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.

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.

The inflammatory response in myocardial injury, repair and remodeling

PubMed Central

Frangogiannis, Nikolaos G.

2015-01-01

Myocardial infarction triggers an intense inflammatory response that is essential for cardiac repair, but which is also implicated in the pathogenesis of post-infarction remodeling and heart failure. Signals in the infarcted myocardium activate toll-like receptor signalling, while complement activation and generation of reactive oxygen species induce cytokine and chemokine upregulation. Leukocytes recruited remove dead cells and matrix debris by phagocytosis, while setting the stage for scar formation. Timely repression of the inflammatory response is critical for effective healing and followed by activation of infarct myofibroblasts that secrete matrix proteins in the infarcted area. Members of the transforming growth factor-β family are critically involved in suppression of inflammation and activation of a pro-fibrotic program. Translation of these concepts in the clinic requires understanding of the pathophysiologic complexity and heterogeneity of post-infarction remodeling in human patients with myocardial infarction. Individuals with overactive and prolonged post-infarction inflammation might exhibit dilation and systolic dysfunction and benefit from targeted anti-IL-1 or anti-chemokine therapies, whereas patients with exaggerated fibrogenic reactions can develop diastolic heart failure and might require inhibition of the smad3 cascade. Biomarker-based approaches are needed to identify patients with distinct pathophysiologic responses and to rationally implement inflammation-modulating strategies. PMID:24663091

Left ventricular eccentricity index measured with SPECT myocardial perfusion imaging: An additional parameter of adverse cardiac remodeling.

PubMed

Gimelli, Alessia; Liga, Riccardo; Clemente, Alberto; Marras, Gavino; Kusch, Annette; Marzullo, Paolo

2017-01-12

Single-photon emission computed-tomography (SPECT) allows the quantification of LV eccentricity index (EI), a measure of cardiac remodeling. We sought to evaluate the feasibility of EI measurement with SPECT myocardial perfusion imaging and its interactions with relevant LV functional and structural parameters. Four-hundred and fifty-six patients underwent myocardial perfusion imaging on a Cadmium-Zinc-Telluride (CZT) camera. The summed rest, stress, and difference scores were calculated. From rest images, the LV end-diastolic (EDV) and end-systolic volumes, ejection fraction (EF), and peak filling rate (PFR) were calculated. In every patient, the EI, ranging from 0 (sphere) to 1 (line), was computed using a dedicated software (QGS/QPS; Cedars-Sinai Medical Center). Three-hundred and thirty-eight/456 (74%) patients showed a normal EF (>50%), while 26% had LV systolic dysfunction. The EI was computed from CZT images with excellent reproducibility (interclass correlation coefficient: 0.99, 95% CI 0.98-0.99). More impaired EI values correlated with the presence of a more abnormal LV perfusion (P < .001), function (EF and PFR, P < .001), and structure (EDV, P < .001). On multivariate analysis, higher EDV (P < .001) and depressed EF (P = .014) values were independent predictors of abnormal EI. The evaluation of LV eccentricity is feasible on gated CZT images. Abnormal EI associates with significant cardiac structural and functional abnormalities.

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.

The extracellular matrix in myocardial injury, repair, and remodeling

PubMed Central

2017-01-01

The cardiac extracellular matrix (ECM) not only provides mechanical support, but also transduces essential molecular signals in health and disease. Following myocardial infarction, dynamic ECM changes drive inflammation and repair. Early generation of bioactive matrix fragments activates proinflammatory signaling. The formation of a highly plastic provisional matrix facilitates leukocyte infiltration and activates infarct myofibroblasts. Deposition of matricellular proteins modulates growth factor signaling and contributes to the spatial and temporal regulation of the reparative response. Mechanical stress due to pressure and volume overload and metabolic dysfunction also induce profound changes in ECM composition that contribute to the pathogenesis of heart failure. This manuscript reviews the role of the ECM in cardiac repair and remodeling and discusses matrix-based therapies that may attenuate remodeling while promoting repair and regeneration. PMID:28459429

Substance P acting via the neurokinin-1 receptor regulates adverse myocardial remodeling in a rat model of hypertension

PubMed Central

Dehlin, Heather M.; Manteufel, Edward J.; Monroe, Andrew L.; Reimer, Michael H.; Levick, Scott P.

2013-01-01

Background Substance P is a sensory nerve neuropeptide located near coronary vessels in the heart. Therefore, substance P may be one of the first mediators released in the heart in response to hypertension, and can contribute to adverse myocardial remodeling via interactions with the neurokinin-1 receptor. We asked: 1) whether substance P promoted cardiac hypertrophy, including the expression of fetal genes known to be re-expressed during pathological hypertrophy; and 2) the extent to which substance P regulated collagen production and fibrosis. Methods and Results Spontaneously hypertensive rats (SHR) were treated with the neurokinin-1 receptor antagonist L732138 (5 mg/kg/d) from 8 to 24 weeks of age. Age-matched WKY served as controls. The gene encoding substance P, TAC1, was up-regulated as blood pressure increased in SHR. Fetal gene expression by cardiomyocytes was increased in SHR and was prevented by L732138. Cardiac fibrosis also occurred in the SHR and was prevented by L732138. Endothelin-1 was up-regulated in the SHR and this was prevented by L732138. In isolated cardiac fibroblasts, substance P transiently up-regulated several genes related to cell-cell adhesion, cell-matrix adhesion, and extracellular matrix regulation, however, no changes in fibroblast function were observed. Conclusions Substance P activation of the neurokinin-1 receptor induced expression of fetal genes related to pathological hypertrophy in the hypertensive heart. Additionally, activation of the neurokinin-1 receptor was critical to the development of cardiac fibrosis. Since no functional changes were induced in isolated cardiac fibroblasts by substance P, we conclude that substance P mediates fibrosis via up-regulation of endothelin-1. PMID:23962787

Cells involved in extracellular matrix remodeling after acute myocardial infarction

PubMed Central

Garcia, Larissa Ferraz; Mataveli, Fábio D’Aguiar; Mader, Ana Maria Amaral Antônio; Theodoro, Thérèse Rachell; Justo, Giselle Zenker; Pinhal, Maria Aparecida da Silva

2015-01-01

Objective Evaluate the effects of VEGF165 gene transfer in the process of remodeling of the extracellular matrix after an acute myocardial infarct. Methods Wistar rats were submitted to myocardial infarction, after the ligation of the left descending artery, and the left ventricle ejection fraction was used to classify the infarcts into large and small. The animals were divided into groups of ten, according to the size of infarcted area (large or small), and received or not VEGF165 treatment. Evaluation of different markers was performed using immunohistochemistry and digital quantification. The primary antibodies used in the analysis were anti-fibronectin, anti-vimentin, anti-CD44, anti-E-cadherin, anti-CD24, anti-alpha-1-actin, and anti-PCNA. The results were expressed as mean and standard error, and analyzed by ANOVA, considering statistically significant if p≤0.05. Results There was a significant increase in the expression of undifferentiated cell markers, such as fibronectin (protein present in the extracellular matrix) and CD44 (glycoprotein present in the endothelial cells). However, there was decreased expression of vimentin and PCNA, indicating a possible decrease in the process of cell proliferation after treatment with VEGF165. Markers of differentiated cells, E-cadherin (adhesion protein between myocardial cells), CD24 (protein present in the blood vessels), and alpha-1-actin (specific myocyte marker), showed higher expression in the groups submitted to gene therapy, compared to non-treated group. The value obtained by the relation between alpha-1-actin and vimentin was approximately three times higher in the groups treated with VEGF165, suggesting greater tissue differentiation. Conclusion The results demonstrated the important role of myocytes in the process of tissue remodeling, confirming that VEGF165 seems to provide a protective effect in the treatment of acute myocardial infarct. PMID:25993074

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.

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

Cardiac DPP-4 inhibition by saxagliptin ameliorates isoproterenol-induced myocardial remodeling and cardiac diastolic dysfunction in rats.

PubMed

Ikeda, Junichi; Kimoto, Naoya; Kitayama, Tetsuya; Kunori, Shunji

2016-09-01

Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure. Copyright © 2016 Kyowa Hakko Kirin Co.,Ltd. Production and hosting by Elsevier B.V. All rights reserved.

Quantitative proteomic changes during post myocardial infarction remodeling reveals altered cardiac metabolism and Desmin aggregation in the infarct region.

PubMed

Datta, Kaberi; Basak, Trayambak; Varshney, Swati; Sengupta, Shantanu; Sarkar, Sagartirtha

2017-01-30

Myocardial infarction is one of the leading causes of cardiac dysfunction, failure and sudden death. Post infarction cardiac remodeling presents a poor prognosis, with 30%-45% of patients developing heart failure, in a period of 5-25years. Oxidative stress has been labelled as the primary causative factor for cardiac damage during infarction, however, the impact it may have during the process of post infarction remodeling has not been well probed. In this study, we have implemented iTRAQ proteomics to catalogue proteins and functional processes, participating both temporally (early and late phases) and spatially (infarct and remote zones), during post myocardial infarction remodeling of the heart as functions of the differential oxidative stress manifest during the remodeling process. Cardiac metabolism was the dominant network to be affected during infarction and the remodeling time points considered in this study. A distinctive expression pattern of cytoskeletal proteins was also observed with increased remodeling time points. Further, it was found that the cytoskeletal protein Desmin, aggregated in the infarct zone during the remodeling process, mediated by the protease Calpain1. Taken together, all of these data in conjunction may lay the foundation to understand the effects of oxidative stress on the remodeling process and elaborate the mechanism behind the compromised cardiac function observed during post myocardial infarction remodeling. Oxidative stress is the major driving force for cardiac damage during myocardial infarction. However, the impact of oxidative stress on the process of post MI remodeling in conducting the heart towards functional failure has not been well explored. In this study, a spatial and temporal approach was taken to elaborate the major proteins and cellular processes involved in post MI remodeling. Based on level/ intensity of ROS, spatially, infarct and noninfarct zones were chosen for analysis while on the temporal scale, early (30

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction.

PubMed

Li, Longhu; Haider, Husnain Kh; Wang, Linlin; Lu, Gang; Ashraf, Muhammad

2012-05-15

We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction.

Adenoviral short hairpin RNA therapy targeting phosphodiesterase 5a relieves cardiac remodeling and dysfunction following myocardial infarction

PubMed Central

Li, Longhu; Haider, Husnain Kh.; Wang, Linlin; Lu, Gang

2012-01-01

We previously showed that treatment with tadalafil, a long-acting phosphodiesterase-5a (PDE5a) inhibitor, effectively prevented adverse left ventricular (LV) remodeling of the infarcted heart. We hypothesized that short-hairpin RNA (shRNA) therapy targeting PDE5a would simulate the effects of pharmacological intervention for treatment of postinfarction LV remodeling and dysfunction. Experimental model of myocardial infarction was developed in female mice by permanent ligation of left coronary artery. Immediately after that, an adenoviral vector encoding for shRNA sequence targeting PDE5a (Ad-shPDE5a) was injected intramyocardially, which specifically inhibited PDE5a in the heart. Four weeks later, Ad-shPDE5a treated mice showed significant mitigation of the left ventricle (LV) dilatation and dysfunction as indicated by smaller LV cavity and more preserved ejection fraction and fractional shortening. Infarction size and fibrosis were significantly reduced in Ad-shPDE5a-treated mice. Additionally, more salvaged cardiomyocytes, significantly reduced collagen contents, and higher blood vessel density were observed in Ad-shPDE5a-treated mice. The cytoprotective effects of Ad-shPDE5a were demonstrated in vitro in Ad-shPDE5a transfected cardiomyocytes cultured under oxygen glucose deprivation. Among downstream mediators of PDE5a signaling, cyclic GMP (cGMP) and cGMP-dependent protein kinase G (PKG) were activated with concomitant reduction in caspase-3 activity. However, no significant change in PKA and cAMP activities were observed in Ad-shPDE5a-treated hearts. Inhibition with shRNA improved cardiac remodeling and dysfunction by reducing infarction size and cardiac fibrosis and increased cGMP and PKG activity. These findings suggest that PDE5 inhibition with Ad-shPDE5a is a novel approach for treatment of myocardial infarction. PMID:22447941

New angiotensin II type 1 receptor blocker, azilsartan, attenuates cardiac remodeling after myocardial infarction.

PubMed

Nakamura, Yuichi; Suzuki, Satoshi; Saitoh, Shu-ichi; Takeishi, Yasuchika

2013-01-01

After an acute myocardial infarction (MI), neurohumoral systems including renin-angiotensin-aldosterone system (RAAS) are activated which in turn aggravate cardiac remodeling. Angiotensin receptor blockers (ARBs) are useful drugs for suppression of RAAS. The purpose of this study was to evaluate a new ARB, azilsartan, for suppressing cardiac remodeling and progression to heart failure after MI. We created MI by left anterior descending coronary artery ligation in male mice, and these mice were orally administered saline (0.2 mL) in the control group (Group C), 0.1 mg/kg/d of azilsartan in the low dose group (Group L), and 1.0 mg/kg/d in the high dose group (Group H) everyday. Blood pressure was decreased in Group H, but not in Group L, compared to Group C. At 2 weeks after MI creation, infarct size and fibrotic change at the site remote to the myocardial infarcted area were attenuated in Group L and Group H compared to Group C. Echocardiography revealed that cardiac remodeling was suppressed in Group L and Group H compared to Group C. Increases of mRNA expression levels related to fibrotic change were attenuated in Group L and Group H compared to Group C. The new ARB, azilsartan, had a cardiac remodeling suppression effect after MI, and this effect was observed without blood pressure lowering.

Incidence and Significance of Spontaneous ST Segment Re-elevation After Reperfused Anterior Acute Myocardial Infarction　- Relationship With Infarct Size, Adverse Remodeling, and Events at 1 Year.

PubMed

Cuenin, Léo; Lamoureux, Sophie; Schaaf, Mathieu; Bochaton, Thomas; Monassier, Jean-Pierre; Claeys, Marc J; Rioufol, Gilles; Finet, Gérard; Garcia-Dorado, David; Angoulvant, Denis; Elbaz, Meyer; Delarche, Nicolas; Coste, Pierre; Metge, Marc; Perret, Thibault; Motreff, Pascal; Bonnefoy-Cudraz, Eric; Vanzetto, Gérald; Morel, Olivier; Boussaha, Inesse; Ovize, Michel; Mewton, Nathan

2018-04-25

Up to 25% of patients with ST elevation myocardial infarction (STEMI) have ST segment re-elevation after initial regression post-reperfusion and there are few data regarding its prognostic significance.Methods and Results:A standard 12-lead electrocardiogram (ECG) was recorded in 662 patients with anterior STEMI referred for primary percutaneous coronary intervention (PPCI). ECGs were recorded 60-90 min after PPCI and at discharge. ST segment re-elevation was defined as a ≥0.1-mV increase in STMax between the post-PPCI and discharge ECGs. Infarct size (assessed as creatine kinase [CK] peak), echocardiography at baseline and follow-up, and all-cause death and heart failure events at 1 year were assessed. In all, 128 patients (19%) had ST segment re-elevation. There was no difference between patients with and without re-elevation in infarct size (CK peak [mean±SD] 4,231±2,656 vs. 3,993±2,819 IU/L; P=0.402), left ventricular (LV) ejection fraction (50.7±11.6% vs. 52.2±10.8%; P=0.186), LV adverse remodeling (20.1±38.9% vs. 18.3±30.9%; P=0.631), or all-cause mortality and heart failure events (22 [19.8%] vs. 106 [19.2%]; P=0.887) at 1 year. Among anterior STEMI patients treated by PPCI, ST segment re-elevation was present in 19% and was not associated with increased infarct size or major adverse events at 1 year.

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

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

Electrotonic remodeling following myocardial infarction in dogs susceptible and resistant to sudden cardiac death.

PubMed

Del Rio, Carlos L; McConnell, Patrick I; Kukielka, Monica; Dzwonczyk, Roger; Clymer, Bradley D; Howie, Michael B; Billman, George E

2008-02-01

Passive electrical remodeling following myocardial infarction (MI) is well established. These changes can alter electrotonic loading and trigger the remodeling of repolarization currents, a potential mechanism for ventricular fibrillation (VF). However, little is known about the role of passive electrical markers as tools to identify VF susceptibility post-MI. This study investigated electrotonic remodeling in the post-MI ventricle, as measured by myocardial electrical impedance (MEI), in animals prone to and resistant to VF. MI was induced in dogs by a two-stage left anterior descending (LAD) coronary artery ligation. Before infarction, MEI electrodes were placed in remote (left circumflex, LCX) and infarcted (LAD) myocardium. MEI was measured in awake animals 1, 2, 7, and 21 days post-MI. Subsequently, VF susceptibility was tested by a 2-min LCX occlusion during exercise; 12 animals developed VF (susceptible, S) and 12 did not (resistant, R). The healing infarct had lower MEI than the normal myocardium. This difference was stable by day 2 post-MI (287 +/- 32 Omega vs. 425 +/- 62 Omega, P < 0.05). Significant differences were observed between resistant and susceptible animals 7 days post-MI; susceptible dogs had a wider electrotonic gradient between remote and infarcted myocardium (R: 89 +/- 60 Omega vs. S: 180 +/- 37 Omega). This difference increased over time in susceptible animals (252 +/- 53 Omega at 21 days) due to post-MI impedance changes on the remote myocardium. These data suggest that early electrotonic changes post-MI could be used to assess later arrhythmia susceptibility. In addition, passive-electrical changes could be a mechanism driving active-electrical remodeling post-MI, thereby facilitating the induction of arrhythmias.

The immune system and the remodeling infarcted heart: cell biological insights and therapeutic opportunities

PubMed Central

Frangogiannis, Nikolaos G

2014-01-01

Extensive necrosis of ischemic cardiomyocytes in the infarcted myocardium activates the innate immune response triggering an intense inflammatory reaction. Release of danger signals from dying cells and damaged matrix activates the complement cascade and stimulates Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, resulting in activation of the Nuclear Factor (NF)-κB system and induction of chemokines, cytokines and adhesion molecules. Subsequent infiltration of the infarct with neutrophils and mononuclear cells serves to clear the wound from dead cells and matrix debris, while stimulating reparative pathways. In addition to its role in repair of the infarcted heart and formation of a scar, the immune system is also involved in adverse remodeling of the infarcted ventricle. Overactive immune responses and defects in suppression, containment and resolution of the post-infarction inflammatory reaction accentuate dilative remodeling in experimental models and may be associated with chamber dilation, systolic dysfunction and heart failure in patients surviving a myocardial infarction. Interventions targeting the inflammatory response to attenuate adverse remodeling may hold promise in patients with myocardial infarction that exhibit accentuated, prolonged, or dysregulated immune responses to the acute injury. PMID:24072174

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

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

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.

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.

Lin28a protects against postinfarction myocardial remodeling and dysfunction through Sirt1 activation and autophagy enhancement.

PubMed

Hao, Yuanyuan; Lu, Qun; Yang, Guodong; Ma, Aiqun

2016-10-28

Myocardial remodeling and cardiac dysfunction prevention may represent a therapeutic approach to reduce mortality in patients with myocardial infarction (MI). We investigated the effects of Lin28a in experimental MI models, as well as the mechanisms underlying these effects. Left anterior descending (LAD) coronary artery ligation was used to construct an MI-induced injury model. Neonatal cardiomyocytes were isolated and cultured to investigate the mechanisms underlying the protective effects of Lin28a against MI-induced injury. Lin28a significantly inhibited left ventricular remodeling and cardiac dysfunction after MI, as demonstrated via echocardiography and hemodynamic measurements. Lin28a reduced cardiac enzyme and inflammatory marker release in mice subjected to MI-induced injury. The mechanisms underlying the protective effects of Lin28a against MI-induced injury were associated with autophagy enhancements and apoptosis inhibition. Consistent with these findings, Lin28a knockdown aggravated cardiac remodeling and dysfunction after MI-induced injury. Lin28a knockdown also inhibited cardiomyocyte autophagy and increased cardiomyocyte apoptosis in mice subjected to MI-induced injury. Interestingly, Sirt1 knockdown abolished the protective effects of Lin28a against cardiac remodeling and dysfunction after MI, and Lin28a failed to increase the numbers of GFP-LC3-positive punctae and decrease aggresome and p62 accumulation in Sirt1-knockdown neonatal cardiomyocytes subjected to hypoxia-induced injury. Lin28a inhibits cardiac remodeling, improves cardiac function, and reduces cardiac enzyme and inflammatory marker release after MI. Lin28a also up-regulates cardiomyocyte autophagy and inhibits cardiomyocyte apoptosis through Sirt1 activation. Copyright © 2016 Elsevier Inc. All rights reserved.

CaM Kinase II mediates maladaptive post-infarct remodeling and pro-inflammatory chemoattractant signaling but not acute myocardial ischemia/reperfusion injury

PubMed Central

Weinreuter, Martin; Kreusser, Michael M; Beckendorf, Jan; Schreiter, Friederike C; Leuschner, Florian; Lehmann, Lorenz H; Hofmann, Kai P; Rostosky, Julia S; Diemert, Nathalie; Xu, Chang; Volz, Hans Christian; Jungmann, Andreas; Nickel, Alexander; Sticht, Carsten; Gretz, Norbert; Maack, Christoph; Schneider, Michael D; Gröne, Hermann-Josef; Müller, Oliver J; Katus, Hugo A; Backs, Johannes

2014-01-01

CaMKII was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. Here, we investigated the roles of different CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury by the use of new genetic CaMKII mouse models. Although CaMKIIδC was upregulated 1 day after I/R injury, cardiac damage 1 day after I/R was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed, nor in cardiomyocyte-specific CaMKIIδ/γ double knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction, which was associated with reduced leukocyte infiltration and attenuated expression of members of the chemokine (C-C motif) ligand family, in particular CCL3 (macrophage inflammatory protein-1α, MIP-1α). Intriguingly, CaMKII was sufficient and required to induce CCL3 expression in isolated cardiomyocytes, indicating a cardiomyocyte autonomous effect. We propose that CaMKII-dependent chemoattractant signaling explains the effects on post-I/R remodeling. Taken together, we demonstrate that CaMKII is not critically involved in acute I/R-induced damage but in the process of post-infarct remodeling and inflammatory processes. PMID:25193973

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.

The sirtuin1 gene associates with left ventricular myocardial hypertrophy and remodeling in two chronic kidney disease cohorts: a longitudinal study.

PubMed

Spoto, Belinda; Ntounousi, Evangelia; Testa, Alessandra; Liakopoulos, Vassilios; D'Arrigo, Graziella; Tripepi, Giovanni; Parlongo, Rosa M; Sanguedolce, Maria C; Mallamaci, Francesca; Zoccali, Carmine

2018-04-26

Oxidative stress and inflammation are major drivers of myocardial hypertrophy in chronic kidney disease (CKD). The silent information regulator gene 1 (Sirt1) is a fundamental mediator of the response to oxidative stress and inflammation and promotes myocardial growth under stress conditions; therefore, it may contribute to myocardial hypertrophy and concentric remodeling of the left ventricle (LV) in CKD. We investigated the cross-sectional and longitudinal relationship between three candidate polymorphisms in the Sirt1 gene and LV parameters in two cohorts of CKD patients including 235 stage G5D patients and 179 stages G1-5 patients, respectively. In both cohorts, the C allele of the Sirt1 rs7069102 polymorphism associated with the posterior wall thickness in separate and combined analyses (beta = 0.15, P = 2 × 10) but was unrelated with the LV volume and the LV mass index indicating a peculiar association of this allele with LV concentric remodeling. Accordingly, the same allele was linked with the LV mass-to-volume ratio in separate and combined (beta = 0.14, P = 2 × 10) analyses in the same cohorts. Furthermore, in longitudinal analyses patients harboring the C allele showed a more pronounced increase in LV mass-to-volume ratio over time than patients without such an allele (regression coefficient = 0.14, 95% confidence interval: 0.05-0.23; P = 3 × 10 in the combined analysis). The rs7069102 polymorphism in the Sirt1 gene is associated with LV concentric remodeling in two independent cohorts of stages G5D and G1-5 CKD patients. These results offer a genetic basis to the hypothesis that the Sirt1 gene plays a causal role in myocardial hypertrophy and LV concentric remodeling in these patients.

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

Mechanical regulation of fibroblast migration and collagen remodelling in healing myocardial infarcts

PubMed Central

Rouillard, Andrew D; Holmes, Jeffrey W

2012-01-01

Effective management of healing and remodelling after myocardial infarction is an important problem in modern cardiology practice. We have recently shown that the level of infarct anisotropy is a critical determinant of heart function following a large anterior infarction, which suggests that therapeutic gains may be realized by controlling infarct anisotropy. However, factors regulating infarct anisotropy are not well understood. Mechanical, structural and chemical guidance cues have all been shown to regulate alignment of fibroblasts and collagen in vitro, and prior studies have proposed that each of these cues could regulate anisotropy of infarct scar tissue, but understanding of fibroblast behaviour in the complex environment of a healing infarct is lacking. We developed an agent-based model of infarct healing that accounted for the combined influence of these cues on fibroblast alignment, collagen deposition and collagen remodelling. We pooled published experimental data from several sources in order to determine parameter values, then used the model to test the importance of each cue for predicting collagen alignment measurements from a set of recent cryoinfarction experiments. We found that although chemokine gradients and pre-existing matrix structures had important effects on collagen organization, a response of fibroblasts to mechanical cues was critical for correctly predicting collagen alignment in infarct scar. Many proposed therapies for myocardial infarction, such as injection of cells or polymers, alter the mechanics of the infarct region. Our modelling results suggest that such therapies could change the anisotropy of the healing infarct, which could have important functional consequences. This model is therefore a potentially important tool for predicting how such interventions change healing outcomes. PMID:22495588

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.

Reverse left ventricular remodeling after acute myocardial infarction: the prognostic impact of left ventricular global torsion.

PubMed

Spinelli, Letizia; Morisco, Carmine; Assante di Panzillo, Emiliano; Izzo, Raffaele; Trimarco, Bruno

2013-04-01

Reverse left ventricular (LV) remodeling (>10 % reduction in LV end-systolic volume) may occur in patients recovering for acute ST-elevation myocardial infarction (STEMI), undergoing percutaneous revascularization of infarct-related coronary artery (PCI). To detect whether LV global torsion obtained by two-dimensional speckle-tracking echocardiography was predictive of reverse LV remodeling, 75 patients with first anterior wall STEMI were studied before (T1) and after PCI (T2) and at 6-month follow-up. Two-year clinical follow-up was also accomplished. LV volumes and both LV sphericity index and conic index were obtained by three-dimensional echocardiography. Reverse remodeling was observed in 25 patients (33 %). By multivariate analysis, independent predictors of reverse LV remodeling were: LV conic index, T2 LV torsion and Δ torsion (difference between T2 and T1 LV torsion expressed as percentage of this latter). According to receiver operating characteristic analysis, 1.34°/cm for T2 LV torsion (sensitivity 88 % and specificity 80 %) and 54 % for Δ torsion (sensitivity 92 % and specificity 82 %) were the optimal cutoff values in predicting reverse LV remodeling. In up to 24 month follow-up, 4 non-fatal re-infarction, 7 hospitalization for heart failure and 4 cardiac deaths occurred. By multivariate Cox analysis, the best variable significantly associated with event-free survival rate was reverse LV remodeling with a hazard ratio = 9.9 (95 % confidence interval, 7.9-31.4, p < 0.01). In conclusion, reverse LV remodeling occurring after anterior wall STEMI is associated with favorable long-term outcome. The improvement of global LV torsion following coronary artery revascularization is the major predictor of reverse LV remodeling.

Intravenously Delivered Mesenchymal Stem Cells: Systemic Anti-Inflammatory Effects Improve Left Ventricular Dysfunction in Acute Myocardial Infarction and Ischemic Cardiomyopathy.

PubMed

Luger, Dror; Lipinski, Michael J; Westman, Peter C; Glover, David K; Dimastromatteo, Julien; Frias, Juan C; Albelda, M Teresa; Sikora, Sergey; Kharazi, Alex; Vertelov, Grigory; Waksman, Ron; Epstein, Stephen E

2017-05-12

Virtually all mesenchymal stem cell (MSC) studies assume that therapeutic effects accrue from local myocardial effects of engrafted MSCs. Because few intravenously administered MSCs engraft in the myocardium, studies have mainly utilized direct myocardial delivery. We adopted a different paradigm. To test whether intravenously administered MSCs reduce left ventricular (LV) dysfunction both post-acute myocardial infarction and in ischemic cardiomyopathy and that these effects are caused, at least partly, by systemic anti-inflammatory activities. Mice underwent 45 minutes of left anterior descending artery occlusion. Human MSCs, grown chronically at 5% O 2 , were administered intravenously. LV function was assessed by serial echocardiography, 2,3,5-triphenyltetrazolium chloride staining determined infarct size, and fluorescence-activated cell sorting assessed cell composition. Fluorescent and radiolabeled MSCs (1×10 6 ) were injected 24 hours post-myocardial infarction and homed to regions of myocardial injury; however, the myocardium contained only a small proportion of total MSCs. Mice received 2×10 6 MSCs or saline intravenously 24 hours post-myocardial infarction (n=16 per group). At day 21, we harvested blood and spleens for fluorescence-activated cell sorting and hearts for 2,3,5-triphenyltetrazolium chloride staining. Adverse LV remodeling and deteriorating LV ejection fraction occurred in control mice with large infarcts (≥25% LV). Intravenous MSCs eliminated the progressive deterioration in LV end-diastolic volume and LV end-systolic volume. MSCs significantly decreased natural killer cells in the heart and spleen and neutrophils in the heart. Specific natural killer cell depletion 24 hours pre-acute myocardial infarction significantly improved infarct size, LV ejection fraction, and adverse LV remodeling, changes associated with decreased neutrophils in the heart. In an ischemic cardiomyopathy model, mice 4 weeks post-myocardial infarction were

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.

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

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.

Relief of mitral leaflet tethering following chronic myocardial infarction by chordal cutting diminishes left ventricular remodeling.

PubMed

Messas, Emmanuel; Bel, Alain; Szymanski, Catherine; Cohen, Iris; Touchot, Bernard; Handschumacher, Mark D; Desnos, Michel; Carpentier, Alain; Menasché, Philippe; Hagège, Albert A; Levine, Robert A

2010-11-01

one of the key targets in treating mitral regurgitation (MR) is reducing the otherwise progressive left ventricular (LV) remodeling that exacerbates MR and conveys adverse prognosis. We have previously demonstrated that severing 2 second-order chordae to the anterior mitral leaflet relieves tethering and ischemic MR acutely. The purpose of this study was to test whether this technique reduces the progression of LV remodeling in the chronic ischemic MR setting. a posterolateral MI was created in 18 sheep by obtuse marginal branch ligation. After chronic remodeling and MR development at 3 months, 6 sheep were randomized to sham surgery (control group) and 12 to second-order chordal cutting (6 each to anterior leaflet [AntL] and bileaflet [BiL] chordal cutting, techniques that are in clinical application). At baseline, chronic infarction (3 months), and follow-up at a mean of 6.6 months post-myocardial infarction (MI) (euthanasia), we measured LV end-diastolic (EDV) and end-systolic volume (ESV), ejection fraction, wall motion score index, and posterior leaflet (PL) restriction angle relative to the annulus by 2D and 3D echocardiography. All measurements were comparable among groups at baseline and chronic MI. At euthanasia, AntL and BiL chordal cutting limited the progressive remodeling seen in controls. LVESV increased relative to chronic MI by 109±8.7% in controls versus 30.5±6.1% with chordal cutting (P<0.01) (LVESV in controls, 82.5±2.6 mL; in AntL, 60.6±5.1 mL; in BiL, 61.8±4.1 mL). LVEDV increased by 63±2.0% in controls versus 26±5.5% and 22±3.4% with chordal cutting (P<0.01). LV ejection fraction and wall motion score index were not significantly different at follow-up among the chordal cutting and control groups. MR progressively increased to moderate in controls but decreased to trace-mild with AntL and BiL chordal cutting (MR vena contracta in controls, 5.9±1.1 mm; in AntL, 2.6±0.1 mm; in BiL, 1.7±0.1 mm; P<0.01). BiL chordal cutting provided

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

Systemic inflammatory response following acute myocardial infarction

PubMed Central

Fang, Lu; Moore, Xiao-Lei; Dart, Anthony M; Wang, Le-Min

2015-01-01

Acute cardiomyocyte necrosis in the infarcted heart generates damage-associated molecular patterns, activating complement and toll-like receptor/interleukin-1 signaling, and triggering an intense inflammatory response. Inflammasomes also recognize danger signals and mediate sterile inflammatory response following acute myocardial infarction (AMI). Inflammatory response serves to repair the heart, but excessive inflammation leads to adverse left ventricular remodeling and heart failure. In addition to local inflammation, profound systemic inflammation response has been documented in patients with AMI, which includes elevation of circulating inflammatory cytokines, chemokines and cell adhesion molecules, and activation of peripheral leukocytes and platelets. The excessive inflammatory response could be caused by a deregulated immune system. AMI is also associated with bone marrow activation and spleen monocytopoiesis, which sustains a continuous supply of monocytes at the site of inflammation. Accumulating evidence has shown that systemic inflammation aggravates atherosclerosis and markers for systemic inflammation are predictors of adverse clinical outcomes (such as death, recurrent myocardial infarction, and heart failure) in patients with AMI. PMID:26089856

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.

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

Serum uric acid level predicts adverse outcomes after myocardial revascularization or cardiac valve surgery.

PubMed

Lazzeroni, Davide; Bini, Matteo; Camaiora, Umberto; Castiglioni, Paolo; Moderato, Luca; Bosi, Davide; Geroldi, Simone; Ugolotti, Pietro T; Brambilla, Lorenzo; Brambilla, Valerio; Coruzzi, Paolo

2018-01-01

Background High levels of serum uric acid have been associated with adverse outcomes in cardiovascular diseases such as myocardial infarction and heart failure. The aim of the current study was to evaluate the prognostic role of serum uric acid levels in patients undergoing cardiac rehabilitation after myocardial revascularization and/or cardiac valve surgery. Design We performed an observational prospective cohort study. Methods The study included 1440 patients with available serum uric acid levels, prospectively followed for 50 ± 17 months. Mean age was 67 ± 11 years; 781 patients (54%) underwent myocardial revascularization, 474 (33%) cardiac valve surgery and 185 (13%) valve-plus-coronary artery by-pass graft surgery. The primary endpoints were overall and cardiovascular mortality while secondary end-points were combined major adverse cardiac and cerebrovascular events. Results Serum uric acid level mean values were 286 ± 95 µmol/l and elevated serum uric acid levels (≥360 µmol/l or 6 mg/dl) were found in 275 patients (19%). Overall mortality (hazard ratio = 2.1; 95% confidence interval: 1.5-3.0; p < 0.001), cardiovascular mortality (hazard ratio = 2.0; 95% confidence interval: 1.2-3.2; p = 0.004) and major adverse cardiac and cerebrovascular events rate (hazard ratio = 1.5; 95% confidence interval: 1.0-2.0; p = 0.019) were significantly higher in patients with elevated serum uric acid levels, even after adjustment for age, gender, arterial hypertension, diabetes, glomerular filtration rate, atrial fibrillation and medical therapy. Moreover, strong positive correlations between serum uric acid level and probability of overall mortality ( p < 0.001), cardiovascular mortality ( p < 0.001) and major adverse cardiac and cerebrovascular events ( p = 0.003) were found. Conclusions Serum uric acid levels predict mortality and adverse cardiovascular outcome in patients undergoing myocardial revascularization

Deficiency of Rac1 Blocks NADPH Oxidase Activation, Inhibits Endoplasmic Reticulum Stress, and Reduces Myocardial Remodeling in a Mouse Model of Type 1 Diabetes

PubMed Central

Li, Jianmin; Zhu, Huaqing; Shen, E; Wan, Li; Arnold, J. Malcolm O.; Peng, Tianqing

2010-01-01

OBJECTIVE Our recent study demonstrated that Rac1 and NADPH oxidase activation contributes to cardiomyocyte apoptosis in short-term diabetes. This study was undertaken to investigate if disruption of Rac1 and inhibition of NADPH oxidase would prevent myocardial remodeling in chronic diabetes. RESEARCH DESIGN AND METHODS Diabetes was induced by injection of streptozotocin in mice with cardiomyocyte-specific Rac1 knockout and their wild-type littermates. In a separate experiment, wild-type diabetic mice were treated with vehicle or apocynin in drinking water. Myocardial hypertrophy, fibrosis, endoplasmic reticulum (ER) stress, inflammatory response, and myocardial function were investigated after 2 months of diabetes. Isolated adult rat cardiomyocytes were cultured and stimulated with high glucose. RESULTS In diabetic hearts, NADPH oxidase activation, its subunits' expression, and reactive oxygen species production were inhibited by Rac1 knockout or apocynin treatment. Myocardial collagen deposition and cardiomyocyte cross-sectional areas were significantly increased in diabetic mice, which were accompanied by elevated expression of pro-fibrotic genes and hypertrophic genes. Deficiency of Rac1 or apocynin administration reduced myocardial fibrosis and hypertrophy, resulting in improved myocardial function. These effects were associated with a normalization of ER stress markers' expression and inflammatory response in diabetic hearts. In cultured cardiomyocytes, high glucose–induced ER stress was inhibited by blocking Rac1 or NADPH oxidase. CONCLUSIONS Rac1 via NADPH oxidase activation induces myocardial remodeling and dysfunction in diabetic mice. The role of Rac1 signaling may be associated with ER stress and inflammation. Thus, targeting inhibition of Rac1 and NADPH oxidase may be a therapeutic approach for diabetic cardiomyopathy. PMID:20522592

Gender-related differences in β-adrenergic receptor-mediated cardiac remodeling.

PubMed

Zhu, Baoling; Liu, Kai; Yang, Chengzhi; Qiao, Yuhui; Li, Zijian

2016-12-01

Cardiac remodeling is the pathological basis of various cardiovascular diseases. In this study, we found gender-related differences in β-adrenergic receptor (AR)-mediated pathological cardiac remodeling. Cardiac remodeling model was established by subcutaneous injection of isoprenaline (ISO) for 14 days. Heart rate (HR), mean arterial pressure (MAP), and echocardiography were obtained on 7th and 14th days during ISO administration. Myocardial cross-sectional area and the ratio of heart mass to tibia length (HM/TL) were detected to assess cardiac hypertrophy. Picro-Sirius red staining (picric acid + Sirius red F3B) was used to evaluate cardiac fibrosis. Myocardial capillary density was assessed by immunohistochemistry for von Willebrand factor. Further, real-time PCR was used to measure the expression of β1-AR and β2-AR. Results showed that ISO induced cardiac remodeling, the extent of which was different between female and male mice. The extent of increase in cardiac wall thickness, myocardial cross-sectional area, and collagen deposition in females was less than that in males. However, no gender-related difference was observed in HR, MAP, cardiac function, and myocardial capillary density. The distinctive decrease of β2-AR expression, rather than a decrease of β1-AR expression, seemed to result in gender-related differences in cardiac remodeling.

Potential adverse cardiac remodelling in highly trained athletes: still unknown clinical significance.

PubMed

Gabrielli, Luigi; Sitges, Marta; Chiong, Mario; Jalil, Jorge; Ocaranza, María; Llevaneras, Silvana; Herrera, Sebastian; Fernandez, Rodrigo; Saavedra, Rodrigo; Yañez, Fernando; Vergara, Luis; Diaz, Alexis; Lavandero, Sergio; Castro, Pablo

2018-06-12

Moderate endurance exercise has long been considered an essential element to maintain cardiovascular health, and sedentary behaviour in the general population has been related to a significant increase in all-causes of mortality, cardiovascular disease mortality and cardiovascular disease incidence. However, a growing group of people performs an intense exercise that leads to multiple heart adaptive changes that are collectively called "athlete's heart". In this review, we discussed the evidence of cardiac remodelling process secondary to repetitive and strenuous exercise in some predisposed athletes that produces intense and probably deleterious changes in cardiac morphology and function with no clear clinical significance in long-term follow-up. Moreover, we also discussed the individual biological response to exercise assessed by myocardial damage, inflammation, oxidative stress, fibrosis and ventricular hypertrophy biomarkers showing different intensities with equivalent exertion.

Focal myocardial infarction induces global remodeling of cardiac sympathetic innervation: neural remodeling in a spatial context

PubMed Central

Ajijola, Olujimi A.; Yagishita, Daigo; Patel, Krishan J.; Vaseghi, Marmar; Zhou, Wei; Yamakawa, Kentaro; So, Eileen; Lux, Robert L.; Mahajan, Aman

2013-01-01

Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms2, P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced. PMID:23893167

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

Assessment of Myocardial Remodeling Using an Elastin/Tropoelastin Specific Agent with High Field Magnetic Resonance Imaging (MRI).

PubMed

Protti, Andrea; Lavin, Begoña; Dong, Xuebin; Lorrio, Silvia; Robinson, Simon; Onthank, David; Shah, Ajay M; Botnar, Rene M

2015-08-13

Well-defined inflammation, proliferation, and maturation phases orchestrate the remodeling of the injured myocardium after myocardial infarction (MI) by controlling the formation of new extracellular matrix. The extracellular matrix consists mainly of collagen but also fractions of elastin. It is thought that elastin is responsible for maintaining elastic properties of the myocardium, thus reducing the risk of premature rupture. An elastin/tropoelastin-specific contrast agent (Gd-ESMA) was used to image tropoelastin and mature elastin fibers for in vivo assessment of extracellular matrix remodeling post-MI. Gd-ESMA enhancement was studied in a mouse model of myocardial infarction using a 7 T MRI scanner and results were compared to those achieved after injection of a nonspecific control contrast agent, gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA). In the infarcted tissue, Gd-ESMA uptake (measured as R1 relaxation rate) steadily increased from day 3 to day 21 as a result of the synthesis of elastin/tropoelastin. R1 values were in good agreement with histological findings. A similar R1 behavior was observed in the remote myocardium. No mature cross-linked elastin was found at any time point. In contrast, Gd-DTPA uptake was only observed in the infarct with no changes in R1 values between 3 and 21 days post-MI. We demonstrate the feasibility of in vivo imaging of extracellular matrix remodeling post-MI using a tropoelastin/elastin binding MR contrast agent, Gd-ESMA. We found that tropoelastin is the main contributor to the increased MRI signal at late stages of MI where its augmentation in areas of infarction was in good agreement with the R1 increase. © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

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.

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.

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

Left and right ventricle late remodeling following myocardial infarction in rats.

PubMed

Stefanon, Ivanita; Valero-Muñoz, María; Fernandes, Aurélia Araújo; Ribeiro, Rogério Faustino; Rodríguez, Cristina; Miana, Maria; Martínez-González, José; Spalenza, Jessica S; Lahera, Vicente; Vassallo, Paula F; Cachofeiro, Victoria

2013-01-01

The mechanisms involved in cardiac remodeling in left (LV) and right ventricles (RV) after myocardial infarction (MI) are still unclear. We assayed factors involved in collagen turnover in both ventricles following MI in rats either presenting signs of heart failure (pulmonary congestion and increased LVEDP) or not (INF-HF or INF, respectively). MI was induced in male rats by ligation of the left coronary artery. Four weeks after MI gene expression of collagen I, connective tissue growth factor (CTGF), transforming growth factor β (TGF-β) and lysyl oxidase (LOX), metalloproteinase-2 (MMP2) and tissue inhibitor metalloproteinase-2 (TIMP2) as well as cardiac hemodynamic in both ventricles were evaluated. Ventricular dilatation, hypertrophy and an increase in interstitial fibrosis and myocyte size were observed in the RV and LV from INF-HF animals, whereas only LV dilatation and fibrosis in RV was present in INF. The LV fibrosis in INF-HF was associated with higher mRNA of collagen I, CTGF, TGF-β and LOX expressions than in INF and SHAM animals, while MMP2/TIMP2 mRNA ratio did not change. RV fibrosis in INF and INF-HF groups was associated with an increase in LOX mRNA and a reduction in MMP2/TIMP2 ratio. CTGF mRNA was increased only in the INF-HF group. INF and INF-HF animals presented different patterns of remodeling in both ventricles. In the INF-HF group, fibrosis seems to be consequence of collagen production in LV, and by reductions in collagen degradation in RV of both INF and INF-HF animals.

Remodelling of action potential and intracellular calcium cycling dynamics during subacute myocardial infarction promotes ventricular arrhythmias in Langendorff-perfused rabbit hearts

PubMed Central

Chou, Chung-Chuan; Zhou, Shengmei; Hayashi, Hideki; Nihei, Motoki; Liu, Yen-Bin; Wen, Ming-Shien; Yeh, San-Jou; Fishbein, Michael C; Weiss, James N; Lin, Shien-Fong; Wu, Delon; Chen, Peng-Sheng

2007-01-01

We hypothesize that remodelling of action potential and intracellular calcium (Cai) dynamics in the peri-infarct zone contributes to ventricular arrhythmogenesis in the postmyocardial infarction setting. To test this hypothesis, we performed simultaneous optical mapping of Cai and membrane potential (Vm) in the left ventricle in 15 rabbit hearts with myocardial infarction for 1 week. Ventricular premature beats frequently originated from the peri-infarct zone, and 37% showed elevation of Cai prior to Vm depolarization, suggesting reverse excitation–contraction coupling as their aetiology. During electrically induced ventricular fibrillation, the highest dominant frequency was in the peri-infarct zone in 61 of 70 episodes. The site of highest dominant frequency had steeper action potential duration restitution and was more susceptible to pacing-induced Cai alternans than sites remote from infarct. Wavebreaks during ventricular fibrillation tended to occur at sites of persistently elevated Cai. Infusion of propranolol flattened action potential duration restitution, reduced wavebreaks and converted ventricular fibrillation to ventricular tachycardia. We conclude that in the subacute phase of myocardial infarction, the peri-infarct zone exhibits regions with steep action potential duration restitution slope and unstable Cai dynamics. These changes may promote ventricular extrasystoles and increase the incidence of wavebreaks during ventricular fibrillation. Whereas increased tissue heterogeneity after subacute myocardial infarction creates a highly arrhythmogenic substrate, dynamic action potential and Cai cycling remodelling also contribute to the initiation and maintenance of ventricular fibrillation in this setting. PMID:17272354

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.

Mineralocorticoid receptor antagonist pretreatment to MINIMISE reperfusion injury after ST-elevation myocardial infarction (the MINIMISE STEMI Trial): rationale and study design.

PubMed

Bulluck, Heerajnarain; Fröhlich, Georg M; Mohdnazri, Shah; Gamma, Reto A; Davies, John R; Clesham, Gerald J; Sayer, Jeremy W; Aggarwal, Rajesh K; Tang, Kare H; Kelly, Paul A; Jagathesan, Rohan; Kabir, Alamgir; Robinson, Nicholas M; Sirker, Alex; Mathur, Anthony; Blackman, Daniel J; Ariti, Cono; Krishnamurthy, Arvindra; White, Steven K; Meier, Pascal; Moon, James C; Greenwood, John P; Hausenloy, Derek J

2015-05-01

Novel therapies capable of reducing myocardial infarct (MI) size when administered prior to reperfusion are required to prevent the onset of heart failure in ST-segment elevation myocardial infarction (STEMI) patients treated by primary percutaneous coronary intervention (PPCI). Experimental animal studies have demonstrated that mineralocorticoid receptor antagonist (MRA) therapy administered prior to reperfusion can reduce MI size, and MRA therapy prevents adverse left ventricular (LV) remodeling in post-MI patients with LV impairment. With these 2 benefits in mind, we hypothesize that initiating MRA therapy prior to PPCI, followed by 3 months of oral MRA therapy, will reduce MI size and prevent adverse LV remodeling in STEMI patients. The MINIMISE-STEMI trial is a prospective, randomized, double-blind, placebo-controlled trial that will recruit 150 STEMI patients from four centers in the United Kingdom. Patients will be randomized to receive either an intravenous bolus of MRA therapy (potassium canrenoate 200 mg) or matching placebo prior to PPCI, followed by oral spironolactone 50 mg once daily or matching placebo for 3 months. A cardiac magnetic resonance imaging scan will be performed within 1 week of PPCI and repeated at 3 months to assess MI size and LV remodeling. Enzymatic MI size will be estimated by the 48-hour area-under-the-curve serum cardiac enzymes. The primary endpoint of the study will be MI size on the 3-month cardiac magnetic resonance imaging scan. The MINIMISE STEMI trial will investigate whether early MRA therapy, initiated prior to reperfusion, can reduce MI size and prevent adverse post-MI LV remodeling. © 2015 The Authors. Clinical Cardiology published by Wiley Periodicals, Inc.

Left and Right Ventricle Late Remodeling Following Myocardial Infarction in Rats

PubMed Central

Stefanon, Ivanita; Valero-Muñoz, María; Fernandes, Aurélia Araújo; Ribeiro, Rogério Faustino; Rodríguez, Cristina; Miana, Maria; Martínez-González, José; Spalenza, Jessica S.; Lahera, Vicente; Vassallo, Paula F.; Cachofeiro, Victoria

2013-01-01

Background The mechanisms involved in cardiac remodeling in left (LV) and right ventricles (RV) after myocardial infarction (MI) are still unclear. We assayed factors involved in collagen turnover in both ventricles following MI in rats either presenting signs of heart failure (pulmonary congestion and increased LVEDP) or not (INF-HF or INF, respectively). Methods MI was induced in male rats by ligation of the left coronary artery. Four weeks after MI gene expression of collagen I, connective tissue growth factor (CTGF), transforming growth factor β (TGF-β) and lysyl oxidase (LOX), metalloproteinase-2 (MMP2) and tissue inhibitor metalloproteinase-2 (TIMP2) as well as cardiac hemodynamic in both ventricles were evaluated. Results Ventricular dilatation, hypertrophy and an increase in interstitial fibrosis and myocyte size were observed in the RV and LV from INF-HF animals, whereas only LV dilatation and fibrosis in RV was present in INF. The LV fibrosis in INF-HF was associated with higher mRNA of collagen I, CTGF, TGF-β and LOX expressions than in INF and SHAM animals, while MMP2/TIMP2 mRNA ratio did not change. RV fibrosis in INF and INF-HF groups was associated with an increase in LOX mRNA and a reduction in MMP2/TIMP2 ratio. CTGF mRNA was increased only in the INF-HF group. Conclusions INF and INF-HF animals presented different patterns of remodeling in both ventricles. In the INF-HF group, fibrosis seems to be consequence of collagen production in LV, and by reductions in collagen degradation in RV of both INF and INF-HF animals. PMID:23741440

Inflammation as a therapeutic target in myocardial infarction: learning from past failures to meet future challenges

PubMed Central

Saxena, Amit; Russo, Ilaria; Frangogiannis, Nikolaos G

2015-01-01

In the infarcted myocardium, necrotic cardiomyocytes release danger signals, activating an intense inflammatory response. Inflammatory pathways play a crucial role in regulation of a wide range of cellular processes involved in injury, repair and remodeling of the infarcted heart. Pro-inflammatory cytokines, such as tumor necrosis factor-a and interleukin (IL)-1, are markedly upregulated in the infarcted myocardium and promote adhesive interactions between endothelial cells and leukocytes, by stimulating chemokine and adhesion molecule expression. Distinct chemokine/chemokine receptor pairs are implicated in recruitment of various leukocyte subpopulations in the infarcted myocardium. Over the last 30 years, extensive experimental work has explored the role of inflammatory signals and the contributions of leukocyte subpopulations, in myocardial infarction. Robust evidence derived from experimental models of myocardial infarction has identified inflammatory targets that may attenuate cardiomyocyte injury, or protect from adverse remodeling. Unfortunately, attempts to translate the promising experimental findings to clinical therapy have failed. This review manuscript discusses the biology of the inflammatory response following myocardial infarction, attempts to identify the causes for the translational failures of the past, and proposes promising new therapeutic directions. Because of their potential involvement in injurious, reparative and regenerative responses, inflammatory cells may hold the key for design of new therapies in myocardial infarction. PMID:26241027

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.

Association of Exercise Training with Tobacco Smoking Prevents Fibrosis but has Adverse Impact on Myocardial Mechanics.

PubMed

Reis Junior, Dermeval; Antonio, Ednei Luiz; de Franco, Marcello Fabiano; de Oliveira, Helenita Antonia; Tucci, Paulo José Ferreira; Serra, Andrey Jorge

2016-12-01

There was no data for cardiac repercussion of exercise training associated with tobacco smoking. This issue is interesting because some smoking people can be enrolled in an exercise-training program. Thus, we evaluated swimming training effects on the function and structural myocardial in rats exposed to tobacco smoking. Male Wistar rats were assigned to one of four groups: C, untrained rats without exposure to tobacco smoking; E, exercised rats without exposure to tobacco smoking; CS, untrained rats exposed to tobacco smoking; ECS, exercised rats exposed to tobacco smoking. Rats swam five times a week twice daily (60min per session) for 8 weeks. Before each bout exercise, rats breathed smoke from 20 cigarettes for 60min. Twenty-four hours after the last day of the protocol, papillary muscles were isolated for in vitro analysis of myocardial mechanics. The myocardial mass and nuclear cardiomyocyte volume were used as hypertrophy markers, and collagen content was determined by picrosirius red staining. There was a well-pronounced myocardial hypertrophic effect for two interventions. The exercise blunted myocardial collagen increases induced by tobacco smoking. However, exercise and tobacco-smoking association was deleterious to myocardial performance. Thereby, in vitro experiments with papillary muscles contracting in isometric showed impairment myocardial inotropism in exercised rats exposed to tobacco smoking. This work presents novel findings on the role of exercise training on cardiac remodeling induced by tobacco smoking. Although exercise has mitigated tissue fibrosis, their association with tobacco smoking exacerbated hypertrophy and in vitro myocardial dysfunction. This is first study to show that the association of an aerobic exercise training with tobacco smoking intensifies the phenotype of pathological cardiac hypertrophy. Therefore, the combination of interventions resulted in exacerbated myocardial hypertrophy and contractility dysfunction. These

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

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.

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

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

Post-infarct sleep disruption and its relation to cardiac remodeling in a rat model of myocardial infarction.

PubMed

Aghajani, Marjan; Faghihi, Mahdieh; Imani, Alireza; Vaez Mahdavi, Mohammad Reza; Shakoori, Abbas; Rastegar, Tayebeh; Parsa, Hoda; Mehrabi, Saman; Moradi, Fatemeh; Kazemi Moghaddam, Ehsan

2017-01-01

Sleep disruption after myocardial infarction (MI) by affecting ubiquitin-proteasome system (UPS) is thought to contribute to myocardial remodeling and progressive worsening of cardiac function. The aim of current study was to test the hypothesis about the increased risk of developing heart failure due to experience of sleep restriction (SR) after MI. Male Wistar rats (n = 40) were randomly assigned to four experimental groups: (1) Sham, (2) MI, (3) MI and SR (MI + SR) (4) Sham and SR (Sham + SR). MI was induced by permanent ligation of left anterior descending coronary artery. Twenty-four hours after surgery, animals were subjected to chronic SR paradigm. Blood sampling was performed at days 1, 8 and 21 after MI for determination of serum levels of creatine kinase-MB (CK-MB), corticosterone, malondialdehyde (MDA) and nitric oxide (NO). Finally, at 21 days after MI, echocardiographic parameters and expression of MuRF1, MaFBx, A20, eNOS, iNOS and NF-kB in the heart were evaluated. We used H&E staining to detect myocardial hypertrophy. We found out that post infarct SR increased corticosterone levels. Our results highlighted deteriorating effects of post-MI SR on NO production, oxidative stress, and echocardiographic indexes (p < 0.05). Moreover, its detrimental effects on myocardial damage were confirmed by overexpression of MuRF1, MaFBx, iNOS and NF-kB (p < 0.001) in left ventricle and downregulation of A20 and eNOS (p < 0.05). Furthermore, histological examination revealed that experience of SR after MI increased myocardial diameter as compared to Sham subjects (p < 0.05). Our data suggest that SR after MI leads to an enlargement of the heart within 21 days, marked by an increase in oxidative stress and NO production as well as an imbalance in UPS that ultimately results in cardiac dysfunction and heart failure.

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.

Prognostic implications of left ventricular mass and geometry following myocardial infarction: the VALIANT (VALsartan In Acute myocardial iNfarcTion) Echocardiographic Study.

PubMed

Verma, Anil; Meris, Alessandra; Skali, Hicham; Ghali, Jalal K; Arnold, J Malcolm O; Bourgoun, Mikhail; Velazquez, Eric J; McMurray, John J V; Kober, Lars; Pfeffer, Marc A; Califf, Robert M; Solomon, Scott D

2008-09-01

This study sought to understand prognostic implications of increased baseline left ventricular (LV) mass and geometric patterns in a high risk acute myocardial infarction. The LV hypertrophy and alterations in LV geometry are associated with an increased risk of adverse cardiovascular events. Quantitative echocardiographic analyses were performed at baseline in 603 patients from the VALIANT (VALsartan In Acute myocardial iNfarcTion) echocardiographic study. The left ventricular mass index (LVMi) and relative wall thickness (RWT) were calculated. Patients were classified into 4 mutually exclusive groups based on RWT and LVMi as follows: normal geometry (normal LVMi and normal RWT), concentric remodeling (normal LVMi and increased RWT), eccentric hypertrophy (increased LVMi and normal RWT), and concentric hypertrophy (increased LVMi and increased RWT). Cox proportional hazards models were used to evaluate the relationships among LVMi, RWT, LV geometry, and clinical outcomes. Mean LVMi and RWT were 98.8 +/- 28.4 g/m(2) and 0.38 +/- 0.08. The risk of death or the composite end point of death from cardiovascular causes, reinfarction, heart failure, stroke, or resuscitation after cardiac arrest was lowest for patients with normal geometry, and increased with concentric remodeling (hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.9 to 4.9), eccentric hypertrophy (HR: 3.1; 95% CI: 1.9 to 4.8), and concentric hypertrophy (HR: 5.4; 95% CI: 3.4 to 8.5), after adjusting for baseline covariates. Also, baseline LVMi and RWT were associated with increased mortality and nonfatal cardiovascular outcomes (HR: 1.22 per 10 g/m(2) increase in LVMi; 95% CI: 1.20 to 1.30; p < 0.001) (HR: 1.60 per 0.1-U increase in RWT; 95% CI: 1.30 to 1.90; p < 0.001). Increased risk associated with RWT was independent of LVMi. Increased baseline LV mass and abnormal LV geometry portend an increased risk for morbidity and mortality following high-risk myocardial infarction. Concentric LV

Remodeling of the transverse tubular system after myocardial infarction in rabbit correlates with local fibrosis: A potential role of biomechanics.

PubMed

Seidel, T; Sankarankutty, A C; Sachse, F B

2017-11-01

The transverse tubular system (t-system) of ventricular cardiomyocytes is essential for efficient excitation-contraction coupling. In cardiac diseases, such as heart failure, remodeling of the t-system contributes to reduced cardiac contractility. However, mechanisms of t-system remodeling are incompletely understood. Prior studies suggested an association with altered cardiac biomechanics and gene expression in disease. Since fibrosis may alter tissue biomechanics, we investigated the local microscopic association of t-system remodeling with fibrosis in a rabbit model of myocardial infarction (MI). Biopsies were taken from the MI border zone of 6 infarcted hearts and from 6 control hearts. Using confocal microscopy and automated image analysis, we quantified t-system integrity (I TT ) and the local fraction of extracellular matrix (f ECM ). In control, f ECM was 18 ± 0.3%. I TT was high and homogeneous (0.07 ± 0.006), and did not correlate with f ECM (R 2  = 0.05 ± 0.02). The MI border zone exhibited increased f ECM within 3 mm from the infarct scar (30 ± 3.5%, p < 0.01 vs control), indicating fibrosis. Myocytes in the MI border zone exhibited significant t-system remodeling, with dilated, sheet-like components, resulting in low I TT (0.03 ± 0.008, p < 0.001 vs control). While both f ECM and t-system remodeling decreased with infarct distance, I TT correlated better with decreasing f ECM (R 2  = 0.44) than with infarct distance (R 2  = 0.24, p < 0.05). Our results show that t-system remodeling in the rabbit MI border zone resembles a phenotype previously described in human heart failure. T-system remodeling correlated with the amount of local fibrosis, which is known to stiffen cardiac tissue, but was not found in regions without fibrosis. Thus, locally altered tissue mechanics may contribute to t-system remodeling. Copyright © 2017 Elsevier Ltd. All rights reserved.

Targeted Imaging of the Spatial and Temporal Variation of Matrix Metalloproteinase Activity in Porcine Model of Post-Infarct Remodeling: Relationship to Myocardial Dysfunction

PubMed Central

Sahul, Zakir H.; Mukherjee, Rupak; Song, James; McAteer, Jarod; Stroud, Robert E.; Dione, Donald P.; Staib, Lawrence; Papademetris, Xenophon; Dobrucki, Lawrence W.; Duncan, James S.; Spinale, Francis G.; Sinusas, Albert J.

2011-01-01

Background Matrix metalloproteinases (MMPs) are known to modulate left ventricular (LV) remodeling after a myocardial infarction (MI). However, the temporal and spatial variation of MMP activation and their relationship to mechanical dysfunction post MI remains undefined. Methods and Results MI was surgically induced in pigs (n=23) and cine MR and dual isotope hybrid SPECT/CT imaging obtained using thallium-201 (201Tl) and a technetium-99m labeled MMP targeted tracer (99mTc-RP805) at 1, 2 and 4 weeks post MI along with controls (n=5). Regional myocardial strain was computed from MR images and related to MMP zymography and ex vivo myocardial 99mTc-RP805 retention. MMP activation as assessed by in vivo and ex vivo 99mTc-RP805 imaging/retention studies was increased nearly 5-fold within the infarct region at 1 week post-MI and remained elevated up to 1 month post-MI. The post-MI change in LV end-diastolic volumes was correlated with MMP activity (y=31.34e0.48x, p=0.04). MMP activity was increased within the border and remote regions early post-MI, but declined over 1 month. There was a high concordance between regional 99mTc-RP805 uptake and ex vivo MMP-2 activity. Conclusions A novel, multimodality non-invasive hybrid SPECT/CT imaging approach was validated and applied for in vivo evaluation of MMP activation in combination with cine MR analysis of LV deformation. Increased 99mTc-RP805 retention was seen throughout the heart early post-MI and was not purely a reciprocal of 201Tl perfusion. 99mTc-RP805 SPECT/CT imaging may provide unique information regarding regional myocardial MMP activation and predict late post-MI LV remodeling. PMID:21505092

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.

Plant-based foods containing cell wall polysaccharides rich in specific active monosaccharides protect against myocardial injury in rat myocardial infarction models.

PubMed

Lim, Sun Ha; Kim, Yaesil; Yun, Ki Na; Kim, Jin Young; Jang, Jung-Hee; Han, Mee-Jung; Lee, Jongwon

2016-12-08

Many cohort studies have shown that consumption of diets containing a higher composition of foods derived from plants reduces mortality from coronary heart disease (CHD). Here, we examined the active components of a plant-based diet and the underlying mechanisms that reduce the risk of CHD using three rat models and a quantitative proteomics approach. In a short-term myocardial infarction (MI) model, intake of wheat extract (WE), the representative cardioprotectant identified by screening approximately 4,000 samples, reduced myocardial injury by inhibiting apoptosis, enhancing ATP production, and maintaining protein homeostasis. In long-term post-MI models, this myocardial protection resulted in ameliorating adverse left-ventricular remodelling, which is a predictor of heart failure. Among the wheat components, arabinose and xylose were identified as active components responsible for the observed efficacy of WE, which was administered via ingestion and tail-vein injections. Finally, the food components of plant-based diets that contained cell wall polysaccharides rich in arabinose, xylose, and possibly fucose were found to confer protection against myocardial injury. These results show for the first time that specific monosaccharides found in the cell wall polysaccharides in plant-based diets can act as active ingredients that reduce CHD by inhibiting postocclusion steps, including MI and heart failure.

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

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

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.

Pyridostigmine ameliorates cardiac remodeling induced by myocardial infarction via inhibition of the transforming growth factor-β1/TGF-β1-activated kinase pathway.

PubMed

Lu, Yi; Liu, Jin-Jun; Bi, Xue-Yuan; Yu, Xiao-Jiang; Kong, Shan-Shan; Qin, Fang-Fang; Zhou, Jun; Zang, Wei-Jin

2014-05-01

Autonomic imbalance characterized by sympathetic predominance coinciding with diminished vagal activity is an independent risk factor in cardiovascular diseases. Several studies show that vagus nerve stimulation exerted beneficial effects on cardiac function and survival. In this study, we investigated the vagomimetic effect of pyridostigmine on left ventricular (LV) remodeling in rats after myocardial infarction. After myocardial infarction, surviving rats were treated with or without pyridostigmine (31 mg·kg⁻¹·d⁻¹) for 2 weeks, and hemodynamic parameters were measured. LV tissue was used to assess infarct size and interstitial fibrosis by Masson's trichrome and 0.1% picrosirius red staining. Protein expression of heart tissues was used to assess the efficacy of the treatment. Pyridostigmine markedly reduced myocardial infarct size and improved cardiac diastolic function. These improvements were accompanied with a significant decrease in matrix metalloproteinase-2 expression and collagen deposition. Additionally, pyridostigmine inhibited both transforming growth factor-β1 (TGF-β1) and TGF-β1-activated kinase expression in hearts postmyocardial infarction. Thus, pyridostigmine reduces collagen deposition, attenuates cardiac fibrosis, and improves LV diastolic function after myocardial infarction via TGF-β1/TGF-β1-activated kinase pathway inhibition.

Frequent premature atrial contractions impair left atrial contractile function and promote adverse left atrial remodeling.

PubMed

John, Anub G; Hirsch, Glenn A; Stoddard, Marcus F

2018-06-10

This study assessed if frequent premature atrial contractions (PACs) were associated with decreased left atrial (LA) strain and adverse remodeling. Left atrial dysfunction and enlargement increases risk of stroke. If frequent PACs cause LA dysfunction and remodeling, PAC suppressive therapy may be beneficial. Inclusion criteria were age ≥18 years and sinus rhythm. Exclusion criteria were atrial fibrillation or any etiology for LA enlargement. Hundred and thirty-two patients with frequent PACs (≥100/24 hours) by Holter were matched to controls. Speckle tracking strain of the left atrium was performed from the 4-chamber view. Strain measurements were LA peak contractile, reservoir and conduit strain and strain rates. In the frequent PAC vs control group, PACs were more frequent (1959 ± 3796 vs 28 ± 25/24 hours, P < .0001). LA peak contractile strain was reduced in the group with frequent PACs vs controls (-7.85 ± 4.12% vs -9.33 ± 4.45%, P = .006). LA peak late negative contractile strain rate was less negative in the frequent PAC vs control group (-0.63 ± 0.27 s -1 vs -0.69 ± 0.32 s -1 , P = .051). LA reservoir and conduit strain and strain rates did not differ. LA volume index (LAVI) was larger in the frequent PAC vs control group (26.6 ± 7.8 vs 24.6 ± 8.8 mL/m 2 , P < .05). Frequent PACs were an independent predictor of reduced LA peak contractile strain and reduced LA peak late negative contractile strain rate. Patients with frequent PACs have reduced LA peak contractile strain and strain rates and larger LAVI compared to controls. Frequent PACs are an independent predictor of reduced LA peak contractile strain and strain rate. These findings support the hypothesis that frequent PACs impair LA contractile function and promote adverse LA remodeling. © 2018 Wiley Periodicals, Inc.

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.

Liposome encapsulated berberine treatment attenuates cardiac dysfunction after myocardial infarction.

PubMed

Allijn, Iris E; Czarny, Bertrand M S; Wang, Xiaoyuan; Chong, Suet Yen; Weiler, Marek; da Silva, Acarilia Eduardo; Metselaar, Josbert M; Lam, Carolyn Su Ping; Pastorin, Giorgia; de Kleijn, Dominique P V; Storm, Gert; Wang, Jiong-Wei; Schiffelers, Raymond M

2017-02-10

Inflammation is a known mediator of adverse ventricular remodeling after myocardial infarction (MI) that may lead to reduction of ejection fraction and subsequent heart failure. Berberine is a isoquinoline quarternary alkaloid from plants that has been associated with anti-inflammatory, anti-oxidative, and cardioprotective properties. Its poor solubility in aqueous buffers and its short half-life in the circulation upon injection, however, have been hampering the extensive usage of this natural product. We hypothesized that encapsulation of berberine into long circulating liposomes could improve its therapeutic availability and efficacy by protecting cardiac function against MI in vivo. Berberine-loaded liposomes were prepared by ethanol injection and characterized. They contained 0.3mg/mL of the drug and were 0.11μm in diameter. Subsequently they were tested for IL-6 secretion inhibition in RAW 264.7 macrophages and for cardiac function protection against adverse remodeling after MI in C57BL/6J mice. In vitro, free berberine significantly inhibited IL-6 secretion (IC 50 =10.4μM), whereas encapsulated berberine did not as it was not released from the formulation in the time frame of the in vitro study. In vivo, berberine-loaded liposomes significantly preserved the cardiac ejection fraction at day 28 after MI by 64% as compared to control liposomes and free berberine. In conclusion, liposomal encapsulation enhanced the solubility of berberine in buffer and preserves ejection fraction after MI. This shows that delivery of berberine-loaded liposomes significantly improves its therapeutic availability and identifies berberine-loaded liposomes as potential treatment of adverse remodeling after MI. Copyright © 2017 Elsevier B.V. All rights reserved.

Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges.

PubMed

Huang, Shuaibo; Frangogiannis, Nikolaos G

2018-05-01

In the infarcted heart, the damage-associated molecular pattern proteins released by necrotic cells trigger both myocardial and systemic inflammatory responses. Induction of chemokines and cytokines and up-regulation of endothelial adhesion molecules mediate leukocyte recruitment in the infarcted myocardium. Inflammatory cells clear the infarct of dead cells and matrix debris and activate repair by myofibroblasts and vascular cells, but may also contribute to adverse fibrotic remodelling of viable segments, accentuate cardiomyocyte apoptosis and exert arrhythmogenic actions. Excessive, prolonged and dysregulated inflammation has been implicated in the pathogenesis of complications and may be involved in the development of heart failure following infarction. Studies in animal models of myocardial infarction (MI) have suggested the effectiveness of pharmacological interventions targeting the inflammatory response. This article provides a brief overview of the cell biology of the post-infarction inflammatory response and discusses the use of pharmacological interventions targeting inflammation following infarction. Therapy with broad anti-inflammatory and immunomodulatory agents may also inhibit important repair pathways, thus exerting detrimental actions in patients with MI. Extensive experimental evidence suggests that targeting specific inflammatory signals, such as the complement cascade, chemokines, cytokines, proteases, selectins and leukocyte integrins, may hold promise. However, clinical translation has proved challenging. Targeting IL-1 may benefit patients with exaggerated post-MI inflammatory responses following infarction, not only by attenuating adverse remodelling but also by stabilizing the atherosclerotic plaque and by inhibiting arrhythmia generation. Identification of the therapeutic window for specific interventions and pathophysiological stratification of MI patients using inflammatory biomarkers and imaging strategies are critical for optimal

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.

Stimulated Emission Depletion Live-Cell Super-Resolution Imaging Shows Proliferative Remodeling of T-Tubule Membrane Structures After Myocardial Infarction

PubMed Central

Wagner, Eva; Lauterbach, Marcel A.; Kohl, Tobias; Westphal, Volker; Williams, George S.B.; Steinbrecher, Julia H.; Streich, Jan-Hendrik; Korff, Brigitte; Tuan, Hoang-Trong M.; Hagen, Brian; Luther, Stefan; Hasenfuss, Gerd; Parlitz, Ulrich; Jafri, M. Saleet; Hell, Stefan W.; Lederer, W. Jonathan; Lehnart, Stephan E.

2014-01-01

Rationale Transverse tubules (TTs) couple electric surface signals to remote intracellular Ca2+ release units (CRUs). Diffraction-limited imaging studies have proposed loss of TT components as disease mechanism in heart failure (HF). Objectives Objectives were to develop quantitative super-resolution strategies for live-cell imaging of TT membranes in intact cardiomyocytes and to show that TT structures are progressively remodeled during HF development, causing early CRU dysfunction. Methods and Results Using stimulated emission depletion (STED) microscopy, we characterized individual TTs with nanometric resolution as direct readout of local membrane morphology 4 and 8 weeks after myocardial infarction (4pMI and 8pMI). Both individual and network TT properties were investigated by quantitative image analysis. The mean area of TT cross sections increased progressively from 4pMI to 8pMI. Unexpectedly, intact TT networks showed differential changes. Longitudinal and oblique TTs were significantly increased at 4pMI, whereas transversal components appeared decreased. Expression of TT-associated proteins junctophilin-2 and caveolin-3 was significantly changed, correlating with network component remodeling. Computational modeling of spatial changes in HF through heterogeneous TT reorganization and RyR2 orphaning (5000 of 20 000 CRUs) uncovered a local mechanism of delayed subcellular Ca2+ release and action potential prolongation. Conclusions This study introduces STED nanoscopy for live mapping of TT membrane structures. During early HF development, the local TT morphology and associated proteins were significantly altered, leading to differential network remodeling and Ca2+ release dyssynchrony. Our data suggest that TT remodeling during HF development involves proliferative membrane changes, early excitation-contraction uncoupling, and network fracturing. PMID:22723297

VALSARTAN REGULATES MYOCARDIAL AUTOPHAGY AND MITOCHONDRIAL TURNOVER IN EXPERIMENTAL HYPERTENSION

PubMed Central

Zhang, Xin; Li, Zi-Lun; Crane, John A.; Jordan, Kyra L.; Pawar, Aditya S.; Textor, Stephen C.; Lerman, Amir; Lerman, Lilach O.

2014-01-01

Renovascular hypertension alters cardiac structure and function. Autophagy is activated during left ventricular hypertrophy and linked to adverse cardiac function. The Angiotensin II receptor blocker Valsartan lowers blood pressure and is cardioprotective, but whether it modulates autophagy in the myocardium is unclear. We hypothesized that Valsartan would alleviate autophagy and improve left ventricular myocardial mitochondrial turnover in swine renovascular hypertension. Domestic pigs were randomized to control, unilateral renovascular hypertension, and renovascular hypertension treated with Valsartan (320 mg/day) or conventional triple therapy (Reserpine+hydralazine+hydrochlorothiazide) for 4 weeks post 6-weeks of renovascular hypertension (n=7 each group). Left ventricular remodeling, function and myocardial oxygenation and microcirculation were assessed by multi-detector computer tomography, blood-oxygen-level-dependent magnetic resonance imaging and microcomputer tomography. Myocardial autophagy, markers for mitochondrial degradation and biogenesis, and mitochondrial respiratory-chain proteins were examined ex vivo. Renovascular hypertension induced left ventricular hypertrophy and myocardial hypoxia, enhanced cellular autophagy and mitochondrial degradation, and suppressed mitochondrial biogenesis. Valsartan and triple therapy similarly decreased blood pressure, but Valsartan solely alleviated left ventricular hypertrophy, ameliorated myocardial autophagy and mitophagy, and increased mitochondrial biogenesis. In contrast, triple therapy only slightly attenuated autophagy and preserved mitochondrial proteins, but elicited no improvement in mitophagy. These data suggest a novel potential role of Valsartan in modulating myocardial autophagy and mitochondrial turnover in renovascular hypertension-induced hypertensive heart disease, which may possibly bolster cardiac repair via a blood pressure-independent manner. PMID:24752430

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

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.

Modification of a Volume-Overload Heart Failure Model to Track Myocardial Remodeling and Device-Related Reverse Remodeling

PubMed Central

Tuzun, Egemen; Bick, Roger; Kadipasaoglu, Cihan; Conger, Jeffrey L.; Poindexter, Brian J.; Gregoric, Igor D.; Frazier, O. H.; Towbin, Jeffrey A.; Radovancevic, Branislav

2011-01-01

Purpose. To provide an ovine model of ventricular remodeling and reverse remodeling by creating congestive heart failure (CHF) and then treating it by implanting a left ventricular assist device (LVAD). Methods. We induced volume-overload heart failure in 2 sheep; 20 weeks later, we implanted an LVAD and assessed recovery 11 weeks thereafter. We examined changes in histologic and hemodynamic data and levels of cellular markers of CHF. Results. After CHF induction, we found increases in LV end-diastolic pressure, LV systolic and diastolic dimensions, wall thickness, left atrial diameter, and atrial natriuretic protein (ANP) and endothelin-1 (ET-1) levels; β-adrenergic receptor (BAR) and dystrophin expression decreased markedly. Biopsies confirmed LV remodeling. After LVAD support, LV systolic and diastolic dimensions, wall thickness, and mass, and ANP and ET-1 levels decreased. Histopathologic and hemodynamic markers improved, and BAR and dystrophin expression normalized. Conclusions. We describe a successful sheep model for ventricular and reverse remodeling. PMID:22347659

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.

Ablation of toll-like receptor 4 attenuates aging-induced myocardial remodeling and contractile dysfunction through NCoRI-HDAC1-mediated regulation of autophagy.

PubMed

Wang, Shuyi; Ge, Wei; Harns, Carrie; Meng, Xianzhong; Zhang, Yingmei; Ren, Jun

2018-04-13

Aging is usually accompanied with overt structural and functional changes as well as suppressed autophagy in the heart although the precise regulatory mechanisms are somewhat unknown. Here we evaluated the role of the innate proinflammatory mediator toll-like receptor 4 (TLR4) in cardiac aging and the underlying mechanism with a focus on autophagy. Cardiac geometry and function were monitored in young or old wild-type (WT) and TLR4 knockout (TLR4 -/- ) mice using echocardiography, IonOptix® edge-detection and fura-2 techniques. Levels of autophagy and mitophagy, nuclear receptor corepressor 1 (NCoR1) and histone deacetylase I (HDAC1) were examined using western blot. Transmission electronic microscopy (TEM) was employed to monitor myocardial ultrastructure. Our results revealed that TLR4 ablation alleviated advanced aging (24 months)-induced changes in myocardial remodeling (increased heart weight, chamber size, cardiomyocyte cross-sectional area), contractile function and intracellular Ca 2+ handling as well as autophagy and mitophagy [Beclin-1, Atg5, LC3B, PTEN-induced putative kinase 1 (PINK1), Parkin and p62]. Aging downregulated levels of NCoR1 and HDAC1 as well as their interaction, the effects were significantly attenuated or negated by TLR4 ablation. Advanced aging disturbed myocardial ultrastructure as evidenced by loss of myofilament alignment and swollen mitochondria, which was obliterated by TLR4 ablation. Moreover, aging suppressed autophagy (GFP-LC3B puncta) in neonatal mouse cardiomyocytes, the effect of which was negated by the TLR4 inhibitor CLI-095. Inhibition of HDCA1 using apicidin cancelled off CLI095-induced beneficial response of GFP-LC3B puncta against aging. Our data collectively indicate a role for TLR4-mediated autophagy in cardiac remodeling and contractile dysfunction in aging through a HDAC1-NCoR1-dependent mechanism. Copyright © 2018 Elsevier Ltd. All rights reserved.

A case report of apical aneurysms and myocardial perfusion deficit with myocardial necrosis due to hypertrophic cardiomyopathy.

PubMed

Gao, Xiangyu; Yang, Jigang; Zhang, Xiaojie; Wang, Ping; Li, Hongwei

2018-05-01

Hypertrophic cardiomyopathy (HCM) is a disease that is characterized by inappropriate left ventricular and/or right ventricular hypertrophy and hypercontractility that is often asymmetrical and associated with microscopic evidence of myocardial fiber disarray. The aim of this study was to present a previously under-recognized subset of HCM patients with left ventricular (LV) apical aneurysms. A 33-year-old man who presented with chest discomfort for 10 days. He had an emerging apical aneurysm in the LV without midventricular obstruction. He had been diagnosed with apical HCM via abnormal electrocardiograms (ECG) and single-photon emission computed tomography (SPECT) for 10 years. This time, a new significant change in ECG and SPECT was identified. Late gadolinium enhancement (LGE) was observed by cardiac magnetic resonance imaging (MRI), and SPECT showed myocardial fibrosis or necrosis involving the apical aneurysm and proximal portion of the heart, which was confirmed by left ventriculography. We present a relatively rare case of HCM patients with apical aneurysms, accompaning by myocardial necrosis markers increased due to ventricular muscle stress increases, rather than obstructive coronary artery disease. The patient was prescribed aspirin, metoprolol tartrate, perindopril, and atorvastatin and was strongly advised to quit cigarettes and reduce weight. Follow-up at half a year turned out well. LGE with a notable progression by ECG and SPECT along with an increase in myocardial necrosis markers in HCM patients with apical aneurysms, as was noted in the present case, is a relatively rare occurrence. Our present case may provide unique insights into the adverse remodelling process and the formation of apical aneurysms in HCM patients.

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

Methylglyoxal-derived advanced glycation end products contribute to negative cardiac remodeling and dysfunction post-myocardial infarction.

PubMed

Blackburn, Nick J R; Vulesevic, Branka; McNeill, Brian; Cimenci, Cagla Eren; Ahmadi, Ali; Gonzalez-Gomez, Mayte; Ostojic, Aleksandra; Zhong, Zhiyuan; Brownlee, Michael; Beisswenger, Paul J; Milne, Ross W; Suuronen, Erik J

2017-09-01

Advanced glycation end-products (AGEs) have been associated with poorer outcomes after myocardial infarction (MI), and linked with heart failure. Methylglyoxal (MG) is considered the most important AGE precursor, but its role in MI is unknown. In this study, we investigated the involvement of MG-derived AGEs (MG-AGEs) in MI using transgenic mice that over-express the MG-metabolizing enzyme glyoxalase-1 (GLO1). MI was induced in GLO1 mice and wild-type (WT) littermates. At 6 h post-MI, mass spectrometry revealed that MG-H1 (a principal MG-AGE) was increased in the hearts of WT mice, and immunohistochemistry demonstrated that this persisted for 4 weeks. GLO1 over-expression reduced MG-AGE levels at 6 h and 4 weeks, and GLO1 mice exhibited superior cardiac function at 4 weeks post-MI compared to WT mice. Immunohistochemistry revealed greater vascular density and reduced cardiomyocyte apoptosis in GLO1 vs. WT mice. The recruitment of c-kit + cells and their incorporation into the vasculature (c-kit + CD31 + cells) was higher in the infarcted myocardium of GLO1 mice. MG-AGEs appeared to accumulate in type I collagen surrounding arterioles, prompting investigation in vitro. In culture, the interaction of angiogenic bone marrow cells with MG-modified collagen resulted in reduced cell adhesion, increased susceptibility to apoptosis, fewer progenitor cells, and reduced angiogenic potential. This study reveals that MG-AGEs are produced post-MI and identifies a causative role for their accumulation in the cellular changes, adverse remodeling and functional loss of the heart after MI. MG may represent a novel target for preventing damage and improving function of the infarcted heart.

Human relaxin gene expression delivered by bioreducible dendrimer polymer for post-infarct cardiac remodeling in rats

PubMed Central

Lee, Young Sook; Choi, Joung-Woo; Oh, Jung-Eun; Yun, Chae-Ok; Kim, Sung Wan

2017-01-01

In consensus, myocardial infarction (MI) is defined as irreversible cell death secondary to prolonged ischemia in heart. The aim of our study was to evaluate the therapeutic potential of anti-fibrotic human Relaxin-expressing plasmid DNA with hypoxia response element (HRE) 12 copies (HR1) delivered by a dendrimer type PAM-ABP polymer G0 (HR1/G0) after MI on functional, hemodynamic, geometric, and cardiac extracellular matrix (ECM) remodeling in rats. HR1/G0 demonstrated significantly improved LV systolic function, hemodynamic parameters, and geometry on 1 wk and 4 wks after MI in rats, compared with I/R group. The resolution of regional wall motional abnormalities and the increased blood flow of infarct-related coronary artery supported functional improvements of HR1/G0. Furthermore, HR1/G0 polyplex showed favorable post-infarct cardiac ECM remodeling reflected on the favorable cardiac ECM compositions. Overall, this is the first study, which presented an advanced platform for the gene therapy that reverses adverse cardiac remodeling after MI with a HR1 gene delivered by a bioreducible dendrimer polymer in the cardiac ECM. PMID:27174688

Mechanisms and Predictors of Mitral Regurgitation after High-Risk Myocardial Infarction

PubMed Central

Meris, Alessandra; Amigoni, Maria; Verma, Anil; Thune, Jens Jakob; Køber, Lars; Velazquez, Eric; McMurray, John J. V.; Pfeffer, Marc A.; Califf, Robert; Levine, Robert A.; Solomon, Scott D.

2012-01-01

Background Mitral regurgitation (MR) has been associated with adverse outcomes after myocardial infarction (MI). Without structural valve disease, functional MR has been related to left ventricular (LV) remodeling and geometric deformation of the mitral apparatus. The aims of this study were to elucidate the mechanistic components of MR after high-risk MI and to identify predictors of MR progression during follow-up. Methods The Valsartan in Acute Myocardial Infarction Echo substudy prospectively enrolled 610 patients with LV dysfunction, heart failure, or both after MI. MR at baseline, 1 month, and 20 months was quantified by mapping jet expansion in the left atrium in 341 patients with good-quality echocardiograms. Indices of LV remodeling, left atrial size, and diastolic function and parameters of mitral valve deformation, including tenting area, coaptation depth, anterior leaflet concavity, annular diameters, and contractility, were assessed and related to baseline MR. The progression of MR was further analyzed, and predictors of worsening among the baseline characteristics were identified. Results Tenting area, coaptation depth, annular dilatation, and left atrial size were all associated with the degree of baseline MR. Tenting area was the only significant and independent predictor of worsening MR; a tenting area of 4 cm2 was a useful cutoff to identify worsening of MR after MI and moderate to severe MR after 20 months. Conclusions Increased mitral tenting and larger mitral annular area are determinants of MR degree at baseline, and tenting area is an independent predictor of progression of MR after MI. Although LV remodeling itself contributes to ischemic MR, this influence is directly dependent on alterations in mitral geometry. PMID:22305962

Aging and the cardiac collagen matrix: Novel mediators of fibrotic remodelling.

PubMed

Horn, Margaux A; Trafford, Andrew W

2016-04-01

Cardiovascular disease is a leading cause of death worldwide and there is a pressing need for new therapeutic strategies to treat such conditions. The risk of developing cardiovascular disease increases dramatically with age, yet the majority of experimental research is executed using young animals. The cardiac extracellular matrix (ECM), consisting predominantly of fibrillar collagen, preserves myocardial integrity, provides a means of force transmission and supports myocyte geometry. Disruptions to the finely balanced control of collagen synthesis, post-synthetic deposition, post-translational modification and degradation may have detrimental effects on myocardial functionality. It is now well established that the aged heart is characterized by fibrotic remodelling, but the mechanisms responsible for this are incompletely understood. Furthermore, studies using aged animal models suggest that interstitial remodelling with disease may be age-dependent. Thus with the identification of new therapeutic strategies targeting fibrotic remodelling, it may be necessary to consider age-dependent mechanisms. In this review, we discuss remodelling of the cardiac collagen matrix as a function of age, whilst highlighting potential novel mediators of age-dependent fibrotic pathways. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

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

Cardiovascular magnetic resonance profiling of coronary atherosclerosis: vessel wall remodelling and related myocardial blood flow alterations.

PubMed

Jahnke, Cosima; Manka, Robert; Kozerke, Sebastian; Schnackenburg, Bernhard; Gebker, Rolf; Marx, Nikolaus; Paetsch, Ingo

2014-12-01

To determine the association between coronary vessel wall morphology and haemodynamic consequences to the myocardium using a combined cardiovascular magnetic resonance (CMR) imaging protocol. Non-invasive CMR profiling of coronary atherosclerotic wall changes and related myocardial blood flow impairment has not been established yet. Sixty-three patients (45 men, 61.5 ± 10.7 years) with suspected or known coronary artery disease underwent 3.0 Tesla CMR imaging. The combined CMR protocol consisted of the following imaging modules at rest: 3D vessel wall imaging and flow measurement of the proximal right coronary artery (RCA), myocardial T2*, and first-pass perfusion imaging. During adenosine stress coronary flow, T2* and first-pass perfusion imaging were repeated. Coronary X-ray angiography classified patient groups: (i) all-smooth (n = 19); (ii) luminal irregular (diameter reduction < 30%; n = 35); and (iii) stenosed RCA (diameter reduction ≥ 50%; n = 9). The ratio of CMR-derived vessel wall area-to-lumen area significantly increased stepwise for the comparison of all-smooth vs. luminal irregular vs. stenosed RCA (1.9 ± 0.6 vs. 2.6 ± 0.6 vs. 3.6 ± 0.9, P < 0.01). Epicardial coronary flow reserve exhibited a stepwise significant decrease (3.4 ± 0.5 vs. 2.9 ± 0.7 vs. 1.7 ± 0.3, P < 0.01). On the myocardial level, stress-induced percentage gain of T2* values (ΔT2*) was significantly decreased between groups (29.2 ± 10.6 vs. 9.0 ± 9.8 vs. 2.2 ± 11.8%, P < 0.01) while perfusion reserve index decreased in the presence of stenosed RCA only (2.2 ± 0.6 vs. 2.0 ± 0.4 vs. 1.3 ± 0.3, P = ns and P < 0.01, respectively). The proposed comprehensive CMR imaging protocol provided a non-invasive approach for direct assessment of coronary vessel wall remodelling and resultant pathophysiological consequences on the level of epicardial coronary and myocardial blood flow in patients. Published on behalf of the European Society of Cardiology. All rights reserved. © The

Targeting Chondroitin Sulfate Glycosaminoglycans to Treat Cardiac Fibrosis in Pathological Remodeling.

PubMed

Zhao, Rong-Rong; Ackers-Johnson, Matthew; Stenzig, Justus; Chen, Chen; Ding, Tao; Zhou, Yue; Wang, Peipei; Ng, Shi Ling; Li, Peter Y; Teo, Gavin; Rudd, Pauline M; Fawcett, James W; Foo, Roger S Y

2018-06-05

Heart failure is a leading cause of mortality and morbidity, and the search for novel therapeutic approaches continues. In the monogenic disease mucopolysaccharidosis VI, loss-of-function mutations in arylsulfatase B lead to myocardial accumulation of chondroitin sulfate (CS) glycosaminoglycans, manifesting as myriad cardiac symptoms. Here, we studied changes in myocardial CS in nonmucopolysaccharidosis failing hearts and assessed its generic role in pathological cardiac remodeling. Healthy and diseased human and rat left ventricles were subjected to histological and immunostaining methods to analyze glycosaminoglycan distribution. Glycosaminoglycans were extracted and analyzed for quantitative and compositional changes with Alcian blue assay and liquid chromatography-mass spectrometry. Expression changes in 20 CS-related genes were studied in 3 primary human cardiac cell types and THP-1-derived macrophages under each of 9 in vitro stimulatory conditions. In 2 rat models of pathological remodeling induced by transverse aortic constriction or isoprenaline infusion, recombinant human arylsulfatase B (rhASB), clinically used as enzyme replacement therapy in mucopolysaccharidosis VI, was administered intravenously for 7 or 5 weeks, respectively. Cardiac function, myocardial fibrosis, and inflammation were assessed by echocardiography and histology. CS-interacting molecules were assessed with surface plasmon resonance, and a mechanism of action was verified in vitro. Failing human hearts displayed significant perivascular and interstitial CS accumulation, particularly in regions of intense fibrosis. Relative composition of CS disaccharides remained unchanged. Transforming growth factor-β induced CS upregulation in cardiac fibroblasts. CS accumulation was also observed in both the pressure-overload and the isoprenaline models of pathological remodeling in rats. Early treatment with rhASB in the transverse aortic constriction model and delayed treatment in the

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

PubMed Central

Mavroidis, Manolis; Katsimpoulas, Michalis; Sfiroera, Irini; Kappa, Niki; Mesa, Angelica; Kostomitsopoulos, Nikolaos G.; Cokkinos, Dennis V.

2017-01-01

Abstract Aim Rasagiline mesylate (N‐propargyl‐1 (R)‐aminoindan) (RG) is a selective, potent irreversible inhibitor of monoamine oxidase‐B with cardioprotective and anti‐apoptotic properties. We investigated whether it could be cardioprotective in a rat model undergoing experimental myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery. Methods and results RG was administered, intraperitoneally, for 28 days (2 mg/kg) starting 24 h after MI induction. Echocardiography analysis revealed a significant reduction in left ventricular end‐systolic and diastolic dimensions and preserved fractional shortening in RG‐treated compared with normal saline group at 28 days post‐MI (31.6 ± 2.3 vs. 19.6 ± 1.8, P < 0.0001), respectively. Treatment with RG prevented tissue fibrosis as indicated by interstitial collagen estimation by immunofluorescence staining and hydroxyproline content and attenuated the number of apoptotic myocytes in the border zone (65%) as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Caspase 3 relative protein levels were significantly decreased in the non‐infarcted myocardium. Markedly decreased malondialdehyde levels in the border zone indicate a reduction in tissue oxidative stress. Conclusions Our study demonstrates a positive effect of RG in the post‐MI period with a significant attenuation in cardiac remodelling. PMID:28772050

[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.

[Adenoviral short hairpin RNA targeting phosphodiesterase 5 attenuates cardiac remodeling and cardiac dysfunction following myocardial infarction in mice].

PubMed

Zhang, Jian; Jin, Zhe; Li, Longhu; Gang, Li; Yu, Qin; Wang, Meilan; Song, Ailin; Hong, Bingzhe

2014-04-01

To observe the impact of PDE5shRNA on cardiac remodeling and heart function following myocardial infarction in mice. Myocardial infarction (MI) was induced in mice by left coronary artery ligation. Mice were randomly assigned to sham group (n = 6), PDE5shRNA group (n = 12), common adenovirus group (n = 15) and DMEM group (n = 8). Four weeks post-MI, the survival rate was evaluated. Cardiac function was examined by echocardiography. HE staining and Masson staining were used to evaluate the myocardial infarction size and fibrosis. The number of blood vessels was evaluated by immunohistochemistry, PDE5 protein expression in the left ventricular was detected using Western blot, level of cGMP or PKG activity in the left ventricle was evaluated with ELISA. Four weeks post-MI, all mice survived in the sham group, 3(37%) mice died in the DMEM group, 1 (8%) died in the PDE5shRNA group and 5 died in the common adenovirus group (33%). Infarct size was significantly reduced in PDE5shRNA group compared with the common adenovirus group and DMEM group [(25.4 ± 2.9)% vs. (42.0 ± 3.2)% and (43.4 ± 2.6) %, P < 0.05]. Cardiac function was significantly improved in PDE5shRNA group compared to common adenovirus group and DMEM group[LVFS: (21.1 ± 3.7)% vs. (14.2 ± 2.9)% and (14.22 ± 2.91)%, all P < 0.05; LVEF: (48.2 ± 7.1)% vs. (34.6 ± 6.2)% and (38.1 ± 2.8)%, all P < 0.05; LVESD: (3.87 ± 0.45) mm vs.(4.91 ± 0.62) mm and (4.63 ± 0.37) mm, all P < 0.05]. The blood vessel density was also higher in PDE5shRNA group compared with common adenovirus group (infarct area:14.3 ± 2.0 vs. 6.6 ± 1.2, P < 0.05; periinfarct area: 23.6 ± 2.1 vs. 13.7 ± 2.4, P < 0.05). Compared with common adenovirus group, level of PDE5 was significantly downregulated and level of cGMP or PKG was significantly upregulated in PDE5shRNA group (all P < 0.05). Present study suggests PDE5shRNA improves cardiac function and attenuates cardiac remodeling through reducing infarction size and cardiac fibrosis

Inhibition of Let-7 microRNA attenuates myocardial remodeling and improves cardiac function postinfarction in mice

PubMed Central

Tolonen, Anna-Maria; Magga, Johanna; Szabó, Zoltán; Viitala, Pirkko; Gao, Erhe; Moilanen, Anne-Mari; Ohukainen, Pauli; Vainio, Laura; Koch, Walter J; Kerkelä, Risto; Ruskoaho, Heikki; Serpi, Raisa

2014-01-01

The members of lethal-7 (Let-7) microRNA (miRNA) family are involved in regulation of cell differentiation and reprogramming of somatic cells into induced pluripotent stem cells. However, their function in the heart is not known. In this study, we examined the effect of inhibiting the function of Let-7c miRNA on the progression of postinfarction left ventricular (LV) remodeling in mice. Myocardial infarction was induced with permanent ligation of left anterior descending coronary artery with a 4-week follow-up period. Let-7c miRNA was inhibited with a specific antagomir administered intravenously. The inhibition of Let-7c miRNA downregulated the levels of mature Let-7c miRNA and its other closely related members of Let-7 family in the heart and resulted in increased expression of pluripotency-associated genes Oct4 and Sox2 in cardiac fibroblasts in vitro and in adult mouse heart in vivo. Importantly, Let-7c inhibitor prevented the deterioration of cardiac function postinfarction, as demonstrated by preserved LV ejection fraction and elevated cardiac output. Improvement in cardiac function by Let-7c inhibitor postinfarction was associated with decreased apoptosis, reduced fibrosis, and reduction in the number of discoidin domain receptor 2–positive fibroblasts, while the number of c-kit+ cardiac stem cells and Ki-67+ proliferating cells remained unaltered. In conclusion, inhibition of Let-7 miRNA may be beneficial for the prevention of postinfarction LV remodeling and progression of heart failure. PMID:25505600

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

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

Tenascin-C promotes chronic pressure overload-induced cardiac dysfunction, hypertrophy and myocardial fibrosis.

PubMed

Podesser, Bruno K; Kreibich, Maximilian; Dzilic, Elda; Santer, David; Förster, Lorenz; Trojanek, Sandra; Abraham, Dietmar; Krššák, Martin; Klein, Klaus U; Tretter, Eva V; Kaun, Christoph; Wojta, Johann; Kapeller, Barbara; Gonçalves, Inês Fonseca; Trescher, Karola; Kiss, Attila

2018-04-01

Left ventricular (LV) hypertrophy is characterized by cardiomyocyte hypertrophy and interstitial fibrosis ultimately leading to increased myocardial stiffness and reduced contractility. There is substantial evidence that the altered expression of matrix metalloproteinases (MMP) and Tenascin-C (TN-C) are associated with the progression of adverse LV remodeling. However, the role of TN-C in the development of LV hypertrophy because of chronic pressure overload as well as the regulatory role of TN-C on MMPs remains unknown. In a knockout mouse model of TN-C, we investigated the effect of 10 weeks of pressure overload using transverse aortic constriction (TAC). Cardiac function was determined by magnetic resonance imaging. The expression of MMP-2 and MMP-9, CD147 as well as myocardial fibrosis were assessed by immunohistochemistry. The expression of TN-C was assessed by RT-qPCR and ELISA. TN-C knockout mice showed marked reduction in fibrosis (P < 0.001) and individual cardiomyocytes size (P < 0.01), in expression of MMP-2 (P < 0.05) and MMP-9 (P < 0.001) as well as preserved cardiac function (P < 0.01) in comparison with wild-type mice after 10 weeks of TAC. In addition, CD147 expression was markedly increased under pressure overload (P < 0.01), irrespectively of genotype. TN-C significantly increased the expression of the markers of hypertrophy such as ANP and BNP as well as MMP-2 in H9c2 cells (P < 0.05, respectively). Our results are pointed toward a novel signaling mechanism that contributes to LV remodeling via MMPs upregulation, cardiomyocyte hypertrophy as well as myocardial fibrosis by TN-C under chronic pressure overload.

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.

Maladaptive hypertrophy after acute myocardial infarction positive effect of bone marrow-derived stem cell therapy on regional remodeling measured by cardiac MRI.

PubMed

Rolf, Andreas; Assmus, Birgit; Schächinger, Volker; Rixe, Johannes; Möllmann, Susanne; Möllmann, Helge; Dimmeler, Stefanie; Zeiher, Andreas M; Hamm, Christian W; Dill, Thorsten

2011-11-01

In the aftermath of myocardial infarction, increased loading conditions will trigger hypertrophy of viable myocardium. This in turn causes deterioration of regional contractility. Cardiac magnetic resonance imaging (cMRI) allows the exact differentiation of viable and infarcted myocardium and therefore the measurement of regional wall thickness and function. Bone marrow-derived stem cell (BMC) transfer has been shown to improve global function and remodeling. The present study examines the effect of BMC transfer on regional remodeling and function after myocardial infarction by cMRI. Fifty-four patients of the MR substudy of the REPAIR-AMI trial have been studied at baseline and 12-month follow-up. Enddiastolic wall thickness (EDWT) and wall thickening (WT%) have been measured on SSFP cine sequences. Enddiastolic wall thickness decreased in both placebo and BMC groups in viable as well as infarcted segments. The effect was largest in the pre-specified subgroup of patients below the median EF of 48.9% (infarcted segments -1.14 mm Placebo vs. -1.91 mm BMC, p for interaction 0.01, remote segments -0.19 mm Placebo vs. -0.94 mm BMC, p for interaction 0.00001). Corrected for baseline values BMC therapy yielded smaller EDWT at 12 months in infarcted and remote segments (infarcted 7.58 mm Placebo vs. 6.13 mm BMC p = 0.0001, remote 8.76 mm Placebo vs. 7.32 mm BMC, p = 0.0001). This was associated with better contractility within the infarcted segments among BMC patients (WT% 24.17% Placebo vs. 49.31% BMC, p = 0.0001). The WT% was inversely correlated with EDWT (r = -0.37, p = 0.0001). Bone marrow-derived stem cell therapy yields smaller EDWT when compared with placebo patients suggesting a positive effect on maladaptive hypertrophy of viable myocardium. This notion is supported by the enhanced regional contractility within the BMC group which is inversely correlated with EDWT.

Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy.

PubMed

von Lueder, Thomas G; Wang, Bing H; Kompa, Andrew R; Huang, Li; Webb, Randy; Jordaan, Pierre; Atar, Dan; Krum, Henry

2015-01-01

Angiotensin receptor neprilysin inhibitors (ARNi), beyond blocking angiotensin II signaling, augment natriuretic peptides by inhibiting their breakdown by neprilysin. The myocardial effects of ARNi have been little studied until recently. We hypothesized that LCZ696 attenuates left ventricular (LV) remodeling after experimental myocardial infarction (MI), and that this may be contributed to by inhibition of hypertrophy and fibrosis in cardiac cells. One week after MI, adult male Sprague-Dawley rats were randomized to treatment for 4 weeks with LCZ696 (68 mg/kg body weight perorally; MI-ARNi, n=11) or vehicle (MI-vehicle, n=6). Five weeks after MI, MI-ARNi versus MI-vehicle demonstrated lower LV end-diastolic diameter (by echocardiography; 9.7±0.2 versus 10.5±0.3 mm), higher LV ejection fraction (60±2 versus 47±5%), diastolic wall strain (0.23±0.02 versus 0.13±0.02), and circular strain (-9.8±0.5 versus -7.3±0.5%; all P<0.05). LV pressure-volume loops confirmed improved LV function. Despite similar infarct size, MI-ARNi versus MI-vehicle had lower cardiac weights (P<0.01) and markedly reduced fibrosis in peri-infarct and remote myocardium. Angiotensin II-stimulated incorporation of 3[H]leucine in cardiac myocytes and 3[H]proline in cardiac fibroblast was used to evaluate hypertrophy and fibrosis, respectively. The neprilysin inhibitor component of LCZ696, LBQ657, inhibited hypertrophy but not fibrosis. The angiotensin receptor blocker component of LCZ696, valsartan inhibited both hypertrophy and fibrosis. Dual valsartan+LBQ augmented the inhibitory effects of valsartan and the highest doses completely abrogated angiotensin II-mediated effects. LCZ696 attenuated cardiac remodeling and dysfunction after MI. This may be contributed to by superior inhibition of LCZ696 on cardiac fibrosis and cardiac hypertrophy than either stand-alone neprilysin inhibitor or angiotensin receptor blocker. © 2014 American Heart Association, Inc.

Nanofibers based tissue engineering and drug delivery approaches for myocardial regeneration.

PubMed

Joshi, Jyotsna; Kothapalli, Chandrasekhar R

2015-01-01

Human heart has endogenous regenerative capability; however, the intrinsic repair mechanism is not sufficient to overcome the impact placed by adverse pathological conditions, such as myocardial infarction (MI). In such circumstances, the damaged tissue initiates a series of remodeling process which results in the deterioration of structural, functional, and mechanical properties of the myocardium. To address such adverse conditions, clinical approaches ranging from surgical interventions, pharmaceutical drugs, and device implantation are administered which have played significant role in reducing the mortality rate. However, these approaches do not replace the lost cardiomyocytes, or restore the degraded structure-function relationship of the myocardium. In this aspect, cell-based therapy has gained substantial interest as a potential clinical approach for myocardial regeneration; however this method is impeded by lower graft retention and poor cell viability. To overcome these limitations, biomaterials are being developed as "trojan horses", i.e., vehicles for homing and deploying cells, and as matrices for delivering specific biological, mechanical, and chemical cues intended for tissue regeneration. Similarly, several candidate drugs, potent synthetic and biological molecules, and advanced drug delivery systems are being examined to provide exogenous cues in a controlled fashion to the diseased myocardium. In this article, we review biomaterials-based drug delivery systems for myocardial regeneration, specifically on the applications of hydrogels, microgels, nanoparticles, and nanofibers in the field. The prime focus of the article is on nanofibers-based drug delivery systems that is gaining considerable attention as a biomimetic pharmacological approach. We highlight literature on fabrication methods of self-assembling and electrospun nanofibers, drug incorporation methods and release kinetics, and in vitro and in vivo outcomes from nanofiber-based drug

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

In Situ Imaging of Tissue Remodeling with Collagen Hybridizing Peptides

PubMed Central

2017-01-01

Collagen, the major structural component of nearly all mammalian tissues, undergoes extensive proteolytic remodeling during developmental states and a variety of life-threatening diseases such as cancer, myocardial infarction, and fibrosis. While degraded collagen could be an important marker of tissue damage, it is difficult to detect and target using conventional tools. Here, we show that a designed peptide (collagen hybridizing peptide: CHP), which specifically hybridizes to the degraded, unfolded collagen chains, can be used to image degraded collagen and inform tissue remodeling activity in various tissues: labeled with 5-carboxyfluorescein and biotin, CHPs enabled direct localization and quantification of collagen degradation in isolated tissues within pathologic states ranging from osteoarthritis and myocardial infarction to glomerulonephritis and pulmonary fibrosis, as well as in normal tissues during developmental programs associated with embryonic bone formation and skin aging. The results indicate the general correlation between the level of collagen remodeling and the amount of denatured collagen in tissue and show that the CHP probes can be used across species and collagen types, providing a versatile tool for not only pathology and developmental biology research but also histology-based disease diagnosis, staging, and therapeutic screening. This study lays the foundation for further testing CHP as a targeting moiety for theranostic delivery in various animal models. PMID:28877431

MYOCARDIAL AKT: THE OMNIPRESENT NEXUS

PubMed Central

Sussman, Mark A.; Völkers, Mirko; Fischer, Kimberlee; Bailey, Brandi; Cottage, Christopher T.; Din, Shabana; Gude, Natalie; Avitabile, Daniele; Alvarez, Roberto; Sundararaman, Balaji; Quijada, Pearl; Mason, Matt; Konstandin, Mathias H.; Malhowski, Amy; Cheng, Zhaokang; Khan, Mohsin; McGregor, Michael

2013-01-01

One of the greatest examples of integrated signal transduction is revealed by examination of effects mediated by AKT kinase in myocardial biology. Positioned at the intersection of multiple afferent and efferent signals, AKT exemplifies a molecular sensing node that coordinates dynamic responses of the cell in literally every aspect of biological responses. The balanced and nuanced nature of homeostatic signaling is particularly essential within the myocardial context, where regulation of survival, energy production, contractility, and response to pathological stress all flow through the nexus of AKT activation or repression. Equally important, the loss of regulated AKT activity is primarily the cause or consequence of pathological conditions leading to remodeling of the heart and eventual decompensation. This review presents an overview compendium of the complex world of myocardial AKT biology gleaned from more than a decade of research. Summarization of the widespread influence that AKT exerts upon myocardial responses leaves no doubt that the participation of AKT in molecular signaling will need to be reckoned with as a seemingly omnipresent regulator of myocardial molecular biological responses. PMID:21742795

Left ventricular energy model predicts adverse events in women with suspected myocardial ischemia: results from the NHLBI-sponsored women’s ischemia syndrome evaluation (WISE) study

PubMed Central

Weinberg, Nicole; Pohost, Gerald M.; Bairey Merz, C. Noel; Shaw, Leslee J.; Sopko, George; Fuisz, Anthon; Rogers, William J.; Walsh, Edward G.; Johnson, B. Delia; Sharaf, Barry L.; Pepine, Carl J.; Mankad, Sunil; Reis, Steven E.; Rayarao, Geetha; Vido, Diane A.; Bittner, Vera; Tauxe, Lindsey; Olson, Marian B.; Kelsey, Sheryl F.; Biederman, Robert WW

2013-01-01

Objectives To assess the prognostic value of a left ventricular energy-model in women with suspected myocardial ischemia. Background The prognostic value of internal energy utilization (IEU) of the left ventricle in women with suspected myocardial ischemia is unknown. Methods Women [n=227, mean age 59±12 years (range, 31-86 years)], with symptoms of myocardial ischemia, underwent myocardial perfusion imaging (MPI) assessment for regional perfusion defects along with measurement of ventricular volumes separately by gated Single Photon Emission Computed Tomography (SPECT) (n=207) and magnetic resonance imaging (MRI) (n=203). During follow-up (40±17 months), time to first major adverse cardiovascular event (MACE, death, myocardial infarction or hospitalization for congestive heart failure) was analyzed using MRI and gated SPECT variables. Results Adverse events occurred in 31 (14%). Multivariable Cox models were formed for each modality: IEU and wall thickness by MRI (Chi-squared 34, P<0.005) and IEU and systolic blood pressure by gated SEPCT (Chi-squared 34, P<0.005). The models remained predictive after adjustment for age, disease history and Framingham risk score. For each Cox model, patients were categorized as high-risk if the model hazard was positive and not high-risk otherwise. Kaplan-Meier analysis of time to MACE was performed for high-risk vs. not high-risk for MR (log rank 25.3, P<0.001) and gated SEPCT (log rank 18.2, P<0.001) models. Conclusions Among women with suspected myocardial ischemia a high internal energy utilization has higher prognostic value than either a low EF or the presence of a myocardial perfusion defect assessed using two independent modalities of MR or gated SPECT. PMID:24015377

Proton pump inhibitor use and risk of adverse cardiovascular events in aspirin treated patients with first time myocardial infarction: nationwide propensity score matched study

PubMed Central

Grove, Erik L; Hansen, Peter Riis; Olesen, Jonas B; Ahlehoff, Ole; Selmer, Christian; Lindhardsen, Jesper; Madsen, Jan Kyst; Køber, Lars; Torp-Pedersen, Christian; Gislason, Gunnar H

2011-01-01

Objective To examine the effect of proton pump inhibitors on adverse cardiovascular events in aspirin treated patients with first time myocardial infarction. Design Retrospective nationwide propensity score matched study based on administrative data. Setting All hospitals in Denmark. Participants All aspirin treated patients surviving 30 days after a first myocardial infarction from 1997 to 2006, with follow-up for one year. Patients treated with clopidogrel were excluded. Main outcome measures The risk of the combined end point of cardiovascular death, myocardial infarction, or stroke associated with use of proton pump inhibitors was analysed using Kaplan-Meier analysis, Cox proportional hazard models, and propensity score matched Cox proportional hazard models. Results 3366 of 19 925 (16.9%) aspirin treated patients experienced recurrent myocardial infarction, stroke, or cardiovascular death. The hazard ratio for the combined end point in patients receiving proton pump inhibitors based on the time dependent Cox proportional hazard model was 1.46 (1.33 to 1.61; P<0.001) and for the propensity score matched model based on 8318 patients it was 1.61 (1.45 to 1.79; P<0.001). A sensitivity analysis showed no increase in risk related to use of H2 receptor blockers (1.04, 0.79 to 1.38; P=0.78). Conclusion In aspirin treated patients with first time myocardial infarction, treatment with proton pump inhibitors was associated with an increased risk of adverse cardiovascular events. PMID:21562004

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.

Tomato (Lycopersicon esculentum) or lycopene supplementation attenuates ventricular remodeling after myocardial infarction through different mechanistic pathways.

PubMed

Pereira, Bruna L B; Reis, Patrícia P; Severino, Fábio E; Felix, Tainara F; Braz, Mariana G; Nogueira, Flávia R; Silva, Renata A C; Cardoso, Ana C; Lourenço, Maria A M; Figueiredo, Amanda M; Chiuso-Minicucci, Fernanda; Azevedo, Paula S; Polegato, Bertha F; Okoshi, Katashi; Fernandes, Ana A H; Paiva, Sergio A R; Zornoff, Leonardo A M; Minicucci, Marcos F

2017-08-01

The objective of this study was to evaluate the influence of tomato or lycopene supplementation on cardiac remodeling after myocardial infarction (MI). Male Wistar rats were assigned to four groups: the sham group (animals that underwent simulated surgery) that received a standard chow (S; n=18), the infarcted group that received a standard chow (MI; n=13), the infarcted group supplemented with lycopene (1 mg of lycopene/kg body weight/day) (MIL; n=16) and the infarcted group supplemented with tomato (MIT; n=16). After 3 months, morphological, functional and biochemical analyses were performed. The groups MIL and MIT showed decreased interstitial fibrosis induced by infarction. Tomato supplementation attenuated the hypertrophy induced by MI. In addition, tomato and lycopene improved diastolic dysfunction evaluated by echocardiographic and isolated heart studies, respectively. The MI group showed higher levels of cardiac TNF-α compared to the MIL and MIT groups. Decreased nuclear factor E2-related factor 2 was measured in the MIL group. Lipid hydroperoxide levels were higher in the infarcted groups; however, the MIT group had a lower concentration than did the MI group [S=223±20.8, MI=298±19.5, MIL=277±26.6, MIT=261±28.8 (nmol/g); n=8; P<.001]. We also examined left ventricle miRNA expression; when compared to the S group, the MIL group uniquely down-regulated the expression of eight miRNAs. No miRNA was found to be up-regulated uniquely in the MIT and MIL groups. In conclusion, tomato or lycopene supplementation attenuated the cardiac remodeling process and improved diastolic function after MI. However, the effect of lycopene and tomato supplementation occurred through different mechanistic pathways. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhibition of Matrix Metalloproteinase Activity Prevents Increases in Myocardial Tumor Necrosis Factor-α

PubMed Central

Murray, David B.; Levick, Scott P; Brower, Gregory L.; Janicki, Joseph S.

2010-01-01

Aim TNF-α is known to cause adverse myocardial remodeling. While we have previously shown a role for cardiac mast cells in mediating myocardial TNF-α, matrix metalloproteinases (MMP) activation of TNF-α may also be contributory. We sought to determine the relative roles of MMPs and cardiac mast cells in the activation of TNF-α in the hearts of rats subjected to chronic volume overload. Methods Interventions with the broad spectrum MMP inhibitor, GM6001, or the mast cell stabilizer, nedocromil, were performed in the rat aortocaval fistula (ACF) model of volume overload. Results Myocardial TNF-α levels were significantly increased in the ACF. This increase was prevented by MMP inhibition with GM6001 (p ≤ 0.001 vs. ACF). Conversely, myocardial TNF-α levels were increased in the ACF + nedocromil treated fistula groups (p ≤ 0.001 vs. sham). The degradation of interstitial collagen volume fraction seen in the untreated ACF group was prevented in both the GM6001 and nedocromil treated hearts. Significant increases in LV myocardial ET-1 levels also occurred in the ACF group at 3 days post-fistula. Whereas administration of GM6001 significantly attenuated this increase, mast cell stabilization with nedocromil markedly exacerbated the increase, producing ET-1 levels 6.5 fold and 2 fold greater than that in the sham-operated control and ACF group, respectively. Conclusion The efficacy of the MMP inhibitor, GM6001, to prevent increased levels of myocardial TNF-α is indicative of MMP-mediated cleavage of latent extracellular membrane bound TNF-α protein as the primary source of bioactive TNF-α in the myocardium of the volume-overload heart. PMID:20403361

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

Assessment of valve haemodynamics, reverse ventricular remodelling and myocardial fibrosis following transcatheter aortic valve implantation compared to surgical aortic valve replacement: a cardiovascular magnetic resonance study

PubMed Central

Fairbairn, Timothy A; Steadman, Christopher D; Mather, Adam N; Motwani, Manish; Blackman, Daniel J; Plein, Sven; McCann, Gerry P; Greenwood, John P

2013-01-01

Objective To compare the effects of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) on aortic valve haemodynamics, ventricular reverse remodelling and myocardial fibrosis (MF) by cardiovascular magnetic resonance (CMR) imaging. Design A 1.5 T CMR scan was performed preoperatively and 6 months postoperatively. Setting University hospitals of Leeds and Leicester, UK. Patients 50 (25 TAVI, 25 SAVR; age 77±8 years) high-risk severe symptomatic aortic stenosis (AS) patients. Main outcome measures Valve haemodynamics, ventricular volumes, ejection fraction (EF), mass and MF. Results Patients were matched for gender and AS severity but not for age (80±6 vs 73±7 years, p=0.001) or EuroSCORE (22±14 vs 7±3, p<0.001). Aortic valve mean pressure gradient decreased to a greater degree post-TAVI compared to SAVR (21±8 mm Hg vs 35±13 mm Hg, p=0.017). Aortic regurgitation reduced by 8% in both groups, only reaching statistical significance for TAVI (p=0.003). TAVI and SAVR improved (p<0.05) left ventricular (LV) end-systolic volumes (46±18 ml/m2 vs 41±17 ml/m2; 44±22 ml/m2 vs32±6 ml/m2) and mass (83±20 g/m2 vs 65±15 g/m2; 74±11 g/m2 vs 59±8 g/m2). SAVR reduced end-diastolic volumes (92±19 ml/m2 vs 74±12 ml/m2, p<0.001) and TAVI increased EF (52±12% vs 56±10%, p=0.01). MF reduced post-TAVI (10.9±6% vs 8.5±5%, p=0.03) but not post-SAVR (4.2±2% vs 4.1±2%, p=0.98). Myocardial scar (p≤0.01) and baseline ventricular volumes (p<0.001) were the major predictors of reverse remodelling. Conclusions TAVI was comparable to SAVR at LV reverse remodelling and superior at reducing the valvular pressure gradient and MF. Future work should assess the prognostic importance of reverse remodelling and fibrosis post-TAVI to aid patient selection. PMID:23749779

[Swim training attenuates myocardial remodeling and the pulmonary congestion in wistar rats with secondary heart failure to myocardial infarction].

PubMed

Portes, Leslie Andrews; Tucci, Paulo José Ferreira

2006-07-01

To evaluate the effects of swimming on pulmonary water content in animals with heart failure (HF) after myocardial infarction (MI). After coronary occlusion, MI size 20% 40% of the LV large. The animals swam for 60 min/day, 5 days/week for 8 weeks. The wet weight of lung, liver, atriums, LV and right ventricle (RV) as well as the dry weight of the liver and lung were determined. ANOVA and Tukey test were used for statistical analysis. An increase in the atrium/body weight ratio was noted in the sedentary animals with moderate (MImod-SED: n=8) and large (MIlg-SED: n=10) infarctions in comparison to the sedentary control (C-SED: n=14) and trained (C-TR: n=16) rats. An increase in the RV/body weight and LV/body weight ratios was noted in the MIlg-SED. The heart/body weight ratio was higher in MIlg-SED when compared to the other groups. The infarcted trained animals presented diminished hypertrophy. The pulmonary water content was higher in MIlg-SED animals (81+/-0.4%) than in C-SED animals (79+/-0.4%). No differences were found for the other comparisons (C-TR: 79+/-0.4%; MImod-SED: 80+/-0.3%; MImod-TR: 80+/-0.6%; MIlg-TR: 79+/-0.7%). The increase of cardiac mass and pulmonary water content presented by MIlg-SED was diminished in the trained animals. The results suggest that the practice of physical exercise can diminish HF and contribute to favorable cardiac remodeling.

Lipoprotein(a) levels predict adverse vascular events after acute myocardial infarction.

PubMed

Mitsuda, Takayuki; Uemura, Yusuke; Ishii, Hideki; Takemoto, Kenji; Uchikawa, Tomohiro; Koyasu, Masayoshi; Ishikawa, Shinji; Miura, Ayako; Imai, Ryo; Iwamiya, Satoshi; Ozaki, Yuta; Kato, Tomohiro; Shibata, Rei; Watarai, Masato; Murohara, Toyoaki

2016-12-01

Lipoprotein(a) [Lp(a)], which is genetically determined, has been reported as an independent risk factor for atherosclerotic vascular disease. However, the prognostic value of Lp(a) for secondary vascular events in patients after coronary artery disease has not been fully elucidated. This 3-year observational study included a total of 176 patients with ST-elevated myocardial infarction (STEMI), whose Lp(a) levels were measured within 24 h after primary percutaneous coronary intervention. We divided enrolled patients into two groups according to Lp(a) level and investigated the association between Lp(a) and the incidence of major adverse cardiac and cerebrovascular events (MACCE). A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of MACCE than those with lower Lp(a) levels (log-rank P = 0.034). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the occurrence of MACCE after adjusting for other classical risk factors of atherosclerotic vascular diseases (hazard ratio 1.030, 95 % confidence interval: 1.011-1.048, P = 0.002). In receiver-operating curve analysis, the cutoff value to maximize the predictive power of Lp(a) was 19.0 mg/dl (area under the curve = 0.674, sensitivity 69.2 %, specificity 62.0 %). Evaluation of Lp(a) in addition to the established coronary risk factors improved their predictive value for the occurrence of MACCE. In conclusion, Lp(a) levels at admission independently predict secondary vascular events in patients with STEMI. Lp(a) might provide useful information for the development of secondary prevention strategies in patients with myocardial infarction.

Worse cardiac remodeling in response to pressure overload in type 2 diabetes mellitus.

PubMed

Gonçalves, N; Gomes-Ferreira, C; Moura, C; Roncon-Albuquerque, R; Leite-Moreira, A F; Falcão-Pires, I

2016-08-15

Diabetic cardiomyopathy is characterized by cardiac structural and functional abnormalities. Additionally, chronic pressure overload conditions are highly prevalent amongst diabetic population and this association leads to a more severe myocardial impairment. The differences in myocardial pathophysiology between type 1 and type 2 diabetes mellitus (DM) still remain to be clarified. Thus, we aimed to investigate biventricular structural and functional changes promoted by the two types of DM and the impact of concomitant chronic pressure overload. Wistar rats were injected with streptozotocin (Type 1 DM, T1DM) or fed with a hypercaloric diet (Type 2 DM, T2DM). Pressure overload was imposed in DM animals by aortic constriction and after 5weeks of DM the cardiac function and structure were evaluated. Both types of DM promoted hypertrophy, increased fibrosis and advanced glycation end-products deposition, in the two ventricles. Interestingly, the induced myocardial alterations were distinct. While T1DM stimulated a pronounced hypertrophy and extracellular matrix remodeling, T2DM induced functional impairment. The negative impact of the association of DM with aortic constriction was more pronounced in T2DM, promoting impaired function and increased stiffness, particularly in the right ventricle. Our study demonstrated that the two types of diabetes induce distinct cardiac alterations per se or when combined with chronic pressure overload. T1DM promoted a more extensive remodeling in cardiac structure while T2DM significantly impaired ventricular function. The impact of pressure overload was more notorious in T2DM as observed by worse myocardial remodeling, suggesting a higher susceptibility to the deleterious effects of chronic pressure overload, namely hypertension, among this diabetic population. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Prognostic significance of infarct core pathology revealed by quantitative non-contrast in comparison with contrast cardiac magnetic resonance imaging in reperfused ST-elevation myocardial infarction survivors.

PubMed

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

2016-04-01

To assess the prognostic significance of infarct core tissue characteristics using cardiac magnetic resonance (CMR) imaging in survivors of acute ST-elevation myocardial infarction (STEMI). We performed an observational prospective single centre cohort study in 300 reperfused STEMI patients (mean ± SD age 59 ± 12 years, 74% male) who underwent CMR 2 days and 6 months post-myocardial infarction (n = 267). Native T1 was measured in myocardial regions of interest (n = 288). Adverse remodelling was defined as an increase in left ventricular (LV) end-diastolic volume ≥20% at 6 months. All-cause death or first heart failure hospitalization was a pre-specified outcome that was assessed during follow-up (median duration 845 days). One hundred and sixty (56%) patients had a hypo-intense infarct core disclosed by native T1. In multivariable regression, infarct core native T1 was inversely associated with adverse remodelling [odds ratio (95% confidence interval (CI)] per 10 ms reduction in native T1: 0.91 (0.82, 0.00); P = 0.061). Thirty (10.4%) of 288 patients died or experienced a heart failure event and 13 of these events occurred post-discharge. Native T1 values (ms) within the hypo-intense infarct core (n = 160 STEMI patients) were inversely associated with the risk of all-cause death or first hospitalization for heart failure post-discharge (for a 10 ms increase in native T1: hazard ratio 0.730, 95% CI 0.617, 0.863; P < 0.001) including after adjustment for left ventricular ejection fraction, infarct core T2 and myocardial haemorrhage. The prognostic results for microvascular obstruction were similar. Infarct core native T1 represents a novel non-contrast CMR biomarker with potential for infarct characterization and prognostication in STEMI survivors. Confirmatory studies are warranted. CLINICALTRIALS. NCT02072850. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

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

Employing Extracellular Volume Cardiovascular Magnetic Resonance Measures of Myocardial Fibrosis to Foster Novel Therapeutics.

PubMed

Schelbert, Erik B; Sabbah, Hani N; Butler, Javed; Gheorghiade, Mihai

2017-06-01

Quantifying myocardial fibrosis (MF) with myocardial extracellular volume measures acquired during cardiovascular magnetic resonance promises to transform clinical care by advancing pathophysiologic understanding and fostering novel therapeutics. Extracellular volume quantifies MF by measuring the extracellular compartment depicted by the myocardial uptake of contrast relative to plasma. MF is a key domain of dysfunctional but viable myocardium among others (eg, microvascular dysfunction and cardiomyocyte/mitochondrial dysfunction). Although anatomically distinct, these domains may functionally interact. MF represents pathological remodeling in the heart associated with cardiac dysfunction and adverse outcomes likely mediated by interactions with the microvasculature and the cardiomyocyte. Reversal of MF improves key measures of cardiac dysfunction, so reversal of MF represents a likely mechanism for improved outcomes. Instead of characterizing the myocardium as homogenous tissue and using important yet still generic descriptors, such as thickness (hypertrophy) and function (diastolic or systolic), which lack mechanistic specificity, paradigms of cardiac disease have evolved to conceptualize myocardial disease and patient vulnerability based on the extent of disease involving its various compartments. Specifying myocardial compartmental involvement may then implicate cellular/molecular disease pathways for treatment and targeted pharmaceutical development and above all highlight the role of the cardiac-specific pathology in heart failure among myriad other changes in the heart and beyond. The cardiology community now requires phase 2 and 3 clinical trials to examine strategies for the regression/prevention of MF and eventually biomarkers to identify MF without reliance on cardiovascular magnetic resonance. It seems likely that efficacious antifibrotic therapy will improve outcomes, but definitive data are needed. © 2017 American Heart Association, Inc.

Role of low-level laser therapy on the cardiac remodeling after myocardial infarction: A systematic review of experimental studies.

PubMed

Carlos, Fernando Pereira; Gradinetti, Vanessa; Manchini, Martha; de Tarso Camillo de Carvalho, Paulo; Silva, José Antonio; Girardi, Adriana Castello Costa; Leal-Junior, Ernesto Cesar Pinto; Bocalini, Danilo Sales; Vieira, Stella; Antonio, Ednei Luiz; Tucci, Paulo; Serra, Andrey Jorge

2016-04-15

We systematically reviewed the role of low-level laser therapy (LLLT) in cardiac remodeling after myocardial infarction. Literatures were systematically searched in several electronic databases. We included only studies with a well-standardized coronary occlusion model in vivo LLLT application. After screening, 14 studies were eligible for review. The study heterogeneity was described in terms of rationality, gender, irradiation parameters, treatment numbers and moment of LLLT application. Three studies showed a null role of LLLT on infarct size, and only one study found positive LLLT effects on the cardiac performance. The cardioprotective role of LLLT was mediated by anti-inflammatory, pro-angiogenic and anti-oxidant actions. The reduction in infarct size is a major finding. The LLLT cardioprotection may be mediated by several molecular and cellular mechanisms. Although these results are exciting, there are many limitations that must be resolved before LLLT clinical trials. Copyright © 2016 Elsevier Inc. All rights reserved.

Application of the HeartLander Crawling Robot for Injection of a Thermally Sensitive Anti-Remodeling Agent for Myocardial Infarction Therapy

PubMed Central

Chapman, Michael P.; López González, Jose L.; Goyette, Brina E.; Fujimoto, Kazuro L.; Ma, Zuwei; Wagner, William R.; Zenati, Marco A.; Riviere, Cameron N.

2011-01-01

The injection of a mechanical bulking agent into the left ventricular (LV) wall of the heart has shown promise as a therapy for maladaptive remodeling of the myocardium after myocardial infarct (MI). The HeartLander robotic crawler presented itself as an ideal vehicle for minimally-invasive, highly accurate epicardial injection of such an agent. Use of the optimal bulking agent, a thermosetting hydrogel developed by our group, presents a number of engineering obstacles, including cooling of the miniaturized injection system while the robot is navigating in the warm environment of a living patient. We present herein a demonstration of an integrated miniature cooling and injection system in the HeartLander crawling robot, that is fully biocompatible and capable of multiple injections of a thermosetting hydrogel into dense animal tissue while the entire system is immersed in a 37°C water bath. PMID:21096276

Current Understanding of the Pathophysiology of Myocardial Fibrosis and Its Quantitative Assessment in Heart Failure

PubMed Central

Liu, Tong; Song, Deli; Dong, Jianzeng; Zhu, Pinghui; Liu, Jie; Liu, Wei; Ma, Xiaohai; Zhao, Lei; Ling, Shukuan

2017-01-01

Myocardial fibrosis is an important part of cardiac remodeling that leads to heart failure and death. Myocardial fibrosis results from increased myofibroblast activity and excessive extracellular matrix deposition. Various cells and molecules are involved in this process, providing targets for potential drug therapies. Currently, the main detection methods of myocardial fibrosis rely on serum markers, cardiac magnetic resonance imaging, and endomyocardial biopsy. This review summarizes our current knowledge regarding the pathophysiology, quantitative assessment, and novel therapeutic strategies of myocardial fibrosis. PMID:28484397

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.

Both cardiomyocyte and endothelial cell Nox4 mediate protection against hemodynamic overload-induced remodelling.

PubMed

Zhang, Min; Mongue-Din, Heloise; Martin, Daniel; Catibog, Norman; Smyrnias, Ioannis; Zhang, Xiaohong; Yu, Bin; Wang, Minshu; Brandes, Ralf P; Schröder, Katrin; Shah, Ajay M

2018-03-01

NADPH oxidase-4 (Nox4) is an important reactive oxygen species (ROS) source that is upregulated in the haemodynamically overloaded heart. Our previous studies using global Nox4 knockout (Nox4KO) mice demonstrated a protective role of Nox4 during chronic abdominal aortic banding, involving a paracrine enhancement of myocardial capillary density. However, other authors who studied cardiac-specific Nox4KO mice reported detrimental effects of Nox4 in response to transverse aortic constriction (TAC). It has been speculated that these divergent results are due to cell-specific actions of Nox4 (i.e. cardiomyocyte Nox4 detrimental but endothelial Nox4 beneficial) and/or differences in the model of pressure overload (i.e. abdominal banding vs. TAC). This study aimed to (i) investigate whether the effects of Nox4 on pressure overload-induced cardiac remodelling vary according to the pressure overload model and (ii) compare the roles of cardiomyocyte vs. endothelial cell Nox4. Global Nox4KO mice subjected to TAC developed worse cardiac remodelling and contractile dysfunction than wild-type littermates, consistent with our previous results with abdominal aortic banding. Next, we generated inducible cardiomyocyte-specific Nox4 KO mice (Cardio-Nox4KO) and endothelial-specific Nox4 KO mice (Endo-Nox4KO) and studied their responses to pressure overload. Both Cardio-Nox4KO and Endo-Nox4KO developed worse pressure overload-induced cardiac remodelling and dysfunction than wild-type littermates, associated with significant decrease in protein levels of HIF1α and VEGF and impairment of myocardial capillarization. Cardiomyocyte as well as endothelial cell Nox4 contributes to protection against chronic hemodynamic overload-induced cardiac remodelling, at least in part through common effects on myocardial capillary density. © The Author 2017 Published by Oxford University Press on behalf of the European Society of Cardiology.

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.

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.

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

INCREASED MYOCARDIAL STIFFNESS DUE TO CARDIAC TITIN ISOFORM SWITCHING IN A MOUSE MODEL OF VOLUME OVERLOAD LIMITS ECCENTRIC REMODELING

PubMed Central

Hutchinson, Kirk R; Saripalli, Chandra; Chung, Charles S.; Granzier, Henk

2014-01-01

We investigated the cellular and molecular mechanisms of diastolic dysfunction in pure volume overload induced by aortocaval fistula (ACF) surgery in the mouse. Four weeks of volume overload resulted in significant biventricular hypertrophy; protein expression analysis in left ventricular (LV) tissue showed a marked decrease in titin's N2BA/N2B ratio with no change in phosphorylation of titin's spring region. Titin-based passive tensions were significantly increased; a result of the decreased N2BA/N2B ratio. Conscious echocardiography in ACF mice revealed eccentric remodeling and pressure volume analysis revealed systolic dysfunction: reductions in ejection fraction (EF), +dP/dt, and the slope of the endsystolic pressure volume relationships (ESPVR). ACF mice also had diastolic dysfunction: increased LV end-diastolic pressure and reduced relaxation rates. Additionally, a decrease in the slope of the end diastolic pressure volume relationship (EDPVR) was found. However, correcting for altered geometry of the LV normalized the change in EDPVR and revealed, in line with our skinned muscle data, increased myocardial stiffness in vivo. ACF mice also had increased expression of the signaling proteins FHL-1, FHL-2, and CARP that bind to titin's spring region suggesting that titin stiffening is important to the volume overload phenotype. To test this we investigated the effect of volume overload in the RBM20 heterozygous (HET) mouse model, which exhibits reduced titin stiffness. It was found that LV hypertrophy was attenuated and that LV eccentricity was exacerbated. We propose that pure volume overload induces an increase in titin stiffness that is beneficial and limits eccentric remodeling. PMID:25450617

Myocardialization of the cardiac outflow tract

NASA Technical Reports Server (NTRS)

van den Hoff, M. J.; Moorman, A. F.; Ruijter, J. M.; Lamers, W. H.; Bennington, R. W.; Markwald, R. R.; Wessels, A.

1999-01-01

During development, the single-circuited cardiac tube transforms into a double-circuited four-chambered heart by a complex process of remodeling, differential growth, and septation. In this process the endocardial cushion tissues of the atrioventricular junction and outflow tract (OFT) play a crucial role as they contribute to the mesenchymal components of the developing septa and valves in the developing heart. After fusion, the endocardial ridges in the proximal portion of the OFT initially form a mesenchymal outlet septum. In the adult heart, however, this outlet septum is basically a muscular structure. Hence, the mesenchyme of the proximal outlet septum has to be replaced by cardiomyocytes. We have dubbed this process "myocardialization." Our immunohistochemical analysis of staged chicken hearts demonstrates that myocardialization takes place by ingrowth of existing myocardium into the mesenchymal outlet septum. Compared to other events in cardiac septation, it is a relatively late process, being initialized around stage H/H28 and being basically completed around stage H/H38. To unravel the molecular mechanisms that are responsible for the induction and regulation of myocardialization, an in vitro culture system in which myocardialization could be mimicked and manipulated was developed. Using this in vitro myocardialization assay it was observed that under the standard culture conditions (i) whole OFT explants from stage H/H20 and younger did not spontaneously myocardialize the collagen matrix, (ii) explants from stage H/H21 and older spontaneously formed extensive myocardial networks, (iii) the myocardium of the OFT could be induced to myocardialize and was therefore "myocardialization-competent" at all stages tested (H/H16-30), (iv) myocardialization was induced by factors produced by, most likely, the nonmyocardial component of the outflow tract, (v) at none of the embryonic stages analyzed was ventricular myocardium myocardialization-competent, and finally

Predicting Adverse Outcomes After Myocardial Infarction Among Patients With Diabetes Mellitus.

PubMed

Arnold, Suzanne V; Spertus, John A; Jones, Philip G; McGuire, Darren K; Lipska, Kasia J; Xu, Yaping; Stolker, Joshua M; Goyal, Abhinav; Kosiborod, Mikhail

2016-07-01

Although patients with diabetes mellitus experience high rates of adverse events after acute myocardial infarction (AMI), including death and recurrent ischemia, some diabetic patients are likely at low risk, whereas others are at high risk. We sought to develop prediction models to stratify risk after AMI in patients with diabetes mellitus. We developed prediction models for long-term mortality and angina among 1613 patients with diabetes mellitus discharged alive after AMI from 24 US hospitals and then validated the models in a separate, multicenter registry of 786 patients with diabetes mellitus. Event rates in the derivation cohort were 27% for 5-year mortality and 27% for 1-year angina. Parsimonious prediction models demonstrated good discrimination (c-indices=0.78 and 0.69, respectively) and excellent calibration. Within the context of the predictors we estimated, the strongest predictors for mortality were higher creatinine, not working at the time of the AMI, older age, lower hemoglobin, left ventricular dysfunction, and chronic heart failure. The strongest predictors for angina were angina burden in the 4 weeks before the AMI, younger age, history of prior coronary bypass graft surgery, and non-white race. The lowest and highest deciles of predicted risk ranged from 4% to 80% for mortality and 12% to 59% for angina. The models also performed well in external validation (c-indices=0.78 and 0.73, respectively). We found a wide range of risk for adverse outcomes after AMI in diabetic patients. Predictive models can identify patients with diabetes mellitus for whom closer follow-up and aggressive secondary prevention strategies should be considered. © 2016 American Heart Association, Inc.

Thioredoxin 1 Enhances Neovascularization and Reduces Ventricular Remodeling During Chronic Myocardial Infarction: A Study Using Thioredoxin 1 Transgenic Mice

PubMed Central

Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Zhan, Lijun; Akita, Yuzo; Samuel, Samson Mathews; Otani, Hajime; Ho, Ye-Shih; Maulik, Gautam; Maulik, Nilanjana

2010-01-01

Oxidative stress plays a crucial role in disruption of neovascularization by alterations in thioredoxin-1 (Trx1) expression and its interaction with other proteins after myocardial infarction (MI). We previously showed that Trx1 has angiogenic properties, but the possible therapeutic significance of overexpressing Trx1 in chronic MI has not been elucidated. Therefore, we explored the angiogenic and cardioprotective potential of Trx1 in an in vivo MI model using transgenic mice overexpressing Trx1. Wild type (W) and Trx1 transgenic (Trx1Tg/+) mice were randomized into W Sham (WS), Trx1Tg/+ Sham (TS), WMI and TMI. MI was induced by permanent occlusion of LAD coronary artery. Hearts from mice overexpressing Trx1 exhibited reduced fibrosis and oxidative stress, and attenuated cardiomyocyte apoptosis along with increased vessel formation compared to WMI. We found significant inhibition of Trx1 regulating proteins, TXNIP and AKAP 12, and increased p-Akt, p-eNOS and p-GSK-3β, HIF-1α, β-catenin, VEGF, Bcl-2 and survivin expression in TMI compared to WMI. Echocardiography performed 30 days after MI revealed significant improvement in myocardial functions in TMI compared to WMI. Our study identifies a potential role for Trx1 overexpression and its association with its regulatory proteins TXNIP, AKAP12 and subsequent activation of Akt/GSK-3β/β-catenin/HIF-1α-mediated VEGF and eNOS expression in inducing angiogenesis and reduced ventricular remodeling. Hence, Trx1 and other proteins identified in our study may prove to be potential therapeutic targets in the treatment of ischemic heart disease. PMID:21074540

Concomitant Phosphodiesterase 5 Inhibition Enhances Myocardial Protection by Inhaled Nitric Oxide in Ischemia-Reperfusion Injury.

PubMed

Lux, Arpad; Pokreisz, Peter; Swinnen, Melissa; Caluwe, Ellen; Gillijns, Hilde; Szelid, Zsolt; Merkely, Bela; Janssens, Stefan P

2016-02-01

Enhanced cyclic guanosine monophosphate (cGMP) signaling may attenuate myocardial ischemia-reperfusion injury (I/R) and improve left ventricular (LV) functional recovery after myocardial infarction (MI). We investigated the cardioprotection afforded by inhaled NO (iNO), the phosphodiesterase 5 (PDE5)-specific inhibitor tadalafil (TAD), or their combination (iNO+TAD) in C57Bl6J mice subjected to 6-minute left anterior descending artery ligation followed by reperfusion. We measured plasma and cardiac concentrations of cGMP during early reperfusion, quantified myocardial necrosis and inflammation by serial troponin-I (TnI) and myeloperoxidase-positive cell infiltration at day 3, and evaluated LV function and remodeling after 4 weeks using echocardiography and pressure-conductance catheterization. Administration of iNO, TAD, or both during I/R was safe and hemodynamically well tolerated. Compared with untreated mice (CON), only iNO+TAD increased plasma and cardiac-cGMP levels during early reperfusion (80 ± 12 versus 36 ± 6 pmol/ml and 0.15 ± 0.02 versus 0.05 ± 0.01 pmol/mg protein, P < 0.05 for both). Moreover, iNO+TAD reduced TnI at 4 hours to a greater extent (P < 0.001 versus CON) than either alone (P < 0.05 versus CON) and was associated with significantly less myocardial inflammatory cell infiltration at day 3. After 4 weeks and compared with CON, iNO+TAD was associated with increased fractional shortening (43 ± 1 versus 33 ± 2%, P < 0.01), larger stroke volumes (14.9 ± 1.2 versus 10.2 ± 0.9 μl, P < 0.05), enhanced septal and posterior wall thickening (P < 0.05 and P < 0.001, respectively), and attenuated LV dilatation (P < 0.001), whereas iNO or TAD alone conferred less benefit. Thus, iNO+TAD has superior efficacy to limit early reperfusion injury and attenuate adverse LV remodeling. Combination of inhaled NO with a long-acting PDE5 inhibitor may represent a promising strategy to reduce ischemic damage following reperfusion and better preserve LV

Persistence of Infarct Zone T2 Hyperintensity at 6 Months After Acute ST-Segment–Elevation Myocardial Infarction

PubMed Central

Carberry, Jaclyn; Carrick, David; Haig, Caroline; 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.

2017-01-01

Background— The incidence and clinical significance of persistent T2 hyperintensity after acute ST-segment–elevation myocardial infarction (STEMI) is uncertain. Methods and Results— Patients who sustained an acute STEMI were enrolled in a cohort study (BHF MR-MI: NCT02072850). Two hundred eighty-three STEMI patients (mean age, 59±12 years; 75% male) had cardiac magnetic resonance with T2 mapping performed at 2 days and 6 months post-STEMI. Persisting T2 hyperintensity was defined as infarct T2 >2 SDs from remote T2 at 6 months. Infarct zone T2 was higher than remote zone T2 at 2 days (66.3±6.1 versus 49.7±2.1 ms; P<0.001) and 6 months (56.8±4.5 versus 49.7±2.3 ms; P<0.001). Remote zone T2 did not change over time (mean change, 0.0±2.7 ms; P=0.837), whereas infarct zone T2 decreased (−9.5±6.4 ms; P<0.001). At 6 months, T2 hyperintensity persisted in 189 (67%) patients, who were more likely to have Thrombus in Myocardial Infarction flow 0 or 1 in the culprit artery (P=0.020), incomplete ST-segment resolution (P=0.037), and higher troponin (P=0.024). Persistent T2 hyperintensity was associated with NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration (0.57 on a log scale [0.42–0.72]; P=0.004) and the likelihood of adverse left ventricular remodeling (>20% change in left ventricular end-diastolic volume; 21.91 [2.75–174.29]; P=0.004). Persistent T2 hyperintensity was associated with all-cause death and heart failure, but the result was not significant (P=0.051). ΔT2 was associated with all-cause death and heart failure (P=0.004) and major adverse cardiac events (P=0.013). Conclusions— Persistent T2 hyperintensity occurs in two thirds of STEMI patients. Persistent T2 hyperintensity was associated with the initial STEMI severity, adverse remodeling, and long-term health outcome. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT02072850. PMID:29242240

Cardiac hypertrophy limits infarct expansion after myocardial infarction in mice.

PubMed

Iismaa, Siiri E; Li, Ming; Kesteven, Scott; Wu, Jianxin; Chan, Andrea Y; Holman, Sara R; Calvert, John W; Haq, Ahtesham Ul; Nicks, Amy M; Naqvi, Nawazish; Husain, Ahsan; Feneley, Michael P; Graham, Robert M

2018-04-17

We have previously demonstrated that adult transgenic C57BL/6J mice with CM-restricted overexpression of the dominant negative W v mutant protein (dn-c-kit-Tg) respond to pressure overload with robust cardiomyocyte (CM) cell cycle entry. Here, we tested if outcomes after myocardial infarction (MI) due to coronary artery ligation are improved in this transgenic model. Compared to non-transgenic littermates (NTLs), adult male dn-c-kit-Tg mice displayed CM hypertrophy and concentric left ventricular (LV) hypertrophy in the absence of an increase in workload. Stroke volume and cardiac output were preserved and LV wall stress was markedly lower than that in NTLs, leading to a more energy-efficient heart. In response to MI, infarct size in adult (16-week old) dn-c-kit-Tg hearts was similar to that of NTL after 24 h but was half that in NTL hearts 12 weeks post-MI. Cumulative CM cell cycle entry was only modestly increased in dn-c-kit-Tg hearts. However, dn-c-kit-Tg mice were more resistant to infarct expansion, adverse LV remodelling and contractile dysfunction, and suffered no early death from LV rupture, relative to NTL mice. Thus, pre-existing cardiac hypertrophy lowers wall stress in dn-c-kit-Tg hearts, limits infarct expansion and prevents death from myocardial rupture.

Myocardial recovery from ischemia-reperfusion is compromised in the absence of tissue inhibitor of metalloproteinase 4.

PubMed

Takawale, Abhijit; Fan, Dong; Basu, Ratnadeep; Shen, Mengcheng; Parajuli, Nirmal; Wang, Wang; Wang, Xiuhua; Oudit, Gavin Y; Kassiri, Zamaneh

2014-07-01

Myocardial reperfusion after ischemia (I/R), although an effective approach in rescuing the ischemic myocardium, can itself trigger several adverse effects including aberrant remodeling of the myocardium and its extracellular matrix. Tissue inhibitor of metalloproteinases (TIMPs) protect the extracellular matrix against excess degradation by matrix metalloproteinases (MMPs). TIMP4 levels are reduced in myocardial infarction; however, its causal role in progression of post-I/R injury has not been explored. In vivo I/R (20-minute ischemia, 1-week reperfusion) resulted in more severe systolic and diastolic dysfunction in TIMP4(-/-) mice with enhanced inflammation, oxidative stress (1 day post-I/R), hypertrophy, and interstitial fibrosis (1 week). After an initial increase in TIMP4 (1 day post-I/R), TIMP4 mRNA and protein decreased in the ischemic myocardium from wild-type mice by 1 week post-I/R and in tissue samples from patients with myocardial infarction, which correlated with enhanced activity of membrane-bound MMP, membrane-type 1 MMP. By 4 weeks post-I/R, wild-type mice showed no cardiac dysfunction, elevated TIMP4 levels (to baseline), and normalized membrane-type 1 MMP activity. TIMP4-deficient mice, however, showed exacerbated diastolic dysfunction, sustained elevation of membrane-type 1 MMP activity, and worsened myocardial hypertrophy and fibrosis. Ex vivo I/R (20- or 30-minute ischemia, 45-minute reperfusion) resulted in comparable cardiac dysfunction in wild-type and TIMP4(-/-) mice. TIMP4 is essential for recovery from myocardial I/R in vivo, primarily because of its membrane-type 1 MMP inhibitory function. TIMP4 deficiency does not increase susceptibility to ex vivo I/R injury. Replenishment of myocardial TIMP4 could serve as an effective therapy in post-I/R recovery for patients with reduced TIMP4. © 2014 American Heart Association, Inc.

In vivo assessment of regional mechanics post-myocardial infarction: A focus on the road ahead.

PubMed

Romito, Eva; Shazly, Tarek; Spinale, Francis G

2017-10-01

Cardiovascular disease, particularly the occurrence of myocardial infarction (MI), remains a leading cause of morbidity and mortality (Go et al., Circulation 127: e6-e245, 2013; Go et al. Circulation 129: e28-e292, 2014). There is growing recognition that a key factor for post-MI outcomes is adverse remodeling and changes in the regional structure, composition, and mechanical properties of the MI region itself. However, in vivo assessment of regional mechanics post-MI can be confounded by the species, temporal aspects of MI healing, as well as size, location, and extent of infarction across myocardial wall. Moreover, MI regional mechanics have been assessed over varying phases of the cardiac cycle, and thus, uniform conclusions regarding the material properties of the MI region can be difficult. This review assesses past studies that have performed in vivo measures of MI mechanics and attempts to provide coalescence on key points from these studies, as well as offer potential recommendations for unifying approaches in terms of regional post-MI mechanics. A uniform approach to biophysical measures of import will allow comparisons across studies, as well as provide a basis for potential therapeutic markers.

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.

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.

Three‐dimensional myocardial scarring along myofibers after coronary ischemia–reperfusion revealed by computerized images of histological assays

PubMed Central

Katz, Monica Y.; Kusakari, Yoichiro; Aoyagi, Hiroko; Higa, Jason K.; Xiao, Chun‐Yang; Abdelkarim, Ahmed Z.; Marh, Karra; Aoyagi, Toshinori; Rosenzweig, Anthony; Lozanoff, Scott; Matsui, Takashi

2014-01-01

Abstract Adverse left ventricular (LV) remodeling after acute myocardial infarction is characterized by LV dilatation and development of a fibrotic scar, and is a critical factor for the prognosis of subsequent development of heart failure. Although myofiber organization is recognized as being important for preserving physiological cardiac function and structure, the anatomical features of injured myofibers during LV remodeling have not been fully defined. In a mouse model of ischemia–reperfusion (I/R) injury induced by left anterior descending coronary artery ligation, our previous histological assays demonstrated that broad fibrotic scarring extended from the initial infarct zone to the remote zone, and was clearly demarcated along midcircumferential myofibers. Additionally, no fibrosis was observed in longitudinal myofibers in the subendocardium and subepicardium. However, a histological analysis of tissue sections does not adequately indicate myofiber injury distribution throughout the entire heart. To address this, we investigated patterns of scar formation along myofibers using three‐dimensional (3D) images obtained from multiple tissue sections from mouse hearts subjected to I/R injury. The fibrotic scar area observed in the 3D images was consistent with the distribution of the midcircumferential myofibers. At the apex, the scar formation tracked along the myofibers in an incomplete C‐shaped ring that converged to a triangular shape toward the end. Our findings suggest that myocyte injury after transient coronary ligation extends along myofibers, rather than following the path of coronary arteries penetrating the myocardium. The injury pattern observed along myofibers after I/R injury could be used to predict prognoses for patients with myocardial infarction. PMID:25347856

Intra-myocardial injection of both growth factors and heart derived Sca-1+/CD31- cells attenuates post-MI LV remodeling more than does cell transplantation alone: neither intervention enhances functionally significant cardiomyocyte regeneration.

PubMed

Wang, Xiaohong; Li, Qinglu; Hu, Qingsong; Suntharalingam, Piradeep; From, Arthur H L; Zhang, Jianyi

2014-01-01

Insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) are two potent cell survival and regenerative factors in response to myocardial injury (MI). We hypothesized that simultaneous delivery of IGF+HGF combined with Sca-1+/CD31- cells would improve the outcome of transplantation therapy in response to the altered hostile microenvironment post MI. One million adenovirus nuclear LacZ-labeled Sca-1+/CD31- cells were injected into the peri-infarction area after left anterior descending coronary artery (LAD) ligation in mice. Recombinant mouse IGF-1+HGF was added to the cell suspension prior to the injection. The left ventricular (LV) function was assessed by echocardiography 4 weeks after the transplantation. The cell engraftment, differentiation and cardiomyocyte regeneration were evaluated by histological analysis. Sca-1+/CD31- cells formed viable grafts and improved LV ejection fraction (EF) (Control, 54.5+/-2.4; MI, 17.6+/-3.1; Cell, 28.2+/-4.2, n = 9, P<0.01). IGF+HGF significantly enhanced the benefits of cell transplantation as evidenced by increased EF (38.8+/-2.2; n = 9, P<0.01) and attenuated adverse structural remodeling. Furthermore, IGF+HGF supplementation increased the cell engraftment rate, promoted the transplanted cell survival, enhanced angiogenesis, and minimally stimulated endogenous cardiomyocyte regeneration in vivo. The in vitro experiments showed that IGF+HGF treatment stimulated Sca-1+/CD31- cell proliferation and inhibited serum free medium induced apoptosis. Supperarray profiling of Sca-1+/CD31- cells revealed that Sca-1+/CD31- cells highly expressed various trophic factor mRNAs and IGF+HGF treatment altered the mRNAs expression patterns of these cells. These data indicate that IGF-1+HGF could serve as an adjuvant to cell transplantation for myocardial repair by stimulating donor cell and endogenous cardiac stem cell survival, regeneration and promoting angiogenesis.

Constitutive glycogen synthase kinase-3α/β activity protects against chronic β-adrenergic remodelling of the heart

PubMed Central

Webb, Ian G.; Nishino, Yasuhiro; Clark, James E.; Murdoch, Colin; Walker, Simon J.; Makowski, Marcus R.; Botnar, Rene M.; Redwood, Simon R.; Shah, Ajay M.; Marber, Michael S.

2010-01-01

Aims Glycogen synthase kinase 3 (GSK-3) signalling is implicated in the growth of the heart during development and in response to stress. However, its precise role remains unclear. We set out to characterize developmental growth and response to chronic isoproterenol (ISO) stress in knockin (KI) mice lacking the critical N-terminal serines, 21 of GSK-3α and 9 of GSK-3β respectively, required for inactivation by upstream kinases. Methods and results Between 5 and 15 weeks, KI mice grew more rapidly, but normalized heart weight and contractile performance were similar to wild-type (WT) mice. Isolated hearts of both genotypes responded comparably to acute ISO infusion with increases in heart rate and contractility. In WT mice, chronic subcutaneous ISO infusion over 14 days resulted in cardiac hypertrophy, interstitial fibrosis, and impaired contractility, accompanied by foetal gene reactivation. These effects were all significantly attenuated in KI mice. Indeed, ISO-treated KI hearts demonstrated reversible physiological remodelling traits with increased stroke volume and a preserved contractile response to acute adrenergic stimulation. Furthermore, simultaneous pharmacological inhibition of GSK-3 in KI mice treated with chronic subcutaneous ISO recapitulated the adverse remodelling phenotype seen in WT hearts. Conclusion Expression of inactivation-resistant GSK-3α/β does not affect eutrophic myocardial growth but protects against pathological hypertrophy induced by chronic adrenergic stimulation, maintaining cardiac function and attenuating interstitial fibrosis. Accordingly, strategies to prevent phosphorylation of Ser-21/9, and consequent inactivation of GSK-3α/β, may enable a sustained cardiac response to chronic β-agonist stimulation while preventing pathological remodelling. PMID:20299330

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.

Nebivolol prevents remodeling in a rat myocardial infarction model: an echocardiographic study.

PubMed

Mercanoğlu, Güldem Olguner; Pamukçu, Burak; Safran, Nurhas; Mercanoğlu, Fehmi; Fici, Francesco; Güngör, Mehmet

2010-02-01

Ventricular remodeling (VR) which develops after myocardial infarction (MI) plays an important role in progressive left ventricular dysfunction. We aimed to investigate the role of nebivolol treatment on VR after a MI in a rat ischemia-reperfusion model. Rats were divided into 3 groups of 12 each: sham operated (sham-control), MI-induced (MI-control) and nebivolol treated (MI-nebivolol). Left ventricular (LV) diameters, volumes, and diastolic filling parameters were evaluated by echocardiography. On the 28th day, after recording the systemic and LV pressures and determining the plasma nitric oxide (NO) and peroxynitrite (ONOO-) levels , animals were sacrificed and heart, body and LV weights (HW, BW, LVW) were measured and infarct sizes were determined. Results were evaluated statistically by ANOVA for repeated measurements 3x3 factorial design with post-hoc Bonferroni test. After MI, while VR (an increase in LV diameters and volumes associated with a decrease in EF, FS and posterior wall thickness change (LWPc) was significant in MI-control rats (p<0.05 for; all comparisons) these changes were significantly less in MI-nebivolol group (p=0.08 and p=0.06 for EF and FS respectively). LV end diastolic pressure (LVEDP) was lower (p<0.005) and Delta+/- dp/dt's (p<0.05) were higher in MI-nebivolol group compared to MI-control animals. Although infarct sizes were similar in MI-induced groups (p=0.79); LVW/HW and HW/BW's were significantly greater in the MI-control group compared to sham-control (p<0.01 for all comparisons), these changes were not statistically significant in MI-nebivolol group. The increase in plasma NO and ONOO- levels were also prevented with nebivolol. Nebivolol therapy reduced the effects of VR in rats after MI. These beneficial effects were not related to its heart rate and blood pressure reducing effects. Nitric oxide regulatory action of this compound may contribute these beneficial effects on VR developed after MI.

Adenosine A2A receptor agonist prevents cardiac remodeling and dysfunction in spontaneously hypertensive male rats after myocardial infarction

PubMed Central

da Silva, Jaqueline S; Gabriel-Costa, Daniele; Sudo, Roberto T; Wang, Hao; Groban, Leanne; Ferraz, Emanuele B; Nascimento, José Hamilton M; Fraga, Carlos Alberto M; Barreiro, Eliezer J; Zapata-Sudo, Gisele

2017-01-01

Background This work evaluated the hypothesis that 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), an agonist of adenosine A2A receptor, could be beneficial for preventing cardiac dysfunction due to hypertension associated with myocardial infarction (MI). Methods Male spontaneously hypertensive rats (SHR) were randomly divided into four groups (six animals per group): sham-operation (SHR-Sham), and myocardial infarction rats (SHR-MI) were treated orally either with vehicle or LASSBio-294 (10 and 20 mg.kg−1.d−1) for 4 weeks. Echocardiography and in vivo hemodynamic parameters measured left ventricle (LV) structure and function. Exercise tolerance was evaluated using a treadmill test. Cardiac remodeling was accessed by LV collagen deposition and tumor necrosis factor α expression. Results Early mitral inflow velocity was significantly reduced in the SHR-MI group, and there was significant recovery in a dose-dependent manner after treatment with LASSBio-294. Exercise intolerance observed in the SHR-MI group was prevented by 10 mg.kg−1.d−1 of LASS-Bio-294, and exercise tolerance exceeded that of the SHR-Sham group at 20 mg.kg−1.d−1. LV end-diastolic pressure increased after MI, and this was prevented by 10 and 20 mg.kg−1.d−1 of LASSBio-294. Sarcoplasmic reticulum Ca2+ ATPase levels were restored in a dose-dependent manner after treatment with LASSBio-294. Fibrosis and inflammatory processes were also counteracted by LASSBio-294, with reductions in LV collagen deposition and tumor necrosis factor α expression. Conclusion In summary, oral administration of LASSBio-294 after MI in a dose-dependent manner prevented the development of cardiac dysfunction, demonstrating this compound’s potential as an alternative treatment for heart failure in the setting of ischemic heart disease with superimposed chronic hypertension. PMID:28293100

Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor.

PubMed

Howangyin, Kiave-Yune; Zlatanova, Ivana; Pinto, Cristina; Ngkelo, Anta; Cochain, Clément; Rouanet, Marie; Vilar, José; Lemitre, Mathilde; Stockmann, Christian; Fleischmann, Bernd K; Mallat, Ziad; Silvestre, Jean-Sébastien

2016-03-01

In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. We generated double-deficient mice for Mertk and Mfge8 (Mertk(-/-)/Mfge8(-/-)) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk(-/-)), or Mfge8-deficient (Mfge8(-/-)) animals, Mertk(-/-)/Mfge8(-/-) mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6C(High and Low) monocytes and macrophages. In parallel, Mertk(-/-)/Mfge8(-/-) bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6C(High) and Ly6C(How) monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6C(High)/Ly6C(Low) monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre(+)/VEGFA(fl/fl) mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the dysfunctional heart. © 2016 The Authors.

Myeloid-Epithelial-Reproductive Receptor Tyrosine Kinase and Milk Fat Globule Epidermal Growth Factor 8 Coordinately Improve Remodeling After Myocardial Infarction via Local Delivery of Vascular Endothelial Growth Factor

PubMed Central

Howangyin, Kiave-Yune; Zlatanova, Ivana; Pinto, Cristina; Ngkelo, Anta; Cochain, Clément; Rouanet, Marie; Vilar, José; Lemitre, Mathilde; Stockmann, Christian; Fleischmann, Bernd K.; Mallat, Ziad

2016-01-01

Background— In infarcted heart, improper clearance of dying cells by activated neighboring phagocytes may precipitate the transition to heart failure. We analyzed the coordinated role of 2 major mediators of efferocytosis, the myeloid-epithelial-reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8), in directing cardiac remodeling by skewing the inflammatory response after myocardial infarction. Methods and Results— We generated double-deficient mice for Mertk and Mfge8 (Mertk−/−/Mfge8−/−) and challenged them with acute coronary ligature. Compared with wild-type, Mertk-deficient (Mertk−/−), or Mfge8-deficient (Mfge8−/−) animals, Mertk−/−/Mfge8−/− mice displayed greater alteration in cardiac function and remodeling. Mertk and Mfge8 were expressed mainly by cardiac Ly6CHigh and Low monocytes and macrophages. In parallel, Mertk−/−/Mfge8−/− bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis. We found that the abrogation of efferocytosis affected neither the ability of circulating monocytes to infiltrate cardiac tissue nor the number of resident Ly6CHigh and Ly6CHow monocytes/macrophages populating the infarcted milieu. In contrast, combined Mertk and Mfge8 deficiency in Ly6CHigh/Ly6CLow monocytes/macrophages either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. Using LysMCre+/VEGFAfl/fl mice, we further identified an important role for myeloid-derived VEGFA in improving cardiac function and angiogenesis. Conclusions— After myocardial infarction, Mertk- and Mfge8-expressing monocyte/macrophages synergistically engage the clearance of injured cardiomyocytes, favoring the secretion of VEGFA to locally repair the

Effect of coronary artery reperfusion on transmural myocardial remodeling in dogs.

PubMed

Ono, S; Waldman, L K; Yamashita, H; Covell, J W; Ross, J

1995-02-15

The effects of reperfusion after coronary occlusion on transmural remodeling of the ischemic region early and late after nontransmural infarction must importantly affect the recovery of regional function. Accordingly, analysis of local volume and three-dimensional strain was performed using a finite element method to determine regional remodeling. Systolic and remodeling strains were measured using radiographic imaging of three columns (approximately 1 cm apart) of four to six gold beads implanted across the left ventricular posterior wall in 6 dogs. After a control study, infarction was produced by 2 to 4 hours of proximal left circumflex coronary artery occlusion followed by reperfusion. Follow-up studies were performed at 2 days, 3 weeks, and 12 weeks with the dogs under anesthesia and in closed-chest conditions. Biplane cineradiography was performed to obtain the three-dimensional coordinates of the beads. At 2 days, end-systolic strains were akinetic with loss of normal transmural gradients of shortening and thickening. Remodeling strains (RS) were determined by use of a nonhomogeneous finite element method by referring the end-diastolic configuration during follow-up studies to its control state at matched end-diastolic pressures and heart rates. Tissue volume at 2 days increased substantially, more at the endocardium (30 +/- 7%) than at the epicardium (5 +/- 12%, P < .01); the increase was associated with an average RS in the wall-thickening direction of 0.18 +/- 0.15 (P < .01) with all other RS near zero. At 12 weeks systolic function partially recovered, with normal wall thickening in the epicardium (radial strain, 0.081 +/- 0.056 [control] versus 0.113 +/- 0.088 [12 weeks]) but with dysfunction in the endocardium (0.245 +/- 0.108 [control] versus 0.111 +/- 0.074 [P < .01] [12 weeks]). This inability of the inner wall to recover function may be related to increased transmural torsional shear and negative longitudinal-radial transverse shear in the inner

Melatonin protects against myocardial hypertrophy induced by lipopolysaccharide.

PubMed

Lu, Qi; Yi, Xin; Cheng, Xiang; Sun, Xiaohui; Yang, Xiangjun

2015-04-01

Melatonin is thought to have the ability of antiatherogenic, antioxidant, and vasodilatory. It is not only a promising protective in acute myocardial infarction but is also a useful tool in the treatment of pathological remodeling. However, its role in myocardial hypertrophy remains unclear. In this study, we investigated the protective effects of melatonin on myocardial hypertrophy induced by lipopolysaccharide (LPS) and to identify their precise mechanisms. The cultured myocardial cell was divided into six groups: control group, LPS group, LPS + ethanol (4%), LPS + melatonin (1.5 mg/ml) group, LPS + melatonin (3 mg/ml) group, and LPS + melatonin (6 mg/ml) group. The morphologic change of myocardial cell was observed by inverted phase contrast microscope. The protein level of myocardial cell was measured by Coomassie brilliant blue protein kit. The secretion level of tumor necrosis factor-α (TNF-α) was evaluated by enzyme-linked immunosorbent assay (ELISA). Ca(2+) transient in Fura-2/AM-loaded cells was measured by Till image system. The expression of Ca(2+)/calmodulin-dependent kinase II (CaMKII) and calcineurin (CaN) was measured by Western blot analysis. Our data demonstrated that LPS induced myocardial hypertrophy, promoted the secretion levels of TNF-α, and increased Ca(2+) transient level and the expression of CaMKII and CaN. Administration of melatonin 30 min prior to LPS stimulation dose-dependently attenuated myocardial hypertrophy. In conclusion, the results revealed that melatonin had the potential to protect against myocardial hypertrophy induced by LPS in vitro through downregulation of the TNF-α expression and retains the intracellular Ca(2+) homeostasis.

Non-Q-wave myocardial infarction: impaired myocardial energy metabolism in regions with reduced 99mTc-MIBI accumulation.

PubMed

Moka, D; Baer, F M; Theissen, P; Schneider, C A; Dietlein, M; Erdmann, E; Schicha, H

2001-05-01

Reduced regional technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) accumulation in patients with chronic non-Q-wave infarction (NQWI) but without significant coronary artery stenosis indicates non-transmural damage of the myocardial wall. The aim of this study was to characterise cardiac energy metabolism after NQWI using phosphorus-31 magnetic resonance spectroscopy (31P-MRS) and to compare the biochemical remodelling with changes in regional 99mTc-MIBI uptake and with morphological and functional parameters assessed by magnetic resonance imaging (MRI). Fifteen patients with a history of NQWI, exclusion of significant coronary artery stenosis (<50% diameter stenosis) and hypokinesia of the anterior wall (group A) were examined with 31P-MRS to study the effects of NQWI on myocardial energy metabolism. Spectroscopic measurements were performed in the infarct-related myocardial region. Corresponding gradient-echo MR images and myocardial 99mTc-MIBI single-photon emission tomography images were acquired for exact localisation of the infarct region. All examinations were performed at rest under anti-ischaemic medication. Data were compared with those of patients in whom coronary artery disease had been excluded by angiography (group B, n=10). All patients of group A displayed anterior wall hypokinesia in the infarcted area on both ventriculography and MRI, with a reduced myocardial accumulation of 99mTc-MIBI (66.3%+/-11.8% vs 95.6%+/-2.2% in group B). The mean wall thickness during the complete cardiac cycle (9.5+/-1.8 mm vs 13.1+/-1.1 mm in group B, P<0.001), the systolic wall thickening (2.6+/-1.4 mm vs 5.8+/-1.5 mm in group B, P<0.01) and the phosphocreatine/adenosine triphosphate ratio (1.12+/-0.22 vs 1.74+/-0.23 in group B, P<0.01) in the hypokinetic area were all significantly reduced. It is concluded that persisting hypokinetic myocardium after NQWI combined with reduced myocellular uptake of 99mTc-MIBI displays a reduced PCr/ATP ratio. Our results indicate

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.

Interleukin-1{beta} regulates cell proliferation and activity of extracellular matrix remodelling enzymes in cultured primary pig heart cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zitta, Karina; Brandt, Berenice; Wuensch, Annegret

Research highlights: {yields} Levels of IL-1{beta} are increased in the pig myocardium after infarction. {yields} Cultured pig heart cells possess IL-1 receptors. {yields} IL-1{beta} increases cell proliferation of pig heart cells in-vitro. {yields} IL-1{beta} increases MMP-2 and MMP-9 activity in pig heart cells in-vitro. {yields} IL-1{beta} may be important for tissue remodelling events after myocardial infarction. -- Abstract: After myocardial infarction, elevated levels of interleukins (ILs) are found within the myocardial tissue and IL-1{beta} is considered to play a major role in tissue remodelling events throughout the body. In the study presented, we have established a cell culture model ofmore » primary pig heart cells to evaluate the effects of different concentrations of IL-1{beta} on cell proliferation as well as expression and activity of enzymes typically involved in tissue remodelling. Primary pig heart cell cultures were derived from three different animals and stimulated with recombinant pig IL-1{beta}. RNA expression was detected by RT-PCR, protein levels were evaluated by Western blotting, activity of matrix metalloproteinases (MMPs) was quantified by gelatine zymography and cell proliferation was measured using colorimetric MTS assays. Pig heart cells express receptors for IL-1 and application of IL-1{beta} resulted in a dose-dependent increase of cell proliferation (P < 0.05 vs. control; 100 ng/ml; 24 h). Gene expression of caspase-3 was increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h), and pro-caspase-3 but not active caspase was detected in lysates of pig heart cells by Western blotting. MMP-2 gene expression as well as enzymatic activities of MMP-2 and MMP-9 were increased by IL-1{beta} (P < 0.05 vs. control; 100 ng/ml; 3 h for gene expression, 48 and 72 h for enzymatic activities of MMP-2 and MMP-9, respectively). Our in vitro data suggest that IL-1{beta} plays a major role in the events of tissue remodelling in the heart

Targeting inflammatory pathways in myocardial infarction

PubMed Central

Christia, Panagiota; Frangogiannis, Nikolaos G

2013-01-01

Acute cardiomyocyte necrosis in the infarcted heart generates Damage-Associated Molecular Patterns (DAMPs), activating complement and Toll-Like Receptor (TLR)/Interleukin (IL)-1 signaling, and triggering an intense inflammatory reaction. Infiltrating leukocytes clear the infarct from dead cells, while activating reparative pathways that lead to formation of a scar. As the infarct heals the ventricle remodels; the geometric, functional and molecular alterations associated with post-infarction remodeling are driven by the inflammatory cascade and are involved in the development of heart failure. Because unrestrained inflammation in the infarcted heart induces matrix degradation and cardiomyocyte apoptosis, timely suppression of the post-infarction inflammatory reaction may be crucial to protect the myocardium from dilative remodeling and progressive dysfunction. Inhibition and resolution of post-infarction inflammation involves mobilization of inhibitory mononuclear cell subsets and requires activation of endogenous STOP signals. Our manuscript discusses the basic cellular and molecular events involved in initiation, activation and resolution of the post-infarction inflammatory response, focusing on identification of therapeutic targets. The failure of anti-integrin approaches in patients with myocardial infarction and a growing body of experimental evidence suggest that inflammation may not increase ischemic cardiomyocyte death, but accentuates matrix degradation causing dilative remodeling. Given the pathophysiologic complexity of post-infarction remodeling, personalized biomarker-based approaches are needed to target patient subpopulations with dysregulated inflammatory and reparative responses. Inhibition of pro-inflammatory signals (such as IL-1 and Monocyte Chemoattractant Protein-1) may be effective in patients with defective resolution of post-infarction inflammation who exhibit progressive dilative remodeling. In contrast, patients with predominant

Subclinical myocardial necrosis and cardiovascular risk in stable patients undergoing elective cardiac evaluation.

PubMed

Tang, W H Wilson; Wu, Yuping; Nicholls, Stephen J; Brennan, Danielle M; Pepoy, Michael; Mann, Shirley; Pratt, Alan; Van Lente, Frederick; Hazen, Stanley L

2010-03-01

The presence of subclinical myocardial necrosis as a prodrome to longer-term adverse cardiac event risk has been debated. The debate has focused predominantly within patients with acute coronary syndrome, and on issues of troponin assay variability and accuracy of detection, rather than on the clinical significance of the presence of subclinical myocardial necrosis (ie, "troponin leak") within stable cardiac patients. Herein, we examine the relationship between different degrees of subclinical myocardial necrosis and long-term adverse clinical outcomes within a stable cardiac patient population with essentially normal renal function. Sequential consenting patients (N=3828; median creatinine clearance, 100 mL/min/1.73m(2)) undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (<0.03 ng/mL) were evaluated. The relationship of subclinical myocardial necrosis with incident major adverse cardiovascular events (defined as any death, myocardial infarction, or stroke) over 3-year follow-up was examined. "Probable" (cTnI 0.001-0.008 ng/mL) and "definite" (cTnI 0.009-0.029 ng/mL) subclinical myocardial necrosis were observed frequently within the cohort (34% and 18%, respectively). A linear relationship was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident major adverse cardiovascular events, particularly in those with cTnI 0.009 ng/mL or higher (hazard ratio, 3.00; 95% confidence interval, 2.4-3.8), even after adjustment for traditional risk factors, C-reactive protein, and creatinine clearance. The presence of subclinical myocardial necrosis was associated with elevations in acute phase proteins (C-reactive protein, ceruloplasmin; P<0.01 each) and reduction in systemic antioxidant enzyme activities (arylesterase; P<0.01) but showed no significant associations with multiple specific measures of oxidant stress, and showed borderline

Cocaine, a risk factor for myocardial infarction.

PubMed

Galasko, G I

1997-06-01

Cocaine usage goes back thousands of years, to the times of the Incas. Over the past 20 years, its use has increased dramatically, especially in America, and adverse cardiovascular reactions to the drug have begun to be reported. The first report of myocardial infarction temporally related to the recreational use of cocaine appeared in 1982. Since then, myocardial infarction has become recognized as the drug's most common cardiovascular consequence, with over 250 cases now documented in the literature. This review discusses the history of cocaine use, its pharmacology, the possible pathological mechanisms underlying the pathogenesis of myocardial ischaemia and infarction, and current ideas on the management of cocaine-induced myocardial infarction.

Myocardial adaptations to recreational marathon training among middle-aged men.

PubMed

Zilinski, Jodi L; Contursi, Miranda E; Isaacs, Stephanie K; Deluca, James R; Lewis, Gregory D; Weiner, Rory B; Hutter, Adolph M; d'Hemecourt, Pierre A; Troyanos, Christopher; Dyer, K Sophia; Baggish, Aaron L

2015-02-01

Myocardial adaptations to exercise have been well documented among competitive athletes. To what degree cardiac remodeling occurs among recreational exercisers is unknown. We sought to evaluate the effect of recreational marathon training on myocardial structure and function comprehensively. Male runners (n=45; age, 48±7 years; 64% with ≥1 cardiovascular risk factor) participated in a structured marathon-training program. Echocardiography, cardiopulmonary exercise testing, and laboratory evaluation were performed pre and post training to quantify changes in myocardial structure and function, cardiorespiratory fitness, and traditional cardiac risk parameters. Completion of an 18-week running program (25±9 miles/wk) led to increased cardiorespiratory fitness (peak oxygen consumption, 44.6±5.2 versus 46.3±5.4 mL/kg per minute; P<0.001). In this setting, there was a significant structural cardiac remodeling characterized by dilation of the left ventricle (end-diastolic volume, 156±26 versus 172±28 mL, P<0.001), right ventricle (end-diastolic area=27.0±4.8 versus 28.6±4.3 cm(2); P=0.02), and left atrium (end-diastolic volume, 65±19 versus 72±19; P=0.02). Functional adaptations included increases in both early (E'=12.4±2.5 versus 13.2±2.0 cm/s; P=0.007) and late (A'=11.5±1.9 versus 12.2±2.1 cm/s; P=0.02) left ventricular diastolic velocities. Myocardial remodeling was accompanied by beneficial changes in cardiovascular risk factors, including body mass index (27.0±2.7 versus 26.7±2.6 kg/m(2); P<0.001), total cholesterol (199±33 versus 192±29 mg/dL; P=0.01), low-density lipoprotein (120±29 versus 114±26 mg/dL; P=0.01), and triglycerides (100±52 versus 85±36 mg/dL; P=0.02). Among middle-aged men, recreational marathon training is associated with biventricular dilation, enhanced left ventricular diastolic function, and favorable changes in nonmyocardial determinants of cardiovascular risk. Recreational marathon training may, therefore, serve as an

Protective effect of N-acetylcysteine activated carbon release microcapsule on myocardial ischemia-reperfusion injury in rats

PubMed Central

Cai, Zhaobin; Shi, Tingting; Zhuang, Rangxiao; Fang, Hongying; Jiang, Xiaojie; Shao, Yidan; Zhou, Hongping

2018-01-01

With the development of science and technology, and development of artery bypass, methods such as cardiopulmonary cerebral resuscitation have been practiced in recent years. Despite this, some methods fail to promote or recover the function of tissues and organs, and in some cases, may aggravate dysfunction and structural damage to tissues. The latter is typical of ischemia-reperfusion (IR) injury. Lipid peroxidation mediated by free radicals is an important process of myocardial IR injury. Myocardial IR has been demonstrated to induce the formation of large numbers of free radicals in rats, which promotes the peroxidation of lipids within unsaturated fatty acids in the myocardial cell membrane. Markers of lipid peroxidation include malondialdehyde, superoxide dismutase and lactic dehydrogenase. Recent studies have demonstrated that N-acetylcysteine (NAC) is able to dilate blood vessels, prevent oxidative damage, improve immunity, inhibit apoptosis and the inflammatory response and promote glutathione synthesis in cells. NAC also improves the systolic function of myocardial cells and cardiac function, prevents myocardial apoptosis, protects ventricular remodeling and vascular remodeling, reduces opiomelanocortin levels in the serum and increases the content of nitric oxide in the serum, thus improving vascular endothelial function. Therefore, NAC has potent pharmacological activity; however, the relatively fast metabolism of NAC, along with its large clinical dose and low bioavailability, limit its applications. The present study combined NAC with medicinal activated carbons, and prepared N-acetylcysteine activated carbon sustained-release microcapsules (ACNACs) to overcome the limitations of NAC. It was demonstrated that ACNACs exerted greater effective protective effects than NAC alone on myocardial IR injury in rats. PMID:29434769

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.

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

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

Prostaglandin F2α receptor silencing attenuates vascular remodeling in rats with type 2 diabetes.

PubMed

Li, Ya; Han, Lu; Ding, Wen-Yuan; Ti, Yun; Li, Yi-Hui; Tang, Meng-Xiong; Wang, Zhi-Hao; Zhang, Yun; Zhang, Wei; Zhong, Ming

2015-12-01

Vascular remodeling is an important feature of diabetic macrovascular complications. The prostaglandin F2α receptor (FP), the expression of which is upregulated by insulin resistance and diabetes, is reportedly involved in myocardial remodeling. In this study, we aimed to investigate whether the FP receptor is implicated in diabetes-induced vascular remodeling. A type 2 diabetic rat model was induced through a high-fat diet and low-dose streptozotocin (STZ). Thirty-two rats were randomized into four groups: control, diabetes, diabetes treated with empty virus and diabetes treated with FP receptor-shRNA. Then, we evaluated the metabolic index, FP receptor expression and vascular remodeling. We used FP receptor gene silencing in vivo to investigate the role that the FP receptor plays in the pathophysiologic features of vascular remodeling. Diabetic rats displayed increased levels of blood glucose, cholesterol, and triglycerides, as well as severe insulin resistance and FP receptor overexpression. In addition, increased medial thickness, excessive collagen deposition and diminished elastic fibers were observed in the diabetic rats, resulting in vascular remodeling. In the FP receptor-shRNA group, the medial thickness, collagen content, elastin/collagen ratio, and collagen I/collagen III content ratio were markedly decreased. Additionally, with FP receptor gene silencing, the JNK phosphorylation level was markedly decreased. Silencing of the FP receptor exerts a protective effect on diabetes-induced vascular remodeling, thereby suggesting a new therapeutic target for vascular remodeling in diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Pathophysiology of Myocardial Infarction and Acute Management Strategies.

PubMed

Tibaut, Miha; Mekis, Dusan; Petrovic, Daniel

2017-01-01

On an annual basis, 13.2% of all deaths are attributable to coronary artery disease (CAD), which makes CAD - with 7.4 million deaths - the leading cause of death in the world. In this review, we discuss current knowledge in the pathophysiology of atherosclerosis with its progression to stable CAD and its destabilization and complication with thrombus formation - myocardial infarction (MI). Next, we describe mechanisms of myocardial cell death in MI, the ischemia-reperfusion injury, leftventricular remodeling and complications of MI. Furthermore, we add acute management strategies concentrating on medical therapy, a decision on the reperfusion strategy, timing and cardiac protection by ischemic preconditioning, post-conditioning and remote ischemic conditioning. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Tissue Engineering Strategies for Myocardial Regeneration: Acellular Versus Cellular Scaffolds?

PubMed

Domenech, Maribella; Polo-Corrales, Lilliana; Ramirez-Vick, Jaime E; Freytes, Donald O

2016-12-01

Heart disease remains one of the leading causes of death in industrialized nations with myocardial infarction (MI) contributing to at least one fifth of the reported deaths. The hypoxic environment eventually leads to cellular death and scar tissue formation. The scar tissue that forms is not mechanically functional and often leads to myocardial remodeling and eventual heart failure. Tissue engineering and regenerative medicine principles provide an alternative approach to restoring myocardial function by designing constructs that will restore the mechanical function of the heart. In this review, we will describe the cellular events that take place after an MI and describe current treatments. We will also describe how biomaterials, alone or in combination with a cellular component, have been used to engineer suitable myocardium replacement constructs and how new advanced culture systems will be required to achieve clinical success.

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.

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.

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.

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.

Rationale and Design of a Clinical Trial to Evaluate the Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With Acute Myocardial Infarction and Left Ventricular Dysfunction: The Randomized Multicenter Double-Blind Controlled CAREMI Trial (Cardiac Stem Cells in Patients With Acute Myocardial Infarction).

PubMed

Sanz-Ruiz, Ricardo; Casado Plasencia, Ana; Borlado, Luis R; Fernández-Santos, María Eugenia; Al-Daccak, Reem; Claus, Piet; Palacios, Itziar; Sádaba, Rafael; Charron, Dominique; Bogaert, Jan; Mulet, Miguel; Yotti, Raquel; Gilaberte, Immaculada; Bernad, Antonio; Bermejo, Javier; Janssens, Stefan; Fernández-Avilés, Franciso

2017-06-23

Stem cell therapy has increased the therapeutic armamentarium in the fight against ischemic heart disease and heart failure. The administration of exogenous stem cells has been investigated in patients suffering an acute myocardial infarction, with the final aim of salvaging jeopardized myocardium and preventing left ventricular adverse remodeling and functional deterioration. However, phase I and II clinical trials with autologous and first-generation stem cells have yielded inconsistent benefits and mixed results. In the search for new and more efficient cellular regenerative products, interesting cardioprotective, immunoregulatory, and cardioregenerative properties have been demonstrated for human cardiac stem cells. On the other hand, allogeneic cells show several advantages over autologous sources: they can be produced in large quantities, easily administered off-the-shelf early after an acute myocardial infarction, comply with stringent criteria for product homogeneity, potency, and quality control, and may exhibit a distinctive immunologic behavior. With a promising preclinical background, CAREMI (Cardiac Stem Cells in Patients With Acute Myocardial Infarction) has been designed as a double-blind, 2:1 randomized, controlled, and multicenter clinical trial that will evaluate the safety, feasibility, and efficacy of intracoronary delivery of allogeneic human cardiac stem cell in 55 patients with large acute myocardial infarction, left ventricular dysfunction, and at high risk of developing heart failure. This phase I/II clinical trial represents a novel experience in humans with allogeneic cardiac stem cell in a rigorously imaging-based selected group of acute myocardial infarction patients, with detailed safety immunologic assessments and magnetic resonance imaging-based efficacy end points. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02439398. © 2017 American Heart Association, Inc.

Impact of aldosterone antagonists on the substrate for atrial fibrillation: Aldosterone promotes oxidative stress and atrial structural/electrical remodeling

PubMed Central

Mayyas, Fadia; Alzoubi, Karem H.; Van Wagoner, David R.

2014-01-01

Atrial fibrillation (AF), the most common cardiac arrhythmia, is an electrocardiographic description of a condition with multiple and complex underlying mechanisms. Oxidative stress is an important driver of structural remodeling that creates a substrate for AF. Oxidant radicals may promote increase of atrial oxidative damage, electrical and structural remodeling, and atrial inflammation. AF and other cardiovascular morbidities activate angiotensin (Ang-II)-dependent and independent cascades. A key component of the renin–angiotensin-aldosterone system (RAAS) is the mineralocorticoid aldosterone. Recent studies provide evidence of myocardial aldosterone synthesis. Aldosterone promotes cardiac oxidative stress, inflammation and structural/electrical remodeling via multiple mechanisms. In HF patients, aldosterone production is enhanced. In patients and in experimental HF and AF models, aldosterone receptor antagonists have favorable influences on cardiac remodeling and oxidative stress. Therapeutic approaches that seek to reduce AF burden by modulating the aldosterone system are likely beneficial but underutilized. PMID:23993726

Vascular remodeling and mineralocorticoids.

PubMed

Weber, K T; Sun, Y; Campbell, S E; Slight, S H; Ganjam, V K

1995-01-01

Circulating mineralocorticoid hormones are so named because of their important homeostatic properties that regulate salt and water balance via their action on epithelial cells. A broader range of functions in nonclassic target cellular sites has been proposed for these steroids and includes their contribution to wound healing following injury. A chronic, inappropriate (relative to intravascular volume and dietary sodium intake) elevation of these circulating hormones evokes a wound healing response in the absence of tissue injury--a wound healing response gone awry. The adverse remodeling of vascularized tissues seen in association with chronic mineralocorticoid excess is the focus of this review.

Cardio-protection of ultrafine granular powder for Salvia miltiorrhiza Bunge against myocardial infarction.

PubMed

Wang, Linlin; Li, Yuanmin; Deng, Wen; Dong, Zhihui; Li, Xue; Liu, Dan; Zhao, Lijie; Fu, Weiguo; Cho, Kenka; Niu, Huaying; Guo, Dean; Cheng, Jinle; Jiang, Baohong

2018-08-10

Myocardial infarction (MI) is considered as the major inducer to the morbidity and mortality related to coronary occlusion. Salvia miltiorrhiza Bunge is widely applied in the clinic for the prevention and treatment of heart diseases. The preparation of traditional herb decoction (THD) is not only time consuming but also difficult to keep uniform for every time. New usage form of Salvia miltiorrhiza Bunge with characteristics of convenience, uniform and efficiency is needed. The aims of present study were to investigate the cardio-protection of ultrafine granular powder (UGP) of Salvia miltiorrhiza Bunge; and further compare the characteristics of UGP with THD. MI was induced by ligation of the left anterior descending coronary artery near the main pulmonary artery. Cardio-protection of UGP or THD was evaluated based on two sets of experiments, one was acute myocardial infarction (AMI) through 7 days preventive administration, and the other one was chronic cardiac remodeling through 28 days therapeutic administration. Hemodynamic measurement was conducted to evaluate heart function and histopathological detection was used to evaluate heart structure. No significant improvement of heart structure and function was detected for preventive administration of UGP or THD on AMI rats. While, more significant improvements on left ventricular systolic and diastolic function were detected with therapeutic treatment with 0.81 g/kg UGP than same dose of THD on rats against chronic cardiac remodeling. Both UGP and THD showed the protective effects on heart structure, especially against fibrosis with long-term therapeutic treatment. As a new usage form of Salvia miltiorrhiza Bunge, UGP showed significant cardio-protection against myocardial remodeling with therapeutic treatment. Comparing with THD, UGP also holds the advantages of uniform, convenience and efficiency. Copyright © 2018 Elsevier B.V. All rights reserved.

Profound bioenergetic abnormalities in peri-infarct myocardial regions.

PubMed

Hu, Qingsong; Wang, Xiaohong; Lee, Joseph; Mansoor, Abdul; Liu, Jingbo; Zeng, Lepeng; Swingen, Cory; Zhang, Ge; Feygin, Julia; Ochiai, Koichi; Bransford, Toni L; From, Arthur H L; Bache, Robert J; Zhang, Jianyi

2006-08-01

Regions of myocardial infarct (MI) are surrounded by a border zone (BZ) of normally perfused but dysfunctional myocardium. Although systolic dysfunction has been attributed to elevated wall stress in this region, there is evidence that intrinsic abnormalities of contractile performance exist in BZ myocardium. This study examined whether decreases of high-energy phosphates (HEP) and mitochondrial F(1)F(0)-ATPase (mtATPase) subunits typical of failing myocardium exist in BZ myocardium of compensated postinfarct remodeled hearts. Eight pigs were studied 6 wk after MI was produced by ligation of the left anterior descending coronary artery (LAD) distal to the second diagonal. Animals developed compensated LV remodeling with a decrease of ejection fraction from 54.6 +/- 5.4% to 31 +/- 2.1% (MRI) 5 wk after LAD occlusion. The remote zone (RZ) myocardium demonstrated modest decreases of ATP and mtATPase components. In contrast, BZ myocardium demonstrated profound abnormalities with ATP levels decreased to 42% of normal, and phosphocreatine-to-ATP ratio ((31)P-magnetic resonance spectroscopy) decreased from 2.06 +/- 0.19 in normal hearts to 1.07 +/- 0.10, with decreases in alpha-, beta-, OSCP, and IF(1) subunits of mtATPase, especially in the subendocardium. The reduction of myocardial creatine kinase isoform protein expression was also more severe in the BZ relative to the RZ myocardium. These abnormalities were independent of a change in mitochondrial content because the mitochondrial citrate synthase protein level was not different between the BZ and RZ. This regional heterogeneity of ATP content and expression of key enzymes in ATP production suggests that energetic insufficiency in the peri-infarct region may contribute to the transition from compensated LV remodeling to congestive heart failure.

OPC-28326, a selective peripheral vasodilator with angiogenic activity, mitigates postinfarction cardiac remodeling.

PubMed

Ogino, Atsushi; Takemura, Genzou; Hashimoto, Ayako; Kanamori, Hiromitsu; Okada, Hideshi; Nakagawa, Munehiro; Tsujimoto, Akiko; Goto, Kazuko; Kawasaki, Masanori; Nagashima, Kenshi; Miyakoda, Goro; Fujiwara, Takako; Yabuuchi, Youichi; Fujiwara, Hisayoshi; Minatoguchi, Shinya

2015-07-01

Although OPC-28326, 4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl) piperidine hydrochloride monohydrate, was developed as a selective peripheral vasodilator with α2-adrenergic antagonist properties, it also reportedly exhibits angiogenic activity in an ischemic leg model. The purpose of this study was to examine the effect of OPC-28326 on the architectural dynamics and function of the infarcted left ventricle during the chronic stage of myocardial infarction. Myocardial infarction was induced in male C3H/He mice, after which the mice were randomly assigned into two groups: a control group receiving a normal diet and an OPC group whose diet contained 0.05% OPC-28326. The survival rate among the mice (n = 18 in each group) 4 wk postinfarction was significantly greater in the OPC than control group (83 vs. 44%; P < 0.05), and left ventricular remodeling and dysfunction were significantly mitigated. Histologically, infarct wall thickness was significantly greater in the OPC group, due in part to an abundance of nonmyocyte components, including blood vessels and myofibroblasts. Five days postinfarction, Ki-67-positive proliferating cells were more abundant in the granulation tissue in the OPC group, and there were fewer apoptotic cells. These effects were accompanied by activation of myocardial Akt and endothelial nitric oxide synthase. Hypoxia within the infarct issue, assessed using pimonidazole staining, was markedly attenuated in the OPC group. In summary, OPC-28326 increased the nonmyocyte population in infarct tissue by increasing proliferation and reducing apoptosis, thereby altering the tissue dynamics such that wall stress was reduced, which might have contributed to a mitigation of postinfarction cardiac remodeling and dysfunction. Copyright © 2015 the American Physiological Society.

Remodeling of ribosomal genes in somatic cells by Xenopus egg extract

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ostrup, Olga, E-mail: osvarcova@gmail.com; Stem Cell Epigenetics Laboratory, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo; Norwegian Center for Stem Cell Research, Oslo

Highlights: {yields} Xenopus egg extract remodels nuclei and alter cell growth characteristics. {yields} Ribosomal genes are reprogrammed within 6 h after extract exposure. {yields} rDNA reprogramming involves promoter targeting of SNF2H remodeling complex. {yields} Xenopus egg extract does not initiate stress-related response in somatic cells. {yields} Aza-cytidine elicits a stress-induced response in reprogrammed cells. -- Abstract: Extracts from Xenopus eggs can reprogram gene expression in somatic nuclei, however little is known about the earliest processes associated with the switch in the transcriptional program. We show here that an early reprogramming event is the remodeling of ribosomal chromatin and gene expression.more » This occurs within hours of extract treatment and is distinct from a stress response. Egg extract elicits remodeling of the nuclear envelope, chromatin and nucleolus. Nucleolar remodeling involves a rapid and stable decrease in ribosomal gene transcription, and promoter targeting of the nucleolar remodeling complex component SNF2H without affecting occupancy of the transcription factor UBF and the stress silencers SUV39H1 and SIRT1. During this process, nucleolar localization of UBF and SIRT1 is not altered. On contrary, azacytidine pre-treatment has an adverse effect on rDNA remodeling induced by extract and elicits a stress-type nuclear response. Thus, an early event of Xenopus egg extract-mediated nuclear reprogramming is the remodeling of ribosomal genes involving nucleolar remodeling complex. Condition-specific and rapid silencing of ribosomal genes may serve as a sensitive marker for evaluation of various reprogramming methods.« less

Targeting Inflammation in Heart Failure with Histone Deacetylase Inhibitors

PubMed Central

McKinsey, Timothy A

2011-01-01

Cardiovascular insults such as myocardial infarction and chronic hypertension can trigger the heart to undergo a remodeling process characterized by myocyte hypertrophy, myocyte death and fibrosis, often resulting in impaired cardiac function and heart failure. Pathological cardiac remodeling is associated with inflammation, and therapeutic approaches targeting inflammatory cascades have shown promise in patients with heart failure. Small molecule histone deacetylase (HDAC) inhibitors block adverse cardiac remodeling in animal models, suggesting unforeseen potential for this class of compounds for the treatment of heart failure. In addition to their beneficial effects on myocardial cells, HDAC inhibitors have potent antiinflammatory actions. This review highlights the roles of HDACs in the heart and the potential for using HDAC inhibitors as broad-based immunomodulators for the treatment of human heart failure. PMID:21267510

The long noncoding RNA Wisper controls cardiac fibrosis and remodeling

PubMed Central

Micheletti, Rudi; Plaisance, Isabelle; Abraham, Brian J.; Sarre, Alexandre; Ting, Ching-Chia; Alexanian, Michael; Maric, Daniel; Maison, Damien; Nemir, Mohamed; Young, Richard A.; Schroen, Blanche; González, Arantxa; Ounzain, Samir; Pedrazzini, Thierry

2017-01-01

Long noncoding RNAs (lncRNAs) are emerging as powerful regulators of cardiac development and disease. However, our understanding of the importance of these molecules in cardiac fibrosis is limited. Using an integrated genomic screen, we identified Wisper (Wisp2 super-enhancer–associated RNA) as a cardiac fibroblast–enriched lncRNA that regulates cardiac fibrosis after injury. Wisper expression was correlated with cardiac fibrosis both in a murine model of myocardial infarction (MI) and in heart tissue from human patients suffering from aortic stenosis. Loss-of-function approaches in vitro using modified antisense oligonucleotides (ASOs) demonstrated that Wisper is a specific regulator of cardiac fibroblast proliferation, migration, and survival. Accordingly, ASO-mediated silencing of Wisper in vivo attenuated MI-induced fibrosis and cardiac dysfunction. Functionally, Wisper regulates cardiac fibroblast gene expression programs critical for cell identity, extracellular matrix deposition, proliferation, and survival. In addition, its association with TIA1-related protein allows it to control the expression of a profibrotic form of lysyl hydroxylase 2, implicated in collagen cross-linking and stabilization of the matrix. Together, our findings identify Wisper as a cardiac fibroblast–enriched super-enhancer–associated lncRNA that represents an attractive therapeutic target to reduce the pathological development of cardiac fibrosis in response to MI and prevent adverse remodeling in the damaged heart. PMID:28637928

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.

Physiological Implications of Myocardial Scar Structure

PubMed Central

Richardson, WJ; Clarke, SA; Quinn, TA; Holmes, JW

2016-01-01

Once myocardium dies during a heart attack, it is replaced by scar tissue over the course of several weeks. The size, location, composition, structure and mechanical properties of the healing scar are all critical determinants of the fate of patients who survive the initial infarction. While the central importance of scar structure in determining pump function and remodeling has long been recognized, it has proven remarkably difficult to design therapies that improve heart function or limit remodeling by modifying scar structure. Many exciting new therapies are under development, but predicting their long-term effects requires a detailed understanding of how infarct scar forms, how its properties impact left ventricular function and remodeling, and how changes in scar structure and properties feed back to affect not only heart mechanics but also electrical conduction, reflex hemodynamic compensations, and the ongoing process of scar formation itself. In this article, we outline the scar formation process following an MI, discuss interpretation of standard measures of heart function in the setting of a healing infarct, then present implications of infarct scar geometry and structure for both mechanical and electrical function of the heart and summarize experiences to date with therapeutic interventions that aim to modify scar geometry and structure. One important conclusion that emerges from the studies reviewed here is that computational modeling is an essential tool for integrating the wealth of information required to understand this complex system and predict the impact of novel therapies on scar healing, heart function, and remodeling following myocardial infarction. PMID:26426470

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

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.

Impact of left ventricular hypertrophy on myocardial injury in patients with ST-segment elevation myocardial infarction.

PubMed

Stiermaier, Thomas; Pöss, Janine; Eitel, Charlotte; de Waha, Suzanne; Fuernau, Georg; Desch, Steffen; Thiele, Holger; Eitel, Ingo

2018-05-16

Left ventricular hypertrophy (LVH) has been suggested as a determinant of outcome in patients with ST-segment elevation myocardial infarction (STEMI). However, available data are inconclusive and the underlying mechanisms remain unclear. Therefore, the aim of this study was to evaluate the impact of LVH on myocardial injury and clinical outcome in a large multicenter STEMI population. Cardiovascular magnetic resonance was performed in 795 patients within 10 days after STEMI to assess left ventricular (LV) mass and parameters of myocardial injury. Gender-specific cutoff values of indexed LV mass were used to define LVH (67 g/m 2 for men and 61 g/m 2 for women). Rates of major adverse cardiac events (MACE) were determined at 12-month follow-up. LVH was present in 438 patients (55%) and associated with a significantly larger infarct size [18.3% of LV mass (%LV) versus 14.0%LV; p < 0.01], a lower myocardial salvage index (47.8 versus 54.4; p < 0.01), larger extent of microvascular obstruction (0.4 versus 0%LV; p < 0.01) and lower LV ejection fraction (47.9 versus 53.2%; p < 0.01) compared to STEMI patients without LVH. The effect of LVH on LV ejection fraction, infarct size and myocardial salvage index remained statistically significant after adjustment for baseline characteristics (p < 0.01 for all). MACE rates at 12 months were numerically higher in patients with versus without LVH without reaching statistical significance (7.5 versus 5.6%; p = 0.32). In STEMI patients, LVH is associated with more pronounced structural and functional alterations in CMR imaging as an indicator for adverse clinical outcomes in STEMI survivors.

Association Between Hyperuricemia and Major Adverse Cardiac Events in Patients with Acute Myocardial Infarction.

PubMed

Ranjith, Naresh; Myeni, Nomcebo N; Sartorius, Ben; Mayise, Chamsanqua

2017-02-01

To investigate the association between hyperuricemia and major adverse cardiac events (MACE) in patients with acute myocardial infarction (AMI). Consecutive patients admitted with AMI to the Coronary Care Unit at R. K. Khan Hospital (Durban, South Africa) between the years 2006 and 2014 were included. Demographic data, including clinical and biochemical information stored in an electronic database, were obtained from all patients. A total of 2683 patients were studied, of whom 65% were males. The mean age of the participants was 57.1 ± 11.5 years, with 79% presenting with ST elevation myocardial infarction. Sixty-one percent were smokers, 59% had diabetes mellitus, 52% had hypertension, and 58% presented with a family history of premature coronary artery disease. Twenty-six percent (n = 690) had hyperuricemia, were older (59 ± 12.1 vs. 56.5 ± 11.2 years) and more likely to present with hypertension (P < 0.001), lower ejection fraction (P < 0.001), and higher median creatinine levels (P < 0.001). A significantly greater proportion of patients with hyperuricemia experienced MACE (45% vs. 30%, P < 0.001). In both sexes, considerable heterogeneity for risk factors and clinical events was noted in individuals with hyperuricemia. Multivariable analyses for risk factors associated with mortality suggest that hyperuricemia conferred a significantly increased risk of mortality after adjustment [odds ratio (OR) 1.7 (95% confidence interval 1.0-2.8); P = 0.042]. A significant increasing risk trend for MACE was observed for increasing tertiles of serum uric acid concentrations above normal (P < 0.001), particularly for cardiac failure (P < 0.001) and death (P = 0.006). Hyperuricemia is significantly associated with hypertension, renal dysfunction, MACE, and independently confers a higher risk of mortality in patients with AMI. Significant heterogeneity was found by gender for risk factors and clinical events in individuals

Chronic miR-29 antagonism promotes favorable plaque remodeling in atherosclerotic mice.

PubMed

Ulrich, Victoria; Rotllan, Noemi; Araldi, Elisa; Luciano, Amelia; Skroblin, Philipp; Abonnenc, Mélanie; Perrotta, Paola; Yin, Xiaoke; Bauer, Ashley; Leslie, Kristen L; Zhang, Pei; Aryal, Binod; Montgomery, Rusty L; Thum, Thomas; Martin, Kathleen; Suarez, Yajaira; Mayr, Manuel; Fernandez-Hernando, Carlos; Sessa, William C

2016-06-01

Abnormal remodeling of atherosclerotic plaques can lead to rupture, acute myocardial infarction, and death. Enhancement of plaque extracellular matrix (ECM) may improve plaque morphology and stabilize lesions. Here, we demonstrate that chronic administration of LNA-miR-29 into an atherosclerotic mouse model improves indices of plaque morphology. This occurs due to upregulation of miR-29 target genes of the ECM (col1A and col3A) resulting in reduced lesion size, enhanced fibrous cap thickness, and reduced necrotic zones. Sustained LNA-miR-29 treatment did not affect circulating lipids, blood chemistry, or ECM of solid organs including liver, lung, kidney, spleen, or heart. Collectively, these data support the idea that antagonizing miR-29 may promote beneficial plaque remodeling as an independent approach to stabilize vulnerable atherosclerotic lesions. © 2016 The Authors. Published under the terms of the CC BY 4.0 license.

Mononuclear Phagocytes Are Dispensable for Cardiac Remodeling in Established Pressure-Overload Heart Failure

PubMed Central

Patel, Bindiya; Ismahil, Mohamed Ameen; Hamid, Tariq; Bansal, Shyam S.; Prabhu, Sumanth D.

2017-01-01

Background Although cardiac and splenic mononuclear phagocytes (MPs), i.e., monocytes, macrophages and dendritic cells (DCs), are key contributors to cardiac remodeling after myocardial infarction, their role in pressure-overload remodeling is unclear. We tested the hypothesis that these immune cells are required for the progression of remodeling in pressure-overload heart failure (HF), and that MP depletion would ameliorate remodeling. Methods and Results C57BL/6 mice were subjected to transverse aortic constriction (TAC) or sham operation, and assessed for alterations in MPs. As compared with sham, TAC mice exhibited expansion of circulating LyC6hi monocytes and pro-inflammatory CD206− cardiac macrophages early (1 w) after pressure-overload, prior to significant hypertrophy and systolic dysfunction, with subsequent resolution during chronic HF. In contrast, classical DCs were expanded in the heart in a biphasic manner, with peaks both early, analogous to macrophages, and late (8 w), during established HF. There was no significant expansion of circulating DCs, or Ly6C+ monocytes and DCs in the spleen. Periodic systemic MP depletion from 2 to 16 w after TAC in macrophage Fas-induced apoptosis (MaFIA) transgenic mice did not alter cardiac remodeling progression, nor did splenectomy in mice with established HF after TAC. Lastly, adoptive transfer of splenocytes from TAC HF mice into naïve recipients did not induce immediate or long-term cardiac dysfunction in recipient mice. Conclusions Mononuclear phagocytes populations expand in a phasic manner in the heart during pressure-overload. However, they are dispensable for the progression of remodeling and failure once significant hypertrophy is evident and blood monocytosis has normalized. PMID:28125666

Parametric techniques for characterizing myocardial tissue by magnetic resonance imaging (part 1): T1 mapping.

PubMed

Perea Palazón, R J; Ortiz Pérez, J T; Prat González, S; de Caralt Robira, T M; Cibeira López, M T; Solé Arqués, M

2016-01-01

The development of myocardial fibrosis is a common process in the appearance of ventricular dysfunction in many heart diseases. Magnetic resonance imaging makes it possible to accurately evaluate the structure and function of the heart, and its role in the macroscopic characterization of myocardial fibrosis by late enhancement techniques has been widely validated clinically. Recent studies have demonstrated that T1-mapping techniques can quantify diffuse myocardial fibrosis and the expansion of the myocardial extracellular space in absolute terms. However, further studies are necessary to validate the usefulness of this technique in the early detection of tissue remodeling at a time when implementing early treatment would improve a patient's prognosis. This article reviews the state of the art for T1 mapping of the myocardium, its clinical applications, and its limitations. Copyright © 2016 SERAM. Published by Elsevier España, S.L.U. All rights reserved.

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.

Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial.

PubMed

Cerisano, Giampaolo; Buonamici, Piergiovanni; Gori, Anna Maria; Valenti, Renato; Sciagrà, Roberto; Giusti, Betti; Sereni, Alice; Raspanti, Silvia; Colonna, Paolo; Gensini, Gian Franco; Abbate, Rosanna; Schulz, Richard; Antoniucci, David

2015-10-15

The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity. Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart. In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

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.

Myocardial Dysfunction and Shock after Cardiac Arrest

PubMed Central

Jentzer, Jacob C.; Chonde, Meshe D.; Dezfulian, Cameron

2015-01-01

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies. PMID:26421284

Myocardial Dysfunction and Shock after Cardiac Arrest.

PubMed

Jentzer, Jacob C; Chonde, Meshe D; Dezfulian, Cameron

2015-01-01

Postarrest myocardial dysfunction includes the development of low cardiac output or ventricular systolic or diastolic dysfunction after cardiac arrest. Impaired left ventricular systolic function is reported in nearly two-thirds of patients resuscitated after cardiac arrest. Hypotension and shock requiring vasopressor support are similarly common after cardiac arrest. Whereas shock requiring vasopressor support is consistently associated with an adverse outcome after cardiac arrest, the association between myocardial dysfunction and outcomes is less clear. Myocardial dysfunction and shock after cardiac arrest develop as the result of preexisting cardiac pathology with multiple superimposed insults from resuscitation. The pathophysiology involves cardiovascular ischemia/reperfusion injury and cardiovascular toxicity from excessive levels of inflammatory cytokine activation and catecholamines, among other contributing factors. Similar mechanisms occur in myocardial dysfunction after cardiopulmonary bypass, in sepsis, and in stress-induced cardiomyopathy. Hemodynamic stabilization after resuscitation from cardiac arrest involves restoration of preload, vasopressors to support arterial pressure, and inotropic support if needed to reverse the effects of myocardial dysfunction and improve systemic perfusion. Further research is needed to define the role of postarrest myocardial dysfunction on cardiac arrest outcomes and identify therapeutic strategies.

The potential role of myocardial serotonin receptor 2B expression in canine dilated cardiomyopathy.

PubMed

Fonfara, Sonja; Hetzel, Udo; Oyama, Mark A; Kipar, Anja

2014-03-01

Serotonin signalling in the heart is mediated by receptor subtype 2B (5-HTR2B). A contribution of serotonin to valvular disease has been reported, but myocardial expression of 5-HTR2B and its role in canine dilated cardiomyopathy (DCM) is not known. The aim of the present study was to investigate myocardial 5-HTR2B mRNA expression in dogs with DCM and to correlate results with expression of markers for inflammation and remodelling. Myocardial samples from eight healthy dogs, four dogs with DCM, five with cardiac diseases other than DCM and six with systemic non-cardiac diseases were investigated for 5-HTR2B mRNA expression using quantitative PCR (qPCR). The results were compared to mRNA expression of selected cytokines, matrix metalloproteinases (MMP) and tissue inhibitors of matrix metalloproteinase (TIMP). Laser microdissection with subsequent qPCR and immunohistochemistry were employed to identify the cells expressing 5-HTR2B. The myocardium of control dogs showed constitutive 5-HTR2B mRNA expression. In dogs with DCM, 5-HTR2B mRNA values were significantly greater than in all other groups, with highest levels of expression in the left ventricle and right atrium. Myocytes were identified as the source of 5-HTR2B mRNA and protein. A significant positive correlation of 5-HTR2B mRNA with expression of several cytokines, MMPs and TIMPs was observed. The findings suggest that serotonin might play a role in normal cardiac structure and function and could contribute to myocardial remodelling and functional impairment in dogs with DCM. Copyright © 2013 Elsevier Ltd. All rights reserved.

Interactive associations of depression and sleep apnea with adverse clinical outcomes after acute myocardial infarction

PubMed Central

Hayano, Junichiro; Carney, Robert M.; Watanabe, Eiichi; Kawai, Kiyohiro; Kodama, Itsuo; Stein, Phyllis K.; Watkins, Lana L.; Freedland, Kenneth E.; Blumenthal, James A.

2012-01-01

Objective Depression and sleep apnea (SA) are common among patients after acute myocardial infarction (AMI), and both are associated with increased risk for adverse outcomes. We tested the hypothesis that there is an interaction between depression and SA in relation to prognosis in post-AMI patients. Methods Participants were 337 depressed and 379 nondepressed post-AMI patients who participated in a substudy of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) clinical trial. SA was identified from Holter ECG at the entry by an algorithm that detects cyclic variation of heart rate. Results During a median follow-up of 25 months, 43 (6.0%) of patients died and 83 (11.6%) either died or experienced a recurrent AMI. Among 94 patients with both depression and SA, these endpoints occurred in 20 (21.3%) and 25 (26.6%), the prevalence that was 6.9 and 3.9 times higher than predicted probabilities by ENRICHD clinical risk scores (P <.001 for both). In the patients with depression alone, SA alone, or neither, the frequencies did not differ significantly from the predicted probability. Although both depression and SA predicted death and the combined endpoint, we observed depression by SA interactions (P = .03 and .02). SA independently predicted these endpoints in depressed (P <.001 and P = .001), but not in nondepressed patients (P = .73 and .84). Similarly, depression independently predicted these endpoints in SA (P <.001 for both), but not in non-SA patients (P = .61 and .12). Conclusion The combination of depression and SA estimated by CVHR is associated with long-term adverse clinical outcomes after AMI. PMID:23023681

Changes in beta-actin mRNA expression in remodeling canine myocardium.

PubMed

Carlyle, W C; Toher, C A; Vandervelde, J R; McDonald, K M; Homans, D C; Cohn, J N

1996-01-01

Beta-actin, a cytoskeletal protein important in the maintenance of cytoarchitecture, has long been thought to be expressed constitutively in myocardial tissue. As such, beta-actin mRNA has been used as a control gene in a wide range of experiments. However, we have uncovered consistent changes in beta-actin mRNA expression in canine myocardium remodeling as a result of insult to the left ventricle. The experimental canine models used were either DC shock damage to the left ventricle or volume overload resulting from severe mitral regurgitation. The remodeling process in both canine models is characterized by an increase in left ventricular mass. PCR amplification using primers designed to selectively amplify the 3' end and a portion of the 3' untranslated region of beta-actin mRNA resulted in the generation of a 297 base pair product predominant only in normal canine myocardium and a 472 base pair product that became increasingly prominent from 1 to 30 days after DC shock damage to the left ventricle and from 10 to 90 days after creation of mitral regurgitation. Northern analysis showed a three-fold increase in beta-actin mRNA after either DC shock or creation of mitral regurgitation. Western analysis revealed an early increase in beta-actin protein followed by an apparent decrease to below baseline levels. These observations suggest that changes in beta-actin mRNA expression accompany the structural alterations that occur in response to myocardial damage. Whether or not the changes in beta-actin mRNA expression play a role in mediating these structural alterations remains to be determined.

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 right ventricular structural and extracellular matrix remodeling by estrogen in severe pulmonary hypertension

PubMed Central

Nadadur, Rangarajan D.; Umar, Soban; Wong, Gabriel; Eghbali, Mansour; Iorga, Andrea; Matori, Humann; Partow-Navid, Rod

2012-01-01

Chronic pulmonary hypertension (PH) leads to right-ventricular failure (RVF) characterized by RV remodeling. Ventricular remodeling is emerging as an important process during heart failure and recovery. Remodeling in RVF induced by PH is not fully understood. Recently we discovered that estrogen (E2) therapy can rescue severe preexisting PH. Here, we focused on whether E2 (42.5 μg·kg−1·day−1, 10 days) can reverse adverse RV structural and extracellular matrix (ECM) remodeling induced by PH using monocrotaline (MCT, 60 mg/kg). RV fibrosis was evident in RVF males. Intact females developed less severe RV remodeling compared with males and ovariectomized (OVX) females. Novel ECM-degrading disintegrin-metalloproteinases ADAM15 and ADAM17 transcripts were elevated ∼2-fold in all RVF animals. E2 therapy reversed RV remodeling in all groups. In vitro, E2 directly inhibited ANG II-induced expression of fibrosis markers as well as the metalloproteinases in cultured cardiac fibroblasts. Estrogen receptor-β agonist diarylpropionitrile (DPN) but not estrogen receptor-α agonist 4,4′,4″-(4-propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT) was as effective as E2 in inhibiting expression of these genes. Expression of ECM-interacting cardiac fetal-gene osteopontin (OPN) also increased ∼9-fold in RVF males. Intact females were partially protected from OPN upregulation (∼2-fold) but OVX females were not. E2 reversed OPN upregulation in all groups. Upregulation of OPN was also reversed in vitro by E2. Plasma OPN was elevated in RVF (∼1.5-fold) and decreased to control levels in the E2 group. RVF resulted in elevated Akt phosphorylation, but not ERK, in the RV, and E2 therapy restored Akt phosphorylation. In conclusion, E2 therapy reverses adverse RV remodeling associated with PH by reversing fibrosis and upregulation of novel ECM enzymes ADAM15, ADAM17, and OPN. These effects are likely mediated through estrogen receptor-β. PMID:22628376

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.

Phenotypic plasticity and remodeling in the stress-induced Caenorhabditis elegans dauer.

PubMed

Androwski, Rebecca J; Flatt, Kristen M; Schroeder, Nathan E

2017-09-01

Organisms are often capable of modifying their development to better suit their environment. Under adverse conditions, the nematode Caenorhabditis elegans develops into a stress-resistant alternative larval stage called dauer. The dauer stage is the primary survival stage for C. elegans in nature. Large-scale tissue remodeling during dauer conveys resistance to harsh environments. The environmental and genetic regulation of the decision to enter dauer has been extensively studied. However, less is known about the mechanisms regulating tissue remodeling. Changes to the cuticle and suppression of feeding in dauers lead to an increased resistance to external stressors. Meanwhile reproductive development arrests during dauer while preserving the ability to reproduce once favorable environmental conditions return. Dramatic remodeling of neurons, glia, and muscles during dauer likely facilitate dauer-specific behaviors. Dauer-specific pulsation of the excretory duct likely mediates a response to osmotic stress. The power of C. elegans genetics has uncovered some of the molecular pathways regulating dauer tissue remodeling. In addition to genes that regulate single remodeling events, several mutants result in pleiotropic defects in dauer remodeling. This review details the individual aspects of morphological changes that occur during dauer formation and discusses molecular mechanisms regulating these processes. The dauer stage provides us with an excellent model for understanding phenotypic plasticity and remodeling from the individual cell to an entire animal. WIREs Dev Biol 2017, 6:e278. doi: 10.1002/wdev.278 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

Late Administration of a Palladium Lipoic Acid Complex (POLY-MVA) Modifies Cardiac Mitochondria but Not Functional or Structural Manifestations of Radiation-Induced Heart Disease in a Rat Model

PubMed Central

Sridharan, Vijayalakshmi; Seawright, John W.; Antonawich, Francis J.; Garnett, Merrill; Cao, Maohua; Singh, Preeti; Boerma, Marjan

2017-01-01

Exposure of the heart to ionizing radiation can cause adverse myocardial remodeling. In small animal models, local heart irradiation causes persistent alterations in cardiac mitochondrial function and swelling. POLY-MVA is a dietary supplement that contains a palladium lipoic acid complex that targets mitochondrial complex I and has been demonstrated to have greater redox potential than lipoic acid alone. POLY-MVA improves mitochondrial function and anti-oxidant enzyme activity in the aged rat heart. In this study, we tested whether POLY-MVA can mitigate cardiac effects of ionizing radiation. Adult male rats were exposed to local heart X rays with a daily dose of 9 Gy for 5 consecutive days. Eighteen weeks after irradiation, POLY-MVA was administered orally at 1 ml/kg bodyweight per day during weekdays, for 6 weeks. Alterations in cardiac function as measured with echocardiography coincided with enhanced mitochondrial swelling, a reduction in mitochondrial expression of complex II, manifestations of adverse remodeling such as a reduction in myocardial microvessel density and an increase in collagen deposition and mast cell numbers. POLY-MVA enhanced left ventricular expression of superoxide dismutase 2, but only in sham-irradiated animals. In irradiated animals, POLY-MVA caused a reduction in markers of inflammatory infiltration, CD2 and CD68. Moreover, POLY-MVA mitigated the effects of radiation on mitochondria. Nonetheless, POLY-MVA did not mitigate adverse cardiac remodeling, suggesting that this tissue remodeling may not be alleviated by altering cardiac mitochondria alone. However, we cannot exclude the possibility that an earlier onset of POLY-MVA administration may have more profound effects on radiation-induced cardiac remodeling. PMID:28231026

Incidence, mechanisms, predictors, and clinical impact of acute and late stent malapposition after primary intervention in patients with acute myocardial infarction: an intravascular ultrasound substudy of the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial.

PubMed

Guo, Ning; Maehara, Akiko; Mintz, Gary S; He, Yong; Xu, Kai; Wu, Xiaofan; Lansky, Alexandra J; Witzenbichler, Bernhard; Guagliumi, Giulio; Brodie, Bruce; Kellett, Mirle A; Dressler, Ovidiu; Parise, Helen; Mehran, Roxana; Stone, Gregg W

2010-09-14

The incidence and mechanisms of acute and late stent malapposition after primary stent implantation in ST-segment elevation myocardial infarction remain unclear. The Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial was a dual-arm, factorial, randomized trial comparing paclitaxel-eluting stents (PES) and otherwise equivalent bare metal stents (BMS) in ST-segment elevation myocardial infarction patients. The intravascular ultrasound substudy enrolled 241 patients with 263 native coronary lesions (201 PES, 62 BMS) with baseline and 13-month follow-up imaging. Postintervention acute stent malapposition (ASM) occurred in 34.3% PES- and 40.3% BMS-treated lesions. Of these, 39.1% PES- and 40.0% BMS-treated lesions resolved at follow-up, especially within the stent body (66.7%); complete resolution was accompanied by a reduction in external elastic membrane area. An ASM area >1.2 mm(2) best separated persistent from resolved ASM. At follow-up, a higher frequency of late stent malapposition was detected in PES-treated lesions (46.8%) mainly because of more late acquired stent malapposition (30.8%) compared with BMS-treated lesions. Late acquired stent malapposition area correlated to the decrease of peri-stent plaque in the subset of lesions without positive remodeling and only to change in external elastic membrane in the group with positive remodeling. Independent predictors of late acquired stent malapposition were plaque/thrombus protrusion (odds ratio, 5.60; 95% confidence interval [CI], 2.32 to 13.54) and PES use (odds ratio, 6.32; 95% CI, 2.15 to 18.62). The incidence of ASM was similar in PES- and BMS-treated lesions, but late acquired stent malapposition was more common in PES-treated lesions. The reason for resolved ASM was negative remodeling, with larger ASM areas separating persistent from resolved ASM. Late acquired stent malapposition was due mainly to positive remodeling and plaque/thrombus resolution

Fibroblasts in myocardial infarction: a role in inflammation and repair

PubMed Central

Shinde, Arti V.; Frangogiannis, Nikolaos G.

2014-01-01

Fibroblasts do not only serve as matrix-producing reparative cells, but exhibit a wide range of functions in inflammatory and immune responses, angiogenesis and neoplasia. The adult mammalian myocardium contains abundant fibroblasts enmeshed within the interstitial and perivascular extracellular matrix. The current review manuscript discusses the dynamic phenotypic and functional alterations of cardiac fibroblasts following myocardial infarction. Extensive necrosis of cardiomyocytes in the infarcted heart triggers an intense inflammatory reaction. In the early stages of infarct healing, fibroblasts become pro-inflammatory cells, activating the inflammasome and producing cytokines, chemokines and proteases. Pro-inflammatory cytokines (such as Interleukin-1) delay myofibroblast transformation, until the wound is cleared from dead cells and matrix debris. Resolution of the inflammatory infiltrate is associated with fibroblast migration, proliferation, matrix protein synthesis and myofibroblast conversion. Growth factors and matricellular proteins play an important role in myofibroblast activation during the proliferative phase of healing. Formation of a mature cross-linked scar is associated with clearance of fibroblasts, as poorly-understood inhibitory signals restrain the fibrotic response. However, in the non-infarcted remodeling myocardium, local fibroblasts may remain activated in response to volume and pressure overload and may promote interstitial fibrosis. Considering their abundance, their crucial role in cardiac inflammation and repair, and their involvement in myocardial dysfunction and arrhythmogenesis, cardiac fibroblasts may be key therapeutic targets in cardiac remodeling. PMID:24321195

Early Anti-inflammatory and Pro-angiogenic Myocardial Effects of Intravenous Serelaxin Infusion for 72 H in an Experimental Rat Model of Acute Myocardial Infarction.

PubMed

Sanchez-Mas, Jesus; Lax, Antonio; Asensio-Lopez, Mari C; Lencina, Miriam; Fernandez-Del Palacio, Maria J; Soriano-Filiu, Angela; de Boer, Rudolf A; Pascual-Figal, Domingo A

2017-12-01

Sprague Dawley rats were subjected to acute myocardial infarction (AMI) by permanent ligation of the left anterior descending coronary artery. At the time of AMI, a subcutaneous mini-osmotic pump was implanted and animals were randomized into three groups, according to the intravenous therapy received during the first 72 h: placebo-treated (saline), serelaxin10-treated (SRLX10 = 10 μg/kg/day), or serelaxin30-treated (SRLX30 = 30 μg/kg/day). Treatment with SRLX30 reduced the expression of inflammatory cytokines and chemokines, as well as the infiltration of macrophages, and increased the expression of pro-angiogenic markers and vessel density in the infarcted myocardium after 7 days. SRLX30 did not reduce early myocardial fibrosis but reduced myocardial levels of sST2 and galectin-3. No significant effects were observed with SRLX10 treatment. A significant correlation was observed between plasma levels of serelaxin and effect measures. The results suggest serelaxin has a protective effect in early processes of cardiac remodeling after AMI.

[Performance of Thallium 201 rest-redistribution spect to predict viability in recent myocardial infarction].

PubMed

Coll, Claudia; González, Patricio; Massardo, Teresa; Sierralta, Paulina; Humeres, Pamela; Jofré, Josefina; Yovanovich, Jorge; Aramburú, Ivonne; Brugère, Solange; Chamorro, Hernán; Ramírez, Alfredo; Kunstmann, Sonia; López, Héctor

2002-03-01

The detection of viability after acute myocardial infarction is primordial to select the most appropriate therapy, to decrease cardiac events and abnormal remodeling. Thallium201 SPECT is one of the radionuclide techniques used to detect viability. To evaluate the use of Thallium201 rest-redistribution SPECT to detect myocardial viability in reperfused patients after a recent myocardial infarction. Forty one patients with up to of 24 days of evolution of a myocardial infarction were studied. All had angiographically demonstrated coronary artery disease and were subjected to a successful thrombolysis, angioplasty or bypass grafting. SPECT Thallium201 images were acquired at rest and after 4 h of redistribution. These results were compared with variations in wall motion score, studied at baseline and after 3 or 4 months with echocardiography. The sensitivity of rest-redistribution Thallium201 SPECT, to predict recovery of wall motion was 91% when patient analysis was performed and 79% when segmental analysis was done in the culprit region. The figures for specificity were 56 and 73% respectively. Rest-distribution Thallium201 SPECT has an excellent sensitivity to predict myocardial viability in recent myocardial infarction. The data obtained in this study is similar to that reported for chronic coronary artery disease.

Impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris at 6months follow-up.

PubMed

Xia, Jinggang; Xu, Ji; Hu, Shaodong; Hao, Hengjian; Yin, Chunlin; Xu, Dong

2017-08-01

We explored the impact of glycemic variability on the occurrence of periprocedural myocardial infarction and major adverse cardiovascular events (MACE) after coronary intervention in patients with stable angina pectoris (SAP) at 6months follow-up. From May 2015 to April 2016, a total of 746 patients with SAP were divided to high glycemic variability group (H group) (n=261) and low glycemic variability group (L group) (n=485). The primary end point was incidence of periprocedural myocardial infarction and MACE at 6months follow-up. The occurrence of periprocedural myocardial infarction occurred in 18.8% of patients in H group and in 12.4% in L group (P=0.03). The incidence of MACE at 6months follow-up was 9.6% in H group and 4.5% in L group (P=0.01). Multivariable analysis suggested that high glycemic variability conferred a 53% risk increment of 6months follow-up MACE (odds ratio 2.13, 95% confidence interval 1.85-5.38; P=0.01). The trial shows that higher blood glucose variability was correlated with higher incidence of periprocedural myocardial infarction and MACE at 6months follow-up. Copyright © 2017. Published by Elsevier B.V.

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.

Calcitriol attenuates cardiac remodeling and dysfunction in a murine model of polycystic ovary syndrome.

PubMed

Gao, Ling; Cao, Jia-Tian; Liang, Yan; Zhao, Yi-Chao; Lin, Xian-Hua; Li, Xiao-Cui; Tan, Ya-Jing; Li, Jing-Yi; Zhou, Cheng-Liang; Xu, Hai-Yan; Sheng, Jian-Zhong; Huang, He-Feng

2016-05-01

Polycystic ovary syndrome (PCOS) is a complex reproductive and metabolic disorder affecting 10 % of reproductive-aged women, and is well associated with an increased prevalence of cardiovascular risk factors. However, there are few data concerning the direct association of PCOS with cardiac pathologies. The present study aims to investigate the changes in cardiac structure, function, and cardiomyocyte survival in a PCOS model, and explore the possible effect of calcitriol administration on these changes. PCOS was induced in C57BL/6J female mice by chronic dihydrotestosterone administration, as evidenced by irregular estrous cycles, obesity and dyslipidemia. PCOS mice progressively developed cardiac abnormalities including cardiac hypertrophy, interstitial fibrosis, myocardial apoptosis, and cardiac dysfunction. Conversely, concomitant administration of calcitriol significantly attenuated cardiac remodeling and cardiomyocyte apoptosis, and improved cardiac function. Molecular analysis revealed that the beneficial effect of calcitriol was associated with normalized autophagy function by increasing phosphorylation levels of AMP-activated protein kinase and inhibiting phosphorylation levels of mammalian target of rapamycin complex. Our findings provide the first evidence for the presence of cardiac remodeling in a PCOS model, and vitamin D supplementation may be a potential therapeutic strategy for the prevention and treatment of PCOS-related cardiac remodeling.

Computer-based assessment of left ventricular regional ejection fraction in patients after myocardial infarction

NASA Astrophysics Data System (ADS)

Teo, S.-K.; Su, Y.; Tan, R. S.; Zhong, L.

2014-03-01

After myocardial infarction (MI), the left ventricle (LV) undergoes progressive remodeling which adversely affects heart function and may lead to development of heart failure. There is an escalating need to accurately depict the LV remodeling process for disease surveillance and monitoring of therapeutic efficacy. Current practice of using ejection fraction to quantitate LV function is less than ideal as it obscures regional variation and anomaly. Therefore, we sought to (i) develop a quantitative method to assess LV regional ejection fraction (REF) using a 16-segment method, and (ii) evaluate the effectiveness of REF in discriminating 10 patients 1-3 months after MI and 9 normal control (sex- and agematched) based on cardiac magnetic resonance (CMR) imaging. Late gadolinium enhancement (LGE) CMR scans were also acquired for the MI patients to assess scar extent. We observed that the REF at the basal, mid-cavity and apical regions for the patient group is significantly lower as compared to the control group (P < 0.001 using a 2-tail student t-test). In addition, we correlated the patient REF over these regions with their corresponding LGE score in terms of 4 categories - High LGE, Low LGE, Border and Remote. We observed that the median REF decreases with increasing severity of infarction. The results suggest that REF could potentially be used as a discriminator for MI and employed to measure myocardium homogeneity with respect to degree of infarction. The computational performance per data sample took approximately 25 sec, which demonstrates its clinical potential as a real-time cardiac assessment tool.

Acute gouty arthritis complicated with acute ST elevation myocardial infarction is independently associated with short- and long-term adverse non-fatal cardiac events.

PubMed

Liu, Kuan-Liang; Lee, Hsin-Fu; Chou, Shing-Hsien; Lin, Yen-Chen; Lin, Chia-Pin; Wang, Chun-Li; Chang, Chi-Jen; Hsu, Lung-An

2014-01-01

Large epidemiologic studies have associated gouty arthritis with the risk of coronary heart disease. However, there has been a lack of information regarding the outcomes for patients who have gout attacks during hospitalization for acute myocardial infarction. We reviewed the data of 444 consecutive patients who were admitted to our hospital between 2005 and 2008 due to acute ST elevation myocardial infarction (STEMI). The clinical outcomes were compared between patients with gout attack and those without. Of the 444, 48 patients with acute STEMI developed acute gouty arthritis during hospitalization. The multivariate analysis identified prior history of gout and estimated glomerular filtration rate as independent risk factors of gout attack for patients with acute STEMI (odds ratio (OR) 21.02, 95 % CI 2.96-149.26, p = 0.002; OR 0.92, 95 % CI 0.86-0.99, p = 0.035, respectively). The in-hospital mortality and duration of hospital stay did not differ significantly between the gouty group and the non-gouty group (controls). During a mean follow-up of 49 ± 28 months, all-cause mortality and stroke were similar for both groups. Multivariate Cox regression showed that gout attack was independently associated with short- and long-term adverse non-fatal cardiac events (hazard ratio (HR) 1.88, 95 % CI 1.09-3.24, p = 0.024; HR 1.82, 95 % CI 1.09-3.03, p = 0.022, respectively). Gout attack among patients hospitalized due to acute STEMI was independently associated with short-term and long-term rates of adverse non-fatal cardiac events.

PDE1C deficiency antagonizes pathological cardiac remodeling and dysfunction

PubMed Central

Knight, Walter E.; Chen, Si; Zhang, Yishuai; Oikawa, Masayoshi; Wu, Meiping; Zhou, Qian; Miller, Clint L.; Cai, Yujun; Mickelsen, Deanne M.; Moravec, Christine; Small, Eric M.; Abe, Junichi; Yan, Chen

2016-01-01

Cyclic nucleotide phosphodiesterase 1C (PDE1C) represents a major phosphodiesterase activity in human myocardium, but its function in the heart remains unknown. Using genetic and pharmacological approaches, we studied the expression, regulation, function, and underlying mechanisms of PDE1C in the pathogenesis of cardiac remodeling and dysfunction. PDE1C expression is up-regulated in mouse and human failing hearts and is highly expressed in cardiac myocytes but not in fibroblasts. In adult mouse cardiac myocytes, PDE1C deficiency or inhibition attenuated myocyte death and apoptosis, which was largely dependent on cyclic AMP/PKA and PI3K/AKT signaling. PDE1C deficiency also attenuated cardiac myocyte hypertrophy in a PKA-dependent manner. Conditioned medium taken from PDE1C-deficient cardiac myocytes attenuated TGF-β–stimulated cardiac fibroblast activation through a mechanism involving the crosstalk between cardiac myocytes and fibroblasts. In vivo, cardiac remodeling and dysfunction induced by transverse aortic constriction, including myocardial hypertrophy, apoptosis, cardiac fibrosis, and loss of contractile function, were significantly attenuated in PDE1C-knockout mice relative to wild-type mice. These results indicate that PDE1C activation plays a causative role in pathological cardiac remodeling and dysfunction. Given the continued development of highly specific PDE1 inhibitors and the high expression level of PDE1C in the human heart, our findings could have considerable therapeutic significance. PMID:27791092

Endocannabinoids as mediators in the heart: a potential target for therapy of remodelling after myocardial infarction?

PubMed Central

Hiley, C Robin; Ford, William R

2003-01-01

Endocannabinoid production by platelets and macrophages is increased in circulatory shock. This may be protective of the cardiovascular system as blockade of CB1 cannabinoid receptors exacerbates endothelial dysfunction in haemorrhagic and endotoxin shock and reduces survival. Now evidence suggests that blockade of CB1 receptors starting 24 h after myocardial infarction in rats has a deleterious effect on cardiac performance, while use of a nonselective cannabinoid receptor agonist prevents hypotension and reduces endothelial dysfunction, although left ventricular end diastolic pressure is elevated. Cannabinoids and endocannabinoid systems may therefore present useful targets for therapy following myocardial infarction. PMID:12711614

G-CSF in acute myocardial infarction - experimental and clinical findings.

PubMed

Ince, Hüseyin; Petzsch, Michael; Rehders, Tim C; Dunkelmann, Simone; Nienaber, Christoph A

2006-09-01

Early data from clinical studies suggest that intracoronary injection of autologous progenitor cells may beneficially affect postinfarction remodeling and perfusion. Beyond intracoronary infusion of autologous bone marrow mononuclear CD34+ cells (MNCCD34+), mobilization of stem cells by G-CSF has recently attracted attention because of various advantages such as the noninvasive nature of MNCCD34+ mobilization by subcutaneous injections. It is the aim of the present work to give an overview about the current experimental and clinical findings of G-CSF treatment in acute myocardial infarction.

Vitamin D attenuates pressure overload-induced cardiac remodeling and dysfunction in mice.

PubMed

Zhang, Liang; Yan, Xiao; Zhang, Yun-Long; Bai, Jie; Hidru, Tesfaldet Habtemariam; Wang, Qing-Shan; Li, Hui-Hua

2018-04-01

Vitamin D (VD) and its analogues play critical roles in metabolic and cardiovascular diseases. Recent studies have demonstrated that VD exerts a protective role in cardiovascular diseases. However, the beneficial effect of VD on pressure overload-induced cardiac remodeling and dysfunction and its underlying mechanisms are not fully elucidated. In this study, cardiac dysfunction and hypertrophic remodeling in mice were induced by pressure overload. Cardiac function was evaluated by echocardiography, and myocardial histology was detected by H&E and Masson's trichrome staining. Cardiomyocyte size was detected by wheat germ agglutinin staining. The protein levels of signaling mediators were examined by western blotting while mRNA expression of hypertrophic and fibrotic markers was examined by qPCR analysis. Oxidative stress was detected by dihydroethidine staining. Our results showed that administration of VD3 significantly ameliorates pressure overload-induced contractile dysfunction, cardiac hypertrophy, fibrosis and inflammation in mice. In addition, VD3 treatment also markedly inhibited cardiac oxidative stress and apoptosis. Moreover, protein levels of calcineurin A, ERK1/2, AKT, TGF-β, GRP78, cATF6, and CHOP were significantly reduced whereas SERCA2 level was upregulated in the VD3-treated hearts compared with control. These results suggest that VD3 attenuates cardiac remodeling and dysfunction induced by pressure overload, and this protective effect is associated with inhibition of multiple signaling pathways. Copyright © 2018 Elsevier Ltd. All rights reserved.

Relationship between Myocardial Extracellular Space Expansion Estimated with Post-Contrast T1 Mapping MRI and Left Ventricular Remodeling and Neurohormonal Activation in Patients with Dilated Cardiomyopathy.

PubMed

Yoon, Ji Hyun; Son, Jung Woo; Chung, Hyemoon; Park, Chul Hwan; Kim, Young-Jin; Chang, Hyuk-Jae; Hong, Geu-Ru; Kim, Tae Hoon; Ha, Jong-Won; Choi, Byoung Wook; Rim, Se-Joong; Chung, Namsik; Choi, Eui-Young

2015-01-01

Post-contrast T1 values are closely related to the degree of myocardial extracellular space expansion. We determined the relationship between post-contrast T1 values and left ventricular (LV) diastolic function, LV remodeling, and neurohormonal activation in patients with dilated cardiomyopathy (DCM). Fifty-nine patients with DCM (mean age, 55 ± 15 years; 41 males and 18 females) who underwent both 1.5T magnetic resonance imaging and echocardiography were enrolled. The post-contrast 10-minute T1 value was generated from inversion time scout images obtained using the Look-Locker inversion recovery sequence and a curve-fitting algorithm. The T1 sample volume was obtained from three interventricular septal points, and the mean T1 value was used for analysis. The N-Terminal pro-B-type natriuretic peptide (NT-proBNP) level was measured in 40 patients. The mean LV ejection fraction was 24 ± 9% and the post-T1 value was 254.5 ± 46.4 ms. The post-contrast T1 value was significantly correlated with systolic longitudinal septal velocity (s'), peak late diastolic velocity of the mitral annulus (a'), the diastolic elastance index (Ed, [E/e']/stroke volume), LV mass/volume ratio, LV end-diastolic wall stress, and LV end-systolic wall stress. In a multivariate analysis without NT-proBNP, T1 values were independently correlated with Ed (β = -0.351, p = 0.016) and the LV mass/volume ratio (β = 0.495, p = 0.001). When NT-proBNP was used in the analysis, NT-proBNP was independently correlated with the T1 values (β = -0.339, p = 0.017). Post-contrast T1 is closely related to LV remodeling, diastolic function, and neurohormonal activation in patients with DCM.

Small interfering RNA therapy against carbohydrate sulfotransferase 15 inhibits cardiac remodeling in rats with dilated cardiomyopathy.

PubMed

Watanabe, Kenichi; Arumugam, Somasundaram; Sreedhar, Remya; Thandavarayan, Rajarajan A; Nakamura, Takashi; Nakamura, Masahiko; Harima, Meilei; Yoneyama, Hiroyuki; Suzuki, Kenji

2015-07-01

Carbohydrate sulfotransferase 15 (CHST15) is a sulfotransferase responsible for biosynthesis of chondroitin sulfate E (CS-E), which plays important roles in numerous biological events such as biosynthesis of proinflammatory cytokines. However, the effects of CHST15 siRNA in rats with chronic heart failure (CHF) after experimental autoimmune myocarditis (EAM) have not yet been investigated. CHF was elicited in Lewis rats by immunization with cardiac myosin, and after immunization, the rats were divided into two groups and treated with either CHST15 siRNA (2μg/week) or vehicle. Age matched normal rats without immunizations were also included in this study. After 7weeks of treatment, we investigated the effects of CHST15 siRNA on cardiac function, proinflammatory cytokines, and cardiac remodeling in EAM rats. Myocardial functional parameters measured by hemodynamic and echocardiographic studies were significantly improved by CHST15 siRNA treatment in rats with CHF compared with that of vehicle-treated CHF rats. CHST15 siRNA significantly reduced cardiac fibrosis, and hypertrophy and its marker molecules (left ventricular (LV) mRNA expressions of transforming growth factor beta1, collagens I and III, and atrial natriuretic peptide) compared with vehicle-treated CHF rats. CHF-induced increased myocardial mRNA expressions of proinflammatory cytokines [interleukin (IL)-6, IL-1β], monocyte chemoattractant protein-1, and matrix metalloproteinases (MMP-2 and -9), and CHST15 were also suppressed by the treatment with CHST15 siRNA. Western blotting study has confirmed the results obtained from mRNA analysis as CHST15 siRNA treated rats expressed reduced levels of inflammatory and cardiac remodeling marker proteins. Our results demonstrate for the first time, that CHST15 siRNA treatment significantly improved LV function and ameliorated the progression of cardiac remodeling in rats with CHF after EAM. Copyright © 2015 Elsevier Inc. All rights reserved.

Temporal and Molecular Analyses of Cardiac Extracellular Matrix Remodeling following Pressure Overload in Adiponectin Deficient Mice

PubMed Central

Dadson, Keith; Turdi, Subat; Boo, Stellar; Hinz, Boris; Sweeney, Gary

2015-01-01

Adiponectin, circulating levels of which are reduced in obesity and diabetes, mediates cardiac extracellular matrix (ECM) remodeling in response to pressure overload (PO). Here, we performed a detailed temporal analysis of progressive cardiac ECM remodelling in adiponectin knockout (AdKO) and wild-type (WT) mice at 3 days and 1, 2, 3 and 4 weeks following the induction of mild PO via minimally invasive transverse aortic banding. We first observed that myocardial adiponectin gene expression was reduced after 4 weeks of PO, whereas increased adiponectin levels were detected in cardiac homogenates at this time despite decreased circulating levels of adiponectin. Scanning electron microscopy and Masson’s trichrome staining showed collagen accumulation increased in response to 2 and 4 weeks of PO in WT mice, while fibrosis in AdKO mice was notably absent after 2 weeks but highly apparent after 4 weeks of PO. Time and intensity of fibroblast appearance after PO was not significantly different between AdKO and WT animals. Gene array analysis indicated that MMP2, TIMP2, collagen 1α1 and collagen 1α3 were induced after 2 weeks of PO in WT but not AdKO mice. After 4 weeks MMP8 was induced in both genotypes, MMP9 only in WT mice and MMP1α only in AdKO mice. Direct stimulation of primary cardiac fibroblasts with adiponectin induced a transient increase in total collagen detected by picrosirius red staining and collagen III levels synthesis, as well as enhanced MMP2 activity detected via gelatin zymography. Adiponectin also enhanced fibroblast migration and attenuated angiotensin-II induced differentiation to a myofibroblast phenotype. In conclusion, these data indicate that increased myocardial bioavailability of adiponectin mediates ECM remodeling following PO and that adiponectin deficiency delays these effects. PMID:25910275

Reading tarot cards.

PubMed

Edmunds, L Henry

2004-02-01

In some patients acute myocardial infarction and/or infarct expansion induces progressive left ventricular dilatation that eventually leads to heart failure and death. The five year mortality after onset of heart failure is 50%. Chronically stretched viable myocardium adjacent to or remote from an expanding infarction initiates a myopathic process that leads to progressive myocyte apoptosis and adverse postinfarction remodeling. Revascularization of stunned or hibernating myocardium restores contractility and benefits patients in heart failure; however, revascularization does not restore contractility to myopathic, remodeling myocardium. Contemporary operations for heart failure temporarily reduce ventricular wall stress, but fail to reverse stretch induced myocyte apoptosis, which may not be reversible. Logically, prevention of this myopathic process after acute infarction seems required to extend survival. It follows that surgeons should operate before adverse postinfarction left ventricular remodeling occurs, using new operations, rather than afterwards.

[Incidence, associated factors, and follow-up of hospital heart failure complicating acute anterior myocardial infarction successfully treated by primary angioplasty].

PubMed

Meimoun, P; M'barek, D; Dragomir, C; Luycx-Bore, A; Elmkies, F; Boulanger, J; Zemir, H; Martis, S; Neykova, A; Tzvetkov, B; Clerc, J

2013-11-01

Heart failure (HF) complicating acute myocardial infarction (AMI) is of poor prognosis and is often associated with patient's characteristics and success of reperfusion strategies. However, few data is available regarding the high-risk subgroup of patients with anterior AMI treated successfully by primary angioplasty. The aim of the study was to assess the incidence, associated factors, and the future of HF occurring during hospitalisation, in the setting of anterior AMI treated successfully by primary angioplasty. Eighty-five consecutive patients with anterior AMI treated successfully by primary angioplasty (final angiographic TIMI flow grade=3, without residual stenosis) were included. Clinical, biochemical, angiographic, and echocardiographic data were prospectively collected and compared between patients with (Killip 2 and 3) and without HF during hospitalisation. Fifteen patients had HF (18%) during hospitalisation and 70 did not. By comparison to patients without HF, patients with HF were more frequently diabetics, had troponin peak and CPK, leucocytes count, and fasting glucose higher, LVEF and wall motion score index in the left anterior descending territory (WMSi-lad) poorer, and a lower non-invasive coronary flow reserve (CFR) in the LAD 24hours after angioplasty (all, P<0.05). In multivariate analysis, fasting glucose, leucocytes count after angioplasty, CFR and WMSi-lad were independently associated with HF, even after adjusting with angiographic variables (all, P<0.05). At 6months, patients with HF had less recovery of LV function and higher frequency of adverse LV remodelling (58% versus 20%, P<0.01) by comparison to patients without HF. In conclusion, HF is not uncommon even after successful primary angioplasty for anterior AMI (nearly one patient out of 5), is associated with hyperglycaemia and inflammation, a poor microvascular reperfusion, and left ventricular systolic function, and is more frequently complicated by adverse LV remodelling and lack

In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

PubMed Central

Shi, Qiang; Liu, Xiaoyan; Bai, Yuanyuan; Cui, Chuanjue; Li, Jun; Li, Yishi; Hu, Shengshou; Wei, Yingjie

2011-01-01

Cardiac fibroblasts (CFs) are the primary cell type responsible for cardiac fibrosis during pathological myocardial remodeling. Several studies have illustrated that pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) attenuates cardiac fibrosis in different animal models. However, the effects of pirfenidone on cardiac fibroblast behavior have not been examined. In this study, we investigated whether pirfenidone directly modulates cardiac fibroblast behavior that is important in myocardial remodeling such as proliferation, myofibroblast differentiation, migration and cytokine secretion. Fibroblasts were isolated from neonatal rat hearts and bioassays were performed to determine the effects of pirfenidone on fibroblast function. We demonstrated that treatment of CFs with pirfenidone resulted in decreased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen contractility. Boyden chamber assay illustrated that pirfenidone inhibited fibroblast migration ability, probably by decreasing the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1. Furthermore, pirfenidone attenuated the synthesis and secretion of transforming growth factor-β1 but elevated that of interleukin-10. These direct and pleiotropic effects of pirfenidone on cardiac fibroblasts point to its potential use in the treatment of adverse myocardial remodeling. PMID:22132230

Both Selenium Deficiency and Modest Selenium Supplementation Lead to Myocardial Fibrosis in Mice via Effects on Redox-Methylation Balance

PubMed Central

Metes-Kosik, Nicole; Luptak, Ivan; DiBello, Patricia M.; Handy, Diane E.; Tang, Shiow-Shih; Zhi, Hui; Qin, Fuzhong; Jacobsen, Donald W.; Loscalzo, Joseph; Joseph, Jacob

2013-01-01

Scope Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function. Methods and Results We examined the effects of selenium deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy. Conclusions Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure. PMID:23097236

Metabolic Remodeling in Moderate Synchronous versus Dyssynchronous Pacing-Induced Heart Failure: Integrated Metabolomics and Proteomics Study

PubMed Central

Shibayama, Junko; Yuzyuk, Tatiana N.; Cox, James; Makaju, Aman; Miller, Mickey; Lichter, Justin; Li, Hui; Leavy, Jane D.; Franklin, Sarah; Zaitsev, Alexey V.

2015-01-01

Heart failure (HF) is accompanied by complex alterations in myocardial energy metabolism. Up to 40% of HF patients have dyssynchronous ventricular contraction, which is an independent indicator of mortality. We hypothesized that electromechanical dyssynchrony significantly affects metabolic remodeling in the course of HF. We used a canine model of tachypacing-induced HF. Animals were paced at 200 bpm for 6 weeks either in the right atrium (synchronous HF, SHF) or in the right ventricle (dyssynchronous HF, DHF). We collected biopsies from left ventricular apex and performed comprehensive metabolic pathway analysis using multi-platform metabolomics (GC/MS; MS/MS; HPLC) and LC-MS/MS label-free proteomics. We found important differences in metabolic remodeling between SHF and DHF. As compared to Control, ATP, phosphocreatine (PCr), creatine, and PCr/ATP (prognostic indicator of mortality in HF patients) were all significantly reduced in DHF, but not SHF. In addition, the myocardial levels of carnitine (mitochondrial fatty acid carrier) and fatty acids (12:0, 14:0) were significantly reduced in DHF, but not SHF. Carnitine parmitoyltransferase I, a key regulatory enzyme of fatty acid ß-oxidation, was significantly upregulated in SHF but was not different in DHF, as compared to Control. Both SHF and DHF exhibited a reduction, but to a different degree, in creatine and the intermediates of glycolysis and the TCA cycle. In contrast to this, the enzymes of creatine kinase shuttle were upregulated, and the enzymes of glycolysis and the TCA cycle were predominantly upregulated or unchanged in both SHF and DHF. These data suggest a systemic mismatch between substrate supply and demand in pacing-induced HF. The energy deficit observed in DHF, but not in SHF, may be associated with a critical decrease in fatty acid delivery to the ß-oxidation pipeline, primarily due to a reduction in myocardial carnitine content. PMID:25790351

[The relation between the low T3 syndrome in the clinical course of myocardial infarction and heart failure].

PubMed

Frączek, Magdalena Maria; Gackowski, Andrzej; Przybylik-Mazurek, Elwira; Nessler, Jadwiga

2016-06-01

It has been proven that either excess or deficiency of thyroid hormones has harmful influence on the cardiovascular system function. On the other hand, severe systemic conditions like myocardial infarction or severe heart failure may affect thyroid hormones secretion and their peripheral conversion, leading to low T3 syndrome. Amongst many mechanisms causing T4 to T3 conversion disturbances, important role plays decreased activity of D1 deiodinase and increased activity of D3 deiodinase. The animal research confirmed that thyroid hormones influence cardiomiocytes phenotype and morphology. They inhibit inflammation, apoptosis and cardiac remodelling after myocardial infarction. It was also proven that free triiodothyronine similarly to brain natriuretic peptide predict long-term prognosis in chronic and acute heart failure patients. Potential influence of low T3 syndrome on the course of myocardial infarction and heart failure may have significant impact on the future research on individualization of myocardial infarction and heart failure treatment depending on patient's thyroid status. © 2016 MEDPRESS.

Hypothyroidism and its rapid correction alter cardiac remodeling.

PubMed

Hajje, Georges; Saliba, Youakim; Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.

Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

PubMed Central

Itani, Tarek; Moubarak, Majed; Aftimos, Georges; Farès, Nassim

2014-01-01

The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease. PMID:25333636

Leukocyte diversity in resolving and nonresolving mechanisms of cardiac remodeling.

PubMed

Tourki, Bochra; Halade, Ganesh

2017-10-01

In response to myocardial infarction (MI), time-dependent leukocyte infiltration is critical to program the acute inflammatory response. Post-MI leukocyte density, residence time in the infarcted area, and exit from the infarcted injury predict resolving or nonresolving inflammation. Overactive or unresolved inflammation is the primary determinant in heart failure pathology post-MI. Here, our review describes supporting evidence that the acute inflammatory response also guides the generation of healing and regenerative mediators after cardiac damage. Time-dependent leukocyte density and diversity and the magnitude of myocardial injury is responsible for the resolving and nonresolving pathway in myocardial healing. Post MI, the diversity of leukocytes, such as neutrophils, macrophages, and lymphocytes, has been explored that regulate the clearance of deceased cardiomyocytes by using the classic and reparative pathways. Among the innovative factors and intermediates that have been recognized as essential in acute the self-healing and clearance mechanism, we highlight specialized proresolving mediators as the emerging factor for post-MI reparative mechanisms-translational leukocyte modifiers, such as aging, the source of leukocytes, and the milieu around the leukocytes. In the clinical setting, it is possible that leukocyte diversity is more prominent as a result of risk factors, such as obesity, diabetes, and hypertension. Pharmacologic agents are critical modifiers of leukocyte diversity in healing mechanisms that may impair or stimulate the clearance mechanism. Future research is needed, with a focused approach to understand the molecular targets, cellular effectors, and receptors. A clear understanding of resolving and nonresolving inflammation in myocardial healing will help to develop novel targets with major emphasis on the resolution of inflammation in heart failure pathology.-Tourki, B., Halade, G. Leukocyte diversity in resolving and nonresolving mechanisms

Endogenous osteopontin induces myocardial CCL5 and MMP-2 activation that contributes to inflammation and cardiac remodeling in a mouse model of chronic Chagas heart disease.

PubMed

Caballero, Eugenia Pérez; Santamaría, Miguel H; Corral, Ricardo S

2018-01-01

Cardiac dysfunction with progressive inflammation and fibrosis is a hallmark of Chagas disease caused by persistent Trypanosoma cruzi infection. Osteopontin (OPN) is a pro-inflammatory cytokine that orchestrates mechanisms controlling cell recruitment and cardiac architecture. Our main goal was to study the role of endogenous OPN as a modulator of myocardial CCL5 chemokine and MMP-2 metalloproteinase, and its pathological impact in a murine model of Chagas heart disease. Wild-type (WT) and OPN-deficient (spp1 -/-) mice were parasite-infected (Brazil strain) for 100days. Both groups developed chronic myocarditis with similar parasite burden and survival rates. However, spp1 -/- infection showed lower heart-to-body ratio (P<0.01) as well as reduced inflammatory pathology (P<0.05), CCL5 expression (P<0.05), myocyte size (P<0.05) and fibrosis (P<0.01) in cardiac tissues. Intense OPN labeling was observed in inflammatory cells recruited to infected heart (P<0.05). Plasma concentration of MMP-2 was higher (P<0.05) in infected WT than in spp1 -/- mice. Coincidently, specific immunostaining revealed increased gelatinase expression (P<0.01) and activity (P<0.05) in the inflamed hearts from T. cruzi WT mice, but not in their spp1 -/- littermates. CCL5 and MMP-2 induction occurred preferentially (P<0.01) in WT heart-invading CD8 + T cells and was mediated via phospho-JNK MAPK signaling. Heart levels of OPN, CCL5 and MMP-2 correlated (P<0.01) with collagen accumulation in the infected WT group only. Endogenous OPN emerges as a key player in the pathogenesis of chronic Chagas heart disease, through the upregulation of myocardial CCL5/MMP-2 expression and activities resulting in pro-inflammatory and pro-hypertrophic events, cardiac remodeling and interstitial fibrosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect and Safety of Morphine Use in Acute Anterior ST-Segment Elevation Myocardial Infarction.

PubMed

Bonin, Mickael; Mewton, Nathan; Roubille, Francois; Morel, Olivier; Cayla, Guillaume; Angoulvant, Denis; Elbaz, Meyer; Claeys, Marc J; Garcia-Dorado, David; Giraud, Céline; Rioufol, Gilles; Jossan, Claire; Ovize, Michel; Guerin, Patrice

2018-02-10

Morphine is commonly used to treat chest pain during myocardial infarction, but its effect on cardiovascular outcome has never been directly evaluated. The aim of this study was to examine the effect and safety of morphine in patients with acute anterior ST-segment elevation myocardial infarction followed up for 1 year. We used the database of the CIRCUS (Does Cyclosporine Improve Outcome in ST Elevation Myocardial Infarction Patients) trial, which included 969 patients with anterior ST-segment elevation myocardial infarction, admitted for primary percutaneous coronary intervention. Two groups were defined according to use of morphine preceding coronary angiography. The composite primary outcome was the combined incidence of major adverse cardiovascular events, including cardiovascular death, heart failure, cardiogenic shock, myocardial infarction, unstable angina, and stroke during 1 year. A total of 554 (57.1%) patients received morphine at first medical contact. Both groups, with and without morphine treatment, were comparable with respect to demographic and periprocedural characteristics. There was no significant difference in major adverse cardiovascular events between patients who received morphine compared with those who did not (26.2% versus 22.0%, respectively; P =0.15). The all-cause mortality was 5.3% in the morphine group versus 5.8% in the no-morphine group ( P =0.89). There was no difference between groups in infarct size as assessed by the creatine kinase peak after primary percutaneous coronary intervention (4023±118 versus 3903±149 IU/L; P =0.52). In anterior ST-segment elevation myocardial infarction patients treated by primary percutaneous coronary intervention, morphine was used in half of patients during initial management and was not associated with a significant increase in major adverse cardiovascular events at 1 year. © 2018 The Authors and Hospices Civils de Lyon. Published on behalf of the American Heart Association, Inc., by Wiley.

Optical metrics of the extracellular matrix predict compositional and mechanical changes after myocardial infarction

NASA Astrophysics Data System (ADS)

Quinn, Kyle P.; Sullivan, Kelly E.; Liu, Zhiyi; Ballard, Zachary; Siokatas, Christos; Georgakoudi, Irene; Black, Lauren D.

2016-11-01

Understanding the organization and mechanical function of the extracellular matrix (ECM) is critical for the development of therapeutic strategies that regulate wound healing following disease or injury. However, these relationships are challenging to elucidate during remodeling following myocardial infarction (MI) due to rapid changes in cellularity and an inability to characterize both ECM microstructure and function non-destructively. In this study, we overcome those challenges through whole organ decellularization and non-linear optical microscopy to directly relate the microstructure and mechanical properties of myocardial ECM. We non-destructively quantify collagen organization, content, and cross-linking within decellularized healthy and infarcted myocardium using second harmonic generation (SHG) and two photon excited autofluorescence. Tensile mechanical testing and compositional analysis reveal that the cumulative SHG intensity within each image volume and the average collagen autofluorescence are significantly correlated with collagen content and elastic modulus of the ECM, respectively. Compared to healthy ECM, infarcted tissues demonstrate a significant increase in collagen content and fiber alignment, and a decrease in cross-linking and elastic modulus. These findings indicate that cross-linking plays a key role in stiffness at the collagen fiber level following infarction, and highlight how this non-destructive approach to assessing remodeling can be used to understand ECM structure-function relationships.

Identification of Temporal and Region-Specific Myocardial Gene Expression Patterns in Response to Infarction in Swine

PubMed Central

Nonell, Lara; Puigdecanet, Eulàlia; Astier, Laura; Solé, Francesc; Bayes-Genis, Antoni

2013-01-01

Molecular mechanisms associated with pathophysiological changes in ventricular remodelling due to myocardial infarction (MI) remain poorly understood. We analyzed changes in gene expression by microarray technology in porcine myocardial tissue at 1, 4, and 6 weeks post-MI. MI was induced by coronary artery ligation in 9 female pigs (30–40 kg). Animals were randomly sacrificed at 1, 4, or 6 weeks post-MI (n = 3 per group) and 3 healthy animals were also included as control group. Total RNA from myocardial samples was hybridized to GeneChip® Porcine Genome Arrays. Functional analysis was obtained with the Ingenuity Pathway Analysis (IPA) online tool. Validation of microarray data was performed by quantitative real-time PCR (qRT-PCR). More than 8,000 different probe sets showed altered expression in the remodelling myocardium at 1, 4, or 6 weeks post-MI. Ninety-seven percent of altered transcripts were detected in the infarct core and 255 probe sets were differentially expressed in the remote myocardium. Functional analysis revealed 28 genes de-regulated in the remote myocardial region in at least one of the three temporal analyzed stages, including genes associated with heart failure (HF), systemic sclerosis and coronary artery disease. In the infarct core tissue, eight major time-dependent gene expression patterns were recognized among 4,221 probe sets commonly altered over time. Altered gene expression of ACVR2B, BID, BMP2, BMPR1A, LMNA, NFKBIA, SMAD1, TGFB3, TNFRSF1A, and TP53 were further validated. The clustering of similar expression patterns for gene products with related function revealed molecular footprints, some of them described for the first time, which elucidate changes in biological processes at different stages after MI. PMID:23372767

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

Effect of granulocyte colony stimulating EPC on cardiac function and myocardial energy expenditure in patients with heart failure after myocardial infarction.

PubMed

Zhao, Zilin; Luo, Jianchun; Ma, Lixian; Luo, Xia; Huang, Liangyan

2015-01-01

To study the changes of cardiac function and myocardial energy expenditure following treatment with granulocyte colony stimulating factor (G-CSF) in patients with heart failure after myocardial infarction. Thirty-eight patients with heart failure after myocardial infarction were randomized into G-CSF treatment group and control group. All the patients received conventional treatment (medication and interventional therapy), and the patients in treatment group were given additional G-CSF (600 μg/day) for 7 consecutive days. The plasma level of brain-type natriuretic peptide (BNP) and the number of endothelial progenitor cells (EPC) in the peripheral blood were detected before and at 7 days and 4 months after the treatment. The cardiac functions (LVEF, FS, LVIDs, PWTs, EDV, SV, ET) was evaluated by ultrasonic imaging before and at 2 weeks and 4 months after the treatment. The MEE and circumferential end-systolic wall stress (cESS) were calculated by correlation formula. The number of EPC was significantly higher in the treatment group than in the control group after the treatment especially at 7 days (P<0.01). In both groups, BNP level was lowered significantly after the treatment to recover the normal level (P<0.01). The cardiac functions and myocardial energy expenditure were improved in all the patients at 2 weeks and 4 months after the treatment, and the improvement was more obvious in the treatment group (P<0.05), especially in terms of the MEE and cESS was significantly lowered in the treatment group than in the control group after the treatment at 2 weeks (P<0.01), the LVEF and FS was significantly increased in the treatment group than in the control group after the treatment at 4 months (P<0.01). EPC mobilization by G-CSF can effectively improve the cardiac functions, lessen ventricular remodeling and reduce myocardial energy expenditure in patients with heart failure after myocardial infarction.

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

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate.

PubMed

O'Farrell, Alice C; Evans, Rhys; Silvola, Johanna M U; Miller, Ian S; Conroy, Emer; Hector, Suzanne; Cary, Maurice; Murray, David W; Jarzabek, Monika A; Maratha, Ashwini; Alamanou, Marina; Udupi, Girish Mallya; Shiels, Liam; Pallaud, Celine; Saraste, Antti; Liljenbäck, Heidi; Jauhiainen, Matti; Oikonen, Vesa; Ducret, Axel; Cutler, Paul; McAuliffe, Fionnuala M; Rousseau, Jacques A; Lecomte, Roger; Gascon, Suzanne; Arany, Zoltan; Ky, Bonnie; Force, Thomas; Knuuti, Juhani; Gallagher, William M; Roivainen, Anne; Byrne, Annette T

2017-01-01

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.

A Novel Positron Emission Tomography (PET) Approach to Monitor Cardiac Metabolic Pathway Remodeling in Response to Sunitinib Malate

PubMed Central

Silvola, Johanna M. U.; Miller, Ian S.; Conroy, Emer; Hector, Suzanne; Cary, Maurice; Murray, David W.; Jarzabek, Monika A.; Maratha, Ashwini; Alamanou, Marina; Udupi, Girish Mallya; Shiels, Liam; Pallaud, Celine; Saraste, Antti; Liljenbäck, Heidi; Jauhiainen, Matti; Oikonen, Vesa; Ducret, Axel; Cutler, Paul; McAuliffe, Fionnuala M.; Rousseau, Jacques A.; Lecomte, Roger; Gascon, Suzanne; Arany, Zoltan; Ky, Bonnie; Force, Thomas; Knuuti, Juhani; Gallagher, William M.; Roivainen, Anne; Byrne, Annette T.

2017-01-01

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid β-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment. PMID:28129334

Early myocardial damage assessment in dystrophinopathies using (99)Tc(m)-MIBI gated myocardial perfusion imaging.

PubMed

Zhang, Li; Liu, Zhe; Hu, Ke-You; Tian, Qing-Bao; Wei, Ling-Ge; Zhao, Zhe; Shen, Hong-Rui; Hu, Jing

2015-01-01

Early detection of muscular dystrophy (MD)-associated cardiomyopathy is important because early medical treatment may slow cardiac remodeling and attenuate symptoms of cardiac dysfunction; however, no sensitive and standard diagnostic method for MD at an earlier stage has been well-recognized. Thus, the aim of this study was to test the early diagnostic value of technetium 99m-methoxyisobutylisonitrile ((99)Tc(m)-MIBI) gated myocardial perfusion imaging (G-MPI) for MD. Ninety-one patients underwent (99)Tc(m)-MIBI G-MPI examinations when they were diagnosed with Duchenne muscular dystrophy (DMD) (n=77) or Becker muscular dystrophy (BMD; n=14). (99)Tc(m)-MIBI G-MPI examinations were repeated in 43 DMD patients who received steroid treatments for 2 years as a follow-up examination. Myocardial defects were observed in nearly every segment of the left ventricular wall in both DMD and BMD patients compared with controls, especially in the inferior walls and the apices by using (99)Tc(m)-MIBI G-MPI. Cardiac wall movement impairment significantly correlated with age in the DMD and BMD groups (r s=0.534 [P<0.05] and r s=0.784 [P<0.05], respectively). Intermittent intravenous doses of glucocorticoids and continuation with oral steroid treatments significantly improved myocardial function in DMD patients (P<0.05), but not in BMD patients. (99)Tc(m)-MIBI G-MPI is a sensitive and safe approach for early evaluation of cardiomyopathy in patients with DMD or BMD, and can serve as a candidate method for the evaluation of progression, prognosis, and assessment of the effect of glucocorticoid treatment in these patients.

Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function

PubMed Central

Saxena, Amit; Dobaczewski, Marcin; Rai, Vikrant; Haque, Zaffar; Chen, Wei; Li, Na

2014-01-01

Regulatory T cells (Tregs) play a pivotal role in suppressing immune responses regulating behavior and gene expression in effector T cells, macrophages, and dendritic cells. Tregs infiltrate the infarcted myocardium; however, their role the inflammatory and reparative response after myocardial infarction remains poorly understood. We used FoxP3EGFP reporter mice to study Treg trafficking in the infarcted heart and examined the effects of Treg depletion on postinfarction remodeling using an anti-CD25 antibody. Moreover, we investigated the in vitro effects of Tregs on cardiac fibroblast phenotype and function. Low numbers of Tregs infiltrated the infarcted myocardium after 24–72 h of reperfusion. Treg depletion had no significant effects on cardiac dysfunction and scar size after reperfused myocardial infarction but accelerated ventricular dilation and accentuated apical remodeling. Enhanced myocardial dilation in Treg-depleted animals was associated with increased expression of chemokine (C-C motif) ligand 2 and accentuated macrophage infiltration. In vitro, Tregs modulated the cardiac fibroblast phenotype, reducing expression of α-smooth muscle actin, decreasing expression of matrix metalloproteinase-3, and attenuating contraction of fibroblast-populated collagen pads. Our findings suggest that endogenous Tregs have modest effects on the inflammatory and reparative response after myocardial infarction. However, the anti-inflammatory and matrix-preserving properties of Tregs may suggest a role for Treg-based cell therapy in the attenuation of adverse postinfarction remodeling. PMID:25128167

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

Regulation of the isozymes of protein kinase C in the surviving rat myocardium after myocardial infarction: distinct modulation for PKC-alpha and for PKC-delta.

PubMed

Simonis, Gregor; Honold, Jörg; Schwarz, Kerstin; Braun, Martin U; Strasser, Ruth H

2002-05-01

The goal of this study was to clarify the regulation of the isozymes of protein kinase C (PKC) in the process of remodeling after myocardial infarction. An in vivo model of regional myocardial infarction induced by ligation of the left anterior coronary artery in rats was used. Hemodynamic parameters and the heart and lung weights were determined 1 week and 1, 2 and 3 months after operation. In transmural biopsies from the non-ischemic left ventricular wall of the infarcted heart, PKC activity (ELISA) and the expression of its major isozymes, PKC-alpha, PKC-delta and PKC-epsilon (Westernblot analysis) were determined. As early as one week after myocardial infarction, heart weight and left ventricular enddiastolic pressures were significantly increased. Lung weights increased after 2 - 3 months, indicating progressive pulmonary congestion. The activity of PKC was significantly increased about 1.8-fold after 1 week, decreasing progressively in the later time course. Whereas the expression of PKC-epsilon did not change, PKC-alpha was increased after 1 month (157%) and then returned to baseline values. In contrast, PKC-delta expression was significantly augmented after 2 and 3 months of myocardial infarction (187%). These data demonstrate for the first time that in the remodeling heart after myocardial infarction, a subtype-selective regulation of the PKC isozymes occurs: The upregulation of PKC-alpha coincides with the development of hypertrophy, whereas the extensive upregulation of PKC-delta outlasts the process of developing hypertrophy and persists in the failing heart. The trigger mechanisms for this newly characterized process remains to be elucidated.

Epicardial infarct repair with bioinductive extracellular matrix promotes vasculogenesis and myocardial recovery.

PubMed

Mewhort, Holly E M; Turnbull, Jeannine D; Satriano, Alessandro; Chow, Kelvin; Flewitt, Jacqueline A; Andrei, Adin-Cristian; Guzzardi, David G; Svystonyuk, Daniyil A; White, James A; Fedak, Paul W M

2016-05-01

Infarcted myocardium can remodel after successful reperfusion, resulting in left ventricular dilation and heart failure. Epicardial infarct repair (EIR) using a bioinductive extracellular matrix (ECM) biomaterial is a novel surgical approach to promote endogenous myocardial repair and functional recovery after myocardial infarction. Using a pre-clinical porcine model of coronary ischemia-reperfusion, we assessed the effects of EIR on regional functional recovery, safety, and possible mechanisms of benefit. An ECM biomaterial (CorMatrix ECM) was applied to the epicardium after 75 minutes of coronary ischemia in a porcine model. Following ischemia-reperfusion injury, animals were randomly assigned in 2:1 fashion to EIR (n = 8) or sham treatment (n = 4). Serial cardiac magnetic resonance imaging was performed on normal (n = 4) and study animals at baseline (1 week) and 6 weeks after treatment. Myocardial function and tissue characteristics were assessed. Functional myocardial recovery was significantly increased by EIR compared with sham treatment (change in regional myocardial contraction at 6 weeks, 28.6 ± 14.0% vs 4.2 ± 13.5% wall thickening, p < 0.05). Animals receiving EIR had reduced adhesions compared with animals receiving sham treatment (1.44 ± 0.51 vs 3.08 ± 0.89, p < 0.05). Myocardial fibrosis was not increased, and EIR did not cause myocardial constriction, as left ventricular compliance by passive pressure distention at matched volumes was similar between groups (13.9 ± 4.0 mm Hg in EIR group vs 16.0 ± 5.2 mm Hg in sham group, p = 0.61). Animals receiving EIR showed evidence of vasculogenesis in the region of functional recovery. In addition to the beneficial effects of successful reperfusion, EIR using a bioinductive ECM enhances myocardial repair and functional recovery. Clinical translation of EIR early after myocardial infarction as an adjunct to surgical revascularization may be warranted in the future. Copyright © 2016 The Authors. Published

Both selenium deficiency and modest selenium supplementation lead to myocardial fibrosis in mice via effects on redox-methylation balance.

PubMed

Metes-Kosik, Nicole; Luptak, Ivan; Dibello, Patricia M; Handy, Diane E; Tang, Shiow-Shih; Zhi, Hui; Qin, Fuzhong; Jacobsen, Donald W; Loscalzo, Joseph; Joseph, Jacob

2012-12-01

Selenium has complex effects in vivo on multiple homeostatic mechanisms such as redox balance, methylation balance, and epigenesis, via its interaction with the methionine-homocysteine cycle. In this study, we examined the hypothesis that selenium status would modulate both redox and methylation balance and thereby modulate myocardial structure and function. We examined the effects of selenium-deficient (<0.025 mg/kg), control (0.15 mg/kg), and selenium-supplemented (0.5 mg/kg) diets on myocardial histology, biochemistry and function in adult C57/BL6 mice. Selenium deficiency led to reactive myocardial fibrosis and systolic dysfunction accompanied by increased myocardial oxidant stress. Selenium supplementation significantly reduced methylation potential, DNA methyltransferase activity and DNA methylation. In mice fed the supplemented diet, inspite of lower oxidant stress, myocardial matrix gene expression was significantly altered resulting in reactive myocardial fibrosis and diastolic dysfunction in the absence of myocardial hypertrophy. Our results indicate that both selenium deficiency and modest selenium supplementation leads to a similar phenotype of abnormal myocardial matrix remodeling and dysfunction in the normal heart. The crucial role selenium plays in maintaining the balance between redox and methylation pathways needs to be taken into account while optimizing selenium status for prevention and treatment of heart failure. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Application of Near Infrared Spectroscopy, Intravascular Ultrasound and the Coronary Calcium Score to Predict Adverse Coronary Events

DTIC Science & Technology

2012-10-01

hospitalization 9. Emergence of rhythm disturbances requiring treatment 10. Development of acute coronary syndrome 11. Cerebrovascular accident Adverse...catheterization. These will include coronary injury including dissection, perforation or occlusion, death, cerebrovascular accident , myocardial... cerebrovascular accident , bleeding, infection, arrhythmia, access site damage, coronary dissection, coronary thrombosis and myocardial infarction, among

Impact of positive and negative lesion site remodeling on clinical outcomes: insights from PROSPECT.

PubMed

Inaba, Shinji; Mintz, Gary S; Farhat, Naim Z; Fajadet, Jean; Dudek, Dariusz; Marzocchi, Antonio; Templin, Barry; Weisz, Giora; Xu, Ke; de Bruyne, Bernard; Serruys, Patrick W; Stone, Gregg W; Maehara, Akiko

2014-01-01

This study investigated coronary artery remodeling patterns associated with clinical outcomes. In the prospective, multicenter PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree: An Imaging Study in Patients With Unstable Atherosclerotic Lesions) study, reported predictors of nonculprit lesion (NCL) major adverse cardiac events (MACE) were an intravascular ultrasound (IVUS) minimal lumen area (MLA) ≤4 mm(2), a plaque burden ≥70%, and a IVUS-virtual histology (VH) thin-cap fibroatheroma (TCFA), but not lesion site remodeling. Overall, 697 consecutive patients with an acute coronary syndrome were enrolled and underwent 3-vessel gray-scale and IVUS-VH; 3,223 NCLs were identified by IVUS. The remodeling index (RI) was calculated as the external elastic membrane area at the MLA site divided by the average of the proximal and distal reference external elastic membrane areas. First, one third of the patients were randomly selected to determine RI cutoffs related to NCL MACE (development cohort). Receiver-operating characteristic analysis showed that there were 2 separate cut points that predicted NCL MACE: RI = 0.8789 and RI = 1.0046 (area under the curve = 0.663). These cut points were used to define negative remodeling as an RI <0.88, intermediate remodeling as an RI of 0.88 to 1.00, and positive remodeling as an RI >1.00. Second, we used the remaining two-thirds of patients to validate these cut points with respect to lesion morphology and clinical outcomes (validation cohort). Kaplan-Meier curve analysis in the validation cohort showed that NCL MACE occurred more frequent (and equally) in negative and positive remodeling lesions compared with intermediate remodeling lesions. In this cohort, negative remodeling lesions had the smallest MLA, positive remodeling lesions had the largest plaque burden, and VH TCFA, especially VH TCFA with multiple necrotic cores, was most common in negatively remodeling lesions. The present

Interleukin-6 and the Risk of Adverse Outcomes in Patients After an Acute Coronary Syndrome: Observations From the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52) Trial.

PubMed

Fanola, Christina L; Morrow, David A; Cannon, Christopher P; Jarolim, Petr; Lukas, Mary Ann; Bode, Christoph; Hochman, Judith S; Goodrich, Erica L; Braunwald, Eugene; O'Donoghue, Michelle L

2017-10-24

Interleukin-6 (IL-6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL-6 post-ACS. IL-6 concentration was assessed at baseline in 4939 subjects in SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS. Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS, ACS type, and randomized treatment arm. For every SD increase in IL-6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR] 1.10, 95% confidence interval [CI] 1.01-1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11-1.34). Patients in the highest IL-6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22-2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6-3.29). After further adjustment for biomarkers (high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A 2 activity, high-sensitivity troponin I, and B-type natriuretic peptide), IL-6 remained significantly associated with the risk of major adverse cardiovascular events (adj HR Q4:Q1 1.43, 95% CI 1.09-1.88) and cardiovascular death or heart failure (adj HR 1.79, 95% CI 1.22-2.63). In patients after ACS, IL-6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL-6 as a potential therapeutic target in patients with unstable ischemic heart disease. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis.

PubMed

Liu, Jiabao; Wu, Peng; Wang, Yunle; Du, Yingqiang; A, Nan; Liu, Shuiyuan; Zhang, Yiming; Zhou, Ningtian; Xu, Zhihui; Yang, Zhijian

2016-01-01

Cell death in MI is the most critical determinant of subsequent left ventricular remodeling and heart failure. Besides apoptosis, autophagy and necroptosis have been recently found to be another two regulated cell death styles. HGF has been reported to have a protective role in MI, but its impact on the three death styles remains unclear. Thus, our study was performed to investigate the distribution of autophagy, apoptosis and necroptosis in cardiac tissues after MI and explore the role and mechanism of Ad-HGF on cardiac remodeling by regulating the three death styles. We firstly showed the distribution of autophagy, apoptosis and necroptosis differs in temporal and spatial context after MI using immunofluorescence. Notably, Ad-HGF treatment improves the cardiac remodeling of SD rats following MI by preserving the heart function, reducing the scar size and aggresomes. Further mechanism study reveals Ad-HGF promotes autophagy and necroptosis and inhibits apoptosis in vivo and in vitro . Co-immunoprecipitation assays showed Ad-HGF treatment significantly decreased the binding of Bcl-2 to Beclin1 but enhanced Bcl-2 binding to Bax in H9c2 cells under hypoxia. Moreover, HGF-induced sequestration of Bax by Bcl-2 allows Bax to become inactive, thereby inhibiting apoptosis. In addition, Ad-HGF markedly increased the formation of Beclin1-Vps34-Atg14L complex, which accounted for promoting autophagy. Both the western blot and activity assay showed Ad-HGF significantly decreased the caspase 8 protein and activity levels, which obligated the cell to undergo necroptosis under hypoxia and block apoptosis. Thus, our findings offer new evidence and strategies for the treatment of MI and post-MI cardiac remodeling.

Ad-HGF improves the cardiac remodeling of rat following myocardial infarction by upregulating autophagy and necroptosis and inhibiting apoptosis

PubMed Central

Liu, Jiabao; Wu, Peng; Wang, Yunle; Du, Yingqiang; A, Nan; Liu, Shuiyuan; Zhang, Yiming; Zhou, Ningtian; Xu, Zhihui; Yang, Zhijian

2016-01-01

Cell death in MI is the most critical determinant of subsequent left ventricular remodeling and heart failure. Besides apoptosis, autophagy and necroptosis have been recently found to be another two regulated cell death styles. HGF has been reported to have a protective role in MI, but its impact on the three death styles remains unclear. Thus, our study was performed to investigate the distribution of autophagy, apoptosis and necroptosis in cardiac tissues after MI and explore the role and mechanism of Ad-HGF on cardiac remodeling by regulating the three death styles. We firstly showed the distribution of autophagy, apoptosis and necroptosis differs in temporal and spatial context after MI using immunofluorescence. Notably, Ad-HGF treatment improves the cardiac remodeling of SD rats following MI by preserving the heart function, reducing the scar size and aggresomes. Further mechanism study reveals Ad-HGF promotes autophagy and necroptosis and inhibits apoptosis in vivo and in vitro. Co-immunoprecipitation assays showed Ad-HGF treatment significantly decreased the binding of Bcl-2 to Beclin1 but enhanced Bcl-2 binding to Bax in H9c2 cells under hypoxia. Moreover, HGF-induced sequestration of Bax by Bcl-2 allows Bax to become inactive, thereby inhibiting apoptosis. In addition, Ad-HGF markedly increased the formation of Beclin1-Vps34-Atg14L complex, which accounted for promoting autophagy. Both the western blot and activity assay showed Ad-HGF significantly decreased the caspase 8 protein and activity levels, which obligated the cell to undergo necroptosis under hypoxia and block apoptosis. Thus, our findings offer new evidence and strategies for the treatment of MI and post-MI cardiac remodeling. PMID:27904666

Ultrasound-targeted microbubble destruction enhances delayed BMC delivery and attenuates post-infarction cardiac remodelling by inducing engraftment signals.

PubMed

Chen, Yanmei; Zhang, Chuanxi; Shen, Shuxin; Guo, Shengcun; Zhong, Lintao; Li, Xinzhong; Chen, Guojun; Chen, Gangbin; He, Xiang; Huang, Chixiong; He, Nvqin; Liao, Wangjun; Liao, Yulin; Bin, Jianping

2016-12-01

Delayed administration of bone marrow cells (BMCs) at 2-4 weeks after successful reperfusion in patients with acute myocardial infarction (MI) does not improve cardiac function. The reduction in engraftment signals observed following this time interval might impair the effects of delayed BMC treatment. In the present study, we aimed to determine whether ultrasound-targeted microbubble destruction (UTMD) treatment could increase engraftment signals, enhance the delivery of delayed BMCs and subsequently attenuate post-infarction cardiac remodelling. A myocardial ischaemia/reperfusion (I/R) model was induced in Wistar rats via left coronary ligation for 45 min followed by reperfusion. Western blotting revealed that engraftment signals peaked at 7 days post-I/R and were dramatically lower at 14 days post-I/R. The lower engraftment signals at 14 days post-I/R could be triggered by UTMD treatment at a mechanical index of 1.0-1.9. The troponin I levels in the 1.9 mechanical index group were higher than in the other groups. Simultaneous haematoxylin and eosin staining and fluorescence revealed that the number of engrafted BMCs in the ischaemic zone was greater in the group treated with both UTMD and delayed BMC transplantation than in the control groups (P<0.05). Both UTMD and delayed BMC transplantation improved cardiac function and decreased cardiac fibrosis at 4 weeks after treatment, as compared with control groups (both P<0.05). Histopathology demonstrated that UTMD combined with delayed BMC transplantation increased capillary density, myocardial cell proliferation and c-kit + cell proliferation. These findings indicated that UTMD treatment could induce engraftment signals and enhance homing of delayed BMCs to ischaemic myocardium, attenuating post-infarction cardiac remodelling by promoting neovascularization, cardiomyogenesis and expansion of cardiac c-kit + cells. © 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.

Two-dimensional speckle tracking echocardiography prognostic parameters in patients after acute myocardial infarction.

PubMed

Haberka, Maciej; Liszka, Jerzy; Kozyra, Andrzej; Finik, Maciej; Gąsior, Zbigniew

2015-03-01

The aim of the study was to evaluate the left ventricle (LV) function with speckle tracking echocardiography (STE) and to assess its relation to prognosis in patients after acute myocardial infarction (AMI). Sixty-three patients (F/M = 16/47 pts; 62.33 ± 11.85 years old) with AMI (NSTEMI/STEMI 24/39 pts) and successful percutaneous coronary intervention (PCI) with stent implantation (thrombolysis in myocardial infarction; TIMI 3 flow) were enrolled in this study. All patients underwent baseline two-dimensional conventional echocardiography and STE 3 days (baseline) and 30 days after PCI. All patients were followed up for cardiovascular clinical endpoints, major adverse cardiovascular endpoint (MACE), and functional status (Canadian Cardiovascular Society and New York Heart Association). During the follow-up (31.9 ± 5.1 months), there were 3 cardiovascular deaths, 15 patients had AMI, 2 patients had cerebral infarction, 24 patients reached the MACE. Baseline LV torsion (P = 0.035), but none of the other strain parameters were associated with the time to first unplanned cardiovascular hospitalization. Univariate analysis showed that baseline longitudinal two-chamber and four-chamber strain (sLa2 0 and sLa4 0) and the same parameters obtained 30 days after the AMI together with transverse four-chamber strain (sLa2 30, sLa4 30, and sTa4 30) were significantly associated with combined endpoint (MACE). The strongest association in the univariate analysis was found for the baseline sLa2. However, in multivariable analysis only a left ventricular remodeling (LVR - 27% pts) was significantly associated with MACE and strain parameters were not associated with the combined endpoint. The assessment of LV function with STE may improve cardiovascular risk prediction in postmyocardial infarction patients. © 2014, Wiley Periodicals, Inc.

No-Regrets Remodeling, 2nd Edition

DOE Office of Scientific and Technical Information (OSTI.GOV)

None

2013-12-01

No-Regrets Remodeling, sponsored by Oak Ridge National Laboratory, is an informative publication that walks homeowners and/or remodelers through various home remodeling projects. In addition to remodeling information, the publication provides instruction on how to incorporate energy efficiency into the remodeling process. The goal of the publication is to improve homeowner satisfaction after completing a remodeling project and to provide the homeowner with a home that saves energy and is comfortable and healthy.

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.

Clinical impacts of inhibition of renin-angiotensin system in patients with acute ST-segment elevation myocardial infarction who underwent successful late percutaneous coronary intervention.

PubMed

Park, Hyukjin; Kim, Hyun Kuk; Jeong, Myung Ho; Cho, Jae Yeong; Lee, Ki Hong; Sim, Doo Sun; Yoon, Nam Sik; Yoon, Hyun Ju; Hong, Young Joon; Kim, Kye Hun; Park, Hyung Wook; Kim, Ju Han; Ahn, Youngkeun; Cho, Jeong Gwan; Park, Jong Chun; Kim, Young Jo; Cho, Myeong Chan; Kim, Chong Jim

2017-01-01

Successful percutaneous coronary intervention (PCI) of the occluded infarct-related artery (IRA) in latecomers may improve long-term survival mainly by reducing left ventricular remodeling. It is not clear whether inhibition of renin-angiotensin system (RAS) brings additional better clinical outcomes in this specific population subset. Between January 2008 and June 2013, 669 latecomer patients with acute ST-segment elevation myocardial infarction (STEMI) (66.2±12.1 years, 71.0% males) in Korea Acute Myocardial Infarction Registry (KAMIR) who underwent a successful PCI were enrolled. The study population underwent a successful PCI for a totally occluded IRA. They were divided into two groups according to whether they were prescribed RAS inhibitors at the time of discharge: group I (RAS inhibition, n=556), and group II (no RAS inhibition, n=113). During the one-year follow-up, major adverse cardiac events (MACE), which consist of cardiac death and myocardial infarction, occurred in 71 patients (10.6%). There were significantly reduced incidences of MACE in the group I (hazard ratio=0.34, 95% confidence interval 0.199-0.588, p=0.001). In subgroup analyses, RAS inhibition was beneficial in patients with male gender, history of hypertension or diabetes mellitus, and even in patients with left ventricular ejection fraction (LVEF) ≥40%. In the baseline and follow-up echocardiographic data, benefit in changes of LVEF and left ventricular end-systolic volume was noted in group I. In latecomers with STEMI, RAS inhibition improved long-term clinical outcomes after a successful PCI, even in patients with low risk who had relatively preserved LVEF. Copyright © 2016 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.

Conditioning the heart to prevent myocardial reperfusion injury during PPCI

PubMed Central

2012-01-01

For patients presenting with a ST-segment elevation myocardial infarction (STEMI), early myocardial reperfusion by primary percutaneous coronary intervention (PPCI) remains the most effective treatment strategy for limiting myocardial infarct size, preserving left ventricular systolic function, and preventing the onset of heart failure. Recent advances in PCI technology to improve myocardial reperfusion and the introduction of novel anti-platelet and anti-thrombotic agents to maintain the patency of the infarct-related coronary artery continue to optimize PPCI procedure. However, despite these improvements, STEMI patients still experience significant major adverse cardiovascular events. One major contributing factor has been the inability to protect the heart against the lethal myocardial reperfusion injury, which accompanies PPCI. Past attempts to translate cardioprotective strategies, discovered in experimental studies to prevent lethal myocardial reperfusion injury, into the clinical setting of PPCI have been disappointing. However, a number of recent proof-of-concept clinical studies suggest that the heart can be ‘conditioned’ to protect itself against lethal myocardial reperfusion injury, as evidenced by a reduction in myocardial infarct size. This can be achieved using either mechanical (such as ischaemic postconditioning, remote ischaemic preconditioning, therapeutic hypothermia, or hyperoxaemia) or pharmacological (such as cyclosporin-A, natriuretic peptide, exenatide) ‘conditioning’ strategies as adjuncts to PPCI. Furthermore, recent developments in cardiac magnetic resonance (CMR) imaging can provide a non-invasive imaging strategy for assessing the efficacy of these novel adjunctive therapies to PPCI in terms of key surrogate clinical endpoints such as myocardial infarct size, myocardial salvage, left ventricular ejection fraction, and the presence of microvascular obstruction or intramyocardial haemorrhage. In this article, we review the

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.

Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning: role of protein kinase B/Akt signaling.

PubMed

Feng, Jianhua; Fischer, Gregor; Lucchinetti, Eliana; Zhu, Min; Bestmann, Lukas; Jegger, David; Arras, Margarete; Pasch, Thomas; Perriard, Jean-Claude; Schaub, Marcus C; Zaugg, Michael

2006-05-01

Postinfarct remodeled myocardium exhibits numerous structural and biochemical alterations. So far, it is unknown whether postconditioning elicited by volatile anesthetics can also provide protection in the remodeled myocardium. Myocardial infarct was induced in male Wistar rats by ligation of the left anterior descending coronary artery. Six weeks later, hearts were buffer-perfused and exposed to 40 min of ischemia followed by 90 min of reperfusion. Anesthetic postconditioning was induced by 15 min of 2.1 vol% isoflurane. In some experiments, LY294002 (15 microM), a phosphatidylinositol 3-kinase inhibitor, was coadministered with isoflurane. Masson's trichrome staining, immunohistochemistry, Western blot analysis, and reverse-transcription polymerase chain reaction served to confirm remodeling. In buffer-perfused hearts, functional recovery was recorded, and acute infarct size was measured using 1% triphenyltetrazolium chloride staining and lactate dehydrogenase release during reperfusion. Western blot analysis was used to determine phosphorylation of reperfusion injury salvage kinases including protein kinase B/Akt and its downstream targets after 15 min of reperfusion. Infarct hearts exhibited typical macroscopic and molecular changes of remodeling. Isoflurane postconditioning improved functional recovery and decreased acute infarct size, as determined by triphenyltetrazolium (35 +/- 5% in unprotected hearts vs. 8 +/- 3% in anesthetic postconditioning; P < 0.05) and lactate dehydrogenase release. This protection was abolished by LY294002, which inhibited phosphorylation of protein kinase B/Akt and its downstream targets glycogen synthase kinase 3beta, endothelial nitric oxide synthase, and p70S6 kinase. Infarct-remodeled myocardium is receptive to protection by isoflurane postconditioning via protein kinase B/Akt signaling. This is the first time to demonstrate that anesthetic postconditioning retains its marked protection in diseased myocardium.

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

Myocardial Scaffold-based Cardiac Tissue Engineering: Application of Coordinated Mechanical and Electrical Stimulations

PubMed Central

Wang, Bo; Wang, Guangjun; To, Filip; Butler, J. Ryan; Claude, Andrew; McLaughlin, Ronald M.; Williams, Lakiesha N.; de Jongh Curry, Amy L.; Liao, Jun

2013-01-01

Recently, we have developed an optimal decellularization protocol to generate 3D porcine myocardial scaffolds, which preserved natural extracellular matrix structure, mechanical anisotropy, and vasculature templates, and also showed good cell recellularization and differentiation potential. In this study, a multi-stimulation bioreactor was built to provide coordinated mechanical and electrical stimulations for facilitating stem cell differentiation and cardiac construct development. The acellular myocardial scaffolds were seeded with mesenchymal stem cells (106 cells/ml) by needle injection and subjected to 5-azacytidine treatment (3 μmol/L, 24 h) and various bioreactor conditioning protocols. We found that, after 2-day culture with mechanical (20% strain) and electrical stimulation (5 V, 1 Hz), high cell density and good cell viability were observed in the reseeded scaffold. Immunofluorescence staining demonstrated that the differentiated cells showed cardiomyocyte-like phenotype, by expressing sarcomeric α-actinin, myosin heavy chain, cardiac troponin T, connexin-43, and N-cadherin. Biaxial mechanical testing demonstrated that positive tissue remodeling took place after 2-day bioreactor conditioning (20% strain + 5 V, 1 Hz); passive mechanical properties of the 2-day and 4-day tissue constructs were comparable to the tissue constructs produced by stirring reseeding followed by 2-week static culture, implying the effectiveness and efficiency of the coordinated simulations in promoting tissue remodeling. In short, the synergistic stimulations might be beneficial not only for the quality of cardiac construct development, but also for patients by reducing the waiting time in future clinical scenarios. PMID:23923967

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.

Chromatin Remodeling and Plant Immunity.

PubMed

Chen, W; Zhu, Q; Liu, Y; Zhang, Q

Chromatin remodeling, an important facet of the regulation of gene expression in eukaryotes, is performed by two major types of multisubunit complexes, covalent histone- or DNA-modifying complexes, and ATP-dependent chromosome remodeling complexes. Snf2 family DNA-dependent ATPases constitute the catalytic subunits of ATP-dependent chromosome remodeling complexes, which accounts for energy supply during chromatin remodeling. Increasing evidence indicates a critical role of chromatin remodeling in the establishment of long-lasting, even transgenerational immune memory in plants, which is supported by the findings that DNA methylation, histone deacetylation, and histone methylation can prime the promoters of immune-related genes required for disease defense. So what are the links between Snf2-mediated ATP-dependent chromosome remodeling and plant immunity, and what mechanisms might support its involvement in disease resistance? © 2017 Elsevier Inc. All rights reserved.

Erythrocyte Stiffness during Morphological Remodeling Induced by Carbon Ion Radiation

PubMed Central

Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

2014-01-01

The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

Erythrocyte stiffness during morphological remodeling induced by carbon ion radiation.

PubMed

Zhang, Baoping; Liu, Bin; Zhang, Hong; Wang, Jizeng

2014-01-01

The adverse effect induced by carbon ion radiation (CIR) is still an unavoidable hazard to the treatment object. Thus, evaluation of its adverse effects on the body is a critical problem with respect to radiation therapy. We aimed to investigate the change between the configuration and mechanical properties of erythrocytes induced by radiation and found differences in both the configuration and the mechanical properties with involving in morphological remodeling process. Syrian hamsters were subjected to whole-body irradiation with carbon ion beams (1, 2, 4, and 6 Gy) or X-rays (2, 4, 6, and 12 Gy) for 3, 14 and 28 days. Erythrocytes in peripheral blood and bone marrow were collected for cytomorphological analysis. The mechanical properties of the erythrocytes were determined using atomic force microscopy, and the expression of the cytoskeletal protein spectrin-α1 was analyzed via western blotting. The results showed that dynamic changes were evident in erythrocytes exposed to different doses of carbon ion beams compared with X-rays and the control (0 Gy). The magnitude of impairment of the cell number and cellular morphology manifested the subtle variation according to the irradiation dose. In particular, the differences in the size, shape and mechanical properties of the erythrocytes were well exhibited. Furthermore, immunoblot data showed that the expression of the cytoskeletal protein spectrin-α1 was changed after irradiation, and there was a common pattern among its substantive characteristics in the irradiated group. Based on these findings, the present study concluded that CIR could induce a change in mechanical properties during morphological remodeling of erythrocytes. According to the unique characteristics of the biomechanical categories, we deduce that changes in cytomorphology and mechanical properties can be measured to evaluate the adverse effects generated by tumor radiotherapy. Additionally, for the first time, the current study provides a new

Dobutamine cardiovascular magnetic resonance for the detection of myocardial ischemia with the use of myocardial tagging.

PubMed

Kuijpers, Dirkjan; Ho, Kai Yiu J A M; van Dijkman, Paul R M; Vliegenthart, Rozemarijn; Oudkerk, Matthijs

2003-04-01

The purpose of this study was to assess the value of high-dose dobutamine cardiovascular magnetic resonance (CMR) with myocardial tagging for the detection of wall motion abnormalities as a measure of myocardial ischemia in patients with known or suspected coronary artery disease. Two hundred eleven consecutive patients with chest pain underwent dobutamine-CMR 4 days after antianginal medication was stopped. Dobutamine-CMR was performed at rest and during increasing doses of dobutamine. Cine-images were acquired during breath-hold with and without myocardial tagging at 3 short-axis levels. Regional wall motion was assessed in a 16-segment short-axis model. Patients with new wall motion abnormalities (NWMA) were examined by coronary angiography. Dobutamine-CMR was successfully performed in 194 patients. Dobutamine-CMR without tagging detected NWMA in 58 patients, whereas NWMA were detected in 68 patients with tagging (P=0.002, McNemar). Coronary angiography showed coronary artery disease in 65 (96%) of these 68 patients. All but 3 of the 65 patients needed revascularization. In the 112 patients with a negative dobutamine-CMR study, without baseline wall motion abnormalities, the cardiovascular occurrence-free survival rate was 98.2% during the mean follow-up period of 17.3 months (range, 7 to 31). Dobutamine-CMR with myocardial tagging detected more NWMA compared with dobutamine-CMR without tagging and reliably separated patients with a normal life expectancy from those at increased risk of major adverse cardiac events.

Fiber architecture in remodeled myocardium revealed with a quantitative diffusion CMR tractography framework and histological validation.

PubMed

Mekkaoui, Choukri; Huang, Shuning; Chen, Howard H; Dai, Guangping; Reese, Timothy G; Kostis, William J; Thiagalingam, Aravinda; Maurovich-Horvat, Pal; Ruskin, Jeremy N; Hoffmann, Udo; Jackowski, Marcel P; Sosnovik, David E

2012-10-12

The study of myofiber reorganization in the remote zone after myocardial infarction has been performed in 2D. Microstructural reorganization in remodeled hearts, however, can only be fully appreciated by considering myofibers as continuous 3D entities. The aim of this study was therefore to develop a technique for quantitative 3D diffusion CMR tractography of the heart, and to apply this method to quantify fiber architecture in the remote zone of remodeled hearts. Diffusion Tensor CMR of normal human, sheep, and rat hearts, as well as infarcted sheep hearts was performed ex vivo. Fiber tracts were generated with a fourth-order Runge-Kutta integration technique and classified statistically by the median, mean, maximum, or minimum helix angle (HA) along the tract. An index of tract coherence was derived from the relationship between these HA statistics. Histological validation was performed using phase-contrast microscopy. In normal hearts, the subendocardial and subepicardial myofibers had a positive and negative HA, respectively, forming a symmetric distribution around the midmyocardium. However, in the remote zone of the infarcted hearts, a significant positive shift in HA was observed. The ratio between negative and positive HA variance was reduced from 0.96 ± 0.16 in normal hearts to 0.22 ± 0.08 in the remote zone of the remodeled hearts (p < 0.05). This was confirmed histologically by the reduction of HA in the subepicardium from -52.03° ± 2.94° in normal hearts to -37.48° ± 4.05° in the remote zone of the remodeled hearts (p < 0.05). A significant reorganization of the 3D fiber continuum is observed in the remote zone of remodeled hearts. The positive (rightward) shift in HA in the remote zone is greatest in the subepicardium, but involves all layers of the myocardium. Tractography-based quantification, performed here for the first time in remodeled hearts, may provide a framework for assessing regional changes in the left ventricle following

The amelioration of cardiac dysfunction after myocardial infarction by the injection of keratin biomaterials derived from human hair.

PubMed

Shen, Deliang; Wang, Xiaofang; Zhang, Li; Zhao, Xiaoyan; Li, Jingyi; Cheng, Ke; Zhang, Jinying

2011-12-01

Cardiac dysfunction following acute myocardial infarction is a major cause of advanced cardiomyopathy. Conventional pharmacological therapies rely on prompt reperfusion and prevention of repetitive maladaptive pathways. Keratin biomaterials can be manufactured in an autologous fashion and are effective in various models of tissue regeneration. However, its potential application in cardiac regeneration has not been tested. Keratin biomaterials were derived from human hair and its structure morphology, carryover of beneficial factors, biocompatibility with cardiomyocytes, and in vivo degradation profile were characterized. After delivery into infarcted rat hearts, the keratin scaffolds were efficiently infiltrated by cardiomyocytes and endothelial cells. Injection of keratin biomaterials promotes angiogenesis but does not exacerbate inflammation in the post-MI hearts. Compared to control-injected animals, keratin biomaterials-injected animals exhibited preservation of cardiac function and attenuation of adverse ventricular remodeling over the 8 week following time course. Tissue western blot analysis revealed up-regulation of beneficial factors (BMP4, NGF, TGF-beta) in the keratin-injected hearts. The salient functional benefits, the simplicity of manufacturing and the potentially autologous nature of this biomaterial provide impetus for further translation to the clinic. Copyright © 2011 Elsevier Ltd. All rights reserved.

Correlation of platelet count and acute ST-elevation in myocardial infarction.

PubMed

Paul, G K; Sen, B; Bari, M A; Rahman, Z; Jamal, F; Bari, M S; Sazidur, S R

2010-07-01

The role of platelets in the pathogenesis of ST-elevation myocardial infarction (STEMI) has been substantiated by studies that demonstrated significant clinical benefits associated with antiplatelet therapy. Initial platelet counts in Acute Myocardial Infarction (AMI) may be a useful adjunct for identifying those patients who may or may not respond to fibrinolytic agents. Patient with acute STEMI has variable level of platelet count and with higher platelet count have poor in hospital outcome. There are many predictors of poor outcome in Acute Myocardial Infarction (AMI) like cardiac biomarkers (Troponin I, Troponin T and CK-MB), C-Reactive Protien (CRP) and WBC (White Blood Cell) counts. Platelet count on presentation of STEMI is one of them. Higher platelet count is associated with higher rate of adverse clinical outcome in ST-Elevation Myocardial Infarction (STEMI), like heart failure, arrhythmia, re-infarction & death. So, categorization of patient with STEMI on the basis of platelet counts may be helpful for risk stratification and management of these patients.

Magnetic resonance imaging in interventional therapy of patients with acute myocardial infarction prior to and after treatment

PubMed Central

Li, Yuzhou; Li, Chunrong; Jin, Hongrui; Huang, Wenqi

2016-01-01

The aim of the study was to investigate the cardiac magnetic resonance (CMR) imaging in interventional therapy of patients with acute myocardial infarction prior to and after treatment. Fifty-six cases of AMI patients with elective treatment by percutaneous coronary intervention (PCI) were continuously selected. Patients with an incidence of 7–10 days were treated with CMR and echocardiography to evaluate the quality of myocardial infarction, visual score method (VSM), wall motion score abnormality, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD) and left ventricular ejection fraction (LVEF). Patients with an incidence of 10–14 days were treated with PCI, and CMR and echocardiography were evaluated after 6 months, after which the occurrence of major adverse cardiac events (MACE) were compared. The infarction quality, VSM score and wall motion abnormality (WMA) score were significantly reduced following surgery, and the difference was statistically significant (P<0.05). Ultrasound evaluation of LVEDD, LVESD, and LVEF prior to and after surgery was compared, and the difference was not statistically significant (P>0.05). Evaluation of the magnetic resonance imaging (MRI) in LVEDD prior to surgery was increased compared with that of the ultrasound in LVEDD, whereas MRI in LVESD and LVEF was decreased compared to that of the ultrasound obtained for LVESD and LVEF. Additionally, postoperative LVEDD was reduced compared with preoperative LVEDD, whereas LVEF was increased, and the difference was statistically significant (P<0.05). However, the evaluation of LVESD using the two methods exhibited no significant change. MACE occurred in 7 (12.5%) of 56 cases. The infarction quality of patients in the MACE group following surgery indicated that VSM and WMA scores were significantly higher than the group without MACE, while LVEF was lower than the MACE group following surgery, and the difference was statistically significant

Low-Level Laser Application in the Early Myocardial Infarction Stage Has No Beneficial Role in Heart Failure.

PubMed

Manchini, Martha T; Antônio, Ednei L; Silva Junior, José Antônio; de Carvalho, Paulo de Tarso C; Albertini, Regiane; Pereira, Fernando C; Feliciano, Regiane; Montemor, Jairo; Vieira, Stella S; Grandinetti, Vanessa; Yoshizaki, Amanda; Chaves, Marcio; da Silva, Móises P; de Lima, Rafael do Nascimento; Bocalini, Danilo S; de Melo, Bruno L; Tucci, Paulo J F; Serra, Andrey J

2017-01-01

Low-level laser therapy (LLLT) has been targeted as a promising approach that can mitigate post-infarction cardiac remodeling. There is some interesting evidence showing that the beneficial role of the LLLT could persist long-term even after the end of the application, but it remains to be systematically evaluated. Therefore, the present study aimed to test the hypothesis that LLLT beneficial effects in the early post-infarction cardiac remodeling could remain in overt heart failure even with the disruption of irradiations. Female Wistar rats were subjected to the coronary occlusion to induce myocardial infarction or Sham operation. A single LLLT application was carried out after 60 s and 3 days post-coronary occlusion, respectively. Echocardiography was performed 3 days and at the end of the experiment (5 weeks) to evaluate cardiac function. After the last echocardiographic examination, LV hemodynamic evaluation was performed at baseline and on sudden afterload increases. Compared with the Sham group, infarcted rats showed increased systolic and diastolic internal diameter as well as a depressed shortening fraction of LV. The only benefit of the LLLT was a higher shortening fraction after 3 days of infarction. However, treated-LLLT rats show a lower shortening fraction in the 5th week of study when compared with Sham and non-irradiated rats. A worsening of cardiac function was confirmed in the hemodynamic analysis as evidenced by the higher LV end-diastolic pressure and lower +dP/dt and -dP/dt with five weeks of study. Cardiac functional reserve was also impaired by infarction as evidenced by an attenuated response of stroke work index and cardiac output to a sudden afterload stress, without LLLT repercussions. No significant differences were found in the myocardial expression of Akt 1 /VEGF pathway. Collectively, these findings illustrate that LLLT improves LV systolic function in the early post-infarction cardiac remodeling. However, this beneficial effect may

Involvement of Inflammation and Adverse Vascular Remodelling in the Blood Pressure Raising Effect of Repeatedly Heated Palm Oil in Rats

PubMed Central

Ng, Chun-Yi; Kamisah, Yusof; Faizah, Othman; Jubri, Zakiah; Qodriyah, Hj Mohd Saad; Jaarin, Kamsiah

2012-01-01

Oil thermoxidation during deep frying generates harmful oxidative free radicals that induce inflammation and increase the risk of hypertension. This study aimed to investigate the effect of repeatedly heated palm oil on blood pressure, aortic morphometry, and vascular cell adhesion molecule-1 (VCAM-1) expression in rats. Male Sprague-Dawley rats were divided into five groups: control, fresh palm oil (FPO), one-time-heated palm oil (1HPO), five-time-heated palm oil (5HPO), or ten-time-heated palm oil (10HPO). Feeding duration was six months. Blood pressure was measured at baseline and monthly using tail-cuff method. After six months, the rats were sacrificed and the aortic arches were dissected for morphometric and immunohistochemical analyses. FPO group showed significantly lower blood pressure than all other groups. Blood pressure was increased significantly in 5HPO and 10HPO groups. The aortae of 5HPO and 10HPO groups showed significantly increased thickness and area of intima-media, circumferential wall tension, and VCAM-1 than other groups. Elastic lamellae were disorganised and fragmented in 5HPO- and 10HPO-treated rats. VCAM-1 expression showed a significant positive correlation with blood pressure. In conclusion, prolonged consumption of repeatedly heated palm oil causes blood pressure elevation, adverse remodelling, and increased VCAM-1, which suggests a possible involvement of inflammation. PMID:22778962

Gender differences in the assessment and treatment of myocardial infarction.

PubMed

Jortveit, Jarle; Govatsmark, Ragna Elise Støre; Langørgen, Jørund; Hole, Torstein; Mannsverk, Jan; Olsen, Siv; Risøe, Cecilie; Halvorsen, Sigrun

2016-08-01

Previous studies have shown that there are gender-related differences in the assessment and treatment of myocardial infarction, despite international guidelines that prescribe identical treatment for women and men. We investigated whether these differences occurred in Norway. All patients admitted to Norwegian hospitals with myocardial infarction from 1 January 2013 to 31 December 2014 and registered in the Norwegian Myocardial Infarction Registry were included. Data from the registry were used to analyse differences in the assessment, treatment, complications and survival of women and men in different age groups. A total of 26 447 myocardial infarctions were registered in the Norwegian Myocardial Infarction Registry in the period 2013 – 2014. Fewer women than men were assessed by means of coronary angiography. Percutaneous coronary intervention (PCI) was used to virtually the same extent for both genders if coronary stenosis was found. Women were recommended secondary prophylactic medication to a lesser extent than men. There were no major differences between men and women in the incidence of complications in the course following myocardial infarction or in survival. Fewer women than men suffering acute myocardial infarction were assessed by means of coronary angiography, and women were recommended secondary prophylactic medication less often than men. The reason for the gender differences is not known, but comorbidity and a potentially greater risk of adverse reactions in women may be contributory factors. The different views of doctors providing treatment may also play a part.

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.

Association between angiotensin II type 1 receptor polymorphism and sudden cardiac death in myocardial infarction.

PubMed

Kruzliak, Peter; Kovacova, Gabriela; Pechanova, Olga; Balogh, Stefan

2013-01-01

The renin-angiotensin system is involved in the pathogenesis of coronary artery disease and myocardial infarction (MI). Angiotensin II (Ang II) has many adverse effects such as vasoconstriction and vascular remodeling, and these actions are mediated by the angiotensin II type 1 receptor (AT1R). A total of 1376 patients were recruited from January 2010 to April 2012. The study group consisted of 749 patients with ACS (317 females and 432 males) and of 627 healthy controls. The ACS patients demonstrated a lower proportion of AA genotypes and AC genotypes but higher proportions of CC genotypes than the control population. The AT1R CC genotype conferred a 2.76-fold higher risk of MI compared with the genotype AC and AA. In addition, the CC genotype was also associated with a 4.08 times higher risk of left anterior descending artery infarction and a 3.07 times higher risk of anterior wall infarction. We also found that the CC genotype was independently associated with sudden cardiac death. This study demonstrated that the AT1R CC genotype is an independent risk factor for ACS incidence, and this genotype is associated with a greater ACS severity and greater risk of sudden cardiac death.

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

Pulsatile Fluid Shear in Bone Remodeling

NASA Technical Reports Server (NTRS)

Frangos, John A.

1997-01-01

The objective of this investigation was to elucidate the sensitivity to transients in fluid shear stress in bone remodeling. Bone remodeling is clearly a function of the local mechanical environment which includes interstitial fluid flow. Traditionally, load-induced remodeling has been associated with low frequency (1-2 Hz) signals attributed to normal locomotion. McLeod and Rubin, however, demonstrated in vivo remodeling events associated with high frequency (15-30 Hz) loading. Likewise, other in vivo studies demonstrated that slowly applied strains did not trigger remodeling events. We therefore hypothesized that the mechanosensitive pathways which control bone maintenance and remodeling are differentially sensitive to varying rates of applied fluid shear stress.

Troponin Limit of Detection Plus Cardiac Risk Stratification Scores to Rule Out Acute Myocardial Infarction and 30-Day Major Adverse Cardiac Events in ED Patients.

PubMed

Datlow, Mitchell D; Gray, Kelly M; Watts, Adriel; Diercks, Deborah B; Mumma, Bryn E

2017-12-01

When screening for acute myocardial infarction (AMI), troponin levels below the 99th percentile, including those below the limit of detection (LOD), are considered normal. We hypothesized that a low-risk HEART score (0-3) or ACS Pretest Probability Assessment <2% plus a single troponin below the LOD would rule out both AMI and 30-day major adverse cardiac events (MACE). We studied all patients who presented to a single academic emergency department and received a troponin I (Siemens Ultra Troponin I) from September 1, 2013, to November 13, 2013 (n=888). Demographic and clinical data were abstracted from the electronic medical record. Primary outcome was a final encounter diagnosis of myocardial infarction. Secondary outcome was 30-day MACE, defined as composite of myocardial infarction, revascularization, or death from a cardiac or uncertain etiology. Sensitivities of low-risk HEART score and ACS Pretest Probability <2% alone were 98% (95% confidence interval [CI], 89%-100%) and 96% (95% CI, 86%-100%) for AMI and 94% (95% CI, 86%-98%) and 95% (95% CI, 88%-99%), respectively, for 30-day MACE. When combined with troponin below the LOD, sensitivity for AMI was 100% (95% CI, 93%-100%; difference 2%; 95% CI, -2% to 6%) for low-risk HEART Score and 100% (95% CI, 93%-100%; difference 4%; 95% CI, -1.5% to 10%) for ACS Pretest Probability <2%. When combined with troponin below the LOD, sensitivity for 30-day MACE was 100% (95% CI, 95%-100%; difference 6%; 95% CI, 1%-12%) for low-risk HEART Score and 100% (95% CI, 95%-100%; difference 5%; 95% CI, 0.2%-10%) for ACS Pretest Probability <2%. Addition of a single troponin below the LOD to these scores improves sensitivity for 30-day MACE.

CD36 Is a Matrix Metalloproteinase-9 Substrate That Stimulates Neutrophil Apoptosis and Removal During Cardiac Remodeling.

PubMed

DeLeon-Pennell, Kristine Y; Tian, Yuan; Zhang, Bai; Cates, Courtney A; Iyer, Rugmani Padmanabhan; Cannon, Presley; Shah, Punit; Aiyetan, Paul; Halade, Ganesh V; Ma, Yonggang; Flynn, Elizabeth; Zhang, Zhen; Jin, Yu-Fang; Zhang, Hui; Lindsey, Merry L

2016-02-01

After myocardial infarction, the left ventricle undergoes a wound healing response that includes the robust infiltration of neutrophils and macrophages to facilitate removal of dead myocytes as well as turnover of the extracellular matrix. Matrix metalloproteinase (MMP)-9 is a key enzyme that regulates post-myocardial infarction left ventricular remodeling. Infarct regions from wild-type and MMP-9 null mice (n=8 per group) analyzed by glycoproteomics showed that of 541 N-glycosylated proteins quantified, 45 proteins were at least 2-fold upregulated or downregulated with MMP-9 deletion (all P<0.05). Cartilage intermediate layer protein and platelet glycoprotein 4 (CD36) were identified as having the highest fold increase in MMP-9 null mice. By immunoblotting, CD36 but not cartilage intermediate layer protein decreased steadily during the time course post-myocardial infarction, which identified CD36 as a candidate MMP-9 substrate. MMP-9 was confirmed in vitro and in vivo to proteolytically degrade CD36. In vitro stimulation of day 7 post-myocardial infarction macrophages with MMP-9 or a CD36-blocking peptide reduced phagocytic capacity. Dual immunofluorescence revealed concomitant accumulation of apoptotic neutrophils in the MMP-9 null group compared with wild-type group. In vitro stimulation of isolated neutrophils with MMP-9 decreased neutrophil apoptosis, indicated by reduced caspase-9 expression. Our data reveal a new cell-signaling role for MMP-9 through CD36 degradation to regulate macrophage phagocytosis and neutrophil apoptosis. © 2015 American Heart Association, Inc.

Assessment of myocardial fibrosis with T1 mapping MRI.

PubMed

Everett, R J; Stirrat, C G; Semple, S I R; Newby, D E; Dweck, M R; Mirsadraee, S

2016-08-01

Myocardial fibrosis can arise from a range of pathological processes and its presence correlates with adverse clinical outcomes. Cardiac magnetic resonance (CMR) can provide a non-invasive assessment of cardiac structure, function, and tissue characteristics, which includes late gadolinium enhancement (LGE) techniques to identify focal irreversible replacement fibrosis with a high degree of accuracy and reproducibility. Importantly the presence of LGE is consistently associated with adverse outcomes in a range of common cardiac conditions; however, LGE techniques are qualitative and unable to detect diffuse myocardial fibrosis, which is an earlier form of fibrosis preceding replacement fibrosis that may be reversible. Novel T1 mapping techniques allow quantitative CMR assessment of diffuse myocardial fibrosis with the two most common measures being native T1 and extracellular volume (ECV) fraction. Native T1 differentiates normal from infarcted myocardium, is abnormal in hypertrophic cardiomyopathy, and may be particularly useful in the diagnosis of Anderson-Fabry disease and amyloidosis. ECV is a surrogate measure of the extracellular space and is equivalent to the myocardial volume of distribution of the gadolinium-based contrast medium. It is reproducible and correlates well with fibrosis on histology. ECV is abnormal in patients with cardiac failure and aortic stenosis, and is associated with functional impairment in these groups. T1 mapping techniques promise to allow earlier detection of disease, monitor disease progression, and inform prognosis; however, limitations remain. In particular, reference ranges are lacking for T1 mapping values as these are influenced by specific CMR techniques and magnetic field strength. In addition, there is significant overlap between T1 mapping values in healthy controls and most disease states, particularly using native T1, limiting the clinical application of these techniques at present. Copyright © 2016 The Royal College

The GSK-3 family as therapeutic target for myocardial diseases

PubMed Central

Lal, Hind; Ahmad, Firdos; Woodgett, James; Force, Thomas

2014-01-01

GSK-3 is one of the very few signaling molecules that regulate a truly astonishing number of critical intracellular signaling pathways. It has been implicated in a number of diseases including heart failure, bipolar disorder, diabetes, Alzheimer’s disease, aging, inflammation and cancer. Furthermore, a recent clinical trial has validated the feasibility of targeting GSK-3 with small molecule inhibitors for human diseases. In the current review we will focus on its expanding role in the heart, concentrating primarily on recent studies that have employed cardiomyocyte- and fibroblast-specific conditional gene deletion in mouse models. We will highlight the role of the GSK-3 isoforms in various pathological conditions including myocardial aging, ischemic injury, myocardial fibrosis and cardiomyocyte proliferation. We will discuss our recent findings that deletion of GSK-3α specifically in cardiomyocytes attenuates ventricular remodeling and cardiac dysfunction post-MI by limiting scar expansion and promoting cardiomyocyte proliferation. The recent emergence of GSK-3β as a regulator of myocardial fibrosis will also be discussed. We will review our very recent findings that specific deletion of GSK-3β in cardiac fibroblasts leads to fibrogenesis, left ventricular dysfunction and excessive scarring in the ischemic heart. Finally, we will examine the underlying mechanisms that drive the aberrant myocardial fibrosis in the models in which GSK-3β is specifically deleted in cardiac fibroblasts. We will summarize these recent results and offer explanations, whenever possible, and hypotheses when not. For these studies we will rely heavily on our models and those of others to reconcile some of the apparent inconsistencies in the literature. PMID:25552693

Preemptive heme oxygenase-1 gene delivery reveals reduced mortality and preservation of left ventricular function 1 yr after acute myocardial infarction.

PubMed

Liu, Xiaoli; Simpson, Jeremy A; Brunt, Keith R; Ward, Christopher A; Hall, Sean R R; Kinobe, Robert T; Barrette, Valerie; Tse, M Yat; Pang, Stephen C; Pachori, Alok S; Dzau, Victor J; Ogunyankin, Kofo O; Melo, Luis G

2007-07-01

We reported previously that predelivery of heme oxygenase-1 (HO-1) gene to the heart by adeno-associated virus-2 (AAV-2) markedly reduces ischemia and reperfusion (I/R)-induced myocardial injury. However, the effect of preemptive HO-1 gene delivery on long-term survival and prevention of postinfarction heart failure has not been determined. We assessed the effect of HO-1 gene delivery on long-term survival, myocardial function, and left ventricular (LV) remodeling 1 yr after myocardial infarction (MI) using echocardiographic imaging, pressure-volume (PV) analysis, and histomorphometric approaches. Two groups of Lewis rats were injected with 2 x 10(11) particles of AAV-LacZ (control) or AAV-human HO-1 (hHO-1) in the anterior-posterior apical region of the LV wall. Six weeks after gene transfer, animals were subjected to 30 min of ischemia by ligation of the left anterior descending artery followed by reperfusion. Echocardiographic measurements and PV analysis of LV function were obtained at 2 wk and 12 mo after I/R. One year after acute MI, mortality was markedly reduced in the HO-1-treated animals compared with the LacZ-treated animals. PV analysis demonstrated significantly enhanced LV developed pressure, elevated maximal dP/dt, and lower end-diastolic volume in the HO-1 animals compared with the LacZ animals. Echocardiography showed a larger apical anterior-to-posterior wall ratio in HO-1 animals compared with LacZ animals. Morphometric analysis revealed extensive myocardial scarring and fibrosis in the infarcted LV area of LacZ animals, which was reduced by 62% in HO-1 animals. These results suggest that preemptive HO-1 gene delivery may be useful as a therapeutic strategy to reduce post-MI LV remodeling and heart failure.

Myocardial Bridge

MedlinePlus

... Center > Myocardial Bridge Menu Topics Topics FAQs Myocardial Bridge En español Your heart is made of muscle, ... surface of the heart. What is a myocardial bridge? A myocardial bridge is a band of heart ...

Human umbilical cord tissue-derived mesenchymal stromal cells attenuate remodeling after myocardial infarction by proangiogenic, antiapoptotic, and endogenous cell-activation mechanisms

PubMed Central

2014-01-01

Introduction Among the plethora of cells under investigation to restore a functional myocardium, mesenchymal stromal cells (MSCs) have been granted considerable interest. However, whereas the beneficial effects of bone marrow MSCs (BM-MSCs) in the context of the diseased heart are widely reported, data are still scarce on MSCs from the umbilical cord matrix (UCM-MSCs). Herein we report on the effect of UCM-MSC transplantation to the infarcted murine heart, seconded by the dissection of the molecular mechanisms at play. Methods Human umbilical cord tissue-derived MSCs (UCX®), obtained by using a proprietary technology developed by ECBio, were delivered via intramyocardial injection to C57BL/6 females subjected to permanent ligation of the left descending coronary artery. Moreover, medium produced by cultured UCX® preconditioned under normoxia (CM) or hypoxia (CMH) was collected for subsequent in vitro assays. Results Evaluation of the effects upon intramyocardial transplantation shows that UCX® preserved cardiac function and attenuated cardiac remodeling subsequent to myocardial infarction (MI). UCX® further led to increased capillary density and decreased apoptosis in the injured tissue. In vitro, UCX®-conditioned medium displayed (a) proangiogenic activity by promoting the formation of capillary-like structures by human umbilical vein endothelial cells (HUVECs), and (b) antiapoptotic activity in HL-1 cardiomyocytes subjected to hypoxia. Moreover, in adult murine cardiac Sca-1+ progenitor cells (CPCs), conditioned medium enhanced mitogenic activity while activating a gene program characteristic of cardiomyogenic differentiation. Conclusions UCX® preserve cardiac function after intramyocardial transplantation in a MI murine model. The cardioprotective effects of UCX® were attributed to paracrine mechanisms that appear to enhance angiogenesis, limit the extent of the apoptosis, augment proliferation, and activate a pool of resident CPCs. Overall, these results

Changing paradigms in thrombolysis in acute myocardial infarction.

PubMed

Gotsman, M S; Rozenman, Y; Admon, D; Mosseri, M; Lotan, C; Zahger, D; Weiss, A T

1997-05-23

Acute myocardial infarction occurs when a ruptured coronary artery plaque causes sudden thrombotic occlusion of a coronary artery and cessation of coronary artery blood flow. This paper reviews the underlying coronary pathology in progressive coronary atherosclerosis, mechanisms of plaque rupture and arterial occlusion and the time relationship between coronary occlusion and myocardial necrosis. Reperfusion can be achieved by chemical thrombolysis with different thrombolytic agents. Early lysis is achieved best by prehospital administration, a transtelephonic monitor, a mobile intensive care unit, active general practitioner treatment or by warning the emergency room of impending arrival of a patient. Thrombolytic therapy may be unsuccessful and not achieve Grade III TIMI flow in less than 4 h (or even 2 h) due to inadequate or intermittent perfusion or reocclusion. Adjuvant therapy includes aspirin and platelet receptor antagonists. Bleeding is a constant danger. Direct percutaneous transluminal coronary angioplasty (PTCA) may be as effective or better than chemical thrombolysis. Reperfusion protects the myocardium and salvages viable tissue. It also improves mechanical remodelling of the ventricle. Long-term follow-up has shown that quantum leaps of fresh coronary occlusion causes step-wise progression in patient disability and that further early, prompt reperfusion can salvage myocardium and prevent this inexorable progress of the disease.

Overview of large animal myocardial infarction models (review).

PubMed

Lukács, E; Magyari, B; Tóth, L; Petrási, Zs; Repa, I; Koller, A; Horváth, Iván

2012-12-01

There are several experimental models for the in vivo investigation of myocardial infarction (MI) in small (mouse, rat) and large animals (dog, pig, sheep and baboons). The application of large animal models raises ethical concerns, the design of experiments needs longer follow-up times, requiring proper breeding and housing conditions, therefore resulting in higher cost, than in vitro or small animal studies. On the other hand, the relevance of large animal models is very important, since they mostly resemble to human physiological and pathophysiological processes. The first main difference among MI models is the method of induction (open or closed chest, e.g. surgical or catheter based); the second main difference is the presence or absence of reperfusion. The former (i.e. reperfused MI) allows the investigation of reperfusion injury and new catheter based techniques during percutaneous coronary interventions, while the latter (i.e. nonreperfused MI) serves as a traditional coronary occlusion model, to test the effects of new pharmacological agents and biological therapies, as cell therapy. The reperfused and nonreperfused myocardial infarction has different outcomes, regarding left ventricular function, remodelling, subsequent heart failure, aneurysm formation and mortality. Our aim was to review the literature and report our findings regarding experimental MI models, regarding the differences among species, methods, reproducibility and interpretation.

Myocardial scaffold-based cardiac tissue engineering: application of coordinated mechanical and electrical stimulations.

PubMed

Wang, Bo; Wang, Guangjun; To, Filip; Butler, J Ryan; Claude, Andrew; McLaughlin, Ronald M; Williams, Lakiesha N; de Jongh Curry, Amy L; Liao, Jun

2013-09-03

Recently, we developed an optimal decellularization protocol to generate 3D porcine myocardial scaffolds, which preserve the natural extracellular matrix structure, mechanical anisotropy, and vasculature templates and also show good cell recellularization and differentiation potential. In this study, a multistimulation bioreactor was built to provide coordinated mechanical and electrical stimulation for facilitating stem cell differentiation and cardiac construct development. The acellular myocardial scaffolds were seeded with mesenchymal stem cells (10(6) cells/mL) by needle injection and subjected to 5-azacytidine treatment (3 μmol/L, 24 h) and various bioreactor conditioning protocols. We found that after 2 days of culturing with mechanical (20% strain) and electrical stimulation (5 V, 1 Hz), high cell density and good cell viability were observed in the reseeded scaffold. Immunofluorescence staining demonstrated that the differentiated cells showed a cardiomyocyte-like phenotype by expressing sarcomeric α-actinin, myosin heavy chain, cardiac troponin T, connexin-43, and N-cadherin. Biaxial mechanical testing demonstrated that positive tissue remodeling took place after 2 days of bioreactor conditioning (20% strain + 5 V, 1 Hz); passive mechanical properties of the 2 day and 4 day tissue constructs were comparable to those of the tissue constructs produced by stirring reseeding followed by 2 weeks of static culturing, implying the effectiveness and efficiency of the coordinated simulations in promoting tissue remodeling. In short, the synergistic stimulations might be beneficial not only for the quality of cardiac construct development but also for patients by reducing the waiting time in future clinical scenarios.

Callus remodelling model

NASA Astrophysics Data System (ADS)

Miodowska, Justyna; Bielski, Jan; Kromka-Szydek, Magdalena

2018-01-01

The objective of this paper is to investigate the healing process of the callus using bone remodelling approach. A new mathematical model of bone remodelling is proposed including both underload and overload resorption, as well as equilibrium and bone growth states. The created model is used to predict the stress-stimulated change in the callus density. The permanent and intermittent loading programs are considered. The analyses indicate that obtaining a sufficiently high values of the callus density (and hence the elasticity) modulus is only possible using time-varying load parameters. The model predictions also show that intermittent loading program causes delayed callus healing. Understanding how mechanical conditions influence callus remodelling process may be relevant in the bone fracture treatment and initial bone loading during rehabilitation.

Transmural gradients of myocardial structure and mechanics: Implications for fiber stress and strain in pressure overload.

PubMed

Carruth, Eric D; McCulloch, Andrew D; Omens, Jeffrey H

2016-12-01

Although a truly complete understanding of whole heart activation, contraction, and deformation is well beyond our current reach, a significant amount of effort has been devoted to discovering and understanding the mechanisms by which myocardial structure determines cardiac function to better treat patients with cardiac disease. Several experimental studies have shown that transmural fiber strain is relatively uniform in both diastole and systole, in contrast to predictions from traditional mechanical theory. Similarly, mathematical models have largely predicted uniform fiber stress across the wall. The development of this uniform pattern of fiber stress and strain during filling and ejection is due to heterogeneous transmural distributions of several myocardial structures. This review summarizes these transmural gradients, their contributions to fiber mechanics, and the potential functional effects of their remodeling during pressure overload hypertrophy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Aucubin protects against pressure overload-induced cardiac remodelling via the β3 -adrenoceptor-neuronal NOS cascades.

PubMed

Wu, Qing-Qing; Xiao, Yang; Duan, Ming-Xia; Yuan, Yuan; Jiang, Xiao-Han; Yang, Zheng; Liao, Hai-Han; Deng, Wei; Tang, Qi-Zhu

2018-05-01

Aucubin, the predominant component of Eucommia ulmoides Oliv., has been shown to have profound effects on oxidative stress. As oxidative stress has previously been demonstrated to contribute to acute and chronic myocardial injury, we tested the effects of aucubin on cardiac remodelling and heart failure. Initially, H9c2 cardiomyocytes and neonatal rat cardiomyocytes pretreated with aucubin (1, 3, 10, 25 and 50 μM) were challenged with phenylephrine. Secondly, the transverse aorta was constricted in C57/B6 and neuronal NOS (nNOS)-knockout mice, then aucubin (1 or 5 mg·kg -1 body weight day -1 ) was injected i.p. for 25 days. Hypertrophy was evaluated by assessing morphological changes, echocardiographic parameters, histological analyses and hypertrophic markers. Oxidative stress was evaluated by examining ROS generation, oxidase activity and NO generation. NOS expression was determined by Western blotting. Aucubin effectively suppressed cardiac remodelling; in mice, aucubin substantially inhibited pressure overload-induced cardiac hypertrophy, fibrosis and inflammation, whereas knocking out nNOS abolished these cardioprotective effects of aucubin. Blocking or knocking down the β 3 -adrenoceptor abolished the protective effects of aucubin in vitro. Furthermore, aucubin enhanced the protective effects of a β 3 -adrenoceptor agonist in vitro by increasing cellular cAMP levels, whereas treatment with an adenylate cyclase (AC) inhibitor abolished the cardioprotective effects of aucubin. Aucubin suppresses oxidative stress during cardiac remodelling by increasing the expression of nNOS in a process that requires activation of the β 3 -adrenoceptor/AC/cAMP pathway. These findings suggest that aucubin could have potential as a treatment for cardiac remodelling and heart failure. © 2018 The British Pharmacological Society.

Myocardial Rupture in Acute Myocardial Infarction: Mechanistic Explanation Based on the Ventricular Myocardial Band Hypothesis.

PubMed

Vargas-Barron, Jesús; Antunez-Montes, Omar-Yassef; Roldán, Francisco-Javier; Aranda-Frausto, Alberto; González-Pacheco, Hector; Romero-Cardenas, Ángel; Zabalgoitia, Miguel

2015-01-01

Torrent-Guasp explains the structure of the ventricular myocardium by means of a helical muscular band. Our primary purpose was to demonstrate the utility of echocardiography in human and porcine hearts in identifying the segments of the myocardial band. The second purpose was to evaluate the relation of the topographic distribution of the myocardial band with some post-myocardial infarction ruptures. Five porcine and one human heart without cardiopathy were dissected and the ventricular myocardial segments were color-coded for illustration and reconstruction purposes. These segments were then correlated to the conventional echocardiographic images. Afterwards in three cases with post-myocardial infarction rupture, a correlation of the topographic location of the rupture with the distribution of the ventricular band was made. The human ventricular band does not show any differences from the porcine band, which confirms the similarities of the four segments; these segments could be identified by echocardiography. In three cases with myocardial rupture, a correlation of the intra-myocardial dissection with the distribution of the ventricular band was observed. Echocardiography is helpful in identifying the myocardial band segments as well as the correlation with the topographic distribution of some myocardial post-infarction ruptures.

Impact of admission blood glucose levels on prognosis of elderly patients with ST elevation myocardial infarction treated by primary percutaneous coronary intervention

PubMed Central

Ekmekci, Ahmet; Uluganyan, Mahmut; Tufan, Fatif; Uyarel, Huseyin; Karaca, Gurkan; Kul, Seref; Gungor, Barış; Ertas, Gokhan; Erer, Betul; Sayar, Nurten; Gul, Mehmet; Eren, Mehmet

2013-01-01

Objective Admission hyperglycemia in acute myocardial infarction (MI) is related with increased in-hospital and long term mortality and major cardiac adverse events. We aimed to investigate how admission hyperglycemia affects the short and long term outcomes in elderly patients (> 65 years) after primary percutaneous coronary intervention for ST elevation myocardial infarction. Methods We retrospectively analyzed 677 consecutive elderly patients (mean age 72.2 ± 5.4). Patients were divided into two groups according to admission blood glucose levels. Group 1: low glucose group (LLG), glucose < 168 mg/dL; and Group 2: high glucose group (HGG), glucose > 168 mg/dL. Results In-hospital, long term mortality and in-hospital major adverse cardiac events were higher in the high admission blood glucose group (P < 0.001). Multivariate regression analysis showed: Killip > 1, post-thrombolysis in MI < 3 and admission blood glucose levels were independent predictors of in-hospital adverse cardiac events (P < 0.001). Conclusions Admission hyperglycemia in elderly patients presented with ST elevation myocardial infarction is an independent predictor of in-hospital major adverse cardiac events and is associated with in-hospital and long term mortality. PMID:24454322

Disorders of Bone Remodeling

PubMed Central

Feng, Xu; McDonald, Jay M.

2013-01-01

The skeleton provides mechanical support for stature and locomotion, protects vital organs, and controls mineral homeostasis. A healthy skeleton must be maintained by constant bone modeling to carry out these crucial functions throughout life. Bone remodeling involves the removal of old or damaged bone by osteoclasts (bone resorption) and the subsequent replacement of new bone formed by osteoblasts (bone formation). Normal bone remodeling requires a tight coupling of bone resorption to bone formation to guarantee no alteration in bone mass or quality after each remodeling cycle. However, this important physiological process can be derailed by a variety of factors, including menopause-associated hormonal changes, age-related factors, changes in physical activity, drugs, and secondary diseases, which lead to the development of various bone disorders in both women and men. We review the major diseases of bone remodeling, emphasizing our current understanding of the underlying pathophysiological mechanisms. PMID:20936937

Positive T wave in lead aVR as an independent predictor for 1-year major adverse cardiac events in patients with first anterior wall ST-segment elevation myocardial infarction.

PubMed

Kobayashi, Akihiro; Misumida, Naoki; Aoi, Shunsuke; Kanei, Yumiko

2017-11-01

Positive T wave in lead aVR has been shown to predict an adverse in-hospital outcome in patients with anterior wall ST-segment elevation myocardial infarction (STEMI). However, the prognostic value of positive T wave in lead aVR on a long-term outcome has not been fully explored. We performed a retrospective analysis of 190 consecutive patients with first anterior wall STEMI who underwent an emergent coronary angiogram. Patients were divided into those with positive T wave > 0 mV and those with negative T wave ≦ 0 mV in lead aVR. Baseline and angiographic characteristics, and in-hospital revascularization procedures were recorded. In addition, in-hospital and 1-year major adverse cardiac events (MACE) including death, recurrent myocardial infarction, and target vessel revascularization were recorded. Among 190 patients, 37 patients (19%) had positive T wave and 153 patients (81%) had negative T wave in lead aVR. Patients with positive T wave had higher rate of left main disease defined as stenosis ≥50% (11% vs. 2%, p = .028) than those with negative T wave. Patients with positive T wave had higher rate of 1-year MACE (38% vs. 13%, p < .001) driven by higher all-cause mortality (27% vs. 5%, p < .001). Positive T wave was an independent predictor for 1-year MACE (OR 2.74; 95% CI 1.04-7.15; p = .04). Positive T wave in lead aVR was an independent predictor for 1-year MACE in patients with first anterior wall STEMI. © 2017 Wiley Periodicals, Inc.

Psilocybin mushroom (Psilocybe semilanceata) intoxication with myocardial infarction.

PubMed

Borowiak, K S; Ciechanowski, K; Waloszczyk, P

1998-01-01

Intentional intoxication with natural hallucinogenic substances such as hallucinogenic mushrooms continues to be a major problem in the US and Europe, particularly in the harbor complex of northwest Poland (Pomerania). A case is described of Psilocybe intoxication in an 18-year-old man resulting in Wolff-Parkinson-White syndrome, arrhythmia, and myocardial infarction. The indole concentrations of hallucinogenic mushrooms may predict the risk for adverse central nervous system and cardiac toxicity.

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

Predictive values of D-dimer assay, GRACE scores and TIMI scores for adverse outcome in patients with non-ST-segment elevation myocardial infarction

PubMed Central

Satilmisoglu, Muhammet Hulusi; Ozyilmaz, Sinem Ozbay; Gul, Mehmet; Ak Yildirim, Hayriye; Kayapinar, Osman; Gokturk, Kadir; Aksu, Huseyin; Erkanli, Korhan; Eksik, Abdurrahman

2017-01-01

Purpose To determine the predictive values of D-dimer assay, Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) risk scores for adverse outcome in patients with non-ST-segment elevation myocardial infarction (NSTEMI). Patients and methods A total of 234 patients (mean age: 57.2±11.7 years, 75.2% were males) hospitalized with NSTEMI were included. Data on D-dimer assay, GRACE and TIMI risk scores were recorded. Logistic regression analysis was conducted to determine the risk factors predicting increased mortality. Results Median D-dimer levels were 349.5 (48.0–7,210.0) ng/mL, the average TIMI score was 3.2±1.2 and the GRACE score was 90.4±27.6 with high GRACE scores (>118) in 17.5% of patients. The GRACE score was correlated positively with both the D-dimer assay (r=0.215, P=0.01) and TIMI scores (r=0.504, P=0.000). Multivariate logistic regression analysis revealed that higher creatinine levels (odds ratio =18.465, 95% confidence interval: 1.059–322.084, P=0.046) constituted the only significant predictor of increased mortality risk with no predictive values for age, D-dimer assay, ejection fraction, glucose, hemoglobin A1c, sodium, albumin or total cholesterol levels for mortality. Conclusion Serum creatinine levels constituted the sole independent determinant of mortality risk, with no significant values for D-dimer assay, GRACE or TIMI scores for predicting the risk of mortality in NSTEMI patients. PMID:28408834

Epicatechin as a Therapeutic Strategy to Mitigate the Development of Cardiac Remodeling and Fibrosis

DTIC Science & Technology

2017-09-01

Currently, no drugs target HFpEF and the development of animal models can assist in therapy evaluation. We developed a female rat model of aging...allocated into an aging group, aging + ovariectomy and aging + ovariectomy + 10% fructose in drinking water. At 22 months of age, animals were...epicatechin (Epi) will ameliorate adverse tissue remodeling and cardiac fibrosis in female animal models developing diastolic dysfunction as seen in women

Nonuniformity of axial and circumferential remodeling of large coronary veins in response to ligation.

PubMed

Choy, Jenny Susana; Dang, Quang; Molloi, Sabee; Kassab, Ghassan S

2006-04-01

The pressure-induced remodeling of coronary veins is important in coronary venous retroperfusion. Our hypothesis is that the response of the large coronary veins to pressure overload will depend on the degree of myocardial support. Eleven normal Yorkshire swine from either sex, weighing 31-39 kg, were studied. Five pigs underwent ligation of the left anterior descending (LAD) vein, and six served as sham-operated controls. The ligation of the coronary vein caused an increase in pressure intermediate to arterial and venous values. After 2 wk of ligation, the animals were euthanized and the coronary vessels were perfusion-fixed with glutaraldehyde. The LAD vein was sectioned, and detailed morphometric measurements were made along its length from the point of ligation near the base down to the apex of the heart. The structural remodeling of the vein was circumferentially nonuniform because the vein is partially embedded in the myocardium; it was also axially nonuniform because it is tethered to the myocardium to different degrees along its axial length. The wall area was significantly larger in the experimental group, whereas luminal area in the proximal LAD vein was significantly smaller in the same group compared with sham-operated controls. The wall thickness-to-radius ratio was also significantly larger in the experimental group in proportion to the increase in pressure. The major conclusion of this study is that the response of the vein depends on the local wall stress, which is, in part, determined by the surrounding tissue. Furthermore, the geometric remodeling of the coronary vein restores the circumferential stress to the homeostatic value.

Systematic drug safety evaluation based on public genomic expression (Connectivity Map) data: Myocardial and infectious adverse reactions as application cases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Kejian, E-mail: kejian.wang.bio@gmail.com; Weng, Zuquan; Sun, Liya

Adverse drug reaction (ADR) is of great importance to both regulatory agencies and the pharmaceutical industry. Various techniques, such as quantitative structure–activity relationship (QSAR) and animal toxicology, are widely used to identify potential risks during the preclinical stage of drug development. Despite these efforts, drugs with safety liabilities can still pass through safety checkpoints and enter the market. This situation raises the concern that conventional chemical structure analysis and phenotypic screening are not sufficient to avoid all clinical adverse events. Genomic expression data following in vitro drug treatments characterize drug actions and thus have become widely used in drug repositioning. Inmore » the present study, we explored prediction of ADRs based on the drug-induced gene-expression profiles from cultured human cells in the Connectivity Map (CMap) database. The results showed that drugs inducing comparable ADRs generally lead to similar CMap expression profiles. Based on such ADR-gene expression association, we established prediction models for various ADRs, including severe myocardial and infectious events. Drugs with FDA boxed warnings of safety liability were effectively identified. We therefore suggest that drug-induced gene expression change, in combination with effective computational methods, may provide a new dimension of information to facilitate systematic drug safety evaluation. - Highlights: • Drugs causing common toxicity lead to similar in vitro gene expression changes. • We built a model to predict drug toxicity with drug-specific expression profiles. • Drugs with FDA black box warnings were effectively identified by our model. • In vitro assay can detect severe toxicity in the early stage of drug development.« less

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.

Role of Soluble ST2 Levels and Beta-Blockers Dosage on Cardiovascular Events of Patients with Unselected ST-Segment Elevation Myocardial Infarction

PubMed Central

Huang, Wei-Ping; Zheng, Xuan; He, Lei; Su, Xi; Liu, Cheng-Wei; Wu, Ming-Xiang

2018-01-01

Background: Serum soluble ST2 (sST2) levels are elevated early after acute myocardial infarction and are related to adverse left ventricular (LV) remodeling and cardiovascular outcomes in ST-segment elevation myocardial infarction (STEMI). Beta-blockers (BB) have been shown to improve LV remodeling and survival. However, the relationship between sST2, final therapeutic BB dose, and cardiovascular outcomes in STEMI patients remains unknown. Methods: A total of 186 STEMI patients were enrolled at the Wuhan Asia Heart Hospital between January 2015 and June 2015. All patients received standard treatment and were followed up for 1 year. Serum sST2 was measured at baseline. Patients were divided into four groups according to their baseline sST2 values (high >56 ng/ml vs. low ≤56 ng/ml) and final therapeutic BB dose (high ≥47.5 mg/d vs. low <47.5 mg/d). Cox regression analyses were performed to determine whether sST2 and BB were independent risk factors for cardiovascular events in STEMI. Results: Baseline sST2 levels were positively correlated with heart rate (r = 0.327, P = 0.002), Killip class (r = 0.408, P = 0.000), lg N-terminal prohormone B-type natriuretic peptide (r = 0.467, P = 0.000), lg troponin I (r = 0.331, P = 0.000), and lg C-reactive protein (r = 0.307, P = 0.000) and negatively correlated to systolic blood pressure (r = −0.243, P = 0.009) and LV ejection fraction (r = −0.402, P = 0.000). Patients with higher baseline sST2 concentrations who were not titrated to high-dose BB therapy (P < 0.0001) had worse outcomes. Baseline high sST2 (hazard ratio [HR]: 2.653; 95% confidence interval [CI]: 1.201–8.929; P = 0.041) and final low BB dosage (HR: 1.904; 95% CI, 1.084–3.053; P = 0.035) were independent predictors of cardiovascular events in STEMI. Conclusions: High baseline sST2 levels and final low BB dosage predicted cardiovascular events in STEMI. Hence, sST2 may be a useful biomarker in cardiac pathophysiology. PMID:29786039

Myocardial Hypertrophy and Its Role in Heart Failure with Preserved Ejection Fraction

PubMed Central

Heinzel, Frank R.; Hohendanner, Felix; Jin, Ge; Sedej, Simon; Edelmann, Frank

2015-01-01

Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, increased mechanical load and cytokines associated with arterial hypertension, chronic kidney disease, diabetes and other co-morbidities. Here we discuss the experimental and clinical evidence that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. Mechanisms leading to diastolic dysfunction in LVH are incompletely understood but may include extracellular matrix changes, vascular dysfunction as well as altered cardiomyocyte mechano-elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we and others have shown increased Ca2+ turnover and impaired relaxation in cardiomyocytes from hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical setting of patients with compound co-morbidities, diastolic dysfunction may occur independently of LVH. This may be one explanation why current approaches to reduce LVH have not been effective to improve symptoms and prognosis in HFpEF. Exercise training on the other hand, in clinical trials improved exercise tolerance and diastolic function but did not reduce LVH. Thus, current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF. PMID:26183480

Heart repair by reprogramming non-myocytes with cardiac transcription factors

PubMed Central

Song, Kunhua; Nam, Young-Jae; Luo, Xiang; Qi, Xiaoxia; Tan, Wei; Huang, Guo N.; Acharya, Asha; Smith, Christopher L.; Tallquist, Michelle D.; Neilson, Eric G.; Hill, Joseph A.; Bassel-Duby, Rhonda; Olson, Eric N.

2012-01-01

The adult mammalian heart possesses little regenerative potential following injury. Fibrosis due to activation of cardiac fibroblasts impedes cardiac regeneration and contributes to loss of contractile function, pathological remodeling and susceptibility to arrhythmias. Cardiac fibroblasts account for a majority of cells in the heart and represent a potential cellular source for restoration of cardiac function following injury through phenotypic reprogramming to a myocardial cell fate. Here we show that four transcription factors, GATA4, Hand2, MEF2C and Tbx5 can cooperatively reprogram adult mouse tail-tip and cardiac fibroblasts into beating cardiac-like myocytes in vitro. Forced expression of these factors in dividing non-cardiomyocytes in mice reprograms these cells into functional cardiac-like myocytes, improves cardiac function and reduces adverse ventricular remodeling following myocardial infarction. Our results suggest a strategy for cardiac repair through reprogramming fibroblasts resident in the heart with cardiogenic transcription factors or other molecules. PMID:22660318

Right ventricular relative wall thickness as a predictor of outcomes and of right ventricular reverse remodeling for patients with pulmonary hypertension.

PubMed

Sano, Hiroyuki; Tanaka, Hidekazu; Motoji, Yoshiki; Fukuda, Yuko; Mochizuki, Yasuhide; Hatani, Yutaka; Matsuzoe, Hiroki; Hatazawa, Keiko; Shimoura, Hiroyuki; Ooka, Junichi; Ryo-Koriyama, Keiko; Nakayama, Kazuhiko; Matsumoto, Kensuke; Emoto, Noriaki; Hirata, Ken-Ichi

2017-03-01

Mid-term right ventricular (RV) reverse remodeling after treatment in patients with pulmonary hypertension (PH) is associated with long-term outcome as well as baseline RV remodeling. However, baseline factors influencing mid-term RV reverse remodeling after treatment and its prognostic capability remain unclear. We studied 54 PH patients. Mid-term RV remodeling was assessed in terms of the RV area, which was traced planimetrically at the end-systole (RVESA). RV reverse remodeling was defined as a relative decrease in the RVESA of at least 15% at 10.2 ± 9.4 months after treatment. Long-term follow-up was 5 years. Adverse events occurred in ten patients (19%) and mid-term RV reverse remodeling after treatment was observed in 37 (69%). Patients with mid-term RV reverse remodeling had more favorable long-term outcomes than those without (log-rank: p = 0.01). Multivariate logistic regression analysis showed that RV relative wall thickness (RV-RWT), as calculated as RV free-wall thickness/RV basal linear dimension at end-diastole, was an independent predictor of mid-term RV reverse remodeling (OR 1.334; 95% CI, 1.039-1.713; p = 0.03). Moreover, patients with RV-RWT ≥0.21 showed better long-term outcomes than did those without (log-rank p = 0.03), while those with RV-RWT ≥0.21 and mid-term RV reverse remodeling had the best long-term outcomes. Patients with RV-RWT <0.21 and without mid-term RV reverse remodeling, on the other hand, had worse long-term outcomes than other sub-groups. In conclusions, RV-RWT could predict mid-term RV reverse remodeling after treatment in PH patients, and was associated with long-term outcomes. Our finding may have clinical implications for better management of PH patients.

Myocardial Energetics and Heart Failure: a Review of Recent Therapeutic Trials.

PubMed

Bhatt, Kunal N; Butler, Javed

2018-06-01

Several novel therapeutics being tested in patients with heart failure are based on myocardial energetics. This review will provide a summary of the recent trials in this area, including therapeutic options targeting various aspects of cellular and mitochondrial metabolism. Agents that improve the energetic balance in myocardial cells have the potential to improve clinical heart failure status. The most promising therapies currently under investigation in this arena include (1) elamipretide, a cardiolipin stabilizer; (2) repletion of iron deficiency with intravenous ferrous carboxymaltose; (3) coenzyme Q10; and (4) the partial adenosine receptor antagonists capadenoson and neladenosone. Myocardial energetics-based therapeutics are groundbreaking in that they utilize novel mechanisms of action to improve heart failure symptoms, without causing the adverse neurohormonal side effects associated with current guideline-based therapies. The drugs appear likely to be added to the heart failure therapy armamentarium as adjuncts to current regimens in the near future.

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.

Fabrication of Cardiac Patch with Decellularized Porcine Myocardial Scaffold and Bone Marrow Mononuclear Cells

PubMed Central

Wang, Bo; Borazjani, Ali; Tahai, Mina; de Jongh Curry, Amy L.; Simionescu, Dan T.; Guan, Jianjun; To, Filip; Elder, Steve H.; Liao, Jun

2010-01-01

Tissue engineered cardiac grafts are a promising therapeutic mode for ventricular wall reconstruction. Recently, it has been found that acellular tissue scaffolds provide natural ultrastructural, mechanical, and compositional cues for recellularization and tissue remodeling. We thus assess the potential of decellularized porcine myocardium as a scaffold for thick cardiac patch tissue engineering. Myocardial sections with 2 mm thickness were decellularized using 0.1% sodium dodecyl sulfate (SDS), and then reseeded with differentiated bone marrow mononuclear cells. We found that thorough decellularization could be achieved after 2.5 weeks treatment. Reseeded cells were found to infiltrate and proliferate in the tissue constructs. Immunohistological staining studies showed that the reseeded cells maintained cardiomyocyte-like phenotype and possible endothelialization was found in locations close to vasculature channels, indicating angiogenesis potential. Both biaxial and uniaxial mechanical testing showed a stiffer mechanical response of the acellular myocardial scaffolds; however, tissue extensibility and tensile modulus were found to recover in the constructs along with the culture time, as expected from increased cellular content. The cardiac patch that we envision for clinical application will benefit from the natural architecture of myocardial extracellular matrix, which has the potential to promote stem cell differentiation, cardiac regeneration, and angiogenesis. PMID:20694977

Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload.

PubMed

Dassanayaka, Sujith; Zheng, Yuting; Gibb, Andrew A; Cummins, Timothy D; McNally, Lindsey A; Brittian, Kenneth R; Jagatheesan, Ganapathy; Audam, Timothy N; Long, Bethany W; Brainard, Robert E; Jones, Steven P; Hill, Bradford G

2018-06-01

Pathological cardiac remodeling during heart failure is associated with higher levels of lipid peroxidation products and lower abundance of several aldehyde detoxification enzymes, including aldehyde dehydrogenase 2 (ALDH2). An emerging idea that could explain these findings concerns the role of electrophilic species in redox signaling, which may be important for adaptive responses to stress or injury. The purpose of this study was to determine whether genetically increasing ALDH2 activity affects pressure overload-induced cardiac dysfunction. Mice subjected to transverse aortic constriction (TAC) for 12 weeks developed myocardial hypertrophy and cardiac dysfunction, which were associated with diminished ALDH2 expression and activity. Cardiac-specific expression of the human ALDH2 gene in mice augmented myocardial ALDH2 activity but did not improve cardiac function in response to pressure overload. After 12 weeks of TAC, ALDH2 transgenic mice had larger hearts than their wild-type littermates and lower capillary density. These findings show that overexpression of ALDH2 augments the hypertrophic response to pressure overload and imply that downregulation of ALDH2 may be an adaptive response to certain forms of cardiac pathology. Copyright © 2018. Published by Elsevier B.V.

β-Arrestin2 Improves Post-Myocardial Infarction Heart Failure via Sarco(endo)plasmic Reticulum Ca2+-ATPase-Dependent Positive Inotropy in Cardiomyocytes.

PubMed

McCrink, Katie A; Maning, Jennifer; Vu, Angela; Jafferjee, Malika; Marrero, Christine; Brill, Ava; Bathgate-Siryk, Ashley; Dabul, Samalia; Koch, Walter J; Lymperopoulos, Anastasios

2017-11-01

Heart failure is the leading cause of death in the Western world, and new and innovative treatments are needed. The GPCR (G protein-coupled receptor) adapter proteins βarr (β-arrestin)-1 and βarr-2 are functionally distinct in the heart. βarr1 is cardiotoxic, decreasing contractility by opposing β 1 AR (adrenergic receptor) signaling and promoting apoptosis/inflammation post-myocardial infarction (MI). Conversely, βarr2 inhibits apoptosis/inflammation post-MI but its effects on cardiac function are not well understood. Herein, we sought to investigate whether βarr2 actually increases cardiac contractility. Via proteomic investigations in transgenic mouse hearts and in H9c2 rat cardiomyocytes, we have uncovered that βarr2 directly interacts with SERCA2a (sarco[endo]plasmic reticulum Ca 2+ -ATPase) in vivo and in vitro in a β 1 AR-dependent manner. This interaction causes acute SERCA2a SUMO (small ubiquitin-like modifier)-ylation, increasing SERCA2a activity and thus, cardiac contractility. βarr1 lacks this effect. Moreover, βarr2 does not desensitize β 1 AR cAMP-dependent procontractile signaling in cardiomyocytes, again contrary to βarr1. In vivo, post-MI heart failure mice overexpressing cardiac βarr2 have markedly improved cardiac function, apoptosis, inflammation, and adverse remodeling markers, as well as increased SERCA2a SUMOylation, levels, and activity, compared with control animals. Notably, βarr2 is capable of ameliorating cardiac function and remodeling post-MI despite not increasing cardiac βAR number or cAMP levels in vivo. In conclusion, enhancement of cardiac βarr2 levels/signaling via cardiac-specific gene transfer augments cardiac function safely, that is, while attenuating post-MI remodeling. Thus, cardiac βarr2 gene transfer might be a novel, safe positive inotropic therapy for both acute and chronic post-MI heart failure. © 2017 American Heart Association, Inc.

Sodium 4-Phenylbutyrate Attenuates Myocardial Reperfusion Injury by Reducing the Unfolded Protein Response.

PubMed

Takatori, Osamu; Usui, Soichiro; Okajima, Masaki; Kaneko, Shuichi; Ootsuji, Hiroshi; Takashima, Shin-Ichiro; Kobayashi, Daisuke; Murai, Hisayoshi; Furusho, Hiroshi; Takamura, Masayuki

2017-05-01

The unfolded protein response (UPR) plays a pivotal role in ischemia-reperfusion (I/R) injury in various organs such as heart, brain, and liver. Sodium 4-phenylbutyrate (PBA) reportedly acts as a chemical chaperone that reduces UPR. In the present study, we evaluated the effect of PBA on reducing the UPR and protecting against myocardial I/R injury in mice. Male C57BL/6 mice were subjected to 30-minute myocardial I/R, and were treated with phosphate-buffered saline (as a vehicle) or PBA. At 4 hours after reperfusion, mice treated with PBA had reduced serum cardiac troponin I levels and numbers of apoptotic cells in left ventricles (LVs) in myocardial I/R. Infarct size had also reduced in mice treated with PBA at 48 hours after reperfusion. At 2 hours after reperfusion, UPR markers, including eukaryotic initiation of the factor 2α-subunit, activating transcription factor-6, inositol-requiring enzyme-1, glucose-regulated protein 78, CCAAT/enhancer-binding protein (C/EBP) homologous protein, and caspase-12, were significantly increased in mice treated with vehicle compared to sham-operated mice. Administration of PBA significantly reduced the I/R-induced increases of these markers. Cardiac function and dimensions were assessed at 21 days after I/R. Sodium 4-phenylbutyrate dedicated to the improvement of cardiac parameters deterioration including LV end-diastolic diameter and LV fractional shortening. Consistently, PBA reduced messenger RNA expression levels of cardiac remodeling markers such as collagen type 1α1, brain natriuretic peptide, and α skeletal muscle actin in LV at 21 days after I/R. Unfolded protein response mediates myocardial I/R injury. Administration of PBA reduces the UPR, apoptosis, infarct size, and preserved cardiac function. Hence, PBA may be a therapeutic option to attenuate myocardial I/R injury in clinical practice.

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.

Cytochrome c release in acute myocardial infarction predicts poor prognosis and myocardial reperfusion on contrast-enhanced magnetic resonance imaging.

PubMed

Liu, Zhen-Bing; Fu, Xiang-Hua; Wei, Geng; Gao, Jun-Ling

2014-01-01

Myocardial ischemia and reperfusion injury in ST-segment elevation myocardial infarction (STEMI) can trigger no-flow, resulting in myocardial necrosis and apoptosis, even a poor prognosis. Cytochrome c can induce an apoptotic process. The aim of our study was to assess the relationship between systemic cytochrome c levels and the occurrence of no-reflow in STEMI. One hundred and sixty patients with STEMI undergoing a primary percutaneous coronary intervention (PPCI) were randomly chosen. Patients were divided into two groups defined by the mean cytochrome c peak level after PPCI. No-reflow was assessed using three different methods after PPCI: myocardial blush grade, electrocardiographic ST-resolution, and microvascular obstruction (MO) assessed by cardiovascular magnetic resonance imaging. The primary clinical end points were major adverse cardiovascular events (defined as cardiac death, reinfarction, or new congestive heart failure). Clinical follow-up was carried out for 1 year. Patients with a cytochrome c level of at least the mean peak level had a greater creatine kinase-MB isoenzyme peak level (P=0.044), a lower left ventricular ejection fraction (P=0.029), a significantly higher occurrence of early MO (P=0.008), and a significantly larger extent of early MO (P=0.020). The cytochrome c peak level was elevated in patients with early MO (P=0.025), myocardial blush grade 0-1 (P=0.002), and ST-resolution less than 30% (P=0.003) after PPCI. A higher incidence of cardiac death at the 1-year follow-up was found in the patients with cytochrome c levels of at least the mean peak level (log rank, P=0.029). Cytochrome c levels above the mean peak level were related to no-reflow and mortality in patients with STEMI.

A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record

PubMed Central

Bolland, Mark J; Grey, Andrew

2014-01-01

Objective Recently, the European Medicines Agency reported that strontium ranelate increases myocardial infarction risk in postmenopausal women, 8.5 years after it was registered for use in osteoporosis. Unreported serious adverse events in clinical trials for other pharmaceuticals have been described in recent years. We assessed reporting of adverse events and fracture efficacy of strontium. Methods We compared data on adverse effects (myocardial infarction, venous thromboembolism and pulmonary embolism) and fracture efficacy of strontium in publicly available regulatory documents with data in publications retrieved from searching PubMed. Results We identified 5 regulatory documents and 9 primary publications of 7 randomised, placebo-controlled trials of strontium that reported relevant data. We identified several areas of concern in these reports: the increased risk of myocardial infarction with strontium was not identified in a pivotal phase 3 clinical trial despite specific regulatory review of cardiovascular events; data on myocardial infarction were not included in any primary publication; increased risks of venous thromboembolism and pulmonary embolism with strontium were not reported in either of the phase 3 clinical trials; data on venous thromboembolism were reported in only 5 of 9 primary publications, data on pulmonary embolism in only 2 of 9 primary publications, and either was discussed in <50% of subsequent review articles. There were differences in participant numbers, fracture cases and venous thromboembolism cases between regulatory documents and primary publications. Based on all available data from primary publications and regulatory documents, the number of fractures prevented by strontium use is similar to the number of extra cases of venous thromboembolism, pulmonary embolism and myocardial infarction caused by strontium use. Conclusions The risks of strontium use are similar to the benefits. Full disclosure of the clinical trial data and

Myocyte repolarization modulates myocardial function in aging dogs

PubMed Central

Sorrentino, Andrea; Signore, Sergio; Borghetti, Giulia; Meo, Marianna; Cannata, Antonio; Zhou, Yu; Wybieralska, Ewa; Luciani, Marco; Kannappan, Ramaswamy; Zhang, Eric; Matsuda, Alex; Webster, Andrew; Cimini, Maria; Kertowidjojo, Elizabeth; D'Alessandro, David A.; Wunimenghe, Oriyanhan; Michler, Robert E.; Royer, Christopher; Goichberg, Polina; Leri, Annarosa; Barrett, Edward G.; Anversa, Piero; Hintze, Thomas H.

2016-01-01

Studies of myocardial aging are complex and the mechanisms involved in the deterioration of ventricular performance and decreased functional reserve of the old heart remain to be properly defined. We have studied a colony of beagle dogs from 3 to 14 yr of age kept under a highly regulated environment to define the effects of aging on the myocardium. Ventricular, myocardial, and myocyte function, together with anatomical and structural properties of the organ and cardiomyocytes, were evaluated. Ventricular hypertrophy was not observed with aging and the structural composition of the myocardium was modestly affected. Alterations in the myocyte compartment were identified in aged dogs, and these factors negatively interfere with the contractile reserve typical of the young heart. The duration of the action potential is prolonged in old cardiomyocytes contributing to the slower electrical recovery of the myocardium. Also, the remodeled repolarization of cardiomyocytes with aging provides inotropic support to the senescent muscle but compromises its contractile reserve, rendering the old heart ineffective under conditions of high hemodynamic demand. The defects in the electrical and mechanical properties of cardiomyocytes with aging suggest that this cell population is an important determinant of the cardiac senescent phenotype. Collectively, the delayed electrical repolarization of aging cardiomyocytes may be viewed as a critical variable of the aging myopathy and its propensity to evolve into ventricular decompensation under stressful conditions. PMID:26801307

Sympathetic Nervous System Modulation of Inflammation and Remodeling in the Hypertensive Heart

PubMed Central

Levick, Scott P.; Murray, David B.; Janicki, Joseph S.; Brower, Gregory L.

2010-01-01

Chronic activation of the sympathetic nervous system (SNS) is a key component of cardiac hypertrophy and fibrosis. However, previous studies have provided evidence to also implicate inflammatory cells, including mast cells, in the development of cardiac fibrosis. The current study investigated the potential interaction of cardiac mast cells with the SNS. Eight week old male SHR were sympathectomized to establish the effect of the SNS on cardiac mast cell density, myocardial remodeling and cytokine production in the hypertensive heart. Age-matched WKY served as controls. Cardiac fibrosis and hypertension were significantly attenuated and left ventricular mass normalized while cardiac mast cell density was markedly increased in sympathectomized SHR. Sympathectomy normalized myocardial levels of IFN-γ, IL-6 and IL-10, but had no effect on IL-4. The effect of norepinephrine and substance P on isolated cardiac mast cell activation was investigated as potential mechanisms of interaction between the two. Only substance P elicited mast cell degranulation. Substance P was also shown to induce the production of angiotensin II by a mixed population of isolated cardiac inflammatory cells, including mast cells, lymphocytes and macrophages. These results demonstrate the ability of neuropeptides to regulate inflammatory cell function, providing a potential mechanism by which the SNS and afferent nerves may interact with inflammatory cells in the hypertensive heart. PMID:20048196

Using the laws of thermodynamics to understand how matrix metalloproteinases coordinate the myocardial response to injury.

PubMed

Iyer, Rugmani Padmanabhan; Jung, Mira; Lindsey, Merry L

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of molecular, cellular, and functional alterations that are both part of the wound healing response to form a scar in the infarct region and the consequence of that response. Using the laws of thermodynamics as an analogy, we present here three laws for categorizing the post-MI LV remodeling process. The first law is that the LV will attempt to maintain equilibrium and compensate as a way to maximize function, the second law is that remodeling is progressive and unidirectional, and the third law is that the final goal is (ideally, but not always achievable) a stable, equilibrated scar. This comparison helps to define the boundaries of the system, whether it be the infarct zone, the LV, the heart, or the entire body. This review provides an overview for those not directly in the field and establishes a framework to help prioritize future research directions.

Using the laws of thermodynamics to understand how matrix metalloproteinases coordinate the myocardial response to injury

PubMed Central

Iyer, Rugmani Padmanabhan; Jung, Mira; Lindsey, Merry L

2016-01-01

Following myocardial infarction (MI), the left ventricle (LV) undergoes a series of molecular, cellular, and functional alterations that are both part of the wound healing response to form a scar in the infarct region and the consequence of that response. Using the laws of thermodynamics as an analogy, we present here three laws for categorizing the post-MI LV remodeling process. The first law is that the LV will attempt to maintain equilibrium and compensate as a way to maximize function, the second law is that remodeling is progressive and unidirectional, and the third law is that the final goal is (ideally, but not always achievable) a stable, equilibrated scar. This comparison helps to define the boundaries of the system, whether it be the infarct zone, the LV, the heart, or the entire body. This review provides an overview for those not directly in the field and establishes a framework to help prioritize future research directions. PMID:27376092

The apoptotic effect and the plausible mechanism of microwave radiation on rat myocardial cells.

PubMed

Zhu, Wenhe; Cui, Yan; Feng, Xianmin; Li, Yan; Zhang, Wei; Xu, Junjie; Wang, Huiyan; Lv, Shijie

2016-08-01

Microwaves may exert adverse biological effects on the cardiovascular system at the integrated system and cellular levels. However, the mechanism underlying such effects remains poorly understood. Here, we report a previously uncharacterized mechanism through which microwaves damage myocardial cells. Rats were treated with 2450 MHz microwave radiation at 50, 100, 150, or 200 mW/cm(2) for 6 min. Microwave treatment significantly enhanced the levels of various enzymes in serum. In addition, it increased the malondialdehyde content while decreasing the levels of antioxidative stress enzymes, activities of enzyme complexes I-IV, and ATP in myocardial tissues. Notably, irradiated myocardial cells exhibited structural damage and underwent apoptosis. Furthermore, Western blot analysis revealed significant changes in expression levels of proteins involved in oxidative stress regulation and apoptotic signaling pathways, indicating that microwave irradiation could induce myocardial cell apoptosis by interfering with oxidative stress and cardiac energy metabolism. Our findings provide useful insights into the mechanism of microwave-induced damage to the cardiovascular system.

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)

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.

Correlation of Admission Heart Rate With Angiographic and Clinical Outcomes in Patients With Right Coronary Artery ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: HORIZONS-AMI (The Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) Trial.

PubMed

Kosmidou, Ioanna; McAndrew, Thomas; Redfors, Björn; Embacher, Monica; Dizon, José M; Mehran, Roxana; Ben-Yehuda, Ori; Mintz, Gary S; Stone, Gregg W

2017-07-19

Bradycardia on presentation is frequently observed in patients with right coronary artery ST-segment elevation myocardial infarction, but it is largely unknown whether it predicts poor angiographic or clinical outcomes in that patient population. We sought to determine the prognostic implications of admission heart rate (AHR) in patients with ST-segment elevation myocardial infarction and a right coronary artery culprit lesion. We analyzed 1460 patients with ST-segment elevation myocardial infarction and a right coronary artery culprit lesion enrolled in the randomized HORIZONS-AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction) trial who underwent primary percutaneous coronary intervention. Patients presenting with high-grade atrioventricular block were excluded. Outcomes were examined according to AHR range (AHR <60, 61-79, 80-99, and ≥100 beats per minute). Baseline and procedural characteristics did not vary significantly with AHR except for a more frequent history of diabetes mellitus, longer symptom-to-balloon time, more frequent cardiogenic shock, and less frequent restoration of thrombolysis in myocardial infarction 3 flow in patients with admission tachycardia (AHR >100 beats per minute). Angiographic analysis showed no significant association between AHR and lesion location or complexity. On multivariate analysis, admission bradycardia (AHR <60 beats per minute) was not associated with increased 1-year mortality (hazard ratio 1.33; 95% CI 0.41-4.34, P =0.64) or major adverse cardiac events (hazard ratio 1.08; 95% CI 0.62-1.88, P =0.78), whereas admission tachycardia was a strong independent predictor of mortality (hazard ratio 5.02; 95% CI 1.95-12.88, P =0.0008) and major adverse cardiac events (hazard ratio 2.20; 95% CI 1.29-3.75, P =0.0004). In patients with ST-segment elevation myocardial infarction and a right coronary artery culprit lesion undergoing primary percutaneous coronary intervention, admission

Assessment of mitral apparatus in patients with acute inferoposterior myocardial infarction and ischaemic mitral regurgitation with two-dimensional echocardiography from anatomically correct imaging planes.

PubMed

Mėlinytė, Karolina; Valuckiene, Živile; Jurkevičius, Renaldas

2017-01-01

Ischaemic mitral regurgitation (IMR) is associated with adverse prognosis after myocardial infarction (MI) as a result of left ventricular remodelling and geometric deformation of the mitral apparatus (MA). The aim of this study was to assess MA from anatomically correct imaging planes in acute inferoposterior MI and IMR. Ninety-three patients with no structural cardiac valve abnormalities and the first acute inferoposterior MI were prospectively enrolled into the study. Two-dimensional transthoracic echocardiography for MA assessment was performed within 48 h of presentation after reperfusion therapy. Based on the degree of mitral regurgitation (MR), patients were divided into either a no significant MR (NMR) group (n = 52 with no or mild, grade 0-I MR) or an IMR group (n = 41 with grade ≥ 2 MR). The control group consisted of 45 healthy individuals. Ischaemic MR was related with dilatation of the left ventricle chambers, decrease in ejection fraction, increase in mitral annulus diameter and area, and changes in subvalvular apparatus when compared with the NMR group or healthy individuals. Ischaemic MR in acute inferoposterior MI is related with worse lesions in MA geometry that cause insufficiency of mitral valve function.

Association between plasma ceramides and inducible myocardial ischemia in patients with established or suspected coronary artery disease undergoing myocardial perfusion scintigraphy.

PubMed

Mantovani, Alessandro; Bonapace, Stefano; Lunardi, Gianluigi; Salgarello, Matteo; Dugo, Clementina; Canali, Guido; Byrne, Christopher D; Gori, Stefania; Barbieri, Enrico; Targher, Giovanni

2018-05-16

Recent studies have suggested that specific plasma ceramides are independently associated with major adverse cardiovascular events in patients with coronary artery disease (CAD), but it is currently unknown whether plasma ceramide levels are associated with stress-induced reversible myocardial ischemia. We measured six previously identified high-risk plasma ceramide molecules [Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/20:0), Cer(d18:1/22:0), Cer(d18:1/24:0), and Cer(d18:1/24:1)] in 167 consecutive patients with established or suspected CAD who underwent either exercise or dypiridamole myocardial perfusion scintigraphy (MPS) for various clinical indications. Plasma ceramide levels were measured by a targeted liquid chromatography-tandem mass spectrometry assay both at baseline and after MPS. Seventy-eight patients had inducible myocardial ischemia on stress MPS. Women had significantly higher circulating levels of basal and post-stress Cer(d18:1/16:0) and Cer(d18:1/18:0) compared to men, whereas all other plasma ceramides did not differ between the sexes. Of the six measured plasma ceramides, basal Cer(d18:1/24:1) showed the strongest association with the presence of stress-induced myocardial perfusion defects in univariate analysis (unadjusted-odds ratio 1.48 per 1-SD increment, 95% confidence interval 1.08-2.04). Notably, after adjustment for age, sex, smoking, dyslipidemia, hypertension, diabetes, prior history of CAD, left ventricular ejection fraction, and type of stress testing (exercise vs. dypiridamole), all measured ceramides, except for plasma Cer(d18:1/24:0), were independently associated with the presence of inducible myocardial ischemia. Distinct plasma ceramides are positive and independent predictors of stress-induced myocardial perfusion defects in patients with established or suspected CAD referred for clinically indicated MPS. Further research is needed to examine whether distinct plasma ceramides could be a useful therapeutic target for

Moderate elevation of intracellular creatine by targeting the creatine transporter protects mice from acute myocardial infarction

PubMed Central

Lygate, Craig A.; Bohl, Steffen; ten Hove, Michiel; Faller, Kiterie M.E.; Ostrowski, Philip J.; Zervou, Sevasti; Medway, Debra J.; Aksentijevic, Dunja; Sebag-Montefiore, Liam; Wallis, Julie; Clarke, Kieran; Watkins, Hugh; Schneider, Jürgen E.; Neubauer, Stefan

2012-01-01

Aims Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury. Methods and results CrT-OE mice were selected for left ventricular (LV) creatine 20–100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury. Conclusion Elevation of myocardial creatine by 20–100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia. PMID:22915766

Dynamic micro- and macrovascular remodeling in coronary circulation of obese Ossabaw pigs with metabolic syndrome

PubMed Central

Katz, Paige S.; Kelly, Amy P.; Galantowicz, Maarten L.; Cismowski, Mary J.; West, T. Aaron; Neeb, Zachary P.; Berwick, Zachary C.; Goodwill, Adam G.; Alloosh, Mouhamad; Tune, Johnathan D.; Sturek, Michael; Lucchesi, Pamela A.

2012-01-01

Previous studies from our laboratory showed that coronary arterioles from type 2 diabetic mice undergo inward hypertrophic remodeling and reduced stiffness. The aim of the current study was to determine if coronary resistance microvessels (CRMs) in Ossabaw swine with metabolic syndrome (MetS) undergo remodeling distinct from coronary conduit arteries. Male Ossabaw swine were fed normal (n = 7, Lean) or hypercaloric high-fat (n = 7, MetS) diets for 6 mo, and then CRMs were isolated and mounted on a pressure myograph. CRMs isolated from MetS swine exhibited decreased luminal diameters (126 ± 5 and 105 ± 9 μm in Lean and MetS, respectively, P < 0.05) with thicker walls (18 ± 3 and 31 ± 3 μm in Lean and MetS, respectively, P < 0.05), which doubled the wall-to-lumen ratio (14 ± 2 and 30 ± 2 in Lean and MetS, respectively, P < 0.01). Incremental modulus of elasticity (IME) and beta stiffness index (BSI) were reduced in CRMs isolated from MetS pigs (IME: 3.6 × 106 ± 0.7 × 106 and 1.1 × 106 ± 0.2 × 106 dyn/cm2 in Lean and MetS, respectively, P < 0.001; BSI: 10.3 ± 0.4 and 7.3 ± 1.8 in Lean and MetS, respectively, P < 0.001). BSI in the left anterior descending coronary artery was augmented in pigs with MetS. Structural changes were associated with capillary rarefaction, decreased hyperemic-to-basal coronary flow velocity ratio, and augmented myogenic tone. MetS CRMs showed a reduced collagen-to-elastin ratio, while immunostaining for the receptor for advanced glycation end products was selectively increased in the left anterior descending coronary artery. These data suggest that MetS causes hypertrophic inward remodeling of CRMs and capillary rarefaction, which contribute to decreased coronary flow and myocardial ischemia. Moreover, our data demonstrate novel differential remodeling between coronary micro- and macrovessels in a clinically relevant model of MetS. PMID:22837170

Prognostic Value of Real Time Myocardial Contrast Echocardiography after Percutaneous Coronary Intervention.

PubMed

Yang, Lixia; Xia, Chunmei; Mu, Yuming; Guan, Lina; Wang, Chunmei; Tang, Qi; Verocai, Flavia Gomes; Fonseca, Lea Mirian Barbosa da; Shih, Ming Chi

2016-03-01

Real time myocardial contrast echocardiography (RTMCE) is a cost-effective and simple method to quantify coronary flow reserve (CFR). We aimed to determine the value of RTMCE to predict cardiac events after percutaneous coronary intervention (PCI). We have studied myocardial blood volume (A), velocity (β), flow indexes (MBF, A × β), and vasodilator reserve (stress-to-rest ratios) in 36 patients with acute coronary syndrome (ACS) who underwent PCI. CFR (MBF at stress/MBF at rest) was calculated for each patient. Perfusion scores were used for visual interpretation by MCE and correlation with TIMI flow grade. In qualitative RTMCE assessment, post-PCI visual perfusion scores were higher than pre-PCI (Z = -7.26, P < 0.01). Among 271 arteries with TIMI flow grade 3 post-PCI, 72 (36%) did not reach visual perfusion score 1. The β- and A × β-reserve of the abnormal segments supplied by obstructed arteries increased after PCI comparing to pre-PCI values (P < 0.01). Patients with adverse cardiac events had significantly lower β- and lower A × β-reserve than patients without adverse cardiac events. In the former group, the CFR was ≥ 1.5 both pre- and post-PCI. CFR estimation by RTMCE can quantify myocardial perfusion in patients with ACS who underwent PCI. The parameters β-reserve and CFR combined might predict cardiac events on the follow-up. © 2015, Wiley Periodicals, Inc.

Glycated hemoglobin level is an independent predictor of major adverse cardiac events after nonfatal acute myocardial infarction in nondiabetic patients: A retrospective observational study.

PubMed

Chen, Chin-Lan; Yen, David H-T; Lin, Chin-Sheng; Tsai, Shih-Hung; Chen, Sy-Jou; Sheu, Wayne H-H; Hsu, Chin-Wang

2017-05-01

The effect of glycemic control on the prognosis of nondiabetic patients after acute myocardial infarction (AMI) remains uncertain. We investigated whether glycated hemoglobin (HbA1c) is associated with adverse outcomes after AMI in nondiabetic patients. In this observational study, we enrolled nondiabetic patients with AMI in the emergency department of 2 medical centers from January 2011 to September 2014. All patients received primary percutaneous coronary intervention and were divided into 4 groups according to the interquartile range of average HbA1c level (Group I, ≤5.6%; Group II, 5.6%-5.8%; Group III, 5.8%-6.0%; and Group IV, >6.0%). Multivariate logistic analysis was performed to estimate the correlation of HbA1c with major adverse cardiac events (MACEs) after AMI. In total, 267 eligible patients were enrolled; 48 patients (18%) developed MACEs within a median follow-up of 178 days. Univariate analysis showed HbA1c > 6.0%, with a higher risk of MACEs in Group IV than in Group I (odds ratio [OR]: 2.733; 95% confidence interval [CI]: 1.123-6.651 vs OR: 1.511; 95% CI: 0.595-3.835). Multivariate analysis revealed an approximately 3.8 times higher risk of MACEs in Group IV than in Group I (OR: 3.769; 95% CI: 1.30-10.86). The HbA1 level is a significant predictor of MACEs after AMI in nondiabetic patients.

Impact of iso-osmolar versus low-osmolar contrast agents on contrast-induced nephropathy and tissue reperfusion in unselected patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention (from the Contrast Media and Nephrotoxicity Following Primary Angioplasty for Acute Myocardial Infarction [CONTRAST-AMI] Trial).

PubMed

Bolognese, Leonardo; Falsini, Giovanni; Schwenke, Carsten; Grotti, Simone; Limbruno, Ugo; Liistro, Francesco; Carrera, Arcangelo; Angioli, Paolo; Picchi, Andrea; Ducci, Kenneth; Pierli, Carlo

2012-01-01

Conflicting data have been reported on the effects of low-osmolar and iso-osmolar contrast media on contrast-induced acute kidney injury (CI-AKI). In particular, no clinical trial has yet focused on the effect of contemporary contrast media on CI-AKI, epicardial flow, and microcirculatory function in patients with ST-segment elevation acute myocardial infarction who undergo primary percutaneous coronary intervention. The Contrast Media and Nephrotoxicity Following Coronary Revascularization by Angioplasty for Acute Myocardial Infarction (CONTRAST-AMI) trial is a prospective, randomized, single-blind, parallel-group, noninferiority study aiming to evaluate the effects of the low-osmolar contrast medium iopromide compared to the iso-osmolar agent iodixanol on CI-AKI and tissue-level perfusion in patients with ST-segment elevation acute myocardial infarction. Four hundred seventy-five consecutive, unselected patients who underwent primary percutaneous coronary intervention were randomized to iopromide (n = 239) or iodixanol (n = 236). All patients received high-dose N-acetylcysteine and hydration. The primary end point was the proportion of patients with serum creatinine (sCr) increases ≥25% from baseline to 72 hours. Secondary end points were Thrombolysis In Myocardial Infarction (TIMI) myocardial perfusion grade, increase in sCr ≥50%, increase in sCr ≥0.5 or ≥1 mg/dl, and 1-month major adverse cardiac events. The primary end point occurred in 10% of the iopromide group and in 13% of the iodixanol group (95% confidence interval -9% to 3%, p for noninferiority = 0.0002). A TIMI myocardial perfusion grade of 0 or 1 was present in 14% of patients in the 2 groups. No differences between the 2 groups were found in any of the secondary analyses of sCr increase. No significant difference in 1-month major adverse cardiac events was found (8% vs 6%, p = 0.37). In conclusion, in a population of unselected patients with ST-segment elevation acute myocardial infarction

To Remodel or To Build?

ERIC Educational Resources Information Center

Rosenblum, Todd

2009-01-01

The question of remodeling an existing house to make it wheelchair accessible or building a new barrier-free house is a difficult decision. This article presents some initial questions and considerations followed by a list of pros and cons for remodeling an existing house vs. building a new house.

Safety of preoperative erythropoietin in surgical calvarial remodeling: an 8-year retrospective review and analysis.

PubMed

Naran, Sanjay; Cladis, Franklyn; Fearon, Jeffrey; Bradley, James; Michelotti, Brett; Cooper, Gregory; Cray, James; Katchikian, Hurig; Grunwaldt, Lorelei; Pollack, Ian F; Losee, Joseph

2012-08-01

Calvarial remodeling is typically associated with significant blood loss. Although preoperative erythropoiesis-stimulating agents have proven to significantly decrease the need for blood transfusions, recent data in adults have raised concerns that elevating hemoglobin levels greater than 12.5 g/dl may increase the risk of thrombotic events. This study was designed to assess the risks of erythropoietin in the pediatric population. Records were retrospectively reviewed from 2000 to 2008 at three major metropolitan children's hospitals of all children undergoing calvarial remodeling after receiving preoperative erythropoietin. Demographic and perioperative outcome data were reviewed, including transfusion reactions, pressure ulcer secondary to prolonged positioning, pneumonia, infection, deep vein thrombosis, cerebrovascular accident, pulmonary embolism, sagittal sinus thrombosis, pure red cell aplasia, and myocardial infarction. A total of 369 patients met the inclusion criteria (mean age, 0.86±1.1 years). On average, three preoperative doses of erythropoietin were administered (600 U/kg). Iron was also supplemented. No complications associated with dosing were noted, there were no thrombotic events identified, and no other major complications were seen (i.e., death or blindness). Thirty-one patients (8.40 percent) experienced one or more postoperative complications. There was no significant correlation between hemoglobin levels greater than 12.5 g/dl and the occurrence of any noted complication. With zero thrombotic postoperative complications, the authors estimate the risk of a thrombotic event in the pediatric population to be less than 0.81 percent (95 percent confidence). These data suggest that preoperative administration of erythropoietin in children undergoing calvarial remodeling does not appear to increase the incidence of thrombotic events or other significant complications. Therapeutic, IV.

[Study on mechanisms and myocardial protective effect of Qishen Yiqi dropping pills on rats with myocardial infarction].

PubMed

Yang, Quan; Cao, Yunshan

2017-06-01

TGF-β/Smads signal transduction pathway related protein and the cell apoptosis related factors protein in model group were all significantly elevated, while LVSP and ±dp/dt max were obviously decreased in model group. Compared with the model group, the levels of inflammatory factor in serum [LTB4 (ng/L): 370.11±46.98 vs. 633.23±83.37, PGE 2 (ng/L): 48.75±26.35 vs. 131.25±29.75, TNF-α (μg/L): 177.28±22.65 vs. 248.47±16.21, IL-6 (μg/L): 493.22±165.99 vs. 638.41±191.66], LVEDP [mmHg (1 mmHg = 0.133 kPa): -2.03±2.98 vs. 7.03±1.39], the ratio of the heart weight/body weight [(6.53±0.11)% vs. (7.14±0.24)%], LVW/HW (0.26±0.01 vs. 0.32±0.02), myocardial infarction area [(27.21±2.87)% vs. (44.98±1.52)%], mRNA and protein expression of myocardial inflammatory factors, the expression of TGF-β/Smads signal transduction pathway related protein, and the protein expression of Bax were all significantly decreased in observation group (all P < 0.05), LVSP (mmHg: 129.01±11.93 vs. 108.11±12.69), the +dp/dt max (mmHg/s: 3 101.3±378.6 vs. 2 105.3±245.9), the -dp/dt max (mmHg/s: 2 612.4±249.7 vs. 1 654.4±188.1), while the protein expression of Bcl-2 in observation group were obviously increased (all P < 0.05). It was demonstrated by hematoxylin-eosin (HE) staining that there were no obvious pathological changes in the sham operation group; obvious infiltration of inflammatory factors in myocardium was shown in model group; pathological changes in the observation group were significantly improved as compared with those in the model group. It was shown by Masson staining that there were slight hyperplasia of myocardial fibers and no obvious pathological changes in the sham operation group. Severe collagen hyperplasia was found in model group, and the degree of fibrosis in the observation group was significantly improved. Qishen Yiqi dropping pills can reduce the degree of myocardial fibrosis and inhibit the ventricular remodeling via TGF-β/Smads signal

Differences in the Korea Acute Myocardial Infarction Registry Compared with Western Registries

PubMed Central

2017-01-01

The Korea Acute Myocardial Infarction Registry (KAMIR) is the first nationwide registry that reflects current therapeutic approaches and acute myocardial infarction (AMI) management in Korea. The results of the KAMIR demonstrated different risk factors and responses to medical and interventional treatments. The results indicated that the incidence of ST-elevation myocardial infarction (STEMI) was relatively high, and that the prevalence of dyslipidemia was relatively low with higher triglyceride and lower high-density lipoprotein cholesterol levels. Percutaneous coronary intervention (PCI) rates were high for both STEMI and non-ST-elevation myocardial infarction (NSTEMI) with higher use of drug-eluting stents (DESs). DES were effective and safe without increased risk of stent thrombosis in Korean AMI patients. Triple antiplatelet therapy, consisting of aspirin, clopidogrel, and cilostazol, was effective in preventing adverse clinical outcomes after PCI. Statin therapy was effective in Korean AMI patients, including those with very low levels of low-density lipoprotein cholesterol and those with cardiogenic shock. The KAMIR score had a greater predictive value than Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) scores for long-term mortality in AMI patients. Based on these results, the KAMIR will be instrumental for establishing new therapeutic strategies and effective methods for secondary prevention of AMI and guidelines for Asian patients. PMID:29035427

Normal stress-only myocardial single photon emission computed tomography predicts good outcome in patients with coronary artery stenoses between 40 and 70.

PubMed

Jiang, Zhixin; Liu, Yangqing; Xin, Chaofan; Zhou, Yanli; Wang, Cheng; Zhao, Zhongqiang; Li, Chunxiang; Li, Dianfu

2016-09-01

Normal stress myocardial single photon emission computed tomography (SPECT) usually indicates good physiologic function of all coronary lesions, and also indicates a good outcome. We hypothesize that it can still predict good outcome in patients with coronary stenoses between 40 and 70%. A group of patients who underwent stress myocardial SPECT after coronary angiography were consecutively recruited in our center. Patients were eligible if they had one or more coronary stenoses between 40 and 70%. Patients with coronary stenoses greater than 50% diameter of left main or greater than 70% diameter of nonleft main epicardial vessels, and left ventricular ejection fraction less than 50% were excluded. The outcome was defined as major adverse events, including cardiac death, nonfatal myocardial infarction, and revascularization. Patients' survival curves were constructed accorded to the method of Kaplan and Meier and compared using the log-rank test. A study cohort of 77 patients was enrolled. According to the summed stress score, 43 patients were assigned to the perfusion defect group and 34 patients were assigned to the perfusion normal group. The follow-up duration was 6.4±0.3 years. In the perfusion normal group, only one of 34 (2.9%) patients developed major adverse events. In the perfusion defect group, six of 43 (14%) developed major adverse events, P-value of 0.041. It is safe to defer a percutaneous coronary intervention in patients with coronary stenoses between 40 and 70% and normal stress myocardial SPECT.

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

Myocardial infarction increases progressive visual field defects in well treated early primary open angle glaucoma--a prospective case control study.

PubMed

Mondal, Lakshmikanta; Baidya, Krishnapada; Choudhury, Himadri; Roy, Rupam

2013-06-01

The purpose of the study was to evaluate the progression of glaucomatous field damage in patients with stable primary open angle glaucoma after an attack of myocardial infarction. In this case control study, 62 open angle glaucoma patients were selected and regularly followed up. Among 62 patients, 9 had an attack of myocardial infarction. The intra-ocular pressure and visual field progression of both the groups (myocardial infarction versus no myocardial infarction) were analysed. Three (33.3%) out of 9 patients who had suffered from myocardial infarction showed progressive visual field loss whereas only 9 (16.9%) out of 53 patients who did not suffer from myocardial infarction, showed progressive field changes. Both the groups had stable target intra-ocular pressure between 14 and 16 mm Hg. Myocardial infarction may adversely influence the progression of primary open angle glaucoma which is suspected to result from ischaemia induced neuronal loss and only control of intraocular pressure is not the only solution. We have to look for other drugs that prevents ischaemia induced neuronal damage.

Myocardial protection during minimally invasive cardiac surgery through right mini-thoracotomy.

PubMed

De Palo, Micaela; Guida, Pietro; Mastro, Florinda; Nanna, Daniela; Quagliara, Teresa A P; Rociola, Ruggiero; Lionetti, Giosuè; Paparella, Domenico

2017-04-01

Myocardial damage is an independent predictor of adverse outcome following cardiac surgery and myocardial protection is one of the key factors to achieve successful outcomes. Cardioplegia with Custodiol is currently the most used cardioplegia during minimally invasive cardiac surgery (MICS). Different randomized controlled trials compared blood and Custodiol cardioplegia in the context of traditional cardiac surgery. No data are available for MICS. The aim of this study was to compare the efficacy of cold blood versus Custodiol cardioplegia during MICS. We retrospectively evaluated 90 patients undergoing MICS through a right mini-thoracotomy in a three-year period. Myocardial protection was performed using cold blood (44 patients, CBC group) or Custodiol (46 patients, Custodiol group) cardioplegia, based on surgeon preference and complexity of surgery. The primary outcomes were post-operative cardiac troponin I (cTnI) and creatine kinase MB (CKMB) serum release and the incidence of Low Cardiac Output Syndrome (LCOS). Aortic cross-clamp and cardiopulmonary bypass times were higher in the Custodiol group. No difference was observed in myocardial injury enzyme release (peak cTnI value was 18±46 ng/ml in CBC and 21±37 ng/ml in Custodiol; p=0.245). No differences were observed for mortality, LCOS, atrial or ventricular arrhythmias onset, transfusions, mechanical ventilation time duration, intensive care unit and total hospital stay. Custodiol and cold blood cardioplegic solutions seem to assure similar myocardial protection in patients undergoing cardiac surgery through a right mini-thoracotomy approach.

Posttranslational modulation of FoxO1 contributes to cardiac remodeling in post-ischemic heart failure.

PubMed

Kappel, Ben Arpad; Stöhr, Robert; De Angelis, Lorenzo; Mavilio, Maria; Menghini, Rossella; Federici, Massimo

2016-06-01

Forkhead box protein O1 (FoxO1) plays a key role in energy homeostasis, stress response and autophagy and is dysregulated in diabetes and ischemia. We investigated cardiac FoxO1 expression and posttranstranslational modifications after myocardial infarction (MI) and further tested if active posttranstranslational modulation of FoxO1 can alter cardiac remodeling in postischemic heart failure. Non-diabetic and diabetic C57BL/6 mice were subjected to MI by ligation of left anterior descending artery. In selected experiments we combined this model with intramyocardial injection of adenovirus expressing different isoforms of FoxO1. We used Millar catheter, histology, Western blot and metabolomics for further analyses. We show that after MI total cardiac FoxO1 is downregulated and partly recovers after 7 days. This downregulation is accompanied by fundamental posttranslational modifications of FoxO1, particularly acetylation. Adenovirus experiments revealed smaller infarction size and improved heart function in mice expressing a constitutively deacetylated variant of FoxO1 compared to a wild type variant of FoxO1 in both non-diabetic (MI size: -13.4 ± 3.5%; LVDP: +29.1 ± 9.4  mmHg; p < 0.05) and diabetic mice (MI size: -17.6 ± 3.7%; LVDP: +10.9 ± 3.6  mmHg; p < 0.05). Metabolomics analyses showed alterations in metabolites connected to muscle breakdown, collagen/elastin and energy metabolism between the two groups. First, our results demonstrate that myocardial ischemia is associated with downregulation and posttranslational modification of cardiac FoxO1. Second, we show in a mouse model of postischemic heart failure that posttranslational modulation of FoxO1 alters heart function involving collagen and protein metabolism. Therefore, posttranslational modifications of FoxO1 could be an option to target remodeling processes in postischemic heart failure. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Epigenomic regulation of oncogenesis by chromatin remodeling.

PubMed

Kumar, R; Li, D-Q; Müller, S; Knapp, S

2016-08-25

Disruption of the intricate gene expression program represents one of major driving factors for the development, progression and maintenance of human cancer, and is often associated with acquired therapeutic resistance. At the molecular level, cancerous phenotypes are the outcome of cellular functions of critical genes, regulatory interactions of histones and chromatin remodeling complexes in response to dynamic and persistent upstream signals. A large body of genetic and biochemical evidence suggests that the chromatin remodelers integrate the extracellular and cytoplasmic signals to control gene activity. Consequently, widespread dysregulation of chromatin remodelers and the resulting inappropriate expression of regulatory genes, together, lead to oncogenesis. We summarize the recent developments and current state of the dysregulation of the chromatin remodeling components as the driving mechanism underlying the growth and progression of human tumors. Because chromatin remodelers, modifying enzymes and protein-protein interactions participate in interpreting the epigenetic code, selective chromatin remodelers and bromodomains have emerged as new frontiers for pharmacological intervention to develop future anti-cancer strategies to be used either as single-agent or in combination therapies with chemotherapeutics or radiotherapy.

Single High-Sensitivity Cardiac Troponin I to Rule Out Acute Myocardial Infarction.

PubMed

Sandoval, Yader; Smith, Stephen W; Love, Sara A; Sexter, Anne; Schulz, Karen; Apple, Fred S

2017-09-01

This study examined the performance of single high-sensitivity cardiac troponin I (hs-cTnI) measurement strategies to rule out acute myocardial infarction. This was a prospective, observational study of consecutive patients presenting to the emergency department (n = 1631) in whom cTnI measurements were obtained using an investigational hs-cTnI assay. The goals of the study were to determine 1) negative predictive value (NPV) and sensitivity for the diagnosis of acute myocardial infarction, type 1 myocardial infarction, and type 2 myocardial infarction; and 2) safety outcome of acute myocardial infarction or cardiac death at 30 days using hs-cTnI less than the limit of detection (LoD) (<1.9 ng/L) or the High-STEACS threshold (<5 ng/L) alone and in combination with normal electrocardiogram (ECG). Acute myocardial infarction occurred in 170 patients (10.4%), including 68 (4.2%) type 1 myocardial infarction and 102 (6.3%) type 2 myocardial infarction. For hs-cTnImyocardial infarction were 99.6% (95% confidence interval 98.9%-100%) and 98.8 (97.2%-100%). For hs-cTnI<5 ng/L (50%), the NPV and sensitivity for acute myocardial infarction were 98.9% (98.2%-99.6%) and 94.7% (91.3%-98.1%). In combination with a normal ECG, 1) hs-cTnImyocardial infarction and who are at very low risk for adverse events at 30 days. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of supersaturated oxygen delivery on infarct size after percutaneous coronary intervention in acute myocardial infarction.

PubMed

Stone, Gregg W; Martin, Jack L; de Boer, Menko-Jan; Margheri, Massimo; Bramucci, Ezio; Blankenship, James C; Metzger, D Christopher; Gibbons, Raymond J; Lindsay, Barbara S; Weiner, Bonnie H; Lansky, Alexandra J; Krucoff, Mitchell W; Fahy, Martin; Boscardin, W John

2009-10-01

Myocardial salvage is often suboptimal after percutaneous coronary intervention in ST-segment elevation myocardial infarction. Posthoc subgroup analysis from a previous trial (AMIHOT I) suggested that intracoronary delivery of supersaturated oxygen (SSO(2)) may reduce infarct size in patients with large ST-segment elevation myocardial infarction treated early. A prospective, multicenter trial was performed in which 301 patients with anterior ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention within 6 hours of symptom onset were randomized to a 90-minute intracoronary SSO(2) infusion in the left anterior descending artery infarct territory (n=222) or control (n=79). The primary efficacy measure was infarct size in the intention-to-treat population (powered for superiority), and the primary safety measure was composite major adverse cardiovascular events at 30 days in the intention-to-treat and per-protocol populations (powered for noninferiority), with Bayesian hierarchical modeling used to allow partial pooling of evidence from AMIHOT I. Among 281 randomized patients with tc-99m-sestamibi single-photon emission computed tomography data in AMIHOT II, median (interquartile range) infarct size was 26.5% (8.5%, 44%) with control compared with 20% (6%, 37%) after SSO(2). The pooled adjusted infarct size was 25% (7%, 42%) with control compared with 18.5% (3.5%, 34.5%) after SSO(2) (P(Wilcoxon)=0.02; Bayesian posterior probability of superiority, 96.9%). The Bayesian pooled 30-day mean (+/-SE) rates of major adverse cardiovascular events were 5.0+/-1.4% for control and 5.9+/-1.4% for SSO(2) by intention-to-treat, and 5.1+/-1.5% for control and 4.7+/-1.5% for SSO(2) by per-protocol analysis (posterior probability of noninferiority, 99.5% and 99.9%, respectively). Among patients with anterior ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention within 6 hours of symptom onset, infusion of SSO(2) into

Actin binding GFP allows 4D in vivo imaging of myofilament dynamics in the zebrafish heart and the identification of Erbb2 signaling as a remodeling factor of myofibril architecture.

PubMed

Reischauer, Sven; Arnaout, Rima; Ramadass, Radhan; Stainier, Didier Y R

2014-10-24

Dilated cardiomyopathy is a leading cause of congestive heart failure and a debilitating complication of antineoplastic therapies. Despite disparate causes for dilated cardiomyopathy, maladaptive cardiac remodeling and decreased systolic function are common clinical consequences, begging an investigation of in vivo contractile dynamics in development and disease, one that has been impossible to date. To image myocardial contractile filament dynamics in vivo and to assess potential causes of dilated cardiomyopathy in antineoplastic therapies targeting the epidermal growth factor receptor Erbb2. We generated a transgenic zebrafish line expressing an actin-binding green fluorescent protein in cardiomyocytes, allowing an in vivo imaging of myofilaments. Analysis of this line revealed architectural differences in myofibrils of the distinct cardiomyocyte subtypes. We used this model to investigate the effects of Erbb2 signaling on myofibrillar organization because drugs targeting ERBB2 (HER2/NEU) signaling, a mainstay of breast cancer chemotherapy, cause dilated cardiomyopathy in many patients. High-resolution in vivo imaging revealed that Erbb2 signaling regulates a switch between a dense apical network of filamentous myofibrils and the assembly of basally localized myofibrils in ventricular cardiomyocytes. Using this novel line, we compiled a reference for myofibrillar microarchitecture among myocardial subtypes in vivo and at different developmental stages, establishing this model as a tool to analyze in vivo cardiomyocyte contractility and remodeling for a broad range of cardiovascular questions. Furthermore, we applied this model to study Erbb2 signaling in cardiomyopathy. We show a direct link between Erbb2 activity and remodeling of myofibrils, revealing an unexpected mechanism with potentially important implications for prevention and treatment of cardiomyopathy. © 2014 American Heart Association, Inc.

Refining adverse drug reaction signals by incorporating interaction variables identified using emergent pattern mining.

PubMed

Reps, Jenna M; Aickelin, Uwe; Hubbard, Richard B

2016-02-01

To develop a framework for identifying and incorporating candidate confounding interaction terms into a regularised cox regression analysis to refine adverse drug reaction signals obtained via longitudinal observational data. We considered six drug families that are commonly associated with myocardial infarction in observational healthcare data, but where the causal relationship ground truth is known (adverse drug reaction or not). We applied emergent pattern mining to find itemsets of drugs and medical events that are associated with the development of myocardial infarction. These are the candidate confounding interaction terms. We then implemented a cohort study design using regularised cox regression that incorporated and accounted for the candidate confounding interaction terms. The methodology was able to account for signals generated due to confounding and a cox regression with elastic net regularisation correctly ranking the drug families known to be true adverse drug reactions above those that are not. This was not the case without the inclusion of the candidate confounding interaction terms, where confounding leads to a non-adverse drug reaction being ranked highest. The methodology is efficient, can identify high-order confounding interactions and does not require expert input to specify outcome specific confounders, so it can be applied for any outcome of interest to quickly refine its signals. The proposed method shows excellent potential to overcome some forms of confounding and therefore reduce the false positive rate for signal analysis using longitudinal data. Copyright © 2015 Elsevier Ltd. All rights reserved.

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.

A comparison of adverse event and fracture efficacy data for strontium ranelate in regulatory documents and the publication record.

PubMed

Bolland, Mark J; Grey, Andrew

2014-10-07

Recently, the European Medicines Agency reported that strontium ranelate increases myocardial infarction risk in postmenopausal women, 8.5 years after it was registered for use in osteoporosis. Unreported serious adverse events in clinical trials for other pharmaceuticals have been described in recent years. We assessed reporting of adverse events and fracture efficacy of strontium. We compared data on adverse effects (myocardial infarction, venous thromboembolism and pulmonary embolism) and fracture efficacy of strontium in publicly available regulatory documents with data in publications retrieved from searching PubMed. We identified 5 regulatory documents and 9 primary publications of 7 randomised, placebo-controlled trials of strontium that reported relevant data. We identified several areas of concern in these reports: the increased risk of myocardial infarction with strontium was not identified in a pivotal phase 3 clinical trial despite specific regulatory review of cardiovascular events; data on myocardial infarction were not included in any primary publication; increased risks of venous thromboembolism and pulmonary embolism with strontium were not reported in either of the phase 3 clinical trials; data on venous thromboembolism were reported in only 5 of 9 primary publications, data on pulmonary embolism in only 2 of 9 primary publications, and either was discussed in <50% of subsequent review articles. There were differences in participant numbers, fracture cases and venous thromboembolism cases between regulatory documents and primary publications. Based on all available data from primary publications and regulatory documents, the number of fractures prevented by strontium use is similar to the number of extra cases of venous thromboembolism, pulmonary embolism and myocardial infarction caused by strontium use. The risks of strontium use are similar to the benefits. Full disclosure of the clinical trial data and regulatory documents would allow

Staged Percutaneous Intervention for Concurrent Chronic Total Occlusions in Patients With ST-Segment-Elevation Myocardial Infarction: A Systematic Review and Meta-Analysis.

PubMed

Villablanca, Pedro A; Olmedo, Wilman; Weinreich, Michael; Gupta, Tanush; Mohananey, Divyanshu; Albuquerque, Felipe N; Kassas, Ibrahim; Briceño, David; Sanina, Cristina; Brevik, Thomas A; Ong, Emily; Ramakrishna, Harish; Attubato, Michael; Menegus, Mark; Wiley, Jose; Kalra, Ankur

2018-04-13

Studies have shown that chronic total occlusion (CTO) in a noninfarct-related artery in patients with ST-segment-elevation myocardial infarction is linked to increased mortality. It remains unclear whether staged revascularization of a noninfarct-related artery CTO in patients with ST-segment-elevation myocardial infarction translates to improved outcomes. We performed a meta-analysis to compare outcomes between patients presenting with ST-segment-elevation myocardial infarction with concurrent CTO who underwent percutaneous coronary intervention of noninfarct-related artery CTO versus those who did not. We conducted an electronic database search of all published data. The primary end point was major adverse cardiovascular events. Secondary end points were all-cause mortality, cardiovascular mortality, myocardial infarction, repeat revascularization with either percutaneous coronary intervention or coronary artery bypass grafting, stroke, and heart failure readmission. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed. Random effects model was used and heterogeneity was considered if I 2 >25. Six studies (n=1253 patients) were included in the analysis. There was a significant difference in major adverse cardiovascular events (OR, 0.54; 95% CI, 0.32-0.91), cardiovascular mortality (OR, 0.43; 95% CI, 0.20-0.95), and heart failure readmissions (OR, 0.57; 95% CI, 0.36-0.89), favoring the patients in the CTO percutaneous coronary intervention group. No significant differences were observed between the 2 groups for all-cause mortality (OR, 0.47; 95% CI, 0.22-1.00), myocardial infarction (OR, 0.78; 95% CI, 0.41-1.46), repeat revascularization (OR, 1.13; 95% CI, 0.56-2.27), and stroke (OR, 0.51; 95% CI, 0.20-1.33). In this meta-analysis, CTO percutaneous coronary intervention of the noninfarct-related artery in patients presenting with ST-segment-elevation myocardial infarction was associated with a significant reduction in major adverse cardiovascular

The Biological Basis for Cardiac Repair After Myocardial Infarction: From Inflammation to Fibrosis

PubMed Central

Prabhu, Sumanth D.; Frangogiannis, Nikolaos G.

2016-01-01

In adult mammals, massive sudden loss of cardiomyocytes following infarction overwhelms the limited regenerative capacity of the myocardium, resulting in formation of a collagen-based scar. Necrotic cells release danger signals, activating innate immune pathways and triggering an intense inflammatory response. Stimulation of toll-like receptor signaling and complement activation induces expression of pro-inflammatory cytokines (such as interleukin-1 and tumor necrosis factor-α) and chemokines (such as monocyte chemoattractant protein-1/CCL2). Inflammatory signals promote adhesive interactions between leukocytes and endothelial cells, leading to extravasation of neutrophils and monocytes. As infiltrating leukocytes clear the infarct from dead cells, mediators repressing inflammation are released, and anti-inflammatory mononuclear cell subsets predominate. Suppression of the inflammatory response is associated with activation of reparative cells. Fibroblasts proliferate, undergo myofibroblast transdifferentiation, and deposit large amounts of extracellular matrix proteins maintaining the structural integrity of the infarcted ventricle. The renin-angiotensin-aldosterone system and members of the transforming growth factor-β family play an important role in activation of infarct myofibroblasts. Maturation of the scar follows, as a network of cross-linked collagenous matrix is formed and granulation tissue cells become apoptotic. This review discusses the cellular effectors and molecular signals regulating the inflammatory and reparative response following myocardial infarction. Dysregulation of immune pathways, impaired suppression of post-infarction inflammation, perturbed spatial containment of the inflammatory response, and overactive fibrosis may cause adverse remodeling in patients with infarction contributing to the pathogenesis of heart failure. Therapeutic modulation of the inflammatory and reparative response may hold promise for prevention of post

Major adverse cardiac events during endurance sports.

PubMed

Belonje, Anne; Nangrahary, Mary; de Swart, Hans; Umans, Victor

2007-03-15

Major adverse cardiac events in endurance exercise are usually due to underlying and unsuspected heart disease. The investigators present an analysis of major adverse cardiac events that occurred during 2 consecutive annual long distance races (a 36-km beach cycling race and a 21-km half marathon) over the past 5 years. All patients with events were transported to the hospital. Most of the 62,862 participants were men (77%; mean age 40 years). Of these, 4 men (3 runners, 1 cyclist; mean age 48 years) collapsed during (n = 2) or shortly after the races, rendering a prevalence of 0.006%. Two patients collapsed after developing chest pain, 1 of whom needed resuscitation at the event site, which was successful. These patients had acute myocardial infarctions and underwent primary angioplasty. The third patient was resuscitated at the site but did not have coronary disease or inducible ventricular tachycardia or ventricular fibrillation and collapsed presumably because of catecholamine-induced ventricular fibrillation. The fourth patient experienced heat stroke and had elevated creatine kinase-MB and troponins in the absence of electrocardiographic changes. In conclusion, the risk for major adverse cardiac events during endurance sports in well-trained athletes is very low.

L-arginine fails to prevent ventricular remodeling and heart failure in the spontaneously hypertensive rat.

PubMed

Brooks, Wesley W; Conrad, Chester H; Robinson, Kathleen G; Colucci, Wilson S; Bing, Oscar H L

2009-02-01

The effects of long-term oral administration of L-arginine, a substrate for nitric oxide (NO) production, on left ventricular (LV) remodeling, myocardial function and the prevention of heart failure (HF) was compared to the angiotensin-converting enzyme (ACE) inhibitor captopril in a rat model of hypertensive HF (aged spontaneously hypertensive rat (SHR)). SHRs and age-matched normotensive Wistar-Kyoto (WKY) rats were assigned to either no treatment, treatment with L-arginine (7.5 g/l in drinking water) or captopril (1 g/l in drinking water) beginning at 14 months of age, a time when SHRs exhibit stable compensated hypertrophy with no hemodynamic impairment; animals were studied at 23 months of age or at the time of HF. In untreated SHR, relative to WKY, there was significant LV hypertrophy, myocardial fibrosis, and isolated LV muscle performance and response to isoproterenol (ISO) were depressed; and, 7 of 10 SHRs developed HF. Captopril administration to six SHRs attenuated hypertrophy and prevented impaired inotropic responsiveness to ISO, contractile dysfunction, fibrosis, increased passive stiffness, and HF. In contrast, L-arginine administration to SHR increased LV hypertrophy and myocardial fibrosis while cardiac performance was depressed; and 7 of 9 SHRs developed HF. In WKY, L-arginine treatment but not captopril resulted in increased LV weight and the contractile response to ISO was blunted. Neither L-arginine nor captopril treatment of WKY changed fibrosis and HF did not occur. These data demonstrate that in contrast to captopril, long-term treatment with L-arginine exacerbates age-related cardiac hypertrophy, fibrosis, and did not prevent contractile dysfunction or the development of HF in aging SHR.

Living Without Creatine: Unchanged Exercise Capacity and Response to Chronic Myocardial Infarction in Creatine-Deficient Mice

PubMed Central

Lygate, Craig A.; Aksentijevic, Dunja; Dawson, Dana; Hove, Michiel ten; Phillips, Darci; de Bono, Joseph P.; Medway, Debra J.; Sebag-Montefiore, Liam; Hunyor, Imre; Channon, Keith M.; Clarke, Kieran; Zervou, Sevasti; Watkins, Hugh; Balaban, Robert S.; Neubauer, Stefan

2014-01-01

Rationale Creatine is thought to be involved in the spatial and temporal buffering of ATP in energetic organs such as heart and skeletal muscle. Creatine depletion affects force generation during maximal stimulation, while reduced levels of myocardial creatine are a hallmark of the failing heart, leading to the widely held view that creatine is important at high workloads and under conditions of pathological stress. Objective We therefore hypothesised that the consequences of creatine-deficiency in mice would be impaired running capacity, and exacerbation of heart failure following myocardial infarction. Methods and Results Surprisingly, mice with whole-body creatine deficiency due to knockout of the biosynthetic enzyme (guanidinoacetate N-methyltransferase – GAMT) voluntarily ran just as fast and as far as controls (>10km/night) and performed the same level of work when tested to exhaustion on a treadmill. Furthermore, survival following myocardial infarction was not altered, nor was subsequent LV remodelling and development of chronic heart failure exacerbated, as measured by 3D-echocardiography and invasive hemodynamics. These findings could not be accounted for by compensatory adaptations, with no differences detected between WT and GAMT−/− proteomes. Alternative phosphotransfer mechanisms were explored; adenylate kinase activity was unaltered, and although GAMT−/− hearts accumulated the creatine pre-cursor guanidinoacetate, this had negligible energy-transfer activity, while mitochondria retained near normal function. Conclusions Creatine-deficient mice show unaltered maximal exercise capacity and response to chronic myocardial infarction, and no obvious metabolic adaptations. Our results question the paradigm that creatine is essential for high workload and chronic stress responses in heart and skeletal muscle. PMID:23325497

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

Experience of low-dose aminophylline use to relieve minor adverse effects of dipyridamole in patients undergoing stress myocardial perfusion imaging.

PubMed

Lin, Li-Fan; Cheng, Cheng-Yi; Hou, Cheng-Han; Ku, Chih-Hung; Tseng, Neng-Chuan; Shen, Daniel H Y

2014-06-01

Intravenous administration of aminophylline is widely adopted to reverse dipyridamole-related adverse effects (AEs) during stress myocardial perfusion imaging (MPI). The study aimed to investigate the efficacy of lower-dose aminophylline to relieve minor AEs. 2,250 consecutive patients undergoing dipyridamole-stressed MPI were enrolled. Information concerning AE occurrence and dosages of aminophylline was collected to evaluate the efficacy of lower-dose aminophylline. A logistic regression was used to determine independent predictors of dipyridamole-related AE occurrence. No severe AE was noted. Overall mild AE incidence was 37.0% (833/2,250 patients). Initial low-dose (25 mg) aminophylline relieved symptoms in 98.8% of patients with mild AEs (823/833 patients). An extra 25 mg aminophylline sufficed to reverse all such AEs. Mean body mass index (BMI) differed significantly between patients with and without any AE [25.6 vs 25.1 (P = .009)]. There was no significant difference between two subgroups in mean age, male gender prevalence, body height and weight, dipyridamole dose/BMI, or prevalence of significant perfusion defect(s) on MPI. Multivariable logistic regression demonstrated BMI remained the independent predictor of dipyridamole-related AE occurrence (odds ratio 1.028, 95% confidence interval 1.007-1.049, P = .01). Low-dose (≦50 mg, and usually 25 mg) aminophylline seems sufficient to relieve mild dipyridamole-related AEs during stress MPI.

Collagen remodeling after myocardial infarction in the rat heart.

PubMed Central

Cleutjens, J. P.; Verluyten, M. J.; Smiths, J. F.; Daemen, M. J.

1995-01-01

In this study changes in the amount and distribution of types I and III collagen mRNA and protein were investigated in the rat heart after induction of a left ventricular myocardial infarction (MI). Sham operated rats served as controls. The animals were sacrificed at different time intervals after operation. Northern blotting of cardiac RNA and hybridization with cDNA probes for types I and III procollagen revealed a 5- to 15-fold increase in the infarcted left ventricle. Type III procollagen mRNA levels were already increased at day 2 after MI, whereas type I procollagen mRNA followed this response at day 4 after MI. This increase was sustained for at least 21 days in the infarcted left ventricle for type III procollagen mRNA, whereas type 1 procollagen mRNA levels were still elevated at 90 days after MI. In the noninfarcted right ventricle a 5- to 7-fold increase was observed for both type I and type III procollagen mRNA levels, but only at day 4 after MI. In the non-infarcted septum a transient increase was observed for type I procollagen mRNA from day 7-21 (4- to 5-fold increase) and a decline to sham levels thereafter. In the septum type III procollagen mRNA levels were only elevated at 7 days after MI (4- to 5-fold increase) compared with sham operated controls. In situ hybridization with the same types I and III procollagen probes showed procollagen mRNA-producing cells in the infarcted area around necrotic cardiomyocytes, and in the interstitial cells in the non-infarcted part of the myocardium. No labeling was detected above cardiomyocytes. Combined in situ hybridization and immunohistochemistry showed that the collagen mRNA producing cells have a myofibroblast-like phenotype in the infarcted myocardium and are fibroblasts in the noninfarcted septum and right ventricle. The increase in types I and III procollagen mRNA in both infarcted and non-infarcted myocardium was followed by an increased collagen deposition, measured by computerized morphometry on

Collagen remodeling after myocardial infarction in the rat heart.

PubMed

Cleutjens, J P; Verluyten, M J; Smiths, J F; Daemen, M J

1995-08-01

In this study changes in the amount and distribution of types I and III collagen mRNA and protein were investigated in the rat heart after induction of a left ventricular myocardial infarction (MI). Sham operated rats served as controls. The animals were sacrificed at different time intervals after operation. Northern blotting of cardiac RNA and hybridization with cDNA probes for types I and III procollagen revealed a 5- to 15-fold increase in the infarcted left ventricle. Type III procollagen mRNA levels were already increased at day 2 after MI, whereas type I procollagen mRNA followed this response at day 4 after MI. This increase was sustained for at least 21 days in the infarcted left ventricle for type III procollagen mRNA, whereas type 1 procollagen mRNA levels were still elevated at 90 days after MI. In the noninfarcted right ventricle a 5- to 7-fold increase was observed for both type I and type III procollagen mRNA levels, but only at day 4 after MI. In the non-infarcted septum a transient increase was observed for type I procollagen mRNA from day 7-21 (4- to 5-fold increase) and a decline to sham levels thereafter. In the septum type III procollagen mRNA levels were only elevated at 7 days after MI (4- to 5-fold increase) compared with sham operated controls. In situ hybridization with the same types I and III procollagen probes showed procollagen mRNA-producing cells in the infarcted area around necrotic cardiomyocytes, and in the interstitial cells in the non-infarcted part of the myocardium. No labeling was detected above cardiomyocytes. Combined in situ hybridization and immunohistochemistry showed that the collagen mRNA producing cells have a myofibroblast-like phenotype in the infarcted myocardium and are fibroblasts in the noninfarcted septum and right ventricle. The increase in types I and III procollagen mRNA in both infarcted and non-infarcted myocardium was followed by an increased collagen deposition, measured by computerized morphometry on

Adverse postresuscitation myocardial effects elicited by buffer-induced alkalemia ameliorated by NHE-1 inhibition in a rat model of ventricular fibrillation.

PubMed

Lamoureux, Lorissa; Radhakrishnan, Jeejabai; Mason, Thomas G; Kraut, Jeffrey A; Gazmuri, Raúl J

2016-11-01

Major myocardial abnormalities occur during cardiac arrest and resuscitation including intracellular acidosis-partly caused by CO 2 accumulation-and activation of the Na + -H + exchanger isoform-1 (NHE-1). We hypothesized that a favorable interaction may result from NHE-1 inhibition during cardiac resuscitation followed by administration of a CO 2 -consuming buffer upon return of spontaneous circulation (ROSC). Ventricular fibrillation was electrically induced in 24 male rats and left untreated for 8 min followed by defibrillation after 8 min of cardiopulmonary resuscitation (CPR). Rats were randomized 1:1:1 to the NHE-1 inhibitor zoniporide or vehicle during CPR and disodium carbonate/sodium bicarbonate buffer or normal saline (30 ml/kg) after ROSC. Survival at 240 min declined from 100% with Zoniporide/Saline to 50% with Zoniporide/Buffer and 25% with Vehicle/Buffer (P = 0.004), explained by worsening postresuscitation myocardial dysfunction. Marked alkalemia occurred after buffer administration along with lactatemia that was maximal after Vehicle/Buffer, attenuated by Zoniporide/Buffer, and minimal with Zoniporide/Saline [13.3 ± 4.8 (SD), 9.2 ± 4.6, and 2.7 ± 1.0 mmol/l; P ≤ 0.001]. We attributed the intense postresuscitation lactatemia to enhanced glycolysis consequent to severe buffer-induced alkalemia transmitted intracellularly by an active NHE-1. We attributed the worsened postresuscitation myocardial dysfunction also to severe alkalemia intensifying Na + entry via NHE-1 with consequent Ca 2+ overload injuring mitochondria, evidenced by increased plasma cytochrome c Both buffer-induced effects were ameliorated by zoniporide. Accordingly, buffer-induced alkalemia after ROSC worsened myocardial function and survival, likely through enhancing NHE-1 activity. Zoniporide attenuated these effects and uncovered a complex postresuscitation acid-base physiology whereby blood pH drives NHE-1 activity and compromises mitochondrial function and integrity along

Adverse cardiovascular events during treatment with glyburide (glibenclamide) or gliclazide in a high-risk population.

PubMed

Juurlink, D N; Gomes, T; Shah, B R; Mamdani, M M

2012-12-01

Sulphonylureas promote insulin release by inhibiting pancreatic potassium channels. Older sulphonylureas such as glyburide (glibenclamide), but not newer ones such as gliclazide, antagonize similar channels in myocardium, interfering with the protective effects of ischaemic preconditioning. Whether this imparts a higher risk of adverse cardiac events is unknown. We conducted a population-based cohort study of patients aged 66 years and older who were hospitalized for acute myocardial infarction or who underwent percutaneous coronary intervention between 1 April 2007 and 31 March 2010 while receiving either glyburide or gliclazide. We used a high-dimensional propensity score matching process to ensure similarity of glyburide- and gliclazide-treated patients. The primary outcome was a composite of death or hospitalization for myocardial infarction or heart failure. During the 2-year study period, we matched 1690 patients treated with glyburide to 984 patients treated with gliclazide at the time of hospitalization for acute myocardial infarction or percutaneous coronary intervention. We found no difference in the risk of the composite outcome among patients receiving glyburide (adjusted hazard ratio 1.01; 95% CI 0.86-1.18). We found similar results in secondary analyses of each outcome individually, and in two supplementary analyses (haemorrhage and pneumonia) in which we anticipated no difference between the two patient groups. Among older patients hospitalized for acute myocardial infarction or percutaneous coronary intervention, treatment with glyburide is not associated with an increased risk of future adverse cardiovascular events relative to gliclazide, suggesting that the effect of glyburide on ischaemic preconditioning is of little clinical relevance. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Myocardial Blood Flow and Inflammatory Cardiac Sarcoidosis.

PubMed

Kruse, Matthew J; Kovell, Lara; Kasper, Edward K; Pomper, Martin G; Moller, David R; Solnes, Lilja; Chen, Edward S; Schindler, Thomas H

2017-02-01

preserved myocardial flow reserve (MFR) at follow-up, whereas MFR significantly worsened in regions without changes or even increases in inflammation (median ΔMFR: 0.07 [IQR: -0.29 to 0.45] vs. -0.24 [IQR: -0.84 to 0.21]; p < 0.001). There was an inverse correlation between pronounced alterations in myocardial inflammation (Δ regional myocardial volume with standardized uptake value >4.1) and ΔMFR (r = -0.47; p = 0.048). Sarcoid-mediated myocardial inflammation is associated with a regional impairment of coronary circulatory function. The association between immune-suppressive treatment-related alterations in myocardial inflammation and changes in coronary vasodilator capacity suggests direct adverse effect of inflammation on coronary circulatory function in cardiac sarcoidosis. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Genome-wide association study of perioperative myocardial infarction after coronary artery bypass surgery.

PubMed

Kertai, Miklos D; Li, Yi-Ju; Li, Yen-Wei; Ji, Yunqi; Alexander, John; Newman, Mark F; Smith, Peter K; Joseph, Diane; Mathew, Joseph P; Podgoreanu, Mihai V

2015-05-06

Identification of patient subpopulations susceptible to develop myocardial infarction (MI) or, conversely, those displaying either intrinsic cardioprotective phenotypes or highly responsive to protective interventions remain high-priority knowledge gaps. We sought to identify novel common genetic variants associated with perioperative MI in patients undergoing coronary artery bypass grafting using genome-wide association methodology. 107 secondary and tertiary cardiac surgery centres across the USA. We conducted a stage I genome-wide association study (GWAS) in 1433 ethnically diverse patients of both genders (112 cases/1321 controls) from the Genetics of Myocardial Adverse Outcomes and Graft Failure (GeneMAGIC) study, and a stage II analysis in an expanded population of 2055 patients (225 cases/1830 controls) combined from the GeneMAGIC and Duke Perioperative Genetics and Safety Outcomes (PEGASUS) studies. Patients undergoing primary non-emergent coronary bypass grafting were included. The primary outcome variable was perioperative MI, defined as creatine kinase MB isoenzyme (CK-MB) values ≥10× upper limit of normal during the first postoperative day, and not attributable to preoperative MI. Secondary outcomes included postoperative CK-MB as a quantitative trait, or a dichotomised phenotype based on extreme quartiles of the CK-MB distribution. Following quality control and adjustment for clinical covariates, we identified 521 single nucleotide polymorphisms in the stage I GWAS analysis. Among these, 8 common variants in 3 genes or intergenic regions met p<10(-5) in stage II. A secondary analysis using CK-MB as a quantitative trait (minimum p=1.26×10(-3) for rs609418), or a dichotomised phenotype based on extreme CK-MB values (minimum p=7.72×10(-6) for rs4834703) supported these findings. Pathway analysis revealed that genes harbouring top-scoring variants cluster in pathways of biological relevance to extracellular matrix remodelling, endoplasmic reticulum

Myocardial infarction caused by myocardial bridging in a male adolescent athlete.

PubMed

Zhu, Cheng-Gang; Liu, Jun; Liu, Wei-Dong; Xu, Yan-Lu; Wu, Na-Qiong; Guo, Yuan-Lin; Tang, Yi-Da; Jiang, Li-Xin; Li, Jian-Jun

2012-02-01

Myocardial bridging is a common congenital abnormality of a coronary artery, and is usually thought to be a benign anatomical variant. Although rare, previous studies have reported that patients with myocardial bridging may suffer from myocardial ischemia, myocardial infarction (MI), arrhythmias and even sudden death. Here we report the case of an 18-year-old adolescent athlete with myocardial bridging resulting in MI. Coronary angiography revealed 80% luminal narrowing by systolic compression in the proximal and mid segments of the left anterior descending coronary artery, which returned to normal during diastole. We considered that heavy sports might be a potential trigger for his MI attack. Therefore, special attention should be paid to this kind of athlete, especially if adolescent.

Twelve-month clinical outcomes of acute non-ST versus ST-segment elevation myocardial infarction patients with reduced preprocedural thrombolysis in myocardial infarction flow undergoing percutaneous coronary intervention.

PubMed

Baek, Ju Yeol; Kang, Tae Soo; Rha, Seung-Woon; Choi, Byoung Geol; Park, Sang Ho; Jeong, Myung Ho

2018-04-27

Reduced preprocedural thrombolysis in myocardial infarction (TIMI) flow in patients with ST-segment elevation myocardial infarction (STEMI) is known to be associated with increased mortality. However, clinical implications of reduced preprocedural TIMI flow in patients with non-ST-segment elevation myocardial infarction (NSTEMI) have not been fully elucidated as yet. The aim of the present study was to compare the clinical influence of reduced preprocedural TIMI flows between patients with STEMI and NSTEMI undergoing percutaneous coronary intervention (PCI). From the Korea Acute Myocardial Infarction Registry, a total of 7336 AMI patients with angiographically confirmed reduced preprocedural TIMI flow (TIMI 0/1) during PCI were selected and divided into STEMI (n=4852) and NSTEMI (n=2484) groups. The 12-month composite of total death, nonfatal myocardial infarction, coronary artery bypass graft, and repeated PCI was compared between the two groups. After adjustment of baseline confounders by propensity score stratification, the NSTEMI group had lower incidences of major adverse cardiac events than the STEMI group (7.15 vs. 11.19%; hazard ratio: 0.63; 95% confidence interval: 0.47-0.84; P=0.001) at 12 months, which was largely attributable to the lower incidences of total deaths (2.43 vs. 3.99%; P=0.04) and repeated PCI (3.81 vs. 6.41%; P=0.01). Among AMI patients with TIMI 0/1, patients with NSTEMI had better outcomes compared with those of patients with STEMI on the basis of the incidences of 12-month outcomes. This could be attributable to lower total death and repeated revascularization in patients with NSTEMI.

Modulation of mononuclear phagocyte inflammatory response by liposome-encapsulated voltage gated sodium channel inhibitor ameliorates myocardial ischemia/reperfusion injury in rats.

PubMed

Zhou, Xin; Luo, Yue-Chen; Ji, Wen-Jie; Zhang, Li; Dong, Yan; Ge, Lan; Lu, Rui-Yi; Sun, Hai-Ying; Guo, Zao-Zeng; Yang, Guo-Hong; Jiang, Tie-Min; Li, Yu-Ming

2013-01-01

Emerging evidence shows that anti-inflammatory strategies targeting inflammatory monocyte subset could reduce excessive inflammation and improve cardiovascular outcomes. Functional expression of voltage-gated sodium channels (VGSCs) have been demonstrated in monocytes and macrophages. We hypothesized that mononuclear phagocyte VGSCs are a target for monocyte/macrophage phenotypic switch, and liposome mediated inhibition of mononuclear phagocyte VGSC may attenuate myocardial ischemia/reperfusion (I/R) injury and improve post-infarction left ventricular remodeling. Thin film dispersion method was used to prepare phenytoin (PHT, a non-selective VGSC inhibitor) entrapped liposomes. Pharmacokinetic study revealed that the distribution and elimination half-life of PHT entrapped liposomes were shorter than those of free PHT, indicating a rapid uptake by mononuclear phagocytes after intravenous injection. In rat peritoneal macrophages, several VGSC α subunits (NaV1.1, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaVX, Scn1b, Scn3b and Scn4b) and β subunits were expressed at mRNA level, and PHT could suppress lipopolysaccharide induced M1 polarization (decreased TNF-α and CCL5 expression) and facilitate interleukin-4 induced M2 polarization (increased Arg1 and TGF-β1 expression). In vivo study using rat model of myocardial I/R injury, demonstrated that PHT entrapped liposome could partially suppress I/R injury induced CD43+ inflammatory monocyte expansion, along with decreased infarct size and left ventricular fibrosis. Transthoracic echocardiography and invasive hemodynamic analysis revealed that PHT entrapped liposome treatment could attenuate left ventricular structural and functional remodeling, as shown by increased ejection fraction, reduced end-systolic and end-diastolic volume, as well as an amelioration of left ventricular systolic (+dP/dt max) and diastolic (-dP/dt min) functions. Our work for the first time demonstrates the therapeutic potential of VGSC antagonism

CCL22 and CCR4 Gene Polymorphisms in Myocardial Infarction: Risk Assessment of rs4359426 and rs2228428 in Iranian Population.

PubMed

Noori, Farideh; Naeimi, Sirous; Zibaeenezhad, Mohammad J; Gharemirshamlu, Fatemeh R

2018-06-01

Myocardial infarction (MI) is an irreversible damage of myocardial tissue caused by prolonged ischemia and hypoxia. A local hypoxia-induced inflammation causes recruitment of leukocytes to the inflammatory site to aid cardiac remodeling and tissue healing. Among various chemokines involved in the process, CCL22 plays an essential role in cardiac cell migrations. In this study, we evaluated the incidence of rs4359426 and rs2228428 SNPs in CCL22/CCR4 genes of MI patients and studied their association with the physiology of the disease. Two hundred patients aged 30 - 70 years diagnosed with myocardial infarction along with 200 agematched healthy controls were registered in the study and their pathophysiological findings were recorded. Genotypic analysis of rs4359426 and rs2228428 in CCL22 and CCR4 genes, respectively, were carried out in patients using PCR-RFLP method and compared with the control group. Successively genotyped SNPs were reviewed for their possible association with the disease or physiological findings using Fisher's exact test. The frequency of CC genotypes atboth SNPs rs4359426 and rs2228428 in CCL22 and CCR4 genes was significantly higher in MI patients compared to other genotypes. Although we could not establish any direct association with the disease due to restricted population size, it is possible that CC genotypesin CCL22 and CCR4 could be considered as risk factors in myocardial infarction.

TGF-β improves myocardial function and prevents apoptosis induced by anoxia-reoxygenation, through the reduction of endoplasmic reticulum stress.

PubMed

Wang, Yufeng; Zong, Ligeng; Wang, Xiaolei

2016-01-01

Transforming growth factor-β (TGF-β) is known for its role in ventricular remodeling, inflammatory response, cell survival, and apoptosis. However, its role in improving myocardial function in rat hearts subjected to ischemia-reperfusion (I/R) and protecting against apoptosis induced in cardiomyocytes by anoxia-reoxygenation (A/R) has not been elucidated. This study investigated the protective effects and molecular mechanisms of TGF-β on myocardial function and cardiomyocyte apoptosis. We used TUNEL staining, we tested cell viability, and we measured mitochondrial membrane potential and levels of mitochondrial ROS after 6 h of simulated anoxia together with various durations of simulated reoxygenation in H9c2 cells. We further observed the contractile function in rat hearts after they were subjected to 30 min global ischemia and 180 min reperfusion. Pretreatment with TGF-β markedly inhibited apoptosis in H9c2 cells, as evidenced by increased cell viability and decreased numbers of TUNEL-positive cells, maintained mitochondrial membrane potential, and diminished mitochondrial production of reactive oxygen species (ROS). These changes were associated with the inhibition of endoplasmic reticulum (ER) stress-dependent markers of apoptosis (GRP78, CHOP, caspase-12, and JNK), and the modulation of the expression of Bcl2/Bax. Furthermore, TGF-β improved I/R-induced myocardial contractile dysfunction. All of these protective effects were concentration-dependent. Our results show that TGF-β prevents A/R-induced apoptosis of cardiomyocytes and improves myocardial function in rat hearts injured by I/R.

Different Causes of Death in Patients with Myocardial Infarction Type 1, Type 2, and Myocardial Injury.

PubMed

Lambrecht, Sascha; Sarkisian, Laura; Saaby, Lotte; Poulsen, Tina S; Gerke, Oke; Hosbond, Susanne; Diederichsen, Axel C P; Thygesen, Kristian; Mickley, Hans

2018-05-01

Data outlining the mortality and the causes of death in patients with type 1 myocardial infarction, type 2 myocardial infarction, and those with myocardial injury are limited. During a 1-year period from January 2010 to January 2011, all hospitalized patients who had cardiac troponin I measured on clinical indication were prospectively studied. Patients with at least one cardiac troponin I value >30 ng/L underwent case ascertainment and individual evaluation by an experienced adjudication committee. Patients were classified as having type 1 myocardial infarction, type 2 myocardial infarction, or myocardial injury according to the criteria of the universal definition of myocardial infarction. Follow-up was ensured until December 31, 2014. Data on mortality and causes of death were obtained from the Danish Civil Registration System and the Danish Register of Causes of Death. Overall, 3762 consecutive patients were followed for a mean of 3.2 years (interquartile range 1.3-3.6 years). All-cause mortality differed significantly among categories: Type 1 myocardial infarction 31.7%, type 2 myocardial infarction 62.2%, myocardial injury 58.7%, and 22.2% in patients with nonelevated troponin values (log-rank test; P < .0001). In patients with type 1 myocardial infarction, 61.3% died from cardiovascular causes, vs 42.6% in patients with type 2 myocardial infarction (P = .015) and 41.2% in those with myocardial injury (P < .0001). The overall mortality and the causes of death did not differ substantially between patients with type 2 myocardial infarction and those with myocardial injury. Patients with type 2 myocardial infarction and myocardial injury exhibit a significantly higher long-term mortality compared with patients with type 1 myocardial infarction . However, most patients with type 1 myocardial infarction die from cardiovascular causes in contrast to patients with type 2 myocardial infarction and myocardial injury, in whom noncardiovascular causes of death

MicroRNAs in Valvular Heart Diseases: Potential Role as Markers and Actors of Valvular and Cardiac Remodeling

PubMed Central

Oury, Cécile; Servais, Laurence; Bouznad, Nassim; Hego, Alexandre; Nchimi, Alain; Lancellotti, Patrizio

2016-01-01

miRNAs are a class of over 5000 noncoding RNAs that regulate more than half of the protein-encoding genes by provoking their degradation or preventing their translation. miRNAs are key regulators of complex biological processes underlying several cardiovascular disorders, including left ventricular hypertrophy, ischemic heart disease, heart failure, hypertension and arrhythmias. Moreover, circulating miRNAs herald promise as biomarkers in acute myocardial infarction and heart failure. In this context, this review gives an overview of studies that suggest that miRNAs could also play a role in valvular heart diseases. This area of research is still at its infancy, and further investigations in large patient cohorts and cellular or animal models are needed to provide strong data. Most studies focused on aortic stenosis, one of the most common valvular diseases in developed countries. Profiling and functional analyses indicate that miRNAs could contribute to activation of aortic valve interstitial cells to a myofibroblast phenotype, leading to valvular fibrosis and calcification, and to pressure overload-induced myocardial remodeling and hypertrophy. Data also indicate that specific miRNA signatures, in combination with clinical and functional imaging parameters, could represent useful biomarkers of disease progression or recovery after aortic valve replacement. PMID:27420053

Periodontitis and myocardial hypertrophy.

PubMed

Suzuki, Jun-Ichi; Sato, Hiroki; Kaneko, Makoto; Yoshida, Asuka; Aoyama, Norio; Akimoto, Shouta; Wakayama, Kouji; Kumagai, Hidetoshi; Ikeda, Yuichi; Akazawa, Hiroshi; Izumi, Yuichi; Isobe, Mitsuaki; Komuro, Issei

2017-04-01

There is a deep relationship between cardiovascular disease and periodontitis. It has been reported that myocardial hypertrophy may be affected by periodontitis in clinical settings. Although these clinical observations had some study limitations, they strongly suggest a direct association between severity of periodontitis and left ventricular hypertrophy. However, the detailed mechanisms between myocardial hypertrophy and periodontitis have not yet been elucidated. Recently, we demonstrated that periodontal bacteria infection is closely related to myocardial hypertrophy. In murine transverse aortic constriction models, a periodontal pathogen, Aggregatibacter actinomycetemcomitans markedly enhanced cardiac hypertrophy with matrix metalloproteinase-2 activation, while another pathogen Porphyromonas gingivalis (P.g.) did not accelerate these pathological changes. In the isoproterenol-induced myocardial hypertrophy model, P.g. induced myocardial hypertrophy through Toll-like receptor-2 signaling. From our results and other reports, regulation of chronic inflammation induced by periodontitis may have a key role in the treatment of myocardial hypertrophy. In this article, we review the pathophysiological mechanism between myocardial hypertrophy and periodontitis.

Impact of specific training and competition on myocardial structure and function in different age ranges of male handball players

PubMed Central

Agrebi, Brahim; Tkatchuk, Vladimir; Hlila, Nawel; Mouelhi, Emna; Belhani, Ali

2015-01-01

Handball activity involves cardiac changes and demands a mixture of both eccentric and concentric remodeling within the heart. This study seeks to explore heart performance and cardiac remodeling likely to define cardiac parameters which influence specific performance in male handball players across different age ranges. Forty three players, with a regular training and competitive background in handball separated into three groups aged on average 11.78±0.41 for youth players aka “schools”, “elite juniors” 15.99±0.81 and “elite adults” 24.46±2.63 years, underwent echocardiography and ECG examinations. Incremental ergocycle and specific field (SFT) tests have also been conducted. With age and regular training and competition, myocardial remodeling in different age ranges exhibit significant differences in dilatation’s parameters between “schools” and “juniors” players, such as the end-diastolic diameter (LVEDD) and the end-systolic diameter of the left ventricle (LVESD), the root of aorta (Ao) and left atrial (LA), while significant increase is observed between “juniors” and “adults” players in the interventricular septum (IVS), the posterior wall thicknesses (PWT) and LV mass index. ECG changes are also noted but NS differences were observed in studied parameters. For incremental maximal test, players demonstrate a significant increase in duration and total work between “schools” and “juniors” and, in total work only, between “juniors” and “seniors”. The SFT shows improvement in performance which ranged between 26.17±1.83 sec to 31.23±2.34 sec respectively from “seniors” to “schools”. The cross-sectional approach used to compare groups with prior hypothesis that there would be differences in exercise performance and cardiac parameters depending on duration of prior handball practice, leads to point out the early cardiac remodeling within the heart as adaptive change. Prevalence of cardiac chamber dilation

Impact of specific training and competition on myocardial structure and function in different age ranges of male handball players.

PubMed

Agrebi, Brahim; Tkatchuk, Vladimir; Hlila, Nawel; Mouelhi, Emna; Belhani, Ali

2015-01-01

Handball activity involves cardiac changes and demands a mixture of both eccentric and concentric remodeling within the heart. This study seeks to explore heart performance and cardiac remodeling likely to define cardiac parameters which influence specific performance in male handball players across different age ranges. Forty three players, with a regular training and competitive background in handball separated into three groups aged on average 11.78 ± 0.41 for youth players aka "schools", "elite juniors" 15.99 ± 0.81 and "elite adults" 24.46 ± 2.63 years, underwent echocardiography and ECG examinations. Incremental ergocycle and specific field (SFT) tests have also been conducted. With age and regular training and competition, myocardial remodeling in different age ranges exhibit significant differences in dilatation's parameters between "schools" and "juniors" players, such as the end-diastolic diameter (LVEDD) and the end-systolic diameter of the left ventricle (LVESD), the root of aorta (Ao) and left atrial (LA), while significant increase is observed between "juniors" and "adults" players in the interventricular septum (IVS), the posterior wall thicknesses (PWT) and LV mass index. ECG changes are also noted but NS differences were observed in studied parameters. For incremental maximal test, players demonstrate a significant increase in duration and total work between "schools" and "juniors" and, in total work only, between "juniors" and "seniors". The SFT shows improvement in performance which ranged between 26.17 ± 1.83 sec to 31.23 ± 2.34 sec respectively from "seniors" to "schools". The cross-sectional approach used to compare groups with prior hypothesis that there would be differences in exercise performance and cardiac parameters depending on duration of prior handball practice, leads to point out the early cardiac remodeling within the heart as adaptive change. Prevalence of cardiac chamber dilation with less hypertrophy remodeling was found

Is Postoperative Intensive Care Unit Care Necessary following Cranial Vault Remodeling for Sagittal Synostosis?

PubMed

Wolfswinkel, Erik M; Howell, Lori K; Fahradyan, Artur; Azadgoli, Beina; McComb, J Gordon; Urata, Mark M

2017-12-01

Of U.S. craniofacial and neurosurgeons, 94 percent routinely admit patients to the intensive care unit following cranial vault remodeling for correction of sagittal synostosis. This study aims to examine the outcomes and cost of direct ward admission following primary cranial vault remodeling for sagittal synostosis. An institutional review board-approved retrospective review was undertaken of the records of all patients who underwent primary cranial vault remodeling for isolated sagittal craniosynostosis from 2009 to 2015 at a single pediatric hospital. Patient demographics, perioperative course, and outcomes were recorded. One hundred ten patients met inclusion criteria with absence of other major medical problems. Average age at operation was 6.7 months, with a mean follow-up of 19.8 months. Ninety-eight patients (89 percent) were admitted to a general ward for postoperative care, whereas the remaining 12 (11 percent) were admitted to the intensive care unit for preoperative or perioperative concerns. Among ward-admitted patients, there were four (3.6 percent) minor complications; however, there were no major adverse events, with none necessitating intensive care unit transfers from the ward and no mortalities. Average hospital stay was 3.7 days. The institution's financial difference in cost of intensive care unit stay versus ward bed was $5520 on average per bed per day. Omitting just one intensive care unit postoperative day stay for this patient cohort would reduce projected health care costs by a total of $540,960 for the study period. Despite the common practice of postoperative admission to the intensive care unit following cranial vault remodeling for sagittal craniosynostosis, the authors suggest that postoperative care be considered on an individual basis, with only a small percentage requiring a higher level of care. Therapeutic, III.

Extracorporeal low-energy shock-wave therapy exerts anti-inflammatory effects in a rat model of acute myocardial infarction.

PubMed

Abe, Yuzuru; Ito, Kenta; Hao, Kiyotaka; Shindo, Tomohiko; Ogata, Tsuyoshi; Kagaya, Yuta; Kurosawa, Ryo; Nishimiya, Kensuke; Satoh, Kimio; Miyata, Satoshi; Kawakami, Kazuyoshi; Shimokawa, Hiroaki

2014-01-01

It has been previously demonstrated that extracorporeal low-energy shock-wave (SW) therapy ameliorates left ventricular (LV) remodeling through enhanced angiogenesis after acute myocardial infarction (AMI) in pigs in vivo. However, it remains to be examined whether SW therapy also exerts anti-inflammatory effects on AMI. METHODS AND RESULTS: AMI was created by ligating the proximal left anterior descending coronary artery in rats. They were randomly assigned to 2 groups: with (SW group) or without (control group) SW therapy (0.1 mJ/mm(2), 200 shots, 1 Hz to the whole heart at 1, 3 and 5 days after AMI). Four weeks after AMI, SW therapy significantly ameliorated LV remodeling and fibrosis. Histological examinations showed that SW therapy significantly suppressed the infiltration of neutrophils and macrophages at days 3 and 6, in addition to enhanced capillary density in the border area. Molecular examinations demonstrated that SW therapy enhanced the expression of endothelial nitric oxide synthase and suppressed the infiltration of transforming growth factor-β1-positive cells early after AMI. SW therapy also upregulated anti-inflammatory cytokines and downregulated pro-inflammatory cytokines in general. These results suggest that low-energy SW therapy suppressed post-MI LV remodeling in rats in vivo, which was associated with anti-inflammatory effects in addition to its angiogenic effects, and demonstrated a novel aspect of the therapy for AMI.

Cold cardioplegia versus hypothermia for myocardial protection. Randomized clinical study.

PubMed

Conti, V R; Bertranou, E G; Blackstone, E H; Kirklin, J W; Digerness, S B

1978-11-01

Seventeen of 34 consecutive patients undergoing coronary artery bypass grafting were randomly assigned to one of two methods of myocardial preservation. With the cold cardioplegic method (Group A), a 4 degrees C. asanguineous solution with 30 mEq. of potassium per liter was infused into the aortic root for about 2 minutes immediately after aortic cross-clamping and again after about 45 minutes or when myocardial temperature rose above 19 degrees C. External cardiac cooling was provided by constant infusion of 4 degrees C. Ringer's solution into the pericardium. Seventeen patients were assigned to simple cardiac cooling by hypothermic systemic perfusion before aortic cross-clamping plus external cardiac cooling (Group B). Electromechanical activity ceased within 1 to 2 minutes in Group A but continued throughout the ischemic period in 14 patients in Group B. Myocardial temperature (mean for all observations) during aortic cross-clamping was 17.2 +/- 0.44 degrees C. In Group A and 24.0 +/- 0.70 degrees C. in Group B. Operating conditions were better in Group A. Card-ac function early postoperatively was good in both groups clinically and according to measurements, but only in the cold cardioplegic group (A) was cardiac index not adversely affected by longer cross-clamp time. Myocardial necrosis occurred in both groups but was probably less in the cold cardioplegic group. Thirteen patients (76 percent) in Group A had no electrocardiographic evidence of myocardial injury, compared with eight (47 percent) in Group B (p = 0.08). Eleven (65 percent of Group A had no or short-lived appearance of ceatine phosphokinase isoenzyme (CK-MB), compared with six (35 percent) of Group B (p = 0.08). Time-related CK-MB and SGOT mean levels were consistently lower in Group A.

Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial.

PubMed

Bøtker, Hans Erik; Kharbanda, Rajesh; Schmidt, Michael R; Bøttcher, Morten; Kaltoft, Anne K; Terkelsen, Christian J; Munk, Kim; Andersen, Niels H; Hansen, Troels M; Trautner, Sven; Lassen, Jens Flensted; Christiansen, Evald Høj; Krusell, Lars R; Kristensen, Steen D; Thuesen, Leif; Nielsen, Søren S; Rehling, Michael; Sørensen, Henrik Toft; Redington, Andrew N; Nielsen, Torsten T

2010-02-27

Remote ischaemic preconditioning attenuates cardiac injury at elective surgery and angioplasty. We tested the hypothesis that remote ischaemic conditioning during evolving ST-elevation myocardial infarction, and done before primary percutaneous coronary intervention, increases myocardial salvage. 333 consecutive adult patients with a suspected first acute myocardial infarction were randomly assigned in a 1:1 ratio by computerised block randomisation to receive primary percutaneous coronary intervention with (n=166 patients) versus without (n=167) remote conditioning (intermittent arm ischaemia through four cycles of 5-min inflation and 5-min deflation of a blood-pressure cuff). Allocation was concealed with opaque sealed envelopes. Patients received remote conditioning during transport to hospital, and primary percutaneous coronary intervention in hospital. The primary endpoint was myocardial salvage index at 30 days after primary percutaneous coronary intervention, measured by myocardial perfusion imaging as the proportion of the area at risk salvaged by treatment; analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00435266. 82 patients were excluded on arrival at hospital because they did not meet inclusion criteria, 32 were lost to follow-up, and 77 did not complete the follow-up with data for salvage index. Median salvage index was 0.75 (IQR 0.50-0.93, n=73) in the remote conditioning group versus 0.55 (0.35-0.88, n=69) in the control group, with median difference of 0.10 (95% CI 0.01-0.22; p=0.0333); mean salvage index was 0.69 (SD 0.27) versus 0.57 (0.26), with mean difference of 0.12 (95% CI 0.01-0.21; p=0.0333). Major adverse coronary events were death (n=3 per group), reinfarction (n=1 per group), and heart failure (n=3 per group). Remote ischaemic conditioning before hospital admission increases myocardial salvage, and has a favourable safety profile. Our findings merit a larger trial to establish the effect of remote

Regulation of signal transducer and activator of transcription 3 and apoptotic pathways by betaine attenuates isoproterenol-induced acute myocardial injury in rats.

PubMed

Zheng, P; Liu, J; Mai, S; Yuan, Y; Wang, Y; Dai, G

2015-05-01

The present study was designed to investigate the cardioprotective effects of betaine on acute myocardial ischemia induced experimentally in rats focusing on regulation of signal transducer and activator of transcription 3 (STAT3) and apoptotic pathways as the potential mechanism underlying the drug effect. Male Sprague Dawley rats were treated with betaine (100, 200, and 400 mg/kg) orally for 40 days. Acute myocardial ischemic injury was induced in rats by subcutaneous injection of isoproterenol (85 mg/kg), for two consecutive days. Serum cardiac marker enzyme, histopathological variables and expression of protein levels were analyzed. Oral administration of betaine (200 and 400 mg/kg) significantly reduced the level of cardiac marker enzyme in the serum and prevented left ventricular remodeling. Western blot analysis showed that isoproterenol-induced phosphorylation of STAT3 was maintained or further enhanced by betaine treatment in myocardium. Furthermore, betaine (200 and 400 mg/kg) treatment increased the ventricular expression of Bcl-2 and reduced the level of Bax, therefore causing a significant increase in the ratio of Bcl-2/Bax. The protective role of betaine on myocardial damage was further confirmed by histopathological examination. In summary, our results showed that betaine pretreatment attenuated isoproterenol-induced acute myocardial ischemia via the regulation of STAT3 and apoptotic pathways. © The Author(s) 2014.

Sulforaphane effects on postinfarction cardiac remodeling in rats: modulation of redox-sensitive prosurvival and proapoptotic proteins.

PubMed

Fernandes, Rafael Oliveira; De Castro, Alexandre Luz; Bonetto, Jéssica Hellen Poletto; Ortiz, Vanessa Duarte; Müller, Dalvana Daneliza; Campos-Carraro, Cristina; Barbosa, Silvia; Neves, Laura Tartari; Xavier, Léder Leal; Schenkel, Paulo Cavalheiro; Singal, Pawan; Khaper, Neelam; da Rosa Araujo, Alex Sander; Belló-Klein, Adriane

2016-08-01

This study investigated whether sulforaphane (SFN), a compound found in cruciferous vegetables, could attenuate the progression of post-myocardial infarction (MI) cardiac remodeling. Male Wistar rats (350 g) were allocated to four groups: SHAM (n=8), SHAM+SFN (n=7), MI (n=8) and MI+SFN (n=5). On the third day after surgery, cardiac function was assessed and SFN treatment (5 mg/kg/day) was started. At the end of 25 days of treatment, cardiac function was assessed and heart was collected to measure collagen content, oxidative stress and protein kinase. MI and MI+SFN groups presented cardiac dysfunction, without signs of congestion. Sulforaphane reduced fibrosis (2.1-fold) in infarcted rats, which was associated with a slight attenuation in the cardiac remodeling process. Both infarcted groups presented increases in the oxidative markers xanthine oxidase and 4-hydroxinonenal, as well as a parallel increase in the antioxidant enzymes glutathione peroxidase and superoxide dismutase. Moreover, sulforaphane stimulated the cytoprotective heme oxygenase-1 (HO-1) (38%). Oxidative markers correlated with ERK 1/2 activation. In the MI+SFN group, up-regulation of ERK 1/2 (34%) and Akt (35%), as well as down-regulation of p38 (52%), was observed. This change in the prosurvival kinase balance in the MI+SFN group was related to a down-regulation of apoptosis pathways (Bax/Bcl-2/caspase-3). Sulforaphane was unable to modulate autophagy. Taken together, sulforaphane increased HO-1, which may generate a redox environment in the cardiac tissue favorable to activation of prosurvival and deactivation of prodeath pathways. In conclusion, this natural compound contributes to attenuation of the fibrotic process, which may contribute to mitigation against the progression of cardiac remodeling postinfarction. Copyright © 2016 Elsevier Inc. All rights reserved.

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.

Time course of hydrogen peroxide-thioredoxin balance and its influence on the intracellular signalling in myocardial infarction.

PubMed

Schenkel, Paulo Cavalheiro; Tavares, Angela Maria Vicente; Fernandes, Rafael Oliveira; Diniz, Gabriela Placoná; Ludke, Ana Raquel Lehenbauer; Ribeiro, Maria Flavia Marques; Araujo, Alex Sander da Rosa; Barreto-Chaves, Maria Luiza; Belló-Klein, Adriane

2012-06-01

We investigated the myocardial thioredoxin-1 and hydrogen peroxide concentrations and their association with some prosurvival and pro-apoptotic proteins, during the transition from myocardial infarction (MI) to heart failure in rats. Male Wistar rats were divided into the following six groups: three sham-operated groups and three MI groups, each at at 2, 7 and 28 days postsurgery. Cardiac function was analysed by echocardiography; the concentration of H(2)O(2) and the ratio of reduced to oxidized glutathione were measured spectrophotometrically, while the myocardial immunocontent of thioredoxin-1, angiotensin II, angiotensin II type 1 and type 2 receptors, p-JNK/JNK, p-ERK/ERK, p-Akt/Akt, p-mTOR/mTOR and p-GSK3β/GSK3β was evaluated by Western blot. Our results show that thioredoxin-1 appears to make an important contribution to the reduced H(2)O(2) concentration. It was associated with lower JNK expression in the early period post-MI (2 days). However, thioredoxin-1 decreased, while renin-angiotensin system markers and levels of H(2)O(2) increased, over 28 days post-MI, in parallel with some signalling proteins involved in maladaptative cardiac remodelling and ventricular dysfunction. These findings provide insight into the time course profile of endogenous antioxidant adaptation to ischaemic injury, which may be useful for the design of therapeutical strategies targeting oxidative stress post-MI.

Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction

PubMed Central

Valero-Munoz, Maria; Li, Shanpeng; Wilson, Richard M.; Boldbaatar, Batbold; Iglarz, Marc; Sam, Flora

2017-01-01

Background Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension. Methods and Results In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF. Conclusions These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF. PMID:27810862

Dual Endothelin-A/Endothelin-B Receptor Blockade and Cardiac Remodeling in Heart Failure With Preserved Ejection Fraction.

PubMed

Valero-Munoz, Maria; Li, Shanpeng; Wilson, Richard M; Boldbaatar, Batbold; Iglarz, Marc; Sam, Flora

2016-11-01

Despite the increasing prevalence of heart failure with preserved ejection fraction (HFpEF) in humans, there remains no evidence-based therapies for HFpEF. Endothelin-1 (ET-1) antagonists are a possibility because elevated ET-1 levels are associated with adverse cardiovascular effects, such as arterial and pulmonary vasoconstriction, impaired left ventricular (LV) relaxation, and stimulation of LV hypertrophy. LV hypertrophy is a common phenotype in HFpEF, particularly when associated with hypertension. In the present study, we found that ET-1 levels were significantly elevated in patients with chronic stable HFpEF. We then sought to investigate the effects of chronic macitentan, a dual ET-A/ET-B receptor antagonist, on cardiac structure and function in a murine model of HFpEF induced by chronic aldosterone infusion. Macitentan caused LV hypertrophy regression independent of blood pressure changes in HFpEF. Although macitentan did not modulate diastolic dysfunction in HFpEF, it significantly reduced wall thickness and relative wall thickness after 2 weeks of therapy. In vitro studies showed that macitentan decreased the aldosterone-induced cardiomyocyte hypertrophy. These changes were mediated by a reduction in the expression of cardiac myocyte enhancer factor 2a. Moreover, macitentan improved adverse cardiac remodeling, by reducing the stiffer cardiac collagen I and titin n2b expression in the left ventricle of mice with HFpEF. These findings indicate that dual ET-A/ET-B receptor inhibition improves HFpEF by abrogating adverse cardiac remodeling via antihypertrophic mechanisms and by reducing stiffness. Additional studies are needed to explore the role of dual ET-1 receptor antagonists in patients with HFpEF. © 2016 American Heart Association, Inc.

Effects of nucleosome stability on remodeler-catalyzed repositioning

NASA Astrophysics Data System (ADS)

Morgan, Aaron M.; LeGresley, Sarah E.; Briggs, Koan; Al-Ani, Gada; Fischer, Christopher J.

2018-03-01

Chromatin remodelers are molecular motors that play essential roles in the regulation of nucleosome positioning and chromatin accessibility. These machines couple the energy obtained from the binding and hydrolysis of ATP to the mechanical work of manipulating chromatin structure through processes that are not completely understood. Here we present a quantitative analysis of nucleosome repositioning by the imitation switch (ISWI) chromatin remodeler and demonstrate that nucleosome stability significantly impacts the observed activity. We show how DNA damage induced changes in the affinity of DNA wrapping within the nucleosome can affect ISWI repositioning activity and demonstrate how assay-dependent limitations can bias studies of nucleosome repositioning. Together, these results also suggest that some of the diversity seen in chromatin remodeler activity can be attributed to the variations in the thermodynamics of interactions between the remodeler, the histones, and the DNA, rather than reflect inherent properties of the remodeler itself.

Control of bone remodelling by applied dynamic loads

NASA Technical Reports Server (NTRS)

Lanyon, L. E.; Rubin, C. T.

1984-01-01

The data showing the relationship between bone mass and peak strain magnitude prepared and submitted for publication. The data from experiments relating remodelling activity with static or dynamic loads were prepared and submitted for publication. Development of programs to relate the location of remodelling activity with he natural and artificial dynamic strain distributions continued. Experiments on the effect of different strain rates on the remodelling response continued.

Differential MR Delayed Enhancement Patterns of Chronic Myocardial Infarction between Extracellular and Intravascular Contrast Media

PubMed Central

Wang, Jian; Xiang, Bo; Lin, Hung Yu; Liu, Hongyu; Freed, Darren; Arora, Rakesh C.; Tian, Ganghong

2015-01-01

Objectives Because the distribution volume and mechanism of extracellular and intravascular MR contrast media differ considerably, the enhancement pattern of chronic myocardial infarction with extracellular or intravascular media might also be different. This study aims to investigate the differences in MR enhancement patterns of chronic myocardial infarction between extracellular and intravascular contrast media. Materials and Methods Twenty pigs with myocardial infarction underwent cine MRI, first pass perfusion MRI and delayed enhancement MRI with extracellular or intravascular media at four weeks after coronary occlusion. Myocardial blood flow (MBF) was determined with microsphere measurement. The infarction histopathological changes were evaluated by hematoxylin and eosin staining and Masson's trichrome method. Results Cine MRI revealed the reduced wall thickening in chronic infarction compared with normal myocardium. Moreover, significant wall thinning in chronic infarction was observed in cine MRI. Peak first-pass signal intensity didn’t significantly differ between chronic infarction and normal myocardium no matter what kinds of contrast media. At the following delayed enhancement phase, extracellular media-enhanced signal intensity was significantly higher in chronic infarction than in normal myocardium. Conversely, intravascular media-enhanced signal intensity was almost equivalent among chronic infarction and normal myocardium. At four weeks after infarction, MBF in chronic infarction approached to that in normal myocardium. Large thick-walled vessels were detected at peri-infarction zones. The cardiomyocytes were replaced by scar tissue consisting of dilated blood vessels and discrete fibers of collagen. Conclusions Chronic infarction was characterized by the significantly reduced wall thickening and the definite wall thinning. First-pass myocardial perfusion defect was not detected in chronic infarction with two media due to the significantly

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.

Qiliqiangxin inhibits the development of cardiac hypertrophy, remodeling, and dysfunction during 4 weeks of pressure overload in mice.

PubMed

Zou, Yunzeng; Lin, Li; Ye, Yong; Wei, Jianming; Zhou, Ning; Liang, Yanyan; Gong, Hui; Li, Lei; Wu, Jian; Li, Yunbo; Jia, Zhenhua; Wu, Yiling; Zhou, Jingmin; Ge, Junbo

2012-03-01

Qiliqiangxin (QL), a traditional Chinese medicine, has been used in the treatment of chronic heart failure. However, whether QL can benefit cardiac remodeling in the hypertensive state is unknown. We here examined the effects of QL on the development of cardiac hypertrophy through comparing those of losartan in C57BL/6 mice underlying transverse aorta constriction for 4 weeks. QL and losartan were administrated at 0.6 mg and 13.4 mg·kg·d, respectively. Cardiac hypertrophy, function, and remodeling were evaluated by echocardiography, catheterization, histology, and examination of specific gene expression and ERK phosphorylation. Cardiac apoptosis, autophagy, tumor necrosis factor α/insulin-like growth factor-1, and angiotensin II type 1 receptor expression and especially the proliferation of cardiomyocytes and phosphorylation of ErbB receptors were examined in vivo to elucidate the mechanisms. Transverse aorta constriction for 2 weeks resulted in a significant cardiac hypertrophy, which was significantly suppressed by either QL or losartan treatment. At 4 weeks after transverse aorta constriction, although the development of cardiac dysfunction and remodeling and the increases in apoptosis, autophagy, tumor necrosis factor α/insulin-like growth factor-1, and angiotensin II type 1 receptor expression were abrogated comparably between QL and losartan treatments, QL, but not losartan, enhanced proliferation of cardiomyocytes, which was paralleled with dowregulation of CCAAT/enhancer-binding protein β, upregulation of CBP/p300-interacting transactivator with ED-rich carboxy-terminal domain 4, and increases in ErbB2 and ErbB4 phosphorylation. Furthermore, inhibition of either ErbB2 or CBP/p300-interacting transactivator with ED-rich carboxy-terminal domain 4 abolished the cardiac protective effects of QL. Thus, QL inhibits myocardial inflammation and cardiomyocyte death and promotes cardiomyocyte proliferation, leading to an ameliorated cardiac remodeling and

[Effect of Combined Intervention of Electroacupuncture and Astragaloside IV on Myocardial Hypertrophy and TGF-β 1/Smad Signaling in Rats with Myocardial Fibrosis].

PubMed

Li, Jia-Shen; Zhu, Xiao-Yu; Lu, Mei-Li; Gao, Jun-Hong; Wang, Hong-Xin; Yu, Xiao-Chun

2017-12-25

To observe the effect of combined intervention of electroacupuncture (EA) and astragaloside IV(ASIV) on cardiac hypertrophy and transforming growth factor β 1 (TGF-β 1)/Smad signaling in isoproterenol (ISO) induced cardiac hypertrophy rats, so as to investigate its underlying mechanisms in improving myocardial fibrosis. A total of 50 SD rats were randomly divided into 5 groups: normal control, model (ISO), Propranolol (PRO)，ASIV and EA＋ASIV groups ( n ＝10 in each group). The myocardial fibrosis model was established by intraperitoneal injection (i.p.) of ISO (10 mg·kg －1 ·d －1 ), once daily for 30 days. Rats of the control group were given normal saline (i.p.), those of the PRO group given with PRO (40 mg·kg －1 ·d －1 , gavage), and those of the ASIV and EA＋ASIV groups were treated by gavage of ASIV (40 mg·kg －1 ·d －1 ), once daily for 30 days. EA (20 Hz, 6 V) was applied to bilateral "Neiguan" (PC 6) for 10 min, once every day for 30 d. The heart mass index (HMI, whole heart weight/body weight) and left ventricular (LV) mass index (LVMI, weight of the LV/body weight) were calculated to assess the state of cardiac hypertrophy. The enzyme linked immunosorbent assay (ELISA) was used to determine the levels of procollagen I carboxy-terminal propeptide (PICP，a marker of extracellular matrix remodeling) and carboxyterminal telopeptide of type I collagen (ICTP, a metabolite of type I collagen) in serum, and Western blot was used to test protein contents of TGF- β 1, Smad 2 / 3, Smad 4, Smad 7 in the left ventricle tissue of the heart. After modeling, the HMI and LVMI, serum PICP and ICTP contents and the expression levels of myocardial TGF-β 1, Smad 2/3 and Smad 4 proteins were significantly increased in the model (ISO) group ( P <0.05), suggesting a deposition of collagen and cardiac hypertrophy, and were considerably decreased in PRO, ASIV and EA＋ASIV groups after the intervention ( P <0.05). The expression level of myocardial Smad 7

Microvascular resistance of the culprit coronary artery in acute ST-elevation myocardial infarction

PubMed Central

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

2016-01-01

BACKGROUND. Failed myocardial reperfusion is common and prognostically important after acute ST-elevation myocardial infarction (STEMI). The purpose of this study was to investigate coronary flow reserve (CFR), a measure of vasodilator capacity, and the index of microvascular resistance (IMR; mmHg × s) in the culprit artery of STEMI survivors. METHODS. IMR (n = 288) and CFR (n = 283; mean age [SD], 60 [12] years) were measured acutely using guide wire–based thermodilution. Cardiac MRI disclosed left ventricular pathology, function, and volumes at 2 days (n = 281) and 6 months after STEMI (n = 264). All-cause death or first heart failure hospitalization was independently adjudicated (median follow-up 845 days). RESULTS. Myocardial hemorrhage and microvascular obstruction occurred in 89 (42%) and 114 (54%) patients with evaluable T2*-MRI maps. IMR and CFR were associated with microvascular pathology (none vs. microvascular obstruction only vs. microvascular obstruction and myocardial hemorrhage) (median [interquartile range], IMR: 17 [12.0–33.0] vs. 17 [13.0–39.0] vs. 37 [21.0–63.0], P < 0.001; CFR: 1.7 [1.4–2.5] vs. 1.5 [1.1–1.8] vs. 1.4 [1.0–1.8], P < 0.001), whereas thrombolysis in myocardial infarction blush grade was not. IMR was a multivariable associate of changes in left ventricular end-diastolic volume (regression coefficient [95% CI] 0.13 [0.01, 0.24]; P = 0.036), whereas CFR was not (P = 0.160). IMR (5 units) was a multivariable associate of all-cause death or heart failure hospitalization (n = 30 events; hazard ratio [95% CI], 1.09 [1.04, 1.14]; P < 0.001), whereas CFR (P = 0.124) and thrombolysis in myocardial infarction blush grade (P = 0.613) were not. IMR had similar prognostic value for these outcomes as <50% ST-segment resolution on the ECG. CONCLUSIONS. IMR is more closely associated with microvascular pathology, left ventricular remodeling, and health outcomes than the angiogram or CFR. TRIAL REGISTRATION. NCT02072850. FUNDING. A

Cardiac-specific overexpression of metallothionein attenuates myocardial remodeling and contractile dysfunction in l-NAME-induced experimental hypertension: Role of autophagy regulation.

PubMed

Yang, Lifang; Gao, Jian-Yuan; Ma, Jipeng; Xu, Xihui; Wang, Qiurong; Xiong, Lize; Yang, Jian; Ren, Jun

2015-09-02

Hypertension is an independent risk factor for heart disease and is responsible for the increased cardiac morbidity and mortality. Oxidative stress plays a key role in hypertensive heart diseases although the precise mechanism remains unclear. This study was designed to examine the effect of cardiac-specific overexpression of metallothionein, a cysteine-rich antioxidant, on myocardial contractile and intracellular Ca(2+) anomalies in N(G)-nitro-l-arginine methyl ester (l-NAME)-induced experimental hypertension and the mechanism involved with a focus on autophagy. Our results revealed that l-NAME treatment (14 days) led to hypertension and myocardial anomalies evidenced by interstitial fibrosis, cardiomyocyte hypertrophy, increased LV end systolic and diastolic diameters (LVESD and LVEDD) along with suppressed fractional shortening. l-NAME compromised cardiomyocyte contractile and intracellular Ca(2+) properties manifested as depressed peak shortening, maximal velocity of shortening/relengthening, electrically-stimulated rise in intracellular Ca(2+), elevated baseline and peak intracellular Ca(2+). These l-NAME-induced histological and mechanical changes were attenuated or reconciled by metallothionein. Protein levels of autophagy markers LC3B and p62 were decreased and increased, respectively. Autophagy signaling molecules AMPK, TSC2 and ULK1 were inactivated while those of mTOR and p70s6K were activated by l-NAME, the effects of which were ablated by metallothionein. Autophagy induction mimicked whereas autophagy inhibition nullified the beneficial effect of metallothionein against l-NAME. These findings suggested that metallothionein protects against l-NAME-induced myocardial anomalies possibly through restoration of autophagy. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation.

PubMed

Tanaka, Leonardo Y; Laurindo, Francisco R M

2017-08-01

Vascular remodeling, i.e. whole-vessel structural reshaping, determines lumen caliber in (patho)physiology. Here we review mechanisms underlying vessel remodeling, with emphasis in redox regulation. First, we discuss confusing terminology and focus on strictu sensu remodeling. Second, we propose a mechanobiological remodeling paradigm based on the concept of tensional homeostasis as a setpoint regulator. We first focus on shear-mediated models as prototypes of remodeling closely dominated by highly redox-sensitive endothelial function. More detailed discussions focus on mechanosensors, integrins, extracellular matrix, cytoskeleton and inflammatory pathways as potential of mechanisms potentially coupling tensional homeostasis to redox regulation. Further discussion of remodeling associated with atherosclerosis and injury repair highlights important aspects of redox vascular responses. While neointima formation has not shown consistent responsiveness to antioxidants, vessel remodeling has been more clearly responsive, indicating that despite the multilevel redox signaling pathways, there is a coordinated response of the whole vessel. Among mechanisms that may orchestrate redox pathways, we discuss roles of superoxide dismutase activity and extracellular protein disulfide isomerase. We then discuss redox modulation of aneurysms, a special case of expansive remodeling. We propose that the redox modulation of vascular remodeling may reflect (1) remodeling pathophysiology is dominated by a particularly redox-sensitive cell type, e.g., endothelial cells (2) redox pathways are temporospatially coordinated at an organ level across distinct cellular and acellular structures or (3) the tensional homeostasis setpoint is closely connected to redox signaling. The mechanobiological/redox model discussed here can be a basis for improved understanding of remodeling and helps clarifying mechanisms underlying prevalent hard-to-treat diseases. Copyright © 2017 Elsevier Inc. All

Deletion of Apoptosis Inhibitor of Macrophage (AIM)/CD5L Attenuates the Inflammatory Response and Infarct Size in Acute Myocardial Infarction.

PubMed

Nishikido, Toshiyuki; Oyama, Jun-ichi; Shiraki, Aya; Komoda, Hiroshi; Node, Koichi

2016-04-04

An excessive inflammatory response after myocardial infarction (MI) increases myocardial injury. The toll-like receptor (TLR)-4 is activated by the recognition of endogenous ligands and is proinflammatory when there is myocardial tissue injury. The apoptosis inhibitor of the macrophage (AIM) is known to provoke an efflux of saturated free fatty acids (FFA) due to lipolysis, which causes inflammation via the TLR-4 pathway. Therefore, this study investigated the hypothesis that AIM causes a proinflammatory response after MI. The left anterior descending coronary artery was ligated to induce MI in both AIM-knockout (AIM(-/-)) and wild-type (WT) mice. After 3 days, the inflammatory response from activation of the TLR-4/NFκB pathway was assessed, and infarct size was measured by staining with triphenyltetrazolium chloride. In addition, left ventricular remodeling was examined after 28 days. Although the area at risk was similar between AIM(-/-) and WT mice, the infarct size was significantly smaller in AIM(-/-) mice (P=0.02). The heart weight-to-body weight ratio and myocardial fibrosis were also decreased in the AIM(-/-) mice, and the 28-day survival rate was improved (P<0.01). With the reduction of plasma FFA in AIM(-/-) mice, myocardial IRAK4 and NFκB activity were decreased (all P<0.05). Moreover, there was a reduction in myeloperoxidase activity and inducible nitric oxide synthase as part of the inflammatory response (P<0.01, P=0.03, respectively). Furthermore, NFκB DNA-binding activation via TLR-4, neutrophil infiltration, and inflammatory mediators were decreased in AIM(-/-) mice. The deletion of AIM reduced the inflammatory response and infarct size and improved survival after myocardial infarction. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

CD8+CD28+ T cells might mediate injury of cardiomyocytes in acute myocardial infarction.

PubMed

Zhang, Lili; Wang, Zhiyan; Wang, Di; Zhu, Jumo; Wang, Yi

2018-06-07

CD8 + T cells accumulate in the necrotic myocardium of acute myocardial infarction (AMI). It is unclear whether CD8 + CD28 + T cells, a specific subset of CD8 + T cells, contribute to myocardial injury. In this study, 92 consecutive patients with AMI and 28 healthy control subjects were enrolled. The frequency of CD8 + CD28 + T cells in peripheral blood samples was assayed by flow cytometry. Plasma cardiac troponin I (TNI) and left ventricular ejection fraction (LVEF) were determined. Long-term prognosis of the patients was evaluated by major adverse cardiac and cerebrovascular events (MACCE) over a 12-month follow-up period. Our findings indicated that patients with AMI who presented with high numbers of CD8 + CD28 + T cells had an increased infarction size and aggravated ventricular function. We proposed that cytotoxic CD8 + CD28 + T cell-mediated myocardial necrosis may act as a novel and alternative pathway of AMI. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction.

PubMed

Ngkelo, Anta; Richart, Adèle; Kirk, Jonathan A; Bonnin, Philippe; Vilar, Jose; Lemitre, Mathilde; Marck, Pauline; Branchereau, Maxime; Le Gall, Sylvain; Renault, Nisa; Guerin, Coralie; Ranek, Mark J; Kervadec, Anaïs; Danelli, Luca; Gautier, Gregory; Blank, Ulrich; Launay, Pierre; Camerer, Eric; Bruneval, Patrick; Menasche, Philippe; Heymes, Christophe; Luche, Elodie; Casteilla, Louis; Cousin, Béatrice; Rodewald, Hans-Reimer; Kass, David A; Silvestre, Jean-Sébastien

2016-06-27

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit-independent MC-deficient (Cpa3(Cre/+)) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca(2+) desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force-Ca(2+) interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators. ©2016 Ngkelo et al.

Mast cells regulate myofilament calcium sensitization and heart function after myocardial infarction

PubMed Central

Richart, Adèle; Vilar, Jose; Lemitre, Mathilde; Marck, Pauline; Branchereau, Maxime; Guerin, Coralie; Gautier, Gregory; Blank, Ulrich; Heymes, Christophe; Luche, Elodie; Cousin, Béatrice; Rodewald, Hans-Reimer

2016-01-01

Acute myocardial infarction (MI) is a severe ischemic disease responsible for heart failure and sudden death. Inflammatory cells orchestrate postischemic cardiac remodeling after MI. Studies using mice with defective mast/stem cell growth factor receptor c-Kit have suggested key roles for mast cells (MCs) in postischemic cardiac remodeling. Because c-Kit mutations affect multiple cell types of both immune and nonimmune origin, we addressed the impact of MCs on cardiac function after MI, using the c-Kit–independent MC-deficient (Cpa3Cre/+) mice. In response to MI, MC progenitors originated primarily from white adipose tissue, infiltrated the heart, and differentiated into mature MCs. MC deficiency led to reduced postischemic cardiac function and depressed cardiomyocyte contractility caused by myofilament Ca2+ desensitization. This effect correlated with increased protein kinase A (PKA) activity and hyperphosphorylation of its targets, troponin I and myosin-binding protein C. MC-specific tryptase was identified to regulate PKA activity in cardiomyocytes via protease-activated receptor 2 proteolysis. This work reveals a novel function for cardiac MCs modulating cardiomyocyte contractility via alteration of PKA-regulated force–Ca2+ interactions in response to MI. Identification of this MC-cardiomyocyte cross-talk provides new insights on the cellular and molecular mechanisms regulating the cardiac contractile machinery and a novel platform for therapeutically addressable regulators. PMID:27353089

The Novel Extracellular Cyclophilin A (CyPA) - Inhibitor MM284 Reduces Myocardial Inflammation and Remodeling in a Mouse Model of Troponin I -Induced Myocarditis.

PubMed

Heinzmann, David; Bangert, Anna; Müller, Anna-Maria; von Ungern-Sternberg, Saskia N I; Emschermann, Frederic; Schönberger, Tanja; Chatterjee, Madhumita; Mack, Andreas F; Klingel, Karin; Kandolf, Reinhard; Malesevic, Miroslav; Borst, Oliver; Gawaz, Meinrad; Langer, Harald F; Katus, Hugo; Fischer, Gunter; May, Andreas E; Kaya, Ziya; Seizer, Peter

2015-01-01

Cyclophilins are a group of highly conserved cytosolic enzymes that have a peptidylprolyl cis/trans isomerase activity. Cyclophilin A (CyPA) can be secreted in the extracellular space by inflammatory cells and upon cell death. The presence of CyPA in patients with non-ischemic cardiomyopathy is associated with poor clinical prognosis. Here, we investigated the inhibition of extracellular CyPA in a mouse model of troponin I-induced autoimmune myocarditis using the strictly extracellular CyPA-inhibitor MM284. Since A/J mice develop severe inflammation and fibrosis after immunization with murine cardiac troponin I (mcTn I), we used this model to analyze the effects of an extracellular CyPA inhibition. As extracellular CyPA-inhibitor we used the recently described CsA-derivate MM284. In vitro studies confirmed that MM284 inhibits CyPA-induced monocytic migration and adhesion. A/J mice immunized with mcTnI were treated with MM284 or vehicle every second day. After 28 days, we found a considerable reduction of myocardial injury and fibrosis. Further analysis revealed a reduced myocardial presence of T-cells and macrophages compared to control treated animals. Whereas MMP-9 expression was reduced significantly by MM284, we observed no significant reduction of inflammatory cytokines such as IL-6 or TNFα. Extracellular CyPA plays an important role in autoimmune myocarditis for myocardial damage and fibrosis. Our data suggest a new pharmacological approach for the treatment of myocardial inflammation and reduction of cardiac fibrosis by inhibition of extracellular CyPA.

Perioperative Assessment of Myocardial Deformation

PubMed Central

Duncan, Andra E.; Alfirevic, Andrej; Sessler, Daniel I.; Popovic, Zoran B.; Thomas, James D.

2014-01-01

Evaluation of left ventricular performance improves risk assessment and guides anesthetic decisions. However, the most common echocardiographic measure of myocardial function, the left ventricular ejection fraction (LVEF), has important limitations. LVEF is limited by subjective interpretation which reduces accuracy and reproducibility, and LVEF assesses global function without characterizing regional myocardial abnormalities. An alternative objective echocardiographic measure of myocardial function is thus needed. Myocardial deformation analysis, which performs quantitative assessment of global and regional myocardial function, may be useful for perioperative care of surgical patients. Myocardial deformation analysis evaluates left ventricular mechanics by quantifying strain and strain rate. Strain describes percent change in myocardial length in the longitudinal (from base to apex) and circumferential (encircling the short-axis of the ventricle) direction and change in thickness in the radial direction. Segmental strain describes regional myocardial function. Strain is a negative number when the ventricle shortens longitudinally or circumferentially and is positive with radial thickening. Reference values for normal longitudinal strain from a recent meta-analysis using transthoracic echocardiography are (mean ± SD) −19.7 ± 0.4%, while radial and circumferential strain are 47.3 ± 1.9 and −23.3 ± 0.7%, respectively. The speed of myocardial deformation is also important and is characterized by strain rate. Longitudinal systolic strain rate in healthy subjects averages −1.10 ± 0.16 sec−1. Assessment of myocardial deformation requires consideration of both strain (change in deformation), which correlates with LVEF, and strain rate (speed of deformation), which correlates with rate of rise of left ventricular pressure (dP/dt). Myocardial deformation analysis also evaluates ventricular relaxation, twist, and untwist, providing new and noninvasive methods to

Re-initiating professional working activity after myocardial infarction in primary percutaneous coronary intervention networks era.

PubMed

Babić, Zdravko; Pavlov, Marin; Oštrić, Mirjana; Milošević, Milan; Misigoj Duraković, Marjeta; Pintarić, Hrvoje

2015-01-01

To investigate the aspects of return to work, socio-economic and quality of life aspects in 145 employed patients under 60 years of age treated with primary percutaneous coronary intervention for acute ST-elevation myocardial infarction. During hospital treatment demographic and clinical data was collected. Data about major adverse cardiovascular events, rehabilitation, sick leave, discharge from job and retirement, salary, major life events and estimation of quality of life after myocardial infarction were obtained after follow-up (mean: 836±242 days). Average sick leave was 126±125 days. Following myocardial infarction, 3.4% of patients were discharged from their jobs while 31.7% retired. Lower salary was reported in 17.9% patients, major life events in 9.7%, while 40.7% estimated quality of life as worse following the event. Longer hospitalization was reported in patients transferred from surrounding counties, those with inferior myocardial wall and right coronary artery affected. Age, hyperlipoproteinemia and lower education degree were connected to permanent working cessation. Significant salary decrease was observed in male patients. Employer type was related to sick leave duration. Impaired quality of life was observed in patients who underwent in-hospital rehabilitation and those from surrounding counties. Longer sick leave was observed in patients with lower income before and after myocardial infarction. These patients reported lower quality of life after myocardial infarction. Inadequate health policy and delayed cardiac rehabilitation after myocardial infarction may lead to prolonged hospitalization and sick leave as well as lower quality of life after the event, regardless of optimal treatment in acute phase of disease. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Chromatin remodelling: the industrial revolution of DNA around histones.

PubMed

Saha, Anjanabha; Wittmeyer, Jacqueline; Cairns, Bradley R

2006-06-01

Chromatin remodellers are specialized multi-protein machines that enable access to nucleosomal DNA by altering the structure, composition and positioning of nucleosomes. All remodellers have a catalytic ATPase subunit that is similar to known DNA-translocating motor proteins, suggesting DNA translocation as a unifying aspect of their mechanism. Here, we explore the diversity and specialization of chromatin remodellers, discuss how nucleosome modifications regulate remodeller activity and consider a model for the exposure of nucleosomal DNA that involves the use of directional DNA translocation to pump 'DNA waves' around the nucleosome.

Do prescription stimulants increase the risk of adverse cardiovascular events?: A systematic review

PubMed Central

2012-01-01

Background There is increasing concern that prescription stimulants may be associated with adverse cardiovascular events such as stroke, myocardial infarction, and sudden death. Public health concerns are amplified by increasing use of prescription stimulants among adults. Methods The objective of this study was to conduct a systematic review of the evidence of an association between prescription stimulant use and adverse cardiovascular outcomes. PUBMED, MEDLINE, EMBASE and Google Scholar searches were conducted using key words related to these topics (MESH): ADHD; Adults; Amphetamine; Amphetamines; Arrhythmias, Cardiac; Cardiovascular Diseases; Cardiovascular System; Central Nervous Stimulants; Cerebrovascular; Cohort Studies; Case–control Studies; Death; Death, Sudden, Cardiac; Dextroamphetamine; Drug Toxicity; Methamphetamine; Methylphenidate; Myocardial Infarction; Stimulant; Stroke; Safety. Eligible studies were population-based studies of children, adolescents, or adults using prescription stimulant use as the independent variable and a hard cardiovascular outcome as the dependent variable. Results Ten population-based observational studies which evaluated prescription stimulant use with cardiovascular outcomes were reviewed. Six out of seven studies in children and adolescents did not show an association between stimulant use and adverse cardiovascular outcomes. In contrast, two out of three studies in adults found an association. Conclusions Findings of an association between prescription stimulant use and adverse cardiovascular outcomes are mixed. Studies of children and adolescents suggest that statistical power is limited in available study populations, and the absolute risk of an event is low. More suggestive of a safety signal, studies of adults found an increased risk for transient ischemic attack and sudden death/ventricular arrhythmia. Interpretation was limited due to differences in population, cardiovascular outcome selection/ascertainment, and

Neutrophil/Lymphocyte Ratio as a Predictor of In-Hospital Major Adverse Cardiac Events, New-Onset Atrial Fibrillation, and No-Reflow Phenomenon in Patients with ST Elevation Myocardial Infarction.

PubMed

Wagdy, Sherif; Sobhy, Mohamed; Loutfi, Mohamed

2016-01-01

Neutrophil/lymphocyte (N/L) ratio represents the balance between neutrophil and lymphocyte counts in the body and can be utilized as an index for systemic inflammatory status. The no-reflow phenomenon is defined as inadequate myocardial perfusion through a given segment of the coronary circulation without angiographic evidence of mechanical vessel obstruction. Systemic inflammatory status has been associated with new-onset atrial fibrillation (NOAF) as well as no-reflow. To evaluate the predictive value of N/L ratio for in-hospital major adverse events, NOAF, and no-reflow in patients with ST elevation myocardial infarction (STEMI). Two hundred consecutive patients with STEMI presenting to Alexandria Main University Hospital and International Cardiac Center Hospital, Alexandria, Egypt, from April 2013 to October 2013 were included in this study. Laboratory investigation upon admission included complete blood count with mean platelet volume (MPV) and N/L ratio, and random plasma glucose (RPG) level. The results of coronary angiography indicating the infarct-related artery (IRA), initial thrombolysis in myocardial infarction (TIMI) flow in the IRA, and the TIMI flow after stenting were recorded. The patients were studied according to the presence of various clinical and laboratory variables, such as age, gender, pain-to-balloon time, location of the infarction, RPG level and complete blood count including N/L ratio and MPV on admission, and initial TIMI flow in the IRA. They were also evaluated for the final TIMI flow after the primary percutaneous coronary intervention, incidence of NOAF, and the incidence of in-hospital major adverse cardiac events (MACE). The incidence rate of no-reflow, NOAF, and in-hospital MACE was 13.2%, 8%, and 5%, respectively, with cardiac death as the predominant form of in-hospital MACE. The group of no-reflow, NOAF, and/or MACE showed significantly older age (62.29 ± 7.90 vs 56.30 ± 10.34, P = 0.014), longer pain-to-balloon time (15

Development of bioartificial myocardium using stem cells and nanobiotechnology templates.

PubMed

Chachques, Juan Carlos

2010-12-29

Cell-based regenerative therapy is undergoing experimental and clinical trials in cardiology, in order to limit the consequences of decreased contractile function and compliance of damaged ventricles following myocardial infarction. Over 1000 patients have been treated worldwide with cell-based procedures for myocardial regeneration. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit adverse postischemic remodelling, and improve diastolic function. The development of a bioartificial myocardium is a new challenge; in this approach, tissue-engineered procedures are associated with cell therapy. Organ decellularization for bioscaffolds fabrication is a new investigated concept. Nanomaterials are emerging as the main candidates to ensure the achievement of a proper instructive cellular niche with good drug release/administration properties. Investigating the electrophysiological properties of bioartificial myocardium is the challenging objective of future research, associating a multielectrode network to provide electrical stimulation could improve the coupling of grafted cells and scaffolds with host cardiomyocytes. In summary, until now stem cell transplantation has not achieved clear hemodynamic benefits for myocardial diseases. Supported by relevant scientific background, the development of myocardial tissue engineering may constitute a new avenue and hope for the treatment of myocardial diseases.

A 35-month profilometric and clinical evaluation of non-ablative remodeling using a 1540-nm Er:glass laser.

PubMed

Fournier, Nathalie; Lagarde, Jean Michel; Turlier, Virginie; Courrech, Laetitia; Mordon, Serge

2004-11-01

As remodeling is getting more popular with patients, long-term studies are becoming necessary. The aim of this 35-month clinical study was to evaluate the long-term benefits obtained using a 1540-nm Er:glass laser for non-ablative remodeling of perioral and periorbital rhytids. The role of maintenance treatments was also investigated. Eleven women with periorbital and perioral rhytids underwent a series of five treatments at 6-week intervals with an Er:glass laser. Five patients subsequently received two maintenance retreatments and six did not. The maintenance treatments were performed at 14 and 20 months. Silicone imprints were performed to measure anisotropy before treatment, at 6 months, at 14 months and at 35 months. Patient self-evaluation/questionnaire was also done to assess adverse effects and subjective clinical improvement. For all 11 patients, the percentage of anisotropy reduction was 41.21% at 6 months, 51.76% at 14 months and 29.87% at 35 months. No adverse effects were noted. Patient satisfaction was high at the end of the evaluation. Retreated patients were more satisfied than non-retreated ones. However, there was no difference in the anisotropy factor between the two groups. Treatment of facial rhytids with a non-ablative 1540-nm Er:glass laser system can produce benefits that persist over 2 years after the last treatment.

Micro-structurally detailed model of a therapeutic hydrogel injectate in a rat biventricular cardiac geometry for computational simulations

PubMed Central

Sirry, Mazin S.; Davies, Neil H.; Kadner, Karen; Dubuis, Laura; Saleh, Muhammad G.; Meintjes, Ernesta M.; Spottiswoode, Bruce S.; Zilla, Peter; Franz, Thomas

2013-01-01

Biomaterial injection based therapies have showed cautious success in restoration of cardiac function and prevention of adverse remodelling into heart failure after myocardial infarction (MI). However, the underlying mechanisms are not well understood. Computational studies utilised simplified representations of the therapeutic myocardial injectates. Wistar rats underwent experimental infarction followed by immediate injection of polyethylene glycol hydrogel in the infarct region. Hearts were explanted, cryo-sectioned and the region with the injectate histologically analysed. Histological micrographs were used to reconstruct the dispersed hydrogel injectate. Cardiac magnetic resonance imaging (CMRI) data from a healthy rat were used to obtain an end-diastolic biventricular geometry which was subsequently adjusted and combined with the injectate model. The computational geometry of the injectate exhibited microscopic structural details found the in situ. The combination of injectate and cardiac geometry provides realistic geometries for multiscale computational studies of intra-myocardial injectate therapies for the rat model that has been widely used for MI research. PMID:23682845

Prevalence and Prognosis of Hyperkalemia in Patients with Acute Myocardial Infarction

PubMed Central

Grodzinsky, Anna; Goyal, Abhinav; Gosch, Kensey; McCullough, Peter A.; Fonarow, Gregg C.; Mebazaa, Alexandre; Masoudi, Frederick A.; Spertus, John A.; Palmer, Biff F.; Kosiborod, Mikhail

2016-01-01

Background Hyperkalemia is common and potentially dangerous in hospitalized patients; its contemporary prevalence and prognostic importance following acute myocardial infarction are not well described. Methods In 38,689 consecutive acute myocardial infarction patients from the Cerner Health Facts database, we evaluated the association between maximum in-hospital potassium levels (max K) and in-hospital mortality. Patients were stratified by dialysis status, and grouped by max K as follows: <5 mEq/L, 5–<5.5 mEq/L, 5.5–<6.0 mEq/L, 6.0–<6.5 mEq/L, and ≥ 6.5 mEq/L. Multivariable logistic regression was used to adjust for multiple patient and site characteristics. The relationship between number of hyperkalemic values and in-hospital mortality was also evaluated. Results Of 38,689 acute myocardial infarction patients, 886 were on dialysis. The rate of hyperkalemia (max K ≥ 5.0 mEq/L) was 22.6% in non-dialysis and 66.8% in dialysis patients. Moderate-severe hyperkalemia (max K ≥ 5.5 mEq/L) occurred in 9.8% of patients. There was a steep increase in mortality with higher max K levels. In-hospital mortality exceeded 15% once max K ≥5.5 mEq/L regardless of dialysis status. The relationship between higher max K and increased mortality risk persisted after multivariable adjustment. In addition, patients with greater number of hyperkalemic values (vs. a single value) experienced higher in-hospital mortality. Conclusions Hyperkalemia is common in patients hospitalized with acute myocardial infarction. Higher max K levels and number of hyperkalemic events are associated with a steep mortality increase; with higher risks for adverse outcomes observed even at mild levels of hyperkalemia. Whether more intensive management of hyperkalemia may improve outcomes in acute myocardial infarction patients merits further study. PMID:27060233

Endothelial Bmx tyrosine kinase activity is essential for myocardial hypertrophy and remodeling

PubMed Central

Holopainen, Tanja; Räsänen, Markus; Anisimov, Andrey; Tuomainen, Tomi; Zheng, Wei; Tvorogov, Denis; Hulmi, Juha J.; Andersson, Leif C.; Cenni, Bruno; Tavi, Pasi; Mervaala, Eero; Kivelä, Riikka; Alitalo, Kari

2015-01-01

Cardiac hypertrophy accompanies many forms of heart disease, including ischemic disease, hypertension, heart failure, and valvular disease, and it is a strong predictor of increased cardiovascular morbidity and mortality. Deletion of bone marrow kinase in chromosome X (Bmx), an arterial nonreceptor tyrosine kinase, has been shown to inhibit cardiac hypertrophy in mice. This finding raised the possibility of therapeutic use of Bmx tyrosine kinase inhibitors, which we have addressed here by analyzing cardiac hypertrophy in gene-targeted mice deficient in Bmx tyrosine kinase activity. We found that angiotensin II (Ang II)-induced cardiac hypertrophy is significantly reduced in mice deficient in Bmx and in mice with inactivated Bmx tyrosine kinase compared with WT mice. Genome-wide transcriptomic profiling showed that Bmx inactivation suppresses myocardial expression of genes related to Ang II-induced inflammatory and extracellular matrix responses whereas expression of RNAs encoding mitochondrial proteins after Ang II administration was maintained in Bmx-inactivated hearts. Very little or no Bmx mRNA was expressed in human cardiomyocytes whereas human cardiac endothelial cells expressed abundant amounts. Ang II stimulation of endothelial cells increased Bmx phosphorylation, and Bmx gene silencing inhibited downstream STAT3 signaling, which has been implicated in cardiac hypertrophy. Furthermore, activation of the mechanistic target of rapamycin complex 1 pathway by Ang II treatment was decreased in the Bmx-deficient hearts. Our results demonstrate that inhibition of the cross-talk between endothelial cells and cardiomyocytes by Bmx inactivation suppresses Ang II-induced signals for cardiac hypertrophy. These results suggest that the endothelial Bmx tyrosine kinase could provide a target to attenuate the development of cardiac hypertrophy. PMID:26430242

The chromatin remodeler SPLAYED regulates specific stress signaling pathways.

PubMed

Walley, Justin W; Rowe, Heather C; Xiao, Yanmei; Chehab, E Wassim; Kliebenstein, Daniel J; Wagner, Doris; Dehesh, Katayoon

2008-12-01

Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD) is required for the expression of selected genes downstream of the jasmonate (JA) and ethylene (ET) signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks.

Acetylcholine beyond bronchoconstriction: roles in inflammation and remodeling.

PubMed

Kistemaker, Loes E M; Gosens, Reinoud

2015-03-01

Acetylcholine is the primary parasympathetic neurotransmitter in the airways, where it not only induces bronchoconstriction and mucus secretion, but also regulates airway inflammation and remodeling. In this review, we propose that these effects are all primarily mediated via the muscarinic M3 receptor. Acetylcholine promotes inflammation and remodeling via direct effects on airway cells, and via mechanical stress applied to the airways sequential to bronchoconstriction. The effects on inflammation and remodeling are regulated by both neuronal and non-neuronal acetylcholine. Taken together, we believe that the combined effects of anticholinergic therapy on M3-mediated bronchoconstriction, mucus secretion, inflammation, and remodeling may account for the positive outcome of treatment with these drugs for patients with chronic pulmonary obstructive disease (COPD) or asthma. Copyright © 2014 Elsevier Ltd. All rights reserved.

Combined assessment of left ventricular end-diastolic pressure and ejection fraction by left ventriculography predicts long-term outcomes of patients with ST-segment elevation myocardial infarction.

PubMed

Saito, Daiga; Nakanishi, Rine; Watanabe, Ippei; Yabe, Takayuki; Okubo, Ryo; Amano, Hideo; Toda, Mikihito; Ikeda, Takanori

2018-05-01

In patients with ST-segment elevation myocardial infarction (STEMI), it is unclear if combined assessment of left ventricular end-diastolic pressure (LVEDP) and left ventricular ejection fraction (LVEF) improves prediction of major adverse cardiac events (MACE). We analyzed data from 266 STEMI patients who underwent successful percutaneous coronary intervention and subsequent left ventriculography (LVG). Patients were divided into 4 groups, as follows: Group 1, LVEDP < 21 mmHg and LVEF ≥ 55%; Group 2, LVEDP < 21 mmHg and LVEF < 55%; Group 3, LVEDP ≥ 21 mmHg and LVEF ≥ 55%; and Group 4, LVEDP ≥ 21 mmHg and LVEF < 55%. Multivariate Cox proportional hazards analysis was used to determine if LVEDP and LVEF were associated with MACE (including cardiac death, non-fatal myocardial infarction, and heart failure requiring hospitalization). Change in LV parameters was assessed in the subset of 183 patients who underwent serial LVG (mean interval 6.3 ± 1.6 months). During a mean follow-up of 43 ± 31 months, 29 patients (10.9%) had a MACE. As compared to Group 1, MACE risk was significantly higher in Group 3 [hazard ratio (HR) 3.26; 95% confidence interval (CI) 1.05-10.0] and Group 4 (HR 3.99; 95% CI 1.44-11.0), but not in Group 2 (HR 0.46, 95% CI 0.54-3.96). In sub-analyses, LV end-systolic volume index after PCI was significantly higher in Group 4 than in the other groups and remained higher during follow-up. Combined LVEDP/LVEF assessment was useful in predicting MACE after successful PCI for STEMI patients and could facilitate risk stratification, as it predicts LV remodeling.

Connective tissue growth factor and bone morphogenetic protein 2 are induced following myocardial ischemia in mice and humans.

PubMed

Rutkovskiy, Arkady; Sagave, Julia; Czibik, Gabor; Baysa, Anton; Zihlavnikova Enayati, Katarina; Hillestad, Vigdis; Dahl, Christen Peder; Fiane, Arnt; Gullestad, Lars; Gravning, Jørgen; Ahmed, Shakil; Attramadal, Håvard; Valen, Guro; Vaage, Jarle

2017-09-01

We aimed to study the cardiac expression of bone morphogenetic protein 2, its receptor 1 b, and connective tissue growth factor, factors implicated in cardiac embryogenesis, following ischemia/hypoxia, heart failure, and in remodeling hearts from humans and mice. Biopsies from the left ventricle of patients with end-stage heart failure due to dilated cardiomyopathy or coronary artery disease were compared with donor hearts and biopsies from patients with normal heart function undergoing coronary artery bypass grafting. Mouse model of post-infarction remodeling was made by permanent ligation of the left coronary artery. Hearts were analyzed by real-time polymerase chain reaction and Western blotting after 24 hours and after 2 and 4 weeks. Patients with dilated cardiomyopathy and mice post-infarction had increased cardiac expression of connective tissue growth factor. Bone morphogenetic protein 2 was increased in human hearts failing due to coronary artery disease and in mice post-infarction. Gene expression of bone morphogenetic protein receptor 1 beta was reduced in hearts of patients with failure, but increased two weeks following permanent ligation of the left coronary artery in mice. In conclusion, connective tissue growth factor is upregulated in hearts of humans with dilated cardiomyopathy, bone morphogenetic protein 2 is upregulated in remodeling due to myocardial infarction while its receptor 1 b in human failing hearts is downregulated. A potential explanation might be an attempt to engage regenerative processes, which should be addressed by further, mechanistic studies.

Myocardial contusion in patients with blunt chest trauma as evaluated by thallium 201 myocardial scintigraphy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bodin, L.; Rouby, J.J.; Viars, P.

1988-07-01

Fifty five patients suffering from blunt chest trauma were studied to assess the diagnosis of myocardial contusion using thallium 201 myocardial scintigraphy. Thirty-eight patients had consistent scintigraphic defects and were considered to have a myocardial contusion. All patients with scintigraphic defects had paroxysmal arrhythmias and/or ECG abnormalities. Of 38 patients, 32 had localized ST-T segment abnormalities; 29, ST-T segment abnormalities suggesting involvement of the same cardiac area as scintigraphic defects; 21, echocardiographic abnormalities. Sixteen patients had segmental hypokinesia involving the same cardiac area as the scintigraphic defects. Fifteen patients had clinical signs suggestive of myocardial contusion and scintigraphic defects. Almostmore » 70 percent of patients with blunt chest trauma had scintigraphic defects related to areas of myocardial contusion. When thallium 201 myocardial scintigraphy directly showed myocardial lesion, two-dimensional echocardiography and standard ECG detected related functional consequences of cardiac trauma.« less

Shengmai injection reduces apoptosis and enhances angiogenesis after myocardial ischaemia and reperfusion injury in rats.

PubMed

Liu, Xuan; Tan, Wangxiao; Yang, Fengwen; Wang, Yu; Yue, Shaoqian; Wang, Ting; Wang, Xiaoying

2018-08-01

To investigate whether Shengmai injection (SMI) helps to improve cardiac function and enhances angiogenesis after myocardial ischaemia reperfusion injury (MIRI). A rat model of MIRI was created via occlusion of the left anterior descending coronary artery for 30 min, followed by 3 days or 7 days of reperfusion (n = 6 each group). SMI is widely used for the treatment of myocardial infarction. The mechanism underlying the effect on cardiac function is not known and whether SMI has any effects on angiogenesis during treatment of MIRI is not clear. Echocardiography showed that SMI improved the left ventricular ejection fraction (LVEF) in the rat model of MIRI. TUNEL staining indicated that SMI decreased the myocardial apoptosis rate after MIRI. This result may be related to the increase of Bcl-2 expression in the SMI group and a reduction in Bax and caspase 3 expression, as determined by immunohistochemical staining. Small vessels (<60 μm in diameter) of the heart of rats in the group treated with SMI were denser (more numerous) than those in the heart of rats in the other groups. Real-time PCR indicated that the SMI-driven reduction in apoptosis was associated with a change in the ratio of Bcl-2 to Bax expression, and treatment-induced angiogenesis was associated with enhanced vascular endothelial growth factor A (VEGF) expression. We elucidated that SMI promotes angiogenesis, which is important for the development of cardiac remodelling after MIRI. Copyright © 2018. Published by Elsevier Masson SAS.

Effect of low-level laser-treated mesenchymal stem cells on myocardial infarction.

PubMed

El Gammal, Zaynab H; Zaher, Amr M; El-Badri, Nagwa

2017-09-01

Cardiovascular disease is the leading cause of death worldwide. Although cardiac transplantation is considered the most effective therapy for end-stage cardiac diseases, it is limited by the availability of matching donors and the complications of the immune suppressive regimen used to prevent graft rejection. Application of stem cell therapy in experimental animal models was shown to reverse cardiac remodeling, attenuate cardiac fibrosis, improve heart functions, and stimulate angiogenesis. The efficacy of stem cell therapy can be amplified by low-level laser radiation. It is well established that the bio-stimulatory effect of low-level laser is influenced by the following parameters: wavelength, power density, duration, energy density, delivery time, and the type of irradiated target. In this review, we evaluate the available experimental data on treatment of myocardial infarction using low-level laser. Eligible papers were characterized as in vivo experimental studies that evaluated the use of low-level laser therapy on stem cells in order to attenuate myocardial infarction. The following descriptors were used separately and in combination: laser therapy, low-level laser, low-power laser, stem cell, and myocardial infarction. The assessed low-level laser parameters were wavelength (635-804 nm), power density (6-50 mW/cm 2 ), duration (20-150 s), energy density (0.96-1 J/cm 2 ), delivery time (20 min-3 weeks after myocardial infarction), and the type of irradiated target (bone marrow or in vitro-cultured bone marrow mesenchymal stem cells). The analysis focused on the cardioprotective effect of this form of therapy, the attenuation of scar tissue, and the enhancement of angiogenesis as primary targets. Other effects such as cell survival, cell differentiation, and homing are also included. Among the evaluated protocols using different parameters, the best outcome for treating myocardial infarction was achieved by treating the bone marrow by one dose of low

An Analysis of the Residential Remodeling Occupation.

ERIC Educational Resources Information Center

Scruggs, Kenneth

The general purpose of the occupational analysis is to provide workable, basic information dealing with the many and varied duties performed in the residential remodeling occupation. The analysis only briefly covers the many areas of residential remodeling. The document opens with a brief introduction followed by a job description. The bulk of the…

Effect of early versus late AT(1) receptor blockade with losartan on postmyocardial infarction ventricular remodeling in rabbits.

PubMed

González, Germán E; Seropian, Ignacio M; Krieger, Maria Laura; Palleiro, Jimena; Lopez Verrilli, Maria A; Gironacci, Mariela M; Cavallero, Susana; Wilensky, Luciana; Tomasi, Victor H; Gelpi, Ricardo J; Morales, Celina

2009-07-01

To characterize the temporal activation of the renin-angiotensin system after myocardial infarction (MI) in rabbits, we examined cardiac ANG II type 1 receptor (AT(1)R) expression and ANG II levels from 3 h to 35 days. The effects of losartan (12.5 mg.kg(-1).day(-1)) on functional and histomorphometric parameters when treatment was initiated early (3 h) and late (day 15) post-MI and maintained for different periods of time [short term (4 days), midterm (20 days), and long term (35 days)] were also studied. AT(1)R expression increased in the MI zone at 15 and 35 days (P < 0.05). ANG II levels increased (P < 0.05) in the non-MI zone at 24 h and in the MI zone as well as in plasma at 4 days and then progressively decreased until 35 days. The survival rate was significantly lower in untreated MI and early long-term-treated animals. Diastolic pressure-volume curves in MI at 35 and 56 days shifted to the right (P < 0.05). This shift was even more pronounced in long-term-treated groups (P < 0.05). Contractility decreased (P < 0.05 vs. sham) in the untreated and long-term-treated groups and was attenuated in the midterm-treated group. The early administration of losartan reduced RAM 11-positive macrophages from 4.15 +/- 0.05 to 3.05 +/- 0.02 cells/high-power field (HPF; P < 0.05) and CD45 RO-positive lymphocytes from 2.23 +/- 0.05 to 1.48 +/- 0.01 cells/HPF (P < 0.05) in the MI zone at 4 days. Long-term treatment reduced the scar collagen (MI: 70.50 +/- 2.35% and MI + losartan: 57.50 +/- 2.48, P < 0.05), determined the persistency of RAM 11-positive macrophages (3.02 +/- 0.13 cells/HPF) and CD45 RO-positive lymphocytes (2.77 +/- 0.58 cells/HPF, P < 0.05 vs. MI), and reduced the scar thinning ratio at 35 days (P < 0.05). Consequently, the temporal expressions of cardiac AT(1)R and ANG II post-MI in rabbits are different from those described in other species. Long-term treatment unfavorably modified post-MI remodeling, whereas midterm treatment attenuated this harmful effect

HGF and IGF-1 promote protective effects of allogeneic BMSC transplantation in rabbit model of acute myocardial infarction.

PubMed

Zhang, Guang-Wei; Gu, Tian-Xiang; Guan, Xiao-Yu; Sun, Xue-Jun; Qi, Xun; Li, Xue-Yuan; Wang, Xiao-Bing; Lv, Feng; Yu, Lei; Jiang, Da-Qing; Tang, Rui

2015-12-01

To explore effects of hepatocyte growth factor (HGF) combined with insulin-like growth factor 1 (IGF-1) on transplanted bone marrow mesenchymal stem cells (BMSCs), for treatment of acute myocardial ischaemia. After ligation of the left anterior descending artery, rabbits were divided into a Control group, a Factors group (HGF+IGF-1), a BMSC group and a Factors+BMSCs group. Allogenous BMSCs (1 × 10(7)) and/or control-released microspheres of 2 μg HGF+2 μg IGF-1 were intramyocardially injected into infarcted regions. Apoptosis and differentiation of implanted BMSCs, histological and morphological results, and cardiac remodelling and function were evaluated at different time points. In vitro, BMSCs were exposed to HGF, IGF-1 and both (50 ng/ml) and subsequently proliferation, migration, myocardial differentiation and apoptosis induced by hypoxia, were analysed. Four weeks post-operatively, the above indices were significantly improved in Factors+BMSCs group compared to the others (P < 0.01), although Factors and BMSCs group also showed better results than Control group (P < 0.05). In vitro, HGF promoted BMSC migration and differentiation into cardiomyocytes, but inhibited proliferation (P < 0.05), while IGF-1 increased proliferation and migration, and inhibited apoptosis induced by hypoxia (P < 0.05), but did not induce myocardial differentiation. Combination of HGF and IGF-1 significantly promoted BMSCs capacity for migration, differentiation and lack of apoptosis (P < 0.05). Combination of HGF and IGF-1 activated BMSCs complementarily, and controlled release of the two factors promoted protective potential of transplanted BMSCs to repair infarcted myocardium. This suggests a new strategy for cell therapies to overcome acute ischemic myocardial injury. © 2015 John Wiley & Sons Ltd.

Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

PubMed

Nagata, Takanobu; Yasukawa, Hideo; Kyogoku, Sachiko; Oba, Toyoharu; Takahashi, Jinya; Nohara, Shoichiro; Minami, Tomoko; Mawatari, Kazutoshi; Sugi, Yusuke; Shimozono, Koutatsu; Pradervand, Sylvain; Hoshijima, Masahiko; Aoki, Hiroki; Fukumoto, Yoshihiro; Imaizumi, Tsutomu

2015-01-01

Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules

PubMed Central

Nagata, Takanobu; Yasukawa, Hideo; Kyogoku, Sachiko; Oba, Toyoharu; Takahashi, Jinya; Nohara, Shoichiro; Minami, Tomoko; Mawatari, Kazutoshi; Sugi, Yusuke; Shimozono, Koutatsu; Pradervand, Sylvain; Hoshijima, Masahiko; Aoki, Hiroki; Fukumoto, Yoshihiro; Imaizumi, Tsutomu

2015-01-01

Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT–activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI. PMID:26010537

A 1-year randomized controlled trial of deferasirox vs deferoxamine for myocardial iron removal in β-thalassemia major (CORDELIA)

PubMed Central

Porter, John B.; Piga, Antonio; Lai, Yongrong; El-Beshlawy, Amal; Belhoul, Khawla M.; Elalfy, Mohsen; Yesilipek, Akif; Kilinç, Yurdanur; Lawniczek, Tomasz; Habr, Dany; Weisskopf, Marianne; Zhang, Yiyun; Aydinok, Yesim

2014-01-01

Randomized comparison data on the efficacy and safety of deferasirox for myocardial iron removal in transfusion dependent patients are lacking. CORDELIA was a prospective, randomized comparison of deferasirox (target dose 40 mg/kg per day) vs subcutaneous deferoxamine (50-60 mg/kg per day for 5-7 days/week) for myocardial iron removal in 197 β-thalassemia major patients with myocardial siderosis (T2* 6-20 milliseconds) and no signs of cardiac dysfunction (mean age, 19.8 years). Primary objective was to demonstrate noninferiority of deferasirox for myocardial iron removal, assessed by changes in myocardial T2* after 1 year using a per-protocol analysis. Geometric mean (Gmean) myocardial T2* improved with deferasirox from 11.2 milliseconds at baseline to 12.6 milliseconds at 1 year (Gmeans ratio, 1.12) and with deferoxamine (11.6 milliseconds to 12.3 milliseconds; Gmeans ratio, 1.07). The between-arm Gmeans ratio was 1.056 (95% confidence interval [CI], 0.998, 1.133). The lower 95% CI boundary was greater than the prespecified margin of 0.9, establishing noninferiority of deferasirox vs deferoxamine (P = .057 for superiority of deferasirox). Left ventricular ejection fraction remained stable in both arms. Frequency of drug-related adverse events was comparable between deferasirox (35.4%) and deferoxamine (30.8%). CORDELIA demonstrated the noninferiority of deferasirox compared with deferoxamine for myocardial iron removal. This trial is registered at www.clinicaltrials.gov as #NCT00600938. PMID:24385534

Experimental myocardial infarction

PubMed Central

Kumar, Raj; Joison, Julio; Gilmour, David P.; Molokhia, Farouk A.; Pegg, C. A. S.; Hood, William B.

1971-01-01

The hemodynamic effects of tachycardia induced by atrial pacing were investigated in left ventricular failure of acute and healing experimental myocardial infarction in 20 intact, conscious dogs. Myocardial infarction was produced by gradual inflation of a balloon cuff device implanted around the left anterior descending coronary artery 10-15 days prior to the study. 1 hr after acute myocardial infarction, atrial pacing at a rate of 180 beats/min decreased left ventricular end-diastolic pressure from 19 to 8 mm Hg and left atrial pressure from 17 to 12 mm Hg, without change in cardiac output. In the healing phase of myocardial infarction 1 wk later, atrial pacing decreased left ventricular end-diastolic pressure from 17 to 9 mm Hg and increased the cardiac output by 37%. This was accompanied by evidence of peripheral vasodilation. In two dogs with healing anterior wall myocardial infarction, left ventricular failure was enhanced by partial occlusion of the circumflex coronary artery. Both the dogs developed pulmonary edema. Pacing improved left ventricular performance and relieved pulmonary edema in both animals. In six animals propranolol was given after acute infarction, and left ventricular function deteriorated further. However the pacing-induced augmentation of cardiac function was unaltered and, hence, is not mediated by sympathetics. The results show that the spontaneous heart rate in left ventricular failure of experimental canine myocardial infarction may be less than optimal and that maximal cardiac function may be achieved at higher heart rates. Images PMID:4395910

The Chromatin Remodeler SPLAYED Regulates Specific Stress Signaling Pathways

PubMed Central

Walley, Justin W.; Rowe, Heather C.; Xiao, Yanmei; Chehab, E. Wassim; Kliebenstein, Daniel J.; Wagner, Doris; Dehesh, Katayoon

2008-01-01

Organisms are continuously exposed to a myriad of environmental stresses. Central to an organism's survival is the ability to mount a robust transcriptional response to the imposed stress. An emerging mechanism of transcriptional control involves dynamic changes in chromatin structure. Alterations in chromatin structure are brought about by a number of different mechanisms, including chromatin modifications, which covalently modify histone proteins; incorporation of histone variants; and chromatin remodeling, which utilizes ATP hydrolysis to alter histone-DNA contacts. While considerable insight into the mechanisms of chromatin remodeling has been gained, the biological role of chromatin remodeling complexes beyond their function as regulators of cellular differentiation and development has remained poorly understood. Here, we provide genetic, biochemical, and biological evidence for the critical role of chromatin remodeling in mediating plant defense against specific biotic stresses. We found that the Arabidopsis SWI/SNF class chromatin remodeling ATPase SPLAYED (SYD) is required for the expression of selected genes downstream of the jasmonate (JA) and ethylene (ET) signaling pathways. SYD is also directly recruited to the promoters of several of these genes. Furthermore, we show that SYD is required for resistance against the necrotrophic pathogen Botrytis cinerea but not the biotrophic pathogen Pseudomonas syringae. These findings demonstrate not only that chromatin remodeling is required for selective pathogen resistance, but also that chromatin remodelers such as SYD can regulate specific pathways within biotic stress signaling networks. PMID:19079584

Testosterone deficiency prevents left ventricular contractility dysfunction after myocardial infarction.

PubMed

Ribeiro Júnior, R F; Ronconi, K S; Jesus, I C G; Almeida, P W M; Forechi, L; Vassallo, D V; Guatimosim, S; Stefanon, I; Fernandes, A A

2018-01-15

Testosterone may affect myocardial contractility since its deficiency decreases the contraction and relaxation of the heart. Meanwhile, testosterone replacement therapy has raised concerns because it may worsen cardiac dysfunction and remodeling after myocardial infarction (MI). In this study, we evaluate cardiac contractility 60 days after MI in rats with suppressed testosterone. Male Wistar rats underwent bilateral orchidectomy one week before the ligation of the anterior descending left coronary artery. The animals were divided into orchidectomized (OCT); MI; orchidectomized + MI (OCT + MI); orchidectomized + MI + testosterone (OCT + MI + T) and control (Sham) groups. Eight weeks after MI, papillary muscle contractility was analyzed under increasing calcium (0.62, 1.25, 2.5 and 3.75 mM) and isoproterenol (10 -8 to 10 -2  M) concentrations. Ventricular myocytes were isolated for intracellular calcium measurements and assessment of Ca 2+ handling proteins. Contractility was preserved in the orchidectomized animals after myocardial infarction and was reduced when testosterone was replaced (Ca 2+ 3.75 mM: Sham: 608 ± 70 (n = 11); OCT: 590 ± 37 (n = 16); MI: 311 ± 33* (n = 9); OCT + MI: 594 ± 76 (n = 7); OCT + MI + T: 433 ± 38* (n=4), g/g *p < 0.05 vs Sham). Orchidectomy also increased the Ca 2+ transient amplitude of the ventricular myocytes and SERCA-2a protein expression levels. PLB phosphorylation levels at Thr 17 were not different in the orchidectomized animals compared to the Sham animals but were reduced after testosterone replacement. CAMKII phosphorylation and protein nitrosylation increased in the orchidectomized animals. Our results support the view that testosterone deficiency prevents MI contractility dysfunction by altering the key proteins involved in Ca 2+ handling. Copyright © 2017 Elsevier B.V. All rights reserved.

Treatment with the CC chemokine-binding protein Evasin-4 improves post-infarction myocardial injury and survival in mice.

PubMed

Braunersreuther, Vincent; Montecucco, Fabrizio; Pelli, Graziano; Galan, Katia; Proudfoot, Amanda E; Belin, Alexandre; Vuilleumier, Nicolas; Burger, Fabienne; Lenglet, Sébastien; Caffa, Irene; Soncini, Debora; Nencioni, Alessio; Vallée, Jean-Paul; Mach, François

2013-10-01

Chemokines trigger leukocyte trafficking and are implicated in cardiovascular disease pathophysiology. Chemokine-binding proteins, called "Evasins" have been shown to inhibit both CC and CXC chemokine-mediated bioactivities. Here, we investigated whether treatment with Evasin-3 (CXC chemokine inhibitor) and Evasin-4 (CC chemokine inhibitor) could influence post-infarction myocardial injury and remodelling. C57Bl/6 mice were submitted in vivo to left coronary artery permanent ligature and followed up for different times (up to 21 days). After coronary occlusion, three intraperitoneal injections of 10 μg Evasin-3, 1 μg Evasin-4 or equal volume of vehicle (PBS) were performed at 5 minutes, 24 hours (h) and 48 h after ischaemia onset. Both anti-chemokine treatments were associated with the beneficial reduction in infarct size as compared to controls. This effect was accompanied by a decrease in post-infarction myocardial leukocyte infiltration, reactive oxygen species release, and circulating levels of CXCL1 and CCL2. Treatment with Evasin-4 induced a more potent effect, abrogating the inflammation already at one day after ischaemia onset. At days 1 and 21 after ischaemia onset, both anti-chemokine treatments failed to significantly improve cardiac function, remodelling and scar formation. At 21-day follow-up, mouse survival was exclusively improved by Evasin-4 treatment when compared to control vehicle. In conclusion, we showed that the selective inhibition of CC chemokines (i.e. CCL5) with Evasin-4 reduced cardiac injury/inflammation and improved survival. Despite the inhibition of CXC chemokine bioactivities, Evasin-3 did not affect mouse survival. Therefore, early inhibition of CC chemokines might represent a promising therapeutic approach to reduce the development of post-infarction heart failure in mice.

RosettaRemodel: A Generalized Framework for Flexible Backbone Protein Design

PubMed Central

Huang, Po-Ssu; Ban, Yih-En Andrew; Richter, Florian; Andre, Ingemar; Vernon, Robert; Schief, William R.; Baker, David

2011-01-01

We describe RosettaRemodel, a generalized framework for flexible protein design that provides a versatile and convenient interface to the Rosetta modeling suite. RosettaRemodel employs a unified interface, called a blueprint, which allows detailed control over many aspects of flexible backbone protein design calculations. RosettaRemodel allows the construction and elaboration of customized protocols for a wide range of design problems ranging from loop insertion and deletion, disulfide engineering, domain assembly, loop remodeling, motif grafting, symmetrical units, to de novo structure modeling. PMID:21909381

Value of Low Triiodothyronine and Subclinical Myocardial Injury for Clinical Outcomes in Chest Pain.

PubMed

Lee, Young-Min; Ki, Young-Jae; Choi, Dong-Hyun; Kim, Bo-Bae; Shin, Byung Chul; Song, Heesang; Kim, Dong-Min

2015-11-01

Low triiodothyronine (T3) levels and subclinical myocardial injury may be associated with adverse cardiac and cerebrovascular (CCV) events in individuals without clinically apparent coronary heart disease (CHD). The aim of this study was to determine the associations of a low T3 level and subclinical myocardial injury with the development of adverse CCV events in individuals without clinically apparent CHD. T3 and high-sensitivity cardiac troponin T (hs-cTnT) levels were analyzed in 250 patients with chest pain free of CHD and heart failure. The primary end point was the composite of sudden cardiac death, ischemic stroke, newly developed atrial fibrillation, pericardial effusion and thrombosis. Throughout a mean follow-up of 15.6 months, the primary end point happened in 17 patients (6.8%). Kaplan-Meier analysis disclosed a notably higher overall occurrence rate in patients with hs-cTnT levels ≥0.014 ng/mL and in patients with T3 <60 ng/dL. An exaggerated hazard was observed in patients with combined high hs-cTnT and low T3 levels. After adjustment, the hazard ratio for overall events in patients with high hs-cTnT/low T3 versus normal hs-cTnT/T3 was 11.72 (95% confidence interval, 2.83-48.57; P = 0.001). In patients with chest pain without clinically obvious CHD, high hs-cTnT combined with low T3 was associated with adverse cardiac/CCV events and was an independent predictor of overall events even after adjustment. These data suggest the importance of systemic factors, such as low T3 syndrome, in the development of adverse cardiac/CCV events beyond advancing clinical atherosclerotic coronary disease in patients with chest pain.

Coronary revascularization and adverse events in joint arthroplasty.

PubMed

Tabatabaee, Reza Mostafavi; Rasouli, Mohammad R; Rezapoor, Maryam; Maltenfort, Mitchell G; Ong, Alvin C; Parvizi, Javad

2015-09-01

There is a paucity of literature about outcome of total joint arthroplasty in patients with the history of angioplasty and/or stent or coronary artery bypass graft (CABG). The present study aimed to evaluate perioperative complications and mortality in these patients. We used the Nationwide Inpatient Sample data from 2002-2011. Using the Ninth Revision of the International Classification of Disease, Clinical Modification codes for disorders and procedures, we identified patients with a history of coronary revascularization (angioplasty and/or stent or CABG) and compared the inhospital adverse events in these patients with patients without a history of coronary revascularization. Cardiac complications occurred in 1.06% patients with a history of CABG; 0.95% of patients with a coronary angioplasty and/or stent and 0.82% of the control patients. In the multivariate analysis, neither the history of CABG (P = 0.07) nor the history of angioplasty and/or stenting (P = 0.86) was associated with a higher risk of cardiac complications. However, myocardial infarction occurred in a significantly higher proportion of patients with the history of CABG (0.66%, odds ratio, 1.24, P = 0.001) and coronary angioplasty and/or stenting (0.67%, odds ratio, 1.96, P < 0.001) compared with that in the controls (0.27%). History of coronary revascularization did not increase the risk of respiratory, renal, and wound complications, surgical site infection, and mortality. Based on the findings of this study, it appears that there is no increased risk of inhospital mortality and complications (except for myocardial infarction) in patients with a history of coronary artery revascularization undergoing total joint arthroplasty. We also found perioperative cardiac arrhythmia, particularly atrial fibrillation, to be an independent predictor of inhospital adverse events. Copyright © 2015 Elsevier Inc. All rights reserved.

Relation of cardiac troponin I and microvascular obstruction following ST-elevation myocardial infarction.

PubMed

Hallén, Jonas; Jensen, Jesper K; Buser, Peter; Jaffe, Allan S; Atar, Dan

2011-03-01

Presence of microvascular obstruction (MVO) following primary percutaneous coronary intervention (pPCI) for ST-elevation myocardial infarction (STEMI) confers higher risk of left-ventricular remodelling and dysfunction. Measurement of cardiac troponin I (cTnI) after STEMI reflects the extent of myocardial destruction. We aimed to explore whether cTnI values were associated with presence of MVO independently of infarct size in STEMI patients receiving pPCI. 175 patients with STEMI were included. cTnI was sampled at 24 and 48 h. MVO and infarct size was determined by delayed enhancement with cardiac magnetic resonance at five to seven days post index event. The presence of MVO following STEMI was associated with larger infarct size and higher values of cTnI at 24 and 48 h. For any given infarct size or cTnI value, there was a greater risk of MVO development in non-anterior infarctions. cTnI was strongly associated with MVO in both anterior and non-anterior infarctions (P < 0.01) after adjustment for covariates (including infarct size); and was reasonably effective in predicting MVO in individual patients (area-under-the-curve ≥0.81). Presence of MVO is reflected in levels of cTnI sampled at an early time-point following STEMI and this association persists after adjustment for infarct size.

Adverse Left Ventricular Remodeling and Age Assessed with Cardiac MR Imaging: The Multi-Ethnic Study of Atherosclerosis

PubMed Central

McClelland, Robyn L.; Gomes, Antoinette S.; Hundley, W. Gregory; Cheng, Susan; Wu, Colin O.; Carr, J. Jeffrey; Shea, Steven; Bluemke, David A.; Lima, Joao A. C.

2016-01-01

Purpose To evaluate age-related left ventricular (LV) remodeling during longitudinal observation of a large cohort of asymptomatic individuals who were free of clinical cardiovascular disease at baseline. Materials and Methods The applicable institutional review boards approved this study, and all participants gave informed consent. Cardiac magnetic resonance (MR) imaging was used to identify longitudinal changes in LV structure and function in 2935 participants who underwent baseline and follow-up cardiac MR imaging in the Multi-Ethnic Study of Atherosclerosis. Participants were free of clinical cardiovascular disease at baseline. Participants who experienced an incident coronary heart disease event were excluded. Data were analyzed with multivariable mixed-effects regression models in which the outcome was cardiac MR imaging measurement, and the covariates included follow-up time and cardiac risk factors. Results Participants were aged 54–94 years at follow-up, and 53% of the participants were women. Median time between baseline and follow-up cardiac MR imaging was 9.4 years. Over this period, LV mass increased in men and decreased slightly in women (8.0 and −1.6 g per decade, respectively; P < .001). In both men and women, LV end-diastolic volume decreased (−9.8 and −13.3 mL per decade, respectively; P < .001), stroke volume decreased (−8.8 and −8.6 mL per decade, respectively; P < .001), and mass-to-volume ratio increased (0.14 and 0.11 g/mL per decade, respectively; P < .001). Change in LV mass was positively associated with systolic blood pressure and body mass index and negatively associated with treated hypertension and high-density lipoprotein cholesterol level. In men, the longitudinal LV mass increase was in contrast to a cross-sectional pattern of LV mass decrease. Conclusion As patients age, the LV responds differently in its mass and volume between men and women, although both men and women experience increased concentric LV remodeling

Thrombus aspiration in non-ST-elevation myocardial infarction - 12-month clinical outcome of the randomised TATORT-NSTEMI trial.

PubMed

Meyer-Saraei, Roza; de Waha, Suzanne; Eitel, Ingo; Desch, Steffen; Scheller, Bruno; Böhm, Michael; Lauer, Bernward; Gawaz, Meinrad; Geisler, Tobias; Gunkel, Oliver; Bruch, Leonhard; Klein, Norbert; Pfeiffer, Dietrich; Schuler, Gerhard; Zeymer, Uwe; Thiele, Holger

2017-02-01

In the randomised TATORT-NSTEMI trial routine thrombus aspiration in comparison with standard percutaneous coronary intervention (PCI) did not reduce the primary endpoint of microvascular obstruction assessed by cardiac magnetic resonance imaging in patients with non-ST-elevation myocardial infarction (NSTEMI). So far, no data on long-term outcome of head-to-head comparisons between both treatment strategies in NSTEMI patients have been reported. The prospective, controlled, multicentre, randomised, open-label TATORT-NSTEMI trial assigned patients with NSTEMI and thrombus-containing lesions to aspiration thrombectomy plus PCI ( n=221) or standard PCI only ( n=219). The primary endpoint of the current analysis was the occurrence of major adverse cardiac events defined as the composite of death, myocardial reinfarction, target vessel revascularisation, and new congestive heart failure at 12-month follow-up. In addition, functional outcome and quality of life were assessed. At one year, major adverse cardiac events occurred in 19 patients in the thrombectomy arm and 29 patients in the standard PCI group (8.7% vs. 13.4%, relative risk 0.63, 95% confidence interval 0.35-1.12, p=0.11). The individual components of the combined endpoint such as death ( p=0.20), myocardial reinfarction ( p=0.73), target vessel revascularisation ( p=0.42), and congestive heart failure ( p=0.18) were similar in both groups. Functional outcome and quality of life did not differ significantly between both groups (Canadian Cardiovascular Society class: p=0.68, New York Heart Association class: p=0.70 and EuroQol5D score: p=0.96). Post-hoc analyses revealed consistent results with regard to the occurrence of major adverse cardiac events across a wide range of subgroups (all p>0.05). In this first randomised trial on thrombectomy in NSTEMI patients, routine thrombus aspiration before PCI did not improve clinical outcome at 12-month follow-up.

Mesenchymal Stem Cells and Cardiomyocytes Interplay to Prevent Myocardial Hypertrophy

PubMed Central

Tan, Xueying; Zhang, Yong; Li, Xingda; Wang, Xinyue; Zhu, Jiuxin; Wang, Yang; Yang, Fan; Wang, Baoqiu; Liu, Yanju; Xu, Chaoqian; Pan, Zhenwei; Wang, Ning; Yang, Baofeng

2015-01-01

first evidence for the treatment of myocardial hypertrophy using BMSCs. Significance This study found that mesenchymal stem cells may crosstalk with cardiomyocytes, which causes a synergistic vascular endothelial growth factor (VEGF) release from both kinds of cells and then inhibits pathological cardiac remodeling following hypertrophic stimulation in cardiomyocytes in vitro and in vivo. Blockage of VEGF release from bone marrow-derived mesenchymal stem cells (BMSCs) abolishes the antihypertrophic actions of BMSCs in vitro and in vivo. On the contrary, VEGF administration attenuates hypertrophic signaling of calcineurin/ nuclear factor of activated T cell cytoplasmic 3 signal pathways. This study provides the first evidence for the treatment of myocardial hypertrophy using BMSCs. PMID:26586774

Clinical Implications of Sleep Disordered Breathing in Acute Myocardial Infarction

PubMed Central

Aronson, Doron; Nakhleh, Morad; Zeidan-Shwiri, Tawfiq; Mutlak, Michael; Lavie, Peretz; Lavie, Lena

2014-01-01

Background Sleep disordered breathing (SDB), characterized by nightly intermittent hypoxia, is associated with multiple pathophysiologic alterations that may adversely affect patients with acute myocardial infarction (AMI). This prospective study investigated whether the metabolic perturbations associated with SDB are present when these patients develop AMI and if they affect clinical outcomes. Methods We prospectively enrolled 180 AMI patients. SDB was defined as oxygen desaturation index (ODI) >5 events/hour based on a Watch Pat-100 sleep study. Blood samples were obtained for high-sensitivity C-reactive protein (hs-CRP) and markers of oxidative stress (lipid peroxides [PD] and serum paraoxonase-1 [PON-1] (arylesterase activity). Echocardiography was performed to evaluate cardiac dimensions and pulmonary artery systolic pressure. Results SDB was present in 116 (64%) patients. Hs-CRP levels, PD and PON-1 were similar in patients with and without SDB. Echocardiography revealed higher left atrial dimension (4.1±0.5 vs 3.8±0.5 cm; P = 0.003) and a significant positive correlation between ODI and pulmonary artery systolic pressure (r = 0.41, P<0.0001). After a median follow up of 68 months, no significant differences were observed between the study groups with regard to clinical outcomes, including death, heart failure, myocardial infarction and unstable angina. Conclusion There is a high prevalence of previously undiagnosed SDB among patients with AMI. SDB in the setting of AMI is associated with higher pulmonary artery systolic pressure. SDB was not associated with adverse clinical outcomes. PMID:24523943

C-terminal provasopressin (copeptin) as a novel and prognostic marker in acute myocardial infarction: Leicester Acute Myocardial Infarction Peptide (LAMP) study.

PubMed

Khan, Sohail Q; Dhillon, Onkar S; O'Brien, Russell J; Struck, Joachim; Quinn, Paulene A; Morgenthaler, Nils G; Squire, Iain B; Davies, Joan E; Bergmann, Andreas; Ng, Leong L

2007-04-24

The role of the vasopressin system after acute myocardial infarction is unclear. Copeptin, the C-terminal part of the vasopressin prohormone, is secreted stoichiometrically with vasopressin. We compared the prognostic value of copeptin and an established marker, N-terminal pro-B-type natriuretic peptide (NTproBNP), after acute myocardial infarction. In this prospective single-hospital study, we recruited 980 consecutive post-acute myocardial infarction patients (718 men, median [range] age 66 [24 to 95] years), with follow-up over 342 (range 0 to 764) days. Plasma copeptin was highest on admission (n=132, P<0.001, day 1 versus days 2 to 5) and reached a plateau at days 3 to 5. In the 980 patients, copeptin (measured at days 3 to 5) was elevated in patients who died (n=101) or were readmitted with heart failure (n=49) compared with survivors (median [range] 18.5 [0.6 to 441.0] versus 6.5 [0.3 to 267.0] pmol/L, P<0.0005). With logistic regression analysis, copeptin (odds ratio, 4.14, P<0.0005) and NTproBNP (odds ratio, 2.26, P<0.003) were significant independent predictors of death or heart failure at 60 days. The area under the receiver operating characteristic curves for copeptin (0.75) and NTproBNP (0.76) were similar. The logistic model with both markers yielded a larger area under the curve (0.84) than for NTproBNP (P<0.013) or copeptin (P<0.003) alone, respectively. Cox modeling predicted death or heart failure with both biomarkers (log copeptin [hazard ratio, 2.33], log NTproBNP [hazard ratio, 2.70]). In patients stratified by NTproBNP (above the median of approximately 900 pmol/L), copeptin above the median (approximately 7 pmol/L) was associated with poorer outcome (P<0.0005). Findings were similar for death and heart failure as individual end points. The vasopressin system is activated after acute myocardial infarction. Copeptin may predict adverse outcome, especially in those with an elevated NTproBNP (more than approximately 900 pmol/L).

Continued Statin Prescriptions After Adverse Reactions and Patient Outcomes: A Cohort Study.