined that increasing of anisotropy of erythrocytic suspension along LV remodeling patterns continuum correlates with aggravation of structural and functional state of LV and is associated with unfavorable prognosis.

Mechanisms of Post-Infarct Left Ventricular Remodeling

PubMed Central

French, Brent A.; Kramer, Christopher M.

2008-01-01

Heart failure secondary to myocardial infarction (MI) remains a major source of morbidity and mortality. Long-term outcome after MI can be largely be defined in terms of its impact on the size and shape of the left ventricle (i.e., LV remodeling). Three major mechanisms contribute to LV remodeling: 1) early infarct expansion, 2) subsequent infarct extension into adjacent noninfarcted myocardium, and 3) late hypertrophy in the remote LV. Future developments in preventing post-MI heart failure will depend not only on identifying drugs targeting each of these individual mechanisms, but also on diagnostic techniques capable of assessing efficacy against each mechanism. PMID:18690295

Cerebrovasculoprotective Effects of Azilsartan Medoxomil in Diabetes

PubMed Central

Abdelsaid, Mohammed; Coucha, Maha; Ergul, Adviye

2014-01-01

We have shown that Goto-Kakizaki (GK) rats, a lean model of type 2 diabetes, develop significant cerebrovascular remodeling by 18 weeks of age, which is characterized by increased media thickness and matrix deposition. While early glycemic control prevents diabetes-mediated remodeling of the cerebrovasculature, whether the remodeling can be reversed is unknown. Given that angiotensin II Type 1 receptor blockers (ARBs) reverse pathological vascular remodeling and function independent of changes in blood pressure in other vascular beds, we hypothesized that azilsartan medoxomil, a new ARB, is vasculoprotective by preventing and reversing cerebrovascular remodeling in diabetes. Control Wistar and diabetic GK rats (n=6–8/group), were treated with vehicle (water) or azilsartan medoxomil (3 mg/kg/day) from 14 to 18 or 18 to 22 weeks of age before or after vascular remodeling is established, respectively. Blood glucose and blood pressure were monitored and middle cerebral artery structure and function were evaluated using pressurized arteriography. Blood glucose was higher in GK rats compared to Wistar rats. Azilsartan treatment lowered blood glucose in diabetes with no effect on blood pressure. Diabetic animals exhibited lower myogenic tone, increased wall thickness, and cross sectional area compared to controls, which were corrected by azilsartan treatment when started at the onset of diabetes or later after vascular remodeling is established. Azilsartan medoxomil offers preventive and therapeutic vasculoprotection in diabetes-induced cerebrovascular remodeling and myogenic dysfunction and this is independent of blood pressure. PMID:24999268

Mechanical compression and hydrostatic pressure induce reversible changes in actin cytoskeletal organisation in chondrocytes in agarose.

PubMed

Knight, M M; Toyoda, T; Lee, D A; Bader, D L

2006-01-01

In numerous cell types, the cytoskeleton has been widely implicated in mechanotransduction pathways involving stretch-activated ion channels, integrins and deformation of intracellular organelles. Studies have also demonstrated that the cytoskeleton can undergo remodelling in response to mechanical stimuli such as tensile strain or fluid flow. In articular chondrocytes, the mechanotransduction pathways are complex, inter-related and as yet, poorly understood. Furthermore, little is known of how the chondrocyte cytoskeleton responds to physiological mechanical loading. This study utilises the well-characterised chondrocyte-agarose model and an established confocal image-analysis technique to demonstrate that both static and cyclic, compressive strain and hydrostatic pressure all induce remodelling of actin microfilaments. This remodelling was characterised by a change from a uniform to a more punctate distribution of cortical actin around the cell periphery. For some loading regimes, this remodelling was reversed over a subsequent 1h unloaded period. This reversible remodelling of actin cytoskeleton may therefore represent a mechanism through which the chondrocyte alters its mechanical properties and mechanosensitivity in response to physiological mechanical loading.

Divergent Effects of Losartan and Metoprolol on Cardiac Remodeling, C‐kit+ Cells, Proliferation and Apoptosis in the Left Ventricle after Myocardial Infarction

PubMed Central

Serpi, Raisa; Tolonen, Anna‐Maria; Tenhunen, Olli; Pieviläinen, Oskari; Kubin, Anna‐Maria; Vaskivuo, Tommi; Soini, Ylermi; Kerkelä, Risto; Leskinen, Hanna; Ruskoaho, Heikki

2009-01-01

Abstract There is strong evidence for the use of angiotensin converting enzyme inhibitors and beta‐blockers to reduce morbidity and mortality in patients with myocardial infarction (MI), whereas the effect of angiotensin receptor blockers is less clear. We evaluated the effects of an angiotensin receptor blocker losartan and a beta‐blocker metoprolol on left ventricular (LV) remodeling, c‐kit+ cells, proliferation, fibrosis, apoptosis, and angiogenesis using a model of coronary ligation in rats. Metoprolol treatment for 2 weeks improved LV systolic function. In contrast, losartan triggered deleterious structural remodeling and functional deterioration of LV systolic function, ejection fraction being 41% and fractional shortening 47% lower in losartan group than in controls 2 weeks after MI. The number of c‐kit+ cells as well as expression of Ki‐67 was increased by metoprolol. Losartan‐induced thinning of the anterior wall and ventricular dilation were associated with increased apoptosis and fibrosis, while losartan had no effect on the expression of c‐kit or Ki‐67. Metoprolol or losartan had no effect on microvessel density. These results demonstrate that beta‐blocker treatment attenuated adverse remodeling via c‐kit+ cells and proliferation, whereas angiotensin receptor blocker‐induced worsening of LV systolic function was associated with increased apoptosis and fibrosis in the peri‐infarct region. PMID:20443934

Sildenafil ameliorates left ventricular T-tubule remodeling in a pressure overload-induced murine heart failure model

PubMed Central

Huang, Chun-kai; Chen, Bi-yi; Guo, Ang; Chen, Rong; Zhu, Yan-qi; Kutschke, William; Hong, Jiang; Song, Long-sheng

2016-01-01

Aim: Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, has been shown to exert beneficial effects in heart failure. The purpose of this study was to test whether sildenafil suppressed transverse-tubule (T-tubule) remodeling in left ventricular (LV) failure and thereby providing the therapeutic benefits. Methods: A pressure overload-induced murine heart failure model was established in mice by thoracic aortic banding (TAB). One day after TAB, the mice received sildenafil (100 mg·kg−1·d−1, sc) or saline for 5 weeks. At the end of treatment, echocardiography was used to examine LV function. Then the intact hearts were dissected out and placed in Langendorff-perfusion chamber for in situ confocal imaging of T-tubule ultrastructure from epicardial myocytes. Results: TAB surgery resulted in heart failure accompanied by remarkable T-tubule remodeling. Sildenafil treatment significantly attenuated TAB-induced cardiac hypertrophy and congestive heart failure, improved LV contractile function, and preserved T-tubule integrity in LV cardiomyocytes. But sildenafil treatment did not significantly affect the chamber dilation. The integrity of LV T-tubule structure was correlated with cardiac hypertrophy (R2=0.74, P<0.01) and global LV function (R2=0.47, P<0.01). Conclusion: Sildenafil effectively ameliorates LV T-tubule remodeling in TAB mice, revealing a novel mechanism underlying the therapeutic benefits of sildenafil in heart failure. PMID:26972492

The role of the sca-1+/CD31- cardiac progenitor cell population in postinfarction left ventricular remodeling.

PubMed

Wang, Xiaohong; Hu, Qingsong; Nakamura, Yasuhiro; Lee, Joseph; Zhang, Ge; From, Arthur H L; Zhang, Jianyi

2006-07-01

Cardiac stem cell-like populations exist in adult hearts, and their roles in cardiac repair remain to be defined. Sca-1 is an important surface marker for cardiac and other somatic stem cells. We hypothesized that heart-derived Sca-1(+)/CD31(-) cells may play a role in myocardial infarction-induced cardiac repair/remodeling. Mouse heart-derived Sca-1(+)/CD31(-) cells cultured in vitro could be induced to express both endothelial cell and cardiomyocyte markers. Immunofluorescence staining and fluorescence-activated cell sorting analysis indicated that endogenous Sca-1(+)/CD31(-) cells were significantly increased in the mouse heart 7 days after myocardial infarction (MI). Western blotting confirmed elevated Sca-1 protein expression in myocardium 7 days after MI. Transplantation of Sca-1(+)/CD31(-) cells into the acutely infarcted mouse heart attenuated the functional decline and adverse structural remodeling initiated by MI as evidenced by an increased left ventricular (LV) ejection fraction, a decreased LV end-diastolic dimension, a decreased LV end-systolic dimension, a significant increase of myocardial neovascularization, and modest cardiomyocyte regeneration. Attenuation of LV remodeling was accompanied by remarkably improved myocardial bioenergetic characteristics. The beneficial effects of cell transplantation appear to primarily depend on paracrine effects of the transplanted cells on new vessel formation and native cardiomyocyte function. Sca-1(+)/CD31(-) cells may hold therapeutic possibilities with regard to the treatment of ischemic heart disease.

Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction

PubMed Central

Yoshizumi, Tomo; Zhu, Yang; Jiang, Hongbin; D’Amore, Antonio; Sakaguchi, Hirokazu; Tchao, Jason; Tobita, Kimimasa; Wagner, William R.

2016-01-01

Intramyocardial injection of various injectable hydrogel materials has shown benefit in positively impacting the course of left ventricular (LV) remodeling after myocardial infarction (MI). However, since LV remodeling is a complex, time dependent process, the most efficacious time of hydrogel injection is not clear. In this study, we injected a relatively stiff, thermoresponsive and bioabsorbable hydrogel in rat hearts at 3 different time points - immediately after MI (IM), 3 d post-MI (3D), and 2 w post-MI (2W), corresponding to the beginnings of the necrotic, fibrotic and chronic remodeling phases. The employed left anterior descending coronary artery ligation model showed expected infarction responses including functional loss, inflammation and fibrosis with distinct time dependent patterns. Changes in LV geometry and contractile function were followed by longitudinal echocardiography for 10 w post-MI. While all injection times positively affected LV function and wall thickness, the 3D group gave better functional outcomes than the other injection times and also exhibited more local vascularization and less inflammatory markers than the earlier injection time. The results indicate an important role for injection timing in the increasingly explored concept of post-MI biomaterial injection therapy and suggest that for hydrogels with mechanical support as primary function, injection at the beginning of the fibrotic phase may provide improved outcomes. PMID:26774561

Timing effect of intramyocardial hydrogel injection for positively impacting left ventricular remodeling after myocardial infarction.

PubMed

Yoshizumi, Tomo; Zhu, Yang; Jiang, Hongbin; D'Amore, Antonio; Sakaguchi, Hirokazu; Tchao, Jason; Tobita, Kimimasa; Wagner, William R

2016-03-01

Intramyocardial injection of various injectable hydrogel materials has shown benefit in positively impacting the course of left ventricular (LV) remodeling after myocardial infarction (MI). However, since LV remodeling is a complex, time dependent process, the most efficacious time of hydrogel injection is not clear. In this study, we injected a relatively stiff, thermoresponsive and bioabsorbable hydrogel in rat hearts at 3 different time points - immediately after MI (IM), 3 d post-MI (3D), and 2 w post-MI (2W), corresponding to the beginnings of the necrotic, fibrotic and chronic remodeling phases. The employed left anterior descending coronary artery ligation model showed expected infarction responses including functional loss, inflammation and fibrosis with distinct time dependent patterns. Changes in LV geometry and contractile function were followed by longitudinal echocardiography for 10 w post-MI. While all injection times positively affected LV function and wall thickness, the 3D group gave better functional outcomes than the other injection times and also exhibited more local vascularization and less inflammatory markers than the earlier injection time. The results indicate an important role for injection timing in the increasingly explored concept of post-MI biomaterial injection therapy and suggest that for hydrogels with mechanical support as primary function, injection at the beginning of the fibrotic phase may provide improved outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Time Course of Electrical Remodeling of Native Conduction After Cardiac Resynchronization Therapy and Its Impact on Clinical Outcome.

PubMed

Cvijić, Marta; Žižek, David; Antolič, Bor; Zupan, Igor

2017-03-01

Cardiac resynchronization therapy (CRT) induces structural and electrical remodeling (ER) in heart failure (HF) patients. Our aim was to assess time course of ER of native conduction and mechanical remodeling after CRT and impact of CRT-induced ER on clinical outcome. We prospectively included 62 patients (aged 66 ± 10 years). Echocardiographic and ECG parameters were measured at baseline and 1, 3, 6, 9, and 12 months after implantation. Biventricular pacing was temporary inhibited during each follow-up to record intrinsic ECG. ER was defined as a decrease in native pre-implantation QRS duration ≥10 ms. During follow-up HF hospitalizations, cardiovascular death and transplantation (combined end point) were recorded. There were significant changes in intrinsic ECG parameters during follow-up; the narrowing of QRS duration was already observed after 1 month (median 185 ms [interquartile range (IQR) 175-194] vs 180 ms [170-194]; P < .001). Left ventricular (LV) volumes decreased only after 3 months of CRT (median end-systolic volume 167 mL [137-206] vs 140 mL [112-196]; P < .001). Only patients with ER (n = 24) exhibited significant mechanical remodeling and showed superior survival free from the combined end point compared with patients without ER (log-rank P = .028). Electrical remodeling of native conduction precedes detectable left ventricular structural changes after CRT. ER of native conduction is associated with better clinical outcome following CRT. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardioprotection Induced by Activation of GPER in Ovariectomized Rats With Pulmonary Hypertension.

PubMed

Alencar, Allan K N; Montes, Guilherme C; Costa, Daniele G; Mendes, Luiza V P; Silva, Ananssa M S; Martinez, Sabrina T; Trachez, Margarete M; Cunha, Valéria do M N; Montagnoli, Tadeu L; Fraga, Aline G M; Wang, Hao; Groban, Leanne; Fraga, Carlos A M; Sudo, Roberto T; Zapata-Sudo, Gisele

2018-05-21

Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1), and is associated with cardiac and skeletal muscle dysfunction. Herein, the activation of a new estrogen receptor (GPER) by the agonist G1 was evaluated in oophorectomized rats with monocrotaline (MCT)-induced PH. Depletion of estrogen was induced by bilateral oophorectomy (OVX) in Wistar rats. Experimental groups included SHAM or OVX rats that received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Animals received s.c. injection of either vehicle or G1, a GPER agonist, (400 µg/kg/day) for 14 days after the onset of disease. Rats with PH exhibited exercise intolerance and cardiopulmonary alterations, including reduced pulmonary artery flow, biventricular remodeling, and left ventricular systolic and diastolic dysfunction. The magnitude of these PH-induced changes was significantly greater in OVX versus SHAM rats. G1 treatment reversed both cardiac and skeletal muscle functional aberrations caused by PH in OVX rats. G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in females after the loss of endogenous estrogens.

Myocardial Adeno-Associated Virus Serotype 6–βARKct Gene Therapy Improves Cardiac Function and Normalizes the Neurohormonal Axis in Chronic Heart Failure

PubMed Central

Rengo, Giuseppe; Lymperopoulos, Anastasios; Zincarelli, Carmela; Donniacuo, Maria; Soltys, Stephen; Rabinowitz, Joseph E.; Koch, Walter J.

2009-01-01

Background The upregulation of G protein–coupled receptor kinase 2 in failing myocardium appears to contribute to dysfunctional β-adrenergic receptor (βAR) signaling and cardiac function. The peptide βARKct, which can inhibit the activation of G protein–coupled receptor kinase 2 and improve βAR signaling, has been shown in transgenic models and short-term gene transfer experiments to rescue heart failure (HF). This study was designed to evaluate long-term βARKct expression in HF with the use of stable myocardial gene delivery with adeno-associated virus serotype 6 (AAV6). Methods and Results In HF rats, we delivered βARKct or green fluorescent protein as a control via AAV6-mediated direct intramyocardial injection. We also treated groups with concurrent administration of the β-blocker metoprolol. We found robust and long-term transgene expression in the left ventricle at least 12 weeks after delivery. βARKct significantly improved cardiac contractility and reversed left ventricular remodeling, which was accompanied by a normalization of the neurohormonal (catecholamines and aldosterone) status of the chronic HF animals, including normalization of cardiac βAR signaling. Addition of metoprolol neither enhanced nor decreased βARKct-mediated beneficial effects, although metoprolol alone, despite not improving contractility, prevented further deterioration of the left ventricle. Conclusions Long-term cardiac AAV6-βARKct gene therapy in HF results in sustained improvement of global cardiac function and reversal of remodeling at least in part as a result of a normalization of the neurohormonal signaling axis. In addition, βARKct alone improves outcomes more than a β-blocker alone, whereas both treatments are compatible. These findings show that βARKct gene therapy can be of long-term therapeutic value in HF. PMID:19103992

Multipoint Pacing versus conventional ICD in Patients with a Narrow QRS complex (MPP Narrow QRS trial): study protocol for a pilot randomized controlled trial.

PubMed

Gasparini, Maurizio; Galimberti, Paola; Bragato, Renato; Ghio, Stefano; Raineri, Claudia; Landolina, Maurizio; Chieffo, Enrico; Lunati, Maurizio; Mulargia, Ederina; Proclemer, Alessandro; Facchin, Domenico; Rordorf, Roberto; Vicentini, Alessandro; Marcantoni, Lina; Zanon, Francesco; Klersy, Catherine

2016-12-03

Despite an intensive search for predictors of the response to cardiac resynchronization therapy (CRT), the QRS duration remains the simplest and most robust predictor of a positive response. QRS duration of ≥ 130 ms is considered to be a prerequisite for CRT; however, some studies have shown that CRT may also be effective in heart failure (HF) patients with a narrow QRS (<130 ms). Since CRT can now be performed by pacing the left ventricle from multiple vectors via a single quadripolar lead, it is possible that multipoint pacing (MPP) might be effective in HF patients with a narrow QRS. This article reports the design of the MPP Narrow QRS trial, a prospective, randomized, multicenter, controlled feasibility study to investigate the efficacy of MPP using two LV pacing vectors in patients with a narrow QRS complex (100-130 ms). Fifty patients with a standard ICD indication will be enrolled and randomized (1:1) to either an MPP group or a Standard ICD group. All patients will undergo a low-dose dobutamine stress echo test and only those with contractile reserve will be included in the study and randomized. The primary endpoint will be the percentage of patients in each group that have reverse remodeling at 12 months, defined as a reduction in left ventricular end-systolic volume (LVESV) of >15% from the baseline. This feasibility study will determine whether MPP improves reverse remodeling, as compared with standard ICD, in HF patients who have a narrow QRS complex (100-130 ms). ClinicalTrials.gov, NCT02402816 . Registered on 25 March 2015.

Metoprolol Inhibits Cardiac Apoptosis and Fibrosis in a Canine Model of Chronic Obstructive Sleep Apnea.

PubMed

Li, Wenpeng; Yan, Sen; Zhao, Jing; Ding, Xue; Zhang, Song; Wang, Dingyu; Liu, Lei; Peng, Wenpeng; Li, Hui; Wang, Dongyang; Liu, Zhaorui; Li, Yue

2015-01-01

Emerging evidence suggested that obstructive sleep apnea (OSA) was independently associated with the development of heart failure. In this study, we explored the influence of chronic OSA on left ventricular structural remodeling in canines, and the potential therapeutical role of metoprolol. Chronic OSA model was established by stopping the ventilator and closing the airway for 4 h/day apnea-ventilation cycles every other day for 12 weeks while metoprolol (5 mg· kg(-1)· day(-1)) were administered continuously. Norepinephrine concentration was measured by Enzyme Linked Immunosorbent Assay. Transmission electron microscopy, Hematoxylin and eosin, TUNEL and Masson trichrome staining were employed to detect the morphology, apoptosis and fibrosis of cardiomyocytes. Protein expression of apoptosis and fibrosis-related factors including apoptosis-inducing factor (AIF), caspase 3, Bcl-2, Bax, α-smooth muscle actin (α-SMA), transforming growth factor-β1 (TGF-β1), and p38 mitogen-activated protein kinase (MAPK) were examined by Western blotting. Norepinephrine concentration was markedly increased in chronic OSA dogs and reduced by metoprolol. Both the apoptotic ratio and collagen volume fraction were significantly increased in left ventricular myocytes of chronic OSA dogs, and was reversed by metoprolol. Moreover, chronic OSA-induced upregulation of AIF, cleaved caspase 3, Bax, α-SMA, and TGF-β1 as well as downregulation of Bcl-2 was markedly recovered by metoprolol, which was mediated by p38 MAPK. Metoprolol protects against chronic OSA-induced cardiac apoptosis and fibrosis in left ventricular myocytes of canines, which may provide new potential strategy for drug therapy of OSA. © 2015 S. Karger AG, Basel.

Reversal of subcellular remodelling by losartan in heart failure due to myocardial infarction

PubMed Central

Babick, Andrea; Chapman, Donald; Zieroth, Shelley; Elimban, Vijayan; Dhalla, Naranjan S

2012-01-01

This study tested the reversal of subcellular remodelling in heart failure due to myocardial infarction (MI) upon treatment with losartan, an angiotensin II receptor antagonist. Twelve weeks after inducing MI, rats were treated with or without losartan (20 mg/kg; daily) for 8 weeks and assessed for cardiac function, cardiac remodelling, subcellular alterations and plasma catecholamines. Cardiac hypertrophy and lung congestion in 20 weeks MI-induced heart failure were associated with increases in plasma catecholamine levels. Haemodynamic examination revealed depressed cardiac function, whereas echocardiographic analysis showed impaired cardiac performance and marked increases in left ventricle wall thickness and chamber dilatation at 20 weeks of inducing MI. These changes in cardiac function, cardiac remodelling and plasma dopamine levels in heart failure were partially or fully reversed by losartan. Sarcoplasmic reticular (SR) Ca2+-pump activity and protein expression, protein and gene expression for phospholamban, as well as myofibrillar (MF) Ca2+-stimulated ATPase activity and α-myosin heavy chain mRNA levels were depressed, whereas β-myosin heavy chain expression was increased in failing hearts; these alterations were partially reversed by losartan. Although SR Ca2+-release activity and mRNA levels for SR Ca2+-pump were decreased in failing heart, these changes were not reversed upon losartan treatment; no changes in mRNA levels for SR Ca2+-release channels were observed in untreated or treated heart failure. These results suggest that the partial improvement of cardiac performance in heart failure due to MI by losartan treatment is associated with partial reversal of cardiac remodelling as well as partial recovery of SR and MF functions. PMID:22947202

Prevention of Adverse Electrical and Mechanical Remodeling with Bi-Ventricular Pacing in a Rabbit Model of Myocardial Infarction

PubMed Central

Saba, Samir; Mathier, Michael A.; Mehdi, Haider; Gursoy, Erdal; Liu, Tong; Choi, Bum-Rak; Salama, Guy; London, Barry

2008-01-01

Background: Biventricular (BIV) pacing can improve cardiac function in heart failure (HF). Objective: To investigate the mechanisms of benefit of BIV pacing using a rabbit model of myocardial infarction (MI). Methods: New Zealand White rabbits were divided into 4 groups: sham-operated (C), MI with no pacing (MI), MI with right ventricular pacing (MI+RV), and MI with BIV pacing (MI+BIV), and underwent serial electrocardiograms and echocardiograms. At 4 weeks, hearts were excised and tissue was extracted from various areas of the left ventricle (LV). Results: Four weeks after coronary ligation, BIV pacing prevented systolic and diastolic dilation of the LV as well as the reduction in its fractional shortening, restored the QRS width and the rate-dependent QT intervals to their baseline values, and prevented the decline of the ether-a-go-go (erg) protein levels. This prevention of remodeling was not documented in the MI+RV groups. Conclusions: In this rabbit model of BIV pacing and MI, we demonstrate prevention of adverse mechanical and electrical remodeling of the heart. These changes may underlie some of the benefits seen with BIV pacing in HF patients with more severe LV dysfunction. PMID:18180026

The pathophysiology of heart failure.

PubMed

Kemp, Clinton D; Conte, John V

2012-01-01

Heart failure is a clinical syndrome that results when the heart is unable to provide sufficient blood flow to meet metabolic requirements or accommodate systemic venous return. This common condition affects over 5 million people in the United States at a cost of $10-38 billion per year. Heart failure results from injury to the myocardium from a variety of causes including ischemic heart disease, hypertension, and diabetes. Less common etiologies include cardiomyopathies, valvular disease, myocarditis, infections, systemic toxins, and cardiotoxic drugs. As the heart fails, patients develop symptoms which include dyspnea from pulmonary congestion, and peripheral edema and ascites from impaired venous return. Constitutional symptoms such as nausea, lack of appetite, and fatigue are also common. There are several compensatory mechanisms that occur as the failing heart attempts to maintain adequate function. These include increasing cardiac output via the Frank-Starling mechanism, increasing ventricular volume and wall thickness through ventricular remodeling, and maintaining tissue perfusion with augmented mean arterial pressure through activation of neurohormonal systems. Although initially beneficial in the early stages of heart failure, all of these compensatory mechanisms eventually lead to a vicious cycle of worsening heart failure. Treatment strategies have been developed based upon the understanding of these compensatory mechanisms. Medical therapy includes diuresis, suppression of the overactive neurohormonal systems, and augmentation of contractility. Surgical options include ventricular resynchronization therapy, surgical ventricular remodeling, ventricular assist device implantation, and heart transplantation. Despite significant understanding of the underlying pathophysiological mechanisms in heart failure, this disease causes significant morbidity and carries a 50% 5-year mortality. Copyright © 2012 Elsevier Inc. All rights reserved.

Renal Allograft Function Is a Risk Factor of Left Ventricular Remodeling After Kidney Transplantation.

PubMed

Koo, T Y; Ahn, C; Yang, J

2017-06-01

Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplantation (KT) patients. The prevalence of left ventricular hypertrophy increases with the progression of renal insufficiency. We investigated the association between the progression of renal insufficiency and left ventricular hypertrophy after KT. We reviewed KT patients at Seoul National University Hospital from January 1973 to December 2009. The creatinine elevation ratio (CER, the percentage change in the creatinine level from 1 month to 5 years after transplant) was calculated as follows: (creatinine level at 5 years minus creatinine level at 1 month)/creatinine level at 1 month × 100. The study population was classified into a high-CER group (CER ≥25%) and low-CER group (CER <25%). Mean left ventricular mass index (LVMI) values were 135.7 and 134.7 g/m 2 before KT and 101.7 and 123.7 g/m 2 at 5 years after KT in the low-CER and high-CER groups, respectively. The LVMI before or 1 year after KT was not different between the 2 groups, but the LVMI at 5 years post-transplant was higher in the high-CER group than in the low-CER group. The LVMI increased after its initial decrease in the high-CER group, whereas its reduction was maintained in the low-CER group during the 5 years after KT (P = .009, repeated-measures analysis of variance). These data suggest that deterioration of renal allograft function is associated with left ventricular remodeling after KT. Copyright © 2017 Elsevier Inc. All rights reserved.

Cartilage intermediate layer protein-1 alleviates pressure overload-induced cardiac fibrosis via interfering TGF-β1 signaling.

PubMed

Zhang, Cheng-Lin; Zhao, Qian; Liang, Hui; Qiao, Xue; Wang, Jin-Yu; Wu, Dan; Wu, Li-Ling; Li, Li

2018-03-01

Cardiac fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins in the myocardium and results in decreased ventricular compliance and diastolic dysfunction. Cartilage intermediate layer protein-1 (CILP-1), a novel identified cardiac matricellular protein, is upregulated in most conditions associated with cardiac remodeling, however, whether CILP-1 is involved in pressure overload-induced fibrotic response is unknown. Here, we investigated whether CILP-1 was critically involved in the fibrotic remodeling induced by pressure overload. Western blot analysis and immunofluorescence staining showed that CILP-1 was predominantly detected in cardiac myocytes and to a less extent in the interstitium. In isolated adult mouse ventricular myocytes and nonmyocytes, CILP-1 was found to be mainly synthesized by myocytes. CILP-1 expression in left ventricles was upregulated in C57BL/6 mice undergoing transverse aortic constriction (TAC). Myocardial CILP-1 knockdown aggravated whereas CILP-1 overexpression attenuated TAC-induced ventricular remodeling and dysfunction, as measured by echocardiography test, morphological examination, and gene expressions of fibrotic molecules. Incubation of cardiac fibroblasts with the conditioned medium containing full-length, N-terminal, or C-terminal CILP-1 inhibited transforming growth factor (TGF)-β1-induced Smad3 phosphorylation and the subsequent profibrotic events. We first demonstrated that C-terminal CILP-1 increased Akt phosphorylation, promoted the interaction between Akt and Smad3, and suppressed Smad3 phosphorylation. Blockade of PI3K-Akt pathway attenuated the inhibitory effect of C-CILP-1 on TGF-β1-induced Smad3 activation. We conclude that CILP-1 is a novel ECM protein possessing anti-fibrotic ability in pressure overload-induced fibrotic remodeling. This anti-fibrotic effect of CILP-1 attributes to interfering TGF-β1 signaling through its N- and C- terminal fragments. Copyright © 2018 Elsevier Ltd. All rights reserved.

Economic Value and Cost-Effectiveness of Cardiac Resynchronization Therapy Among Patients With Mild Heart Failure: Projections From the REVERSE Long-Term Follow-Up.

PubMed

Gold, Michael R; Padhiar, Amie; Mealing, Stuart; Sidhu, Manpreet K; Tsintzos, Stelios I; Abraham, William T

2017-03-01

This study investigated the cost effectiveness of early cardiac resynchronization therapy (CRT) implantation among patients with mild heart failure (HF). The differential cost effectiveness between CRT using a defibrillator (CRT-Ds) and CRT using a pacemaker (CRT-P) was also assessed. Cardiac resynchronization has been shown to be cost effective in New York Heart Association (NYHA) functional classes III/IV but is less studied in class II HF. The incremental costs of early CRT implementation in mild HF compared with the costs potentially avoided because of delaying disease progression to advanced HF are also unknown. Finally, combined biventricular pacing and defibrillator (CRT-D) devices are more expensive than biventricular pacemakers (CRT-P), but the relative cost effectiveness is controversial. Data from the 5-year follow-up phase of REVERSE (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction) were used. The economics were evaluated from the U.S. Medicare perspective based on published clinical projections. Probabilistic estimates yielded $8,840/quality-adjusted life year (QALY) gained (95% confidence interval [CI]: $6,705 to $10,804/QALY gained) for CRT-ON versus CRT-OFF (i.e., programmed "ON" or "OFF" at pre-specified post-implantation timings) and $43,678/QALY gained for CRT-D versus CRT-P (95% CI: $35,164 to $53,589/QALY gained) over the patient's lifetime. Results were robust to choice of patient subgroup and alterations of ±10% to key model parameters. An "early" CRT-D class II strategy totaled $95,292 compared with $91,511 for a "late" implantation. An "early" implant offered on average 1.00 year of additional survival for $3,781, resulting in an ICER of $3,795/LY gained. This study demonstrates CRT cost effectiveness in mild HF. The incremental CRT-D costs are justified by the anticipated benefits, despite increased procurement costs and shorter generator longevities. "Early" CRT-D implants have essential cost parity with "late" implants while increasing the patient's survival. (REsynchronization reVErses Remodeling in Systolic Left vEntricular Dysfunction [REVERSE]; NCT00271154). Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Intramyocardial injection of autologous cardiospheres or cardiosphere-derived cells preserves function and minimizes adverse ventricular remodeling in pigs with heart failure post-myocardial infarction.

PubMed

Lee, Shuo-Tsan; White, Anthony J; Matsushita, Satoshi; Malliaras, Konstantinos; Steenbergen, Charles; Zhang, Yiqiang; Li, Tao-Sheng; Terrovitis, John; Yee, Kristine; Simsir, Sinan; Makkar, Raj; Marbán, Eduardo

2011-01-25

The purpose of this study was to test the safety and efficacy of direct injection of cardiosphere-derived cells (CDCs) and their 3-dimensional precursors, cardiospheres, for cellular cardiomyoplasty in a mini-pig model of heart failure after myocardial infarction. Intracoronary administration of CDCs has been demonstrated to reduce infarct size and improve hemodynamic indexes in the mini-pig model, but intramyocardial injection of CDCs or cardiospheres has not been assessed in large animals. Autologous cardiospheres or CDCs grown from endomyocardial biopsies were injected through thoracotomy 4 weeks after anteroseptal myocardial infarction. Engraftment optimization with luciferase-labeled CDCs guided the choice of cell dose (0.5 million cells/site) and target tissue (20 peri-infarct sites). Pigs were randomly allocated to placebo (n = 11), cardiospheres (n = 8), or CDCs (n = 10). Functional data were acquired before injection and again 8 weeks later, after which organs were harvested for histopathology. Beyond the immediate perioperative period, all animals survived to protocol completion. Ejection fraction was equivalent at baseline, but at 8 weeks was higher than placebo in both of the cell-treated groups (placebo vs. CDC, p = 0.01; placebo vs. cardiospheres, p = 0.01). Echocardiographic and hemodynamic indexes of efficacy improved disproportionately with cardiospheres; likewise, adverse remodeling was more attenuated with cardiospheres than with CDCs. Provocative electrophysiologic testing showed no differences among groups, and no tumors were found. Dosage-optimized direct injection of cardiospheres or CDCs is safe and effective in preserving ventricular function in porcine ischemic cardiomyopathy. Although CDCs and cardiospheres have equivalent effects on left ventricular ejection fraction, cardiospheres are superior in improving hemodynamics and regional function, and in attenuating ventricular remodeling. Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice.

PubMed

Cero, Fadila Telarevic; Hillestad, Vigdis; Sjaastad, Ivar; Yndestad, Arne; Aukrust, Pål; Ranheim, Trine; Lunde, Ida Gjervold; Olsen, Maria Belland; Lien, Egil; Zhang, Lili; Haugstad, Solveig Bjærum; Løberg, Else Marit; Christensen, Geir; Larsen, Karl-Otto; Skjønsberg, Ole Henning

2015-08-15

Pulmonary hypertension is a serious condition that can lead to premature death. The mechanisms involved are incompletely understood although a role for the immune system has been suggested. Inflammasomes are part of the innate immune system and consist of the effector caspase-1 and a receptor, where nucleotide-binding oligomerization domain-like receptor pyrin domain-containing 3 (NLRP3) is the best characterized and interacts with the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). To investigate whether ASC and NLRP3 inflammasome components are involved in hypoxia-induced pulmonary hypertension, we utilized mice deficient in ASC and NLRP3. Active caspase-1, IL-18, and IL-1β, which are regulated by inflammasomes, were measured in lung homogenates in wild-type (WT), ASC(-/-), and NLRP3(-/-) mice, and phenotypical changes related to pulmonary hypertension and right ventricular remodeling were characterized after hypoxic exposure. Right ventricular systolic pressure (RVSP) of ASC(-/-) mice was significantly lower than in WT exposed to hypoxia (40.8 ± 1.5 mmHg vs. 55.8 ± 2.4 mmHg, P < 0.001), indicating a substantially reduced pulmonary hypertension in mice lacking ASC. Magnetic resonance imaging further supported these findings by demonstrating reduced right ventricular remodeling. RVSP of NLRP3(-/-) mice exposed to hypoxia was not significantly altered compared with WT hypoxia. Whereas hypoxia increased protein levels of caspase-1, IL-18, and IL-1β in WT and NLRP3(-/-) mice, this response was absent in ASC(-/-) mice. Moreover, ASC(-/-) mice displayed reduced muscularization and collagen deposition around arteries. In conclusion, hypoxia-induced elevated right ventricular pressure and remodeling were attenuated in mice lacking the inflammasome adaptor protein ASC, suggesting that inflammasomes play an important role in the pathogenesis of pulmonary hypertension. Copyright © 2015 the American Physiological Society.

β-Adrenergic receptor stimulation inhibits proarrhythmic alternans in postinfarction border zone cardiomyocytes: a computational analysis.

PubMed

Tomek, Jakub; Rodriguez, Blanca; Bub, Gil; Heijman, Jordi

2017-08-01

The border zone (BZ) of the viable myocardium adjacent to an infarct undergoes extensive autonomic and electrical remodeling and is prone to repolarization alternans-induced cardiac arrhythmias. BZ remodeling processes may promote or inhibit Ca 2+ and/or repolarization alternans and may differentially affect ventricular arrhythmogenesis. Here, we used a detailed computational model of the canine ventricular cardiomyocyte to study the determinants of alternans in the BZ and their regulation by β-adrenergic receptor (β-AR) stimulation. The BZ model developed Ca 2+ transient alternans at slower pacing cycle lengths than the control model, suggesting that the BZ may promote spatially heterogeneous alternans formation in an infarcted heart. β-AR stimulation abolished alternans. By evaluating all combinations of downstream β-AR stimulation targets, we identified both direct (via ryanodine receptor channels) and indirect [via sarcoplasmic reticulum (SR) Ca 2+ load] modulation of SR Ca 2+ release as critical determinants of Ca 2+ transient alternans. These findings were confirmed in a human ventricular cardiomyocyte model. Cell-to-cell coupling indirectly modulated the likelihood of alternans by affecting the action potential upstroke, reducing the trigger for SR Ca 2+ release in one-dimensional strand simulations. However, β-AR stimulation inhibited alternans in both single and multicellular simulations. Taken together, these data highlight a potential antiarrhythmic role of sympathetic hyperinnervation in the BZ by reducing the likelihood of alternans and provide new insights into the underlying mechanisms controlling Ca 2+ transient and repolarization alternans. NEW & NOTEWORTHY We integrated, for the first time, postmyocardial infarction electrical and autonomic remodeling in a detailed, validated computer model of β-adrenergic stimulation in ventricular cardiomyocytes. Here, we show that β-adrenergic stimulation inhibits alternans and provide novel insights into underlying mechanisms, adding to a recent controversy about pro-/antiarrhythmic effects of postmyocardial infarction hyperinnervation.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/%CE%B2-ar-stimulation-and-alternans-in-border-zone-cardiomyocytes/. Copyright © 2017 the American Physiological Society.

Characterizing the spectrum of right ventricular remodelling in response to chronic training.

PubMed

Sitges, Marta; Merino, Beatriz; Butakoff, Constatine; de la Garza, Maria Sanz; Paré, Carles; Montserrat, Silvia; Vidal, Barbara; Azqueta, Manel; Sarquella, Georgia; Gutierrez, Josep Antoni; Canal, Ramon; Brugada, Josep; Bijnens, Bart H

2017-03-01

The significance and spectrum of reduced right ventricular (RV) deformation, reported in endurance athletes, is unclear. To comprehensively analyze the cardiac performance at rest of athletes, especially focusing on integrating RV size and deformation to unravel the underlying triggers of this ventricular remodelling. Hundred professional male athletes and 50 sedentary healthy males of similar age were prospectively studied. Conventional echocardiographic parameters of all four chambers were obtained, as well as 2D echo-derived strain (2DSE) in the left (LV) and in the RV free wall with separate additional analysis of the RV basal and apical segments. Left and right-sided dimensions were larger in athletes than in controls, but with a disproportionate RA enlargement. RV global strain was lower in sportsmen (-26.8 ± 2.8% vs -28.5 ± 3.4%, p < 0.001) due to a decrease in the basal segment (-22.8 ± 3.5% vs -25.8 ± 4.0%, p < 0.001) resulting in a marked gradient of deformation from the RV inlet towards the apex. By integrating size, deformation and stroke volume, we observed that the LV working conditions were similar in all sportsmen while a wider variability existed in the RV. Cardiac remodelling in athletes is more pronounced in the right heart cavities with specific regional differences within the right ventricle, but with a wide variability among individuals. The large inter-individual differences, as well as its acute and chronic relevance warrant further investigation.

Interleukin-6 Mediates Myocardial Fibrosis, Concentric Hypertrophy and Diastolic Dysfunction in Rats

PubMed Central

Meléndez, Giselle C.; McLarty, Jennifer L.; Levick, Scott P.; Du, Yan; Janicki, Joseph S.; Brower, Gregory L.

2010-01-01

While there is a correlation between hypertension and levels of IL-6, the exact role of this cytokine in myocardial remodeling is unknown. This is complicated by the variable tissue and circulating levels of IL-6 reported in numerous experimental models of hypertension. Accordingly, we explored the hypothesis that elevated levels of IL-6 mediate adverse myocardial remodeling. To this end, adult male Sprague Dawley rats were infused with IL-6 (2.5 μg·kg-1·hr-1, IP) for 7 days via osmotic minipump and compared to vehicle infused aged-matched controls. Left ventricular function was evaluated using a blood-perfused isolated heart preparation. In addition, myocardial interstitial collagen volume fraction and isolated cardiomyocyte size were also assessed. Isolated adult cardiac fibroblast experiments were performed to determine the importance of the soluble IL-6 receptor in mediating cardiac fibrosis. IL-6 infusions in vivo resulted in concentric left ventricular hypertrophy, increased ventricular stiffness, a marked increase in collagen volume fraction (6.2 vs. 1.7%; p < 0.001), and proportional increases in cardiomyocyte width and length; all independent of blood pressure. The soluble IL-6 receptor in combination with IL-6 was found to be essential in increasing collagen content regulated by isolated cardiac fibroblasts, and also played a role in mediating a phenotypic conversion to myofibroblasts. These novel observations demonstrate that IL-6 induces a myocardial phenotype almost identical to that of the hypertensive heart, identifying IL-6 as potentially important in this remodeling process. PMID:20606113

Calorie restriction attenuates cardiac remodeling and diastolic dysfunction in a rat model of metabolic syndrome.

PubMed

Takatsu, Miwa; Nakashima, Chieko; Takahashi, Keiji; Murase, Tamayo; Hattori, Takuya; Ito, Hiromi; Murohara, Toyoaki; Nagata, Kohzo

2013-11-01

Calorie restriction (CR) can modulate the features of obesity-related metabolic and cardiovascular diseases. We have recently characterized DahlS.Z-Lepr(fa)/Lepr(fa) (DS/obese) rats, derived from a cross between Dahl salt-sensitive and Zucker rats, as a new animal model of metabolic syndrome. DS/obese rats develop hypertension and manifest left ventricular remodeling and diastolic dysfunction, as well as increased cardiac oxidative stress and inflammation. We have now investigated the effects of CR on cardiac pathophysiology in DS/obese rats. DS/obese rats were fed either normal laboratory chow ad libitum or a calorie-restricted diet (65% of the average food intake for ad libitum) from 9 to 13 weeks. Age-matched homozygous lean (DahlS.Z-Lepr(+)/Lepr(+) or DS/lean) littermates served as controls. CR reduced body weight in both DS/obese and DS/lean rats, as well as attenuated the development of hypertension in DS/obese rats without affecting blood pressure in DS/lean rats. CR also reduced body fat content, ameliorated left ventricular hypertrophy, fibrosis, and diastolic dysfunction, and attenuated cardiac oxidative stress and inflammation in DS/obese rats. In addition, it increased serum adiponectin concentration, as well as downregulated the expression of angiotensin-converting enzyme and angiotensin II type 1A receptor genes in the heart of DS/obese rats. Our results thus show that CR attenuated obesity and hypertension, as well as left ventricular remodeling and diastolic dysfunction in DS/obese rats, with these latter effects being associated with reduced cardiac oxidative stress and inflammation.

Cerebrovasculoprotective effects of azilsartan medoxomil in diabetes.

PubMed

Abdelsaid, Mohammed; Coucha, Maha; Ergul, Adviye

2014-11-01

We have shown that Goto-Kakizaki (GK) rats, a lean model of type 2 diabetes, develop significant cerebrovascular remodeling by the age of 18 weeks, which is characterized by increased media thickness and matrix deposition. Although early glycemic control prevents diabetes-mediated remodeling of the cerebrovasculature, whether the remodeling can be reversed is unknown. Given that angiotensin II type 1 receptor blockers reverse pathologic vascular remodeling and function independent of changes in blood pressure in other vascular beds, we hypothesized that azilsartan medoxomil, a new angiotensin II type 1 receptor blocker, is vasculoprotective by preventing and reversing cerebrovascular remodeling in diabetes. Control Wistar and diabetic GK rats (n = 6-8 per group) were treated with vehicle (water) or azilsartan medoxomil (3 mg/kg/d) from the age of 14 to 18 or 18 to 22 weeks before or after vascular remodeling is established, respectively. Blood glucose and blood pressure were monitored and middle cerebral artery structure and function were evaluated using pressurized arteriography. Blood glucose was higher in GK rats compared with Wistar rats. Azilsartan treatment lowered blood glucose in diabetic animals with no effect on blood pressure. Diabetic animals exhibited lower myogenic tone, increased wall thickness, and cross-sectional area compared with control group animals, which were corrected by azilsartan treatment when started at the onset of diabetes or later after vascular remodeling is established. Azilsartan medoxomil offers preventive and therapeutic vasculoprotection in diabetes-induced cerebrovascular remodeling and myogenic dysfunction and this is independent of blood pressure. Published by Elsevier Inc.

Cardiac Remodeling in Response to 1 Year of Intensive Endurance Training

PubMed Central

Arbab-Zadeh, Armin; Perhonen, Merja; Howden, Erin; Peshock, Ronald M.; Zhang, Rong; Adams-Huet, Beverly; Haykowsky, Mark J.; Levine, Benjamin D.

2017-01-01

Background It is unclear whether, and to what extent, the striking cardiac morphological manifestations of endurance athletes are a result of exercise training or a genetically determined characteristic of talented athletes. We hypothesized that prolonged and intensive endurance training in previously sedentary healthy young individuals could induce cardiac remodeling similar to that observed cross-sectionally in elite endurance athletes. Methods and Results Twelve previously sedentary subjects (aged 29±6 years; 7 men and 5 women) trained progressively and intensively for 12 months such that they could compete in a marathon. Magnetic resonance images for assessment of right and left ventricular mass and volumes were obtained at baseline and after 3, 6, 9, and 12 months of training. Maximum oxygen uptake (V̇o2 max) and cardiac output at rest and during exercise (C2H2 rebreathing) were measured at the same time periods. Pulmonary artery catheterization was performed before and after 1 year of training, and pressure-volume and Starling curves were constructed during decreases (lower body negative pressure) and increases (saline infusion) in cardiac volume. Mean V̇o2 max rose from 40.3±1.6 to 48.7±2.5 mL/kg per minute after 1 year (P<0.00001), associated with an increase in both maximal cardiac output and stroke volume. Left and right ventricular mass increased progressively with training duration and intensity and reached levels similar to those observed in elite endurance athletes. In contrast, left ventricular volume did not change significantly until 6 months of training, although right ventricular volume increased progressively from the outset; Starling and pressure-volume curves approached but did not match those of elite athletes. Conclusions One year of prolonged and intensive endurance training leads to cardiac morphological adaptations in previously sedentary young subjects similar to those observed in elite endurance athletes; however, it is not sufficient to achieve similar levels of cardiac compliance and performance. Contrary to conventional thinking, the left ventricle responds to exercise with initial concentric but not eccentric remodeling during the first 6 to 9 months after commencement of endurance training depending on the duration and intensity of exercise. Thereafter, the left ventricle dilates and restores the baseline mass-to-volume ratio. In contrast, the right ventricle responds to endurance training with eccentric remodeling at all levels of training. PMID:25281664

Early and late effects of the DPP-4 inhibitor vildagliptin in a rat model of post-myocardial infarction heart failure

PubMed Central

2011-01-01

Background Progressive remodeling after myocardial infarction (MI) is a leading cause of morbidity and mortality. Recently, glucagon-like peptide (GLP)-1 was shown to have cardioprotective effects, but treatment with GLP-1 is limited by its short half-life. It is rapidly degraded by the enzyme dipeptidyl peptidase-4 (DPP-4), an enzyme which inhibits GLP-1 activity. We hypothesized that the DPP-4 inhibitor vildagliptin will increase levels of GLP-1 and may exert protective effects on cardiac function after MI. Methods Sprague-Dawley rats were either subjected to coronary ligation to induce MI and left ventricular (LV) remodeling, or sham operation. Parts of the rats with an MI were pre-treated for 2 days with the DPP-4 inhibitor vildagliptin (MI-Vildagliptin immediate, MI-VI, 15 mg/kg/day). The remainder of the rats was, three weeks after coronary artery ligation, subjected to treatment with DPP-4 inhibitor vildagliptin (MI-Vildagliptin Late, MI-VL) or control (MI). At 12 weeks, echocardiography and invasive hemodynamics were measured and molecular analysis and immunohistochemistry were performed. Results Vildagliptin inhibited the DPP-4 enzymatic activity by almost 70% and increased active GLP-1 levels by about 3-fold in plasma in both treated groups (p < 0.05 vs. non-treated groups). Cardiac function (ejection fraction) was decreased in all 3 MI groups compared with Sham group (p < 0.05); treatment with vildagliptin, either early or late, did not reverse cardiac remodeling. ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide) mRNA levels were significantly increased in all 3 MI groups, but no significant reductions were observed in both vildagliptin groups. Vildagliptin also did not change cardiomyocyte size or capillary density after MI. No effects were detected on glucose level and body weight in the post-MI remodeling model. Conclusion Vildagliptin increases the active GLP-1 level via inhibition of DPP-4, but it has no substantial protective effects on cardiac function in this well established long-term post-MI cardiac remodeling model. PMID:21955567

Hyperthyroidism as a reversible cause of right ventricular overload and congestive heart failure

PubMed Central

Di Giovambattista, Raniero

2008-01-01

We describe a case of severe congestive heart failure and right ventricular overload associated with overt hyperthyroidism, completely reversed with antithyroid therapy in a few week. It represents a very unusual presentation of overt hyperthyroidism because of the severity of right heart failure. The impressive right ventricular volume overload made mandatory to perform transesophageal echo and angio-TC examination to exclude the coexistence of ASD or anomalous pulmonary venous return. Only a few cases of reversible right heart failure, with or without pulmonary hypertension, have been reported worldwide. In our case the most striking feature has been the normalization of the cardiovascular findings after six weeks of tiamazole therapy. PMID:18549503

Plasma tissue inhibitor of metalloproteinase-1 and matrix metalloproteinase-9: novel indicators of left ventricular remodelling and prognosis after acute myocardial infarction.

PubMed

Kelly, Dominic; Khan, Sohail Q; Thompson, Matt; Cockerill, Gillian; Ng, Leong L; Samani, Nilesh; Squire, Iain B

2008-09-01

Matrix metalloproteinase (MMP) activity is central to the development of left ventricular (LV) remodelling and dysfunction after acute myocardial infarction (AMI). We assessed the relationships with LV structure and function and outcome, of tissue inhibitors of metalloproteinase-1 (TIMP-1) and MMP-9, and compared with N-terminal pro-B-type natriuretic peptide (NTproBNP). We studied 404 patients with AMI. Primary outcome measures were the associations of TIMP-1, MMP-9, and NTproBNP with death or heart failure, and with LV dimensions, function and remodelling (ΔLVEDV, change in LV end-diastolic volume between discharge and follow-up). Cut-off concentrations for prediction of death or heart failure were identified from receiver operator characteristic (ROC) curves. In multivariable analysis, TIMP-1 and NTproBNP had predictive value for LV ejection fraction pre-discharge (TIMP-1 P = 0.023; N-BNP P = 0.007) and at follow-up (TIMP-1 P = 0.001; N-BNP P = 0.003). MMP-9, TIMP-1, and NTproBNP correlated directly with LV volumes. MMP-9 (P = 0.005) and TIMP-1 (P = 0.036), but not NTproBNP, correlated with ΔLVEDV. For the combined endpoint of death or heart failure the area under the ROC curve was 0.640 for MMP-9, 0.799 for NTproBNP and 0.811 for TIMP-1. Patients with TIMP-1 > 135 ng/mL (P < 0.001) or NTproBNP >1472 fmol/mL (P < 0.001) had increased risk of endpoint. Consideration of both NTproBNP and TIMP-1 further improved risk stratification. TIMP-1 and MMP-9 correlate with echocardiographic parameters of LV dysfunction and remodelling after AMI and may identify patients at risk of subsequent LV remodelling and adverse prognosis.

Activation of NADPH oxidase mediates increased endoplasmic reticulum stress and left ventricular remodeling after myocardial infarction in rabbits.

PubMed

Li, Bao; Tian, Jing; Sun, Yi; Xu, Tao-Rui; Chi, Rui-Fang; Zhang, Xiao-Li; Hu, Xin-Ling; Zhang, Yue-An; Qin, Fu-Zhong; Zhang, Wei-Fang

2015-05-01

Nicotinamide adenine dinucleotide 3-phosphate (NADPH) oxidase activity and endoplasmic reticulum (ER) stress are increased after myocardial infarction (MI). In this study, we proposed to test whether activation of the NADPH oxidase in the remote non-infarcted myocardium mediates ER stress and left ventricular (LV) remodeling after MI. Rabbits with MI or sham operation were randomly assigned to orally receive an NADPH oxidase inhibitor apocynin or placebo for 30 days. The agents were administered beginning at 1 week after surgery. MI rabbits exhibited decreases in LV fractional shortening, LV ejection fraction and the first derivative of the LV pressure rise, which were abolished by apocynin treatment. NADPH oxidase Nox2 protein and mRNA expressions were increased in the remote non-infarcted myocardium after MI. Immunolabeling further revealed that Nox2 was increased in cardiac myocytes in the remote myocardium. The apocynin treatment prevented increases in the Nox2 expression, NADPH oxidase activity, oxidative stress, myocyte apoptosis and GRP78, CHOP and cleaved caspase 12 protein expression in the remote myocardium. The apocynin treatment also attenuated increases in myocyte diameter and cardiac fibrosis. In cultured H9C2 cardiomyocytes exposed to angiotensin II, an important stimulus for post-MI remodeling, Nox2 knockdown with siRNA significantly inhibited angiotensin II-induced NADPH oxidase activation, reactive oxygen species and GRP78 and CHOP protein expression. We conclude that NADPH oxidase inhibition attenuates increased ER stress in the remote non-infarcted myocardium and LV remodeling late after MI in rabbits. These findings suggest that the activation of NADPH oxidase in the remote non-infarcted myocardium mediates increased ER stress, contributing to myocyte apoptosis and LV remodeling after MI. Copyright © 2015 Elsevier B.V. All rights reserved.

Targeted Injection of a Biocomposite Material Alters Macrophage and Fibroblast Phenotype and Function following Myocardial Infarction: Relation to Left Ventricular Remodeling

PubMed Central

McGarvey, Jeremy R.; Pettaway, Sara; Shuman, James A.; Novack, Craig P.; Zellars, Kia N.; Freels, Parker D.; Echols, Randall L.; Burdick, Jason A.; Gorman, Joseph H.; Gorman, Robert C.

2014-01-01

A treatment target for progressive left ventricular (LV) remodeling prevention following myocardial infarction (MI) is to affect structural changes directly within the MI region. One approach is through targeted injection of biocomposite materials, such as calcium hydroxyapatite microspheres (CHAM), into the MI region. In this study, the effects of CHAM injections upon key cell types responsible for the MI remodeling process, the macrophage and fibroblast, were examined. MI was induced in adult pigs before randomization to CHAM injections (20 targeted 0.1-ml injections within MI region) or saline. At 7 or 21 days post-MI (n = 6/time point per group), cardiac magnetic resonance imaging was performed, followed by macrophage and fibroblast isolation. Isolated macrophage profiles for monocyte chemotactic macrophage inflammatory protein-1 as measured by real-time polymerase chain reaction increased at 7 days post-MI in the CHAM group compared with MI only (16.3 ± 6.6 versus 1.7 ± 0.6 cycle times values, P < 0.05), and were similar by 21 days post-MI. Temporal changes in fibroblast function and smooth muscle actin (SMA) expression relative to referent control (n = 5) occurred with MI. CHAM induced increases in fibroblast proliferation, migration, and SMA expression—indicative of fibroblast transformation. By 21 days, CHAM reduced LV dilation (diastolic volume: 75 ± 2 versus 97 ± 4 ml) and increased function (ejection fraction: 48 ± 2% versus 38 ± 2%) compared with MI only (both P < 0.05). This study identified that effects on macrophage and fibroblast differentiation occurred with injection of biocomposite material within the MI, which translated into reduced adverse LV remodeling. These unique findings demonstrate that biomaterial injections impart biologic effects upon the MI remodeling process over any biophysical effects. PMID:25022514

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes

PubMed Central

Tae, Hyun-Jin; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2015-01-01

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/− mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2–4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6–14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS. PMID:26566724

Cardiac remodeling in the mouse model of Marfan syndrome develops into two distinctive phenotypes.

PubMed

Tae, Hyun-Jin; Petrashevskaya, Natalia; Marshall, Shannon; Krawczyk, Melissa; Talan, Mark

2016-01-15

Marfan syndrome (MFS) is a systemic disorder of connective tissue caused by mutations in fibrillin-1. Cardiac dysfunction in MFS has not been characterized halting the development of therapies of cardiac complication in MFS. We aimed to study the age-dependent cardiac remodeling in the mouse model of MFS FbnC1039G+/- mouse [Marfan heterozygous (HT) mouse] and its association with valvular regurgitation. Marfan HT mice of 2-4 mo demonstrated a mild hypertrophic cardiac remodeling with predominant decline of diastolic function and increased transforming growth factor-β canonical (p-SMAD2/3) and noncanonical (p-ERK1/2 and p-p38 MAPK) signaling and upregulation of hypertrophic markers natriuretic peptides atrium natriuretic peptide and brain natriuretic peptide. Among older HT mice (6-14 mo), cardiac remodeling was associated with two distinct phenotypes, manifesting either dilated or constricted left ventricular chamber. Dilatation of left ventricular chamber was accompanied by biochemical evidence of greater mechanical stress, including elevated ERK1/2 and p38 MAPK phosphorylation and higher brain natriuretic peptide expression. The aortic valve regurgitation was registered in 20% of the constricted group and 60% of the dilated group, whereas mitral insufficiency was observed in 40% of the constricted group and 100% of the dilated group. Cardiac dysfunction was not associated with the increase of interstitial fibrosis and nonmyocyte proliferation. In the mouse model fibrillin-1, haploinsufficiency results in the early onset of nonfibrotic hypertrophic cardiac remodeling and dysfunction, independently from valvular abnormalities. MFS heart is vulnerable to stress-induced cardiac dilatation in the face of valvular regurgitation, and stress-activated MAPK signals represent a potential target for cardiac management in MFS.

The cardioprotective efficacy of TVP1022 against ischemia/reperfusion injury and cardiac remodeling in rats.

PubMed

Malka, Assaf; Ertracht, Offir; Bachner-Hinenzon, Noa; Reiter, Irina; Binah, Ofer

2016-12-01

Following acute myocardial infarction (MI), early and successful reperfusion is the most effective strategy for reducing infarct size and improving the clinical outcome. However, immediate restoration of blood flow to the ischemic zone results in myocardial damage, defined as "reperfusion-injury". Whereas we previously reported that TVP1022 (the S-isomer of rasagiline, FDA-approved anti-Parkinson drug) decreased infarct size 24 h post ischemia reperfusion (I/R) in rats, in this study we investigated the chronic cardioprotective efficacy of TVP1022 14 days post-I/R. To simulate the clinical settings of acute MI followed by reperfusion therapy, we employed a rat model of left anterior descending artery occlusion for 30 min followed by reperfusion and a follow-up for 14 days. TVP1022 was initially administered postocclusion-prereperfusion, followed by chronic daily administrations. Cardiac performance and remodeling were evaluated using customary and advanced echocardiographic methods, hemodynamic measurements by Millar Mikro-Tip ® catheter, and histopathological techniques. TVP1022 administration markedly decreased the remodeling process as illustrated by attenuation of left ventricular enlargement and cardiac hypertrophy (both at the whole heart and the cellular level). Furthermore, TVP1022 inhibited cardiac fibrosis and reduced ventricular BNP levels. Functionally, TVP1022 treatment preserved cardiac wall motion. Specifically, the echocardiographic and most of the direct hemodynamic measures were pronouncedly improved by TVP1022. Collectively, these findings indicate that TVP1022 provides prominent cardioprotection against I/R injury and post-MI remodeling in this I/R model.

Long-Term Simulated Microgravity Causes Cardiac RyR2 Phosphorylation and Arrhythmias in Mice

PubMed Central

Respress, Jonathan L.; Gershovich, Pavel M.; Wang, Tiannan; Reynolds, Julia O.; Skapura, Darlene G.; Sutton, Jeffrey P.; Miyake, Christina Y.; Wehrens, Xander H.T.

2014-01-01

Background Long-term exposure to microgravity during space flight may lead to cardiac remodeling and rhythm disturbances. In mice, hindlimb unloading (HU) mimics the effects of microgravity and stimulates physiological adaptations, including cardiovascular deconditioning. Recent studies have demonstrated an important role played by changes in intracellular Ca handling in the pathogenesis of heart failure and arrhythmia. In this study, we tested the hypothesis that cardiac remodeling following HU in mice involves abnormal intracellular Ca regulation through the cardiac ryanodine receptor (RyR2). Methods and Results Mice were subjected to HU by tail suspension for 28 to 56 days in order to induce cardiac remodeling (n=15). Control mice (n=19) were treated equally, with the exception of tail suspension. Echocardiography revealed cardiac enlargement and depressed contractility starting at 28 days post-HU versus control. Moreover, mice were more susceptible to pacing-induced ventricular arrhythmias after HU. Ventricular myocytes isolated from HU mice exhibited an increased frequency of spontaneous sarcoplasmic reticulum (SR) Ca release events and enhanced SR Ca leak via RyR2. Western blotting revealed increased RyR2 phosphorylation at S2814, and increased CaMKII auto-phosphorylation at T287, suggesting that CaMKII activation of RyR2 might underlie enhanced SR Ca release in HU mice. Conclusion These data suggest that abnormal intracellular Ca handling, likely due to increased CaMKII phosphorylation of RyR2, plays a role in cardiac remodeling following simulated microgravity in mice. PMID:25227892

Improvement of left ventricular remodeling after myocardial infarction with eight weeks L-thyroxine treatment in rats.

PubMed

Chen, Yue-Feng; Weltman, Nathan Y; Li, Xiang; Youmans, Steven; Krause, David; Gerdes, Anthony Martin

2013-02-14

Left ventricular (LV) remodeling following large transmural myocardial infarction (MI) remains a pivotal clinical issue despite the advance of medical treatment over the past few decades. Identification of new medications to improve the remodeling process and prevent progression to heart failure after MI is critical. Thyroid hormones (THs) have been shown to improve LV function and remodeling in animals post-MI and in the human setting. However, changes in underlying cellular remodeling resulting from TH treatment are not clear. MI was produced in adult female Sprague-Dawley rats by ligation of the left descending coronary artery. L-thyroxine (T4) pellet (3.3 mg, 60 days sustained release) was used to treat MI rats for 8 weeks. Isolated myocyte shape, arterioles, and collagen deposition in the non-infarcted area were measured at terminal study. T4 treatment improved LV ±dp/dt, normalized TAU, and increased myocyte cross-sectional area without further increasing myocyte length in MI rats. T4 treatment increased the total LV tissue area by 34%, increased the non-infarcted tissue area by 41%, and increased the thickness of non-infarcted area by 36% in MI rats. However, myocyte volume accounted for only ~1/3 of the increase in myocyte mass in the non-infarct area, indicating the presence of more myocytes with treatment. T4 treatment tended to increase the total length of smaller arterioles (5 to 15 μm) proportional to LV weight increase and also decreased collagen deposition in the LV non-infarcted area. A tendency for increased metalloproteinase-2 (MMP-2) expression and tissue inhibitor of metalloproteinases (TIMPs) -1 to -4 expression was also observed in T4 treated MI rats. These results suggest that long-term T4 treatment after MI has beneficial effects on myocyte, arteriolar, and collagen matrix remodeling in the non-infarcted area. Most importantly, results suggest improved survival of myocytes in the peri-infarct area.

Cardiac troponin I for the prediction of functional recovery and left ventricular remodelling following primary percutaneous coronary intervention for ST-elevation myocardial infarction.

PubMed

Hallén, Jonas; Jensen, Jesper K; Fagerland, Morten W; Jaffe, Allan S; Atar, Dan

2010-12-01

To investigate the ability of cardiac troponin I (cTnI) to predict functional recovery and left ventricular remodelling following primary percutaneous coronary intervention (pPCI) in ST-elevation myocardial infarction (STEMI). Post hoc study extending from randomised controlled trial. 132 patients with STEMI receiving pPCI. Left ventricular ejection fraction (LVEF), end-diastolic and end-systolic volume index (EDVI and ESVI) and changes in these parameters from day 5 to 4 months after the index event. Cardiac magnetic resonance examination performed at 5 days and 4 months for evaluation of LVEF, EDVI and ESVI. cTnI was sampled at 24 and 48 h. In linear regression models adjusted for early (5 days) assessment of LVEF, ESVI and EDVI, single-point cTnI at either 24 or 48 h were independent and strong predictors of changes in LVEF (p<0.01), EDVI (p<0.01) and ESVI (p<0.01) during the follow-up period. In a logistic regression analysis for prediction of an LVEF below 40% at 4 months, single-point cTnI significantly improved the prognostic strength of the model (area under the curve = 0.94, p<0.01) in comparison with the combination of clinical variables and LVEF at 5 days. Single-point sampling of cTnI after pPCI for STEMI provides important prognostic information on the time-dependent evolution of left ventricular function and volumes.

Two-dimensional knowledge-based volumetric reconstruction of the right ventricle documents short-term improvement in pulmonary hypertension.

PubMed

Schwaiger, Johannes P; Knight, Daniel S; Kaier, Thomas; Gallimore, Adele; Denton, Christopher P; Schreiber, Benjamin E; Handler, Clive; Coghlan, John G

2017-06-01

Data are scarce about short-term right ventricular changes in pulmonary hypertension. Two-dimensional knowledge-based reconstruction of the right ventricle with 2D echocardiography (2DKBR) has been shown to be a valid alternative to Cardiac MRI. In this longitudinal study 25 pulmonary hypertension patients underwent 2DKBR of the right ventricle, assessment of NT-proBNP levels and functional class at baseline and after a mean follow-up of 6.1 months. Patients were followed up clinically for a further mean of 8.2 months. The majority of patients had connective tissue disease (CTD) associated pulmonary arterial hypertension (n=15) or chronic thromboembolic pulmonary hypertension (CTEPH; n=6). A total of 15 patients underwent an intervention, either new targeted therapy, escalation of targeted therapy or pulmonary endarterectomy. A total of 10 clinically stable patients were routinely followed up without any change in therapy. There were significant improvements in the right ventricular end-diastolic volume index (111±29 mL/m² vs 100±36 mL/m²; P=.038), end-systolic volume index (72±23 mL/m² vs 61±25 mL/m²; P=.001), and ejection fraction (35±10% vs 40±9%; P=.030). Changes in NT-proBNP levels correlated strongest with changes in end-systolic volume index (r=-.77; P=<.0001). Four patients experienced clinical worsening during extended follow-up, dilatation of the right ventricle was associated with clinical worsening. In a CTD and CTEPH dominated patient population significant reverse remodeling and improvement of ejection fraction occurred despite a short follow-up and was paralleled by significant changes in NT-proBNP levels. Further right ventricular dilatation was associated with worse clinical outcome. 2DKBR is a feasible substitute for Cardiac MRI to follow-up right ventricular indices in pulmonary hypertension. © 2017, Wiley Periodicals, Inc.

Does permanent atrial fibrillation modify response to cardiac resynchronization therapy in heart failure patients?

PubMed

Abreu, Ana; Oliveira, Mário; Silva Cunha, Pedro; Santa Clara, Helena; Portugal, Guilherme; Gonçalves Rodrigues, Inês; Santos, Vanessa; Morais, Luís; Selas, Mafalda; Soares, Rui; Branco, Luísa; Ferreira, Rui; Mota Carmo, Miguel

2017-10-01

The benefits of cardiac resynchronization therapy (CRT) documented in heart failure (HF) may be influenced by atrial fibrillation (AF). We aimed to compare CRT response in patients in AF and in sinus rhythm (SR). We prospectively studied 101 HF patients treated by CRT. Rates of clinical, echocardiographic and functional response, baseline NYHA class and variation, left ventricular ejection fraction, volumes and mass, atrial volumes, cardiopulmonary exercise test (CPET) duration (CPET dur), peak oxygen consumption (VO 2 max) and ventilatory efficiency (VE/VCO 2 slope) were compared between AF and SR patients, before and at three and six months after implantation of a CRT device. All patients achieved ≥95% biventricular pacing, and 5.7% underwent atrioventricular junction ablation. Patients were divided into AF (n=35) and SR (n=66) groups; AF patients were older, with larger atrial volumes and lower CPET dur and VO 2 max before CRT. The percentages of clinical and echocardiographic responders were similar in the two groups, but there were more functional responders in the AF group (71% vs. 39% in SR patients; p=0.012). In SR patients, left atrial volume and left ventricular mass were significantly reduced (p=0.015 and p=0.021, respectively), whereas in AF patients, CPET dur (p=0.003) and VO 2 max (p=0.001; 0.083 age-adjusted) showed larger increases. Clinical and echocardiographic response rates were similar in SR and AF patients, with a better functional response in AF. Improvement in left ventricular function and volumes occurred in both groups, but left ventricular mass reduction and left atrial reverse remodeling were seen exclusively in SR patients (ClinicalTrials.gov identifier: NCT02413151; FCT code: PTDC/DES/120249/2010). Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

Ketamine-induced ventricular structural, sympathetic and electrophysiological remodelling: pathological consequences and protective effects of metoprolol

PubMed Central

Li, Y; Shi, J; Yang, BF; Liu, L; Han, CL; Li, WM; Dong, DL; Pan, ZW; Liu, GZ; Geng, JQ; Sheng, L; Tan, XY; Sun, DH; Gong, ZH; Gong, YT

2012-01-01

BACKGROUND AND PURPOSE Growing evidence suggests that long-term abuse of ketamine does harm the heart and increases the risk of sudden death. The present study was performed to explore the cardiotoxicity of ketamine and the protective effects of metoprolol. EXPERIMENTAL APPROACH Rats and rabbits were divided into control, ketamine, metoprolol alone and ketamine plus metoprolol groups. Ketamine (40 mg·kg−1·day−1, i.p.) and metoprolol (20 mg·kg−1·day−1, p.o.) were administered continuously for 12 weeks in rats and 8 weeks in rabbits. Cardiac function, electrophysiological disturbances, cardiac collagen, cardiomyocte apoptosis and the remodelling-related proteins were evaluated. KEY RESULTS Rabbits treated with ketamine showed decreased left ventricular ejection fraction, slowed ventricular conduction velocity and increased susceptibility to ventricular arrhythmia. Metoprolol prevented these pathophysiological alterations. In ketamine-treated rats, cardiac collagen volume fraction and apoptotic cell number were higher than those of control animals; these effects were prevented by co-administration of metoprolol. Consistently, the expressions of poly (ADP-ribose) polymerases-1, apoptosis-inducing factor and NF-κB-light-chain-enhancer of activated B cells were all increased after ketamine treatment and sharply reduced after metoprolol administration. Moreover, ketamine enhanced sympathetic sprouting, manifested as increased growth-associated protein 43 and tyrosine TH expression. These effects of ketamine were prevented by metoprolol. CONCLUSIONS AND IMPLICATIONS Chronic treatment with ketamine caused significant ventricular myocardial apoptosis, fibrosis and sympathetic sprouting, which altered the electrophysiological properties of the heart and increased its susceptibility to malignant arrhythmia that may lead to sudden cardiac death. Metoprolol prevented the cardiotoxicity of ketamine, indicating a promising new therapeutic strategy. PMID:21883145

Adaptive servo-ventilation for central sleep apnoea in systolic heart failure: results of the major substudy of SERVE-HF.

PubMed

Cowie, Martin R; Woehrle, Holger; Wegscheider, Karl; Vettorazzi, Eik; Lezius, Susanne; Koenig, Wolfgang; Weidemann, Frank; Smith, Gillian; Angermann, Christiane; d'Ortho, Marie-Pia; Erdmann, Erland; Levy, Patrick; Simonds, Anita K; Somers, Virend K; Zannad, Faiez; Teschler, Helmut

2018-03-01

The SERVE-HF trial investigated the impact of treating central sleep apnoea (CSA) with adaptive servo-ventilation (ASV) in patients with systolic heart failure. A preplanned substudy was conducted to provide insight into mechanistic changes underlying the observed effects of ASV, including assessment of changes in left ventricular function, ventricular remodelling, and cardiac, renal and inflammatory biomarkers. In a subset of the 1325 randomised patients, echocardiography, cardiac magnetic resonance imaging (cMRI) and biomarker analysis were performed at baseline, and 3 and 12 months. In secondary analyses, data for patients with baseline and 12-month values were evaluated; 312 patients participated in the substudy. The primary endpoint, change in echocardiographically determined left ventricular ejection fraction from baseline to 12 months, did not differ significantly between the ASV and the control groups. There were also no significant between-group differences for changes in left ventricular dimensions, wall thickness, diastolic function or right ventricular dimensions and ejection fraction (echocardiography), and on cMRI (in small patient numbers). Plasma N-terminal pro B-type natriuretic peptide concentration decreased in both groups, and values were similar at 12 months. There were no significant between-group differences in changes in cardiac, renal and systemic inflammation biomarkers. In patients with systolic heart failure and CSA, addition of ASV to guideline-based medical management had no statistically significant effect on cardiac structure and function, or on cardiac biomarkers, renal function and systemic inflammation over 12 months. The increased cardiovascular mortality reported in SERVE-HF may not be related to adverse remodelling or worsening heart failure. © 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Sulforaphane, a Natural Isothiocyanate Compound, Improves Cardiac Function and Remodeling by Inhibiting Oxidative Stress and Inflammation in a Rabbit Model of Chronic Heart Failure.

PubMed

Ma, Tongliang; Zhu, Decai; Chen, Duoxue; Zhang, Qiaoyun; Dong, Huifang; Wu, Wenwu; Lu, Huihe; Wu, Guangfu

2018-03-12

BACKGROUND The aim of this study was to investigate the effects of sulforaphane (SFN), a natural isothiocyanate compound, in a rabbit ascending aortic cerclage model of chronic heart failure (CHF). MATERIAL AND METHODS Thirty New Zealand White rabbits were divided into the sham operation group (n=10), the CHF group (n=10), and the CHF + SFN group (n=10) treated with subcutaneous SFN (0.5 mg/kg) for five days per week for 12 weeks. After 12 weeks, echocardiography and biometric analysis were performed, followed by the examination of the rabbit hearts. Enzyme-linked immunosorbent assay (ELISA) and Western blot were used to detect levels of inflammatory cytokines, superoxide dismutase (SOD), and malondialdehyde (MDA). RESULTS In the CHF group, compared with the sham operation group, there was an increase in the heart weight to body weight ratio (HW/BW), the left ventricular weight to body weight ratio (LVW/BW), the left ventricular end diastolic diameter (LVEDD), the left ventricular end systolic diameter (LVESD), plasma brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) levels, the cardiac collagen volume fraction (CVF), apoptotic index, expression levels of collagen I, collagen III, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and malondialdehyde (MDA) in the myocardial tissue, and a decrease in the left ventricular shortening fraction (LVFS) and left ventricular ejection fraction (LVEF), and cardiac superoxide dismutase (SOD) activity. These changes were corrected in the SFN-treated group. CONCLUSIONS In a rabbit model of CHF, treatment with SFN improved cardiac function and remodeling by inhibiting oxidative stress and inflammation.

Comparison of the Young-Laplace law and finite element based calculation of ventricular wall stress: implications for postinfarct and surgical ventricular remodeling.

PubMed

Zhang, Zhihong; Tendulkar, Amod; Sun, Kay; Saloner, David A; Wallace, Arthur W; Ge, Liang; Guccione, Julius M; Ratcliffe, Mark B

2011-01-01

Both the Young-Laplace law and finite element (FE) based methods have been used to calculate left ventricular wall stress. We tested the hypothesis that the Young-Laplace law is able to reproduce results obtained with the FE method. Magnetic resonance imaging scans with noninvasive tags were used to calculate three-dimensional myocardial strain in 5 sheep 16 weeks after anteroapical myocardial infarction, and in 1 of those sheep 6 weeks after a Dor procedure. Animal-specific FE models were created from the remaining 5 animals using magnetic resonance images obtained at early diastolic filling. The FE-based stress in the fiber, cross-fiber, and circumferential directions was calculated and compared to stress calculated with the assumption that wall thickness is very much less than the radius of curvature (Young-Laplace law), and without that assumption (modified Laplace). First, circumferential stress calculated with the modified Laplace law is closer to results obtained with the FE method than stress calculated with the Young-Laplace law. However, there are pronounced regional differences, with the largest difference between modified Laplace and FE occurring in the inner and outer layers of the infarct borderzone. Also, stress calculated with the modified Laplace is very different than stress in the fiber and cross-fiber direction calculated with FE. As a consequence, the modified Laplace law is inaccurate when used to calculate the effect of the Dor procedure on regional ventricular stress. The FE method is necessary to determine stress in the left ventricle with postinfarct and surgical ventricular remodeling. Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Elevated ventricular wall stress disrupts cardiomyocyte t-tubule structure and calcium homeostasis.

PubMed

Frisk, Michael; Ruud, Marianne; Espe, Emil K S; Aronsen, Jan Magnus; Røe, Åsmund T; Zhang, Lili; Norseng, Per Andreas; Sejersted, Ole M; Christensen, Geir A; Sjaastad, Ivar; Louch, William E

2016-10-01

Invaginations of the cellular membrane called t-tubules are essential for maintaining efficient excitation-contraction coupling in ventricular cardiomyocytes. Disruption of t-tubule structure during heart failure has been linked to dyssynchronous, slowed Ca(2+) release and reduced power of the heartbeat. The underlying mechanism is, however, unknown. We presently investigated whether elevated ventricular wall stress triggers remodelling of t-tubule structure and function. MRI and blood pressure measurements were employed to examine regional wall stress across the left ventricle of sham-operated and failing, post-infarction rat hearts. In failing hearts, elevated left ventricular diastolic pressure and ventricular dilation resulted in markedly increased wall stress, particularly in the thin-walled region proximal to the infarct. High wall stress in this proximal zone was associated with reduced expression of the dyadic anchor junctophilin-2 and disrupted cardiomyocyte t-tubular structure. Indeed, local wall stress measurements predicted t-tubule density across sham and failing hearts. Elevated wall stress and disrupted cardiomyocyte structure in the proximal zone were also associated with desynchronized Ca(2+) release in cardiomyocytes and markedly reduced local contractility in vivo. A causative role of wall stress in promoting t-tubule remodelling was established by applying stretch to papillary muscles ex vivo under culture conditions. Loads comparable to wall stress levels observed in vivo in the proximal zone reduced expression of junctophilin-2 and promoted t-tubule loss. Elevated wall stress reduces junctophilin-2 expression and disrupts t-tubule integrity, Ca(2+) release, and contractile function. These findings provide new insight into the role of wall stress in promoting heart failure progression. © The Author 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

Left ventricular geometric patterns in newly presenting nigerian hypertensives: An echocardiographic study

PubMed Central

Aje, Akinyemi; Adebiyi, Adewole A; Oladapo, Olulola O; Dada, Adekola; Ogah, Okechukwu S; Ojji, Dike B; Falase, Ayodele O

2006-01-01

Background Hypertension is a global problem and it is prevalent in Nigeria. Left ventricular hypertrophy is a major complication of hypertension with risk of sudden death and arrhythmias among others. Abnormal left ventricular geometric patterns also increase the burden of morbidity and mortality. It is therefore important to know the different left ventricular geometric patterns in Nigerian hypertensives because of their prognostic significance. Methods One hundred (100) newly presenting hypertensives (53 males and 47 females) and 100 controls (53 males and 47 females) were recruited for the study. All were subjected to clinical evaluation and full echocardiographic examination was performed according to the ASE recommendation. The relative wall thickness and the presence or absence of echocardiographic left ventricular hypertrophy were used to determine the various geometric patterns Results The mean age of the hypertensive subjects was 56.06 (± 7.68) years while that of the control subjects was 56.10 (± 7.68) years. There was no significant difference in the mean ages of the two groups. In the hypertensive subjects 28% had normal geometry, 26% had concentric remodeling, 28% had concentric hypertrophy and 18% had eccentric hypertrophy. In the control group, 86% had normal geometry, 11% had concentric remodeling, 3% had eccentric hypertrophy and none had concentric hypertrophy. There was statistical significance when the geometric patterns of the hypertensive and controls were compared (χ2 = 74.30, p value < 0.0001). Conclusion The study showed that only 28% of the hypertensive subjects had normal LV geometric pattern while 86% of the normal subjects had normal geometry. There is need for longitudinal studies in order to prognosticate the various geometric patterns. PMID:16426452

Baicalein Ameliorates Pulmonary Arterial Hypertension Caused by Monocrotaline through Downregulation of ET-1 and ETAR in Pneumonectomized Rats.

PubMed

Hsu, Wen-Lin; Lin, Yu-Chieh; Jeng, Jing-Ren; Chang, Heng-Yuan; Chou, Tz-Chong

2018-05-08

Baicalein (BE) extracted from Scutellaria baicalensis Georgi is able to alleviate various cardiovascular and inflammatory diseases. However, the effects of BE on pulmonary arterial hypertension (PAH) remain unknown. Therefore, the present study aimed to examine whether BE ameliorates pneumonectomy and monocrotaline-induced PAH in rats and further investigate the underlying molecular mechanisms. Administration of BE greatly attenuated the development of PAH as evidenced by an improvement of its characteristic features, including elevation of right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Moreover, the increased protein expression of endothelin-1 (ET-1) and ET A receptor (ET A R), superoxide overproduction, and activation of Akt/ERK1/2/GSK3[Formula: see text]/[Formula: see text]-catenin pathway that occurred in the lungs of PAH rats were markedly reversed by BE treatment. Compared with the untreated PAH rats, higher expression of endothelial nitric oxide synthase (eNOS), but lower levels of inducible nitric oxide synthase and vWF were observed in BE-treated PAH rats. Collectively, treatment with BE remarkably attenuates the pathogenesis of PAH, and the protection of BE may be associated with suppressing Akt/Erk1/2/GSK3[Formula: see text]/[Formula: see text]-catenin/ET-1/ET A R signaling and preventing endothelial dysfunction. These results suggest that BE is a potential agent for treatment of PAH.

Exercise training in patients with heart disease: review of beneficial effects and clinical recommendations.

PubMed

Gielen, Stephan; Laughlin, M Harold; O'Conner, Christopher; Duncker, Dirk J

2015-01-01

Over the last decades exercise training has evolved into an established evidence-based therapeutic strategy with prognostic benefits in many cardiovascular diseases (CVDs): In stable coronary artery disease (CAD) exercise training attenuates disease progression by beneficially influencing CVD risk factors (i.e., hyperlipidemia, hypertension) and coronary endothelial function. In heart failure (HF) with reduced ejection fraction (HFrEF) training prevents the progressive loss of exercise capacity by antagonizing peripheral skeletal muscle wasting and by promoting left ventricular reverse remodeling with reduction in cardiomegaly and improvement of ejection fraction. Novel areas for exercise training interventions include HF with preserved ejection fraction (HFpEF), pulmonary hypertension, and valvular heart disease. In HFpEF, randomized studies indicate a lusitropic effect of training on left ventricular diastolic function associated with symptomatic improvement of exercise capacity. In pulmonary hypertension, reductions in pulmonary artery pressure were observed following endurance exercise training. Recently, innovative training methods such as high-intensity interval training, resistance training and others have been introduced. Although their prognostic value still needs to be determined, these approaches may achieve superior improvements in aerobic exercise capacity and gain in muscle mass, respectively. In this review, we give an overview of the prognostic and symptomatic benefits of exercise training in the most common cardiac disease entities. Additionally, key guideline recommendations for the initiation of training programs are summarized. Copyright © 2014 Elsevier Inc. All rights reserved.

Heart-Derived Stem Cells in Miniature Swine with Coronary Microembolization: Novel Ischemic Cardiomyopathy Model to Assess the Efficacy of Cell-Based Therapy

PubMed Central

Young, Rebeccah F.; Leiker, Merced M.; Suzuki, Takayuki

2016-01-01

A major problem in translating stem cell therapeutics is the difficulty of producing stable, long-term severe left ventricular (LV) dysfunction in a large animal model. For that purpose, extensive infarction was created in sinclair miniswine by injecting microspheres (1.5 × 106 microspheres, 45 μm diameter) in LAD. At 2 months after embolization, animals (n = 11) were randomized to receive allogeneic cardiosphere-derived cells derived from atrium (CDCs: 20 × 106, n = 5) or saline (untreated, n = 6). Four weeks after therapy myocardial function, myocyte proliferation (Ki67), mitosis (phosphor-Histone H3; pHH3), apoptosis, infarct size (TTC), myocyte nuclear density, and cell size were evaluated. CDCs injected into infarcted and remodeled remote myocardium (global infusion) increased regional function and global function contrasting no change in untreated animals. CDCs reduced infarct volume and stimulated Ki67 and pHH3 positive myocytes in infarct and remote regions. As a result, myocyte number (nuclear density) increased and myocyte cell diameter decreased in both infarct and remote regions. Coronary microembolization produces stable long-term ischemic cardiomyopathy. Global infusion of CDCs stimulates myocyte regeneration and improves left ventricular ejection fraction. Thus, global infusion of CDCs could become a new therapy to reverse LV dysfunction in patients with asymptomatic heart failure. PMID:27738436

Impact of mitral valve intervention with left ventricular assist device implantation on postoperative outcomes and morphologic change.

PubMed

Hata, Hiroki; Fujita, Tomoyuki; Ishibashi-Ueda, Hatsue; Kuroda, Kensuke; Seguchi, Osamu; Matsumoto, Yorihiko; Yanase, Masanobu; Sato, Takuma; Nakajima, Seiko; Fukushima, Norihide; Kobayashi, Junjiro

2018-06-01

Although mitral regurgitation (MR) is prevalent in patients with end-stage heart failure, the impact of mitral valve (MV) surgery on outcomes after left ventricular assist device (LVAD) implantation and morphologic changes of MV remains unclear. We retrospectively reviewed 74 patients who underwent LVAD implantation as a bridge to transplant. Of these, 11 (15%) underwent MV repair concomitant with or prior to LVAD implantation, while 27 patients with preoperative significant (moderate or greater) MR did not undergo concomitant MV surgery. The mean interval between LVAD implantation and the last echocardiographic examination was 913 days. Irrespective of MV surgery, significant LV reverse remodeling including decreased LV and left atrial dimension and improved MR severity was observed in all patients except for patients with prior MV surgery. Histopathological examination of explanted hearts removed at heart transplantation (n = 69) or autopsy (n = 5) revealed that the MV annulus was still dilated (mean perimeter 11.7 cm) in the patients with preoperative significant MR and no concomitant MV surgery. Concomitant MV surgery at the time of LVAD implantation for significant MR might not be always necessary for bridge to transplant or destination therapy cases. However, it might be required in patients having potential for cardiac recovery or patients with severe pulmonary hypertension and depressed right ventricle.

d,l-Sotalol reverses abbreviated atrial refractoriness and prevents promotion of atrial fibrillation in a canine model with left ventricular dysfunction induced by atrial tachypacing.

PubMed

Sakamoto, Tamotsu; Fujiki, Akira; Nakatani, Yosuke; Sakabe, Masao; Mizumaki, Koichi; Hashimoto, Norio; Inoue, Hiroshi

2009-10-01

This study evaluated antiarrhythmic effects of d,l-sotalol in a canine atrial fibrillation (AF) model with left ventricular dysfunction. Thirteen beagles (Sotalol group n=7 and Control group n=6) were subjected to atrial tachypacing (ATP) (400 beats/min) with intact atrioventricular conduction for 4 weeks. Oral d,l-sotalol (2 mg/kg) was administered 1 week after starting ATP and continued throughout the experiment. One week after starting ATP, atrial effective refractory periods (AERPs) were shortened in both groups. However, d,l-sotalol treatment gradually prolonged AERP, resulting in a significant prolongation of AERP compared with the Control group at 4 weeks (Control 76 +/-4 and Sotalol 126 +/-5 ms, p<0.01). d,l-Sotalol treatment showed lower AF inducibility and shorter AF duration at 4 weeks. In the control group, expressions of L-type Ca(2+) channel alpha1c and Kv4.3 mRNA were downregulated by 46.2% and 43.0%, respectively, after 4 weeks of ATP; d,l-sotalol treatment did not affect these changes. d,l-Sotalol treatment prolonged AERP, even after atrial electrical remodeling had developed, and prevented AF perpetuation without affecting downregulated expression of L-type Ca(2+) channel alpha1c and Kv4.3 mRNA in an ATP-induced canine AF model.

Prevalence, clinical and echocardiographic characteristics of various flow and gradient patterns in mild or moderate aortic stenosis with normal left ventricular ejection fraction.

PubMed

Tan, Yong-Qiang Benjamin; Ngiam, Jinghao Nicholas; Kong, William K F; Yeo, Tiong-Cheng; Poh, Kian-Keong

2016-10-15

Paradoxical low-flow aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF) has only been described in severe AS. Controversy surrounds prognosis and management but no studies have reported this phenomenon in mild or moderate AS. We investigated the prevalence of flow and gradient patterns in this population, characterising their clinical and echocardiographic profile. Consecutive subjects (n=1362) with isolated AS: mild (n=462, aortic valve area≥1.5cm(2), 2.5m/s

Soft skills turned into hard facts: nucleosome remodelling at developmental switches.

PubMed

Chioda, M; Becker, P B

2010-07-01

Nucleosome remodelling factors are regulators of DNA accessibility in chromatin and lubricators of all major functions of eukaryotic genomes. Their action is transient and reversible, yet can be decisive for irreversible cell-fate decisions during development. In addition to the well-known local actions of nucleosome remodelling factors during transcription initiation, more global and fundamental roles for remodelling complexes in shaping the epigenome during development are emerging.

Valsartan attenuates pulmonary hypertension via suppression of mitogen activated protein kinase signaling and matrix metalloproteinase expression in rodents.

PubMed

Lu, Yuyan; Guo, Haipeng; Sun, Yuxi; Pan, Xin; Dong, Jia; Gao, Di; Chen, Wei; Xu, Yawei; Xu, Dachun

2017-08-01

It has previously been demonstrated that the renin-angiotensin system is involved in the pathogenesis and development of pulmonary hypertension (PH). However, the efficacy of angiotensin II type I (AT1) receptor blockers in the treatment of PH is variable. The present study examined the effects of the AT1 receptor blocker valsartan on monocrotaline (MCT)‑induced PH in rats and chronic hypoxia‑induced PH in mice. The results demonstrated that valsartan markedly attenuated development of PH in rats and mice, as indicated by reduced right ventricular systolic pressure, diminished lung vascular remodeling and decreased right ventricular hypertrophy, compared with vehicle treated animals. Immunohistochemical analyses of proliferating cell nuclear antigen expression revealed that valsartan suppressed smooth muscle cell proliferation. Western blot analysis demonstrated that valsartan limited activation of p38, c‑Jun N‑terminal kinase 1/2 and extracellular signal‑regulated kinase 1/2 signaling pathways and significantly reduced MCT‑induced upregulation of pulmonary matrix metalloproteinases‑2 and ‑9, and transforming growth factor‑β1 expression. The results suggested that valsartan attenuates development of PH in rodents by reducing expression of extracellular matrix remodeling factors and limiting smooth muscle cell proliferation to decrease pathological vascular remodeling. Therefore, valsartan may be a valuable future therapeutic approach for the treatment of PH.

Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig

PubMed Central

Beaumont, Eric; Wright, Gary L.; Southerland, Elizabeth M.; Li, Ying; Chui, Ray; KenKnight, Bruce H.; Armour, J. Andrew

2016-01-01

Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15–20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P < 0.004), as well as systolic (114%, P < 0.04) and diastolic (49%, P < 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P < 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling. PMID:26993230

Vagus nerve stimulation mitigates intrinsic cardiac neuronal remodeling and cardiac hypertrophy induced by chronic pressure overload in guinea pig.

PubMed

Beaumont, Eric; Wright, Gary L; Southerland, Elizabeth M; Li, Ying; Chui, Ray; KenKnight, Bruce H; Armour, J Andrew; Ardell, Jeffrey L

2016-05-15

Our objective was to determine whether chronic vagus nerve stimulation (VNS) mitigates pressure overload (PO)-induced remodeling of the cardioneural interface. Guinea pigs (n = 48) were randomized to right or left cervical vagus (RCV or LCV) implant. After 2 wk, chronic left ventricular PO was induced by partial (15-20%) aortic constriction. Of the 31 animals surviving PO induction, 10 were randomized to RCV VNS, 9 to LCV VNS, and 12 to sham VNS. VNS was delivered at 20 Hz and 1.14 ± 0.03 mA at a 22% duty cycle. VNS commenced 10 days after PO induction and was maintained for 40 days. Time-matched controls (n = 9) were evaluated concurrently. Echocardiograms were obtained before and 50 days after PO. At termination, intracellular current-clamp recordings of intrinsic cardiac (IC) neurons were studied in vitro to determine effects of therapy on soma characteristics. Ventricular cardiomyocyte sizes were assessed with histology along with immunoblot analysis of selected proteins in myocardial tissue extracts. In sham-treated animals, PO increased cardiac output (34%, P < 0.004), as well as systolic (114%, P < 0.04) and diastolic (49%, P < 0.002) left ventricular volumes, a hemodynamic response prevented by VNS. PO-induced enhancements of IC synaptic efficacy and muscarinic sensitivity of IC neurons were mitigated by chronic VNS. Increased myocyte size, which doubled in PO (P < 0.05), was mitigated by RCV. PO hypertrophic myocardium displayed decreased glycogen synthase (GS) protein levels and accumulation of the phosphorylated (inactive) form of GS. These PO-induced changes in GS were moderated by left VNS. Chronic VNS targets IC neurons accompanying PO to obtund associated adverse cardiomyocyte remodeling. Copyright © 2016 the American Physiological Society.

New Concepts in the Invasive and Non Invasive Evaluation of Remodelling of the Right Ventricle and Pulmonary Vasculature in Pulmonary Arterial Hypertension

PubMed Central

Domingo, Enric; Aguilar, Rio; López-Meseguer, Manuel; Teixidó, Gisela; Vazquez, Manuel; Roman, Antonio

2009-01-01

Pulmonary arterial hypertension (PAH) is a rare fatal disease defined as a sustained elevation of pulmonary arterial pressure to more than 25 mmHg at rest, with a mean pulmonary-capillary wedge pressure and left ventricular enddiastolic pressure of less than 15 mmHg at rest. Histopathology of PAH is founded on structural modifications on the vascular wall of small pulmonary arteries characterized by thickening of all its layers. These changes, named as vascular remodelling, include vascular proliferation, fibrosis, and vessel obstruction. In clinical practice the diagnosis of PAH relies on measurements of pulmonary vascular pressure and cardiac output, and calculation of pulmonary vascular resistances. Direct evaluation of pulmonary vascular structure is not routinely performed in pulmonary hypertension since current imaging techniques are limited and since little is known about the relationship between structural changes and functional characteristics of the pulmonary vasculature. Intravascular ultrasound studies in patients with pulmonary hypertension have shown a thicker middle layer, increased wall-thickness ratio and diminished pulsatility than in control patients. Optical Coherence Tomography, a new high resolution imaging modality that has proven its superiority over intravascular ultrasound (IVUS) for the detection and characterization of coronary atherosclerotic plaque composition, may potentially be a useful technique for the in vivo study of the pulmonary arterial wall. In addition current progress in Echo Doppler technique will quantify right ventricular function with parameters independent of loading conditions and not requiring volumetric approximations of the complex geometry of the right ventricle. This would allow the in vivo study of right ventricular and pulmonary artery remodelling in PAH. PMID:19452037

Regular endurance training in adolescents impacts atrial and ventricular size and function.

PubMed

Rundqvist, Louise; Engvall, Jan; Faresjö, Maria; Carlsson, Emma; Blomstrand, Peter

2017-06-01

The aims of the study were to explore the effects of long-term endurance exercise on atrial and ventricular size and function in adolescents and to examine whether these changes are related to maximal oxygen uptake (VO2max). Twenty-seven long-term endurance-trained adolescents aged 13-19 years were individually matched by age and gender with 27 controls. All participants, 22 girls and 32 boys, underwent an echocardiographic examination at rest, including standard and colour tissue Doppler investigation. VO2max was assessed during treadmill exercise. All heart dimensions indexed for body size were larger in the physically active group compared with controls: left ventricular end-diastolic volume 60 vs. 50 mL/m2 (P <0.001), left atrial volume 27 vs. 19 mL/m2 (P < 0.001), and right ventricular (RV) and right atrial area 15 vs. 13 and 9 vs. 7 cm2/m2, respectively (P <0.001 for both). There were strong associations between the size of the cardiac chambers and VO2max. Further, we found improved systolic function in the active group compared with controls: left ventricular ejection fraction 61 vs. 59% (P= 0.036), tricuspid annular plane systolic excursion 12 vs. 10 mm/m2 (P= 0.008), and RV early peak systolic velocity s' 11 vs. 10 cm/s (P = 0.031). Cardiac remodelling to long-term endurance exercise in adolescents is manifested by an increase in atrial as well as ventricular dimensions. The physically active group also demonstrated functional remodelling with an increase in TAPSE and systolic RV wall velocity. These findings have practical implications when assessing cardiac enlargement and function in physically active youngsters. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

The effects of poloxamer-188 on left ventricular function in chronic heart failure after myocardial infarction.

PubMed

Juneman, Elizabeth B; Saleh, Laith; Lancaster, Jordan J; Thai, Hoang M; Markham, Bruce; Goldman, Steven

2012-09-01

Poloxamer-188 (P-188) is a biological membrane sealant that prevents the unregulated entry of Ca into cardiomyocytes and has been shown to have the ability to act as a membrane-repair agent in isolated cardiac myocytes. The purpose of this study was to determine if treatment with P-188 would improve left ventricular (LV) function in a rat chronic heart failure (CHF) model. We ligated the left coronary artery of adult male Sprague-Dawley rats to induce a myocardial infarction (MI). The rats were allowed to recover for 8 weeks until stable CHF was present and treated with a range of P-188 doses [1.5 mg/kg (N = 6), 4.6 mg/kg (N = 11), 15.3 mg/kg (N = 11), and 460 mg/kg (N = 6)] delivered via 30 minutes of intravenous infusion. The rats were randomized to study groups: control, 2 hours, 24 hours, 48 hours, 1 week, and 2 weeks posttreatment (N = 8 in each group). Two weeks after high dose (460 mg/kg) administration, P-188 improved (P < 0.05) left ventricular ejection fraction from 34% to 51%, which persisted over 38 hours and decreased (P < 0.05) LV end systolic diameter from 0.9 ± 0.07 to 0.6 ± 0.08 cm, in the rats with CHF. There was no statistical change in hemodynamics. Additionally, P-188 reduced (P < 0.05) circulating troponin levels 2 weeks after treatment. Treatment with P-188 improves the LV function and partially reverses maladaptive LV remodeling in rats with moderate CHF after MI. These data introduce the idea of using a biological membrane sealant as a new approach to treating CHF after MI.

What happens to non-responders in cardiac resynchronization therapy?

PubMed

Rio, Pedro; Oliveira, Mário Martins; Cunha, Pedro Silva; da Silva, Manuel Nogueira; Branco, Luísa Moura; Galrinho, Ana; Soares, Rui; Feliciano, Joana; Pimenta, Ricardo; Ferreira, Rui Cruz

2017-12-01

Left ventricular reverse remodeling (LVRR) is strongly related to the long-term prognosis of patients undergoing cardiac resynchronization therapy (CRT). The aim of this study was to assess the long-term clinical outcome of patients without LVRR at six months after CRT implantation and to determine the prognostic impact of clinical response in this population. We analyzed 178 consecutive patients who underwent successful CRT device implantation (age 64±11 years; 69% male; 89% in New York Heart Association [NYHA] functional class III; 35% with ischemic cardiomyopathy). Clinical status and echocardiographic parameters were determined before and six months after CRT implantation. We identified those without criteria for LVRR (≥10% increase in left ventricular ejection fraction with ≥15% reduction in left ventricular end-systolic diameter compared to baseline). Clinical responders were defined by a sustained improvement of at least one NYHA functional class. At six-month assessment after CRT, 109 (61%) patients showed LVRR. During a mean follow-up of 56±21 months, 47 (26%) patients died, with higher mortality in the group without LVRR (36% vs. 20%, p=0.023). Clinical response was greater in patients with LVRR (88% vs. 55%, p<0.001). In patients without LVRR, clinical response to CRT was the strongest independent predictor of survival (hazard ratio: 0.120; 95% confidence interval: 0.039-0.366; p<0.001). Although patients without LVRR six months after CRT implantation had a worse prognosis, with higher all-cause mortality, clinical response can be an independent predictor of survival in this population. Copyright © 2017 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

The overloaded right heart and ventricular interdependence.

PubMed

Naeije, Robert; Badagliacca, Roberto

2017-10-01

The right and the left ventricle are interdependent as both structures are nested within the pericardium, have the septum in common and are encircled with common myocardial fibres. Therefore, right ventricular volume or pressure overloading affects left ventricular function, and this in turn may affect the right ventricle. In normal subjects at rest, right ventricular function has negligible interaction with left ventricular function. However, the right ventricle contributes significantly to the normal cardiac output response to exercise. In patients with right ventricular volume overload without pulmonary hypertension, left ventricular diastolic compliance is decreased and ejection fraction depressed but without intrinsic alteration in contractility. In patients with right ventricular pressure overload, left ventricular compliance is decreased with initial preservation of left ventricular ejection fraction, but with eventual left ventricular atrophic remodelling and altered systolic function. Breathing affects ventricular interdependence, in healthy subjects during exercise and in patients with lung diseases and altered respiratory system mechanics. Inspiration increases right ventricular volumes and decreases left ventricular volumes. Expiration decreases both right and left ventricular volumes. The presence of an intact pericardium enhances ventricular diastolic interdependence but has negligible effect on ventricular systolic interdependence. On the other hand, systolic interdependence is enhanced by a stiff right ventricular free wall, and decreased by a stiff septum. Recent imaging studies have shown that both diastolic and systolic ventricular interactions are negatively affected by right ventricular regional inhomogeneity and prolongation of contraction, which occur along with an increase in pulmonary artery pressure. The clinical relevance of these observations is being explored. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Human Umbilical Cord-Derived Mesenchymal Stromal Cells Improve Left Ventricular Function, Perfusion, and Remodeling in a Porcine Model of Chronic Myocardial Ischemia

PubMed Central

Liu, Chuan-Bin; Huang, He; Sun, Ping; Ma, Shi-Ze; Liu, An-Heng; Xue, Jian; Fu, Jin-Hui; Liang, Yu-Qian; Liu, Bing; Wu, Dong-Ying

2016-01-01

Stem cell therapy has emerged as a new strategy for treatment of ischemic heart disease. Although umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have been used preferentially in the acute ischemia model, data for the chronic ischemia model are lacking. In this study, we investigated the effect of UC-MSCs originated from Wharton’s jelly in the treatment of chronic myocardial ischemia in a porcine model induced by ameroid constrictor. Four weeks after ameroid constrictor placement, the surviving animals were divided randomly into two groups to undergo saline injection (n = 6) or UC-MSC transplantation (n = 6) through the left main coronary artery. Two additional intravenous administrations of UC-MSCs were performed in the following 2 weeks to enhance therapeutic effect. Cardiac function and perfusion were examined just before and at 4 weeks after intracoronary transplantation. The results showed that pigs with UC-MSC transplantation exhibited significantly greater left ventricular ejection fraction compared with control animals (61.3% ± 1.3% vs. 50.3% ± 2.0%, p < .05). The systolic thickening fraction in the infarcted left ventricular wall was also improved (41.2% ± 3.3% vs. 46.2% ± 2.3%, p < .01). Additionally, the administration of UC-MSCs promoted collateral development and myocardial perfusion. The indices of fibrosis and apoptosis were also significantly reduced. Immunofluorescence staining showed clusters of CM-DiI-labeled cells in the border zone, some of which expressed von Willebrand factor. These results suggest that UC-MSC treatment improves left ventricular function, perfusion, and remodeling in a porcine model with chronic myocardial ischemia. Significance Ischemic heart disease is the leading cause of death worldwide. Many patients with chronic myocardial ischemia are not suitable for surgery and have no effective drug treatment; they are called “no-option” patients. This study finds that umbilical cord-derived mesenchymal stromal cells transplanted by intracoronary delivery combined with two intravenous administrations was safe and could significantly improve left ventricular function, perfusion, and remodeling in a large-animal model of chronic myocardial ischemia, which provides a new choice for the no-option patients. In addition, this study used clinical-grade mesenchymal stem cells with delivery and assessment methods commonly used clinically to facilitate further clinical transformation. PMID:27334487

Human Umbilical Cord-Derived Mesenchymal Stromal Cells Improve Left Ventricular Function, Perfusion, and Remodeling in a Porcine Model of Chronic Myocardial Ischemia.

PubMed

Liu, Chuan-Bin; Huang, He; Sun, Ping; Ma, Shi-Ze; Liu, An-Heng; Xue, Jian; Fu, Jin-Hui; Liang, Yu-Qian; Liu, Bing; Wu, Dong-Ying; Lü, Shuang-Hong; Zhang, Xiao-Zhong

2016-08-01

: Stem cell therapy has emerged as a new strategy for treatment of ischemic heart disease. Although umbilical cord-derived mesenchymal stromal cells (UC-MSCs) have been used preferentially in the acute ischemia model, data for the chronic ischemia model are lacking. In this study, we investigated the effect of UC-MSCs originated from Wharton's jelly in the treatment of chronic myocardial ischemia in a porcine model induced by ameroid constrictor. Four weeks after ameroid constrictor placement, the surviving animals were divided randomly into two groups to undergo saline injection (n = 6) or UC-MSC transplantation (n = 6) through the left main coronary artery. Two additional intravenous administrations of UC-MSCs were performed in the following 2 weeks to enhance therapeutic effect. Cardiac function and perfusion were examined just before and at 4 weeks after intracoronary transplantation. The results showed that pigs with UC-MSC transplantation exhibited significantly greater left ventricular ejection fraction compared with control animals (61.3% ± 1.3% vs. 50.3% ± 2.0%, p < .05). The systolic thickening fraction in the infarcted left ventricular wall was also improved (41.2% ± 3.3% vs. 46.2% ± 2.3%, p < .01). Additionally, the administration of UC-MSCs promoted collateral development and myocardial perfusion. The indices of fibrosis and apoptosis were also significantly reduced. Immunofluorescence staining showed clusters of CM-DiI-labeled cells in the border zone, some of which expressed von Willebrand factor. These results suggest that UC-MSC treatment improves left ventricular function, perfusion, and remodeling in a porcine model with chronic myocardial ischemia. Ischemic heart disease is the leading cause of death worldwide. Many patients with chronic myocardial ischemia are not suitable for surgery and have no effective drug treatment; they are called "no-option" patients. This study finds that umbilical cord-derived mesenchymal stromal cells transplanted by intracoronary delivery combined with two intravenous administrations was safe and could significantly improve left ventricular function, perfusion, and remodeling in a large-animal model of chronic myocardial ischemia, which provides a new choice for the no-option patients. In addition, this study used clinical-grade mesenchymal stem cells with delivery and assessment methods commonly used clinically to facilitate further clinical transformation. ©AlphaMed Press.

Identification of a Novel Hybridization from Isosorbide 5-Mononitrate and Bardoxolone Methyl with Dual Activities of Pulmonary Vasodilation and Vascular Remodeling Inhibition on Pulmonary Arterial Hypertension Rats.

PubMed

Cheng, Yusheng; Gong, Yan; Qian, Shuai; Mou, Yi; Li, Hanrui; Chen, Xijing; Kong, Hui; Xie, Weiping; Wang, Hong; Zhang, Yihua; Huang, Zhangjian

2018-02-22

Given the clinical therapeutic efficacy of oral-dosed bardoxolone methyl (1) and the selective vasodilatory effect caused by inhalation of nitric oxide (NO) on pulmonary arterial hypertension (PAH) patients, a new hybrid (CDDO-NO, 2) from 1 and NO donor isosorbide 5-mononitrate (3) was designed and synthesized. This hybrid could liberate 1 and NO in the lungs of rats after trachea injection. Significantly, 2 lowered mean pulmonary artery pressure (mPAP) and right ventricular systolic pressure (RVSP), decreased right ventricular hypertrophy (RVH), and attenuated pulmonary artery medial thickness (PAMT) and vascular muscularization in monocrotaline (MCT)-induced PAH rats. Meanwhile, 2 inhibited overproliferation of perivascular cells and diminished macrophage infiltration and oxidative stress by inactivation of NOX4. In addition, 2 markedly reduced cardiac hypertrophy and fibrosis in the PAH rats. Overall, 2 exhibited potent dual activities of pulmonary vasodilation and vascular remodeling inhibition, suggesting that it may be a promising agent for PAH intervention.

Association between central sleep apnea and left ventricular structure: the Multi-Ethnic Study of Atherosclerosis.

PubMed

Javaheri, Sogol; Sharma, Ravi K; Bluemke, David A; Redline, Susan

2017-08-01

We assessed whether the presence of central sleep apnea is associated with adverse left ventricular structural changes. We analysed 1412 participants from the Multi-Ethnic Study of Atherosclerosis who underwent both overnight polysomnography and cardiac magnetic resonance imaging. Subjects had been recruited 10 years earlier when free of cardiovascular disease. Our main exposure is the presence of central sleep apnea as defined by central apnea-hypopnea index = 5 or the presence of Cheyne-Stokes breathing. Outcome variables were left ventricular mass/height, left ventricular ejection fraction, and left ventricular mass/volume ratio. Multivariate linear regression models adjusted for age, gender, race, waist circumference, tobacco use, hypertension, and the obstructive apnea-hypopnea index were fit for the outcomes. Of the 1412 participants, 27 (2%) individuals had central sleep apnea. After adjusting for covariates, the presence of central sleep apnea was significantly associated with elevated left ventricular mass/volume ratio (β = 0.11 ± 0.04 g mL -1 , P = 0.0071), an adverse cardiac finding signifying concentric remodelling. © 2017 European Sleep Research Society.

The late open infarct-related artery hypothesis: evidence-based medicine or not?

PubMed

Brueck, Martin; Bandorski, Dirk; Kramer, Wilfried; Vogt, Paul R; Heidt, Martin C

2007-11-01

Randomized clinical trials have clearly shown that early reperfusion of coronary arteries is the established treatment of myocardial infarction preserving left ventricular function and reducing mortality. However, late patency of the infarct-related artery is an independent predictor of survival leading to the late open-artery hypothesis. This concept implies restoration of antegrade blood flow of the infarct-related artery in patients with myocardial infarction to improve survival by mechanisms less time-dependent or even time-independent. Possible explanations for this benefit include improved left ventricular function and electrical stability by perfusion of hibernating myocardium, accelerated infarct healing and limitation of ventricular remodeling. This review focuses on the evidence of late recanalization of occluded infarct-related arteries in patients with coronary artery disease.

Partially silencing brain toll-like receptor 4 prevents in part left ventricular remodeling with sympathoinhibition in rats with myocardial infarction-induced heart failure.

PubMed

Ogawa, Kiyohiro; Hirooka, Yoshitaka; Kishi, Takuya; Ide, Tomomi; Sunagawa, Kenji

2013-01-01

Left ventricular (LV) remodeling and activation of sympathetic nervous system (SNS) are cardinal features of heart failure. We previously demonstrated that enhanced central sympathetic outflow is associated with brain toll-like receptor 4 (TLR4) probably mediated by brain angiotensin II type 1 receptor in mice with myocardial infarction (MI)-induced heart failure. The purpose of the present study was to examine whether silencing brain TLR4 could prevent LV remodeling with sympathoinhibition in MI-induced heart failure. MI-induced heart failure model rats were created by ligation of left coronary artery. The expression level of TLR4 in brainstem was significantly higher in MI-induced heart failure treated with intracerebroventricular (ICV) injection of hGAPDH-SiRNA than in sham. TLR4 in brainstem was significantly lower in MI-induced heart failure treated with ICV injection of TLR4-SiRNA than in that treated with ICV injection of hGAPDH-SiRNA. Lung weight, urinary norepinephrine excretion, and LV end-diastolic pressure were significantly lower and LV dimension was significantly smaller in MI-induced heart failure treated with TLR4-SiRNA than in that treated with hGAPDH-SiRNA for 2 weeks. Partially silencing brain TLR4 by ICV injection of TLR4-SiRNA for 2 weeks could in part prevent LV remodeling with sympathoinhibition in rats with MI-induced heart failure. Brain TLR4 has a potential to be a target of the treatment for MI-induced heart failure.

Delayed expression of cytokines after reperfused myocardial infarction: possible trigger for cardiac dysfunction and ventricular remodeling.

PubMed

Moro, Cécile; Jouan, Marie-Gabrielle; Rakotovao, Andry; Toufektsian, Marie-Claire; Ormezzano, Olivier; Nagy, Norbert; Tosaki, Arpad; de Leiris, Joël; Boucher, François

2007-11-01

Previous studies have shown that 1 wk after permanent coronary artery ligation in rats, some cellular mechanisms involving TNF-alpha occur and contribute to the development of cardiac dysfunction and subsequent heart failure. The aim of the present study was to determine whether similar phenomena also occur after ischemia-reperfusion and whether cytokines other than TNF-alpha can also be involved. Anesthetized male Wistar rats were subjected to 1 h coronary occlusion followed by reperfusion. Cardiac geometry and function were assessed by echocardiography at days 5, 7, 8, and 10 postligation. Before death, heart function was assessed in vivo under basal conditions, as well as after volume overload. Finally, hearts were frozen for histoenzymologic assessment of infarct size and remodeling. The profile of cardiac cytokines was determined by ELISA and ChemiArray on heart tissue extracts. As expected, ischemia-reperfusion induced a progressive remodeling of the heart, characterized by left ventricular free-wall thinning and cavity dilation. Heart function was also decreased in ischemic rats during the first week after surgery. Interestingly, a transient and marked increase in TNF-alpha, IL-1beta, IL-6, cytokine-induced neutrophil chemoattractant (CINC) 2, CINC3, and macrophage inflammatory protein-3alpha was also observed in the myocardium of myocardial ischemia (MI) animals at day 8, whereas the expression of anti-inflammatory interleukins IL-4 and IL-10 remained unchanged. These results suggest that overexpression of proinflammatory cytokines occurring during the first week after ischemia-reperfusion may play a role in the adaptative process in the myocardium and contribute to early dysfunction and remodeling.

Left ventricular hypertrophy: virtuous intentions, malign consequences.

PubMed

Pokharel, Saraswati; Sharma, Umesh C; Pinto, Yigal M

2003-06-01

Left ventricular hypertrophy (LVH) is currently the focus of intense cardiovascular research, with the resultant rapid evolution of novel concepts relating to its exceedingly complex pathophysiology. In addition to the alterations in signal transduction and disturbances in Ca(2+) homeostasis, there are structural changes in myofilaments, disorganization of the cytoskeletal framework and increased collagen synthesis. LVH is associated with progressive left ventricular remodeling that culminates to heart failure. The modern treatment of left ventricular hypertrophy is now largely based on the hypothesis that neuroendocrine activation is important in the progression of the disease and inhibition of neurohormones is likely to have long-term benefit with regard to morbidity and mortality. Drugs specifically designed to unload the left ventricle, such as diuretics and vasodilators, appears to be less effective in reducing LV mass and improving prognosis. Thus, the evolution of treatment for LVH itself has provided much enlightenment for our understanding of the fundamental biology of the disorder.

Right ventricular strain in heart failure: Clinical perspective.

PubMed

Tadic, Marijana; Pieske-Kraigher, Elisabeth; Cuspidi, Cesare; Morris, Daniel A; Burkhardt, Franziska; Baudisch, Ana; Haßfeld, Sabine; Tschöpe, Carsten; Pieske, Burket

2017-10-01

The number of studies demonstrating the importance of right ventricular remodelling in a wide range of cardiovascular diseases has increased in the past two decades. Speckle-tracking imaging provides new variables that give comprehensive information about right ventricular function and mechanics. In this review, we summarize current knowledge of right ventricular mechanics in heart failure with reduced ejection fraction and preserved ejection fraction. We searched PubMed, MEDLINE, Ovid and Embase databases for studies published from January 2000 to December 2016 in the English language using the following keywords: "right ventricle"; "strain"; "speckle tracking"; "heart failure with reduced ejection fraction"; and "heart failure with preserved ejection fraction". Investigations showed that right ventricular dysfunction is associated with higher cardiovascular and overall mortality in patients with heart failure, irrespective of ejection fraction. The number of studies investigating right ventricular strain in patients with heart failure with reduced ejection fraction is constantly increasing, whereas data on right ventricular mechanics in patients with heart failure with preserved ejection fraction are limited. Given the high feasibility, accuracy and clinical implications of right ventricular strain in the population with heart failure, it is of great importance to try to include the evaluation of right ventricular strain as a regular part of each echocardiographic examination in patients with heart failure. However, further investigations are necessary to establish right ventricular strain as a standard variable for decision-making. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Effect of endurance exercise training on left ventricular size and remodeling in older adults with hypertension.

PubMed

Turner, M J; Spina, R J; Kohrt, W M; Ehsani, A A

2000-04-01

It is not known whether exercise training can induce a reduction of blood pressure (BP) and a regression of left ventricular hypertrophy (LVH) in older hypertensive subjects. This study was designed to determine whether endurance exercise training, by lowering BP, can induce regression of LVH and left ventricular (LV) concentric remodeling in older hypertensive adults. We studied 11 older adults with mild to moderate hypertension (BP 152.0 +/- 2.5/91.3 +/- 1.5 mm Hg, mean +/- SE), 65.5 +/- 1.2 years old, who exercised for 6.8 +/- 3.8 months. Seven sedentary hypertensive (BP 153 +/- 3/89 +/- 2 mm Hg) subjects, 68.5 +/- 1 years old, served as controls. LV size and geometry and function were assessed with the use of two-dimensional echocardiography. Exercise training increased aerobic power by 16% (p < .001), and it decreased systolic (p < .05) and diastolic (p < .05) BP, LV wall thickness (from 12.8 +/- 0.4 mm to 11.3 +/- 0.3 mm; p < .05), and the wall thickness-to-radius (h/r) ratio (from 0.48 +/- 0.02 to 0.41 +/- 0.01; p < .05). There were no significant changes in the controls. The changes in LV mass index (deltaLVMI) were different between the two groups. LV mass index decreased in the exercise group (deltaLVMI - 14.3 +/- 3.3 g) but not in the controls (deltaLVMI 1.4 +/- 4.1 g; p = .009). A multiple stepwise regression analysis showed that among clinical and physiological variables including changes in resting systolic BP, aerobic power, body mass index, and systolic BP during submaximal and maximal exercise, only the reduction in resting systolic BP correlated significantly with a regression of concentric remodeling (delta h/r ratio r = .80; p = .003). The other variables did not add to the ability of the model to predict changes in the h/r ratio. The data suggest that exercise training can reduce BP and induce partial regression of LVH and LV concentric remodeling in older adults with mild or moderate hypertension.

MicroRNA 21 Inhibits Left Ventricular Remodeling in the Early Phase of Rat Model with Ischemia-reperfusion Injury by Suppressing Cell Apoptosis

PubMed Central

Qin, Yanjun; Yu, Yueqing; Dong, Hua; Bian, Xiaohua; Guo, Xuan; Dong, Shimin

2012-01-01

Objective: To determine the role of microRNA 21(miR-21) on left ventricular remodeling of rat heart with ischemia-reperfusion (I/R) injury and to investigate the underlying mechanism of miR-21 mediated myocardium protection. Methods: Rats were randomly divided into three groups: an I/R model group with Ad-GFP (Ad-GFP group), an I/R model group with Ad-miR-21 (Ad-miR-21 group) and a sham-surgery group. Changes in hemodynamic parameters were recorded at 1 week after I/R. Histological diagnosis was achieved by hematoxylin and eosin (H&E). Left ventricular (LV) dimensions, myocardial infarct size, LV/BW, collagen type Ⅰ, type Ⅲ and PCNA positive cells were measured. Primary cultures of neonatal rat cardiac ventricular myocytes were performed and cell ischemic injury was induced by hypoxia in a serum- and glucose-free medium, and reoxygenation (H/R).MiR-21 inhibitor and pre-miR-21 were respectively added to the culture medium for the miR-21 knockdown and for the miR-21 up-regulation. qRT-PCR was used to determine the miR-21 levels in cultured cells. Flow cytometry was performed to examine the cell apoptosis. Results: In the Ad-miR-21 group, LV dimensions, myocardial infarct size, LV/BW, collagen type Ⅰ, type Ⅲ and PCNA positive cells all significantly decreased compared with the Ad-GFP group. At 1 week after I/R, the Ad-miR-21 significantly improved LVSP, LV +dp/dtmax, LV − dp/dtmin, and decreased heart rate (HR) and LVEDP compared with the Ad-GFP group. Compared with the Ad-GFP, the cell apoptotic rate significantly decreased in the Ad-miR-21 group. The miR-21 inhibitor exacerbated cardiac myocyte apoptosis and the pre-miR-21 decreased hypoxia/reoxygenation- induced cardiac myocyte apoptosis. Conclusions: Ad-miR-21 improves LV remodeling and decreases the apoptosis of myocardial cells, suggesting the possible mechanism by which Ad-miR-21 functions in protecting against I/R injury. PMID:22859901

Passive Ventricular Mechanics Modelling Using MRI of Structure and Function

PubMed Central

Wang, V.Y.; Lam, H.I.; Ennis, D.B.; Young, A.A.; Nash, M.P.

2009-01-01

Patients suffering from dilated cardiomyopathy or myocardial infarction can develop left ventricular (LV) diastolic impairment. The LV remodels its structure and function to adapt to pathophysiological changes in geometry and loading conditions and this remodeling process can alter the passive ventricular mechanics. In order to better understand passive ventricular mechanics, a LV finite element model was developed to incorporate physiological and mechanical information derived from in vivo magnetic resonance imaging (MRI) tissue tagging, in vivo LV cavity pressure recording and ex vivo diffusion tensor MRI (DTMRI) of a canine heart. MRI tissue tagging enables quantitative evaluation of cardiac mechanical function with high spatial and temporal resolution, whilst the direction of maximum water diffusion (the primary eigenvector) in each voxel of a DTMRI directly correlates with the myocardial fibre orientation. This model was customized to the geometry of the canine LV during diastasis by fitting the segmented epicardial and endocardial surface data from tagged MRI using nonlinear finite element fitting techniques. Myofibre orientations, extracted from DTMRI of the same heart, were incorporated into this geometric model using a free form deformation methodology. Pressure recordings, temporally synchronized to the tissue tagging MRI data, were used to simulate the LV deformation during diastole. Simulation of the diastolic LV mechanics allowed us to estimate the stiffness of the passive LV myocardium based on kinematic data obtained from tagged MRI. This integrated physiological model will allow more insight into the regional passive diastolic mechanics of the LV on an individualized basis, thereby improving our understanding of the underlying structural basis of mechanical dysfunction in pathological conditions. PMID:18982680

Cigarette Smoke-induced Left Ventricular Remodelling is Associated with Activation of Mitogen-activated Protein Kinases

PubMed Central

Gu, Lianzhi; Pandey, Vikas; Geenen, David L.; Chowdhury, Shamim A. K.; Piano, Mariann R.

2008-01-01

Aim To determine the effects of cigarette smoke (CS) exposure on the expression/activation of mitogen-activated protein kinases (MAPKs) (extracellular signal-regulated kinase [ERK1/2], p38-kinase [p38] and c-Jun NH2–terminal protein kinase [JNK]), norepinephrine (NE) levels and myocardial structure and function. Methods Rats were randomised to two groups: CS–exposed (n = 10) or room air (CON) (n = 12). After 5 weeks, the animals underwent echocardiography with pulse-wave Doppler flow measurements. Hearts were removed for microscopy and Western blot analysis. Results CS exposure was associated with significant increases in NE urinary levels and larger ventricular dimensions (mm) (CON = left ventricular end diastolic dimension [LVEDD] 7.99 ± 0.10, LV end systolic dimension [LVESD] 4.55 ± 0.20, CS = LVEDD 8.3 ± 0.10, LVESD 5.3 ± 0.09, p = 0.026, p = 0.003). There was also evidence of systolic dysfunction in the CS-exposed group compared to the CON group (fractional shortening %, CON = 43 ± 2, CS = 36 ± .09, p = 0.010). In CS-exposed hearts, significant increases in phosphorylated p38/total p38 (0.975 ± 0.05) and phosphorylated ERK1/2/totalERK1/2 (1.919 ± 0.050) were found compared to CON hearts (0.464 ± 0.008, 0.459 ± 0.050, respectively). No significant differences were found in JNK levels between the groups. Conclusions Increased NE levels and MAPK activation are associated with CS-related left ventricular remodelling. PMID:18815071

Passive ventricular mechanics modelling using MRI of structure and function.

PubMed

Wang, V Y; Lam, H I; Ennis, D B; Young, A A; Nash, M P

2008-01-01

Patients suffering from dilated cardiomyopathy or myocardial infarction can develop left ventricular (LV) diastolic impairment. The LV remodels its structure and function to adapt to pathophysiological changes in geometry and loading conditions and this remodeling process can alter the passive ventricular mechanics. In order to better understand passive ventricular mechanics, a LV finite element model was developed to incorporate physiological and mechanical information derived from in vivo magnetic resonance imaging (MRI) tissue tagging, in vivo LV cavity pressure recording and ex vivo diffusion tensor MRI (DTMRI) of a canine heart. MRI tissue tagging enables quantitative evaluation of cardiac mechanical function with high spatial and temporal resolution, whilst the direction of maximum water diffusion (the primary eigenvector) in each voxel of a DTMRI directly correlates with the myocardial fibre orientation. This model was customized to the geometry of the canine LV during diastasis by fitting the segmented epicardial and endocardial surface data from tagged MRI using nonlinear finite element fitting techniques. Myofibre orientations, extracted from DTMRI of the same heart, were incorporated into this geometric model using a free form deformation methodology. Pressure recordings, temporally synchronized to the tissue tagging MRI data, were used to simulate the LV deformation during diastole. Simulation of the diastolic LV mechanics allowed us to estimate the stiffness of the passive LV myocardium based on kinematic data obtained from tagged MRI. This integrated physiological model will allow more insight into the regional passive diastolic mechanics of the LV on an individualized basis, thereby improving our understanding of the underlying structural basis of mechanical dysfunction in pathological conditions.

The left ventricle as a mechanical engine: from Leonardo da Vinci to the echocardiographic assessment of peak power output-to-left ventricular mass.

PubMed

Dini, Frank L; Guarini, Giacinta; Ballo, Piercarlo; Carluccio, Erberto; Maiello, Maria; Capozza, Paola; Innelli, Pasquale; Rosa, Gian M; Palmiero, Pasquale; Galderisi, Maurizio; Razzolini, Renato; Nodari, Savina

2013-03-01

The interpretation of the heart as a mechanical engine dates back to the teachings of Leonardo da Vinci, who was the first to apply the laws of mechanics to the function of the heart. Similar to any mechanical engine, whose performance is proportional to the power generated with respect to weight, the left ventricle can be viewed as a power generator whose performance can be related to left ventricular mass. Stress echocardiography may provide valuable information on the relationship between cardiac performance and recruited left ventricular mass that may be used in distinguishing between adaptive and maladaptive left ventricular remodeling. Peak power output-to-mass, obtained during exercise or pharmacological stress echocardiography, is a measure that reflects the number of watts that are developed by 100 g of left ventricular mass under maximal stimulation. Power output-to-mass may be calculated as left ventricular power output per 100 g of left ventricular mass: 100× left ventricular power output divided by left ventricular mass (W/100 g). A simplified formula to calculate power output-to-mass is as follows: 0.222 × cardiac output (l/min) × mean blood pressure (mmHg)/left ventricular mass (g). When the integrity of myocardial structure is compromised, a mismatch becomes apparent between maximal cardiac power output and left ventricular mass; when this occurs, a reduction of the peak power output-to-mass index is observed.

5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection.

PubMed

Iskandar, Muhammad Zaid; Quasem, Wahid; El-Omar, Magdi

2015-05-02

A 33-year-old man presented to hospital with acute shortness of breath and evolving ST segment changes on ECG 3 days following a cycle of 5-fluorouracil (5-FU) for colon cancer. Despite no cardiac history, subsequent echocardiogram showed severe left ventricular systolic dysfunction. The patient was initially treated with heart failure medications and his coronary angiogram was normal. Chemotherapy was stopped and he was started on nitrates and calcium channel blockers. A repeat echocardiogram and cardiac MRI a week later showed complete resolution of his left ventricular dysfunction and he was discharged home. This case report summarises 5-FU cardiotoxicity, and emphasises the importance of early recognition and correct treatment, as left ventricular systolic dysfunction in this context is potentially reversible. 2015 BMJ Publishing Group Ltd.

5-Fluorouracil cardiotoxicity: reversible left ventricular systolic dysfunction with early detection

PubMed Central

Iskandar, Muhammad Zaid; Quasem, Wahid; El-Omar, Magdi

2015-01-01

A 33-year-old man presented to hospital with acute shortness of breath and evolving ST segment changes on ECG 3 days following a cycle of 5-fluorouracil (5-FU) for colon cancer. Despite no cardiac history, subsequent echocardiogram showed severe left ventricular systolic dysfunction. The patient was initially treated with heart failure medications and his coronary angiogram was normal. Chemotherapy was stopped and he was started on nitrates and calcium channel blockers. A repeat echocardiogram and cardiac MRI a week later showed complete resolution of his left ventricular dysfunction and he was discharged home. This case report summarises 5-FU cardiotoxicity, and emphasises the importance of early recognition and correct treatment, as left ventricular systolic dysfunction in this context is potentially reversible. PMID:25935919

Athlete's Heart: Is the Morganroth Hypothesis Obsolete?

PubMed

Haykowsky, Mark J; Samuel, T Jake; Nelson, Michael D; La Gerche, Andre

2018-05-01

In 1975, Morganroth and colleagues reported that the increased left ventricular (LV) mass in highly trained endurance athletes versus nonathletes was primarily due to increased end-diastolic volume while the increased LV mass in resistance trained athletes was solely due to an increased LV wall thickness. Based on the divergent remodelling patterns observed, Morganroth and colleagues hypothesised that the increased "volume" load during endurance exercise may be similar to that which occurs in patients with mitral or aortic regurgitation while the "pressure" load associated with performing a Valsalva manoeuvre (VM) during resistance exercise may mimic the stress imposed on the heart by systemic hypertension or aortic stenosis. Despite widespread acceptance of the four-decade old Morganroth hypothesis in sports cardiology, some investigators have questioned whether such a divergent "athlete's heart" phenotype exists. Given this uncertainty, the purpose of this brief review is to re-evaluate the Morganroth hypothesis regarding: i) the acute effects of resistance exercise performed with a brief VM on LV wall stress, and the patterns of LV remodelling in resistance-trained athletes; ii) the acute effects of endurance exercise on biventricular wall stress, and the time course and pattern of LV and right ventricular (RV) remodelling with endurance training; and iii) the value of comparing "loading" conditions between athletes and patients with cardiac pathology. Copyright © 2018. Published by Elsevier B.V.

Intra-myocardial growth hormone administration ameliorates arrhythmogenesis during ischemia-reperfusion in rats.

PubMed

Kontonika, Marianthi; Barka, Eleonora; Roumpi, Maria; Vilaeti, Agapi D; Baltogiannis, Giannis G; Vlahos, Antonios P; Agathopoulos, Simeon; Kolettis, Theofilos M

Growth hormone, currently under evaluation for the prevention of left ventricular remodeling post-myocardial infarction, displays antiarrhythmic properties in the acute setting. However, it is uncertain whether these actions are retained after ischemia/reperfusion. Using implanted telemetry transmitters, we examined the effects of prolonged, intra-myocardial growth hormone administration in conscious rats. During a 24-h observation period, ventricular tachyarrhythmias and sympathetic activation were attenuated in treated rats, whereas infarct-size was unchanged. These findings call for further study on the antiarrhythmic effects of growth hormone and on the underlying mechanisms. Copyright © 2016 Elsevier Inc. All rights reserved.

Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

PubMed Central

Lee, An-Sheng; Chen, Wei-Yu; Chan, Hua-Chen; Chung, Ching-Hu; Peng, Hsien-Yu; Chang, Chia-Ming; Su, Ming-Jai; Chen, Chu-Huang; Chang, Kuan-Cheng

2017-01-01

The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD. PMID:28094801

Right ventricular sex differences in patients with idiopathic pulmonary arterial hypertension characterised by magnetic resonance imaging: pair-matched case controlled study.

PubMed

Swift, Andrew J; Capener, Dave; Hammerton, Charlotte; Thomas, Steven M; Elliot, Charlie; Condliffe, Robin; Wild, Jim M; Kiely, David G

2015-01-01

Sex differences exist in both the prevalence and survival of patients with idiopathic pulmonary arterial hypertension (IPAH). Men are less frequently affected by the condition but have worse outcome as compared to females. We sought to characterise the sex related differences in right ventricular remodelling in age matched male and female patients with IPAH using cardiac magnetic resonance imaging (MRI). A case controlled pair-matched study was conducted with patients matched by age and sex. Steady state free precession (SSFP) MRI of the heart was performed at 1.5T. Cardiac volume, function and mass measurements were corrected for age, sex and BSA according to reference data. 40 age and sex matched patients with IPAH were identified. The mean age was 57 (SD 17) in both male and female cohorts. Men had proportionally lower right ventricular (RV) ejection fraction, RV stroke volume and LV stroke volume than females, p=0.028, p=0.007 and p=0.013, respectively. However, there was no significant difference in RV mass or haemodynamic indices of mPAP and PVR between males and females. Male patients with IPAH have proportionally worse RV function despite similar afterload. We hypothesise that adaptive remodelling of the RV in response to increased afterload in IPAH is more effective in females.

Right Ventricular Sex Differences in Patients with Idiopathic Pulmonary Arterial Hypertension Characterised by Magnetic Resonance Imaging: Pair-Matched Case Controlled Study

PubMed Central

Swift, Andrew J.; Capener, Dave; Hammerton, Charlotte; Thomas, Steven M.; Elliot, Charlie; Condliffe, Robin; Wild, Jim M.; Kiely, David G.

2015-01-01

Purpose Sex differences exist in both the prevalence and survival of patients with idiopathic pulmonary arterial hypertension (IPAH). Men are less frequently affected by the condition but have worse outcome as compared to females. We sought to characterise the sex related differences in right ventricular remodelling in age matched male and female patients with IPAH using cardiac magnetic resonance imaging (MRI). Methods A case controlled pair-matched study was conducted with patients matched by age and sex. Steady state free precession (SSFP) MRI of the heart was performed at 1.5T. Cardiac volume, function and mass measurements were corrected for age, sex and BSA according to reference data. Results 40 age and sex matched patients with IPAH were identified. The mean age was 57 (SD 17) in both male and female cohorts. Men had proportionally lower right ventricular (RV) ejection fraction, RV stroke volume and LV stroke volume than females, p=0.028, p=0.007 and p=0.013, respectively. However, there was no significant difference in RV mass or haemodynamic indices of mPAP and PVR between males and females. Conclusion Male patients with IPAH have proportionally worse RV function despite similar afterload. We hypothesise that adaptive remodelling of the RV in response to increased afterload in IPAH is more effective in females. PMID:25996939

Residual Myocardial Iron Following Intramyocardial Hemorrhage During the Convalescent Phase of Reperfused ST-Segment-Elevation Myocardial Infarction and Adverse Left Ventricular Remodeling.

PubMed

Bulluck, Heerajnarain; Rosmini, Stefania; Abdel-Gadir, Amna; White, Steven K; Bhuva, Anish N; Treibel, Thomas A; Fontana, Marianna; Ramlall, Manish; Hamarneh, Ashraf; Sirker, Alex; Herrey, Anna S; Manisty, Charlotte; Yellon, Derek M; Kellman, Peter; Moon, James C; Hausenloy, Derek J

2016-10-01

The presence of intramyocardial hemorrhage (IMH) in ST-segment-elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual myocardial iron at follow-up, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here. Forty-eight ST-segment-elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 4±2 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5±2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 [54-64] ms versus 53 [51-56] ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson's rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison). The majority of ST-segment-elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with persistently elevated T2 values in the surrounding infarct tissue and adverse LV remodeling. IMH and residual myocardial iron may be potential therapeutic targets for preventing adverse LV remodeling in reperfused ST-segment-elevation myocardial infarction patients. © 2016 The Authors.

Surgical treatment of moderate ischemic mitral regurgitation.

PubMed

Smith, Peter K; Puskas, John D; Ascheim, Deborah D; Voisine, Pierre; Gelijns, Annetine C; Moskowitz, Alan J; Hung, Judy W; Parides, Michael K; Ailawadi, Gorav; Perrault, Louis P; Acker, Michael A; Argenziano, Michael; Thourani, Vinod; Gammie, James S; Miller, Marissa A; Pagé, Pierre; Overbey, Jessica R; Bagiella, Emilia; Dagenais, François; Blackstone, Eugene H; Kron, Irving L; Goldstein, Daniel J; Rose, Eric A; Moquete, Ellen G; Jeffries, Neal; Gardner, Timothy J; O'Gara, Patrick T; Alexander, John H; Michler, Robert E

2014-12-04

Ischemic mitral regurgitation is associated with increased mortality and morbidity. For surgical patients with moderate regurgitation, the benefits of adding mitral-valve repair to coronary-artery bypass grafting (CABG) are uncertain. We randomly assigned 301 patients with moderate ischemic mitral regurgitation to CABG alone or CABG plus mitral-valve repair (combined procedure). The primary end point was the left ventricular end-systolic volume index (LVESVI), a measure of left ventricular remodeling, at 1 year. This end point was assessed with the use of a Wilcoxon rank-sum test in which deaths were categorized as the lowest LVESVI rank. At 1 year, the mean LVESVI among surviving patients was 46.1±22.4 ml per square meter of body-surface area in the CABG-alone group and 49.6±31.5 ml per square meter in the combined-procedure group (mean change from baseline, -9.4 and -9.3 ml per square meter, respectively). The rate of death was 6.7% in the combined-procedure group and 7.3% in the CABG-alone group (hazard ratio with mitral-valve repair, 0.90; 95% confidence interval, 0.38 to 2.12; P=0.81). The rank-based assessment of LVESVI at 1 year (incorporating deaths) showed no significant between-group difference (z score, 0.50; P=0.61). The addition of mitral-valve repair was associated with a longer bypass time (P<0.001), a longer hospital stay after surgery (P=0.002), and more neurologic events (P=0.03). Moderate or severe mitral regurgitation was less common in the combined-procedure group than in the CABG-alone group (11.2% vs. 31.0%, P<0.001). There were no significant between-group differences in major adverse cardiac or cerebrovascular events, deaths, readmissions, functional status, or quality of life at 1 year. In patients with moderate ischemic mitral regurgitation, the addition of mitral-valve repair to CABG did not result in a higher degree of left ventricular reverse remodeling. Mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation but an increased number of untoward events. Thus, at 1 year, this trial did not show a clinically meaningful advantage of adding mitral-valve repair to CABG. Longer-term follow-up may determine whether the lower prevalence of mitral regurgitation translates into a net clinical benefit. (Funded by the National Institutes of Health and the Canadian Institutes of Health Research; ClinicalTrials.gov number, NCT00806988.).

Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression.

PubMed

Ng, Fu Siong; Holzem, Katherine M; Koppel, Aaron C; Janks, Deborah; Gordon, Fabiana; Wit, Andrew L; Peters, Nicholas S; Efimov, Igor R

2014-10-01

Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia-reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression. We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia-reperfusion, with greater action potential duration shortening (P<0.001 at 8-minute ischemia; P=0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P<0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia-reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes. © 2014 American Heart Association, Inc.

Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension

PubMed Central

Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R.; Song, Shanshan; Sysol, Justin R.; Drennan, Abigail R.; Offermanns, Stefan; Ye, Richard D.; Bonini, Marcelo G.; Minshall, Richard D.; Garcia, Joe G. N.; Machado, Roberto F.; Makino, Ayako

2014-01-01

Pulmonary vascular remodeling, mainly attributable to enhanced pulmonary arterial smooth muscle cell proliferation and migration, is a major cause for elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary hypertension. The signaling cascade through Akt, comprised of three isoforms (Akt1–3) with distinct but overlapping functions, is involved in regulating cell proliferation and migration. This study aims to investigate whether the Akt/mammalian target of rapamycin (mTOR) pathway, and particularly which Akt isoform, contributes to the development and progression of pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Compared with the wild-type littermates, Akt1−/− mice were protected against the development and progression of chronic HPH, whereas Akt2−/− mice did not demonstrate any significant protection against the development of HPH. Furthermore, pulmonary vascular remodeling was significantly attenuated in the Akt1−/− mice, with no significant effect noted in the Akt2−/− mice after chronic exposure to normobaric hypoxia (10% O2). Overexpression of the upstream repressor of Akt signaling, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and conditional and inducible knockout of mTOR in smooth muscle cells were also shown to attenuate the rise in right ventricular systolic pressure and the development of right ventricular hypertrophy. In conclusion, Akt isoforms appear to have a unique function within the pulmonary vasculature, with the Akt1 isoform having a dominant role in pulmonary vascular remodeling associated with HPH. The PTEN/Akt1/mTOR signaling pathway will continue to be a critical area of study in the pathogenesis of pulmonary hypertension, and specific Akt isoforms may help specify therapeutic targets for the treatment of pulmonary hypertension. PMID:25416384

The Post-Myocardial Infarction Pacing Remodeling Prevention Therapy (PRomPT) Trial: Design and Rationale.

PubMed

Chung, Eugene S; Fischer, Trent M; Kueffer, Fred; Anand, Inder S; Bax, Jeroen J; Gold, Michael R; Gorman, Robert C; Theres, Heinz; Udelson, James E; Stancak, Branislav; Svendsen, Jesper H; Stone, Gregg W; Leon, Angel

2015-07-01

Despite considerable improvements in the medical management of patients with myocardial infarction (MI), patients with large MI still have substantial risk of developing heart failure. In the early post-MI setting, implantable cardioverter defibrillators have reduced arrhythmic deaths but have no impact on overall mortality. Therefore, additional interventions are required to further reduce the overall morbidity and mortality of patients with large MI. The Pacing Remodeling Prevention Therapy (PRomPT) trial is designed to study the effects of peri-infarct pacing in preventing adverse post-MI remodeling. Up to 120 subjects with peak creatine phosphokinase >3,000 U/L (or troponin T >10 μg/L) at time of MI will be randomized to either dual-site or single-site biventricular pacing with the left ventricular lead implanted in a peri-infarct region or to a nonimplanted control group. Those randomized to a device will be blinded to the pacing mode, but randomization to a device or control cannot be blinded. Subjects randomized to pacing will have the device implanted within 10 days of MI. The primary objective is to assess the change in left ventricular end-diastolic volume from baseline to 18 months. Secondary objectives are to assess changes in clinical and mechanistic parameters between the groups, including rates of hospitalization for heart failure and cardiovascular events, the incidence of sudden cardiac death and all-cause mortality, New York Heart Association functional class, 6-minute walking distance, and quality of life. The PRomPT trial will provide important evidence regarding the potential of peri-infarct pacing to interrupt adverse remodeling in patients with large MI. Copyright © 2015 Elsevier Inc. All rights reserved.

Monocrotaline-Induced Pulmonary Hypertension Involves Downregulation of Antiaging Protein Klotho and eNOS Activity.

PubMed

Varshney, Rohan; Ali, Quaisar; Wu, Chengxiang; Sun, Zhongjie

2016-11-01

The objective of this study is to investigate whether stem cell delivery of secreted Klotho (SKL), an aging-suppressor protein, attenuates monocrotaline-induced pulmonary vascular dysfunction and remodeling. Overexpression of SKL in mesenchymal stem cells (MSCs) was achieved by transfecting MSCs with lentiviral vectors expressing SKL-green fluorescent protein (GFP). Four groups of rats were treated with monocrotaline, whereas an additional group was given saline (control). Three days later, 4 monocrotaline-treated groups received intravenous delivery of nontransfected MSCs, MSC-GFP, MSC-SKL-GFP, and PBS, respectively. Ex vivo vascular relaxing responses to acetylcholine were diminished in small pulmonary arteries (PAs) in monocrotaline-treated rats, indicating pulmonary vascular endothelial dysfunction. Interestingly, delivery of MSCs overexpressing SKL (MSC-SKL-GFP) abolished monocrotaline-induced pulmonary vascular endothelial dysfunction and PA remodeling. Monocrotaline significantly increased right ventricular systolic blood pressure, which was attenuated significantly by MSC-SKL-GFP, indicating improved PA hypertension. MSC-SKL-GFP also attenuated right ventricular hypertrophy. Nontransfected MSCs slightly, but not significantly, improved PA hypertension and pulmonary vascular endothelial dysfunction. MSC-SKL-GFP attenuated monocrotaline-induced inflammation, as evidenced by decreased macrophage infiltration around PAs. MSC-SKL-GFP increased SKL levels, which rescued the downregulation of SIRT1 (Sirtuin 1) expression and endothelial NO synthase (eNOS) phosphorylation in the lungs of monocrotaline-treated rats. In cultured endothelial cells, SKL abolished monocrotaline-induced downregulation of eNOS activity and NO levels and enhanced cell viability. Therefore, stem cell delivery of SKL is an effective therapeutic strategy for pulmonary vascular endothelial dysfunction and PA remodeling. SKL attenuates monocrotaline-induced PA remodeling and PA smooth muscle cell proliferation, likely by reducing inflammation and restoring SIRT1 levels and eNOS activity. © 2016 American Heart Association, Inc.

Transmural Heterogeneity and Remodeling of Ventricular Excitation-Contraction Coupling in Human Heart Failure

PubMed Central

Lou, Qing; Fedorov, Vadim V.; Glukhov, Alexey V.; Moazami, Nader; Fast, Vladimir G.; Efimov, Igor R.

2011-01-01

Background Excitation-contraction (EC) coupling is altered in the end-stage heart failure (HF). However, spatial heterogeneity of this remodeling has not been established at the tissue level in failing human heart. The objective is to study functional remodeling of EC coupling and calcium handling in failing and nonfailing human hearts. Methods and Results We simultaneously optically mapped action potentials (AP) and calcium transients (CaT) in coronary-perfused left ventricular wedge preparations from nonfailing (n = 6) and failing (n = 5) human hearts. Our major findings are: (1) CaT duration minus AP duration was longer at sub-endocardium in failing compared to nonfailing hearts during bradycardia (40 beats/min). (2) The transmural gradient of CaT duration was significantly smaller in failing hearts compared with nonfailing hearts at fast pacing rates (100 beats/min). (3) CaT in failing hearts had a flattened plateau at the midmyocardium; and exhibited a “two-component” slow rise at sub-endocardium in three failing hearts. (4) CaT relaxation was slower at sub-endocardium than that at sub-epicardium in both groups. Protein expression of sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a) was lower at sub-endocardium than that at sub-epicardium in both nonfailing and failing hearts. SERCA2a protein expression at sub-endocardium was lower in hearts with ischemic cardiomyopathy compared with nonischemic cardiomyopathy. Conclusions For the first time, we present direct experimental evidence of transmural heterogeneity of EC coupling and calcium handling in human hearts. End-stage HF is associated with the heterogeneous remodeling of EC coupling and calcium handling. PMID:21502574

Effects of hawthorn on cardiac remodeling and left ventricular dysfunction after 1 month of pressure overload-induced cardiac hypertrophy in rats.

PubMed

Hwang, Hyun Seok; Bleske, Barry E; Ghannam, Michael M J; Converso, Kimber; Russell, Mark W; Hunter, James C; Boluyt, Marvin O

2008-02-01

Hawthorn (Crataegus) is a natural product used to treat patients with heart failure. The effects of hawthorn on cardiac remodeling, however, are not known. The purpose was to determine the effects of hawthorn treatment on remodeling and function of the left ventricle (LV) after 1 month of pressure overload-induced cardiac hypertrophy. Sprague-Dawley rats (male, 300 g) were subjected to sham operation (SH) or aortic constriction (AC) for 4 weeks and treated with Hawthorn (Crataegus-Extract- WS1442;1.3, 13, 130 mg kg(-1) day(-1); AC-L, AC-M, AC-H) or vehicle (SH-V, AC-V) for 3 weeks after surgery. Systolic and diastolic function were measured using echocardiographic assessment at baseline and 4 weeks after AC. AC increased the LV/body weight ratio by 34% in vehicle and hawthorn treated rats. Hawthorn markedly reduced LV chamber volumes (VOL) after AC [systolic VOL, mean +/- SEM, mm(3): SH-V, 87 +/- 13; AC-V, 93 +/- 12; AC-L, 62 +/- 9; AC-M, 68 +/- 12; AC-H; 50 +/- 11 and diastolic VOL: SH-V, 433 +/- 45; AC-V, 412 +/- 57; AC-L, 313 +/- 25; AC-M, 319 +/- 37; AC-H, 264 +/- 25 (p < 0.05)] and augmented relative wall thickness, mm: SH-V, 0.45 +/- 0.02; AC-V, 0.65 +/- 0.05; AC-L, 0.71 +/- 0.03; AC-M, 0.74 +/- 0.06; AC-H, 0.80 +/- 0.09 (p < 0.05). AC reduced velocity of circumferential shortening (Vcf(c)) by 28% compared with SH-V. Hawthorn attenuated the AC-induced decrease in Vcf(c) (p < 0.05). Hawthorn treatment modifies left ventricular remodeling and counteracts myocardial dysfunction in early pressure overload-induced cardiac hypertrophy.

Intrafamilial aggregation and heritability of left ventricular geometric remodeling is independent of cardiac mass in families of African ancestry.

PubMed

Peterson, Vernice R; Norton, Gavin R; Redelinghuys, Michelle; Libhaber, Carlos D; Maseko, Muzi J; Majane, Olebogeng H I; Brooksbank, Richard; Woodiwiss, Angela J

2015-05-01

Whether left ventricular (LV) geometric remodeling, as indexed by relative wall thickness (RWT), aggregates in families and is inherited independent of LV mass (LVM) and additional confounders is uncertain. We determined whether RWT as assessed from 2D targeted M-mode echocardiography shows intrafamilial aggregation and heritability independent of LVM in 181 nuclear families (73 spouse pairs, 403 parent-child pairs, and 177 sibling-sibling pairs) with 16 families including 3 generations from an urban developing community of black Africans. Intrafamilial aggregation and heritability estimates (S.A.G.E. software) were assessed independent of confounders, including central aortic systolic blood pressure (SBPc) (radial applanation tonometry and SphygmoCor software). Independent of confounders including SBPc, LV RWT was correlated in parent-child (r = 0.32, P < 0.0001) and sibling-sibling (r = 0.29, P < 0.0001), but not in spouse (r = 0.11, P = 0.33) pairs. The relationships between parent-child (r = 0.28, P < 0.0001) and sibling-sibling (r = 0.24, P < 0.001) pairs persisted with further adjustments for LVM or LVM indexed to height(2.7) (LVMI). Similarly, independent of confounders, LV RWT showed significant heritability (h(2) ± SEM = 0.56 ± 0.09, P < 0.0001) and this persisted with further adjustments for LVM (h(2) ± SEM = 0.48 ± 0.09, P < 0.0001) or LVMI (h(2) ± SEM = 0.49 ± 0.09, P < 0.0001). In a group of African ancestry, independent of LVM, LV geometric remodeling shows significant intrafamilial aggregation and heritability. Genetic factors may in-part determine the LV geometric remodeling process independent of the extent of cardiac hypertrophy. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Kinin B1 receptor blockade and ACE inhibition attenuate cardiac postinfarction remodeling and heart failure in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, Xinchun

Introduction: The aim of the present study was to evaluate the effects of the novel kinin B1 receptor antagonist BI113823 on postinfarction cardiac remodeling and heart failure, and to determine whether B1 receptor blockade alters the cardiovascular effects of an angiotensin 1 converting enzyme (ACE) inhibitor in rats. Methods and results: Sprague Dawley rats were subjected to permanent occlusion of the left coronary artery. Cardiovascular function was determined at 6 weeks postinfarction. Treatment with either B1 receptor antagonist (BI113823) or an ACE inhibitor (lisinopril) alone or in combination significantly reduced the heart weight-to-body weight and lung weight-to-body weight ratios, andmore » improved postinfarction cardiac function as evidenced by greater cardiac output, the maximum rate of left ventricular pressure rise (± dP/dtmax), left ventricle ejection fraction, fractional shorting, better wall motion, and attenuation of elevated left ventricular end diastolic pressure (LVEDP). Furthermore, all three treatment groups exhibited significant reduction in cardiac interstitial fibrosis, collagen deposition, CD68 positive macrophages, neutrophils, and proinflammatory cytokine production (TNF-α and IL-1β), compared to vehicle controls. Conclusion: The present study shows that treatment with the novel kinin B1 receptor antagonist, BI113823, reduces postinfarction cardiac remodeling and heart failure, and does not influence the cardiovascular effects of the ACE inhibitor. - Highlights: • We examined the role of kinin B1 receptors in the development of heart failure. • Kinin B1 receptor blockade attenuates post-infarction cardiac remodeling. • Kinin B1 receptor blockade improves dysfunction, and prevented heart failure. • B1 receptor blockade does not affect the cardio-protection of an ACE inhibitor.« less

The importance of integrated left atrial evaluation: From hypertension to heart failure with preserved ejection fraction.

PubMed

Beltrami, Matteo; Palazzuoli, Alberto; Padeletti, Luigi; Cerbai, Elisabetta; Coiro, Stefano; Emdin, Michele; Marcucci, Rossella; Morrone, Doralisa; Cameli, Matteo; Savino, Ketty; Pedrinelli, Roberto; Ambrosio, Giuseppe

2018-02-01

Functional analysis and measurement of left atrium are an integral part of cardiac evaluation, and they represent a key element during non-invasive analysis of diastolic function in patients with hypertension (HT) and/or heart failure with preserved ejection fraction (HFpEF). However, diastolic dysfunction remains quite elusive regarding classification, and atrial size and function are two key factors for left ventricular (LV) filling evaluation. Chronic left atrial (LA) remodelling is the final step of chronic intra-cavitary pressure overload, and it accompanies increased neurohormonal, proarrhythmic and prothrombotic activities. In this systematic review, we aim to purpose a multi-modality approach for LA geometry and function analysis, which integrates diastolic flow with LA characteristics and remodelling through application of both traditional and new diagnostic tools. The most important studies published in the literature on LA size, function and diastolic dysfunction in patients with HFpEF, HT and/or atrial fibrillation (AF) are considered and discussed. In HFpEF and HT, pulsed and tissue Doppler assessments are useful tools to estimate LV filling pressure, atrio-ventricular coupling and LV relaxation but they need to be enriched with LA evaluation in terms of morphology and function. An integrated evaluation should be also applied to patients with a high arrhythmic risk, in whom eccentric LA remodelling and higher LA stiffness are associated with a greater AF risk. Evaluation of LA size, volume, function and structure are mandatory in the management of patients with HT, HFpEF and AF. A multi-modality approach could provide additional information, identifying subjects with more severe LA remodelling. Left atrium assessment deserves an accurate study inside the cardiac imaging approach and optimised measurement with established cut-offs need to be better recognised through multicenter studies. © 2017 John Wiley & Sons Ltd.

Identification of new biophysical markers for pathological ventricular remodelling in tachycardia-induced dilated cardiomyopathy.

PubMed

Benitez-Amaro, Aleyda; Samouillan, Valerie; Jorge, Esther; Dandurand, Jany; Nasarre, Laura; de Gonzalo-Calvo, David; Bornachea, Olga; Amoros-Figueras, Gerard; Lacabanne, Colette; Vilades, David; Leta, Ruben; Carreras, Francesc; Gallardo, Alberto; Lerma, Enrique; Cinca, Juan; Guerra, Jose M; Llorente-Cortés, Vicenta

2018-06-19

Our aim was to identify biophysical biomarkers of ventricular remodelling in tachycardia-induced dilated cardiomyopathy (DCM). Our study includes healthy controls (N = 7) and DCM pigs (N = 10). Molecular analysis showed global myocardial metabolic abnormalities, some of them related to myocardial hibernation in failing hearts, supporting the translationality of our model to study cardiac remodelling in dilated cardiomyopathy. Histological analysis showed unorganized and agglomerated collagen accumulation in the dilated ventricles and a higher percentage of fibrosis in the right (RV) than in the left (LV) ventricle (P = .016). The Fourier Transform Infrared Spectroscopy (FTIR) 1st and 2nd indicators, which are markers of the myofiber/collagen ratio, were reduced in dilated hearts, with the 1st indicator reduced by 45% and 53% in the RV and LV, respectively, and the 2nd indicator reduced by 25% in the RV. The 3rd FTIR indicator, a marker of the carbohydrate/lipid ratio, was up-regulated in the right and left dilated ventricles but to a greater extent in the RV (2.60-fold vs 1.61-fold, P = .049). Differential scanning calorimetry (DSC) showed a depression of the freezable water melting point in DCM ventricles - indicating structural changes in the tissue architecture - and lower protein stability. Our results suggest that the 1st, 2nd and 3rd FTIR indicators are useful markers of cardiac remodelling. Moreover, the 2nd and 3rd FITR indicators, which are altered to a greater extent in the right ventricle, are associated with greater fibrosis. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Mechanical unloading of the failing human heart fails to activate the protein kinase B/Akt/glycogen synthase kinase-3beta survival pathway.

PubMed

Razeghi, Peter; Bruckner, Brian A; Sharma, Saumya; Youker, Keith A; Frazier, O H; Taegtmeyer, Heinrich

2003-01-01

Left ventricular assist device (LVAD) support of the failing human heart improves myocyte function and increases cell survival. One potential mechanism underlying this phenomenon is activation of the protein kinase B (PKB)/Akt/glycogen synthase kinase-3beta (GSK-3beta) survival pathway. Left ventricular tissue was obtained both at the time of implantation and explantation of the LVAD (n = 11). Six patients were diagnosed with idiopathic dilated cardiomyopathy, 4 patients with ischemic cardiomyopathy and 1 patient with peripartum cardiomyopathy. The mean duration of LVAD support was 205 +/- 35 days. Myocyte diameter and phosphorylation of ERK were used as indices for reverse remodeling. Transcript levels of genes required for the activation of PKB/Akt (insulin-like growth factor-1, insulin receptor substrate-1) were measured by quantitative RT-PCR. In addition, we measured the relative activity of PKB/Akt and GSK-3beta, and assayed for molecular and histological indices of PKB/Akt activation (cyclooxygenase mRNA levels and glycogen levels). Myocyte diameter and phosphorylation of ERK decreased with LVAD support. In contrast, none of the components of the PKB/Akt/GSK-3beta pathway changed significantly with mechanical unloading. The PKB/Akt/GSK-3beta pathway is not activated during LVAD support. Other signaling pathways must be responsible for the improvement of cellular function and cell survival during LVAD support. Copyright 2003 S. Karger AG, Basel

Possible involvement of mitochondrial energy-producing ability in the development of right ventricular failure in monocrotaline-induced pulmonary hypertensive rats.

PubMed

Daicho, Takuya; Yagi, Tatsuya; Abe, Yohei; Ohara, Meiko; Marunouchi, Tetsuro; Takeo, Satoshi; Tanonaka, Kouichi

2009-09-01

The present study was undertaken to explore the possible involvement of alterations in the mitochondrial energy-producing ability in the development of the right ventricular failure in monocrotaline-administered rats. The rats at the 6th week after subcutaneous injection of 60 mg/kg monocrotaline revealed marked myocardial hypertrophy and fibrosis, that is, severe cardiac remodeling. The time-course study on the cardiac hemodynamics of the monocrotaline-administered rat by the cannula and echocardiographic methods showed a reduction in cardiac double product, a decrease in cardiac output index, and an increase in the right ventricular Tei index, suggesting that the right ventricular failure was induced at the 6th week after monocrotaline administration in rats. The mitochondrial oxygen consumption rate of the right ventricular muscle isolated from the monocrotaline-administered animal was decreased, which was associated with a reduction in myocardial high-energy phosphates. Furthermore, the decrease in mitochondrial oxygen consumption rate was inversely related to the increase in the right ventricular Tei index of the monocrotaline-administered rats. These results suggest that impairment of the mitochondrial energy-producing ability is involved in the development of the right ventricular failure in monocrotaline-induced pulmonary hypertensive rats.

Cardiac RNAi therapy using RAGE siRNA/deoxycholic acid-modified polyethylenimine complexes for myocardial infarction.

PubMed

Hong, Jueun; Ku, Sook Hee; Lee, Min Sang; Jeong, Ji Hoon; Mok, Hyejung; Choi, Donghoon; Kim, Sun Hwa

2014-08-01

Inflammatory response in myocardial ischemia-reperfusion injury plays a critical role in ventricular remodeling. To avoid deleterious effects of overwhelming inflammation, we blocked the expression of receptor for advanced glycation end-products (RAGE), a key mediator of the local and systemic inflammatory responses, via RNAi mechanism. Herein, a facial amphipathic deoxycholic acid-modified low molecular weight polyethylenimine (DA-PEI) was used as a siRNA delivery carrier to myocardium. The DA-PEI conjugate formed a stable complex with siRNA via electrostatic and hydrophobic interactions. The siRAGE/DA-PEI formulation having negligible toxicity could enhance intracellular delivery efficiency and successfully suppress RAGE expression both in vitro and in vivo. Furthermore, the cardiac administration of siRAGE/DA-PEI reduced apoptosis and inflammatory cytokine release, subsequently led to attenuation of left ventricular remodeling in rat myocardial infarction model. The potential therapeutic effects of RAGE gene silencing on myocardial ischemia-reperfusion injury may suggest that the siRAGE/DA-PEI delivery system can be considered as a promising strategy for treating myocardial infarction. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of Adjuvant Chemotherapy on Left Ventricular Remodeling in Women with Newly Diagnosed Primary Breast Cancer: A Pilot Prospective Longitudinal Cardiac Magnetic Resonance Imaging Study.

PubMed

Avelar, Erick; Truong, Quynh A; Inyangetor, David; Marfatia, Ravi; Yang, Clifford; Kaloudis, Electra; Tannenbaum, Susan; Rosito, Guido; Litwin, Sheldon

2017-11-01

The aim of this study was to assess the left ventricular (LV) remodeling response to chemotherapy in low-cardiac-risk women with newly diagnosed nonmetastatic breast cancer. Cardiotoxic effects of chemotherapy are an increasing concern. To effectively interpret cardiac imaging studies performed for screening purposes in patients undergoing cancer therapy it is necessary to understand the normal changes in structure and function that may occur. Twenty women without preexisting cardiovascular disease, of a mean age of 50 years, newly diagnosed with nonmetastatic breast cancer and treated with anthracycline or trastuzumab, were prospectively enrolled and evaluated at four time points (at baseline, during chemotherapy, 2 weeks after chemotherapy, and 6 months after chemotherapy) using cardiac magnetic resonance imaging, blood samples, and a clinical questionnaire. Over a 6-month period, the left ventricular ejection fraction (%) decreased (64.15±5.30 to 60.41±5.77, P<0.002) and the LV end-diastolic (mm) and end-systolic (mm) volumes increased (124.73±20.25 to 132.21±19.33, P<0.04 and 45.16±11.88 to 52.57±11.65, P<0.00, respectively). The LV mass (g) did not change (73.06±11.51 to 69.21±15.3, P=0.08), but the LV mass to LVEDV ratio (g/mm) decreased (0.594±0.098 to 0.530±0.124, P<0.04). In low-cardiac-risk women with nonmetastatic breast cancer, the increased LV volume and a mildly decreased left ventricular ejection fraction during and after chemotherapy do not seem to be associated with laboratory or clinical evidence of increased risk for heart failure.

Remodeling of repolarization and arrhythmia susceptibility in a myosin-binding protein C knockout mouse model.

PubMed

Toib, Amir; Zhang, Chen; Borghetti, Giulia; Zhang, Xiaoxiao; Wallner, Markus; Yang, Yijun; Troupes, Constantine D; Kubo, Hajime; Sharp, Thomas E; Feldsott, Eric; Berretta, Remus M; Zalavadia, Neil; Trappanese, Danielle M; Harper, Shavonn; Gross, Polina; Chen, Xiongwen; Mohsin, Sadia; Houser, Steven R

2017-09-01

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic cardiac diseases and among the leading causes of sudden cardiac death (SCD) in the young. The cellular mechanisms leading to SCD in HCM are not well known. Prolongation of the action potential (AP) duration (APD) is a common feature predisposing hypertrophied hearts to SCD. Previous studies have explored the roles of inward Na + and Ca 2+ in the development of HCM, but the role of repolarizing K + currents has not been defined. The objective of this study was to characterize the arrhythmogenic phenotype and cellular electrophysiological properties of mice with HCM, induced by myosin-binding protein C (MyBPC) knockout (KO), and to test the hypothesis that remodeling of repolarizing K + currents causes APD prolongation in MyBPC KO myocytes. We demonstrated that MyBPC KO mice developed severe hypertrophy and cardiac dysfunction compared with wild-type (WT) control mice. Telemetric electrocardiographic recordings of awake mice revealed prolongation of the corrected QT interval in the KO compared with WT control mice, with overt ventricular arrhythmias. Whole cell current- and voltage-clamp experiments comparing KO with WT mice demonstrated ventricular myocyte hypertrophy, AP prolongation, and decreased repolarizing K + currents. Quantitative RT-PCR analysis revealed decreased mRNA levels of several key K + channel subunits. In conclusion, decrease in repolarizing K + currents in MyBPC KO ventricular myocytes contributes to AP and corrected QT interval prolongation and could account for the arrhythmia susceptibility. NEW & NOTEWORTHY Ventricular myocytes isolated from the myosin-binding protein C knockout hypertrophic cardiomyopathy mouse model demonstrate decreased repolarizing K + currents and action potential and QT interval prolongation, linking cellular repolarization abnormalities with arrhythmia susceptibility and the risk for sudden cardiac death in hypertrophic cardiomyopathy. Copyright © 2017 the American Physiological Society.

Changes in pulmonary arterial wall mechanical properties and lumenal architecture with induced vascular remodeling

NASA Astrophysics Data System (ADS)

Molthen, Robert C.; Heinrich, Amy E.; Haworth, Steven T.; Dawson, Christopher A.

2004-04-01

To explore and quantify pulmonary arterial remodeling we used various methods including micro-CT, high-resolution 3-dimensional x-ray imaging, to examine the structure and function of intact pulmonary vessels in isolated rat lungs. The rat is commonly used as an animal model for studies of pulmonary hypertension (PH) and the accompanying vascular remodeling, where vascular remodeling has been defined primarily by changes in the vessel wall composition in response to hypertension inducing stimuli such as chronic hypoxic exposure (CHE) or monocrotaline (MCT) injection. Little information has been provided as to how such changes affect the vessel wall mechanical properties or the lumenal architecture of the pulmonary arterial system that actually account for the hemodynamic consequences of the remodeling. In addition, although the link between primary forms of pulmonary hypertension and inherited genetics is well established, the role that genetic coding plays in hemodynamics and vascular remodeling is not. Therefore, we are utilizing Fawn-Hooded (FH), Sprague-Dawley (SD) and Brown Norway (BN)rat strains along with unique imaging methods to parameterize both vessel distensibility and lumenal morphometry using a principal pulmonary arterial pathway analysis based on self-consistency. We have found for the hypoxia model, in addition to decreased body weight, increased hematocrit, increased right ventricular hypertrophy, the distensibility of the pulmonary arteries is shown to decrease significantly in the presence of remodeling.

Structural and functional alterations in the atrioventricular node and atrioventricular ring tissue in ischaemia-induced heart failure.

PubMed

Yanni, Joseph; Maczewski, Michal; Mackiewicz, Urszula; Siew, Samuel; Fedorenko, Olga; Atkinson, Andrew; Price, Marcus; Beresewicz, Andrzej; Anderson, Robert H; Boyett, Mark R; Dobrzynski, Halina

2014-07-01

Heart failure (HF) causes dysfunction of the atrioventricular node (AVN) - first or second-degree heart block is a risk factor for sudden cardiac death in HF patients. The aim of the study was to determine if HF causes remodelling of the AVN and right atrioventricular ring (RAVR). HF was induced in rats (n=4) by ligation of the proximal left coronary artery, which resulted in a large infarct of the left ventricle. Sham-operated rats (n=4) were used as controls. Eight weeks after surgery, functional experiments were performed and the hearts were frozen. The body weight of HF rats was similar to control rats, but the mean heart weight of HF rats was significantly enlarged. In HF rats compared to controls, the left ventricle was dilated, left ventricular end-diastolic pressure elevated (21.0 ± 0.6 and 5.4 ± 0.2 mm Hg), left ventricular ejection fraction reduced (0.2 ± 0.02 and 0.5 ± 0.02) and left ventricular end-systolic pressure reduced (102 ± 4.2 and 127 ± 3.1 mm Hg). In HF rats, the in vivo and in vitro PR intervals were increased (41% and 20%), as was the Wenckebach cycle length, indicative of AVN dysfunction. The collagen content was significantly increased in the AVN and RAVR indicating fibrosis. Immunolabelling of caveolin3 (cell membrane marker) showed that there was hypertrophy in HF (cell diameter was increased by 63%, 39% in AVN, RAVR). The TUNEL assay showed that the myocytes of the AVN and RAVR in HF undergo apoptotic cell death. Immunolabelling showed that expression of HCN4 was significantly decreased in the AVN and RAVR (43% and 47%) in HF. We conclude that in HF there is remodelling of the AVN and RAVR and this remodelling may explain the AVN dysfunction.

Stimulation of ganglionated plexus attenuates cardiac neural remodeling and heart failure progression in a canine model of acute heart failure post-myocardial infarction.

PubMed

Luo, Da; Hu, Huihui; Qin, Zhiliang; Liu, Shan; Yu, Xiaomei; Ma, Ruisong; He, Wenbo; Xie, Jing; Lu, Zhibing; He, Bo; Jiang, Hong

2017-12-01

Heart failure (HF) is associated with autonomic dysfunction. Vagus nerve stimulation has been shown to improve cardiac function both in HF patients and animal models of HF. The purpose of this present study is to investigate the effects of ganglionated plexus stimulation (GPS) on HF progression and autonomic remodeling in a canine model of acute HF post-myocardial infarction. Eighteen adult mongrel male dogs were randomized into the control (n=8) and GPS (n=10) groups. All dogs underwent left anterior descending artery ligation followed by 6-hour high-rate (180-220bpm) ventricular pacing to induce acute HF. Transthoracic 2-dimensional echocardiography was performed at different time points. The plasma levels of norepinephrine, B-type natriuretic peptide (BNP) and Ang-II were measured using ELISA kits. C-fos and nerve growth factor (NGF) proteins expressed in the left stellate ganglion as well as GAP43 and TH proteins expressed in the peri-infarct zone were measured using western blot. After 6h of GPS, the left ventricular end-diastolic volume, end-systolic volume and ejection fraction showed no significant differences between the 2 groups, but the interventricular septal thickness at end-systole in the GPS group was significantly higher than that in the control group. The plasma levels of norepinephrine, BNP, Ang-II were increased 1h after myocardial infarction while the increase was attenuated by GPS. The expression of c-fos and NGF proteins in the left stellate ganglion as well as GAP43 and TH proteins in cardiac peri-infarct zone in GPS group were significantly lower than that in control group. GPS inhibits cardiac sympathetic remodeling and attenuates HF progression in canines with acute HF induced by myocardial infarction and ventricular pacing. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of gene knockdown of CNP on ventricular remodeling after myocardial ischemia-reperfusion injury through NPRB/Cgmp signaling pathway in rats.

PubMed

Wu, Lian-He; Zhang, Qi; Zhang, Shen; Meng, Lu-Yu; Wang, Yan-Chi; Sheng, Cun-Jian

2018-02-01

This study aimed to explore effects of CNP on ventricular remodeling following myocardial ischemia-reperfusion (I/R) injury through the NPRB/cGMP signaling pathway. Rat cardiomyocytes were assigned into: control, I/R, I/R + CNP, and I/R + 8-Br-cGMP groups. ELISA, qRT-PCR, and Western blotting were used to detect cGMP content and expression, respectively. After model establishment of I/R rats, normal control, CNP -/- control, I/R, and CNP -/- groups were set. Indexes of heart were detected using echocardiography and hemodynamics. ELISA was used to measure serum CNP, cGMP, LDH, cTn I, CK-MB, TNF-α, and IL-6 levels. Myocardial infarct was identified by TTC staining, and apoptosis conditions by TUNEL staining. QRT-PCR and Western blotting were adopted to detect expressions of CNP, NPRB, cGMP, and apoptosis-related genes. Compared with control group, cGMP contents and expression in the I/R, I/R + CNP and I/R + 8-Br-cGMP groups were decreased. Levels of LVEDV, LVESV, LVDS, LVDD, IVSD, LVM, LVEDP, and LVSP were higher in the I/R, CNP -/- control, and CNP -/- groups than normal control group while LVEF, SV, CO, and ±dp/dtmax were lower. Compared with the normal control group, LDH, cTn I, CK-MB, TNF-α, and IL-6 were higher in the I/R, CNP -/- control and CNP -/- groups; pathological changes and myocardial infarction were observed in the I/R, CNP -/- control, and CNP -/- groups; expressions of apoptosis-related genes in those groups were higher; while CNP, NPRB, cGMP, and Bcl-2 expressions were decreased. We came to the conclusion that gene knockdown of CNP blocks the NPRB/cGMP signaling pathway, thereby aggravating myocardial I/R injury and causing ventricular remodeling in rats. © 2017 Wiley Periodicals, Inc.

Molecular biology of myocardial recovery.

PubMed

Zhang, Jianyi; Narula, Jagat

2004-02-01

The use of LVADs that leads to a dramatic mechanical and hemodynamic unloading of the failing left ventricle offers a unique opportunity to investigate the mechanisms of remodeling and reverse remodeling. Although it is being increasingly realized that the LVAD unloading results in regression of hypertrophy and improvement of myocyte function and LV geometry, the cellular and molecular mechanisms responsible for these beneficial effects remain undefined. The favorable alterations in geometry that occur in parallel fashion at the organ, cellular, and molecular levels are most likely caused by the reduced LV wall stress/stretch as a consequence of the mechanical support provided by LVAD. If it is confirmed that LVAD unloading can contribute significantly to reverse remodeling, the role of LVADs may graduate from bridge-to-transplantation or destination therapy to bridge-to-recovery.

Myocardial recovery during mechanical circulatory support: long-term outcome and elective ventricular assist device implantation to promote recovery as a treatment goal.

PubMed

Dandel, Michael; Hetzer, Roland

2015-01-01

Even after incomplete myocardial recovery during mechanical circulatory support, long-term survival rates after ventricular assist device (VAD) explantation can be better than those expected after heart transplantation even for patients with chronic non-ischemic cardiomyopathy as the underlying cause for VAD implantation. The elective therapeutic use of ventricular assist devices for heart failure reversal in its early stage is a future goal. It may be possible to achieve it by developing tools to predict heart failure reversibility even before ventricular assist device implantation and increasing the number of weaning candidates by improvement of adjunctive therapies to optimize unloading-promoted recovery.  Special attention is focused on the long-term stability of cardiac remission after VAD removal, the clinical relevance unloading-promoted myocardial recovery and on the current knowledge about a potential prediction of myocardial recovery during long-term VAD support already before VAD implantation.

Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model.

PubMed

Alrifai, Mohammed; Marsh, Leigh M; Dicke, Tanja; Kılıç, Ayse; Conrad, Melanie L; Renz, Harald; Garn, Holger

2014-01-01

Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes. Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth muscle thickening. Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued. Utilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy.

The NRF2 activator DH404 attenuates adverse ventricular remodeling post-myocardial infarction by modifying redox signalling.

PubMed

Bubb, Kristen J; Kok, Cindy; Tang, Owen; Rasko, Nathalie B; Birgisdottir, Asa B; Hansen, Thomas; Ritchie, Rebecca; Bhindi, Ravinay; Reisman, Scott A; Meyer, Colin; Ward, Keith; Karimi Galougahi, Keyvan; Figtree, Gemma A

2017-07-01

The novel synthetic triterpenoid, bardoxolone methyl, has the ability to upregulate cytoprotective proteins via induction of the nuclear factor erythroid-2-related factor 2 (Nrf2) pathway. This makes it a promising therapeutic agent in disease states characterized by dysregulated oxidative signalling. We have examined the effect of a Nrf2 activator, dihydro-CDDO-trifluoroethyl amide (DH404), a derivative of bardoxolone methyl, on post-infarct cardiac remodeling in rats. DH404, administered from day 2 post myocardial infarction (MI: 30min transient ischemia followed by reperfusion) resulted in almost complete protection against adverse ventricular remodeling as assessed at day 28 (left ventricular end-systolic area: sham 0.14±0.01cm 2 , MI vehicle 0.29±0.04cm 2 vs. MI DH404 0.18±0.02cm 2 , P<0.05); infarct size (21.3±3.4% MI vehicle vs. 10.9±2.3% MI DH404, P<0.05) with associated benefits on systolic function (fractional shortening: sham 71.9±2.6%, MI vehicle 36.2±1.9% vs. MI DH404 58.6±4.0%, P<0.05). These structural and functional benefits were associated with lower myocardial expression of atrial natriuretic peptide (ANP, P<0.01 vs. MI vehicle), and decreased fibronectin (P<0.01 vs. MI vehicle) in DH404-treated MI rats at 28 days. MI increased glutathionylation of endothelial nitric oxide synthase (eNOS) in vitro - a molecular switch that uncouples the enzyme, increasing superoxide production and decreasing nitric oxide (NO) bioavailability. MI-induced eNOS glutathionylation was substantially ameliorated by DH404. An associated increase in glutaredoxin 1 (Grx1) co-immunoprecipitation with eNOS without a change in expression was mechanistically intriguing. Indeed, in parallel in vitro experiments, silencing of Grx1 abolished the protective effect of DH404 against Angiotensin II-induced eNOS uncoupling. The bardoxolone derivative DH404 significantly attenuated cardiac remodeling post MI, at least in part, by re-coupling of eNOS and increasing the functional interaction of Grx1 with eNOS. This agent may have clinical benefits protecting against post MI cardiomyopathy. Copyright © 2017. Published by Elsevier Inc.

Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts.

PubMed

Lee, Tsung-Ming; Chang, Nen-Chung; Lin, Shinn-Zong

2017-03-01

During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling. Copyright © 2017 Elsevier Inc. All rights reserved.

Deep RNA sequencing reveals dynamic regulation of myocardial noncoding RNAs in failing human heart and remodeling with mechanical circulatory support.

PubMed

Yang, Kai-Chien; Yamada, Kathryn A; Patel, Akshar Y; Topkara, Veli K; George, Isaac; Cheema, Faisal H; Ewald, Gregory A; Mann, Douglas L; Nerbonne, Jeanne M

2014-03-04

Microarrays have been used extensively to profile transcriptome remodeling in failing human heart, although the genomic coverage provided is limited and fails to provide a detailed picture of the myocardial transcriptome landscape. Here, we describe sequencing-based transcriptome profiling, providing comprehensive analysis of myocardial mRNA, microRNA (miRNA), and long noncoding RNA (lncRNA) expression in failing human heart before and after mechanical support with a left ventricular (LV) assist device (LVAD). Deep sequencing of RNA isolated from paired nonischemic (NICM; n=8) and ischemic (ICM; n=8) human failing LV samples collected before and after LVAD and from nonfailing human LV (n=8) was conducted. These analyses revealed high abundance of mRNA (37%) and lncRNA (71%) of mitochondrial origin. miRNASeq revealed 160 and 147 differentially expressed miRNAs in ICM and NICM, respectively, compared with nonfailing LV. Among these, only 2 (ICM) and 5 (NICM) miRNAs are normalized with LVAD. RNASeq detected 18 480, including 113 novel, lncRNAs in human LV. Among the 679 (ICM) and 570 (NICM) lncRNAs differentially expressed with heart failure, ≈10% are improved or normalized with LVAD. In addition, the expression signature of lncRNAs, but not miRNAs or mRNAs, distinguishes ICM from NICM. Further analysis suggests that cis-gene regulation represents a major mechanism of action of human cardiac lncRNAs. The myocardial transcriptome is dynamically regulated in advanced heart failure and after LVAD support. The expression profiles of lncRNAs, but not mRNAs or miRNAs, can discriminate failing hearts of different pathologies and are markedly altered in response to LVAD support. These results suggest an important role for lncRNAs in the pathogenesis of heart failure and in reverse remodeling observed with mechanical support.

DIOL Triterpenes Block Profibrotic Effects of Angiotensin II and Protect from Cardiac Hypertrophy

PubMed Central

Jurado-López, Raquel; Martínez-Martínez, Ernesto; Gómez-Hurtado, Nieves; Delgado, Carmen; Visitación Bartolomé, Maria; San Román, José Alberto; Cordova, Claudia; Lahera, Vicente; Nieto, Maria Luisa; Cachofeiro, Victoria

2012-01-01

Background The natural triterpenes, erythrodiol and uvaol, exert anti-inflammatory, vasorelaxing and anti-proliferative effects. Angiotensin II is a well-known profibrotic and proliferative agent that participates in the cardiac remodeling associated with different pathological situations through the stimulation and proliferation of cardiac fibroblasts. Therefore, the aim of the study was to investigate the preventive effects of the natural triterpenes erythrodiol and uvaol on the proliferation and collagen production induced by angiotensin II in cardiac myofibroblasts. Their actions on cardiac hypertrophy triggered by angiotensin II were also studied. Methodology/Principal Findings The effect of erythrodiol and uvaol on angiotensin II-induced proliferation was evaluated in cardiac myofibroblasts from adult rats in the presence or the absence of the inhibitors of PPAR-γ, GW9662 or JNK, SP600125. The effect on collagen levels induced by angiotensin II was evaluated in cardiac myofibroblasts and mouse heart. The presence of low doses of both triterpenes reduced the proliferation of cardiac myofibroblasts induced by angiotensin II. Pretreatment with GW9662 reversed the effect elicited by both triterpenes while SP600125 did not modify it. Both triterpenes at high doses produced an increase in annexing-V binding in the presence or absence of angiotensin II, which was reduced by either SP600125 or GW9662. Erythrodiol and uvaol decreased collagen I and galectin 3 levels induced by angiotensin II in cardiac myofribroblasts. Finally, cardiac hypertrophy, ventricular remodeling, fibrosis, and increases in myocyte area and brain natriuretic peptide levels observed in angiotensin II-infused mice were reduced in triterpene-treated animals. Conclusions/Significance Erythrodiol and uvaol reduce cardiac hypertrophy and left ventricle remodeling induced by angiotensin II in mice by diminishing fibrosis and myocyte area. They also modulate growth and survival of cardiac myofibroblasts. They inhibit the angiotensin II-induced proliferation in a PPAR-γ-dependent manner, while at high doses they activate pathways of programmed cell death that are dependent on JNK and PPAR-γ. PMID:22844495

Mechanisms of physiological and pathological cardiac hypertrophy.

PubMed

Nakamura, Michinari; Sadoshima, Junichi

2018-04-19

Cardiomyocytes exit the cell cycle and become terminally differentiated soon after birth. Therefore, in the adult heart, instead of an increase in cardiomyocyte number, individual cardiomyocytes increase in size, and the heart develops hypertrophy to reduce ventricular wall stress and maintain function and efficiency in response to an increased workload. There are two types of hypertrophy: physiological and pathological. Hypertrophy initially develops as an adaptive response to physiological and pathological stimuli, but pathological hypertrophy generally progresses to heart failure. Each form of hypertrophy is regulated by distinct cellular signalling pathways. In the past decade, a growing number of studies have suggested that previously unrecognized mechanisms, including cellular metabolism, proliferation, non-coding RNAs, immune responses, translational regulation, and epigenetic modifications, positively or negatively regulate cardiac hypertrophy. In this Review, we summarize the underlying molecular mechanisms of physiological and pathological hypertrophy, with a particular emphasis on the role of metabolic remodelling in both forms of cardiac hypertrophy, and we discuss how the current knowledge on cardiac hypertrophy can be applied to develop novel therapeutic strategies to prevent or reverse pathological hypertrophy.

Chitosan hydrogels significantly limit left ventricular infarction and remodeling and preserve myocardial contractility.

PubMed

Henning, Robert J; Khan, Abraham; Jimenez, Ernesto

2016-04-01

Left ventricular myocardial infarctions (MIs) consist of a central area of myocardial necrosis that is surrounded by areas of myocardial injury and ischemia. We hypothesized that chitosan hydrogels, when injected around the perimeter of MIs in rats, could decrease left ventricle (LV) wall stress by the Law of LaPlace, and therefore myocardial oxygen requirements, and prevent the ischemic and injured myocardium from becoming necrotic. In this manner, chitosan gels could limit LV infraction size and LV remodeling. Chitosan hydrogels are liquid at 25°C but gel at 37°C. Seventy Sprague-Dawley rats with ligation of the left coronary artery were treated with either Dulbecco's Modified Eagle Medium (DMEM) or chitosan hydrogel in DMEM, which was injected around the infarct perimeter. Echocardiograms were obtained before MI and at 2, 4, 8, 12, and 16 wk after MI. Hearts from randomly selected rats were harvested at baseline and at the time of echocardiography for determinations of LV infarct size, remodeling, and histopathology. Infarct sizes as a percentage of the total ventricular myocardium in the DMEM group averaged 17% versus 14% in the chitosan group at 4 wk (P < 0.05), 18% versus 14% at 8 wk (P < 0.01), 19% versus 14% at 12 wk (P < 0.001), and 20% versus 14% at 16 wk (P < 0.001). Injection of chitosan into the infarctions produced LV wall thicknesses in the MI border zones that averaged 0.66 cm at 4 wk, which were greater than the LV wall thicknesses in the border zones of rats treated with DMEM, which averaged 0.33 cm (P < 0.01). Arteriole densities in the MI border zones were 160/mm(2) in the chitosan group but only 92/mm(2) in the DMEM rats (P < 0.01). The left ventricular end-diastolic diameters (LVEDs) in the rats averaged 0.73 cm before MI. After MI, LVED increased in the DMEM rats to 0.84 cm at 2 wk, then 0.89 cm at 4 wk, 0.89 cm at 8 wk, 0.89 m at 12 wk, and 0.87 cm at 16 wk. In contrast, LVED in the chitosan rats were on average 19% smaller in comparison with the DMEM rats (P < 0.05) and did not significantly change in comparison with their baseline LVEDs. Left ventricular ejection fraction (LVEF) in the rats averaged 83% before infarctions. In the infarction + DMEM group, the LVEFs significantly decreased after MI and averaged 59.7% at 2 wk, 52.5% at 4 wk, 46.1% at 8 wk, 52.4% at 12 wk, and 53.6% at 16 wk (P < 0.05). In the infarction + chitosan-treated rats, the LVEFs were greater and averaged 67.8% at 2 wk (P < 0.02), 68.9% (P < 0.02) at 4 wk, 69% (P < 0.003) at 8 wk, 65.2% at 12 wk (P < 0.05), and 67% at 16 wk (P < 0.05). Chitosan gel can increase LV myocardial wall thickness, decrease infarct size and LV remodeling, and preserve LV contractility. Copyright © 2016 Elsevier Inc. All rights reserved.

Impaired right ventricular contractile function in childhood obesity and its association with right and left ventricular changes: a cine DENSE cardiac magnetic resonance study.

PubMed

Jing, Linyuan; Pulenthiran, Arichanah; Nevius, Christopher D; Mejia-Spiegeler, Abba; Suever, Jonathan D; Wehner, Gregory J; Kirchner, H Lester; Haggerty, Christopher M; Fornwalt, Brandon K

2017-06-28

Pediatric obesity is a growing public health problem, which is associated with increased risk of cardiovascular disease and premature death. Left ventricular (LV) remodeling (increased myocardial mass and thickness) and contractile dysfunction (impaired longitudinal strain) have been documented in obese children, but little attention has been paid to the right ventricle (RV). We hypothesized that obese/overweight children would have evidence of RV remodeling and contractile dysfunction. One hundred and three children, ages 8-18 years, were prospectively recruited and underwent cardiovascular magnetic resonance (CMR), including both standard cine imaging and displacement encoding with stimulated echoes (DENSE) imaging, which allowed for quantification of RV geometry and function/mechanics. RV free wall longitudinal strain was quantified from the end-systolic four-chamber DENSE image. Linear regression was used to quantify correlations of RV strain with LV strain and measurements of body composition (adjusted for sex and height). Analysis of variance was used to study the relationship between RV strain and LV remodeling types (concentric remodeling, eccentric/concentric hypertrophy). The RV was sufficiently visualized with DENSE in 70 (68%) subjects, comprising 36 healthy weight (13.6 ± 2.7 years) and 34 (12.1 ± 2.9 years) obese/overweight children. Obese/overweight children had a 22% larger RV mass index (8.2 ± 0.9 vs 6.7 ± 1.1 g/m 2.7 , p < 0.001) compared to healthy controls. RV free wall longitudinal strain was impaired in obese/overweight children (-16 ± 4% vs -19 ± 5%, p = 0.02). Ten (14%) out of 70 children had LV concentric hypertrophy, and these children had the most impaired RV longitudinal strain compared to those with normal LV geometry (-13 ± 4% vs -19 ± 5%, p = 0.002). RV longitudinal strain was correlated with LV longitudinal strain (r = 0.34, p = 0.004), systolic blood pressure (r = 0.33, p = 0.006), as well as BMI z-score (r = 0.28, p = 0.02), waist (r = 0.31, p = 0.01), hip (r = 0.40, p = 0.004) and abdominal (r = 0.38, p = 0.002) circumference, height and sex adjusted. Obese/overweight children have evidence of RV remodeling (increased RV mass) and RV contractile dysfunction (impaired free wall longitudinal strain). Moreover, RV longitudinal strain correlates with LV longitudinal strain, and children with LV concentric hypertrophy show the most impaired RV function. These results suggest there may be a common mechanism underlying both remodeling and dysfunction of the left and right ventricles in obese/overweight children.

Metabolic Modulation by Medium-Chain Triglycerides Reduces Oxidative Stress and Ameliorates CD36-Mediated Cardiac Remodeling in Spontaneously Hypertensive Rat in the Initial and Established Stages of Hypertrophy.

PubMed

Saifudeen, Ismael; Subhadra, Lakshmi; Konnottil, Remani; Nair, R Renuka

2017-03-01

Left ventricular hypertrophy (LVH) is characterized by a decrease in oxidation of long-chain fatty acids, possibly mediated by reduced expression of the cell-surface protein cluster of differentiation 36 (CD36). Spontaneously hypertensive rats (SHRs) were therefore supplemented with medium-chain triglycerides (MCT), a substrate that bypasses CD36, based on the assumption that the metabolic modulation will ameliorate ventricular remodeling. The diet of 2-month-old and 6-month-old SHRs was supplemented with 5% MCT (Tricaprylin), for 4 months. Metabolic modulation was assessed by mRNA expression of peroxisome proliferator-activated receptor α and medium-chain acyl-CoA dehydrogenase. Blood pressure was measured noninvasively. LVH was assessed with the use of hypertrophy index, cardiomyocyte cross-sectional area, mRNA expression of B-type natriuretic peptide, cardiac fibrosis, and calcineurin-A levels. Oxidative stress indicators (cardiac malondialdehyde, protein carbonyl, and 3-nitrotyrosine levels), myocardial energy level (ATP, phosphocreatine), and lipid profile were determined. Supplementation of MCT stimulated fatty acid oxidation in animals of both age groups, reduced hypertrophy and oxidative stress along with the maintenance of energy level. Blood pressure, body weight, and lipid profile were unaffected by the treatment. The results indicate that modulation of myocardial fatty acid metabolism by MCT prevents progressive cardiac remodeling in SHRs, possibly by maintenance of energy level and decrease in oxidative stress. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiac mechanics and heart rate variability in patients with systemic sclerosis: the association that we should not miss.

PubMed

Zlatanovic, Maja; Tadic, Marijana; Celic, Vera; Ivanovic, Branislava; Stevanovic, Ana; Damjanov, Nemanja

2017-01-01

We aimed to determine left ventricular (LV) and right ventricular (RV) structure, function and mechanics, as well as heart rate variability (HRV), and their relationship, in patients with systemic sclerosis (SSc). The study included 41 SSc patients and 30 age-matched healthy volunteers. All the patients underwent clinical examination, serological tests, pulmonary function testing, 24-h Holter monitoring and complete two-dimensional echocardiography including strain analysis. The parameters of LV structure (interventricular septum thickness and LV mass index) and RV structure (RV wall thickness) were significantly higher in SSc patients. LV and RV diastolic function (estimated by mitral and tricuspid E/e' ratio) was significantly impaired in SSc group comparing with the healthy controls. LV and RV longitudinal function was significantly deteriorated in SSc patients. LV circumferential strain was also significantly lower in SSc group, whereas LV radial strain was similar between the observed groups. All parameters of time and frequency domain of HRV were decreased in SSc patients. LV and RV cardiac remodeling parameters, particularly diastolic function and longitudinal strain, were associated with HRV indices without regard to the main demographic or the clinical and echocardiographic characteristics. Rodnan Skin Score was also independently associated with biventricular cardiac remodeling in SSc patients. LV and RV structure, function and mechanics, as well as autonomic nervous function, were significantly impaired in SSc patients. There is the significant association between biventricular cardiac remodeling and autonomic function in these patients, which could be useful for their everyday clinical assessment.

Differential phenotype profile between main right ventricular chamber and outflow tract in chronic pulmonary hypertension: echocardiographic observation.

PubMed

López-Candales, Angel

2014-07-01

Right ventricular (RV) dilatation and systolic dysfunction are known remodeling changes occurring in chronic pulmonary hypertension and are likely the result of increases in pulmonary vascular resistance (PVR). It remains unclear whether PVR affects primarily the main RV chamber (mRVc) or the RV outflow tract (RVOT). Standard echocardiography data were collected from a heterogeneous population of 85 consecutive patients (mean age of 54 ± 12 years and mean pulmonary artery systolic pressure of 56 ± 28 mm Hg) to determine how PVR affected size and function of both RV chambers. Regarding size, PVR correlated more with mRVc end systolic area (r = 0.77; P < 0.0001) than either mRVc end diastolic area (r = 0.58; P < 0.0001) or RVOT systolic length (r = 0.54; P < 0.0001), although it did not correlate with RVOT end diastolic length. In terms of fractional area change, a stronger negative correlation was seen between PVR and mRVc (r = -0.77; P < 0.0001) than with PVR and RVOT (r = -0.69; P < 0.0001). Systolic velocity of the tricuspid annulus was the best parameter in identifying elevated PVR. Based on the echocardiography results, increasing PVR values appear to result in differential RV remodeling with significant mRVc dilation and systolic dysfunction when compared with RVOT. It is important to determine whether the different RV remodeling processes occur in all patients with chronic pulmonary hypertension, regardless of etiology; alter therapeutic response; or determine clinical outcomes.

Effect of Renin-Angiotensin Blockers on Left Ventricular Remodeling in Severe Aortic Stenosis.

PubMed

Goh, Serene Si-Ning; Sia, Ching-Hui; Ngiam, Nicholas Jinghao; Tan, Benjamin Yong-Qiang; Lee, Poay Sian; Tay, Edgar Lik-Wui; Kong, William Kok-Fai; Yeo, Tiong Cheng; Poh, Kian-Keong

2017-06-01

Studies have shown that medical therapy with renin-angiotensin blockers (RABs) may benefit patients with aortic stenosis (AS). However, its use and efficacy remains controversial, including in patients with low flow (LF) with preserved left ventricular ejection fraction (LVEF). We examined the effects of RAB use on LV remodeling in patients with severe AS with preserved LVEF, analyzing the differential effects in patients with LF compared with normal flow (NF). This is a retrospective study of 428 consecutive subjects from 2005 to 2014 with echocardiographic diagnosis of severe AS and preserved LVEF. Clinical and echocardiographic parameters were systematically collected and analyzed. Two hundred forty-two (57%) patients had LF. Sixty-four LF patients (26%) were treated with RAB. Patients on RAB treatment had a higher incidence of hyperlipidemia (69% vs 44%) and diabetes mellitus (53% vs 34%). Severity of AS in terms of valve area, transvalvular mean pressure gradient, and aortic valve resistance were similar between both groups as was the degree of LV diastolic function. The RAB group demonstrated significantly lower LV mass index with a correspondingly lower incidence of concentric LV hypertrophy. Regardless of the duration of RAB therapy, patients had increased odds of having a preserved LV mass index compared with those without RAB therapy. In conclusion, RAB therapy may be associated with less LV pathological remodeling and have a role in delaying patients from developing cardiovascular complications of AS. Copyright © 2017 Elsevier Inc. All rights reserved.

Review in Translational Cardiology: MicroRNAs and Myocardial Fibrosis in Aortic Valve Stenosis, a Deep Insight on Left Ventricular Remodeling.

PubMed

Iacopo, Fabiani; Lorenzo, Conte; Calogero, Enrico; Matteo, Passiatore; Riccardo, Pugliese Nicola; Veronica, Santini; Valentina, Barletta; Riccardo, Liga; Cristian, Scatena; Maria, Mazzanti Chiara; Vitantonio, Di Bello

2016-01-01

MicroRNAs (miRNAs) are a huge class of noncoding RNAs that regulate protein-encoding genes (degradation/inhibition of translation). miRNAs are nowadays recognized as regulators of biological processes underneath cardiovascular disorders including hypertrophy, ischemia, arrhythmias, and valvular disease. In particular, circulating miRNAs are promising biomarkers of pathology. This review gives an overview of studies in aortic valve stenosis (AS), exclusively considering myocardial remodeling processes. We searched through literature (till September 2016), all studies and reviews involving miRNAs and AS (myocardial compartment). Although at the beginning of a new era, clear evidences exist on the potential diagnostic and prognostic implementation of miRNAs in the clinical setting. In particular, for AS, miRNAs are modulators of myocardial remodeling and hypertrophy. In our experience, here presented in summary, the principal findings of our research were a confirm of the pathophysiological role in AS of miRNA-21, in particular, the interdependence between textural miRNA-21 and fibrogenic stimulus induced by an abnormal left ventricular pressure overload. Moreover, circulating miRNA-21 (biomarker) levels are able to reflect the presence of significant myocardial fibrosis (MF). Thus, the combined evaluation of miRNA-21, a marker of MF, and hypertrophy, together with advanced echocardiographic imaging (two-dimensional speckle tracking), could fulfill many existing gaps, renewing older guidelines paradigms, also allowing a better risk prognostic and diagnostic strategies.

Novel putative pharmacological therapies to protect the right ventricle in pulmonary hypertension: a review of current literature

PubMed Central

Schulz, Rainer; Sliwa, Karen; Schermuly, Ralph Theo; Lecour, Sandrine

2017-01-01

Pulmonary hypertension (PH) is defined by elevated mean pulmonary artery pressure following the pathological remodelling of small pulmonary arteries. An increase in right ventricular (RV) afterload results in RV hypertrophy and RV failure. The pathophysiology of PH, and RV remodelling in particular, is not well understood, thus explaining, at least in part, why current PH therapies have a limited effect. Existing therapies mostly target the pulmonary circulation. Because the remodelled RV fails to support normal cardiac function, patients eventually succumb from RV failure. Developing novel therapies that directly target the function of the RV may therefore benefit patients with PH. In the past decade, several promising studies have investigated novel cardioprotective strategies in experimental models of PH. This review aims to comprehensively discuss and highlight these novel experimental approaches to confer, in the long‐term, greater health benefit in patients with PH. PMID:28099680

Adiponectin downregulation is associated with volume overload-induced myocyte dysfunction in rats

PubMed Central

Wang, Li-li; Miller, Dori; Wanders, Desiree; Nanayakkara, Gayani; Amin, Rajesh; Judd, Robert; Morrison, Edward E; Zhong, Ju-ming

2016-01-01

Aim: Adiponectin has been reported to exert protective effects during pathological ventricular remodeling, but the role of adiponectin in volume overload-induced heart failure remains unclear. In this study we investigated the effect of adiponectin on cardiac myocyte contractile dysfunction following volume overload in rats. Methods: Volume overload was surgically induced in rats by infrarenal aorta-vena cava fistula. The rats were intravenously administered adenoviral adiponectin at 2-, 6- and 9-weeks following fistula. The protein expression of adiponectin, adiponectin receptors (AdipoR1/R2 and T-cadherin) and AMPK activity were measured using Western blot analyses. Isolated ventricular myocytes were prepared at 12 weeks post-fistula to examine the contractile performance of myocytes and intracellular Ca2+ transient. Results: A-V fistula resulted in significant reductions in serum and myocardial adiponectin levels, myocardial adiponectin receptor (AdipoR1/R2 and T-cadherin) levels, as well as myocardial AMPK activity. Consistent with these changes, the isolated myocytes exhibited significant depression in cell shortening and intracellular Ca2+ transient. Administration of adenoviral adiponectin significantly increased serum adiponectin levels and prevented myocyte contractile dysfunction in fistula rats. Furthermore, pretreatment of isolated myocytes with recombinant adiponectin (2.5 μg/mL) significantly improved their contractile performance in fistula rats, but had no effects in control or adenoviral adiponectin-administered rats. Conclusion: These results demonstrate a positive correlation between adiponectin downregulation and volume overload-induced ventricular remodeling. Adiponectin plays a protective role in volume overload-induced heart failure. PMID:26616727

Inhibition of the reverse mode of the Na+/Ca2+ exchange by KB-R7943 augments arrhythmogenicity in the canine heart during rapid heart rates.

PubMed

Shinada, Takuro; Hirayama, Yoshiyuki; Maruyama, Mitsunori; Ohara, Toshihiko; Yashima, Masaaki; Kobayashi, Yoshinori; Atarashi, Hirotsugu; Takano, Teruo

2005-07-01

To test the hypothesis that the reverse mode of the Na+/Ca2+ exchange augmented by a rapid heart rate has an antiarrhythmic effect by shortening the action potential duration, we examined the effects of KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl] isothiourea methanesulfonate), a selective inhibitor of the reverse mode of the Na+/Ca2+ exchange, to attenuate this effect. We recorded the electrocardiogram, monophasic action potential (MAP), and left ventricular pressure in canine beating hearts. In comparison to the control, KB-R7943 significantly increased the QTc value and MAP duration. MAP alternans and left ventricular pressure alternans were observed after changing the cycle length to 300 milliseconds in the control studies. KB-R7943 magnified both types of alternans and produced spatially discordant alternans between right and left ventricles. Early after-depolarizations and nonsustained ventricular tachycardia occurred in the presence of KB-R7943. Our data suggest that the reverse mode of the Na+/Ca2+ exchange may contribute to suppression of arrhythmias by abbreviating action potential duration under pathophysiological conditions. This conclusion is based on further confirmation by future studies of the specificity of KB-R7943 for block of the reverse mode of the Na+/Ca2+ exchange.

Profilin-1 Promotes the Development of Hypertension-induced Artery Remodeling

PubMed Central

Wang, Yan; Zhang, Jun; Gao, Haiqing; Zhao, Shaohua; Ji, Xiang; Liu, Xiangju; You, Beian; Li, Xiao

2014-01-01

Hypertension is associated with the structural remodeling and stiffening of arteries and is known to increase cardiovascular risk. In the present study, we investigated the effects of overexpression and knock down of profilin-1 on the vascular structural remodeling in spontaneous hypertensive rats (SHRs) using an adenovirus injection to knock down or overexpress profilin-1 mRNA. As a control, blank adenovirus was injected into age-matched SHRs and Wistar-Kyoto rats (WKYs). We quantified arterial structural remodeling through morphological methods, with thoracic aortas stained with hematoxylin–eosin and picosirius red. Western blotting was performed to measure the protein expression of inducible nitric oxide synthase (iNOS) and p38 mitogen-activated protein kinase (p38), and peroxynitrite was quantified by immunohistochemical staining. Overexpression of profilin-1 significantly promoted aortic remodeling, including an increase in vessel size, wall thickness, and collagen content, whereas the knockdown of profilin-1 could reverse these effects. In addition, the expression of phosphorylated p38, iNOS and peroxynitrite was significantly upregulated in SHRs with profilin-1 overexpression along with an increased level of interleukin- 6 (IL-6). These changes could be reversed by knockdown of profilin-1. Our results demonstrate a crucial role for profilin-1 in hypertension-induced arterial structural remodeling at least in part through the p38–iNOS–peroxynitrite pathway. PMID:24399041

Cardiac AAV9-S100A1 gene therapy rescues postischemic heart failure in a preclinical large animal model

PubMed Central

Pleger, Sven T.; Shan, Changguang; Ksienzyk, Jan; Bekeredjian, Raffi; Boekstegers, Peter; Hinkel, Rabea; Schinkel, Stefanie; Leuchs, Barbara; Ludwig, Jochen; Qiu, Gang; Weber, Christophe; Kleinschmidt, Jürgen A.; Raake, Philip; Koch, Walter J.; Katus, Hugo A.; Müller, Oliver J.; Most, Patrick

2014-01-01

As a prerequisite to clinical application, we determined the long-term therapeutic effectiveness and safety of adeno-associated viral (AAV) S100A1 gene therapy in a preclinical, large animal model of heart failure. S100A1, a positive inotropic regulator of myocardial contractility, becomes depleted in failing cardiomyocytes in humans and various animal models, and myocardial-targeted S100A1 gene transfer rescues cardiac contractile function by restoring sarcoplasmic reticulum calcium Ca2+ handling in acutely and chronically failing hearts in small animal models. We induced heart failure in domestic pigs by balloon-occlusion of the left circumflex coronary artery, resulting in myocardial infarction. After 2 weeks, when the pigs displayed significant left ventricular contractile dysfunction, we administered through retrograde coronary venous delivery, AAV9-S100A1 to the left ventricular non-infarcted myocardium. AAV9-luciferase and saline treatment served as control. At 14 weeks, both control groups showed significantly decreased myocardial S100A1 protein expression along with progressive deterioration of cardiac performance and left ventricular remodeling. AAV9-S100A1 treatment prevented and reversed this phenotype by restoring cardiac S100A1 protein levels. S100A1 treatment normalized cardiomyocyte Ca2+ cycling, sarcoplasmic reticulum calcium handling and energy homeostasis. Transgene expression was restricted to cardiac tissue and extra-cardiac organ function was uncompromised indicating a favorable safety profile. This translational study shows the pre-clinical feasibility, long-term therapeutic effectiveness and a favorable safety profile of cardiac AAV9-S100A1 gene therapy in a preclinical model of heart failure. Our study presents a strong rational for a clinical trial of S100A1 gene therapy for human heart failure that could potentially complement current strategies to treat end-stage heart failure. PMID:21775667

Injectable Microsphere Gel Progressively Improves Global Ventricular Function, Regional Contractile Strain, and Mitral Regurgitation after Myocardial Infarction

PubMed Central

McGarvey, Jeremy R; Kondo, Norihiro; Witschey, Walter RT; Takebe, Manabu; Aoki, Chikashi; Burdick, Jason A.; Spinale, Francis G; Gorman, Joseph H; Pilla, James J; Gorman, Robert C

2014-01-01

Background There is continued need for therapies which reverse or abate the remodeling process following myocardial infarction (MI). In this study, we evaluate the longitudinal effects of calcium hydroxyapatite microsphere gel on regional strain, global ventricular function, and mitral regurgitation (MR) in a porcine MI model. Methods Twenty five Yorkshire swine were enrolled. Five were dedicated weight-matched controls. Twenty underwent posterolateral infarction by direct ligation of the circumflex artery and its branches. Infarcted animals were randomly divided into four groups: one week treatment, one week control, four week treatment, and four week control. Following infarction, animals received either twenty 150μl calcium hydroxyapatite gel or saline injections within the infarct. At their respective timepoints, echocardiograms, cardiac MRI, and tissue were collected for evaluation of MR, regional and global left ventricular function, wall thickness, and collagen content. Results Global and regional LV function were depressed in all infarcted subjects at one week compared to healthy controls. By four weeks post-infarction, global function had significantly improved in the calcium hydroxyapatite group compared to infarcted controls (EF 48.5±1.9% vs. 38.0±1.7%, p<0.01). Similarly, regional borderzone radial contractile strain (16.3±1.5% vs. 11.2±1.5%, p=0.04), MR grade (0.4±0.2 vs. 1.2±0.2, p=0.04), and infarct thickness (7.8±0.5mm vs. 4.5±0.2mm, p<0.01) were improved at this timepoint in the treatment group compared to infarct controls. Conclusions Calcium hydroxyapatite injection following MI progressively improves global LV function, borderzone function, and mitral regurgitation. Using novel biomaterials to augment infarct material properties is viable alternative in the current management of heart failure. PMID:25524397

Alterations in left ventricular curvature and principal strains in dilated cardiomyopathy with functional mitral regurgitation.

PubMed

Tibayan, Frederick A; Lai, David T M; Timek, Tomasz A; Dagum, Paul; Liang, David; Zasio, Mary K; Daughters, George T; Miller, D Craig; Ingels, Neil B

2003-05-01

Functional mitral regurgitation (FMR) is increasingly recognized as a left ventricular (LV) disease. Dilated cardiomyopathy (DCM) is commonly accompanied by FMR and reduction of LV torsion. Therapeutic targets for DCM include LV size reduction, altered LV shape, elimination of MR, and increasing LV torsion. It was hypothesized that, in addition to increasing LV size, DCM with FMR would alter normal LV shape and reduce and alter the direction of principal strains across the LV wall. This hypothesis was tested by measuring changes in epicardial and endocardial 2-D principal strains and regional radii of curvature accompanying tachycardia-induced cardiomyopathy in ovine hearts. Radio-opaque marker arrays were implanted into the left ventricle of eight sheep, including one subepicardial triangle and one subendocardial triangle in the anterior wall of the left ventricle. At one week postoperatively, biplane videofluoroscopy was used to determine marker dynamics. Rapid ventricular pacing was then instituted until FMR and signs of heart failure developed, and fluoroscopy was repeated. Circumferential LV radii of curvature were determined from marker triplets. DCM changed the normal epicardial oval LV cross-section to a more circular configuration. The endocardium maintained its normal circular shape as the left ventricle dilated. Deformations of the triangles from end-diastole to end-systole were determined, and the magnitude and direction of 2-D principal strains calculated. DCM was associated with decreased magnitude of both epicardial (-0.095 +/- 0.055 versus -0.040 +/- 0.032, p = 0.006) and endocardial (-0.117 +/- 0.047 versus -0.073 +/- 0.037, p = 0.023) principal strains. DCM reduced the angle of epicardial but not endocardial principal strain. DCM with FMR is associated with LV dilation, circularization of the normally oval equatorial circumferential LV epicardium, transmural reduction in principal strain, and decrease in angle of principal epicardial strain. These changes contribute to a reduction in the net torsional moment and may guide the development of reverse remodeling procedures for the dilated, failing ventricle with FMR.

Management of pulmonary arterial hypertension with a focus on combination therapies.

PubMed

Benza, Raymond L; Park, Myung H; Keogh, Anne; Girgis, Reda E

2007-05-01

Pulmonary arterial hypertension (PAH) is a rare but frequently fatal condition marked by vasoconstriction and vascular remodeling within small pulmonary arteries. The pathobiology of PAH involves imbalances in a multitude of endogenous mediators, which promote aberrant cellular growth, vasoconstriction and hemostasis within the pulmonary vascular tree. The mechanisms promoting these pathologic effects are complex. This complexity is highlighted by the many overlapping secondary messenger systems through which these mediators work. In light of this natural redundancy, it is not surprising that many of the drugs used to treat PAH, which have shown short-term efficacy, fall "short of the mark" in reversing or halting the progression of this disease in the long run. This very redundancy in pathways makes the case for the use of combination of drugs with differing mechanisms of action to treat PAH. Similar to what is now accepted as the standard of care for the treatment of cancer and left ventricular dysfunction, combination therapy has the greatest promise for inducing the most complete vascular remodeling of the pulmonary vasculature by "shutting down" as many of these pathologic pathways as possible. Combination therapies involving existing therapies or new agents with improved pharmacokinetic and/or pharmacodynamic properties represent an emerging clinical paradigm for patients with sub-optimally managed disease. As emerging data in this field of therapy comes to fruition, further reductions in the morbidity and mortality associated with PAH will manifest. The goal of this report is to review the philosophy of combination therapy and present the available data in this area of study.

Mechanotransduction Mechanisms for Intraventricular Diastolic Vortex Forces and Myocardial Deformations: Part 1

PubMed Central

Pasipoularides, Ares

2015-01-01

Epigenetic mechanisms are fundamental in cardiac adaptations, remodeling, reverse remodeling, and disease. This 2-article series proposes that variable forces associated with diastolic RV/LV rotatory intraventricular flows can exert physiologically and clinically important, albeit still unappreciated, epigenetic actions influencing functional and morphological cardiac adaptations and/or maladaptations. Taken in-toto, the 2-part survey formulates a new paradigm in which intraventricular diastolic filling vortex-associated forces play a fundamental epigenetic role, and examines how heart cells react to these forces. The objective is to provide a perspective on vortical epigenetic effects, to introduce emerging ideas and suggest directions of multidisciplinary translational research. The main goal is to make pertinent biophysics and cytomechanical dynamic systems concepts accessible to interested translational and clinical cardiologists. I recognize that the diversity of the epigenetic problems can give rise to a diversity of approaches and multifaceted specialized research undertakings. Specificity may dominate the picture. However, I take a contrasting approach. Are there concepts that are central enough that they should be developed in some detail? Broadness competes with specificity. Would however this viewpoint allow for a more encompassing view that may otherwise be lost by generation of fragmented results? Part 1 serves as a general introduction, focusing on background concepts, on intracardiac vortex imaging methods, and on diastolic filling vortex-associated forces acting epigenetically on RV/LV endocardium and myocardium. Part 2 will describe pertinent available pluridisciplinary knowledge/research relating to mechanotransduction mechanisms for intraventricular diastolic vortex forces and myocardial deformations and to their epigenetic actions on myocardial and ventricular function and adaptations. PMID:25624114

Septal and Anterior Reverse Mismatch of Myocardial Perfusion and Metabolism in Patients With Coronary Artery Disease and Left Bundle Branch Block

PubMed Central

Wang, Jian-Guang; Fang, Wei; Yang, Min-Fu; Tian, Yue-Qin; Zhang, Xiao-Li; Shen, Rui; Sun, Xiao-Xin; Guo, Feng; Wang, Dao-Yu; He, Zuo-Xiang

2015-01-01

Abstract The effects of left bundle branch block (LBBB) on left ventricular myocardial metabolism have not been well investigated. This study evaluated these effects in patients with coronary artery disease (CAD). Sixty-five CAD patients with complete LBBB (mean age, 61.8 ± 9.7 years) and 65 without LBBB (mean age, 59.9 ± 8.4 years) underwent single photon emission computed tomography, positron emission tomography, and contrast coronary angiography. The relationship between myocardial perfusion and metabolism and reverse mismatch score, and that between QRS length and reverse mismatch score and wall motion score were evaluated. The incidence of left ventricular septum and anterior wall reverse mismatching between the two groups was significantly different (P < 0.001 and P = 0.002, respectively). The incidences of normal myocardial perfusion and metabolism in the left ventricular lateral and inferior walls were also significantly different between the two groups (P < 0.001 and P < 0.001, respectively). The incidence of septal reverse mismatching in patients with mild to moderate perfusion was significantly higher among those with LBBB than among those without LBBB (P < 0.001). In CAD patients with LBBB, septal reverse mismatching was significantly more common among those with mild to moderate perfusion than among those with severe perfusion defects (P = 0.002). The correlation between the septal reverse mismatch score and QRS length was significant (P = 0.026). In patients with CAD and LBBB, septal and anterior reverse mismatching of myocardial perfusion and metabolism was frequently present; the septal reverse mismatch score negatively correlated with the QRS interval. PMID:25997045

Compensatory Hypertrophy Induced by Ventricular Cardiomyocyte Specific COX-2 Expression in Mice

PubMed Central

Streicher, John M.; Kamei, Kenichiro; Ishikawa, Tomo-o; Herschman, Harvey; Wang, Yibin

2010-01-01

Cyclooxygenase-2 (COX-2) is an important mediator of inflammation in stress and disease states. Recent attention has focused on the role of COX-2 in human heart failure and diseases, due to the finding that highly specific COX-2 inhibitors (i.e. Vioxx) increased the risk of myocardial infarction and stroke in chronic users. However, the specific impact of COX-2 expression in the intact heart remains to be determined. We report here the development of a transgenic mouse model, using a loxP-Cre approach, that displays robust COX-2 overexpression and subsequent prostaglandin synthesis specifically in ventricular myocytes. Histological, functional and molecular analyses showed that ventricular myocyte specific COX-2 overexpression led to cardiac hypertrophy and fetal gene marker activation, but with preserved cardiac function. Therefore, specific induction of COX-2 and prostaglandin in vivo is sufficient to induce compensated hypertrophy and molecular remodeling. PMID:20170663

Transient severe left ventricular dysfunction following percutaneous patent ductus arteriosus closure in an adult with bicuspid aortic valve: A case report

PubMed Central

HWANG, HUI-JEONG; YOON, KYUNG LIM; SOHN, IL SUK

2016-01-01

The present study reported the case of a 60-year-old female with patent ductus arteriosus (PDA) and a bicuspid aortic valve, who presented with transient severe left ventricular (LV) dysfunction following percutaneous closure of PDA, as identified by speckle tracking analysis. Transient LV dysfunction following PDA closure has previously been reported; however, severe LV dysfunction is rare. In the present case, the combination of a large PDA size, large amount of shunting, LV remodeling and bicuspid aortic valve may have induced serious deterioration of LV function following PDA closure. Furthermore, speckle-tracking echocardiography may be useful in the estimation of functional alterations in the myocardium of the LV following PDA closure. The observations detailed in the present study may improve the understanding of the pathophysiology and myocardial patterns of transient left ventricular dysfunction following PDA closure in adult humans. PMID:26998021

Transient severe left ventricular dysfunction following percutaneous patent ductus arteriosus closure in an adult with bicuspid aortic valve: A case report.

PubMed

Hwang, Hui-Jeong; Yoon, Kyung Lim; Sohn, Il Suk

2016-03-01

The present study reported the case of a 60-year-old female with patent ductus arteriosus (PDA) and a bicuspid aortic valve, who presented with transient severe left ventricular (LV) dysfunction following percutaneous closure of PDA, as identified by speckle tracking analysis. Transient LV dysfunction following PDA closure has previously been reported; however, severe LV dysfunction is rare. In the present case, the combination of a large PDA size, large amount of shunting, LV remodeling and bicuspid aortic valve may have induced serious deterioration of LV function following PDA closure. Furthermore, speckle-tracking echocardiography may be useful in the estimation of functional alterations in the myocardium of the LV following PDA closure. The observations detailed in the present study may improve the understanding of the pathophysiology and myocardial patterns of transient left ventricular dysfunction following PDA closure in adult humans.

Trefoil factor-2 reverses airway remodeling changes in allergic airways disease.

PubMed

Royce, Simon G; Lim, Clarice; Muljadi, Ruth C; Samuel, Chrishan S; Ververis, Katherine; Karagiannis, Tom C; Giraud, Andrew S; Tang, Mimi L K

2013-01-01

Trefoil factor 2 (TFF2) is a small peptide with an important role in mucosal repair. TFF2 is up-regulated in asthma, suggesting a role in asthma pathogenesis. Given its known biological role in promoting epithelial repair, TFF2 might be expected to exert a protective function in limiting the progression of airway remodeling in asthma. The contribution of TFF2 to airway remodeling in asthma was investigated by examining the expression of TFF2 in the airway and lung, and evaluating the effects of recombinant TFF2 treatment on established airway remodeling in a murine model of chronic allergic airways disease (AAD). BALB/c mice were sensitized and challenged with ovalbumin (OVA) or saline for 9 weeks, whereas mice with established OVA-induced AAD were treated with TFF2 or vehicle control (intranasally for 14 d). Effects on airway remodeling, airway inflammation, and airway hyperresponsiveness were then assessed, whereas TFF2 expression was determined by immunohistochemistry. TFF2 expression was significantly increased in the airways of mice with AAD, compared with expression levels in control mice. TFF2 treatment resulted in reduced epithelial thickening, subepithelial collagen deposition, goblet-cell metaplasia, bronchial epithelium apoptosis, and airway hyperresponsiveness (all P < 0.05, versus vehicle control), but TFF2 treatment did not influence airway inflammation. The increased expression of endogenous TFF2 in response to chronic allergic inflammation is insufficient to prevent the progression of airway inflammation and remodeling in a murine model of chronic AAD. However, exogenous TFF2 treatment is effective in reversing aspects of established airway remodeling. TFF2 has potential as a novel treatment for airway remodeling in asthma.

Weighted gene co‑expression network analysis in identification of key genes and networks for ischemic‑reperfusion remodeling myocardium.

PubMed

Guo, Nan; Zhang, Nan; Yan, Liqiu; Lian, Zheng; Wang, Jiawang; Lv, Fengfeng; Wang, Yunfei; Cao, Xufen

2018-06-14

Acute myocardial infarction induces ventricular remodeling, which is implicated in dilated heart and heart failure. The pathogenical mechanism of myocardium remodeling remains to be elucidated. The aim of the present study was to identify key genes and networks for myocardium remodeling following ischemia‑reperfusion (IR). First, the mRNA expression data from the National Center for Biotechnology Information database were downloaded to identify differences in mRNA expression of the IR heart at days 2 and 7. Then, weighted gene co‑expression network analysis, hierarchical clustering, protein‑protein interaction (PPI) network, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were used to identify key genes and networks for the heart remodeling process following IR. A total of 3,321 differentially expressed genes were identified during the heart remodeling process. A total of 6 modules were identified through gene co‑expression network analysis. GO and KEGG analysis results suggested that each module represented a different biological function and was associated with different pathways. Finally, hub genes of each module were identified by PPI network construction. The present study revealed that heart remodeling following IR is a complicated process, involving extracellular matrix organization, neural development, apoptosis and energy metabolism. The dysregulated genes, including SRC proto‑oncogene, non‑receptor tyrosine kinase, discs large MAGUK scaffold protein 1, ATP citrate lyase, RAN, member RAS oncogene family, tumor protein p53, and polo like kinase 2, may be essential for heart remodeling following IR and may be used as potential targets for the inhibition of heart remodeling following acute myocardial infarction.

Matrix metalloproteinases in acute coronary syndromes: current perspectives.

PubMed

Kampoli, Anna-Maria; Tousoulis, Dimitris; Papageorgiou, Nikolaos; Antoniades, Charalambos; Androulakis, Emmanuel; Tsiamis, Eleftherios; Latsios, George; Stefanadis, Christodoulos

2012-01-01

Matrix metalloproteinases (MMPs) are a family of zinc metallo-endopeptidases secreted by cells and are responsible for much of the turnover of matrix components. Several studies have shown that MMPs are involved in all stages of the atherosclerotic process, from the initial lesion to plaque rupture. Recent evidence suggests that MMP activity may facilitate atherosclerosis, plaque destabilization, and platelet aggregation. In the heart, matrix metalloproteinases participate in vascular remodeling, plaque instability, and ventricular remodelling after cardiac injury. The aim of the present article is to review the structure, function, regulation of MMPs and to discuss their potential role in the pathogenesis of acute coronary syndromes, as well as their contribution and usefullness in the setting of the disease.

Comprehensive characterisation of hypertensive heart disease left ventricular phenotypes

PubMed Central

Rodrigues, Jonathan C L; Amadu, Antonio Matteo; Dastidar, Amardeep Ghosh; Szantho, Gergley V; Lyen, Stephen M; Godsave, Cattleya; Ratcliffe, Laura E K; Burchell, Amy E; Hart, Emma C; Hamilton, Mark C K; Nightingale, Angus K; Paton, Julian F R; Manghat, Nathan E; Bucciarelli-Ducci, Chiara

2016-01-01

Objective Myocardial intracellular/extracellular structure and aortic function were assessed among hypertensive left ventricular (LV) phenotypes using cardiovascular magnetic resonance (CMR). Methods An observational study from consecutive tertiary hypertension clinic patients referred for CMR (1.5 T) was performed. Four LV phenotypes were defined: (1) normal with normal indexed LV mass (LVM) and LVM to volume ratio (M/V), (2) concentric remodelling with normal LVM but elevated M/V, (3) concentric LV hypertrophy (LVH) with elevated LVM but normal indexed end-diastolic volume (EDV) or (4) eccentric LVH with elevated LVM and EDV. Extracellular volume fraction was measured using T1-mapping. Circumferential strain was calculated by voxel-tracking. Aortic distensibility was derived from high-resolution aortic cines and contemporaneous blood pressure measurements. Results 88 hypertensive patients (49±14 years, 57% men, systolic blood pressure (SBP): 167±30 mm Hg, diastolic blood pressure (DBP): 96±14 mm Hg) were compared with 29 age-matched/sex-matched controls (47±14 years, 59% men, SBP: 128±12 mm Hg, DBP: 79±10 mm Hg). LVH resulted from increased myocardial cell volume (eccentric LVH: 78±19 mL/m2 vs concentric LVH: 73±15 mL/m2 vs concentric remodelling: 55±9 mL/m2, p<0.05, respectively) and interstitial fibrosis (eccentric LVH: 33±10 mL/m2 vs concentric LVH: 30±10 mL/m2 vs concentricremodelling: 19±2 mL/m2, p<0.05, respectively). LVH had worst circumferential impairment (eccentric LVH: −12.8±4.6% vs concentric LVH: −15.5±3.1% vs concentric remodelling: –17.1±3.2%, p<0.05, respectively). Concentric remodelling was associated with reduced aortic distensibility, but not with large intracellular/interstitial expansion or myocardial dysfunction versus controls. Conclusions Myocardial interstitial fibrosis varies across hypertensive LV phenotypes with functional consequences. Eccentric LVH has the most fibrosis and systolic impairment. Concentric remodelling is only associated with abnormal aortic function. Understanding these differences may help tailor future antihypertensive treatments. PMID:27260191

Antifailure therapy including spironolactone improves left ventricular energy supply-demand relations in nonischemic dilated cardiomyopathy.

PubMed

Bell, Susan P; Adkisson, Douglas W; Lawson, Mark A; Wang, Li; Ooi, Henry; Sawyer, Douglas B; Kronenberg, Marvin W

2014-08-27

Left ventricular (LV) energy supply-demand imbalance is postulated to cause "energy starvation" and contribute to heart failure (HF) in nonischemic dilated cardiomyopathy (NIDCM). Using cardiac magnetic resonance (CMR) and [(11)C] acetate positron emission tomography (PET), we evaluated LV perfusion and oxidative metabolism in NIDCM and the effects of spironolactone on LV supply-demand relations. Twelve patients with NIDCM underwent CMR and PET at baseline and after ≥6 months of spironolactone therapy added to a standard HF regimen. The myocardial perfusion reserve index (MPRI) was calculated after gadolinium injection during adenosine, as compared to rest. The monoexponential clearance rate of [(11)C] acetate (kmono) was used to calculate the work metabolic index (WMI), an index of LV mechanical efficiency, and kmono/RPP (rate-pressure product), an index of energy supply/demand. At baseline, the subendocardium was hypoperfused versus the subepicardium (median MPRI, 1.63 vs. 1.80; P<0.001), but improved to 1.80 (P<0.001) after spironolactone. The WMI increased (P=0.001), as did kmono/RPP (P=0.003). These improvements were associated with reverse remodeling, increased LV ejection fraction, and decreases in LV mass and systolic wall stress (all P<0.002). NIDCM is associated with subendocardial hypoperfusion and impaired myocardial oxidative metabolism, consistent with energy starvation. Antifailure therapy improves parameters of energy starvation and is associated with augmented LV performance. http://www.clinicaltrials.gov/ Unique identifier: ID NCT00574119. © 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Reduction in dynamin-2 is implicated in ischaemic cardiac arrhythmias

PubMed Central

Shi, Dan; Xie, Duanyang; Zhang, Hong; Zhao, Hong; Huang, Jian; Li, Changming; Liu, Yi; Lv, Fei; The, Erlinda; Liu, Yuan; Yuan, Tianyou; Wang, Shiyi; Chen, Jinjin; Pan, Lei; Yu, Zuoren; Liang, Dandan; Zhu, Weidong; Zhang, Yuzhen; Li, Li; Peng, Luying; Li, Jun; Chen, Yi-Han

2014-01-01

Ischaemic cardiac arrhythmias cause a large proportion of sudden cardiac deaths worldwide. The ischaemic arrhythmogenesis is primarily because of the dysfunction and adverse remodelling of sarcolemma ion channels. However, the potential regulators of sarcolemma ion channel turnover and function in ischaemic cardiac arrhythmias remains unknown. Our previous studies indicate that dynamin-2 (DNM2), a cardiac membrane-remodelling GTPase, modulates ion channels membrane trafficking in the cardiomyocytes. Here, we have found that DNM2 plays an important role in acute ischaemic arrhythmias. In rat ventricular tissues and primary cardiomyocytes subjected to acute ischaemic stress, the DNM2 protein and transcription levels were markedly down-regulated. This DNM2 reduction was coupled with severe ventricular arrhythmias. Moreover, we identified that the down-regulation of DNM2 within cardiomyocytes increases the action potential amplitude and prolongs the re-polarization duration by depressing the retrograde trafficking of Nav1.5 and Kir2.1 channels. These effects are likely to account for the DNM2 defect-induced arrhythmogenic potentials. These results suggest that DNM2, with its multi-ion channel targeting properties, could be a promising target for novel antiarrhythmic therapies. PMID:25092467

Right ventricular remodeling and dysfunction with subsequent annular dilatation and tethering as a mechanism of isolated tricuspid regurgitation.

PubMed

Seo, Hye-Sun; Ha, Jong-Won; Moon, Jae Youn; Choi, Eui-Young; Rim, Se-Joong; Jang, Yangsoo; Chung, Namsik; Shim, Won-Heum; Cho, Seung-Yun; Kim, Sung Soon

2008-10-01

Secondary tricuspid regurgitation (TR) as a result of pulmonary hypertension and/or left-sided heart disease is caused by tricuspid valve (TV) annular dilatation and tethering of the tricuspid leaflet after right ventricular (RV) dilatation. However, the mechanism of isolated TR without significant pulmonary hypertension remains unknown. The present study investigated the RV function and TV deformations in patients with isolated TR to find out the mechanism and etiology of the disease. Twelve patients with isolated, severe TR were included. RV area, volume, ejection fraction (EF), tenting distance and tenting area were measured. These parameters were compared with 12 age-and gender-matched controls and 12 patients with secondary TR. The cause of isolated TR was incomplete coaptation associated with annular dilatation without other problems. Compared with the controls, RV end-diastolic volumes and annular diameters were significantly larger and RVEF was significantly lower in patients with isolated TR. Tenting area and tenting distance were also significantly higher. However, there were no significant differences in these parameters between patients with isolated and secondary TR. Isolated TR was associated with RV remodeling, systolic dysfunction and resultant annular dilatation and tethering of tricuspid leaflets.

Diuretics as pathogenetic treatment for heart failure

PubMed Central

Guglin, Maya

2011-01-01

Increased intracardiac filling pressure or congestion causes symptoms and leads to hospital admissions in patients with heart failure, regardless of their systolic function. A history of hospital admission, in turn, predicts further hospitalizations and morbidity, and a higher number of hospitalizations determine higher mortality. Congestion is therefore the driving force of the natural history of heart failure. Congestion is the syndrome shared by heart failure with preserved and reduced systolic function. These two conditions have almost identical morbidity, mortality, and survival because the outcomes are driven by congestion. A small difference in favor of heart failure with preserved systolic function comes from decreased ejection fraction and left ventricular remodeling which is only present in heart failure with decreased systolic function. The magnitude of this difference reflects the contribution of decreased systolic function and ventricular remodeling to the progression of heart failure. The only treatment available for congestion is fluid removal via diuretics, ultrafiltration, or dialysis. It is the only treatment that works equally well for heart failure with reduced and preserved systolic function because it affects congestion, the main pathogenetic feature of the disease. Diuretics are pathogenetic therapy for heart failure. PMID:21403798

Kcne2 Deletion Creates a Multisystem Syndrome Predisposing to Sudden Cardiac Death

PubMed Central

Hu, Zhaoyang; Kant, Ritu; Anand, Marie; King, Elizabeth C.; Krogh-Madsen, Trine; Christini, David J.; Abbott, Geoffrey W.

2014-01-01

Background Sudden cardiac death (SCD) is the leading global cause of mortality, exhibiting increased incidence in diabetics. Ion channel gene perturbations provide a well-established ventricular arrhythmogenic substrate for SCD. However, most arrhythmia susceptibility genes - including the KCNE2 K+ channel β subunit - are expressed in multiple tissues, suggesting potential multiplex SCD substrates. Methods and Results Using “whole transcript” transcriptomics, we uncovered cardiac angiotensinogen upregulation and remodeling of cardiac angiotensinogen interaction networks in P21 Kcne2−/− mouse pups, and adrenal remodeling consistent with metabolic syndrome in adult Kcne2−/− mice. This led to the discovery that Kcne2 disruption causes multiple acknowledged SCD substrates of extracardiac origin: diabetes, hypercholesterolemia, hyperkalemia, anemia and elevated angiotensin II. Kcne2 deletion was also prerequisite for aging-dependent QT prolongation, ventricular fibrillation and SCD immediately following transient ischemia, and fasting-dependent hypoglycemia, myocardial ischemia and atrioventricular block. Conclusions Disruption of a single, widely expressed arrhythmia susceptibility gene can generate a multisystem syndrome comprising manifold electrical and systemic substrates and triggers of SCD. This paradigm is expected to apply to other arrhythmia susceptibility genes, the majority of which encode ubiquitously expressed ion channel subunits or regulatory proteins. PMID:24403551

So little source, so much sink: requirements for afterdepolarizations to propagate in tissue.

PubMed

Xie, Yuanfang; Sato, Daisuke; Garfinkel, Alan; Qu, Zhilin; Weiss, James N

2010-09-08

How early (EADs) and delayed afterdepolarizations (DADs) overcome electrotonic source-sink mismatches in tissue to trigger premature ventricular complexes remains incompletely understood. To study this question, we used a rabbit ventricular action potential model to simulate tissues in which a central area of contiguous myocytes susceptible to EADs or DADs was surrounded by unsusceptible tissue. In 1D tissue with normal longitudinal conduction velocity (0.55 m/s), the numbers of contiguous susceptible myocytes required for an EAD and a barely suprathreshold DAD to trigger a propagating action potential were 70 and 80, respectively. In 2D tissue, these numbers increased to 6940 and 7854, and in 3D tissue to 696,910 and 817,280. These numbers were significantly decreased by reduced gap junction conductance, simulated fibrosis, reduced repolarization reserve and heart failure electrical remodeling. In conclusion, the source-sink mismatch in well-coupled cardiac tissue powerfully protects the heart from arrhythmias due to sporadic afterdepolarizations. Structural and electrophysiological remodeling decrease these numbers significantly but still require synchronization mechanisms for EADs and DADs to overcome the robust protective effects of source-sink mismatch. Copyright 2010 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Distinguishing hypertrophic cardiomyopathy from athlete's heart physiological remodelling: clinical significance, diagnostic strategies and implications for preparticipation screening.

PubMed

Maron, B J

2009-09-01

Sudden cardiac death in young competitive athletes is an important public health problem, although a relatively low-event-rate phenomenon. The single most common cardiovascular cause of these unexpected catastrophes is hypertrophic cardiomyopathy (HCM), accounting for about one-third of cases. Since the phenotypic expression of HCM is variable, and not uncommonly includes patients with mild and localised left ventricular hypertrophy, the differential diagnosis with physiological remodelling of athlete's heart not uncommonly arises. This review discusses those non-invasive strategies that are useful in distinguishing the benign consequences of systematic athletic training from pathological left ventricular hypertrophy with the potential for sudden cardiac death. Preparticipation screening in healthy general athlete populations may raise the suspicion of HCM, and ultimately lead to definitive diagnosis. However, recently controversy has arisen regarding the most effective and practical strategy for the screening of athletes. European investigators have promoted routine 12-lead ECGs as part of a national mandatory programme distinct from the customary practice in the US which is limited to history and physical examinations. Consensus criteria and recommendations for eligibility and disqualification of athletes with HCM (and other cardiovascular abnormalities) have proved useful to the practising community.

Systemic hypertension and the right-sided cardiovascular system: a review of the available evidence.

PubMed

Pedrinelli, Roberto; Dell'Omo, Giulia; Talini, Enrica; Canale, Maria Laura; Di Bello, Vitantonio

2009-02-01

Abnormal vasoconstriction of the lesser circulation characterizes a subset of patients with essential hypertension, a possible effect of mechanisms, such as enhanced sympathetic tone, increased delivery of blood-borne vasoconstrictor substances or abnormal local release of vasoactive factors, acting on both sides of the circulation or to backward transmission of increased pressure due to stiffer left ventricles with more advanced diastolic dysfunction. Elevated systemic pressure also associates with thickening of the right ventricle, a central element of the low-pressure system. Right ventricular remodelling develops in parallel with a similar process occurring at the left side, likely as a result of ventricular interdependence under the influence of trophic factors targeting both ventricles, though other mechanisms, including increased pulmonary afterload, may also be operative. By and large independent of the extent of structural remodelling of both ventricles, systemic hypertension also conditions an impaired filling rate of the right ventricle that accompanies a similar phenomenon at the left side. Thus, quite in contrast with the common and simplistic assumption of a separate behaviour of the two ventricles, the right-sided cardiovascular system is not immune to the effect of systemic hypertension, a concept whose clinical and pathophysiological implications require further studies.

Pathological Left Ventricular Hypertrophy and Stem Cells: Current Evidence and New Perspectives.

PubMed

Marketou, Maria E; Parthenakis, Fragiskos; Vardas, Panos E

2016-01-01

Left ventricular hypertrophy (LVH) is a strong predictor of adverse cardiovascular outcomes. It is the result of complex mechanisms that include not only an increase in protein synthesis and cell size but also proliferating cardiac progenitor cells and the influx of bone marrow-derived cells developing into cardiomyocytes. Stem and progenitor cells are known to contribute to the renewal of adult mammalian cardiomyocytes in case of myocardial injury or pressure and volume overload. They are activated in LVH and play a regulatory role in myocardial repair. They have high proliferative potential and secrete numerous cytokines, growth factors, and microRNAs that play important roles in cell differentiation, cardiac remodeling, and neovascularization. They are mobilized in response to either mechanical or chemical stimuli, hormones, or pharmacologic agents. Another important source of progenitor cells is the epicardial layer. It appears that precursor cells migrate from the epicardium to the myocardium in order to interact with myocardial cells. In addition, migratory cells participate in the formation of almost all cardiac structures in myocardial hypertrophy. Although the pathophysiological mechanisms are still obscure and further studies are required, their properties may open the door to regenerative cell therapy for the prevention of adverse remodeling.

VIP Gene Deletion in Mice Causes Cardiomyopathy Associated with Upregulation of Heart Failure Genes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Szema, Anthony M.; Hamidi, Sayyed A.; Smith, S. David

2013-05-20

Vasoactive Intestinal Peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, is absent in pulmonary arteries of patients with idiopathic pulmonary arterial hypertension (PAH). We previously determined that targeted deletion of the VIP gene in mice leads to PAH with pulmonary vascular remodeling and right ventricular (RV) dilatation. Whether the left ventricle is also affected by VIP gene deletion is unknown. In the current study, we examined if VIP knockout mice (VIP-/-) develop both right (RV) and left ventricular (LV) cardiomyopathy, manifested by LV dilatation and systolic dysfunction, as well as overexpression of genes conducive to heartmore » failure.« less

Reversible catecholamine-induced cardiomyopathy due to pheochromocytoma: case report.

PubMed

Satendra, Milan; de Jesus, Cláudia; Bordalo e Sá, Armando L; Rosário, Luís; Rocha, José; Bicha Castelo, Henrique; Correia, Maria José; Nunes Diogo, António

2014-03-01

Pheochromocytoma is a tumor originating from chromaffin tissue. It commonly presents with symptoms and signs of catecholamine excess, such as hypertension, tachycardia, headache and sweating. Cardiovascular manifestations include catecholamine-induced cardiomyopathy, which may present as severe left ventricular dysfunction and congestive heart failure. We report a case of pheochromocytoma which was diagnosed following investigation of dilated cardiomyopathy. We highlight the dramatic symptomatic improvement and reversal of cardiomyopathy, with recovery of left ventricular function after treatment. Copyright © 2013 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

END-DIASTOLIC FLOW REVERSAL LIMITS THE EFFICACY OF PEDIATRIC INTRAAORTIC BALLOON PUMP COUNTERPULSATION

PubMed Central

Bartoli, Carlo R.; Rogers, Benjamin D.; Ionan, Constantine E.; Koenig, Steven C.; Pantalos, George M.

2013-01-01

OBJECTIVE Counterpulsation with an intraaortic balloon pump (IABP) has not achieved the same successes or clinical use in pediatric patients as in adults. In a pediatric animal model, IABP efficacy was investigated to determine whether IABP timing with a high-fidelity blood pressure signal may improve counterpulsation therapy versus a low-fidelity signal. METHODS In Yorkshire piglets (n=19, 13.0±0.5 kg) with coronary ligation-induced acute ischemic left ventricular failure, pediatric IABPs (5 or 7cc) were placed in the descending thoracic aorta. Inflation and deflation were timed with traditional criteria from low-fidelity (fluid-filled) and high-fidelity (micromanometer) blood pressure signals during 1:1 support. Aortic, carotid, and coronary hemodynamics were measured with pressure and flow transducers. Myocardial oxygen consumption was calculated from coronary sinus and arterial blood samples. Left ventricular myocardial blood flow and end-organ blood flow were measured with microspheres. RESULTS Despite significant suprasystolic diastolic augmentation and afterload reduction at heart rates of 105±3bmp, left ventricular myocardial blood flow, myocardial oxygen consumption, the myocardial oxygen supply/demand relationship, cardiac output, and end-organ blood flow did not change. Statistically significant end-diastolic coronary, carotid, and aortic flow reversal occurred with IABP deflation. Inflation and deflation timed with a high-fidelity versus low-fidelity signal did not attenuate systemic flow reversal or improve the myocardial oxygen supply/demand relationship. CONCLUSIONS Systemic end-diastolic flow reversal limited counterpulsation efficacy in a pediatric model of acute left ventricular failure. Adjustment of IABP inflation and deflation timing with traditional criteria and a high-fidelity blood pressure waveform did not improve IABP efficacy or attenuate flow reversal. End-diastolic flow reversal may limit the efficacy of IABP counterpulsation therapy in pediatric patients with traditional timing criteria. Investigation of alternative deflation timing strategies is warranted. PMID:24139614

End-diastolic flow reversal limits the efficacy of pediatric intra-aortic balloon pump counterpulsation.

PubMed

Bartoli, Carlo R; Rogers, Benjamin D; Ionan, Constantine E; Pantalos, George M

2014-05-01

Counterpulsation with an intra-aortic balloon pump (IABP) has not achieved the same success or clinical use in pediatric patients as in adults. In a pediatric animal model, IABP efficacy was investigated to determine whether IABP timing with a high-fidelity blood pressure signal may improve counterpulsation therapy versus a low-fidelity signal. In Yorkshire piglets (n = 19; weight, 13.0 ± 0.5 kg) with coronary ligation-induced acute ischemic left ventricular failure, pediatric IABPs (5 or 7 mL) were placed in the descending thoracic aorta. Inflation and deflation were timed with traditional criteria from low-fidelity (fluid-filled) and high-fidelity (micromanometer) blood pressure signals during 1:1 support. Aortic, carotid, and coronary hemodynamics were measured with pressure and flow transducers. Myocardial oxygen consumption was calculated from coronary sinus and arterial blood samples. Left ventricular myocardial blood flow and end-organ blood flow were measured with microspheres. Despite significant suprasystolic diastolic augmentation and afterload reduction at heart rates of 105 ± 3 beats per minute, left ventricular myocardial blood flow, myocardial oxygen consumption, the myocardial oxygen supply/demand relationship, cardiac output, and end-organ blood flow did not change. Statistically significant end-diastolic coronary, carotid, and aortic flow reversal occurred with IABP deflation. Inflation and deflation timed with a high-fidelity versus low-fidelity signal did not attenuate systemic flow reversal or improve the myocardial oxygen supply/demand relationship. Systemic end-diastolic flow reversal limited counterpulsation efficacy in a pediatric model of acute left ventricular failure. Adjustment of IABP inflation and deflation timing with traditional criteria and a high-fidelity blood pressure waveform did not improve IABP efficacy or attenuate flow reversal. End-diastolic flow reversal may limit the efficacy of IABP counterpulsation therapy in pediatric patients with traditional timing criteria. Investigation of alternative deflation timing strategies is warranted. Copyright © 2014 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Race-related differences in left ventricular structural and functional remodeling in response to increased afterload: the Atherosclerosis Risk in Communities Study

PubMed Central

Fernandes-Silva, Miguel M; Shah, Amil M; Hegde, Sheila; Goncalves, Alexandra; Claggett, Brian; Cheng, Susan; Nadruz, Wilson; Kitzman, Dalane W.; Konety, Suma H.; Matsushita, Kunihiro; Mosley, Thomas; Lam, Carolyn S.P.; Borlaug, Barry A.; Solomon, Scott D

2016-01-01

Background Chronic increasing in arterial afterload may be an important trigger for left ventricular (LV) remodeling and dysfunction that lead to heart failure (HF). Racial differences in the predisposition to HF are well described, but the underlying mechanisms remain unclear. Objective We evaluated the racial differences in arterial elastance (Ea), which reflects the arterial afterload faced by the LV, and its associations with cardiac structure and function. We hypothesize that the LV in blacks displays heightened afterload sensitivity as compared to whites. Methods We studied 5727 community-based, elderly Atherosclerosis Risk in Community (ARIC) Study participants (22% black), who underwent echocardiography between 2011 and 2013. Results Blacks were younger (75 ± 5 vs 76 ± 5 years old), more frequently women (66 vs 57%), and had higher prevalence of obesity (46 vs 31%), hypertension (94 vs 80%), and diabetes mellitus (47 vs 34%) than whites. Adjusting for these baseline differences, Ea was higher among blacks (1.96 ± 0.01 vs 1.80 ± 0.01 mmHg/mL). In blacks, Ea was associated with greater LV remodeling (LV mass index, β = 3.21 ± 0.55 g/m2, p<0.001) and higher LV filling pressures (E/e′ ratio, β = 0.42 ± 0.11, p<0.001). These relationships were not observed in whites (LV mass, β = 0.16 ± 0.32 g/m2, p=0.61, p for interaction <0.001; E/e′ratio, β = −0.32 ± 0.06, p<0.001, p for interaction <0.001).. Conclusion These community-based data suggest that black Americans display heightened afterload sensitivity as a stimulus for LV structural and functional remodeling, which may contribute to their greater risk of HF, as compared to white Americans. PMID:28017356

Air Pollution Exposure with Fine Dust. Responses in the Pulmonary Vasculature and the Right Heart.

PubMed

Durmus, Nedim; Grunig, Gabriele

2018-04-01

Detrimental effects of air pollution with fine dust (particulate matter ≤2.5 μm in aerodynamic diameter, or PM 2.5 ) on the systemic circulation and the left heart have been studied intensely during the past decade. In comparison, knowledge regarding the effects of exposure to air pollution with PM 2.5 on the pulmonary vasculature and the right heart lags far behind. A report on severe lung disease and right heart failure in coal miners was published nearly 170 years ago. However, today, we still do not have a clear picture of how the effect of air pollution on the pulmonary circulation or the right heart should be viewed from a clinical, mechanistic biological, therapeutic, or economic angle. In the laboratory, we have established a model of immune response-induced vascular remodeling that is significantly worsened by adding PM 2.5 to the intranasal antigen challenge solution. Importantly, the PM 2.5 is given at a concentration that by itself does not induce significant inflammation or pulmonary vascular remodeling. However, when added to antigen, this low-dose PM 2.5 exposure induces severe pulmonary vascular remodeling, significantly increased right ventricular pressures, and significant molecular changes in the right heart. Our data also show that these PM 2.5 -exaggerated responses are dependent on interleukin-13, interleukin-17A, and antigen-specific antibody. The experimental model is being used to address a few questions: 1. Which mechanism protects the animals from severe right ventricular failure despite the severity of the pulmonary artery remodeling? 2. What is the mechanism by which PM 2.5 worsens the response to antigen? 3. How does PM 2.5 exert its effects across the small airways to the small blood vessels? In conclusion, further investigation is urgently needed to understand the effects of exposure to ambient or occupational air pollution on the pulmonary vasculature, because better knowledge could lead to immediate beneficial actions for patients with pulmonary hypertension and persons at risk.

The CD147/MMP-2 signaling pathway may regulate early stage cardiac remodelling in spontaneously hypertensive rats.

PubMed

Li, Bowei; Zhou, Wanxing; Yang, Xiaorong; Zhou, Yuliang; Tan, Yongjing; Yuan, Congcong; Song, Yulan; Chen, Xiao; Zhang, Wei

2016-11-01

Previous studies have reported that decreased matrix metalloproteinase-2 (MMP-2) is associated with early stage (age 8-16 weeks) ventricular remodelling in spontaneously hypertensive rats (SHR). We hypothesized that inhibited CD147/MMP-2 signalling might down-regulate MMP-2 expression and augment remodelling in spontaneously hypertensive rats. Twenty-nine male SHR (8 weeks) were randomly assigned to SHR, CD147, and CD147+DOX groups. The control group included eight age-matched WKY rats. CD147 and CD147+DOX groups received recombinant human CD147 (600 ng/kg in 1.5 mL saline, weekly). The SHR and WKY groups received the vehicle. The CD147+DOX group also received doxycycline, an inhibitor of MMPs (daily, 30 mg/kg in 1.5 mL saline, iG). On day 56 echocardiography and left ventricular mass index (LVWI) measurements were collected and histological sections were stained for cell and collagen content. Myocardium MMP-2, TIMP-1, CD147, and collagens types I and III were estimated by western blot. CD147 and the ratio of MMP-2/TIMP-1 were lower in SHR than WKY rats (P<.05). Myocyte hypertrophy, partial fibre breaks, plasmolysis, necrosis and collagen content (collagen volume fraction [CVF], I and III) in SHR were above control levels (P<.05). CD147 rats showed CD147, MMP-2 and MMP-2/TIMP-1 were increased (P<.05), CVF, LVWI, and collagen I and III were decreased (P<.05) and myocyte morphology was improved. CD147 levels did not differ between CD147+DOX and CD147 groups, CVF, collagens type I and III and partial fiber breaks were more abundant in CD147+DOX (P<.05). In summary, an inhibited CD147/MMP-2 pathway was associated with early stage cardiac remodelling, and CD147 supplementation may attenuate this response. © 2016 John Wiley & Sons Australia, Ltd.

Sex Differences in the Biology and Pathology of the Aging Heart.

PubMed

Keller, Kaitlyn M; Howlett, Susan E

2016-09-01

The knowledge that advanced age is a major risk factor for cardiovascular disease (CVD) has stimulated interest in cardiac aging. Understanding how the heart remodels with age can help us appreciate why older individuals are more likely to acquire heart disease. Growing evidence in both humans and animals shows that the heart exhibits distinct structural and functional changes as a consequence of age. These changes occur even in the absence of overt cardiovascular disease and are often maladaptive. For example, atrial hypertrophy and fibrosis may increase susceptibility to atrial fibrillation in older adults. Age-dependent increases in left ventricular fibrosis, stiffness, and wall thickness promote diastolic dysfunction, predisposing to heart failure with preserved ejection fraction. The influence of age on the heart is evident at rest but is even more prominent during exercise. There is also evidence for sex-specific variation in age-associated remodelling. For instance, there is some evidence that the number of ventricular myocytes declines with age through apoptosis in men but not in women. This helps explain why older men are more likely than women to experience heart failure with reduced ejection fraction. Emerging evidence from preclinical studies suggests that frailty rather than chronological age promotes adverse cardiac remodelling. Mechanisms implicated in cardiac aging include impaired calcium handling, excessive activation of the ß-adrenergic and renin-angiotensin systems, and mitochondrial dysfunction. Further research into cardiac aging in both sexes is needed, because it may be possible to modify disease treatment if the substrate upon which the disease first develops is better understood. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Absence of cystatin C involvement in ventricular remodelling and heart failure.

PubMed

Pérez-Calvo, J I; Castiella Muruzábal, T; Búcar Barjud, M; Josa Laorden, C; Sánchez Marteles, M; Lacambra Blasco, I; Asensio López, M C; Pascual Figal, D A

2016-03-01

Cystatin C (CysC) is a protease encoded by housekeeping genes. Although its prognostic value in heart failure (HF) is well known, it is debatable whether this value is due to the greater accuracy of CysC in calculating the glomerular filtration rate or to its involvement in pathological ventricular remodelling. The aim of this study was to determine whether CysC expression changes in the myocardium of foetuses of different ages and in the myocardium of adults with various cardiovascular diseases, as well as to analyse the correlation between its serum concentrations and cardiac structure and morphology in a patient group with HF. We analysed the correlations (Pearson's r and Spearman's test) between the serum CysC levels and echocardiographic parameters of 351 patients with HF. We also performed immunohistochemical staining for CysC, metalloproteinase-9 (MMP-9) and desmin in 9 cardiac tissue samples from autopsies of 4 foetuses of different gestational ages and 5 healthy adults or adults with cardiovascular disease. For the patients with HF, there was no correlation between the CysC concentrations and the cardiac parameters measured by 2D echocardiography. The immunohistochemistry showed a weak background staining for CysC in all samples, regardless of age and the presence or absence of cardiovascular diseases. Our results suggest that CysC does not have a significant role in the pathological remodelling of the left ventricle in HF. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

Left ventricular remodelling in patients with moderate systolic dysfunction after myocardial infarction: favourable effects of exercise training and predictive role of N-terminal pro-brain natriuretic peptide.

PubMed

Giallauria, Francesco; Cirillo, Plinio; Lucci, Rosa; Pacileo, Mario; De Lorenzo, Anna; D'Agostino, Mariantonietta; Moschella, Sabino; Psaroudaki, Marianna; Del Forno, Domenico; Orio, Francesco; Vitale, Dino Franco; Chiariello, Massimo; Vigorito, Carlo

2008-02-01

To investigate the effects of exercise training (ET) on left ventricular (LV) volumes, cardiopulmonary functional capacity and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in postinfarction patients with moderate LV dysfunction. Sixty-one postinfarction patients were randomized into two groups: group T [n=30, LV ejection fraction (EF) 41.6+/-11.3%, mean+/-SD] entered a 6-month ET programme, whereas group C (n=31, EF 42.0+/-7.6%, P=NS) did not. NT-proBNP assay, Doppler-echocardiography and cardiopulmonary exercise test were performed upon enrolment and at sixth months. At sixth months, trained patients showed an improvement in workload (+26%, P<0.001), Vo2peak (+31%, P<0.001), LV end-diastolic volume index (LVEDVI; -9%, P<0.001), a reduction in NT-proBNP (-71%, P<0.001) and a significant correlation between changes in NT-proBNP and in LVEDVI (r=0.858, P<0.001). Baseline NT-proBNP correlated with changes in LVEDVI in both trained (r=0.673, P<0.001) and untrained (r=0.623, P<0.001) patients. Group C showed unfavourable LVEDVI dilation (+8%, P<0.001; T vs. C group, P<0.001) and a smaller reduction in NT-proBNP (-40%, P<0.001; T vs. C group, P<0.001). Six month ET induced a favourable LV remodelling and a marked fall in NT-proBNP that could predict LV remodelling in postinfarction patients with moderate LV dysfunction.

Krill oil attenuates left ventricular dilatation after myocardial infarction in rats.

PubMed

Fosshaug, Linn E; Berge, Rolf K; Beitnes, Jan O; Berge, Kjetil; Vik, Hogne; Aukrust, Pål; Gullestad, Lars; Vinge, Leif E; Øie, Erik

2011-12-29

In the western world, heart failure (HF) is one of the most important causes of cardiovascular mortality. Supplement with n-3 polyunsaturated fatty acids (PUFA) has been shown to improve cardiac function in HF and to decrease mortality after myocardial infarction (MI). The molecular structure and composition of n-3 PUFA varies between different marine sources and this may be of importance for their biological effects. Krill oil, unlike fish oil supplements, contains the major part of the n-3 PUFA in the form of phospholipids. This study investigated effects of krill oil on cardiac remodeling after experimental MI. Rats were randomised to pre-treatment with krill oil or control feed 14 days before induction of MI. Seven days post-MI, the rats were examined with echocardiography and rats in the control group were further randomised to continued control feed or krill oil feed for 7 weeks before re-examination with echocardiography and euthanization. The echocardiographic evaluation showed significant attenuation of LV dilatation in the group pretreated with krill oil compared to controls. Attenuated heart weight, lung weight, and levels of mRNA encoding classical markers of LV stress, matrix remodeling and inflammation reflected these findings. The total composition of fatty acids were examined in the left ventricular (LV) tissue and all rats treated with krill oil showed a significantly higher proportion of n-3 PUFA in the LV tissue, although no difference was seen between the two krill oil groups. Supplement with krill oil leads to a proportional increase of n-3 PUFA in myocardial tissue and supplement given before induction of MI attenuates LV remodeling.

The importance of capillary density-stroke work mismatch for right ventricular adaptation to chronic pressure overload.

PubMed

Noly, Pierre-Emmanuel; Haddad, François; Arthur-Ataam, Jennifer; Langer, Nathaniel; Dorfmüller, Peter; Loisel, Fanny; Guihaire, Julien; Decante, Benoit; Lamrani, Lilia; Fadel, Elie; Mercier, Olaf

2017-12-01

Mechanisms of right ventricular (RV) adaptation to chronic pressure overload are not well understood. We hypothesized that a lower capillary density (CD) to stroke work ratio would be associated with more fibrosis and RV maladaptive remodeling. We induced RV chronic pressure overload over a 20-week period in 2 piglet models of pulmonary hypertension; that is, a shunt model (n = 5) and a chronic thromboembolic pulmonary hypertension model (n = 5). We assessed hemodynamic parameters and RV remodeling as well as RV CD, fibrosis, and angiogenic factors expression. Although RV was similarly hypertrophied in both models, maladapted RV remodeling with impaired systolic function was only seen in chronic thromboembolic pulmonary hypertension group members who had lower CD (484 ± 99 vs 1213 ± 74 cap/mm 2 ; P < .01), lower CD to stroke work ratio (0.29 ± 0.07 vs 0.82 ± 0.16; P = .02), higher myocardial fibrosis (15.4% ± 3.8% vs 8.0% ± 2.5%; P < .01), as well as a higher angiogenic and fibrosis factors expression. The RV adaptive response to chronic pressure overload differs between 2 different piglet models of PH. Mismatch between angiogenesis and workload (CD to stroke work ratio) was associated with greater degree of myocardial fibrosis and RV dysfunction and could be a promising index of RV maladaptation. Further studies are needed to understand the underlying mechanisms. Copyright © 2017 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

Autoantibodies against β1 receptor and AT1 receptor in type 2 diabetes patients with left ventricular dilatation.

PubMed

Zhao, Linshuang; Xu, Chunyan; Xu, Jinling

2014-01-01

To explore the relationship between the autoantibodies against the β1 and AT1 receptors and left ventricular dilatation in patients with type 2 diabetes (T2DM). The autoantibodies against the β1 and angiotensin II type 1 (AT1) receptors of T2DM patients with and without hypertension were screened by ELISA. Multiple logistic regression was used to analyze the risk factors for left ventricular dilatation. The reversing effect of left ventricular dilatation was evaluated after receptor blocker treatment. The positive rates of autoantibodies against the β1 and AT1 receptors (43.0 and 44.1%, respectively) in T2DM patients with hypertension were significantly higher than those in normotensive patients (16.0 and 10.4%, respectively; all p < 0.01). Furthermore, among T2DM patients with hypertension, the positive rates (61.4 and 64.9%, respectively) in patients with left ventricular dilatation were remarkably higher than those with normal left ventricular dimensions (34.4 and 36.1%, respectively; all p < 0.01). The presence of β1 receptor antibody and AT1 receptor antibody were risk factors for left ventricular dilatation (p < 0.05). The curative effect of metoprolol tartrate and valsartan in reversing left ventricular hypertrophy in the group positive for autoantibodies was much better than in the negative group. The findings show that autoantibodies against the β1 and AT1 receptors may play a role in predicting left ventricular dilatation in T2DM patients in combination with hypertension. Metoprolol tartrate and valsartan are effective and safe in the treatment of these patients. © 2014 S. Karger AG, Basel.

Aldosterone is associated with left ventricular hypertrophy in hemodialysis patients.

PubMed

Feniman De Stefano, Greicy Mara Mengue; Zanati-Basan, Silméia Garcia; De Stefano, Laercio Martins; Silva, Viviana Rugolo Oliveira E; Xavier, Patrícia Santi; Barretti, Pasqual; da Silva Franco, Roberto Jorge; Caramori, Jacqueline Costa Teixeira; Martin, Luis Cuadrado

2016-10-01

Patients with chronic kidney disease present a higher degree of left ventricular hypertrophy than expected for hypertension levels. In chronic kidney disease the plot between the quotient extracellular water/total body water and aldosterone is shifted up and to the right. There are few studies that verified the role of aldosterone in cardiac remodeling in this set of patients. The aim of this study was to evaluate the relationship between serum aldosterone and left ventricular mass index in patients with chronic kidney disease on hemodialysis. The patients were submitted to clinical and laboratory evaluation, bioelectrical impedance, echocardiography and ambulatory blood pressure monitoring. The 27 patients included were divided into two groups according to aldosterone level and compared with each other. The group of patients with higher aldosterone levels had higher left ventricular mass index. These groups were heterogeneous with regard to ambulatory systolic blood pressure, body mass index, and aldosterone levels and homogeneous with regard to the quotient extracellular water/total body water, renin-angiotensin-aldosterone system blockers, beta blocker use and other clinical characteristics. The association between aldosterone levels and left ventricular mass index was adjusted to confounding variables by a multiple linear regression analysis in which aldosterone was independently associated with left ventricular mass index. The data presented are consistent with a pathogenic role of aldosterone in left ventricular hypertrophy in patients with chronic kidney dialysis in dialysis patients. ClinicalTrials.gov identifier: NCT01128101. © The Author(s), 2016.

Cardiac structure and function in the obese: a cardiovascular magnetic resonance imaging study.

PubMed

Danias, Peter G; Tritos, Nicholas A; Stuber, Matthias; Kissinger, Kraig V; Salton, Carol J; Manning, Warren J

2003-07-01

Obesity is a major health problem in the Western world. Among obese subjects cardiac pathology is common, but conventional noninvasive imaging modalities are often suboptimal for detailed evaluation of cardiac structure and function. We investigated whether cardiovascular magnetic resonance imaging (CMR) can better characterize possible cardiac abnormalities associated with obesity, in the absence of other confounding comorbidities. In this prospective cross-sectional study, CMR was used to quantify left and right ventricular volumes, ejection fraction, mass, cardiac output, and apical left ventricular rotation in 25 clinically healthy obese men and 25 age-matched lean controls. Obese subjects had higher left ventricular mass (203 +/- 38 g vs. 163 +/- 22 g, p < 0.001), end-diastolic volume (176 +/- 29 mL vs. 156 +/- 25 mL, p < 0.05), and cardiac output (8.2 +/- 1.2 L/min vs. 6.4 +/- 1.3 L/min, p < 0.001). The obese also had increased right ventricular mass (105 +/- 25 g vs. 87 +/- 18 g, p < 0.005) and end-diastolic volume (179 +/- 36 mL vs. 155 +/- 28 mL, p < 0.05). When indexed for height, differences in left and right ventricular mass, and left ventricular end-diastolic volume remained significant. Apical left ventricular rotation and rotational velocity patterns were also different between obese and lean subjects. Obesity is independently associated with remodeling of the heart. Cardiovascular magnetic resonance imaging identifies subtle cardiac abnormalities and may be the preferred imaging technique to evaluate cardiac structure and function in the obese.

Intra-renal delivery of mesenchymal stem cells attenuates myocardial injury after reversal of hypertension in porcine renovascular disease.

PubMed

Eirin, Alfonso; Zhu, Xiang-Yang; Ferguson, Christopher M; Riester, Scott M; van Wijnen, Andre J; Lerman, Amir; Lerman, Lilach O

2015-01-19

Percutaneous transluminal renal angioplasty (PTRA) fails to fully improve cardiac injury and dysfunction in patients with renovascular hypertension (RVH). Mesenchymal stem cells (MSCs) restore renal function, but their potential for attenuating cardiac injury after reversal of RVH has not been explored. We hypothesized that replenishment of MSCs during PTRA would improve cardiac function and oxygenation, and decrease myocardial injury in porcine RVH. Pigs were studied after 16 weeks of RVH, RVH treated 4 weeks earlier with PTRA with or without adjunct intra-renal delivery of MSC (10^6 cells), and controls. Cardiac structure, function (fast-computed tomography (CT)), and myocardial oxygenation (Blood-Oxygen-Level-Dependent- magnetic resonance imaging) were assessed in-vivo. Myocardial microvascular density (micro-CT) and myocardial injury were evaluated ex-vivo. Kidney venous and systemic blood levels of inflammatory markers were measured and their renal release calculated. PTRA normalized blood pressure, yet stenotic-kidney glomerular filtration rate, similarly blunted in RVH and RVH + PTRA, normalized only in PTRA + MSC-treated pigs. PTRA attenuated left ventricular remodeling, whereas myocardial oxygenation, subendocardial microvascular density, and diastolic function remained decreased in RVH + PTRA, but normalized in RVH + PTRA-MSC. Circulating isoprostane levels and renal release of inflammatory cytokines increased in RVH and RVH + PTRA, but normalized in RVH + PTRA-MSC, as did myocardial oxidative stress, inflammation, collagen deposition, and fibrosis. Intra-renal MSC delivery during PTRA preserved stenotic-kidney function, reduced systemic oxidative stress and inflammation, and thereby improved cardiac function, oxygenation, and myocardial injury four weeks after revascularization, suggesting a therapeutic potential for adjunctive MSC delivery to preserve cardiac function and structure after reversal of experimental RVH.

A slow-releasing form of prostacyclin agonist (ONO1301SR) enhances endogenous secretion of multiple cardiotherapeutic cytokines and improves cardiac function in a rapid-pacing-induced model of canine heart failure.

PubMed

Shirasaka, Tomonori; Miyagawa, Shigeru; Fukushima, Satsuki; Saito, Atsuhiro; Shiozaki, Motoko; Kawaguchi, Naomasa; Matsuura, Nariaki; Nakatani, Satoshi; Sakai, Yoshiki; Daimon, Takashi; Okita, Yutaka; Sawa, Yoshiki

2013-08-01

Cardiac functional deterioration in dilated cardiomyopathy (DCM) is known to be reversed by intramyocardial up-regulation of multiple cardioprotective factors, whereas a prostacyclin analog, ONO1301, has been shown to paracrinally activate interstitial cells to release a variety of protective factors. We here hypothesized that intramyocardial delivery of a slow-releasing form of ONO1301 (ONO1301SR) might activate regional myocardium to up-regulate cardiotherapeutic factors, leading to regional and global functional recovery in DCM. ONO1301 elevated messenger RNA and protein level of hepatocyte growth factor, vascular endothelial growth factor, and stromal-derived factor-1 of normal human dermal fibroblasts in a dose-dependent manner in vitro. Intramyocardial delivery of ONO1301SR, which is ONO1301 mixed with polylactic and glycolic acid polymer (PLGA), but not that of PLGA only, yielded significant global functional recovery in a canine rapid pacing-induced DCM model, assessed by echocardiography and cardiac catheterization (n = 5 each). Importantly, speckle-tracking echocardiography unveiled significant regional functional recovery in the ONO1301-delivered territory, consistent to significantly increased vascular density, reduced interstitial collagen accumulation, attenuated myocyte hypertrophy, and reversed mitochondrial structure in the corresponding area. Intramyocardial delivery of ONO1301SR, which is a PLGA-coated slow-releasing form of ONO1301, up-regulated multiple cardiotherapeutic factors in the injected territory, leading to region-specific reverse left ventricular remodeling and consequently a global functional recovery in a rapid-pacing-induced canine DCM model, warranting a further preclinical study to optimize this novel drug-delivery system to treat DCM. Copyright © 2013 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Prolongation of atrio-ventricular node conduction in a rabbit model of ischaemic cardiomyopathy: Role of fibrosis and connexin remodelling.

PubMed

Nisbet, Ashley M; Camelliti, Patrizia; Walker, Nicola L; Burton, Francis L; Cobbe, Stuart M; Kohl, Peter; Smith, Godfrey L

2016-05-01

Conduction abnormalities are frequently associated with cardiac disease, though the mechanisms underlying the commonly associated increases in PQ interval are not known. This study uses a chronic left ventricular (LV) apex myocardial infarction (MI) model in the rabbit to create significant left ventricular dysfunction (LVD) 8weeks post-MI. In vivo studies established that the PQ interval increases by approximately 7ms (10%) with no significant change in average heart rate. Optical mapping of isolated Langendorff perfused rabbit hearts recapitulated this result: time to earliest activation of the LV was increased by 14ms (16%) in the LVD group. Intra-atrial and LV transmural conduction times were not altered in the LVD group. Isolated AVN preparations from the LVD group demonstrated a significantly longer conduction time (by approximately 20ms) between atrial and His electrograms than sham controls across a range of pacing cycle lengths. This difference was accompanied by increased effective refractory period and Wenckebach cycle length, suggesting significantly altered AVN electrophysiology post-MI. The AVN origin of abnormality was further highlighted by optical mapping of the isolated AVN. Immunohistochemistry of AVN preparations revealed increased fibrosis and gap junction protein (connexin43 and 40) remodelling in the AVN of LVD animals compared to sham. A significant increase in myocyte-non-myocyte connexin co-localization was also observed after LVD. These changes may increase the electrotonic load experienced by AVN muscle cells and contribute to slowed conduction velocity within the AVN. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effect of Right Ventricular versus Biventricular Pacing on Electrical Remodeling in the Normal Heart

PubMed Central

Saba, Samir; Mehdi, Haider; Mathier, Michael A.; Islam, M. Zahadul; Salama, Guy; London, Barry

2010-01-01

Background Biventricular (BIV) pacing can improve cardiac function in heart failure by altering the mechanical and electrical substrates. We investigated the effect of BIV versus right ventricular (RV) pacing on the normal heart. Methods and Results Male New Zealand White rabbits (n=33) were divided into 3 groups: sham-operated (control), RV pacing, and BIV pacing groups. Four weeks after surgery, the native QT (p=0.004) interval was significantly shorter in the BIV group compared to the RV or sham-operated groups. Also, compared to rabbits in the RV group, rabbits in the BIV group had shorter RV ventricular effective refractory period (VERP) at all cycle lengths, and shorter LV paced QT interval during the drive train of stimuli and close to refractoriness (p<0.001 for all comparisons). Protein expression of the KVLQT1 was significantly increased in the BIV group compared to the RV and control groups, while protein expression of SCN5A and connexin43 was significantly decreased in the RV compared to the other study groups. Erg protein expression was significantly increased in both pacing groups compared to the controls. Conclusions In this rabbit model, we demonstrate a direct effect of BIV but not RV pacing on shortening the native QT interval as well as the paced QT interval during burst pacing and close to the VERP. These findings underscore the fact that the effect of BIV pacing is partially mediated through direct electrical remodeling and may have implications as to the effect of BIV pacing on arrhythmia incidence and burden. PMID:20042767

Dose-related ethanol intake, Cx43 and Nav1.5 remodeling: Exploring insights of altered ventricular conduction and QRS fragmentation in excessive alcohol users.

PubMed

Hung, Chung-Lieh; Lai, Yu-Jun; Chi, Po-Ching; Chen, Liang-Chia; Tseng, Ya-Ming; Kuo, Jen-Yuan; Lin, Cheng-I; Chen, Yao-Chang; Lin, Shing-Jong; Yeh, Hung-I

2018-01-01

Chronic, excessive ethanol intake has been linked with various electrical instabilities, conduction disturbances, and even sudden cardiac death, but the underlying cause for the latter is insufficiently delineated. We studied surface electrocardiography (ECG) in a community-dwelling cohort with moderate-to-heavy daily alcohol intake (grouped as >90g/day, ≤90g/day, and nonintake). Compared with nonintake, heavier alcohol users showed markedly widened QRS duration and higher prevalence of QRS fragmentation (64.3%, 50.9%, and 33.7%, respectively, χ 2 12.0, both p<0.05) on surface ECG across the 3 groups. These findings were successfully recapitulated in 14-week-old C57BL/6 mice that were chronically given a 4% or 6% alcohol diet and showed dose-related slower action potential upstroke, reduced resting membrane potential, and disorganized or decreased intraventricular conduction (all p<0.05). Immunodetection further revealed increased ventricular collagen I depots with Cx43 downregulation and remodeling, together with clustered and diminished membrane Nav1.5 distribution. Administration of Cx43 blocker (heptanol) and Nav1.5 inhibitor (tetrodotoxin) in the mice each attenuated the suppression ventricular conduction compared with nonintake mice (p<0.05). Chronic excessive alcohol ingestion is associated with dose-related phenotypic intraventricular conduction disturbances and QRS fragmentation that can be recapitulated in mice. The mechanisms may involve suppressed gap junction and sodium channel functions, together with enhanced cardiac fibrosis that may contribute to arrhythmogenesis. Copyright © 2017 Elsevier Ltd. All rights reserved.

The zebrafish as a novel animal model to study the molecular mechanisms of mechano-electrical feedback in the heart

PubMed Central

Werdich, Andreas A; Brzezinski, Anna; Jeyaraj, Darwin; Ficker, Eckhard; Wan, Xiaoping; McDermott, Brian M; Sabeh, M Khaled; MacRae, Calum A; Rosenbaum, David S

2013-01-01

Altered mechanical loading of the heart leads to hypertrophy, decompensated heart failure and fatal arrhythmias. However, the molecular mechanisms that link mechanical and electrical dysfunction remain poorly understood. Growing evidence suggest that ventricular electrical remodeling (VER) is a process that can be induced by altered mechanical stress, creating persistent electrophysiological changes that predispose the heart to life-threatening arrhythmias. While VER is clearly a physiological property of the human heart, as evidenced by “T wave memory”, it is also thought to occur in a variety of pathological states associated with altered ventricular activation such as bundle branch block, myocardial infarction, and cardiac pacing. Animal models that are currently being used for investigating stretch-induced VER have significant limitations. The zebrafish has recently emerged as an attractive animal model for studying cardiovascular disease and could overcome some of these limitations. Owing to its extensively sequenced genome, high conservation of gene function, and the comprehensive genetic resources that are available in this model, the zebrafish may provide new insights into the molecular mechanisms that drive detrimental electrical remodeling in response to stretch. Here, we have established a zebrafish model to study mechano-electrical feedback in the heart, which combines efficient genetic manipulation with high-precision stretch and high-resolution electrophysiology. In this model, only ninety minutes of ventricular stretch caused VER and recapitulated key features of VER found previously in the mammalian heart. Our data suggest that the zebrafish model is a powerful platform for investigating the molecular mechanisms underlying mechano-electrical feedback and VER in the heart. PMID:22835662

Zinc Levels in Left Ventricular Hypertrophy.

PubMed

Huang, Lei; Teng, Tianming; Bian, Bo; Yao, Wei; Yu, Xuefang; Wang, Zhuoqun; Xu, Zhelong; Sun, Yuemin

2017-03-01

Zinc is one of the most important trace elements in the body and zinc homeostasis plays a critical role in maintaining cellular structure and function. Zinc dyshomeostasis can lead to many diseases, such as cardiovascular disease. Our aim was to investigate whether there is a relationship between zinc and left ventricular hypertrophy (LVH). A total of 519 patients was enrolled and their serum zinc levels were measured in this study. We performed analyses on the relationship between zinc levels and LVH and the four LV geometry pattern patients: normal LV geometry, concentric remodeling, eccentric LVH, and concentric LVH. We performed further linear and multiple regression analyses to confirm the relationship between zinc and left ventricular mass (LVM), left ventricular mass index (LVMI), and relative wall thickness (RWT). Our data showed that zinc levels were 710.2 ± 243.0 μg/L in the control group and were 641.9 ± 215.2 μg/L in LVH patients. We observed that zinc levels were 715 ± 243.5 μg/L, 694.2 ± 242.7 μg/L, 643.7 ± 225.0 μg/L, and 638.7 ± 197.0 μg/L in normal LV geometry, concentric remodeling, eccentric LVH, and concentric LVH patients, respectively. We further found that there was a significant inverse linear relationship between zinc and LVM (p = 0.001) and LVMI (p = 0.000) but did not show a significant relationship with RWT (p = 0.561). Multiple regression analyses confirmed that the linear relationship between zinc and LVM and LVMI remained inversely significant. The present study revealed that serum zinc levels were significantly decreased in the LVH patients, especially in the eccentric LVH and concentric LVH patients. Furthermore, zinc levels were significantly inversely correlated with LVM and LVMI.

Hibernating myocardium, morphological studies on intraoperatory myocardial biopsies and on chronic ischemia experimental model.

PubMed

Laky, D; Parascan, Liliana

2007-01-01

Hibernating myocardium represent a prolonged but potentially reversible myocardial contractile dysfunction, an incomplete adaptation caused by chronic myocardial ischemia and persisting at least until blood flow restored. The purpose of this study was to investigate the morphological changes and weather relations exist among function, metabolism and structure in left ventricular hibernating myocardium. Material and methods. Experimental study is making on 12 dogs incomplete coronary obstruction during six weeks for morphologic studies of ischemic zones. On 48 patients with coronary stenosis myocardial biopsies was effectuated during aorto-coronarian bypass graft. On 60 patients with valvular disease associated with segmental coronary atherosclerotic obstructions during surgical interventions on a effectuated repeatedly biopsies from ischemic zones. Dyskinetic ischemic areas was identified by angiography, scintigraphy, low dose dobutamine echography to identify the cells viability. On myocardial biopsies various histological, histoenzymological, immunohistochemical and ultrastructural methods were performed. The morphological cardiomyocytic changes can summarized: loss of myofilaments, accumulation of glycogen, small mitochondria with reversible lesions, decrease of smooth reticulum, absence of T tubules, depression of titin in puncted pattern, loss of cardiotonin, disorganization of cytoskeleton, dispersed nuclear heterochromatin, embryofetal dedifferentiation, and persistence of viability. Extracellular matrix is enlarged with early matrix protein such fibronectin, tenascin, fibroblasts. In experimental material the morphological changes present similarities with the human biopsies, but intermixed with postinfarction scar tissue. Redifferentiation of hibernanting cells end remodeling of extracellular matrix is possible after quigle revascularization through aorto-coronary bypass grafts.

Atrial Fibrillation: Mechanisms, Therapeutics, and Future Directions

PubMed Central

Pellman, Jason; Sheikh, Farah

2017-01-01

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia, affecting 1% to 2% of the general population. It is characterized by rapid and disorganized atrial activation leading to impaired atrial function, which can be diagnosed on an EKG by lack of a P-wave and irregular QRS complexes. AF is associated with increased morbidity and mortality and is a risk factor for embolic stroke and worsening heart failure. Current research on AF support and explore the hypothesis that initiation and maintenance of AF require pathophysiological remodeling of the atria, either specifically as in lone AF or secondary to other heart disease as in heart failure-associated AF. Remodeling in AF can be grouped into three categories that include: (i) electrical remodeling, which includes modulation of L-type Ca2+ current, various K+ currents and gap junction function; (ii) structural remodeling, which includes changes in tissues properties, size, and ultrastructure; and (iii) autonomic remodeling, including altered sympathovagal activity and hyperinnervation. Electrical, structural, and autonomic remodeling all contribute to creating an AF-prone substrate which is able to produce AF-associated electrical phenomena including a rapidly firing focus, complex multiple reentrant circuit or rotors. Although various remodeling events occur in AF, current AF therapies focus on ventricular rate and rhythm control strategies using pharmacotherapy and surgical interventions. Recent progress in the field has started to focus on the underlying substrate that drives and maintains AF (termed upstream therapies); however, much work is needed in this area. Here, we review current knowledge of AF mechanisms, therapies, and new areas of investigation. PMID:25880508

Evaluation of structural remodeling of the atria with OCT in a chronic rat model of myocardial infarction (Conference Presentation)

NASA Astrophysics Data System (ADS)

Eberle, Melissa M.; Thorn, Stephanie; Young, Lawerence; Pfau, Daniel; Madwed, Jeffrey; Small, Kersten; Kilmas, Michael; Choma, Michael A.; Sinusas, Albert J.

2017-02-01

Atrial fibrillation (AF) occurs following myocardial infarction (MI) and is associated with left ventricular dysfunction, which promotes the development of atrial remodeling and permanent atrial fibrosis. The purpose of this study was determining the effects of MI on left atrial (LA) remodeling with and without therapy with an angiotensin converting enzyme inhibition (ACEi) utilizing optical coherence tomography (OCT). As the composition of the myocardial tissue changes during LA remodeling the optical attenuation of the light will also change providing a metric to quantify the structural remodeling process. Lewis rats (240-275 g) underwent either surgical ligation of left coronary artery creating chronic MI, or SHAM surgery. 13 weeks post-surgery, ex vivo OCT imaging was performed of the LA appendage. Depth-resolved, attenuation coefficient volumes were calculated and the resulting atrial wall attenuation values were analyzed for four experimental groups: SHAM, SHAM with ACEi, MI no ACEi, and MI with ACEi. Quantification of tissue attenuation was performed and shown to significantly increase with MI in association with increases in collagen as verified with corresponding histological sectioning. Fractal analysis of the LA wall trabeculation patterns, 100 µm below the surface, was performed to quantify wall thickening associated with LA remodeling. A significant increase in fractal dimension was determined post MI compared to SHAM corresponding to a loss of the trabeculation pattern and wall thickening. The results from this study demonstrate OCT as an imaging technique capable of investigate LA remodeling with high resolution and label-free optical contrast processing.

Association between peak neutrophil count, clopidogrel loading dose, and left ventricular systolic function in patients with primary percutaneous coronary intervention.

PubMed

Wang, Xinyu; Yu, Haiyi; Li, Zhaoping; Li, Liuning; Zhang, Youyi; Gao, Wei

2014-01-01

Inflammation plays an important role in plaque development and left ventricular remodeling during acute myocardial infarction (AMI). Clopidogrel may exhibit some anti-inflammatory properties and high loading dose of clopidogrel results in improved clinical outcomes in patients with AMI. 357 patients who received successful primary percutaneous coronary intervention from January 2008 to March 2011 in Peking University Third Hospital were included in this study. Different loading dose of clopidogrel (300 mg, 450 mg, or 600 mg) was given at the discretion of the clinician. Neutrophils reached their peak values on the first day after AMI. Higher levels of peak neutrophil and lower left ventricular ejection fraction (LVEF) were found in patients of low clopidogrel loading dose group (300 mg or 450 mg). After adjusting for the related confounders, a logistic regression model showed that low clopidogrel loading dose remained an independent predictor of low LVEF (LVEF ≤ 50%) [OR: 1.97, 95% CI: 1.03-3.79, P = 0.04]. Low clopidogrel loading dose was associated with higher peak neutrophil count and poor left ventricular systolic function, suggesting an important role of clopidogrel loading dose in the improvement of left ventricular function and high loading dose may exhibit better anti-inflammatory properties.

Effects of renal denervation on cardiac oxidative stress and local activity of the sympathetic nervous system and renin-angiotensin system in acute myocardial infracted dogs.

PubMed

Feng, Qiaoli; Lu, Chengzhi; Wang, Li; Song, Lijun; Li, Chao; Uppada, Ravi Chandra

2017-02-17

This study sought to evaluate the therapeutic effects of renal denervation (RDN) on acute myocardial infarction (MI) in canines and explore its possible mechanisms of action. Eighteen healthy mongrel dogs were randomly assigned to either the control group, the MI group or the MI + RDN group. To assess cardiac function, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and fraction shortening (FS) were recorded. Additionally, haemodynamic parameters such as left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP) and heart rate (HR) were measured. Cardiac oxidative stress levels were evaluated based on the expression of p47 phox mRNA, malondialdehyde (MDA), anti-superoxide anion free radical (ASAFR) and activity of superoxide dismutase (SOD). To measure the local activity of the sympathetic nervous system (SNS) and renin-angiotensin system (RAS), the levels of tyrosine hydroxylase (TH), angiotensin II (AngII), angiotensin-converting enzyme 2 (ACE2), angiotensin (1-7) [Ang(1-7)] and Mas receptor (MasR) in myocardial tissues were recorded. The expression of TH in renal tissue and serum creatinine were used to assess the effectiveness of the RDN procedure and renal function, respectively. We found that MI deteriorated heart function and activated cardiac oxidative stress and the local neurohumoral system, while RDN partially reversed these changes. Compared with the control group, parameters including LVEDD, LVESD, LVEDP and the levels of ASAFR, MDA, p47 phox ,ACE2, Ang(1-7), MasR, AngII and TH-positive nerves were increased (all P < 0.05) in myocardial infracted dogs; meanwhile, LVEF, FS, LVSP and SOD expression were decreased (all P < 0.05). However, after RDN therapy, these changes were significantly improved (P < 0.05), except that there were no significant differences observed in FS or LVSP between the two groups (P = 0.092 and 0.931, respectively). Importantly, the expression of TH, AngII and Ang(1-7) was positively correlated with MDA and negatively correlated with SOD. Between-group comparisons demonstrated no differences in serum creatinine (P = 0.706). RDN attenuated cardiac remodelling and improved heart function by decreasing the level of cardiac oxidative stress and the local activity of the SNS and RAS in cardiac tissues. Additionally, the safety of the RDN procedure was established, as no significant decrease in LVSP or rise in serum creatinine was observed in our study.

Pay attention to cardiac remodeling in cancer cachexia.

PubMed

Zheng, Yawen; Chen, Han; Li, Xiaoqing; Sun, Yuping

2016-07-01

Cancer cachexia is a complex and multifaceted disease state characterized by fatigue, weakness, and loss of skeletal muscle and adipose tissue. Recently, the profound negative effects of cancer cachexia on cardiac tissue draw much attention, which is likely to contribute to mortality in tumor-bearing animals. The mechanism of cardiac remodeling is not so clear and involved with a series of molecular alterations. In cancer cachexia model, progressive loss of left ventricular mass and decrease in myocardial function is observed and cardiac autonomic functions are altered. Levels of several emerging cardiovascular neurohormones are found elevating in patients with cancer, but it is still controversial whether the changes could reflect the heart injury accurately. The remedy for cardiac remodeling has been explored. It is showed that exercise can modulate signaling pathways activated by wasting cytokines and impact on the resulting outcomes on heart adaptation. Some drugs, such as bisoprolol, spironolactone, perindopril, tandospirone, and simvastatin, can mitigate adverse effects of the tumor on the heart and prolong survival.

Cardiac damage in athlete's heart: When the "supernormal" heart fails!

PubMed

Carbone, Andreina; D'Andrea, Antonello; Riegler, Lucia; Scarafile, Raffaella; Pezzullo, Enrica; Martone, Francesca; America, Raffaella; Liccardo, Biagio; Galderisi, Maurizio; Bossone, Eduardo; Calabrò, Raffaele

2017-06-26

Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete's blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete's heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded.

Childhood obesity and cardiac remodeling: from cardiac structure to myocardial mechanics.

PubMed

Tadic, Marijana; Cuspidi, Cesare

2015-08-01

Epidemic of obesity, especially morbid obesity, among children and adolescents, is a key factor associated with the dramatic increase in prevalence of type 2 diabetes mellitus, arterial hypertension, and metabolic syndrome in this population. Furthermore, childhood obesity represents a very important predictor of obesity in adulthood that is related to cardiovascular and cerebrovascular diseases. Overweight and obesity in children and adolescents are associated with impairment of cardiac structure and function. The majority of studies investigated the influence of obesity on left ventricular remodeling. However, the impact of obesity on the right ventricle, both the atria, and myocardial mechanics has been insufficiently studied. The aim of this review article is to summarize all data about heart remodeling in childhood, from cardiac size, throughout systolic and diastolic function, to myocardial mechanics, using a wide range of mainly echocardiographic techniques and parameters. Additionally, we sought to present current knowledge about the influence of weight loss, achieved by various therapeutic approaches, on the improvement of cardiac geometry, structure, and function in obese children and adolescents.

Cardiac damage in athlete’s heart: When the “supernormal” heart fails!

PubMed Central

Carbone, Andreina; D’Andrea, Antonello; Riegler, Lucia; Scarafile, Raffaella; Pezzullo, Enrica; Martone, Francesca; America, Raffaella; Liccardo, Biagio; Galderisi, Maurizio; Bossone, Eduardo; Calabrò, Raffaele

2017-01-01

Intense exercise may cause heart remodeling to compensate increases in blood pressure or volume by increasing muscle mass. Cardiac changes do not involve only the left ventricle, but all heart chambers. Physiological cardiac modeling in athletes is associated with normal or enhanced cardiac function, but recent studies have documented decrements in left ventricular function during intense exercise and the release of cardiac markers of necrosis in athlete’s blood of uncertain significance. Furthermore, cardiac remodeling may predispose athletes to heart disease and result in electrical remodeling, responsible for arrhythmias. Athlete’s heart is a physiological condition and does not require a specific treatment. In some conditions, it is important to differentiate the physiological adaptations from pathological conditions, such as hypertrophic cardiomyopathy, arrhythmogenic dysplasia of the right ventricle, and non-compaction myocardium, for the greater risk of sudden cardiac death of these conditions. Moreover, some drugs and performance-enhancing drugs can cause structural alterations and arrhythmias, therefore, their use should be excluded. PMID:28706583

Losartan attenuates vascular remodeling of the aorta in spontaneously hypertensive rats and the underlying mechanism.

PubMed

Li, Fangxiong; Shi, Ruizheng; Liao, Meichun; Li, Jianzhe; Li, Shixun; Pan, Wei; Yang, Tianlun; Zhang, Guogang

2010-08-01

To determine the effect of losartan on vascular remodeling and the underlying mechanism in spontaneously hypertensive rats(SHR). SHR of 12 weeks old were given losartan orally [0, 15, 30 mg/(kg.d), n=12]. The tail arterial pressure was measured every week. Eight weeks later, the pathological changes and p22(phox) expression in the thoracic aorta, the activity of catalase (CAT), the contents of H(2)O(2) and Ang II in the plasma were evaluated. Blood pressure was increased in the SHR accompanied by the thickened wall and increased p22(phox) expression in the thoracic aorta. The plasma levels of H(2)O(2) and Ang II were elevated while the CAT level was decreased in the SHR. Administration of losartan reversed the thickened wall and increased the CAT activity concomitantly with the decreased plasma levels of H(2)O(2) and p22(phox) expression in the SHR. The plasma level of Ang II increased after the losartan treatment. Oxidative stress induces the vascular remodeling of the aorta in the SHR. Losartan can reverse the vascular remodeling through down-regulating p22(phox) expression and inhibiting the oxidative stress.

Perivascular Delivery of Notch 1 siRNA Inhibits Injury-Induced Arterial Remodeling

PubMed Central

Redmond, Eileen M.; Liu, Weimin; Hamm, Katie; Hatch, Ekaterina; Cahill, Paul A.; Morrow, David

2014-01-01

Objectives To determine the efficacy of perivascular delivery of Notch 1 siRNA in preventing injury-induced arterial remodeling. Methods and Results Carotid artery ligation was performed to induce arterial remodeling. After 14 days, morphometric analysis confirmed increased vSMC growth and subsequent media thickening and neointimal formation. Laser capture microdissection, quantitative qRT-PCR and immunoblot analysis of medial tissue revealed a significant increase in Notch1 receptor and notch target gene, Hrt 1 and 2 expression in the injured vessels. Perivascular delivery of Notch 1 siRNA by pluronic gel inhibited the injury-induced increase in Notch 1 receptor and target gene expression when compared to scrambled siRNA controls while concomitantly reducing media thickening and neointimal formation to pre-injury, sham-operated levels. Selective Notch 1 knockdown also reversed the injury-induced inhibition of pro-apoptotic Bax expression while decreasing injury-induced anti-apoptotic Bcl-XL expression to sham-operated control levels. In parallel experiments, proliferative cyclin levels, as measured by PCNA expression, were reversed to sham-operated control levels following selective Notch 1 knockdown. Conclusion These results suggest that injury-induced arterial remodeling can be successfully inhibited by localized perivascular delivery of Notch 1 siRNA. PMID:24416200

Replication fork reversal triggers fork degradation in BRCA2-defective cells.

PubMed

Mijic, Sofija; Zellweger, Ralph; Chappidi, Nagaraja; Berti, Matteo; Jacobs, Kurt; Mutreja, Karun; Ursich, Sebastian; Ray Chaudhuri, Arnab; Nussenzweig, Andre; Janscak, Pavel; Lopes, Massimo

2017-10-16

Besides its role in homologous recombination, the tumor suppressor BRCA2 protects stalled replication forks from nucleolytic degradation. Defective fork stability contributes to chemotherapeutic sensitivity of BRCA2-defective tumors by yet-elusive mechanisms. Using DNA fiber spreading and direct visualization of replication intermediates, we report that reversed replication forks are entry points for fork degradation in BRCA2-defective cells. Besides MRE11 and PTIP, we show that RAD52 promotes stalled fork degradation and chromosomal breakage in BRCA2-defective cells. Inactivation of these factors restores reversed fork frequency and chromosome integrity in BRCA2-defective cells. Conversely, impairing fork reversal prevents fork degradation, but increases chromosomal breakage, uncoupling fork protection, and chromosome stability. We propose that BRCA2 is dispensable for RAD51-mediated fork reversal, but assembles stable RAD51 nucleofilaments on regressed arms, to protect them from degradation. Our data uncover the physiopathological relevance of fork reversal and illuminate a complex interplay of homologous recombination factors in fork remodeling and stability.BRCA2 is involved in both homologous recombination (HR) and the protection of stalled replication forks from degradation. Here the authors reveal how HR factors cooperate in fork remodeling, showing that BRCA2 supports RAD51 loading on the regressed arms of reversed replication forks to protect them from degradation.

Autonomic nervous system involvement in pulmonary arterial hypertension.

PubMed

Vaillancourt, Mylène; Chia, Pamela; Sarji, Shervin; Nguyen, Jason; Hoftman, Nir; Ruffenach, Gregoire; Eghbali, Mansoureh; Mahajan, Aman; Umar, Soban

2017-12-04

Pulmonary arterial hypertension (PAH) is a chronic pulmonary vascular disease characterized by increased pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Autonomic nervous system involvement in the pathogenesis of PAH has been demonstrated several years ago, however the extent of this involvement is not fully understood. PAH is associated with increased sympathetic nervous system (SNS) activation, decreased heart rate variability, and presence of cardiac arrhythmias. There is also evidence for increased renin-angiotensin-aldosterone system (RAAS) activation in PAH patients associated with clinical worsening. Reduction of neurohormonal activation could be an effective therapeutic strategy for PAH. Although therapies targeting adrenergic receptors or RAAS signaling pathways have been shown to reverse cardiac remodeling and improve outcomes in experimental pulmonary hypertension (PH)-models, the effectiveness and safety of such treatments in clinical settings have been uncertain. Recently, novel direct methods such as cervical ganglion block, pulmonary artery denervation (PADN), and renal denervation have been employed to attenuate SNS activation in PAH. In this review, we intend to summarize the multiple aspects of autonomic nervous system involvement in PAH and overview the different pharmacological and invasive strategies used to target autonomic nervous system for the treatment of PAH.

Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: possible involvement of angiotensin-converting enzyme-2.

PubMed

Han, Su-Xia; He, Guang-Ming; Wang, Tao; Chen, Lei; Ning, Yun-Ye; Luo, Feng; An, Jin; Yang, Ting; Dong, Jia-Jia; Liao, Zeng-Lin; Xu, Dan; Wen, Fu-Qiang

2010-05-15

Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along with increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.

Dominant frequency increase rate predicts transition from paroxysmal to long-term persistent atrial fibrillation.

PubMed

Martins, Raphael P; Kaur, Kuljeet; Hwang, Elliot; Ramirez, Rafael J; Willis, B Cicero; Filgueiras-Rama, David; Ennis, Steven R; Takemoto, Yoshio; Ponce-Balbuena, Daniela; Zarzoso, Manuel; O'Connell, Ryan P; Musa, Hassan; Guerrero-Serna, Guadalupe; Avula, Uma Mahesh R; Swartz, Michael F; Bhushal, Sandesh; Deo, Makarand; Pandit, Sandeep V; Berenfeld, Omer; Jalife, José

2014-04-08

Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (CaV1.2, NaV1.5, and KV4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up. In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.

Losartan attenuates chronic cigarette smoke exposure-induced pulmonary arterial hypertension in rats: Possible involvement of angiotensin-converting enzyme-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Han Suxia; He Guangming; Wang Tao

Chronic cigarette smoking induces pulmonary arterial hypertension (PAH) by largely unknown mechanisms. Renin-angiotensin system (RAS) is known to function in the development of PAH. Losartan, a specific angiotensin II receptor antagonist, is a well-known antihypertensive drug with a potential role in regulating angiotensin-converting enzyme-2 (ACE2), a recently found regulator of RAS. To determine the effect of losartan on smoke-induced PAH and its possible mechanism, rats were daily exposed to cigarette smoke for 6 months in the absence and in the presence of losartan. Elevated right ventricular systolic pressure (RVSP), thickened wall of pulmonary arteries with apparent medial hypertrophy along withmore » increased angiotensin II (Ang II) and decreased ACE2 levels were observed in smoke-exposed-only rats. Losartan administration ameliorated pulmonary vascular remodeling, inhibited the smoke-induced RVSP and Ang II elevation and partially reversed the ACE2 decrease in rat lungs. In cultured primary pulmonary artery smooth muscle cells (PASMCs) from 3- and 6-month smoke-exposed rats, ACE2 levels were significantly lower than in those from the control rats. Moreover, PASMCs from 6-month exposed rats proliferated more rapidly than those from 3-month exposed or control rats, and cells grew even more rapidly in the presence of DX600, an ACE2 inhibitor. Consistent with the in vivo study, in vitro losartan pretreatment also inhibited cigarette smoke extract (CSE)-induced cell proliferation and ACE2 reduction in rat PASMCs. The results suggest that losartan may be therapeutically useful in the chronic smoking-induced pulmonary vascular remodeling and PAH and ACE2 may be involved as part of its mechanism. Our study might provide insight into the development of new therapeutic interventions for PAH smokers.« less

Direct implantation versus platelet-rich fibrin-embedded adipose-derived mesenchymal stem cells in treating rat acute myocardial infarction.

PubMed

Sun, Cheuk-Kwan; Zhen, Yen-Yi; Leu, Steve; Tsai, Tzu-Hsien; Chang, Li-Teh; Sheu, Jiunn-Jye; Chen, Yung-Lung; Chua, Sarah; Chai, Han-Tan; Lu, Hung-I; Chang, Hsueh-Wen; Lee, Fan-Yen; Yip, Hon-Kan

2014-05-15

This study tested whether adipose-derived mesenchymal stem cells (ADMSC) embedded in platelet-rich fibrin (PRF) scaffold is superior to direct ADMSC implantation in improving left ventricular (LV) performance and reducing LV remodeling in a rat acute myocardial infarction (AMI) model of left anterior descending coronary artery (LAD) ligation. Twenty-eight male adult Sprague Dawley rats equally divided into group 1 [sham control], group 2 (AMI only), group 3 (AMI+direct ADMSC implantation), and group 4 (AMI+PRF-embedded autologous ADMSC) were sacrificed on day 42 after AMI. LV systolic and diastolic dimensions and volumes, and infarct/fibrotic areas were highest in group 2, lowest in group 1 and significantly higher in group 3 than in group 4, whereas LV performance and LV fractional shortening exhibited a reversed pattern (p<0.005). Protein expressions of inflammation (oxidative stress, IL-1β, MMP-9), apoptosis (mitochondrial Bax, cleaved PARP), fibrosis (Smad3, TGF-β), and pressure-overload biomarkers (BNP, MHC-β) displayed a pattern similar to that of LV dimensions, whereas anti-inflammatory (IL-10), anti-apoptotic (Bcl-2), and anti-fibrotic (Smad1/5, BMP-2) indices showed a pattern similar to that of LV performance among the four groups (all p<0.05). Angiogenesis biomarkers at protein (CXCR4, SDF-1α, VEGF), cellular (CD31+, CXCR4+, SDF-1α+), and immunohistochemical (small vessels) levels, and cardiac stem cell markers (C-kit+, Sca-1+) in infarct myocardium were highest in group 4, lowest in group 1, and significantly higher in group 3 than in group 2 (all p<0.005). PRF-embedded ADMSC is superior to direct ADMSC implantation in preserving LV function and attenuating LV remodeling. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Endothelial deletion of Ino80 disrupts coronary angiogenesis and causes congenital heart disease.

PubMed

Rhee, Siyeon; Chung, Jae I; King, Devin A; D'amato, Gaetano; Paik, David T; Duan, Anna; Chang, Andrew; Nagelberg, Danielle; Sharma, Bikram; Jeong, Youngtae; Diehn, Maximilian; Wu, Joseph C; Morrison, Ashby J; Red-Horse, Kristy

2018-01-25

During development, the formation of a mature, well-functioning heart requires transformation of the ventricular wall from a loose trabecular network into a dense compact myocardium at mid-gestation. Failure to compact is associated in humans with congenital diseases such as left ventricular non-compaction (LVNC). The mechanisms regulating myocardial compaction are however still poorly understood. Here, we show that deletion of the Ino80 chromatin remodeler in vascular endothelial cells prevents ventricular compaction in the developing mouse heart. This correlates with defective coronary vascularization, and specific deletion of Ino80 in the two major coronary progenitor tissues-sinus venosus and endocardium-causes intermediate phenotypes. In vitro, endothelial cells promote myocardial expansion independently of blood flow in an Ino80-dependent manner. Ino80 deletion increases the expression of E2F-activated genes and endothelial cell S-phase occupancy. Thus, Ino80 is essential for coronary angiogenesis and allows coronary vessels to support proper compaction of the heart wall.

EVALUATION OF RIGHT AND LEFT VENTRICULAR DIASTOLIC FILLING

PubMed Central

Pasipoularides, Ares

2013-01-01

A conceptual fluid-dynamics framework for diastolic filling is developed. The convective deceleration load (CDL) is identified as an important determinant of ventricular inflow during the E-wave (A-wave) upstroke. Convective deceleration occurs as blood moves from the inflow anulus through larger-area cross-sections toward the expanding walls. Chamber dilatation underlies previously unrecognized alterations in intraventricular flow dynamics. The larger the chamber, the larger become the endocardial surface and the CDL. CDL magnitude affects strongly the attainable E-wave (A-wave) peak. This underlies the concept of diastolic ventriculoannular disproportion. Large vortices, whose strength decreases with chamber dilatation, ensue after the E-wave peak and impound inflow kinetic energy, averting an inflow-impeding, convective Bernoulli pressure-rise. This reduces the CDL by a variable extent depending on vortical intensity. Accordingly, the filling vortex facilitates filling to varying degrees, depending on chamber volume. The new framework provides stimulus for functional genomics research, aimed at new insights into ventricular remodeling. PMID:23585308

Timing of myocardial trpm7 deletion during cardiogenesis variably disrupts adult ventricular function, conduction, and repolarization.

PubMed

Sah, Rajan; Mesirca, Pietro; Mason, Xenos; Gibson, William; Bates-Withers, Christopher; Van den Boogert, Marjolein; Chaudhuri, Dipayan; Pu, William T; Mangoni, Matteo E; Clapham, David E

2013-07-09

Transient receptor potential (TRP) channels are a superfamily of broadly expressed ion channels with diverse physiological roles. TRPC1, TRPC3, and TRPC6 are believed to contribute to cardiac hypertrophy in mouse models. Human mutations in TRPM4 have been linked to progressive familial heart block. TRPM7 is a divalent-permeant channel and kinase of unknown function, recently implicated in the pathogenesis of atrial fibrillation; however, its function in ventricular myocardium remains unexplored. We generated multiple cardiac-targeted knockout mice to test the hypothesis that TRPM7 is required for normal ventricular function. Early cardiac Trpm7 deletion (before embryonic day 9; TnT/Isl1-Cre) results in congestive heart failure and death by embryonic day 11.5 as a result of hypoproliferation of the compact myocardium. Remarkably, Trpm7 deletion late in cardiogenesis (about embryonic day 13; αMHC-Cre) produces viable mice with normal adult ventricular size, function, and myocardial transcriptional profile. Trpm7 deletion at an intermediate time point results in 50% of mice developing cardiomyopathy associated with heart block, impaired repolarization, and ventricular arrhythmias. Microarray analysis reveals elevations in transcripts of hypertrophy/remodeling genes and reductions in genes important for suppressing hypertrophy (Hdac9) and for ventricular repolarization (Kcnd2) and conduction (Hcn4). These transcriptional changes are accompanied by action potential prolongation and reductions in transient outward current (Ito; Kcnd2). Similarly, the pacemaker current (If; Hcn4) is suppressed in atrioventricular nodal cells, accounting for the observed heart block. Trpm7 is dispensable in adult ventricular myocardium under basal conditions but is critical for myocardial proliferation during early cardiogenesis. Loss of Trpm7 at an intermediate developmental time point alters the myocardial transcriptional profile in adulthood, impairing ventricular function, conduction, and repolarization.

High- and moderate-intensity training normalizes ventricular function and mechanoenergetics in mice with diet-induced obesity.

PubMed

Hafstad, Anne D; Lund, Jim; Hadler-Olsen, Elin; Höper, Anje C; Larsen, Terje S; Aasum, Ellen

2013-07-01

Although exercise reduces several cardiovascular risk factors associated with obesity/diabetes, the metabolic effects of exercise on the heart are not well-known. This study was designed to investigate whether high-intensity interval training (HIT) is superior to moderate-intensity training (MIT) in counteracting obesity-induced impairment of left ventricular (LV) mechanoenergetics and function. C57BL/6J mice with diet-induced obesity (DIO mice) displaying a cardiac phenotype with altered substrate utilization and impaired mechanoenergetics were subjected to a sedentary lifestyle or 8-10 weeks of isocaloric HIT or MIT. Although both modes of exercise equally improved aerobic capacity and reduced obesity, only HIT improved glucose tolerance. Hearts from sedentary DIO mice developed concentric LV remodeling with diastolic and systolic dysfunction, which was prevented by both HIT and MIT. Both modes of exercise also normalized LV mechanical efficiency and mechanoenergetics. These changes were associated with altered myocardial substrate utilization and improved mitochondrial capacity and efficiency, as well as reduced oxidative stress, fibrosis, and intracellular matrix metalloproteinase 2 content. As both modes of exercise equally ameliorated the development of diabetic cardiomyopathy by preventing LV remodeling and mechanoenergetic impairment, this study advocates the therapeutic potential of physical activity in obesity-related cardiac disorders.

High- and Moderate-Intensity Training Normalizes Ventricular Function and Mechanoenergetics in Mice With Diet-Induced Obesity

PubMed Central

Hafstad, Anne D.; Lund, Jim; Hadler-Olsen, Elin; Höper, Anje C.; Larsen, Terje S.; Aasum, Ellen

2013-01-01

Although exercise reduces several cardiovascular risk factors associated with obesity/diabetes, the metabolic effects of exercise on the heart are not well-known. This study was designed to investigate whether high-intensity interval training (HIT) is superior to moderate-intensity training (MIT) in counteracting obesity-induced impairment of left ventricular (LV) mechanoenergetics and function. C57BL/6J mice with diet-induced obesity (DIO mice) displaying a cardiac phenotype with altered substrate utilization and impaired mechanoenergetics were subjected to a sedentary lifestyle or 8–10 weeks of isocaloric HIT or MIT. Although both modes of exercise equally improved aerobic capacity and reduced obesity, only HIT improved glucose tolerance. Hearts from sedentary DIO mice developed concentric LV remodeling with diastolic and systolic dysfunction, which was prevented by both HIT and MIT. Both modes of exercise also normalized LV mechanical efficiency and mechanoenergetics. These changes were associated with altered myocardial substrate utilization and improved mitochondrial capacity and efficiency, as well as reduced oxidative stress, fibrosis, and intracellular matrix metalloproteinase 2 content. As both modes of exercise equally ameliorated the development of diabetic cardiomyopathy by preventing LV remodeling and mechanoenergetic impairment, this study advocates the therapeutic potential of physical activity in obesity-related cardiac disorders. PMID:23493573

Left ventricular geometry in children and adolescents with primary hypertension

PubMed Central

Richey, Phyllis A.; DiSessa, Thomas G.; Somes, Grant W.; Alpert, Bruce S.; Jones, Deborah P.

2009-01-01

Objective Children with hypertension (HTN) are at increased risk for left ventricular hypertrophy (LVH). Increased LV mass by the process of remodeling in response to volume or pressure loading may be eccentric (increased LV diameter) or concentric (increased wall thickness). Our objective was to classify LV geometry among children with primary HTN and examine differences in ambulatory blood pressure (ABP). Study design Subjects aged 7-18 years with suspected HTN were enrolled in this cross-sectional study. ABP and LVM index (LVMI) and were measured within the same 24 hour period. LV geometry was classified as normal, concentric remodeling, concentric LVH or eccentric LVH. Results Children with LVH had significantly higher ambulatory systolic and diastolic BP levels and BMI z-score. Sixty-eight children had HTN based upon ABPM. Thirty-eight percent of the hypertensive subjects had LVH, with equal distribution in the concentric and eccentric groups. There were significant differences in the 24-hour diastolic BP (DBP) parameters when the eccentric LVH group was compared to the normal geometry and concentric LVH groups. Relative wall thickness was inversely associated with nighttime DBP parameters. These relationships persisted after controlling for BMI Z-score. Conclusions While the risk for LVH is associated with increased systolic BP and BMI Z-score, those with eccentric LVH had significantly higher DBP. PMID:19851297

Direct Evidence that Myocardial Insulin Resistance following Myocardial Ischemia Contributes to Post-Ischemic Heart Failure

PubMed Central

Fu, Feng; Zhao, Kun; Li, Jia; Xu, Jie; Zhang, Yuan; Liu, Chengfeng; Yang, Weidong; Gao, Chao; Li, Jun; Zhang, Haifeng; Li, Yan; Cui, Qin; Wang, Haichang; Tao, Ling; Wang, Jing; Quon, Michael J; Gao, Feng

2015-01-01

A close link between heart failure (HF) and systemic insulin resistance has been well documented, whereas myocardial insulin resistance and its association with HF are inadequately investigated. This study aims to determine the role of myocardial insulin resistance in ischemic HF and its underlying mechanisms. Male Sprague-Dawley rats subjected to myocardial infarction (MI) developed progressive left ventricular dilation with dysfunction and HF at 4 wk post-MI. Of note, myocardial insulin sensitivity was decreased as early as 1 wk after MI, which was accompanied by increased production of myocardial TNF-α. Overexpression of TNF-α in heart mimicked impaired insulin signaling and cardiac dysfunction leading to HF observed after MI. Treatment of rats with a specific TNF-α inhibitor improved myocardial insulin signaling post-MI. Insulin treatment given immediately following MI suppressed myocardial TNF-α production and improved cardiac insulin sensitivity and opposed cardiac dysfunction/remodeling. Moreover, tamoxifen-induced cardiomyocyte-specific insulin receptor knockout mice exhibited aggravated post-ischemic ventricular remodeling and dysfunction compared with controls. In conclusion, MI induces myocardial insulin resistance (without systemic insulin resistance) mediated partly by ischemia-induced myocardial TNF-α overproduction and promotes the development of HF. Our findings underscore the direct and essential role of myocardial insulin signaling in protection against post-ischemic HF. PMID:26659007

Potential Adverse Cardiovascular Effects From Excessive Endurance Exercise

PubMed Central

O'Keefe, James H.; Patil, Harshal R.; Lavie, Carl J.; Magalski, Anthony; Vogel, Robert A.; McCullough, Peter A.

2012-01-01

A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases and improves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may induce pathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for and competing in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very long distance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normal within 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchy myocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial and ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronary artery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypothetical and there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have low mortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive endurance exercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulate physical fitness regimens for conferring optimal CV health and longevity. PMID:22677079

Parkin regulation of CHOP modulates susceptibility to cardiac endoplasmic reticulum stress.

PubMed

Han, Kim; Hassanzadeh, Shahin; Singh, Komudi; Menazza, Sara; Nguyen, Tiffany T; Stevens, Mark V; Nguyen, An; San, Hong; Anderson, Stasia A; Lin, Yongshun; Zou, Jizhong; Murphy, Elizabeth; Sack, Michael N

2017-05-18

The regulatory control of cardiac endoplasmic reticulum (ER) stress is incompletely characterized. As ER stress signaling upregulates the E3-ubiquitin ligase Parkin, we investigated the role of Parkin in cardiac ER stress. Parkin knockout mice exposed to aortic constriction-induced cardiac pressure-overload or in response to systemic tunicamycin (TM) developed adverse ventricular remodeling with excessive levels of the ER regulatory C/EBP homologous protein CHOP. CHOP was identified as a Parkin substrate and its turnover was Parkin-dose and proteasome-dependent. Parkin depletion in cardiac HL-1 cells increased CHOP levels and enhanced susceptibility to TM-induced cell death. Parkin reconstitution rescued this phenotype and the contribution of excess CHOP to this ER stress injury was confirmed by reduction in TM-induced cell death when CHOP was depleted in Parkin knockdown cardiomyocytes. Isogenic Parkin mutant iPSC-derived cardiomyocytes showed exaggerated ER stress induced CHOP and apoptotic signatures and myocardium from subjects with dilated cardiomyopathy showed excessive Parkin and CHOP induction. This study identifies that Parkin functions to blunt excessive CHOP to prevent maladaptive ER stress-induced cell death and adverse cardiac ventricular remodeling. Additionally, Parkin is identified as a novel post-translational regulatory moderator of CHOP stability and uncovers an additional stress-modifying function of this E3-ubiquitin ligase.

Pathology of myxomatous mitral valve disease in the dog.

PubMed

Fox, Philip R

2012-03-01

Mitral valve competence requires complex interplay between structures that comprise the mitral apparatus - the mitral annulus, mitral valve leaflets, chordae tendineae, papillary muscles, and left atrial and left ventricular myocardium. Myxomatous mitral valve degeneration is prevalent in the canine, and most adult dogs develop some degree of mitral valve disease as they age, highlighting the apparent vulnerability of canine heart valves to injury. Myxomatous valvular remodeling is associated with characteristic histopathologic features. Changes include expansion of extracellular matrix with glycosaminoglycans and proteoglycans; valvular interstitial cell alteration; and attenuation or loss of the collagen-laden fibrosa layer. These lead to malformation of the mitral apparatus, biomechanical dysfunction, and mitral incompetence. Mitral regurgitation is the most common manifestation of myxomatous valve disease and in advanced stages, associated volume overload promotes progressive valvular regurgitation, left atrial and left ventricular remodeling, atrial tears, chordal rupture, and congestive heart failure. Future studies are necessary to identify clinical-pathologic correlates that track disease severity and progression, detect valve dysfunction, and facilitate risk stratification. It remains unresolved whether, or to what extent, the pathobiology of myxomatous mitral valve degeneration is the same between breeds of dogs, between canines and humans, and how these features are related to aging and genetics. Copyright © 2012 Elsevier B.V. All rights reserved.

Coupled 0D-1D CFD Modeling of Right Heart and Pulmonary Artery Morphometry Tree

NASA Astrophysics Data System (ADS)

Dong, Melody; Yang, Weiguang; Feinstein, Jeffrey A.; Marsden, Alison

2017-11-01

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary artery (PA) pressure and remodeling of the distal PAs resulting in right ventricular (RV) dysfunction and failure. It is hypothesized that patients with untreated ventricular septal defects (VSD) may develop PAH due to elevated flows and pressures in the PAs. Wall shear stress (WSS), due to elevated flows, and circumferential stress, due to elevated pressures, are known to play a role in vascular mechanobiology. Thus, simulating VSD hemodynamics and wall mechanics may facilitate our understanding of mechanical stimuli leading to PAH initiation and progression. Although 3D CFD models can capture detailed hemodynamics in the proximal PAs, they cannot easily model hemodynamics and wave propagation in the distal PAs, where remodeling occurs. To improve current PA models, we will present a new method that couples distal PA hemodynamics with RV function. Our model couples a 0D lumped parameter model of the RV to a 1D model of the PA tree, based on human PA morphometry data, to characterize RV performance and WSS changes in the PA tree. We will compare a VSD 0D-1D model and a 0D-3D model coupled to a mathematical morphometry tree model to quantify WSS in the entire PA vascular tree.

Reversion of left ventricular systolic dysfunction and abnormal stress test: by catheter ablation, in a patient with Wolff-Parkinson-White syndrome from Para-Hisian Kent bundle.

PubMed

Tu, Chung-Ming; Chu, Kai-Ming; Cheng, Cheng-Chung; Cheng, Shu-Mung; Lin, Wei-Shiang

2010-01-01

The diagnosis of Wolff-Parkinson-White syndrome is typically reserved for patients who experience ventricular pre-excitation and symptoms that are related to paroxysmal supraventricular tachycardia, such as chest pain, dyspnea, dizziness, palpitations, or syncope. Herein, we report the case of a 38-year-old woman who presented at our outpatient department because of exercise intolerance. Cardiac auscultation revealed a grade 2/6 pansystolic murmur over the left lower sternal border. Twelve-lead electrocardiography showed sinus rhythm at a rate of 76 beats/min, with a significant delta wave. Transthoracic echocardiography revealed abnormal left ventricular systolic function. The results of a thallium stress test were also abnormal. Coronary artery disease was suspected; however, coronary angiography yielded normal results. Electrophysiologic study revealed a para-Hisian Kent bundle and a dual atrioventricular nodal pathway. After radiofrequency catheter ablation was performed, the patient's left ventricular function improved and her symptoms disappeared. In Wolff-Parkinson-White syndrome, left ventricular systolic dyssynchrony can yield abnormal findings on echocardiography and thallium scanning--even in persons who have no cardiovascular risk factors. Physicians who are armed with this knowledge can avoid performing coronary angiography unnecessarily. Catheter ablation can reverse the dyssynchrony of the ventricle and improve the patient's symptoms.

Reversibility of electrophysiological changes induced by chronic high-altitude hypoxia in adult rat heart.

PubMed

Chouabe, C; Amsellem, J; Espinosa, L; Ribaux, P; Blaineau, S; Mégas, P; Bonvallet, R

2002-04-01

Recent studies indicate that regression of left ventricular hypertrophy normalizes membrane ionic current abnormalities. This work was designed to determine whether regression of right ventricular hypertrophy induced by permanent high-altitude exposure (4,500 m, 20 days) in adult rats also normalizes changes of ventricular myocyte electrophysiology. According to the current data, prolonged action potential, decreased transient outward current density, and increased inward sodium/calcium exchange current density normalized 20 days after the end of altitude exposure, whereas right ventricular hypertrophy evidenced by both the right ventricular weight-to-heart weight ratio and the right ventricular free wall thickness measurement normalized 40 days after the end of altitude exposure. This morphological normalization occurred at both the level of muscular tissue, as shown by the decrease toward control values of some myocyte parameters (perimeter, capacitance, and width), and the level of the interstitial collagenous connective tissue. In the chronic high-altitude hypoxia model, the regression of right ventricular hypertrophy would not be a prerequisite for normalization of ventricular electrophysiological abnormalities.

Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms

PubMed Central

De Silva, Deepa S.; Wilson, Richard M.; Hutchinson, Christoph; Ip, Peter C.; Garcia, Anthony G.; Lancel, Steve; Ito, Masa; Pimentel, David R.; Sam, Flora

2009-01-01

Aldosterone induces extracellular signal-regulated kinase (ERK)-dependent cardiac remodeling. Fenofibrate improves cardiac remodeling in adult rat ventricular myocytes (ARVM) partly via inhibition of aldosterone-induced ERK1/2 phosphorylation and inhibition of matrix metalloproteinases. We sought to determine whether aldosterone caused apoptosis in cultured ARVM and whether fenofibrate ameliorated the apoptosis. Aldosterone (1 μM) induced apoptosis by increasing terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL)-positive nuclei in ARVM. Spironolactone (100 nM), an aldosterone receptor antagonist, but not RU-486, a glucocorticoid receptor, inhibited aldosterone-mediated apoptosis, indicating that the mineralocorticoid receptor (MR) plays a role. SP-600125 (3 μM)—a selective inhibitor of c-Jun NH2-terminal kinase (JNK)—inhibited aldosterone-induced apoptosis in ARVM. Although aldosterone increased the expression of both stress-activated protein kinases, pretreatment with fenofibrate (10 μM) decreased aldosterone-mediated apoptosis by inhibiting only JNK phosphorylation and the aldosterone-induced increases in Bax, p53, and cleaved caspase-3 and decreases in Bcl-2 protein expression in ARVM. In vivo studies demonstrated that chronic fenofibrate (100 mg·kg body wt−1·day−1) inhibited myocardial Bax and increased Bcl-2 expression in aldosterone-induced cardiac hypertrophy. Similarly, eplerenone, a selective MR inhibitor, used in chronic pressure-overload ascending aortic constriction inhibited myocardial Bax expression but had no effect on Bcl-2 expression. Therefore, involvement of JNK MAPK-dependent mitochondrial death pathway mediates ARVM aldosterone-induced apoptosis and is inhibited by fenofibrate, a peroxisome proliferator-activated receptor (PPAR)α ligand. Fenofibrate mediates beneficial effects in cardiac remodeling by inhibiting programmed cell death and the stress-activated kinases. PMID:19395558

Effects of Obstructive Sleep Apnea and Obesity on Cardiac Remodeling: The Wisconsin Sleep Cohort Study.

PubMed

Korcarz, Claudia E; Peppard, Paul E; Young, Terry B; Chapman, Carrie B; Hla, K Mae; Barnet, Jodi H; Hagen, Erika; Stein, James H

2016-06-01

To characterize the prospective associations of obstructive sleep apnea (OSA) with future echocardiographic measures of adverse cardiac remodeling. This was a prospective long-term observational study. Participants had overnight polysomnography followed by transthoracic echocardiography a mean (standard deviation) of 18.0 (3.7) y later. OSA was characterized by the apnea-hypopnea index (AHI, events/hour). Echocardiography was used to assess left ventricular (LV) systolic and diastolic function and mass, left atrial volume and pressure, cardiac output, systemic vascular resistance, and right ventricular (RV) systolic function, size, and hemodynamics. Multivariate regression models estimated associations between log10(AHI+1) and future echocardiographic findings. A secondary analysis looked at oxygen desaturation indices and future echocardiographic findings. At entry, the 601 participants were mean (standard deviation) 47 (8) y old (47% female). After adjustment for age, sex, and body mass index, baseline log10(AHI+1) was associated significantly with future reduced LV ejection fraction and tricuspid annular plane systolic excursion (TAPSE) ≤ 15 mm. After further adjustment for cardiovascular risk factors, participants with higher baseline log10(AHI+1) had lower future LV ejection fraction (β = -1.35 [standard error = 0.6]/log10(AHI+1), P = 0.03) and higher odds of TAPSE ≤ 15 mm (odds ratio = 6.3/log10(AHI+1), 95% confidence interval = 1.3-30.5, P = 0.02). SaO2 desaturation indices were associated independently with LV mass, LV wall thickness, and RV area (all P < 0.03). OSA is associated independently with decreasing LV systolic function and with reduced RV function. Echocardiographic measures of adverse cardiac remodeling are strongly associated with OSA but are confounded by obesity. Hypoxia may be a stimulus for hypertrophy in individuals with OSA. © 2016 Associated Professional Sleep Societies, LLC.

Congestive Heart Failure Leads to Prolongation of the PR Interval and Atrioventricular Junction Enlargement and Ion Channel Remodelling in the Rabbit

PubMed Central

Nikolaidou, Theodora; Cai, Xue J.; Stephenson, Robert S.; Yanni, Joseph; Lowe, Tristan; Atkinson, Andrew J.; Jones, Caroline B.; Sardar, Rida; Corno, Antonio F.; Dobrzynski, Halina; Withers, Philip J.; Jarvis, Jonathan C.; Hart, George; Boyett, Mark R.

2015-01-01

Heart failure is a major killer worldwide. Atrioventricular conduction block is common in heart failure; it is associated with worse outcomes and can lead to syncope and bradycardic death. We examine the effect of heart failure on anatomical and ion channel remodelling in the rabbit atrioventricular junction (AVJ). Heart failure was induced in New Zealand rabbits by disruption of the aortic valve and banding of the abdominal aorta resulting in volume and pressure overload. Laser micro-dissection and real-time polymerase chain reaction (RT-PCR) were employed to investigate the effects of heart failure on ion channel remodelling in four regions of the rabbit AVJ and in septal tissues. Investigation of the AVJ anatomy was performed using micro-computed tomography (micro-CT). Heart failure animals developed first degree heart block. Heart failure caused ventricular myocardial volume increase with a 35% elongation of the AVJ. There was downregulation of HCN1 and Cx43 mRNA transcripts across all regions and downregulation of Cav1.3 in the transitional tissue. Cx40 mRNA was significantly downregulated in the atrial septum and AVJ tissues but not in the ventricular septum. mRNA abundance for ANP, CLCN2 and Navβ1 was increased with heart failure; Nav1.1 was increased in the inferior nodal extension/compact node area. Heart failure in the rabbit leads to prolongation of the PR interval and this is accompanied by downregulation of HCN1, Cav1.3, Cx40 and Cx43 mRNAs and anatomical enlargement of the entire heart and AVJ. PMID:26509807

Anti-thymocyte globulin induces neoangiogenesis and preserves cardiac function after experimental myocardial infarction.

PubMed

Lichtenauer, Michael; Mildner, Michael; Werba, Gregor; Beer, Lucian; Hoetzenecker, Konrad; Baumgartner, Andrea; Hasun, Matthias; Nickl, Stefanie; Mitterbauer, Andreas; Zimmermann, Matthias; Gyöngyösi, Mariann; Podesser, Bruno Karl; Klepetko, Walter; Ankersmit, Hendrik Jan

2012-01-01

Acute myocardial infarction (AMI) followed by ventricular remodeling is the major cause of congestive heart failure and death in western world countries. Of relevance are reports showing that infusion of apoptotic leucocytes or anti-lymphocyte serum after AMI reduces myocardial necrosis and preserves cardiac function. In order to corroborate this therapeutic mechanism, the utilization of an immunosuppressive agent with a comparable mechanism, such as anti-thymocyte globulin (ATG) was evaluated in this study. AMI was induced in rats by ligation of the left anterior descending artery. Initially after the onset of ischemia, rabbit ATG (10 mg/rat) was injected intravenously. In vitro and in vivo experiments showed that ATG induced a pronounced release of pro-angiogenic and chemotactic factors. Moreover, paracrine factors released from ATG co-incubated cell cultures conferred a down-regulation of p53 in cardiac myocytes. Rats that were injected with ATG evidenced higher numbers of CD68+ macrophages in the ischemic myocardium. Animals injected with ATG evidenced less myocardial necrosis, showed a significant reduction of infarct dimension and an improvement of post-AMI remodeling after six weeks (infarct dimension 24.9% vs. 11.4%, p<0.01). Moreover, a higher vessel density in the peri-infarct region indicated a better collateralization in rats that were injected with ATG. These data indicate that ATG, a therapeutic agent successfully applied in clinical transplant immunology, triggered cardioprotective effects after AMI that salvaged ischemic myocardium by down-regulation of p53. This might have raised the resistance against apoptotic cell death during ischemia. The combination of these mechanisms seems to be causative for improved cardiac function and less ventricular remodeling after experimental AMI.

Injection of Peptide nanogels preserves postinfarct diastolic function and prolongs efficacy of cell therapy in pigs.

PubMed

Lin, Yi-Dong; Chang, Ming-Yao; Cheng, Bill; Liu, Yen-Wen; Lin, Lung-Chun; Chen, Jyh-Hong; Hsieh, Patrick C H

2015-05-01

Accumulating evidence suggests that the benefits of cell therapy for cardiac repair are modest and transient due to progressive harmful cardiac remodeling as well as loss of transplanted cells. We previously demonstrated that injection of peptide nanofibers (NFs) reduces ventricular remodeling and facilitates cell retention at 1 month after acute myocardial infarction (MI) in pigs. However, it remains unclear whether these benefits still persist as the material is being degraded. In this study, 2 mL of placebo or NFs, with or without 1×10(8) mononuclear cells (MNCs), was injected into the pig myocardium after MI (n≥5 in each group), and cardiac function was assessed by echocardiography, including myocardial deformation analyses and catheterization at 3 months post-MI. Our results reveal that MNC-only injection slightly improved cardiac systolic function at 1 month post-MI, but this benefit was lost at later time points (ejection fraction: 42.0±2.3 in MI+normal saline [NS] and 43.5±1.1 in MI+MNCs). In contrast, NF-only injection resulted in improved cardiac diastolic function and reduced pathological remodeling at 3 months post-MI. Furthermore, combined injection of MNCs/NFs provided a greater and longer term cardiac performance (52.1±1.2 in MI+MNCs/NFs, p<0.001 versus MI+NS and MI+MNCs) and 11.3-fold transplanted cell retention. We also found that about 30% NFs remained at 3 months after injection; however, endogenous myofibroblasts were recruited to the NF-injected microenvironment to replace the degraded NFs and preserved cardiac dimensions and mechanics. In conclusion, we demonstrated that injection of NFs contributes to preservation of ventricular mechanical integrity and sustains MNC efficacy at 3 months postinjection.

Angiotensin-converting enzyme and matrix metalloproteinase inhibition with developing heart failure: comparative effects on left ventricular function and geometry

NASA Technical Reports Server (NTRS)

McElmurray, J. H. 3rd; Mukherjee, R.; New, R. B.; Sampson, A. C.; King, M. K.; Hendrick, J. W.; Goldberg, A.; Peterson, T. J.; Hallak, H.; Zile, M. R.;

Circulating Endothelial Cells and Endothelial Function predict Major Adverse Cardiac Events and Early Adverse Left Ventricular Remodeling in Patients with ST-Segment Elevation Myocardial Infarction

PubMed Central

Magdy, Abdel Hamid; Bakhoum, Sameh; Sharaf, Yasser; Sabry, Dina; El-Gengehe, Ahmed T; Abdel-Latif, Ahmed

2016-01-01

Endothelial progenitor cells (EPCs) and circulating endothelial cells (CECs) are mobilized from the bone marrow and increase in the early phase after ST-elevation myocardial infarction (STEMI). The aim of this study was to assess the prognostic significance of CECs and indices of endothelial dysfunction in patients with STEMI. In 78 patients with acute STEMI, characterization of CD34+/VEGFR2+ CECs, and indices of endothelial damage/dysfunction such as brachial artery flow mediated dilatation (FMD) were determined. Blood samples for CECs assessment and quantification were obtained within 24 hours of admission and FMD was assessed during the index hospitalization. At 30 days follow up, the primary composite end point of major cardiac adverse events (MACE) consisting of all-cause mortality, recurrent non-fatal MI, or heart failure and the secondary endpoint of early adverse left ventricular (LV) remodeling were analyzed. The 17 patients (22%) who developed MACE had significantly higher CEC level (P = 0.004), vWF level (P =0.028), and significantly lower FMD (P = 0.006) compared to the remaining patients. Logistic regression analysis showed that CECs level and LV ejection fraction were independent predictors of MACE. The areas under the receiver operating characteristic curves (ROC) for CEC level, FMD, and the logistic model with both markers were 0.73, 0.75, and 0.82 respectively for prediction of the MACE. The 16 patients who developed the secondary endpoint had significantly higher CEC level compared to remaining patients (p =0.038). In conclusion, increased circulating endothelial cells and endothelial dysfunction predicted the occurrence of major adverse cardiac events and adverse cardiac remodeling in patients with STEMI. PMID:26864952

Impact of long-term burden of excessive adiposity and elevated blood pressure from childhood on adulthood left ventricular remodeling patterns: the Bogalusa Heart Study.

PubMed

Lai, Chin-Chih; Sun, Dianjianyi; Cen, Ruiqi; Wang, Jian; Li, Shengxu; Fernandez-Alonso, Camilo; Chen, Wei; Srinivasan, Sathanur R; Berenson, Gerald S

2014-10-14

Cardiovascular risk factors are associated with left ventricular hypertrophy (LVH), but little is known regarding related impact of longitudinal measures of childhood adiposity and LV hemodynamic variables. The aim of this study was to examine the impact of cumulative long-term burden and trends of excessive adiposity and elevated blood pressure (BP) during childhood on adulthood LVH and LV geometric remodeling patterns. This longitudinal study consisted of 1,061 adults, age 24 to 46 years, who had been examined 4 or more times for body mass index (BMI) and BP starting in childhood, with a mean follow-up of 28.0 years. The area under the curve (AUC) was calculated as a measure of long-term burden (total AUC) and trends (incremental AUC) of BMI and BP from childhood to adulthood. Four LV geometric types were defined-normal, concentric remodeling (CR), eccentric hypertrophy (EH), and concentric hypertrophy (CH)-all on the basis of LV mass indexed for body height (m(2.7)) and relative wall thickness. Higher values of BMI and systolic and diastolic BP in childhood and adulthood, as well as total AUC and incremental AUC, were all significantly associated with higher LV mass index and LVH, adjusted for race, sex, and age. In addition, higher values of BMI and BP in childhood and adulthood, total AUC, and incremental AUC were significantly associated with EH and CH but not with CR. Importantly, all of these measures of BMI had a consistently and significantly greater influence on EH than did measures of BP. These findings indicate that the adverse influence of excessive adiposity and elevated BP levels on LVH begins in childhood. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction

PubMed Central

Beaumont, Eric; Southerland, Elizabeth M.; Hardwick, Jean C.; Wright, Gary L.; Ryan, Shannon; Li, Ying; KenKnight, Bruce H.; Armour, J. Andrew

2015-01-01

This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions. PMID:26276818

[Effects of Losartan on expression of heme oxygenases in volume-overloaded rats with left-to-right shunt].

PubMed

Yuan, Li-Xing; Liu, Han-Min; Li, Mi; Gao, Ju; Zhou, Tong-Fu

2005-09-01

To study the expression of heme oxygenase-1 mRNA and pulmonary remodeling before and after surgical establishment of left-to-right shunt in volume-overloaded SD rats and rats with Losartan intervention. Left-to-right shunt volume-overloaded SD rat models were established by aortocaval shunt operation. Seven rats with shunt were placed on Losartan (Losartan group), 7 rats with but not given Losartan were included in the operation group, and 4 rats after sham operation served as controls. Pulmonary pressure and right ventricular pressure were measured during catheterization. The relative weights ventricles were determined after execution of the rats. Pulmonary vascular remodeling parameters, including percentage arterial wall thickness and percentage muscularized small arteries, were assessed by morphometry. Heme oxygenase-1 (HO-1) mRNA expression and heme oxygenase-2 (HO-2) mRNA expression were detected RT-PCR method. Pulmonary artery pressure and right ventricular relative weight decreased significantly in the rats of Losartan group; in addition, the percentage arterial wall thickness and percentage of muscularized small arteries in the Losartan group were reduced as compared with those in the operation group. The level 1 mRAN expression in rats with shunt was significantly higher than that in rats without shunt. The level mRNA expression in the Losartan group decreased remarkably as compared against that in the operation The level of HO-1 mRNA expression in lungs was significantly higher than that in ventricles. There statistically significant differences in HO-2 mRNA expression levels between the three rat groups. Losartan intervention can markedly reduce pulmonary pressure, inhibit vascular remodeling in volume-overloaded left-to-right shunt rats, and result in down-regulation of HO-1 mRNA expression.

Selective Class I HDAC Inhibition Suppresses Hypoxia-Induced Cardiopulmonary Remodeling Through an Anti-Proliferative Mechanism

PubMed Central

Cavasin, Maria A.; Demos-Davies, Kim; Horn, Todd R.; Walker, Lori A.; Lemon, Douglas D.; Birdsey, Nicholas; Weiser-Evans, Mary C. M.; Harral, Jules; Irwin, David C.; Anwar, Adil; Yeager, Michael E.; Li, Min; Watson, Peter A.; Nemenoff, Raphael A.; Buttrick, Peter M.; Stenmark, Kurt R.; McKinsey, Timothy A.

2012-01-01

Rationale Histone deacetylase (HDAC) inhibitors are efficacious in models of hypertension-induced left ventricular (LV) heart failure. The consequences of HDAC inhibition in the context of pulmonary hypertension (PH) with associated right ventricular (RV) cardiac remodeling are poorly understood. Objective This study was performed to assess the utility of selective small molecule inhibitors of class I HDACs in a pre-clinical model of PH. Methods and Results Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs −1, −2 and −3. The compound reduced pulmonary arterial pressure (PAP) more dramatically than tadalafil, a standard-of-care therapy for human PH that functions as a vasodilator. MGCD0103 improved pulmonary artery (PA) acceleration time (PAAT) and reduced systolic notching of the PA flow envelope, suggesting a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced PAP in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening due to suppression of smooth muscle cell proliferation. RV function was maintained in MGCD0103 treated animals. Although the class I HDAC inhibitor only modestly reduced RV hypertrophy, it had multiple beneficial effects on the RV, which included suppression of pathological gene expression, inhibition of pro-apoptotic caspase activity, and repression of pro-inflammatory protein expression. Conclusions By targeting distinct pathogenic mechanisms, isoform-selective HDAC inhibitors have potential as novel therapeutics for PH that will complement vasodilator standards-of-care. PMID:22282194

Biventricular Heart Remodeling After Percutaneous or Surgical Pulmonary Valve Implantation: Evaluation by Cardiac Magnetic Resonance.

PubMed

Secchi, Francesco; Resta, Elda C; Cannaò, Paola M; Pluchinotta, Francesca; Piazza, Luciane; Butera, Gianfranco; Carminati, Mario; Sardanelli, Francesco

2017-11-01

The aim of this study was to evaluate the impact of percutaneous pulmonary valve implantation (PPVI) and surgical pulmonary valve replacement (SPVR) on biventricular and pulmonary valve function using cardiac magnetic resonance. Thirty-five patients aged 20±8 years (mean±SD) underwent PPVI, whereas 16 patients aged 30±11 years underwent SPVR. Cardiac magnetic resonance examinations were performed before and after the procedures with an average follow-up interval of 10 months. Cine steady-state free precession sequences for cardiac function and phase-contrast sequences for pulmonary flow were performed. The right ventricle (RV) and left ventricle (LV) functions were evaluated using a dedicated software. The RV end-diastolic volume index (mL/m) decreased significantly after PPVI and SPVR, from 74 to 64 (P=0.030) and from 137 to 83 (P=0.001), respectively. The RV ejection fraction increased significantly after SPVR, from 47% to 53% (P=0.038). The LV end-diastolic volume index increased significantly after PPVI, from 66 to 76 mL/m (P<0.001). The LV stroke volume index increased significantly after PPVI, from 34 to 43 mL/m (P=0.004). The analysis of bivariate correlations showed that in patients undergoing SPVR the RV changes after the procedure were positively correlated to LV changes in terms of end-systolic volume index (r=0587; P=0.017) and ejection fraction (r=0.681; P=0.004). A RV volumetric reduction and a positive effect on ventricular-ventricular interaction were observed after both PPVI and SPVR. After PPVI, a positive volumetric LV remodeling was found. No LV remodeling was found after SPVR. After both procedures, the replaced pulmonary valve functioned well.

Heme oxygenase-1 (HO-1) inhibits postmyocardial infarct remodeling and restores ventricular function.

PubMed

Liu, Xiaoli; Pachori, Alok S; Ward, Christopher A; Davis, J Paul; Gnecchi, Massimiliano; Kong, Deling; Zhang, Lunan; Murduck, Jared; Yet, Shaw-Fang; Perrella, Mark A; Pratt, Richard E; Dzau, Victor J; Melo, Luis G

2006-02-01

We reported previously that predelivery of the anti-oxidant gene heme oxygenase-1 (HO-1) to the heart by adeno associated virus (AAV) markedly reduces injury after acute myocardial infarction (MI). However, the effect of HO-1 gene delivery on postinfarction recovery has not been investigated. In the current study, we assessed the effect of HO-1 gene delivery on post-MI left ventricle (LV) remodeling and function using echocardiographic imaging and histomorphometric approaches. Two groups of Sprague-Dawley rats were injected with 4 x 10(11) particles of AAV-LacZ (control) or AAV-hHO-1 in the LV wall. Eight wk after gene transfer, the animals were subjected to 30 min of ischemia by ligation of left anterior descending artery (LAD) followed by reperfusion. Echocardiographic measurements were obtained in a blinded fashion prior and at 1.5 and 3 months after I/R. Ejection fraction (EF) was reduced by 13% and 40% in the HO-1 and LacZ groups, respectively at 1.5 months after MI. Three months after MI, EF recovered fully in the HO-1, but only partially in the LacZ-treated animals. Post-MI LV dimensions were markedly increased and the anterior wall was markedly thinned in the LacZ-treated animals compared with the HO-1-treated animals. Significant myocardial scarring and fibrosis were observed in the LacZ-group in association with elevated levels of interstitial collagen I and III and MMP-2 activity. Post-MI myofibroblast accumulation was reduced in the HO-1-treated animals, and retroviral overexpression of HO-1 reduced proliferation of isolated cardiac fibroblasts. Our data indicate that rAAV-HO-1 gene transfer markedly reduces fibrosis and ventricular remodeling and restores LV function and chamber dimensions after myocardial infarction.

Age- and Sex-Related Influences on Left Ventricular Mechanics in Elderly Individuals Free of Prevalent Heart Failure: The ARIC Study (Atherosclerosis Risk in Communities).

PubMed

Hung, Chung-Lieh; Gonçalves, Alexandra; Shah, Amil M; Cheng, Susan; Kitzman, Dalane; Solomon, Scott D

2017-01-01

Advanced age is related to left ventricular (LV) remodeling. We sought to investigate the relationships between aging, elevated hemodynamic load, cardiac mechanics, and LV remodeling in an elderly community-based population. We studied 1105 subjects (76±5 years, 61% women) without prevalent heart failure, who attended the visit 5 of the ARIC study (Atherosclerosis Risk in Communities). LV global longitudinal strain, global circumferential strain, and torsion indices were analyzed using 3-dimensional echocardiography. Advanced age was associated with greater LV concentricity, lower myocardial diastolic relaxation, reduced global longitudinal strain (adjusted estimate, 0.39±0.19% (SE)/decade; P=0.038), borderline greater global circumferential strain (adjusted estimate, -0.59±0.36% (SE)/decade; P=0.08), and higher torsion indices (adjusted estimate for torsion, 0.33±0.04° (SE)/decade; P<0.001). In addition, greater concentricity was associated with decreased global longitudinal strain and greater torsion in multivariable models (all P<0.001). Women showed smaller LV cavity size, greater concentricity, lower myocardial relaxation velocity E', though demonstrated greater global longitudinal strain, global circumferential strain, and torsion than men (all P<0.05). Overall, subjects with hypertension and increasing age were more likely to have higher torsion, though the association between advanced age and greater torsion was more pronounced in women than in men (both interaction P<0.05). In an asymptomatic, senescent community-dwelling population, we observed a distinct, sex-specific pattern of cardiac remodeling. Although we observed worse diastolic and longitudinal function with advanced age or elevated load in both sexes, a significant increase of torsion was more pronounced in women. © 2017 American Heart Association, Inc.

Vagus nerve stimulation mitigates intrinsic cardiac neuronal and adverse myocyte remodeling postmyocardial infarction.

PubMed

Beaumont, Eric; Southerland, Elizabeth M; Hardwick, Jean C; Wright, Gary L; Ryan, Shannon; Li, Ying; KenKnight, Bruce H; Armour, J Andrew; Ardell, Jeffrey L

2015-10-01

This paper aims to determine whether chronic vagus nerve stimulation (VNS) mitigates myocardial infarction (MI)-induced remodeling of the intrinsic cardiac nervous system (ICNS), along with the cardiac tissue it regulates. Guinea pigs underwent VNS implantation on the right cervical vagus. Two weeks later, MI was produced by ligating the ventral descending coronary artery. VNS stimulation started 7 days post-MI (20 Hz, 0.9 ± 0.2 mA, 14 s on, 48 s off; VNS-MI, n = 7) and was compared with time-matched MI animals with sham VNS (MI n = 7) vs. untreated controls (n = 8). Echocardiograms were performed before and at 90 days post-MI. At termination, IC neuronal intracellular voltage recordings were obtained from whole-mount neuronal plexuses. MI increased left ventricular end systolic volume (LVESV) 30% (P = 0.027) and reduced LV ejection fraction (LVEF) 6.5% (P < 0.001) at 90 days post-MI compared with baseline. In the VNS-MI group, LVESV and LVEF did not differ from baseline. IC neurons showed depolarization of resting membrane potentials and increased input resistance in MI compared with VNS-MI and sham controls (P < 0.05). Neuronal excitability and sensitivity to norepinephrine increased in MI and VNS-MI groups compared with controls (P < 0.05). Synaptic efficacy, as determined by evoked responses to stimulating input axons, was reduced in VNS-MI compared with MI or controls (P < 0.05). VNS induced changes in myocytes, consistent with enhanced glycogenolysis, and blunted the MI-induced increase in the proapoptotic Bcl-2-associated X protein (P < 0.05). VNS mitigates MI-induced remodeling of the ICNS, correspondingly preserving ventricular function via both neural and cardiomyocyte-dependent actions. Copyright © 2015 the American Physiological Society.

Correlation between ECG changes and early left ventricular remodeling in preadolescent footballers.

PubMed

Zdravkovic, M; Milovanovic, B; Hinic, S; Soldatovic, I; Durmic, T; Koracevic, G; Prijic, S; Markovic, O; Filipovic, B; Lovic, D

2017-03-01

The aim of this study was to assess the early electrocardiogram (ECG) changes induced by physical training in preadolescent elite footballers. This study included 94 preadolescent highly trained male footballers (FG) competing in Serbian Football League (minimum of 7 training hours/week) and 47 age-matched healthy male controls (less than 2 training hours/week) (CG). They were screened by ECG and echocardiography at a tertiary referral cardio center. Sokolow-Lyon index was used as a voltage electrocardiographic criterion for left ventricular hypertrophy diagnosis. Characteristic ECG intervals and voltage were compared and reference range was given for preadolescent footballers. Highly significant differences between FG and CG were registered in all ECG parameters: P-wave voltage (p < 0.001), S-wave (V1 or V2 lead) voltage (p < 0.001), R-wave (V5 and V6 lead) voltage (p < 0.001), ECG sum of S V 1-2  + R V 5-6 (p < 0.001), T-wave voltage (p < 0.001), QRS complex duration (p < 0.001), T-wave duration (p < 0.001), QTc interval duration (p < 0.001), and R/T ratio (p < 0.001). No differences were found in PQ interval duration between these two groups (p > 0.05). During 6-year follow-up period, there was no adverse cardiac event in these footballers. None of them expressed pathological ECG changes. Benign ECG changes are presented in the early stage of athlete's heart remodeling, but they are not related to pathological ECG changes and they should be regarded as ECG pattern of LV remodeling.

Accuracy criteria voltage electrocardiography left ventricular hypertrophy to distinguish types of left ventricular hypertrophy geometry

NASA Astrophysics Data System (ADS)

Tumbur, O.; Safri, Z.; Hassan, R.

2018-03-01

Different types of left ventricular hypertrophy geometry are associated with different risk of cardiovascular disease. The purpose of this study was to determine the role of various ECG voltages of LVH to distinguish the type of LVH geometry. A cross-sectional study from June to November 2015, 100 patients in Adam Malik Hospital Medan. The result of LVH ECG criteria of Sokolow-Lyon was not met then obtained normal left ventricular geometry with 60% sensitivity, 72.22% specificity, and 71% accuracy. The eccentric type of LVH is obtained when the Cornel Voltage is not met; the sensitivity is 25%, specificity 71.88%, and 55% accuracy. Concentric geometric hypertrophy when the RV6/V5> 1 ratio is satisfied, the sensitivity is 55.56%, specificity 56.36%, and 56% accuracy. The RV6/V5>1 ratio was not met, the concentric geometry type of hypertrophy remodeling was determined with a sensitivity of 55.56%, specificity 49.45%, and 50% accuracy. Conclusions, various LVHECG criteria distinguish the type of LVH geometry. Sokolow-Lyon and Cornel Voltage sensitivity and specificity are better than the RV6/V5 ratio.

Post-operative ventricular flow dynamics following atrioventricular valve surgical and device therapies: A review.

PubMed

Nguyen, Yen Ngoc; Ismail, Munirah; Kabinejadian, Foad; Tay, Edgar Lik Wui; Leo, Hwa Liang

2018-04-01

Intra-ventricular flow dynamics has recently emerged as an important evaluation and diagnosis tool in different cardiovascular conditions. The formation of vortex pattern during the cardiac cycle has been suggested to play important epigenetic and energy-modulation roles in cardiac remodelling, adaptations and mal-adaptations. In this new perspective, flow alterations due to different cardiovascular procedures can affect the long-term outcome of those procedures. Especially, repairs and replacements performed on atrioventricular valves are likely to exert direct impact on intra-ventricular flow pattern. In this review, current consensus around the roles of vortex dynamics in cardiac function is discussed. An overview of physiological vortex patterns found in healthy left and right ventricles as well as post-operative ventricular flow phenomenon owing to different atrioventricular valvular procedures are reviewed, followed by the summary of different vortex identification schemes used to characterise intraventricular flow. This paper also emphasises on future research directions towards a comprehensive understanding of intra-cardiac flow and its clinical relevance. The knowledge could encourage more effective pre-operative planning and better outcomes for current clinical practices. Copyright © 2018. Published by Elsevier Ltd.

Atrial fibrillation: effects beyond the atrium?

PubMed

Wijesurendra, Rohan S; Casadei, Barbara

2015-03-01

Atrial fibrillation (AF) is the most common sustained clinical arrhythmia and is associated with significant morbidity, mostly secondary to heart failure and stroke, and an estimated two-fold increase in premature death. Efforts to increase our understanding of AF and its complications have focused on unravelling the mechanisms of electrical and structural remodelling of the atrial myocardium. Yet, it is increasingly recognized that AF is more than an atrial disease, being associated with systemic inflammation, endothelial dysfunction, and adverse effects on the structure and function of the left ventricular myocardium that may be prognostically important. Here, we review the molecular and in vivo evidence that underpins current knowledge regarding the effects of human or experimental AF on the ventricular myocardium. Potential mechanisms are explored including diffuse ventricular fibrosis, focal myocardial scarring, and impaired myocardial perfusion and perfusion reserve. The complex relationship between AF, systemic inflammation, as well as endothelial/microvascular dysfunction and the effects of AF on ventricular calcium handling and oxidative stress are also addressed. Finally, consideration is given to the clinical implications of these observations and concepts, with particular reference to rate vs. rhythm control. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Ventricular dilation and electrical dyssynchrony synergistically increase regional mechanical nonuniformity but not mechanical dyssynchrony: a computational model.

PubMed

Kerckhoffs, Roy C P; Omens, Jeffrey H; McCulloch, Andrew D; Mulligan, Lawrence J

2010-07-01

Heart failure (HF) in combination with mechanical dyssynchrony is associated with a high mortality rate. To quantify contractile dysfunction in patients with HF, investigators have proposed several indices of mechanical dyssynchrony, including percentile range of time to peak shortening (WTpeak), circumferential uniformity ratio estimate (CURE), and internal stretch fraction (ISF). The goal of this study was to compare the sensitivity of these indices to 4 major abnormalities responsible for cardiac dysfunction in dyssynchronous HF: dilation, negative inotropy, negative lusitropy, and dyssynchronous activation. All combinations of these 4 major abnormalities were included in 3D computational models of ventricular electromechanics. Compared with a nonfailing heart model, ventricles were dilated, inotropy was reduced, twitch duration was prolonged, and activation sequence was changed from normal to left bundle branch block. In the nonfailing heart, CURE, ISF, and WTpeak were 0.97+/-0.004, 0.010+/-0.002, and 78+/-1 milliseconds, respectively. With dilation alone, CURE decreased 2.0+/-0.07%, ISF increased 58+/-47%, and WTpeak increased 31+/-3%. With dyssynchronous activation alone, CURE decreased 15+/-0.6%, ISF increased 14-fold (+/-3), and WTpeak increased 121+/-4%. With the combination of dilation and dyssynchronous activation, CURE decreased 23+/-0.8%, ISF increased 20-fold (+/-5), and WTpeak increased 147+/-5%. Dilation and left bundle branch block combined synergistically decreased regional cardiac function. CURE and ISF were sensitive to this combination, but WTpeak was not. CURE and ISF also reflected the relative nonuniform distribution of regional work better than WTpeak. These findings might explain why CURE and ISF are better predictors of reverse remodeling in cardiac resynchronization therapy.

Enhanced pulmonary vasodilator reserve and abnormal right ventricular: pulmonary artery coupling in heart failure with preserved ejection fraction.

PubMed

Andersen, Mads J; Hwang, Seok-Jae; Kane, Garvan C; Melenovsky, Vojtech; Olson, Thomas P; Fetterly, Kenneth; Borlaug, Barry A

2015-05-01

Pulmonary hypertension and right ventricular (RV) dysfunction are common in patients with advanced heart failure with preserved ejection fraction (HFpEF), yet their underlying mechanisms remain poorly understood. We sought to examine RV-pulmonary artery (PA) functional reserve responses and RV-PA coupling at rest and during β-adrenergic stimulation in subjects with earlier stage HFpEF. In a prospective trial, subjects with HFpEF (n=39) and controls (n=18) underwent comprehensive invasive and noninvasive hemodynamic assessment using high fidelity micromanometer catheters, echocardiography, and expired gas analysis at rest and during dobutamine infusion. HFpEF subjects displayed similar RV structure but significantly impaired RV systolic (lower RV dP/dtmax/IP and s') and diastolic function (higher RV τ) coupled with more severe pulmonary vascular disease, manifest by higher PA pressures, higher PA resistance, and lower PA compliance compared with controls. Dobutamine infusion caused greater pulmonary vasodilation in HFpEF compared with controls, with enhanced reductions in PA resistance, greater increase in PA compliance, and a more negative slope in the PA pressure-flow relationship when compared with controls (all P<0.001). RV-PA coupling analysis revealed that dobutamine improved RV ejection in HFpEF subjects through afterload reduction alone, rather than through enhanced contractility, indicating RV systolic reserve dysfunction. Pulmonary hypertension in early stage HFpEF is related to partially reversible pulmonary vasoconstriction coupled with RV systolic and diastolic dysfunction, even in the absence of RV structural remodeling. Pulmonary vascular tone is more favorably responsive to β-adrenergic stimulation in HFpEF than controls, suggesting a potential role for β-agonists in the treatment of patients with HFpEF and pulmonary hypertension. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01418248. © 2015 American Heart Association, Inc.

[Surgical Regeneration Therapy Using Myoblast Sheets for Severe Heart Failure].

PubMed

Sawa, Yoshiki

2017-01-01

Heart failure is a life-threatening disorder worldwide, and the current end-stage therapies for severe heart failure are replacement therapies such as ventricular-assist devices and heart transplantation. Although these therapies have been reported to be useful, there are many issues in terms of the durability, complications, limited donors, adverse effect of continuous administration of immunosuppressive agents, and high costs involved. Recently, regenerative therapy based on genetic, cellular, or tissue engineering techniques has gained attention as a new therapy to overcome the challenges encountered in transplantation medicine. We focused on skeletal myoblasts as the source of progenitor cells for autologous cell transplantation and the cell-sheet technique for site-specific implantation. In vitro studies have reported that myoblast sheets secrete cytoprotective and angiogenic cytokines such as hepatocyte growth factor (HGF). Additionally, in vivo studies using large and small animal models of heart failure, we have shown that myoblast sheets could improve diastolic and systolic performance and enhance angiogenesis and antifibrosis as well as the expression of several cytokines including HGF and vascular endothelial growth factor(VEGF) in the tissues at the transplanted site. Based on the results of these studies, we performed clinical trials using autologous myoblast sheets in ischemic cardiomyopathy (ICM) and dilated cardiomyopathy patients. Some patients showed left ventricular reverse remodeling and improved symptoms and exercise tolerance. Recently, multiple medical institutions including our institution successfully conducted an exploratory, uncontrolled, open-label phase II study in subjects with ICM to validate the efficacy and safety of autologous myoblast sheets. Moreover, as a novel cell source for regenerative medicine, our recent studies demonstrated that induced pluripotent stem cell-derived cardiomyocyte sheets showed electrical and microstructural homogeneity with heart tissue in vitro and in vivo, thus establishing proof of concept in small and large animal models of heart failure.

Impact of Cardiac Resynchronization Therapy on Left Ventricular Mechanics: Understanding the Response through a New Quantitative Approach Based on Longitudinal Strain Integrals.

PubMed

Bernard, Anne; Donal, Erwan; Leclercq, Christophe; Schnell, Frédéric; Fournet, Maxime; Reynaud, Amélie; Thebault, Christophe; Mabo, Philippe; Daubert, J-Claude; Hernandez, Alfredo

2015-06-01

The mechanisms of improvement of left ventricular (LV) function with cardiac resynchronization therapy (CRT) are not yet elucidated. The aim of this study was to describe a new tool based on automatic quantification of the integrals of regional longitudinal strain signals and evaluate changes in LV strain distribution after CRT. This was a retrospective observational study of 130 patients with heart failure before CRT device implantation and after 3 to 6 months of follow-up. Integrals of regional longitudinal strain signals (from the beginning of the cardiac cycle to strain peak [IL,peak] and to the instant of aortic valve closure [IL,avc]) were analyzed retrospectively with custom-made algorithms. Response to CRT was defined as a decrease in LV end-systolic volume of ≥15%. Responders (61%) and nonresponders (39%) showed similar baseline values of regional IL,peak and IL,avc. At follow-up, significant improvements of midlateral IL,peak and of midlateral IL,avc were noted only in responders. Midlateral IL,avc showed a relative increase of 151 ± 276% in responders, whereas a decrease of 33 ± 69% was observed in nonresponders. The difference between IL,avc and IL,peak (representing wasted energy of the LV myocardium) of the lateral wall showed a relative change of -59 ± 103% in responders between baseline and CRT, whereas in nonresponders, the relative change was 21 ± 113% (P = .009). Strain integrals revealed changes between baseline and CRT in the lateral wall, demonstrating the beneficial effects of CRT on LV mechanics with favorable myocardial reverse remodeling. Copyright © 2015 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

Prediction of subtle left ventricular systolic dysfunction in homozygous and heterozygous familial hypercholesterolemia: Genetic analyses and speckle tracking echocardiography study.

PubMed

Saracoglu, Erhan; Kılıç, Salih; Vuruşkan, Ertan; Düzen, Irfan; Çekici, Yusuf; Kuzu, Zülfiye; Yıldırım, Arafat; Küçükosmanoğlu, Mehmet; Çetin, Mustafa

2018-06-05

Few studies have shown the direct effect of familial hypercholesterolemia (FH) on myocardial systolic function. Studies focused on heterozygote FH patients but not homozygote ones, and they did not perform genetic analyses. We aimed to evaluate all types of patients with FH using the potentially more sensitive speckle tracking echocardiography (STE) technique to identify early left ventricular (LV) dysfunction. Genetic analyses of patients with FH were conducted for LDL-receptor, PCSK9, and ApoB100. Nine homozygote, two compound heterozygote, and 82 heterozygote FH patients and 85 healthy subjects were prospectively studied. Longitudinal and circumferential strain measurements and conventional echocardiography findings were obtained. LV ejection fractions were similar for all (homozygote, heterozygote, and control) groups. The LV average longitudinal strain (aLS) and average circumferential strain (aCS) levels were significantly reduced in the homozygote and heterozygote groups when compared with the controls (for aLS, P = .008 (<.001); for aCS, P =< .001). A significant inverse correlation was found between LDL-C levels and LS (P < .001, r = .728) and CS (P < .001, r = .642) for all FH patients. This study demonstrates the potential of using systolic strain values obtained using 2D STE for determining lipotoxicity in the myocardium owing to hypercholesterolemia. Our study found that cardiac functions of homozygote patients who had the highest cholesterol levels were disrupted at very early ages. Therefore, starting lipid reduction treatment and early reverse LV remodelling therapy at early ages may be beneficial for high-risk patients. © 2018 Wiley Periodicals, Inc.

Embryonic Stem Cell Therapy of Heart Failure in Genetic Cardiomyopathy

PubMed Central

Yamada, Satsuki; Nelson, Timothy J.; Crespo-Diaz, Ruben J.; Perez-Terzic, Carmen; Liu, Xiao-Ke; Miki, Takashi; Seino, Susumu; Behfar, Atta; Terzic, Andre

2009-01-01

Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K+ (KATP) channel sub-units. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional KATP channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure. PMID:18669912

Embryonic stem cell therapy of heart failure in genetic cardiomyopathy.

PubMed

Yamada, Satsuki; Nelson, Timothy J; Crespo-Diaz, Ruben J; Perez-Terzic, Carmen; Liu, Xiao-Ke; Miki, Takashi; Seino, Susumu; Behfar, Atta; Terzic, Andre

2008-10-01

Pathogenic causes underlying nonischemic cardiomyopathies are increasingly being resolved, yet repair therapies for these commonly heritable forms of heart failure are lacking. A case in point is human dilated cardiomyopathy 10 (CMD10; Online Mendelian Inheritance in Man #608569), a progressive organ dysfunction syndrome refractory to conventional therapies and linked to mutations in cardiac ATP-sensitive K(+) (K(ATP)) channel subunits. Embryonic stem cell therapy demonstrates benefit in ischemic heart disease, but the reparative capacity of this allogeneic regenerative cell source has not been tested in inherited cardiomyopathy. Here, in a Kir6.2-knockout model lacking functional K(ATP) channels, we recapitulated under the imposed stress of pressure overload the gene-environment substrate of CMD10. Salient features of the human malignant heart failure phenotype were reproduced, including compromised contractility, ventricular dilatation, and poor survival. Embryonic stem cells were delivered through the epicardial route into the left ventricular wall of cardiomyopathic stressed Kir6.2-null mutants. At 1 month of therapy, transplantation of 200,000 cells per heart achieved teratoma-free reversal of systolic dysfunction and electrical synchronization and halted maladaptive remodeling, thereby preventing end-stage organ failure. Tracked using the lacZ reporter transgene, stem cells engrafted into host heart. Beyond formation of cardiac tissue positive for Kir6.2, transplantation induced cell cycle activation and halved fibrotic zones, normalizing sarcomeric and gap junction organization within remuscularized hearts. Improved systemic function induced by stem cell therapy translated into increased stamina, absence of anasarca, and benefit to overall survivorship. Embryonic stem cells thus achieve functional repair in nonischemic genetic cardiomyopathy, expanding indications to the therapy of heritable heart failure. Disclosure of potential conflicts of interest is found at the end of this article.

Characterizing Heart Failure in the Ventricular Volume Domain

PubMed Central

Kerkhof, Peter LM

2015-01-01

Heart failure (HF) may be accompanied by considerable alterations of left ventricular (LV) volume, depending on the particular phenotype. Two major types of HF have been identified, although heterogeneity within each category may be considerable. All variants of HF show substantially elevated LV filling pressures, which tend to induce changes in LV size and shape. Yet, one type of HF is characterized by near-normal values for LV end-diastolic volume (EDV) and even a smaller end-systolic volume (ESV) than in matched groups of persons without cardiac disease. Furthermore, accumulating evidence indicates that, both in terms of shape and size, in men and women, the heart reacts differently to adaptive stimuli as well as to certain pharmacological interventions. Adjustments of ESV and EDV such as in HF patients are associated with (reverse) remodeling mechanisms. Therefore, it is logical to analyze HF subtypes in a graphical representation that relates ESV to EDV. Following this route, one may expect that the two major phenotypes of HF are identified as distinct entities localized in different areas of the LV volume domain. The precise coordinates of this position imply unique characteristics in terms of the actual operating point for LV volume regulation. Evidently, ejection fraction (EF; equal to 1 minus the ratio of ESV and EDV) carries little information within the LV volume representation. Thus far, classification of HF is based on information regarding EF combined with EDV. Our analysis shows that ESV in the two HF groups follows different patterns in dependency of EDV. This observation suggests that a superior HF classification system should primarily be founded on information embodied by ESV. PMID:25780344

Passive hind-limb cycling improves cardiac function and reduces cardiovascular disease risk in experimental spinal cord injury.

PubMed

West, Christopher R; Crawford, Mark A; Poormasjedi-Meibod, Malihe-Sadat; Currie, Katharine D; Fallavollita, Andre; Yuen, Violet; McNeill, John H; Krassioukov, Andrei V

2014-04-15

Spinal cord injury (SCI) causes altered autonomic control and severe physical deconditioning that converge to drive maladaptive cardiac remodelling. We used a clinically relevant experimental model to investigate the cardio-metabolic responses to SCI and to establish whether passive hind-limb cycling elicits a cardio-protective effect. Initially, 21 male Wistar rats were evenly assigned to three groups: uninjured control (CON), T3 complete SCI (SCI) or T3 complete SCI plus passive hind-limb cycling (SCI-EX; 2 × 30 min day(-1), 5 days week(-1) for 4 weeks beginning 6 days post-SCI). On day 32, cardio-metabolic function was assessed using in vivo echocardiography, ex vivo working heart assessments, cardiac histology/molecular biology and blood lipid profiles. Twelve additional rats (n = 6 SCI and n = 6 SCI-EX) underwent in vivo echocardiography and basal haemodynamic assessments pre-SCI and at days 7, 14 and 32 post-SCI to track temporal cardiovascular changes. Compared with CON, SCI exhibited a rapid and sustained reduction in left ventricular dimensions and function that ultimately manifested as reduced contractility, increased myocardial collagen deposition and an up-regulation of transforming growth factor beta-1 (TGFβ1) and mothers against decapentaplegic homolog 3 (Smad3) mRNA. For SCI-EX, the initial reduction in left ventricular dimensions and function at day 7 post-SCI was completely reversed by day 32 post-SCI, and there were no differences in myocardial contractility between SCI-EX and CON. Collagen deposition was similar between SCI-EX and CON. TGFβ1 and Smad3 were down-regulated in SCI-EX. Blood lipid profiles were improved in SCI-EX versus SCI. We provide compelling novel evidence that passive hind-limb cycling prevents cardiac dysfunction and reduces cardiovascular disease risk in experimental SCI.

Therapeutic effect of MG-132 on diabetic cardiomyopathy is associated with its suppression of proteasomal activities: roles of Nrf2 and NF-κB.

PubMed

Wang, Yuehui; Sun, Weixia; Du, Bing; Miao, Xiao; Bai, Yang; Xin, Ying; Tan, Yi; Cui, Wenpeng; Liu, Bin; Cui, Taixing; Epstein, Paul N; Fu, Yaowen; Cai, Lu

2013-02-15

MG-132, a proteasome inhibitor, can upregulate nuclear factor (NF) erythroid 2-related factor 2 (Nrf2)-mediated antioxidative function and downregulate NF-κB-mediated inflammation. The present study investigated whether through the above two mechanisms MG-132 could provide a therapeutic effect on diabetic cardiomyopathy in the OVE26 type 1 diabetic mouse model. OVE26 mice develop hyperglycemia at 2-3 wk after birth and exhibit albuminuria and cardiac dysfunction at 3 mo of age. Therefore, 3-mo-old OVE26 diabetic and age-matched control mice were intraperitoneally treated with MG-132 at 10 μg/kg daily for 3 mo. Before and after MG-132 treatment, cardiac function was measured by echocardiography, and cardiac tissues were then subjected to pathological and biochemical examination. Diabetic mice showed significant cardiac dysfunction, including increased left ventricular systolic diameter and wall thickness and decreased left ventricular ejection fraction with an increase of the heart weight-to-tibia length ratio. Diabetic hearts exhibited structural derangement and remodeling (fibrosis and hypertrophy). In diabetic mice, there was also increased systemic and cardiac oxidative damage and inflammation. All of these pathogenic changes were reversed by MG-132 treatment. MG-132 treatment significantly increased the cardiac expression of Nrf2 and its downstream antioxidant genes with a significant increase of total antioxidant capacity and also significantly decreased the expression of IκB and the nuclear accumulation and DNA-binding activity of NF-κB in the heart. These results suggest that MG-132 has a therapeutic effect on diabetic cardiomyopathy in OVE26 diabetic mice, possibly through the upregulation of Nrf2-dependent antioxidative function and downregulation of NF-κB-mediated inflammation.

Increased Cardiac Arrhythmogenesis Associated With Gap Junction Remodeling With Upregulation of RNA-Binding Protein FXR1.

PubMed

Chu, Miensheng; Novak, Stefanie Mares; Cover, Cathleen; Wang, Anne A; Chinyere, Ikeotunye Royal; Juneman, Elizabeth B; Zarnescu, Daniela C; Wong, Pak Kin; Gregorio, Carol C

2018-02-06

Gap junction remodeling is well established as a consistent feature of human heart disease involving spontaneous ventricular arrhythmia. The mechanisms responsible for gap junction remodeling that include alterations in the distribution of, and protein expression within, gap junctions are still debated. Studies reveal that multiple transcriptional and posttranscriptional regulatory pathways are triggered in response to cardiac disease, such as those involving RNA-binding proteins. The expression levels of FXR1 (fragile X mental retardation autosomal homolog 1), an RNA-binding protein, are critical to maintain proper cardiac muscle function; however, the connection between FXR1 and disease is not clear. To identify the mechanisms regulating gap junction remodeling in cardiac disease, we sought to identify the functional properties of FXR1 expression, direct targets of FXR1 in human left ventricle dilated cardiomyopathy (DCM) biopsy samples and mouse models of DCM through BioID proximity assay and RNA immunoprecipitation, how FXR1 regulates its targets through RNA stability and luciferase assays, and functional consequences of altering the levels of this important RNA-binding protein through the analysis of cardiac-specific FXR1 knockout mice and mice injected with 3xMyc-FXR1 adeno-associated virus. FXR1 expression is significantly increased in tissue samples from human and mouse models of DCM via Western blot analysis. FXR1 associates with intercalated discs, and integral gap junction proteins Cx43 (connexin 43), Cx45 (connexin 45), and ZO-1 (zonula occludens-1) were identified as novel mRNA targets of FXR1 by using a BioID proximity assay and RNA immunoprecipitation. Our findings show that FXR1 is a multifunctional protein involved in translational regulation and stabilization of its mRNA targets in heart muscle. In addition, introduction of 3xMyc-FXR1 via adeno-associated virus into mice leads to the redistribution of gap junctions and promotes ventricular tachycardia, showing the functional significance of FXR1 upregulation observed in DCM. In DCM, increased FXR1 expression appears to play an important role in disease progression by regulating gap junction remodeling. Together this study provides a novel function of FXR1, namely, that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart. © 2017 American Heart Association, Inc.

Fetal cardiac remodeling in twin pregnancy conceived by assisted reproductive technology.

PubMed

Valenzuela-Alcaraz, B; Cruz-Lemini, M; Rodríguez-López, M; Goncé, A; García-Otero, L; Ayuso, H; Sitges, M; Bijnens, B; Balasch, J; Gratacós, E; Crispi, F

2018-01-01

Recent data suggest that singleton fetuses conceived by assisted reproductive technology (ART) present cardiovascular remodeling that may persist postnatally. Twin pregnancies are more frequent in the ART population and are associated with increased adverse perinatal outcomes, such as hypertensive disorders, gestational diabetes and preterm birth. However, it is unknown whether cardiac remodeling is also present in twin pregnancies conceived by ART. Our aim was to assess the presence of fetal cardiac remodeling and dysfunction in twin pregnancies conceived by ART as compared with those conceived spontaneously (SC). This was a prospective cohort study including 50 dichorionic twin fetuses conceived by ART and 50 SC twin fetuses. The study protocol included collection of baseline/perinatal data and a fetal ultrasound examination at 28-30 weeks' gestation, including assessment of estimated fetal weight, fetoplacental Doppler and fetal echocardiography. Measurements of atrial area, atrial/heart ratio, ventricular sphericity index, free wall thickness, mitral and tricuspid annular plane systolic excursions, and systolic and early diastolic peak velocities were assessed. Multilevel analyses were used to compare perinatal and ultrasonographic parameters. Comparisons of echocardiographic variables were adjusted for parental age, paternal body mass index and incidence of pre-eclampsia. Compared with SC twins, ART twin fetuses showed significant cardiac changes, predominantly affecting the right heart, such as dilated atria (right atrial/heart area: 15.7 ± 3.1 vs 18.4 ± 3.2, P < 0.001), more globular ventricles (right ventricular sphericity index: 1.57 ± 0.25 vs 1.41 ± 0.23, P = 0.001) and thicker myocardial walls (septal wall thickness: 2.57 ± 0.45 mm vs 2.84 ± 0.41 mm, P = 0.034) together with reduced longitudinal motion (tricuspid annular plane systolic excursion: 6.36 ± 0.89 mm vs 5.18 ± 0.93 mm, P < 0.001). ART twin fetuses present signs of cardiac remodeling and dysfunction. These changes are similar to those observed in ART singletons and reinforce the concept of fetal cardiac programing in ART. These results open opportunities for early detection and intervention in infants conceived by ART. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction.

PubMed

Lord, Kevin C; Shenouda, Sylvia K; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A; Varner, Kurt J

2010-07-01

Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Echocardiography and Millar pressure-volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased -dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction

PubMed Central

Lord, Kevin C.; Shenouda, Sylvia K.; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A.; Varner, Kurt J.

2010-01-01

Aims Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Methods and results Echocardiography and Millar pressure–volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased −dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. Conclusion This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction. PMID:20139112

Propionyl-L-carnitine limits chronic ventricular dilation after myocardial infarction in rats.

PubMed

Micheletti, R; Di Paola, E D; Schiavone, A; English, E; Benatti, P; Capasso, J M; Anversa, P; Bianchi, G

1993-04-01

To determine whether propionyl-L-carnitine (PLC) administration ameliorates ventricular remodeling after myocardial infarction, we performed coronary occlusion in rats and examined the long-term effects of the drug 19-24 wk after surgery. In view of the well-established role of angiotensin-converting enzyme (ACE) inhibitors in the reduction of ventricular dilation after infarction, the therapeutic impact of oral PLC (60 mg/kg) was compared with that of enalapril (1 mg/kg). Infarct size measured planimetrically was found to be comparable in untreated, PLC-treated, and enalapril-treated rats, averaging 40-46% of the left ventricular free wall. Heart weight was increased 14, 16, and 11% with no treatment, with PLC, and with enalapril, respectively. The relationship between left ventricular filling pressure and chamber volume demonstrated that PLC and enalapril significantly prevented the expansion in cavitary size after infarction. These protective influences were observed throughout the range of filling pressures measured, from 0 to 30 mmHg. At a uniform reference point of filling pressure of 4 mmHg, untreated infarcted hearts showed an expansion in ventricular volume of 2.17-fold (P < 0.0001). Corresponding increases in this parameter after PLC and enalapril were 36 and 43%, respectively, both not statistically significant. Moreover, PLC was capable of reducing the alterations in myocardial compliance associated with myocardial infarction. In conclusion, PLC reduces the magnitude of decompensated eccentric hypertrophy produced by myocardial infarction in a manner similar to that found with ACE inhibition.

Lung tissue remodelling in MCT-induced pulmonary hypertension: a proposal for a novel scoring system and changes in extracellular matrix and fibrosis associated gene expression.

PubMed

Franz, Marcus; Grün, Katja; Betge, Stefan; Rohm, Ilonka; Ndongson-Dongmo, Bernadin; Bauer, Reinhard; Schulze, P Christian; Lichtenauer, Michael; Petersen, Iver; Neri, Dario; Berndt, Alexander; Jung, Christian

2016-12-06

Pulmonary hypertension (PH) is associated with vasoconstriction and remodelling. We studied lung tissue remodelling in a rat model of PH with special focus on histology and extracellular matrix (ECM) remodelling. After induction of PH by monocrotaline, lung tissue was analysed histologically, by gene expression analysis and immunofluorescence labelling of ED-A domain containing fibronectin (ED-A+ Fn), B domain containing tenascin-C (B+ Tn-C) as well as alpha-smooth muscle actin (α-SMA). Serum concentrations of ED-A+ Fn were determined by ELISA. Systolic right ventricular pressure (RVPsys) values were significantly elevated in PH (n = 18; 75 ± 26.4 mmHg) compared to controls (n = 10; 29 ± 19.3 mmHg; p = 0.015). The histological sum-score was significantly increased in PH (8.0 ± 2.2) compared to controls (2.5 ± 1.6; p < 0.001). Gene expression analysis revealed relevant induction of several key genes of extracellular matrix remodelling. Increased protein deposition of ED-A+ Fn but not of B+ Tn-C and α-SMA in lung tissue was found in PH (2.88 ± 3.19 area%) compared to controls (1.32 ± 0.16 area%; p = 0.030). Serum levels of ED-A+ Fn were significantly higher in PH (p = 0.007) positively correlating with RVPsys (r = 0.618, p = 0.019). We here present a novel histological scoring system to assess lung tissue remodelling in PH. Gene expression analysis revealed induction of candidate genes involved in collagen matrix turnover, fibrosis and vascular remodelling. The stable increased tissue deposition of ED-A+ Fn in PH as well as its dynamics in serum suggests a role as a promising novel biomarker and potential therapeutic target.

Effects of hawthorn on the progression of heart failure in a rat model of aortic constriction.

PubMed

Hwang, Hyun Seok; Boluyt, Marvin O; Converso, Kimber; Russell, Mark W; Bleske, Barry E

2009-06-01

To determine the effects of hawthorn (Crataegus oxycantha) on left ventricular remodeling and function in pressure overload-induced heart failure in an animal model. Randomized, parallel, dose-ranging animal study. University research facility. Seventy-four male Sprague-Dawley rats; 44 were included in the final analysis. Rats underwent a sham operation or aortic constriction. Rats subjected to the sham operation were treated with vehicle (10% agar-agar), and those subjected to aortic constriction were treated with vehicle or hawthorn (C. oxycantha special extract WS 1442) 1.3, 13, or 130 mg/kg for 5 months. Rats and their hearts were weighed, and echocardiographic measurements were performed at baseline and at 2, 3, 4, and 5 months after aortic constriction. Protein expression for markers of fibrosis and for atrial natriuretic factor was also measured. Aortic constriction increased the left ventricular:body weight ratio by 53% in vehicle-treated rats; Hawthorn treatment did not significantly affect the aortic constriction-induced increase in this ratio. Left ventricular volumes and dimensions at systole and diastole significantly increased 5 months after aortic constriction compared with baseline in rats given vehicle (> 20% increase, p<0.05) but not in those given hawthorn 130 mg/kg (< 10% increase). After aortic constriction, the velocity of circumferential shortening significantly decreased in the vehicle group but not in the medium- or high-dose groups. In the aortic constriction-vehicle group, the induced increases in messenger RNA expression for atrial natriuretic factor (approximately 1000%) and fibronectin (approximately 80%) were significantly attenuated by high-dose hawthorn treatment by approximately 80% and 50%, respectively. Hawthorn treatment exhibited modest beneficial effects on cardiac remodeling and function during long-term, pressure overload-induced heart failure in rats.

Moxonidine-induced central sympathoinhibition improves prognosis in rats with hypertensive heart failure.

PubMed

Honda, Nobuhiro; Hirooka, Yoshitaka; Ito, Koji; Matsukawa, Ryuichi; Shinohara, Keisuke; Kishi, Takuya; Yasukawa, Keiji; Utsumi, Hideo; Sunagawa, Kenji

2013-11-01

Enhanced central sympathetic outflow is an indicator of the prognosis of heart failure. Although the central sympatholytic drug moxonidine is an established therapeutic strategy for hypertension, its benefits for hypertensive heart failure are poorly understood. In the present study, we investigated the effects of central sympathoinhibition by intracerebral infusion of moxonidine on survival in a rat model of hypertensive heart failure and the possible mechanisms involved. As a model of hypertensive heart failure, we fed Dahl salt-sensitive rats an 8% NaCl diet from 7 weeks of age. Intracerebroventricular (ICV) infusion of moxonidine (moxonidine-ICV-treated group [Mox-ICV]) or vehicle (vehicle-ICV-treated group [Veh-ICV]) was performed at 14-20 weeks of age, during the increased heart failure phase. Survival rates were examined, and sympathetic activity, left ventricular function and remodelling, and brain oxidative stress were measured. Hypertension and left ventricular hypertrophy were established by 13 weeks of age. At around 20 weeks of age, Veh-ICV rats exhibited overt heart failure concomitant with increased urinary norepinephrine (uNE) excretion as an index of sympathetic activity, dilated left ventricle, decreased percentage fractional shortening, and myocardial fibrosis. Survival rates at 21 weeks of age (n = 28) were only 23% in Veh-ICV rats, and 76% (n = 17) in Mox-ICV rats with concomitant decreases in uNE, myocardial fibrosis, collagen type I/III ratio, brain oxidative stress, and suppressed left ventricular dysfunction. Moxonidine-induced central sympathoinhibition attenuated brain oxidative stress, prevented cardiac dysfunction and remodelling, and improved the prognosis in rats with hypertensive heart failure. Central sympathoinhibition can be effective for the treatment of hypertensive heart failure.

Deterioration of left ventricular chamber performance after bed rest : "cardiovascular deconditioning" or hypovolemia?

NASA Technical Reports Server (NTRS)

Perhonen, M. A.; Zuckerman, J. H.; Levine, B. D.; Blomqvist, C. G. (Principal Investigator)

2001-01-01

BACKGROUND: Orthostatic intolerance after bed rest is characterized by hypovolemia and an excessive reduction in stroke volume (SV) in the upright position. We studied whether the reduction in SV is due to a specific adaptation of the heart to head-down tilt bed rest (HDTBR) or acute hypovolemia alone. METHODS AND RESULTS: We constructed left ventricular (LV) pressure-volume curves from pulmonary capillary wedge pressure and LV end-diastolic volume and Starling curves from pulmonary capillary wedge pressure and SV during lower body negative pressure and saline loading in 7 men (25+/-2 years) before and after 2 weeks of -6 degrees HDTBR and after the acute administration of intravenous furosemide. Both HDTBR and hypovolemia led to a similar reduction in plasma volume. However, baseline LV end-diastolic volume decreased by 20+/-4% after HDTBR and by 7+/-2% after hypovolemia (interaction P<0.001). Moreover, SV was reduced more and the Starling curve was steeper during orthostatic stress after HDTBR than after hypovolemia. The pressure-volume curve showed a leftward shift and the equilibrium volume of the left ventricle was decreased after HDTBR; however, after hypovolemia alone, the curve was identical, with no change in equilibrium volume. Lower body negative pressure tolerance was reduced after both conditions; it decreased by 27+/-7% (P<0.05) after HDTBR and by 18+/-8% (P<0.05) after hypovolemia. CONCLUSIONS: Chronic HDTBR leads to ventricular remodeling, which is not seen with equivalent degrees of acute hypovolemia. This remodeling leads to a greater decrease in SV during orthostatic stress after bed rest than hypovolemia alone, potentially contributing to orthostatic intolerance.

Long-term blockade of L/N-type Ca2+ channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart

PubMed Central

Takahara, A; Nakamura, Y; Wagatsuma, H; Aritomi, S; Nakayama, A; Satoh, Y; Akie, Y; Sugiyama, A

2009-01-01

Background and purpose: The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death. Experimental approach: The L-type Ca2+ channel blocker amlodipine (2.5 mg·day−1), L/N-type Ca2+ channel blocker cilnidipine (5 mg·day−1), or the angiotensin II receptor blocker candesartan (12 mg·day−1) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration. Key results: Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed. Conclusions and implications: Long-term blockade of L/N-type Ca2+ channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases. PMID:19785655

Correlation of Arterial Stiffness With Left Atrial Volume Index and Left Ventricular Mass Index in Young Adults: Evaluation by Coronary Computed Tomography Angiography.

PubMed

Osawa, Kazuhiro; Nakanishi, Rine; Miyoshi, Toru; Rahmani, Sina; Ceponiene, Indre; Nezarat, Negin; Kanisawa, Mitsuru; Qi, Hong; Jayawardena, Eranthi; Kim, Nicholas; Ito, Hiroshi; Budoff, Matthew J

2018-04-26

Increased arterial stiffness is reportedly associated with cardiac remodelling, including the left atrium and left ventricle, in middle-aged and older adults. However, little is known about this association in young adults. In total, 73 patients (44 (60%) men) aged 25 to 45 years with suspected coronary artery disease were included in the analysis. The left atrial volume index (LAVI), left ventricular volume index (LVVI), and left ventricular mass index (LVMI) were measured using coronary computed tomography angiography (CCTA). Arterial stiffness was assessed with the cardio-ankle vascular index (CAVI). An abnormally high CAVI was defined as that above the age- and sex-specific cut-off points of the CAVI. Compared with patients with a normal CAVI, those with an abnormally high CAVI were older and had a greater prevalence of diabetes mellitus, higher diastolic blood pressure, greater coronary artery calcification score, and a greater LAVI (33.5±10.3 vs. 43.0±10.3mL/m 2 , p <0.01). In contrast, there were no significant differences in the LVVI or LVMI between the subgroups with a normal CAVI and an abnormally high CAVI. Multivariate linear regression analysis showed that the LAVI was significantly associated with an abnormally high CAVI (standardised regression coefficient=0.283, p=0.03). The present study demonstrated that increased arterial stiffness is associated with the LAVI, which reflects the early stages of cardiac remodelling, independent of various comorbidity factors in young adults with suspected coronary artery disease. Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.

T-tubule Disruption Promotes Calcium Alternans in Failing Ventricular Myocytes: Mechanistic Insights from Computational Modeling

PubMed Central

Nivala, Michael; Song, Zhen; Weiss, James N.; Qu, Zhilin

2015-01-01

In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the mechanisms of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in “orphaned” RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down-regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF. PMID:25450613

T-tubule disruption promotes calcium alternans in failing ventricular myocytes: mechanistic insights from computational modeling.

PubMed

Nivala, Michael; Song, Zhen; Weiss, James N; Qu, Zhilin

2015-02-01

In heart failure (HF), T-tubule (TT) disruption contributes to dyssynchronous calcium (Ca) release and impaired contraction, but its role in arrhythmogenesis remains unclear. In this study, we investigate the effects of TT disruption and other HF remodeling factors on Ca alternans in ventricular myocytes using computer modeling. A ventricular myocyte model with detailed spatiotemporal Ca cycling modeled by a coupled Ca release unit (CRU) network was used, in which the L-type Ca channels and the ryanodine receptor (RyR) channels were simulated by random Markov transitions. TT disruption, which removes the L-type Ca channels from the associated CRUs, results in "orphaned" RyR clusters and thus provides increased opportunity for spark-induced Ca sparks to occur. This effect combined with other HF remodeling factors promoted alternans by two distinct mechanisms: 1) for normal sarco-endoplasmic reticulum Ca ATPase (SERCA) activity, alternans was caused by both CRU refractoriness and coupling. The increased opportunity for spark-induced sparks by TT disruption combined with the enhanced CRU coupling by Ca elevation in the presence or absence of increased RyR leakiness facilitated spark synchronization on alternate beats to promote Ca alternans; 2) for down-regulated SERCA, alternans was caused by the sarcoplasmic reticulum (SR) Ca load-dependent mechanism, independent of CRU refractoriness. TT disruption and increased RyR leakiness shifted and steepened the SR Ca release-load relationship, which combines with down-regulated SERCA to promote Ca alternans. In conclusion, the mechanisms of Ca alternans for normal and down-regulated SERCA are different, and TT disruption promotes Ca alternans by both mechanisms, which may contribute to alternans at different stages of HF. Copyright © 2014 Elsevier Ltd. All rights reserved.

Heart Rate Reduction With Ivabradine Protects Against Left Ventricular Remodeling by Attenuating Infarct Expansion and Preserving Remote-Zone Contractile Function and Synchrony in a Mouse Model of Reperfused Myocardial Infarction.

PubMed

O'Connor, Daniel M; Smith, Robert S; Piras, Bryan A; Beyers, Ronald J; Lin, Dan; Hossack, John A; French, Brent A

2016-04-22

Ivabradine selectively inhibits the pacemaker current of the sinoatrial node, slowing heart rate. Few studies have examined the effects of ivabradine on the mechanical properties of the heart after reperfused myocardial infarction (MI). Advances in ultrasound speckle-tracking allow strain analyses to be performed in small-animal models, enabling the assessment of regional mechanical function. After 1 hour of coronary occlusion followed by reperfusion, mice received 10 mg/kg per day of ivabradine dissolved in drinking water (n=10), or were treated as infarcted controls (n=9). Three-dimensional high-frequency echocardiography was performed at baseline and at days 2, 7, 14, and 28 post-MI. Speckle-tracking software was used to calculate intramural longitudinal myocardial strain (Ell) and strain rate. Standard deviation time to peak radial strain (SD Tpeak Err) and temporal uniformity of strain were calculated from short-axis cines acquired in the left ventricular remote zone. Ivabradine reduced heart rate by 8% to 16% over the course of 28 days compared to controls (P<0.001). On day 28 post-MI, the ivabradine group was found to have significantly smaller end-systolic volumes, greater ejection fraction, reduced wall thinning, and greater peak Ell and Ell rate in the remote zone, as well as globally. Temporal uniformity of strain and SD Tpeak Err were significantly smaller in the ivabradine-treated group by day 28 (P<0.05). High-frequency ultrasound speckle-tracking demonstrated decreased left ventricular remodeling and dyssynchrony, as well as improved mechanical performance in remote myocardium after heart rate reduction with ivabradine. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

High intensity interval and endurance training have opposing effects on markers of heart failure and cardiac remodeling in hypertensive rats.

PubMed

Holloway, Tanya M; Bloemberg, Darin; da Silva, Mayne L; Simpson, Jeremy A; Quadrilatero, Joe; Spriet, Lawrence L

2015-01-01

There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT) in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET) that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P < 0.05), and promoted a 20% (P<0.05) increase in the left ventricular capillary/fibre ratio, an increase in endothelial nitric oxide synthase protein (P<0.05), and a decrease in hypoxia inducible factor 1 alpha protein content (P<0.05). In contrast, HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (P<0.05) and a 20% decrease in cross sectional area (P<0.05). HIIT also increased brain natriuretic peptide by 50% (P<0.05), in the absence of concomitant angiogenesis, strongly suggesting pathological cardiac remodeling. The current data support the longstanding belief in the effectiveness of ET in hypertension. However, HIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease.

Protective Effects of 10-nitro-oleic Acid in a Hypoxia-Induced Murine Model of Pulmonary Hypertension

PubMed Central

Klinke, Anna; Möller, Annika; Pekarova, Michaela; Ravekes, Thorben; Friedrichs, Kai; Berlin, Matthias; Scheu, Katrin M.; Kubala, Lukas; Kolarova, Hana; Ambrozova, Gabriela; Schermuly, Ralph T.; Woodcock, Steven R.; Freeman, Bruce A.; Rosenkranz, Stephan; Baldus, Stephan; Rudolph, Volker

2014-01-01

Pulmonary arterial hypertension (PAH) is characterized by adverse remodeling of pulmonary arteries. Although the origin of the disease and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of electrophilic fatty acid nitroalkene derivatives, which exert potent anti-inflammatory effects. The current study investigated the role of 10-nitro-oleic acid (OA-NO2) in modulating the pathophysiology of PAH in mice. Mice were kept for 28 days under normoxic or hypoxic conditions, and OA-NO2 was infused subcutaneously. Right ventricular systolic pressure (RVPsys) was determined, and right ventricular and lung tissue was analyzed. The effect of OA-NO2 on cultured pulmonary artery smooth muscle cells (PASMCs) and macrophages was also investigated. Changes in RVPsys revealed increased pulmonary hypertension in mice on hypoxia, which was significantly decreased by OA-NO2 administration. Right ventricular hypertrophy and fibrosis were also attenuated by OA-NO2 treatment. The infiltration of macrophages and the generation of reactive oxygen species were elevated in lung tissue of mice on hypoxia and were diminished by OA-NO2 treatment. Moreover, OA-NO2 decreased superoxide production of activated macrophages and PASMCs in vitro. Vascular structural remodeling was also limited by OA-NO2. In support of these findings, proliferation and activation of extracellular signal-regulated kinases 1/2 in cultured PASMCs was less pronounced on application of OA-NO2.Our results show that the oleic acid nitroalkene derivative OA-NO2 attenuates hypoxia-induced pulmonary hypertension in mice. Thus, OA-NO2 represents a potential therapeutic agent for the treatment of PAH. PMID:24521348

Left Ventricular Structure and Risk of Cardiovascular Events: A Framingham Heart Study Cardiac Magnetic Resonance Study

PubMed Central

Tsao, Connie W; Gona, Philimon N; Salton, Carol J; Chuang, Michael L; Levy, Daniel; Manning, Warren J; O’Donnell, Christopher J

2015-01-01

Background Elevated left ventricular mass index (LVMI) and concentric left ventricular (LV) remodeling are related to adverse cardiovascular disease (CVD) events. The predictive utility of LV concentric remodeling and LV mass in the prediction of CVD events is not well characterized. Methods and Results Framingham Heart Study Offspring Cohort members without prevalent CVD (n=1715, 50% men, aged 65±9 years) underwent cardiovascular magnetic resonance for LVMI and geometry (2002–2006) and were prospectively followed for incident CVD (myocardial infarction, coronary insufficiency, heart failure, stroke) or CVD death. Over 13 808 person-years of follow-up (median 8.4, range 0.0 to 10.5 years), 85 CVD events occurred. In multivariable-adjusted proportional hazards regression models, each 10-g/m2 increment in LVMI and each 0.1 unit in relative wall thickness was associated with 33% and 59% increased risk for CVD, respectively (P=0.004 and P=0.009, respectively). The association between LV mass/LV end-diastolic volume and incident CVD was borderline significant (P=0.053). Multivariable-adjusted risk reclassification models showed a modest improvement in CVD risk prediction with the incorporation of cardiovascular magnetic resonance LVMI and measures of LV concentricity (C-statistic 0.71 [95% CI 0.65 to 0.78] for the model with traditional risk factors only, improved to 0.74 [95% CI 0.68 to 0.80] for the risk factor model additionally including LVMI and relative wall thickness). Conclusions Among adults free of prevalent CVD in the community, greater LVMI and LV concentric hypertrophy are associated with a marked increase in adverse incident CVD events. The potential benefit of aggressive primary prevention to modify LV mass and geometry in these adults requires further investigation. PMID:26374295

Relationship of carotid arterial functional and structural changes to left atrial volume in untreated hypertension.

PubMed

Jaroch, Joanna; Rzyczkowska, Barbara; Bociąga, Zbigniew; Vriz, Olga; Driussi, Caterina; Loboz-Rudnicka, Maria; Dudek, Krzysztof; Łoboz-Grudzień, Krystyna

2016-04-01

The contribution of arterial functional and structural changes to left ventricular (LV) diastolic dysfunction has been the area of recent research. There are some studies on the relationship between arterial stiffness (a.s.) and left atrial (LA) remodelling as a marker of diastolic burden. Little is known about the association of arterial structural changes and LA remodelling in hypertension (H). The aim of this study was to examine the relationship between carotid a.s. and intima-media thickness (IMT) and LA volume in subjects with H. The study included 245 previously untreated hypertensives (166 women and 79 men, mean age 53.7 ± 11.8 years). Each patient was subjected to echocardiography with measurement of LA volume, evaluation of left ventricular hypertrophy (LVH) and LV systolic/diastolic function indices, integrated assessment of carotid IMT and echo-tracking of a.s. and wave reflection parameters. Univariate regression analysis revealed significant correlations between indexed LA volume and selected clinical characteristics, echocardiographic indices of LVH and LV diastolic/systolic function and a.s./wave reflection parameters. The following parameters were identified as independent determinants of indexed LA volume on multivariate regression analysis: diastolic blood pressure (beta = -0.229, P < 0.001), left ventricular mass index (LVMI; beta = 0.258, P < 0.001), E/e’ index (ratio of early mitral flow wave velocity – E to early diastolic mitral annular velocity – e’; beta = 0.266, P = 0.001), augmentation index (AI; beta = 0.143, P = 0.008) and body mass index (BMI; beta = 0.132, P = 0.017). No correlations between indexed LA volume and IMT were found. There is a significant relationship between carotid arterial stiffness but not intima-media thickness and LA volume in patients with untreated hypertension.

Material properties of CorCap passive cardiac support device.

PubMed

Chitsaz, Sam; Wenk, Jonathan F; Ge, Liang; Wisneski, Andrew; Mookhoek, Aart; Ratcliffe, Mark B; Guccione, Julius M; Tseng, Elaine E

2013-01-01

Myocardial function deteriorates during ventricular remodeling in patients with congestive heart failure (HF). Ventricular restraint therapy using a cardiac support device (CSD) is designed to reduce the amount of stress inside the dilated ventricles, which in turn halts remodeling. However, as an open mesh surrounding the heart, it is unknown what the mechanical properties of the CSD are in different fiber orientations. Composite specimens of CorCap (Acorn Cardiovascular, Inc, St. Paul, MN) CSD fabric and silicone were constructed in different fiber orientations and tested on a custom-built biaxial stretcher. Silicone controls were made and stretched to detect the parameters of the matrix. CSD coefficients were calculated using the composite and silicone matrix stress-strain data. Stiffness in different fiber orientations was determined. Silicone specimens exerted a linear behavior, with stiffness of 2.57 MPa. For the composites with 1 fiber set aligned with respect to the stretch axes, stiffness in the direction of the aligned fiber set was higher than that in the cross-fiber direction (14.39 MPa versus 5.66 MPa), indicating greater compliance in the cross-fiber direction. When the orientation of the fiber sets in the composite were matched to the expected clinical orientation of the implanted CorCap, the stiffness in the circumferential axis (with respect to the heart) was greater than in the longitudinal axis (10.55 MPa versus 9.70 MPa). The mechanical properties of the CorCap demonstrate directionality with greater stiffness circumferentially than longitudinally. Implantation of the CorCap clinically should take into account the directionality of the biomechanics to optimize ventricular restraint. Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

High Intensity Interval and Endurance Training Have Opposing Effects on Markers of Heart Failure and Cardiac Remodeling in Hypertensive Rats

PubMed Central

Holloway, Tanya M.; Bloemberg, Darin; da Silva, Mayne L.; Simpson, Jeremy A.; Quadrilatero, Joe; Spriet, Lawrence L.

2015-01-01

There has been re-emerging interest and significant work dedicated to investigating the metabolic effects of high intensity interval training (HIIT) in recent years. HIIT is considered to be a time efficient alternative to classic endurance training (ET) that elicits similar metabolic responses in skeletal muscle. However, there is a lack of information on the impact of HIIT on cardiac muscle in disease. Therefore, we determined the efficacy of ET and HIIT to alter cardiac muscle characteristics involved in the development of diastolic dysfunction, such as ventricular hypertrophy, fibrosis and angiogenesis, in a well-established rodent model of hypertension-induced heart failure before the development of overt heart failure. ET decreased left ventricle fibrosis by ~40% (P < 0.05), and promoted a 20% (P<0.05) increase in the left ventricular capillary/fibre ratio, an increase in endothelial nitric oxide synthase protein (P<0.05), and a decrease in hypoxia inducible factor 1 alpha protein content (P<0.05). In contrast, HIIT did not decrease existing fibrosis, and HIIT animals displayed a 20% increase in left ventricular mass (P<0.05) and a 20% decrease in cross sectional area (P<0.05). HIIT also increased brain natriuretic peptide by 50% (P<0.05), in the absence of concomitant angiogenesis, strongly suggesting pathological cardiac remodeling. The current data support the longstanding belief in the effectiveness of ET in hypertension. However, HIIT promoted a pathological adaptation in the left ventricle in the presence of hypertension, highlighting the need for further research on the widespread effects of HIIT in the presence of disease. PMID:25803693

Left ventricular remodeling and change of systolic function after closure of patent ductus arteriosus in adults: device and surgical closure.

PubMed

Jeong, Young-Hoon; Yun, Tae-Jin; Song, Jong-Min; Park, Jung-Jun; Seo, Dong-Man; Koh, Jae-Kon; Lee, Se-Whan; Kim, Mi-Jeong; Kang, Duk-Hyun; Song, Jae-Kwan

2007-09-01

Left ventricular (LV) remodeling and predictors of LV systolic function late after closure of patent ductus arteriosus (PDA) in adults remain to be clearly demonstrated. In 45 patients with PDA, including 28 patients who received successful occlusion using the Amplatzer device (AD group) (AGA, Golden Valley, MN) and 17 patients who received surgical closure (OP group), echocardiography studies were performed before closure and 1 day (AD group) or within 7 days (OP group) after closure, and then were repeated at > or = 6 months (17 +/- 13 months). In both groups, LV ejection fraction (EF) and end-diastolic volume index were significantly decreased immediately after closure, whereas end-systolic volume index did not change. During the long-term follow-up period, end-systolic as well as end-diastolic volume indices decreased significantly in both groups and LV EF recovered compared to the immediate postclosure state. However, LV EF remained low compared to the preclosure state. Five patients (11.1%) including 3 patients in the AD group and 2 patients in the OP group showed persistent late LV systolic dysfunction (EF <50%). In stepwise, multiple logistic regression analysis, preclosure EF was the only independent predictor of late normal postclosure EF (odds ratio, 1.230; 95% CI, 1.054-1.434; P = .008). Receiver operating characteristic curve analysis showed that preclosure EF > or = 62% had a sensitivity of 72% and a specificity of 83% for predicting late normal LV EF after closure. Left ventricular EF remains low late after PDA closure compared with preclosure state in adults. Preclosure LV EF is the best index to predict late postclosure LV EF.

Leaflet area as a determinant of tricuspid regurgitation severity in patients with pulmonary hypertension.

PubMed

Afilalo, Jonathan; Grapsa, Julia; Nihoyannopoulos, Petros; Beaudoin, Jonathan; Gibbs, J Simon R; Channick, Richard N; Langleben, David; Rudski, Lawrence G; Hua, Lanqi; Handschumacher, Mark D; Picard, Michael H; Levine, Robert A

2015-05-01

Tricuspid regurgitation (TR) is a risk factor for mortality in pulmonary hypertension (PH). TR severity varies among patients with comparable degrees of PH and right ventricular remodeling. The contribution of leaflet adaptation to the pathophysiology of TR has yet to be examined. We hypothesized that tricuspid leaflet area (TLA) is increased in PH, and that the adequacy of this increase relative to right ventricular remodeling determines TR severity. A prospective cohort of 255 patients with PH from pre and postcapillary pathogeneses was assembled from 2 centers. Patients underwent a 3-dimensional echocardiogram focused on the tricuspid apparatus. TLA was measured with the Omni 4D software package. Compared with normal controls, patients with PH had a 2-fold increase in right ventricular volumes, 62% increase in annular area, and 49% increase in TLA. Those with severe TR demonstrated inadequate increase in TLA relative to the closure area, such that the ratio of TLA:closure area <1.78 was highly predictive of severe TR (odds ratio, 68.7; 95% confidence interval, 16.2-292.7). The median vena contracta width was 8.5 mm in the group with small TLA and large closure area as opposed to 4.8 mm in the group with large TLA and large closure area. TLA plays a significant role in determining which patients with PH develop severe functional TR. The ratio of TLA:closure area, reflecting the balance between leaflet adaptation versus annular dilation and tethering forces, is an indicator of TR severity that may identify which patients stand to benefit from leaflet augmentation during tricuspid valve repair. © 2015 American Heart Association, Inc.

Spatial variability in T-tubule and electrical remodeling of left ventricular epicardium in mouse hearts with transgenic Gαq overexpression-induced pathological hypertrophy

PubMed Central

Tao, Wen; Shi, Jianjian; Dorn, Gerald W.; Wei, Lei; Rubart, Michael

2012-01-01

Pathological left ventricular hypertrophy (LVH) is consistently associated with prolongation of the ventricular action potentials. A number of previous studies, employing various experimental models of hypertrophy, have revealed marked differences in the effects of hypertrophy on action potential duration (APD) between myocytes from endocardial and epicardial layers of the LV free wall. It is not known, however, whether pathological LVH is also accompanied by redistribution of APD among myocytes from the same layer in the LV free wall. In the experiments here, LV epicardial action potential remodeling was examined in a mouse model of decompensated LVH, produced by cardiac-restricted transgenic Gαq overexpression. Confocal linescanning-based optical recordings of propagated action potentials from individual in situ cardiomyocytes across the outer layer of the anterior LV epicardium demonstrated spatially non-uniform action potential prolongation in transgenic hearts, giving rise to alterations in spatial dispersion of epicardial repolarization. Local density and distribution of anti-Cx43 mmune reactivity in Gαq hearts were unchanged compared to wild-type hearts, suggesting preservation of intercellular coupling. Confocal microscopy also revealed heterogeneous disorganization of T-tubules in epicardial cardiomyocytes in situ. These data provide evidence of the existence of significant electrical and structural heterogeneity within the LV epicardial layer of hearts with transgenic Gαq overexpression-induced hypertrophy, and further support the notion that a small portion of electrically well connected LV tissue can maintain dispersion of action potential duration through heterogeneity in the activities of sarcolemmal ionic currents that control repolarization. It remains to be examined whether other experimental models of pathological LVH, including pressure overload LVH, similarly exhibit alterations in T-tubule organization and/or dispersion of repolarization within distinct layers of LV myocardium. PMID:22728217

BMP type II receptor as a therapeutic target in pulmonary arterial hypertension.

PubMed

Orriols, Mar; Gomez-Puerto, Maria Catalina; Ten Dijke, Peter

2017-08-01

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by a progressive elevation in mean pulmonary arterial pressure. This occurs due to abnormal remodeling of small peripheral lung vasculature resulting in progressive occlusion of the artery lumen that eventually causes right heart failure and death. The most common cause of PAH is inactivating mutations in the gene encoding a bone morphogenetic protein type II receptor (BMPRII). Current therapeutic options for PAH are limited and focused mainly on reversal of pulmonary vasoconstriction and proliferation of vascular cells. Although these treatments can relieve disease symptoms, PAH remains a progressive lethal disease. Emerging data suggest that restoration of BMPRII signaling in PAH is a promising alternative that could prevent and reverse pulmonary vascular remodeling. Here we will focus on recent advances in rescuing BMPRII expression, function or signaling to prevent and reverse pulmonary vascular remodeling in PAH and its feasibility for clinical translation. Furthermore, we summarize the role of described miRNAs that directly target the BMPR2 gene in blood vessels. We discuss the therapeutic potential and the limitations of promising new approaches to restore BMPRII signaling in PAH patients. Different mutations in BMPR2 and environmental/genetic factors make PAH a heterogeneous disease and it is thus likely that the best approach will be patient-tailored therapies.

Ventricular tachyarrhythmia-related basal cardiomyopathy in rabbits with vagal stimulation--a novel experimental model for inverted Takotsubo-like cardiomyopathy.

PubMed

Takato, Tetsuya; Ashida, Terunao; Seko, Yoshinori; Fujii, Jun; Kawai, Sachio

2010-07-01

Electrical stimulation of the intact (unsectioned) cervical vagus in rabbits frequently provokes ventricular tachyarrhythmias that are often accompanied by mitral regurgitation. Unique pathological lesions often arise on the mitral valve, papillary muscles, and mitral annulus (mitral complex), the latter two of which become swollen and stiffened. These lesions are reversible in nature. Previous studies have essentially ignored the basal portion except for the mitral annulus. Therefore, the present study examined pathological lesions on the left ventricular basal portion in rabbits. The intact right vagal nerves of 20 anesthetized rabbits were repeatedly electrically stimulated under electrocardiographic monitoring. Colloidal carbon (lml) was injected intravenously immediately after the end of the stimulation and all animals were killed 1 week later. Pathological lesions were identified as carbon deposits visible at gross examination. Ventricular bigeminy was induced after vagal stimulation in 15 (75%) of the 20 rabbits. Pathological lesions were evident on the basal portion in 16 (80%) and on the mitral valve and papillary muscles of 15 (75%) of the 20 rabbits. Ventricular bigeminy was closely associated with the development of the pathological lesions, which were rarely observed on the ventricular apex. Cardiomyopathic lesions involving the basal portion and mitral complex were frequently induced in rabbits by vagal stimulation. These lesions bear a close similarity in distribution and reversibility to inverted Takotsubo cardiomyopathy. Copyright 2010 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Takotsubo cardiomyopathy in a patient with Addison disease: is apical ballooning always reversible?

PubMed

Barcin, Cem; Kursaklioglu, Hurkan; Kose, Sedat; Amasyali, Basri; Isik, Ersoy

2010-01-07

Takotsubo cardiomyopathy is characterized by acute ventricular dysfunction in the absence of coronary obstruction. Complete improvement of ventricular function is seen in the vast majority of the patients. We describe a 40-year-old woman with Addison disease who experienced Takotsubo cardiomyopathy but with persistent apical dysfunction during 5-month-follow up.

Multimodality Imaging of Myocardial Injury and Remodeling

PubMed Central

Kramer, Christopher M.; Sinusas, Albert J.; Sosnovik, David E.; French, Brent A.; Bengel, Frank M.

2011-01-01

Advances in cardiovascular molecular imaging have come at a rapid pace over the last several years. Multiple approaches have been taken to better understand the structural, molecular, and cellular events that underlie the progression from myocardial injury to myocardial infarction (MI) and, ultimately, to congestive heart failure. Multimodality molecular imaging including SPECT, PET, cardiac MRI, and optical approaches is offering new insights into the pathophysiology of MI and left ventricular remodeling in small-animal models. Targets that are being probed include, among others, angiotensin receptors, matrix metalloproteinases, integrins, apoptosis, macrophages, and sympathetic innervation. It is only a matter of time before these advances are applied in the clinical setting to improve post-MI prognostication and identify appropriate therapies in patients to prevent the onset of congestive heart failure. PMID:20395347

Matrix remodeling between cells and cellular interactions with collagen bundle

NASA Astrophysics Data System (ADS)

Kim, Jihan; Sun, Bo

When cells are surrounded by complex environment, they continuously probe and interact with it by applying cellular traction forces. As cells apply traction forces, they can sense rigidity of their local environment and remodel the matrix microstructure simultaneously. Previous study shows that single human carcinoma cell (MDA-MB-231) remodeled its surrounding extracellular matrix (ECM) and the matrix remodeling was reversible. In this study we examined the matrix microstructure between cells and cellular interaction between them using quantitative confocal microscopy. The result shows that the matrix microstructure is the most significantly remodeled between cells consisting of aligned, and densified collagen fibers (collagen bundle)., the result shows that collagen bundle is irreversible and significantly change micromechanics of ECM around the bundle. We further examined cellular interaction with collagen bundle by analyzing dynamics of actin and talin formation along with the direction of bundle. Lastly, we analyzed dynamics of cellular protrusion and migrating direction of cells along the bundle.

Cardiac remodeling in response to chronic iron deficiency: role of the erythropoietin receptor.

PubMed

Naito, Yoshiro; Sawada, Hisashi; Oboshi, Makiko; Iwasaku, Toshihiro; Okuhara, Yoshitaka; Morisawa, Daisuke; Eguchi, Akiyo; Hirotani, Shinichi; Mano, Toshiaki; Tsujino, Takeshi; Masuyama, Tohru

2015-06-01

Anemia is a common comorbidity of patients with heart failure, and iron deficiency is known as one of the causes of anemia in heart failure. Recent studies have shown that iron deficiency alone, without overt anemia, is associated with poor outcomes in patients with heart failure. Thus, to minimize the mortality in patients with heart failure, it is important to understand the link between iron deficiency and cardiac function. Chronic untreated iron deficiency results in cardiac remodeling, and we have previously reported that erythropoietin (Epo) and cardiac Epo receptor (EpoR) signaling may be associated with its remodeling. However, the link between EpoR signaling and its remodeling remains to be elucidated. Herein, we investigated the role of EpoR signaling on cardiac remodeling in response to chronic iron deficiency. Wild-type mice and transgene-rescued EpoR-null mutant mice, which express EpoR only in the hematopoietic lineage (EpoR-restricted mice), were fed with either a normal or an iron-restricted diet, and the molecular mechanisms were investigated. Dietary iron restriction gradually induced anemia, Epo secretion, and cardiac hypertrophy in wild-type mice. In contrast, EpoR-restricted mice fed with an iron-restricted diet exhibited anemia, left ventricular dilatation, and cardiac dysfunction compared with wild-type mice. Interestingly, altered cardiac mitochondrial biogenesis was observed in EpoR-restricted mice following iron deficiency. Moreover, cardiac p53 expression was increased in EpoR-restricted mice compared with wild-type mice following iron deficiency. These data indicate that EpoR signaling is associated with cardiac remodeling following chronic iron deficiency.

Ventricular efficiency in pregnant women with congenital heart disease.

PubMed

Muneuchi, Jun; Yamasaki, Keiko; Watanabe, Mamie; Fukumitsu, Azusa; Kawakami, Takeshi; Nakahara, Hiromasa; Joo, Kunitaka

2018-06-15

Pregnant women with congenital heart disease (CHD) are at risk of cardiovascular events during pregnancy as well as postpartum. The aim of our study is to address the feasibility of echocardiography-derived ventricular-arterial coupling during pregnancy and postpartum among women with CHD. In 31 pregnant women with CHD, we performed serial echocardiography at the first and third trimesters, early and late postpartum. The indices of contractility (single-beat determined end-systolic elastance, Ees ab ) and afterload (effective arterial elastance, Ea) were approximated on the basis of the systemic blood pressure and systemic ventricular volume. The ratio of stroke work and pressure-volume area (SW/PVA) representing ventricular efficiency was also calculated. Age at the delivery was 28 (24-31) years. ZAHARA score was 0.75 (0.75-1.50). Gestational age and birth weight of newborns were 38 (37-39) weeks and 2.73 (2.42-2.92) kg, respectively. Heart rate, systemic ventricular end-diastolic volume and stroke volume significantly increased from the first trimester to the third trimester and reversed postpartum to the values of the first trimester. Ees ab and Ea significantly decreased from the first trimester to the third trimester (Ees ab ; 4.90 [2.86-7.14] vs 3.41 [2.53-4.61] mm Hg/ml, p = 0.0001, Ea; 2.83 [1.74-3.30] vs 2.18 [1.67-2.68] mm Hg/ml, p = 0.0012), and reversed early postpartum parallelly. Ejection fraction and SW/PVA remained unchanged throughout pregnancy and postpartum. Echocardiography-derived ventricular-arterial coupling is feasible to understand ventricular function in pregnant women with CHD. Copyright © 2018 Elsevier B.V. All rights reserved.

Hypertension and Atrial Fibrillation: An Intimate Association of Epidemiology, Pathophysiology, and Outcomes.

PubMed

Dzeshka, Mikhail S; Shahid, Farhan; Shantsila, Alena; Lip, Gregory Y H

2017-08-01

Atrial fibrillation (AF) is the most prevalent sustained arrhythmia found in clinical practice. AF rarely exists as a single entity but rather as part of a diverse clinical spectrum of cardiovascular diseases, related to structural and electrical remodeling within the left atrium, leading to AF onset, perpetuation, and progression. Due to the high overall prevalence within the AF population arterial hypertension plays a significant role in the pathogenesis of AF and its complications. Fibroblast proliferation, apoptosis of cardiomyocytes, gap junction remodeling, accumulation of collagen both in atrial and ventricular myocardium all accompany ageing-related structural remodeling with impact on electrical activity. The presence of hypertension also stimulates oxidative stress, systemic inflammation, rennin-angiotensin-aldosterone and sympathetic activation, which further drives the remodeling process in AF. Importantly, both hypertension and AF independently increase the risk of cardiovascular and cerebrovascular events, e.g., stroke and myocardial infarction. Given that both AF and hypertension often present with limited on patient wellbeing, treatment may be delayed resulting in development of complications as the first clinical manifestation of the disease. Antithrombotic prevention in AF combined with strict blood pressure control is of primary importance, since stroke risk and bleeding risk are both greater with underlying hypertension. © American Journal of Hypertension, Ltd 2017. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effects of Trichothecenes on Cardiac Cell Electrical Function

DTIC Science & Technology

1985-12-16

toxic effects . These studies demonstrated unequivocal reversible effects of certain mycotoxins on heart cell electrical activity. Preliminary studies...muscle cells shown in Figure 8 illustrate the typical effects of trichothecene mycotoxins in canine ventricular cells. T-2 tetraol, for 3xample...false tendon cells and V ventricular muscle cells (shown in Figure 8) illustrate the typical effects of trichothecene mycotoxins in canine cardiac

Extracellular Superoxide Dismutase Deficiency Exacerbates Pressure Overload–Induced Left Ventricular Hypertrophy and Dysfunction

PubMed Central

Lu, Zhongbing; Xu, Xin; Hu, Xinli; Zhu, Guangshuo; Zhang, Ping; van Deel, Elza D.; French, Joel P.; Fassett, John T.; Oury, Tim D.; Bache, Robert J.; Chen, Yingjie

2008-01-01

Extracellular superoxide dismutase (SOD) contributes only a small fraction to total SOD activity in the normal heart but is strategically located to scavenge free radicals in the extracellular compartment. To examine the physiological significance of extracellular SOD in the response of the heart to hemodynamic stress, we studied the effect of extracellular SOD deficiency on transverse aortic constriction (TAC)–induced left ventricular remodeling. Under unstressed conditions extracellular SOD deficiency had no effect on myocardial total SOD activity, the ratio of glutathione:glutathione disulfide, nitrotyrosine content, or superoxide anion production but resulted in small but significant increases in myocardial fibrosis and ventricular mass. In response to TAC for 6 weeks, extracellular SOD-deficient mice developed more severe left ventricular hypertrophy (heart weight increased 2.56-fold in extracellular SOD-deficient mice as compared with 1.99-fold in wild-type mice) and pulmonary congestion (lung weight increased 2.92-fold in extracellular SOD-deficient mice as compared with 1.84-fold in wild-type mice). Extracellular SOD-deficient mice also had more ventricular fibrosis, dilation, and a greater reduction of left ventricular fractional shortening and rate of pressure development after TAC. TAC resulted in greater increases of ventricular collagen I, collagen III, matrix metalloproteinase-2, matrix metalloproteinase-9, nitrotyrosine, and superoxide anion production. TAC also resulted in a greater decrease of the ratio of glutathione:glutathione disulfide in extracellular SOD-deficient mice. The finding that extracellular SOD deficiency had minimal impact on myocardial overall SOD activity but exacerbated TAC induced myocardial oxidative stress, hypertrophy, fibrosis, and dysfunction indicates that the distribution of extracellular SOD in the extracellular space is critically important in protecting the heart against pressure overload. PMID:17998475

Mechanisms of right heart disease in pulmonary hypertension (2017 Grover Conference Series).

PubMed

Asosingh, Kewal; Erzurum, Serpil

2018-01-01

Current dogma is that pathological hypertrophy of the right ventricle is a direct consequence of pulmonary vascular remodeling. However, progression of right ventricle dysfunction is not always lung-dependent. Increased afterload caused by pulmonary vascular remodeling initiates the right ventricle hypertrophy, but determinants leading to adaptive or maladaptive hypertrophy and failure remain unknown. Ischemia in a hypertrophic right ventricle may directly contribute to right heart failure. Rapidly enlarging cardiomyocytes switch from aerobic to anaerobic energy generation resulting in cell growth under relatively hypoxic conditions. Cardiac muscle reacts to an increased afterload by over-activation of the sympathetic system and uncoupling and downregulation of β-adrenergic receptors. Recent studies suggest that β blocker therapy in PH is safe, well tolerated, and preserves right ventricle function and cardiac output by reducing right ventricular glycolysis. Fibrosis, an evolutionary conserved process in host defense and wound healing, is dysregulated in maladaptive cardiac tissue contributing directly to right ventricle failure. Despite several mechanisms having been suggested in right heart disease, the causes of maladaptive cardiac remodeling remain unknown and require further research.

Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction.

PubMed

Zamani, Payman; Akers, Scott; Soto-Calderon, Haideliza; Beraun, Melissa; Koppula, Maheswara R; Varakantam, Swapna; Rawat, Deepa; Shiva-Kumar, Prithvi; Haines, Philip G; Chittams, Jesse; Townsend, Raymond R; Witschey, Walter R; Segers, Patrick; Chirinos, Julio A

2017-02-20

Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. We randomized 44 patients with heart failure with preserved ejection fraction in a double-blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6-minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14-0.17], 3 months=0.11 [95% CI, 0.10-0.13], 6 months=0.10 [95% CI, 0.08-0.12] mm Hg/mL per second; P =0.003) and forward wave amplitude (P f , mean baseline=54.8 [95% CI, 47.6-62.0], 3 months=42.2 [95% CI, 33.2-51.3]; 6 months=37.0 [95% CI, 27.2-46.8] mm Hg, P =0.04), but had no effect on RM ( P =0.64), left ventricular mass ( P =0.33), or fibrosis ( P =0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35-0.43]; 3 months=0.31 [95% CI, 0.25-0.36]; 6 months=0.44 [95% CI, 0.37-0.51], P =0.03), reduced 6-minute walk distance (mean baseline=343.3 [95% CI, 319.2-367.4]; 6 months=277.0 [95% CI, 242.7-311.4] meters, P =0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7-1029.7]; 6 months=1054.5 [95% CI, 1036.5-1072.3], P =0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P =0.007). ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction. URL: www.clinicaltrials.gov. Unique identifier: NCT01516346. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Mechanistic insight into prolonged electromechanical delay in dyssynchronous heart failure: a computational study

PubMed Central

Constantino, Jason; Hu, Yuxuan; Lardo, Albert C.

2013-01-01

In addition to the left bundle branch block type of electrical activation, there are further remodeling aspects associated with dyssynchronous heart failure (HF) that affect the electromechanical behavior of the heart. Among the most important are altered ventricular structure (both geometry and fiber/sheet orientation), abnormal Ca2+ handling, slowed conduction, and reduced wall stiffness. In dyssynchronous HF, the electromechanical delay (EMD), the time interval between local myocyte depolarization and myofiber shortening onset, is prolonged. However, the contributions of the four major HF remodeling aspects in extending EMD in the dyssynchronous failing heart remain unknown. The goal of this study was to determine the individual and combined contributions of HF-induced remodeling aspects to EMD prolongation. We used MRI-based models of dyssynchronous nonfailing and HF canine electromechanics and constructed additional models in which varying combinations of the four remodeling aspects were represented. A left bundle branch block electrical activation sequence was simulated in all models. The simulation results revealed that deranged Ca2+ handling is the primary culprit in extending EMD in dyssynchronous HF, with the other aspects of remodeling contributing insignificantly. Mechanistically, we found that abnormal Ca2+ handling in dyssynchronous HF slows myofiber shortening velocity at the early-activated septum and depresses both myofiber shortening and stretch rate at the late-activated lateral wall. These changes in myofiber dynamics delay the onset of myofiber shortening, thus giving rise to prolonged EMD in dyssynchronous HF. PMID:23934857