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Sample records for acute cardiac dysfunction

  1. Transpulmonary thermodilution-derived cardiac function index identifies cardiac dysfunction in acute heart failure and septic patients: an observational study

    PubMed Central

    2009-01-01

    Introduction There is limited clinical experience with the single-indicator transpulmonary thermodilution (pulse contour cardiac output, or PiCCO) technique in critically ill medical patients, particularly in those with acute heart failure (AHF). Therefore, we compared the cardiac function of patients with AHF or sepsis using the pulmonary artery catheter (PAC) and the PiCCO technology. Methods This retrospective observational study was conducted in the medical intensive care unit of a university hospital. Twelve patients with AHF and nine patients with severe sepsis or septic shock had four simultaneous hemodynamic measurements by PAC and PiCCO during a 24-hour observation period. Comparisons between groups were made with the use of the Mann-Whitney U test. Including all measurements, correlations between data pairs were established using linear regression analysis and are expressed as the square of Pearson's correlation coefficients (r2). Results Compared to septic patients, AHF patients had a significantly lower cardiac index, cardiac function index (CFI), global ejection fraction, mixed venous oxygen saturation (SmvO2) and pulmonary vascular permeability index, but higher pulmonary artery occlusion pressure. All patients with a CFI less than 4.5 per minute had an SmvO2 not greater than 70%. In both groups, the CFI correlated with the left ventricular stroke work index (sepsis: r2 = 0.30, P < 0.05; AHF: r2 = 0.23, P < 0.05) and cardiac power (sepsis: r2 = 0.39, P < 0.05; AHF: r2 = 0.45, P < 0.05). Conclusions In critically ill medical patients, assessment of cardiac function using transpulmonary thermodilution technique is an alternative to the PAC. A low CFI identifies cardiac dysfunction in both AHF and septic patients. PMID:19671146

  2. Cardiac and mitochondrial dysfunction following acute pulmonary exposure to mountaintop removal mining particulate matter.

    PubMed

    Nichols, Cody E; Shepherd, Danielle L; Knuckles, Travis L; Thapa, Dharendra; Stricker, Janelle C; Stapleton, Phoebe A; Minarchick, Valerie C; Erdely, Aaron; Zeidler-Erdely, Patti C; Alway, Stephen E; Nurkiewicz, Timothy R; Hollander, John M

    2015-12-15

    Throughout the United States, air pollution correlates with adverse health outcomes, and cardiovascular disease incidence is commonly increased following environmental exposure. In areas surrounding active mountaintop removal mines (MTM), a further increase in cardiovascular morbidity is observed and may be attributed in part to particulate matter (PM) released from the mine. The mitochondrion has been shown to be central in the etiology of many cardiovascular diseases, yet its roles in PM-related cardiovascular effects are not realized. In this study, we sought to elucidate the cardiac processes that are disrupted following exposure to mountaintop removal mining particulate matter (PM MTM). To address this question, we exposed male Sprague-Dawley rats to PM MTM, collected within one mile of an active MTM site, using intratracheal instillation. Twenty-four hours following exposure, we evaluated cardiac function, apoptotic indices, and mitochondrial function. PM MTM exposure elicited a significant decrease in ejection fraction and fractional shortening compared with controls. Investigation into the cellular impacts of PM MTM exposure identified a significant increase in mitochondrial-induced apoptotic signaling, as reflected by an increase in TUNEL-positive nuclei and increased caspase-3 and -9 activities. Finally, a significant increase in mitochondrial transition pore opening leading to decreased mitochondrial function was identified following exposure. In conclusion, our data suggest that pulmonary exposure to PM MTM increases cardiac mitochondrial-associated apoptotic signaling and decreases mitochondrial function concomitant with decreased cardiac function. These results suggest that increased cardiovascular disease incidence in populations surrounding MTM mines may be associated with increased cardiac cell apoptotic signaling and decreased mitochondrial function.

  3. Cardiac Function and Dysfunction in Sepsis.

    PubMed

    Fenton, Kimberly E; Parker, Margaret M

    2016-06-01

    Cardiac function and dysfunction are important in the clinical outcomes of sepsis and septic shock. Cardiac dysfunction is not a single entity, but is a broad spectrum of syndromes that result in biventricular cardiac dysfunction manifested by both systolic and diastolic dysfunction and is influenced by cardiac loading conditions (ie, preload and afterload). Elucidating the underlying pathophysiology has proved to be complex. This article emphasizes the underlying pathophysiology of cardiac dysfunction and explores recent evidence related to diagnosis, including the utility of biomarkers, the role of echocardiography, and management goals and treatment. PMID:27229645

  4. Acute toxicant exposure and cardiac autonomic dysfunction from smoking a single narghile waterpipe with tobacco and with a "healthy" tobacco-free alternative.

    PubMed

    Cobb, Caroline O; Sahmarani, Kamar; Eissenberg, Thomas; Shihadeh, Alan

    2012-11-23

    Tobacco smoking using a waterpipe (narghile, hookah, shisha) has become a global epidemic. Unlike cigarette smoking, little is known about the health effects of waterpipe use. One acute effect of cigarette smoke inhalation is dysfunction in autonomic regulation of the cardiac cycle, as indicated by reduction in heart rate variability (HRV). Reduced HRV is implicated in adverse cardiovascular health outcomes, and is associated with inhalation exposure-induced oxidative stress. Using a 32 participant cross-over study design, we investigated toxicant exposure and effects of waterpipe smoking on heart rate variability when, under controlled conditions, participants smoked a tobacco-based and a tobacco-free waterpipe product promoted as an alternative for "health-conscious" users. Outcome measures included HRV, exhaled breath carbon monoxide (CO), plasma nicotine, and puff topography, which were measured at times prior to, during, and after smoking. We found that waterpipe use acutely decreased HRV (p<0.01 for all measures), independent of product smoked. Plasma nicotine, blood pressure, and heart rate increased only with the tobacco-based product (p<0.01), while CO increased with both products (p<0.01). More smoke was inhaled during tobacco-free product use, potentially reflecting attempted regulation of nicotine intake. The data thus indicate that waterpipe smoking acutely compromises cardiac autonomic function, and does so through exposure to smoke constituents other than nicotine. PMID:23059956

  5. Acute toxicant exposure and cardiac autonomic dysfunction from smoking a single narghile waterpipe with tobacco and with a “healthy” tobacco-free alternative

    PubMed Central

    Cobb, Caroline O.; Sahmarani, Kamar; Eissenberg, Thomas; Shihadeh, Alan

    2012-01-01

    Tobacco smoking using a waterpipe (narghile, hookah, shisha) has become a global epidemic. Unlike cigarette smoking, little is known about the health effects of waterpipe use. One acute effect of cigarette smoke inhalation is dysfunction in autonomic regulation of the cardiac cycle, as indicated by reduction in heart rate variability (HRV). Reduced HRV is implicated in adverse cardiovascular health outcomes, and is associated with inhalation exposure-induced oxidative stress. Using a 32 participant cross-over study design, we investigated toxicant exposure and effects of waterpipe smoking on heart rate variability when, under controlled conditions, participants smoked a tobacco-based and a tobacco-free waterpipe product promoted as an alternative for “health-conscious” users. Outcome measures included HRV, exhaled breath carbon monoxide (CO), plasma nicotine, and puff topography, which were measured at times prior to, during, and after smoking. We found that waterpipe use acutely decreased HRV (p<0.01 for all measures), independent of product smoked. Plasma nicotine, blood pressure, and heart rate increased only with the tobacco-based product (p<0.01), while CO increased with both products (p<0.01). More smoke was inhaled during tobacco-free product use, potentially reflecting attempted regulation of nicotine intake. The data thus indicate that waterpipe smoking acutely compromises cardiac autonomic function, and does so through exposure to smoke constituents other than nicotine. PMID:23059956

  6. Effect on short- and long-term major adverse cardiac events of statin treatment in patients with acute myocardial infarction and renal dysfunction.

    PubMed

    Lim, Sang Yup; Bae, Eun Hui; Choi, Joon Seok; Kim, Chang Seong; Park, Jeong Woo; Ma, Seong Kwon; Jeong, Myung Ho; Kim, Soo Wan

    2012-05-15

    The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduce major adverse cardiac events (MACE) and mortality in patients with acute coronary syndrome. We investigated the effectiveness of statin therapy in reducing MACE in patients with acute myocardial infarction (AMI) and renal dysfunction (RD). In the present retrospective study of 12,853 patients with AMI, the patients were categorized into 4 groups: group I, statin therapy and no RD (estimated glomerular filtration rate ≥60 ml/min/1.73 m(2)); group II, neither statin therapy nor RD; group III, statin therapy and RD; group IV, no statin therapy but RD. The primary end points were death and complications during the hospital course. The secondary end points were MACE during 1 year of follow-up after AMI. Significant differences in the composite MACE during 12 months of follow-up were observed among the 4 groups (group I, 11.7%; group II, 19.0%; group III, 26.7%; and group IV, 45.5%; p <0.001). In a Cox proportional hazards model, mortality at 12 months increased stepwise from group II to IV compared to group I. Moreover, MACE-free survival in the severe RD group (estimated glomerular filtration rate <30 mL/min/1.73 m(2)) was also greater in the statin-treated group. In conclusion, statin therapy reduced MACE at 1 year of follow-up in patients with AMI regardless of RD.

  7. A mouse model for juvenile doxorubicin-induced cardiac dysfunction.

    PubMed

    Zhu, Wuqiang; Shou, Weinian; Payne, R Mark; Caldwell, Randall; Field, Loren J

    2008-11-01

    Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases. PMID:18614963

  8. Acute emotional stress and cardiac arrhythmias.

    PubMed

    Ziegelstein, Roy C

    2007-07-18

    Episodes of acute emotional stress can have significant adverse effects on the heart. Acute emotional stress can produce left ventricular contractile dysfunction, myocardial ischemia, or disturbances of cardiac rhythm. Although these abnormalities are often only transient, their consequences can be gravely damaging and sometimes fatal. Despite the many descriptions of catastrophic cardiovascular events in the setting of acute emotional stress, the anatomical substrate and physiological pathways by which emotional stress triggers cardiovascular events are only now being characterized, aided by the advent of functional neuroimaging. Recent evidence indicates that asymmetric brain activity is particularly important in making the heart more susceptible to ventricular arrhythmias. Lateralization of cerebral activity during emotional stress may stimulate the heart asymmetrically and produce areas of inhomogeneous repolarization that create electrical instability and facilitate the development of cardiac arrhythmias. Patients with ischemic heart disease who survive an episode of sudden cardiac death in the setting of acute emotional stress should receive a beta-blocker. Nonpharmacological approaches to manage emotional stress in patients with and without coronary artery disease, including social support, relaxation therapy, yoga, meditation, controlled slow breathing, and biofeedback, are also appropriate to consider and merit additional investigation in randomized trials.

  9. Cardiac autonomic dysfunction in anabolic steroid users.

    PubMed

    Maior, A S; Carvalho, A R; Marques-Neto, S R; Menezes, P; Soares, P P; Nascimento, J H M

    2013-10-01

    This study aimed to evaluate if androgenic-anabolic steroids (AAS) abuse may induce cardiac autonomic dysfunction in recreational trained subjects. Twenty-two men were volunteered for the study. The AAS group (n = 11) utilized AAS at mean dosage of 410 ± 78.6 mg/week. All of them were submitted to submaximal exercise testing using an Astrand-Rhyming protocol. Electrocardiogram (ECG) and respired gas analysis were monitored at rest, during, and post-effort. Mean values of VO2 , VCO2 , and VE were higher in AAS group only at rest. The heart rate variability variables were calculated from ECG using MATLAB-based algorithms. At rest, AAS group showed lower values of the standard deviation of R-R intervals, the proportion of adjacent R-R intervals differing by more than 50 ms (pNN50), the root mean square of successive differences (RMSSD), and the total, the low-frequency (LF) and the high-frequency (HF) spectral power, as compared to Control group. After submaximal exercise testing, pNN50, RMSSD, and HF were lower, and the LF/HF ratio was higher in AAS group when compared to control group. Thus, the use of supraphysiological doses of AAS seems to induce dysfunction in tonic cardiac autonomic regulation in recreational trained subjects.

  10. Sustained release of a p38 inhibitor from non-inflammatory microspheres inhibits cardiac dysfunction

    NASA Astrophysics Data System (ADS)

    Sy, Jay C.; Seshadri, Gokulakrishnan; Yang, Stephen C.; Brown, Milton; Oh, Teresa; Dikalov, Sergey; Murthy, Niren; Davis, Michael E.

    2008-11-01

    Cardiac dysfunction following acute myocardial infarction is a major cause of death in the world and there is a compelling need for new therapeutic strategies. In this report we demonstrate that a direct cardiac injection of drug-loaded microparticles, formulated from the polymer poly(cyclohexane-1,4-diylacetone dimethylene ketal) (PCADK), improves cardiac function following myocardial infarction. Drug-delivery vehicles have great potential to improve the treatment of cardiac dysfunction by sustaining high concentrations of therapeutics within the damaged myocardium. PCADK is unique among currently used polymers in drug delivery in that its hydrolysis generates neutral degradation products. We show here that PCADK causes minimal tissue inflammatory response, thus enabling PCADK for the treatment of inflammatory diseases, such as cardiac dysfunction. PCADK holds great promise for treating myocardial infarction and other inflammatory diseases given its neutral, biocompatible degradation products and its ability to deliver a wide range of therapeutics.

  11. Risk factors for transient dysfunction of gas exchange after cardiac surgery

    PubMed Central

    Rodrigues, Cristiane Delgado Alves; Moreira, Marcos Mello; Lima, Núbia Maria Freire Vieira; de Figueirêdo, Luciana Castilho; Falcão, Antônio Luis Eiras; Petrucci, Orlando; Dragosavac, Desanka

    2015-01-01

    Objective A retrospective cohort study was preformed aiming to verify the presence of transient dysfunction of gas exchange in the postoperative period of cardiac surgery and determine if this disorder is linked to cardiorespiratory events. Methods We included 942 consecutive patients undergoing cardiac surgery and cardiac procedures who were referred to the Intensive Care Unit between June 2007 and November 2011. Results Fifteen patients had acute respiratory distress syndrome (2%), 199 (27.75%) had mild transient dysfunction of gas exchange, 402 (56.1%) had moderate transient dysfunction of gas exchange, and 39 (5.4%) had severe transient dysfunction of gas exchange. Hypertension and cardiogenic shock were associated with the emergence of moderate transient dysfunction of gas exchange postoperatively (P=0.02 and P=0.019, respectively) and were risk factors for this dysfunction (P=0.0023 and P=0.0017, respectively). Diabetes mellitus was also a risk factor for transient dysfunction of gas exchange (P=0.03). Pneumonia was present in 8.9% of cases and correlated with the presence of moderate transient dysfunction of gas exchange (P=0.001). Severe transient dysfunction of gas exchange was associated with patients who had renal replacement therapy (P=0.0005), hemotherapy (P=0.0001), enteral nutrition (P=0.0012), or cardiac arrhythmia (P=0.0451). Conclusion Preoperative hypertension and cardiogenic shock were associated with the occurrence of postoperative transient dysfunction of gas exchange. The preoperative risk factors included hypertension, cardiogenic shock, and diabetes. Postoperatively, pneumonia, ventilator-associated pneumonia, renal replacement therapy, hemotherapy, and cardiac arrhythmia were associated with the appearance of some degree of transient dysfunction of gas exchange, which was a risk factor for reintubation, pneumonia, ventilator-associated pneumonia, and renal replacement therapy in the postoperative period of cardiac surgery and cardiac

  12. Synthetic Marijuana Induced Acute Nonischemic Left Ventricular Dysfunction.

    PubMed

    Elsheshtawy, Moustafa; Sriganesh, Priatharsini; Virparia, Vasudev; Patel, Falgun; Khanna, Ashok

    2016-01-01

    Synthetic marijuana is an uptrending designer drug currently widely spread in the US. We report a case of acute deterioration of nonischemic left ventricular dysfunction after exposure to synthetic marijuana. This case illustrates the importance of history taking in cardiac patients and identifies a negative cardiovascular effect of synthetic marijuana known as K2, not yet well detected by urine toxicology screening tools. PMID:27119030

  13. Synthetic Marijuana Induced Acute Nonischemic Left Ventricular Dysfunction

    PubMed Central

    Sriganesh, Priatharsini; Virparia, Vasudev; Patel, Falgun; Khanna, Ashok

    2016-01-01

    Synthetic marijuana is an uptrending designer drug currently widely spread in the US. We report a case of acute deterioration of nonischemic left ventricular dysfunction after exposure to synthetic marijuana. This case illustrates the importance of history taking in cardiac patients and identifies a negative cardiovascular effect of synthetic marijuana known as K2, not yet well detected by urine toxicology screening tools. PMID:27119030

  14. Acute massive mitral regurgitation from prosthetic valve dysfunction.

    PubMed Central

    Cooper, D K; Sturridge, M F

    1976-01-01

    Two cases of prosthetic valve dysfunction resulting in acute massive mitral regurgitation are reported; emergency operation was successful in both cases. Survival following complete dislodgement of the occluder of a disc valve, as occurred in one case, does not appear to have been reported before. The diffculty in diagnosis of sudden cardiac decompensation in patients with prosthetic valves is stressed, as is the need for urgent operation. Images PMID:973894

  15. Transient sinus node dysfunction with acute hepatitis of unknown etiology.

    PubMed

    Al-Fagih, Ahmed R; Al-Ghamdi, Saleh A; Dagriri, Khaled G; Al-Malki, Ahmed S

    2010-05-01

    We reported a case of a 72-year-old male, known diabetic on insulin, referred because of complete atrioventricular block. He was found to have acute hepatitis during which he developed transient atrial arrhythmia, and sinus node dysfunction. His cardiac symptoms disappeared completely after hepatitis improvement. All of his cardiac investigations were normal including electrocardiogram, echocardiography and thalium stress test. At 3 and 6 months follow up, his Holter monitoring did not show any further arrhythmia, and he denied any further episodes of palpitation or pre-syncope. We reviewed the literature regarding the relationship between hepatitis and atrial arrhythmia. PMID:20464052

  16. Perspectives on the value of biomarkers in acute cardiac care and implications for strategic management.

    PubMed

    Kossaify, Antoine; Garcia, Annie; Succar, Sami; Ibrahim, Antoine; Moussallem, Nicolas; Kossaify, Mikhael; Grollier, Gilles

    2013-01-01

    Biomarkers in acute cardiac care are gaining increasing interest given their clinical benefits. This study is a review of the major conditions in acute cardiac care, with a focus on biomarkers for diagnostic and prognostic assessment. Through a PubMed search, 110 relevant articles were selected. The most commonly used cardiac biomarkers (cardiac troponin, natriuretic peptides, and C-reactive protein) are presented first, followed by a description of variable acute cardiac conditions with their relevant biomarkers. In addition to the conventional use of natriuretic peptides, cardiac troponin, and C-reactive protein, other biomarkers are outlined in variable critical conditions that may be related to acute cardiac illness. These include ST2 and chromogranin A in acute dyspnea and acute heart failure, matrix metalloproteinase in acute chest pain, heart-type fatty acid binding protein in acute coronary syndrome, CD40 ligand and interleukin-6 in acute myocardial infarction, blood ammonia and lactate in cardiac arrest, as well as tumor necrosis factor-alpha in atrial fibrillation. Endothelial dysfunction, oxidative stress and inflammation are involved in the physiopathology of most cardiac diseases, whether acute or chronic. In summary, natriuretic peptides, cardiac troponin, C-reactive protein are currently the most relevant biomarkers in acute cardiac care. Point-of-care testing and multi-markers use are essential for prompt diagnostic approach and tailored strategic management.

  17. Acute kidney injury after pediatric cardiac surgery.

    PubMed

    Singh, Sarvesh Pal

    2016-01-01

    Acute kidney injury is a common complication after pediatric cardiac surgery. The definition, staging, risk factors, biomarkers and management of acute kidney injury in children is detailed in the following review article. PMID:27052074

  18. Cardiac dysfunction and prenatal exposure to venlafaxine.

    PubMed

    Araújo, Ana R; Marçal, Mónica; Tuna, Madalena; Anjos, Rui

    2016-04-01

    Venlofaxine, a widely used antidepressant, is known to cause a withdrawal syndrome. We present a case of neonatal transient ventricular dysfunction in a neonate exposed to venlafaxine in utero. Other causes of ventricular dysfunction were excluded. Neonatal ventricular dysfunction can be a possible side effect of maternal use of this drug. PMID:27099733

  19. Prolonged Cardiac Dysfunction After Intraparenchymal Hemorrhage and Neurogenic Stunned Myocardium.

    PubMed

    Krishnamoorthy, Vijay; Wilson, Thomas; Sharma, Deepak; Vavilala, Monica S

    2016-01-01

    Cardiac dysfunction occurring secondary to neurologic disease, termed neurogenic stunned myocardium, is an incompletely understood phenomenon that has been described after several distinct neurologic processes. We present a case of neurogenic stunned myocardium, discovered intraoperatively after anesthetic induction, in a patient who presented to our operating room with a recent intraparenchymal hemorrhage. We discuss the longitudinal cardiac functional course after neurogenic stunned myocardium. Finally, we discuss the pathophysiology of neurogenic stunned myocardium, as well as its implications for anesthesiologists caring for neurosurgical patients.

  20. Combination of microRNA-21 and microRNA-146a Attenuates Cardiac Dysfunction and Apoptosis During Acute Myocardial Infarction in Mice

    PubMed Central

    Huang, Wei; Tian, Shan-Shan; Hang, Peng-Zhou; Sun, Chuan; Guo, Jing; Du, Zhi-Min

    2016-01-01

    Recent studies have revealed the cytoprotective roles of microRNAs (miRNAs) miR-21 and miR-146a against ischemic cardiac injuries. While these studies investigated each of these miRNAs as an independent individual factor, our previous study has suggested the possible interaction between these two miRNAs. The present study was designed to investigate this possibility by evaluating the effects of miR-21 and miR-146a combination on cardiac ischemic injuries and the underlying mechanisms. MiR-21 and miR-146a synergistically decreased apoptosis under ischemia/hypoxic conditions in cardiomyocytes compared with either miR-21 or miR-146a alone. Mice coinjected with agomiR-21 and agomiR-146a had decreased infarct size, increased ejection fraction (EF), and fractional shortening (FS). These effects were greater than those induced by either of the two agomiRs. Furthermore, greater decreases in p38 mitogen-associated protein kinase phosphorylation (p-p38 MAPK) were observed with miR-21: miR-146a combination as compared to application of either of the miRNAs. These data suggest that combination of miR-21 and miR-146a has a greater protective effect against cardiac ischemia/hypoxia-induced apoptosis as compared to these miRNAs applied individually. This synergistic action is mediated by enhanced potency of inhibition of cardiomyocyte apoptosis by the miR-21—PTEN/AKT—p-p38—caspase-3 and miR-146a—TRAF6—p-p38—caspase-3 signal pathways. PMID:26978580

  1. Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

    PubMed Central

    He, Quan; Harris, Nicole; Ren, Jun; Han, Xianlin

    2014-01-01

    Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress. PMID:25247053

  2. Cardiac Biomarkers and Acute Kidney Injury After Cardiac Surgery

    PubMed Central

    Bucholz, Emily M.; Whitlock, Richard P.; Zappitelli, Michael; Devarajan, Prasad; Eikelboom, John; Garg, Amit X.; Philbrook, Heather Thiessen; Devereaux, Philip J.; Krawczeski, Catherine D.; Kavsak, Peter; Shortt, Colleen

    2015-01-01

    OBJECTIVES: To examine the relationship of cardiac biomarkers with postoperative acute kidney injury (AKI) among pediatric patients undergoing cardiac surgery. METHODS: Data from TRIBE-AKI, a prospective study of children undergoing cardiac surgery, were used to examine the association of cardiac biomarkers (N-type pro–B-type natriuretic peptide, creatine kinase-MB [CK-MB], heart-type fatty acid binding protein [h-FABP], and troponins I and T) with the development of postoperative AKI. Cardiac biomarkers were collected before and 0 to 6 hours after surgery. AKI was defined as a ≥50% or 0.3 mg/dL increase in serum creatinine, within 7 days of surgery. RESULTS: Of the 106 patients included in this study, 55 (52%) developed AKI after cardiac surgery. Patients who developed AKI had higher median levels of pre- and postoperative cardiac biomarkers compared with patients without AKI (all P < .01). Preoperatively, higher levels of CK-MB and h-FABP were associated with increased odds of developing AKI (CK-MB: adjusted odds ratio 4.58, 95% confidence interval [CI] 1.56–13.41; h-FABP: adjusted odds ratio 2.76, 95% CI 1.27–6.03). When combined with clinical models, both preoperative CK-MB and h-FABP provided good discrimination (area under the curve 0.77, 95% CI 0.68–0.87, and 0.78, 95% CI 0.68–0.87, respectively) and improved reclassification indices. Cardiac biomarkers collected postoperatively did not significantly improve the prediction of AKI beyond clinical models. CONCLUSIONS: Preoperative CK-MB and h-FABP are associated with increased risk of postoperative AKI and provide good discrimination of patients who develop AKI. These biomarkers may be useful for risk stratifying patients undergoing cardiac surgery. PMID:25755241

  3. Vortex Formation Time in Progression of Cardiac Dysfunction

    NASA Astrophysics Data System (ADS)

    Kheradvar, Arash; Gharib, Morteza

    2008-11-01

    We previously showed that the trans-mitral vortex formation is affected by functionality of the cardiac left ventricle (LV). Additionally, we showed that in a healthy heart, the vortex formation time (VFT) closely follows the suggested values obtained in vitro by Gharib et al. Here, we assess the changes in VFT during the progress of cardiac dysfunction. In LV, the VFT can be independently derived from volumetric parameters and the ventricular ejection fraction (EF): [ VFT=4(1-β)π.α^3.EF ] where β is the contribution of atrial contraction phase to the LV stroke volume, and α is the ratio of the cubic root of LV end-diastolic volume to the effective mitral valve area diameter. Thus, α^3 is considered a non-dimensional measure for LV geometry. Substituting the values of α, β and EF obtained from patients in different stages of diastolic dysfunction into VFT equation would result in distinct range of VFT for each stage. This equation is also attributable to systolic dysfunction where EF has a significant contribution. Accordingly, by comparing the value of VFT during the progression of cardiac dysfunction, VFT can be considered as a factor that determines the deterioration of LV function, either from systolic and/or diastolic origin.

  4. Cathepsin K knockout alleviates aging-induced cardiac dysfunction.

    PubMed

    Hua, Yinan; Robinson, Timothy J; Cao, Yongtao; Shi, Guo-Ping; Ren, Jun; Nair, Sreejayan

    2015-06-01

    Aging is a major risk factor for cardiovascular disease. It has previously been shown that protein levels of cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age-dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca(2+) properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca(2+) release compared to young (6-month-old) mice, which were attenuated in the cathepsin K knockout mice. Cellular markers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged-cathepsin K knockout mice compared to their wild-type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin-induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis. PMID:25692548

  5. Cathepsin K knockout alleviates aging-induced cardiac dysfunction

    PubMed Central

    Hua, Yinan; Robinson, Timothy J; Cao, Yongtao; Shi, Guo-Ping; Ren, Jun; Nair, Sreejayan

    2015-01-01

    Aging is a major risk factor for cardiovascular disease. It has previously been shown that protein levels of cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age-dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca2+ properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca2+ release compared to young (6-month-old) mice, which were attenuated in the cathepsin K knockout mice. Cellular markers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged-cathepsin K knockout mice compared to their wild-type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin-induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis. PMID:25692548

  6. Cathepsin K knockout alleviates aging-induced cardiac dysfunction.

    PubMed

    Hua, Yinan; Robinson, Timothy J; Cao, Yongtao; Shi, Guo-Ping; Ren, Jun; Nair, Sreejayan

    2015-06-01

    Aging is a major risk factor for cardiovascular disease. It has previously been shown that protein levels of cathepsin K, a lysosomal cysteine protease, are elevated in the failing heart and that genetic ablation of cathepsin K protects against pressure overload-induced cardiac hypertrophy and contractile dysfunction. Here we test the hypothesis that cathepsin K knockout alleviates age-dependent decline in cardiac function. Cardiac geometry, contractile function, intracellular Ca(2+) properties, and cardiomyocyte apoptosis were evaluated using echocardiography, fura-2 technique, immunohistochemistry, Western blot and TUNEL staining, respectively. Aged (24-month-old) mice exhibited significant cardiac remodeling (enlarged chamber size, wall thickness, myocyte cross-sectional area, and fibrosis), decreased cardiac contractility, prolonged relengthening along with compromised intracellular Ca(2+) release compared to young (6-month-old) mice, which were attenuated in the cathepsin K knockout mice. Cellular markers of senescence, including cardiac lipofuscin, p21 and p16, were lower in the aged-cathepsin K knockout mice compared to their wild-type counterpart. Mechanistically, cathepsin K knockout mice attenuated an age-induced increase in cardiomyocyte apoptosis and nuclear translocation of mitochondrial apoptosis-inducing factor (AIF). In cultured H9c2 cells, doxorubicin stimulated premature senescence and apoptosis. Silencing of cathepsin K blocked the doxorubicin-induced translocation of AIF from the mitochondria to the nuclei. Collectively, these results suggest that cathepsin K knockout attenuates age-related decline in cardiac function via suppressing caspase-dependent and caspase-independent apoptosis.

  7. Primary proteasome inhibition results in cardiac dysfunction

    PubMed Central

    Herrmann, Joerg; Wohlert, Christine; Saguner, Ardan M.; Flores, Ana; Nesbitt, Lisa L.; Chade, Alejandro; Lerman, Lilach O.; Lerman, Amir

    2013-01-01

    Aims The proteasome prevents the intracellular accumulation of proteins and its impairment can lead to structural and functional alterations, as noted for the coronary vasculature in a previous study. Utilizing the same model, this study was designed to test the hypothesis that chronic proteasome inhibition (PSI) also leads to structural and functional changes of the heart. Methods and results Female domestic pigs were randomized to a normal diet without (N) or with twice-weekly subcutaneous injections of the proteasome inhibitor MLN-273 (0.08 mg/kg, N + PSI, n = 5 each group). In vivo data on cardiac structure and function as well as myocardial perfusion and microvascular permeability response to adenosine and dobutamine were obtained by electron beam computed tomography after 11 weeks. Subsequent ex vivo myocardial analyses included immunoblotting, immunostaining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labelling), Masson trichrome, and Congo red staining. Compared with N, an increase in LV mass was observed in N + PSI (106.5 ± 16.4 g vs. 183.1 ± 24.2 g, P < 0.05). The early to late diastolic filling ratio was increased in N + PSI vs. N (3.5 ± 0.6 vs. 1.8 ± 0.1, P < 0.05). The EF tended to be lower (46 ± 12% and 53 ± 9%, respectively) and cardiac output was significantly lower in N + PSI than in N (2.9 ± 1.1 vs. 4.7 ± 1.1 L/min, P < 0.05). Tissue analyses demonstrated an accumulation of proteasome substrates, apoptosis, and fibrosis in the PSI group. Compared with N, the myocardial perfusion response was reduced and microvascular permeability was increased in N + PSI. Conclusion The current study demonstrates that chronic proeasome inhibition affects the cardiovascular system, leading to functional and structural alteration of the heart consistent with a hypertrophic–restrictive cardiomyopathy phenotype. PMID:23616520

  8. Testosterone deprivation accelerates cardiac dysfunction in obese male rats.

    PubMed

    Pongkan, Wanpitak; Pintana, Hiranya; Sivasinprasasn, Sivaporn; Jaiwongkam, Thidarat; Chattipakorn, Siriporn C; Chattipakorn, Nipon

    2016-06-01

    Low testosterone level is associated with increased risks of cardiovascular diseases. As obese-insulin-resistant condition could impair cardiac function and that the incidence of obesity is increased in aging men, a condition of testosterone deprivation could aggravate the cardiac dysfunction in obese-insulin-resistant subjects. However, the mechanism underlying this adverse effect is unclear. This study investigated the effects of obesity on metabolic parameters, heart rate variability (HRV), left ventricular (LV) function, and cardiac mitochondrial function in testosterone-deprived rats. Orchiectomized or sham-operated male Wistar rats (n=36per group) were randomly divided into groups and were given either a normal diet (ND, 19.77% of energy fat) or a high-fat diet (HFD, 57.60% of energy fat) for 12weeks. Metabolic parameters, HRV, LV function, and cardiac mitochondrial function were determined at 4, 8, and 12weeks after starting each feeding program. We found that insulin resistance was observed after 8weeks of the consumption of a HFD in both sham (HFS) and orchiectomized (HFO) rats. Neither the ND sham (NDS) group nor ND orchiectomized (NDO) rats developed insulin resistance. The development of depressed HRV, LV contractile dysfunction, and increased cardiac mitochondrial reactive oxygen species production was observed earlier in orchiectomized (NDO and HFO) rats at week 4, whereas HFS rats exhibited these impairments later at week 8. These findings suggest that testosterone deprivation accelerates the impairment of cardiac autonomic regulation and LV function via increased oxidative stress and impaired cardiac mitochondrial function in obese-orchiectomized male rats. PMID:27000685

  9. [Early detection of cancer therapeutics-related cardiac dysfunction].

    PubMed

    Potier, Agathe; Ederhy, Stéphane; Ancedy, Yann; Etienney, Arnaud; Soulat-Dufour, Laurie; Chauvet, Marion; Hollebecque, Antoine; Adavane-Scheuble, Saroumadi; Boccara, Franck; Soria, Jean-Charles; Cohen, Ariel

    2016-01-01

    Anthracyclines and molecular targeted agents have improved prognosis of patients undergoing chemotherapeutics for malignancy. However, the use of these therapies is limited because of risk of cardiac toxicity. The severity of the cardiomyopathy can range from an asymptomatic left ventricular (LV) dysfunction to a severe congestive heart failure. Cardiomyopathy can be reversible or irreversible according to the type of chemotherapy, modality of administration and patient's characteristics. Several studies aimed to early detection and the evaluation of tools to characterize patients at risk to develop cardiac side effects in order to prevent severe LV dysfunction. According to this literature, it is recommended that initial assessment and follow-up of patients undergoing these chemotherapies be performed using troponin dosage, assessment of left ventricle ejection fraction and evaluation of LV myocardial deformation assessing LV global longitudinal strain. PMID:27417336

  10. A porcine model for acute ischaemic right ventricular dysfunction

    PubMed Central

    Haraldsen, Pernille; Lindstedt, Sandra; Metzsch, Carsten; Algotsson, Lars; Ingemansson, Richard

    2014-01-01

    OBJECTIVES To establish an experimental model for acute ischaemic isolated right ventricular dysfunction and the subsequent haemodynamic changes. METHODS An open-chest porcine model with ischaemic dysfunction of the right ventricle induced by ligation of the three main branches supporting the right ventricular free wall. Invasive monitoring of mean arterial blood pressure (MAP), central venous pressure (CVP), left atrial pressure (LAP) and right ventricular pressure (RVP); ultrasonic measurement of cardiac output (CO) and calculation of haemodynamic parameters such as stroke volume (SV), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR) and right ventricular stroke work (RVSW) using standard formulae. RESULTS The ischaemic challenge to the right ventricle resulted in a significant (≥30%) reduction in RVSW associated with an increase (6–25%) in CVP and reduction (8–18%) in pulmonary artery pressure (PAP) despite unchanged PVR, all reflecting the failing right ventricle. There was also a significant drop in CO (14–22%) despite unchanged LAP indicating lessened transpulmonary delivery of left ventricular preload due to the failing right ventricle causing the haemodynamic compromise rather than left ventricular failure. Supraventricular and ventricular arrhythmias occurred in three and two out of seven pigs, respectively—all of which except one were successfully resuscitated with cardioversion and/or defibrillation. CONCLUSIONS This novel open-chest porcine model of induced ischaemia of the right ventricular free wall resulted in significant haemodynamic compromise confirmed using standard haemodynamic measurements making it useful for further research on acute, ischaemic isolated right ventricular failure. PMID:24092465

  11. Cardiac Sympathetic Afferent Denervation Attenuates Cardiac Remodeling and Improves Cardiovascular Dysfunction in Rats with Heart Failure

    PubMed Central

    Wang, Han-Jun; Wang, Wei; Cornish, Kurtis G.; Rozanski, George J.; Zucker, Irving H.

    2014-01-01

    The enhanced cardiac sympathetic afferent reflex (CSAR) contributes to the exaggerated sympatho-excitation in chronic heart failure (CHF). Increased sympatho-excitation is positively related to mortality in CHF patients. However, the potential beneficial effects of chronic CSAR deletion on cardiac and autonomic function in CHF have not been previously explored. Here we determined the effects of chronic CSAR deletion on cardiac remodeling and autonomic dysfunction in CHF. In order to selectively delete the transient receptor potential vanilloid 1 receptor (TRPV1) -expressing CSAR afferents, epicardial application of resiniferatoxin (RTX, 50 μg/ml), an ultrapotent analogue of capsaicin, was performed during myocardium infarction (MI) surgery in rats. This procedure largely abolished the enhanced CSAR, prevented the exaggerated renal and cardiac sympathetic nerve activity and improved baroreflex sensitivity in CHF rats. Most importantly, we found that epicardial application of RTX largely prevented the elevated LVEDP, lung edema and cardiac hypertrophy, partially reduced left ventricular dimensions in the failing heart and increased cardiac contractile reserve in response to β-adrenergic receptor stimulation with isoproterenol in CHF rats. Molecular evidence showed that RTX attenuated cardiac fibrosis and apoptosis and reduced expression of fibrotic markers and TGF β-receptor I in CHF rats. Pressure - volume loop analysis showed that RTX reduced the end diastolic pressure volume relations in CHF rats indicating improved cardiac compliance. In summary, cardiac sympathetic afferent deletion exhibits protective effects against deleterious cardiac remodeling and autonomic dysfunction in CHF. These data suggest a potential new paradigm and therapeutic potential in the management of CHF. PMID:24980663

  12. Cardiac Dysfunction during Exercise in Uncomplicated Type 2 Diabetes

    PubMed Central

    REGENSTEINER, JUDITH G.; BAUER, TIMOTHY A.; REUSCH, JANE E. B.; QUAIFE, ROBERT A.; CHEN, MARCUS Y.; SMITH, SUSAN C.; MILLER, TYLER M.; GROVES, BERTRON M.; WOLFEL, EUGENE E.

    2010-01-01

    Purpose Type 2 diabetes mellitus (T2DM) has been associated with reduced peak exercise capacity (V̇O2peak). The causes of this impairment are not clearly established, but evidence suggests that abnormalities in cardiac function play a significant role. We hypothesized that exercise would be associated with impaired cardiac function and hemodynamics in recently diagnosed T2DM, even in the absence of clinically evident cardiovascular complications. Methods After baseline normal echocardiography screening, 10 premenopausal women with uncomplicated T2DM (average duration of diagnosed T2DM, 3.6 yr) and 10 healthy nondiabetic women of similar age, weight, and activity levels performed a peak cardiopulmonary exercise test while instrumented with an indwelling pulmonary artery catheter for assessing cardiac function. On separate days, technetium-99m sestamibi (cardolite) imaging was performed to assess myocardial perfusion at rest and peak exercise in seven T2DM and seven control patients. Results Resting measures of cardiac hemodynamics were similar in T2DM and control subjects. Absolute V̇O2peak (mL·min−1) and peak cardiac output (L·min−1) tended to be lower in T2DM than in control subjects but did not reach statistical significance. However, pulmonary capillary wedge pressure (PCWP) rose significantly more during exercise in T2DM than in controls (148% vs 109% increase at peak exercise, P < 0.01). Normalized myocardial perfusion index was lower in persons with diabetes than in controls (11.0 ± 3.5 × e−9 vs 17.5 ± 8.1 × e−9, respectively, P < 0.05) and inversely related to peak exercise PCWP (R = −0.56, P < 0.05). Conclusions Cardiac hemodynamics during graded exercise are altered in women with recently diagnosed T2DM as demonstrated by the disproportionate increase in PCWP at peak exercise compared with controls subjects. Cardiac abnormalities observed are potentially early signs of subclinical cardiac dysfunction associated with T2DM, which may

  13. Cardiac acetylcholine inhibits ventricular remodeling and dysfunction under pathologic conditions.

    PubMed

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

    2016-02-01

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

  14. Decreased Polycystin 2 Levels Result in Non-Renal Cardiac Dysfunction with Aging.

    PubMed

    Kuo, Ivana Y; Duong, Sophie L; Nguyen, Lily; Ehrlich, Barbara E

    2016-01-01

    Mutations in the gene for polycystin 2 (Pkd2) lead to polycystic kidney disease, however the main cause of mortality in humans is cardiac related. We previously showed that 5 month old Pkd2+/- mice have altered calcium-contractile activity in cardiomyocytes, but have preserved cardiac function. Here, we examined 1 and 9 month old Pkd2+/- mice to determine if decreased amounts of functional polycystin 2 leads to impaired cardiac function with aging. We observed changes in calcium handling proteins in 1 month old Pkd2+/- mice, and these changes were exacerbated in 9 month old Pkd2+/- mice. Anatomically, the 9 month old Pkd2+/- mice had thinner left ventricular walls, consistent with dilated cardiomyopathy, and the left ventricular ejection fraction was decreased. Intriguingly, in response to acute isoproterenol stimulation to examine β-adrenergic responses, the 9 month old Pkd2+/- mice exhibited a stronger contractile response, which also coincided with preserved localization of the β2 adrenergic receptor. Importantly, the Pkd2+/- mice did not have any renal impairment. We conclude that the cardiac-related impact of decreased polycystin 2 progresses over time towards cardiac dysfunction and altered adrenergic signaling. These results provide further evidence that polycystin 2 provides a critical function in the heart, independent of renal involvement. PMID:27081851

  15. Angiotensin II Induced Cardiac Dysfunction on a Chip

    PubMed Central

    Horton, Renita E.; Yadid, Moran; McCain, Megan L.; Sheehy, Sean P.; Pasqualini, Francesco S.; Park, Sung-Jin; Cho, Alexander; Campbell, Patrick; Parker, Kevin Kit

    2016-01-01

    In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics. PMID:26808388

  16. Angiotensin II Induced Cardiac Dysfunction on a Chip.

    PubMed

    Horton, Renita E; Yadid, Moran; McCain, Megan L; Sheehy, Sean P; Pasqualini, Francesco S; Park, Sung-Jin; Cho, Alexander; Campbell, Patrick; Parker, Kevin Kit

    2016-01-01

    In vitro disease models offer the ability to study specific systemic features in isolation to better understand underlying mechanisms that lead to dysfunction. Here, we present a cardiac dysfunction model using angiotensin II (ANG II) to elicit pathological responses in a heart-on-a-chip platform that recapitulates native laminar cardiac tissue structure. Our platform, composed of arrays of muscular thin films (MTF), allows for functional comparisons of healthy and diseased tissues by tracking film deflections resulting from contracting tissues. To test our model, we measured gene expression profiles, morphological remodeling, calcium transients, and contractile stress generation in response to ANG II exposure and compared against previous experimental and clinical results. We found that ANG II induced pathological gene expression profiles including over-expression of natriuretic peptide B, Rho GTPase 1, and T-type calcium channels. ANG II exposure also increased proarrhythmic early after depolarization events and significantly reduced peak systolic stresses. Although ANG II has been shown to induce structural remodeling, we control tissue architecture via microcontact printing, and show pathological genetic profiles and functional impairment precede significant morphological changes. We assert that our in vitro model is a useful tool for evaluating tissue health and can serve as a platform for studying disease mechanisms and identifying novel therapeutics.

  17. Cardiac surgery-associated acute kidney injury.

    PubMed

    Mao, Huijuan; Katz, Nevin; Ariyanon, Wassawon; Blanca-Martos, Lourdes; Adýbelli, Zelal; Giuliani, Anna; Danesi, Tommaso Hinna; Kim, Jeong Chul; Nayak, Akash; Neri, Mauro; Virzi, Grazia Maria; Brocca, Alessandra; Scalzotto, Elisa; Salvador, Loris; Ronco, Claudio

    2013-10-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a common and serious postoperative complication of cardiac surgery requiring cardiopulmonary bypass (CPB), and it is the second most common cause of AKI in the intensive care unit. Although the complication has been associated with the use of CPB, the etiology is likely multifactorial and related to intraoperative and early postoperative management including pharmacologic therapy. To date, very little evidence from randomized trials supporting specific interventions to protect from or prevent AKI in broad cardiac surgery populations has been found. The definition of AKI employed by investigators influences not only the incidence of CSA-AKI, but also the identification of risk variables. The advent of novel biomarkers of kidney injury has the potential to facilitate the subclinical diagnosis of CSA-AKI, the assessment of its severity and prognosis, and the early institution of interventions to prevent or reduce kidney damage. Further studies are needed to determine how to optimize cardiac surgical procedures, CPB parameters, and intraoperative and early postoperative blood pressure and renal blood flow to reduce the risk of CSA-AKI. No pharmacologic strategy has demonstrated clear efficacy in the prevention of CSA-AKI; however, some agents, such as the natriuretic peptide nesiritide and the dopamine agonist fenoldopam, have shown promising results in renoprotection. It remains unclear whether CSA-AKI patients can benefit from the early institution of such pharmacologic agents or the early initiation of renal replacement therapy. PMID:24454314

  18. Immune dysfunction in acute alcoholic hepatitis

    PubMed Central

    Dhanda, Ashwin D; Collins, Peter L

    2015-01-01

    Acute alcoholic hepatitis (AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates the immune system primarily through the disruption of gut tight junction integrity allowing the escape of pathogen-associated molecular particles (PAMPs) into the portal venous system. PAMPs stimulate cells expressing toll-like receptors (mainly myeloid derived cells) and initiate a network of intercellular signalling by secretion of many soluble mediators including cytokines and chemokines. The latter coordinates the infiltration of neutrophils, monocytes and T cells and results in hepatic stellate cell activation, cellular damage and hepatocyte death by necrosis or apoptosis. On the converse of this immune activation is the growing evidence of impaired microbial defence. Neutrophils have reduced phagocytic capacity and oxidative burst and there is recent evidence that T cell exhaustion plays a role in this. PMID:26576079

  19. Cardiac dysfunction in patients seropositive for the human immunodeficiency virus.

    PubMed Central

    Johnson, J. E.; Slife, D. M.; Anders, G. T.; Bailey, S. R.; Blanton, H. M.; McAllister, C. K.; Latham, R. D.

    1991-01-01

    To confirm the presence of cardiac dysfunction in a group of patients seropositive for the human immunodeficiency virus with either dyspnea on exertion or a reduced anaerobic threshold, 9 patients with no history of opportunistic infection underwent exercise right-sided heart catheterization. When compared with 13 control patients previously exercised in the same manner, the patients showed elevated exercise pulmonary capillary wedge pressure (14.6 +/- 3.3 mm of mercury versus 9.9 +/- 3.3 mm of mercury; P less than .005) and right atrial pressure (10.1 +/- 2.1 mm of mercury versus 4.7 +/- 3.2 mm of mercury; P less than .001) at a similar exercise oxygen consumption and cardiac index. Of the 9 patients, 8 had at least 1 catheterization value outside the 95% confidence limits for the control group and 4 patients had multiple abnormalities. Values for blood CD4 lymphocytes were 0.2 x 10(9) per liter or more for 7 of the 9. One patient underwent endomyocardial biopsy with findings consistent with a cardiomyopathy. We conclude that cardiac disease may occur at any immunologic stage of human immunodeficiency virus infection. These observations suggest an effect of this disease on the heart. Images PMID:1771874

  20. NOD1 Activation Induces Cardiac Dysfunction and Modulates Cardiac Fibrosis and Cardiomyocyte Apoptosis

    PubMed Central

    Fernández-Velasco, María; Prieto, Patricia; Terrón, Verónica; Benito, Gemma; Flores, Juana M.; Delgado, Carmen; Zaragoza, Carlos; Lavin, Begoña; Gómez-Parrizas, Mónica; López-Collazo, Eduardo; Martín-Sanz, Paloma; Boscá, Lisardo

    2012-01-01

    The innate immune system is responsible for the initial response of an organism to potentially harmful stressors, pathogens or tissue injury, and accordingly plays an essential role in the pathogenesis of many inflammatory processes, including some cardiovascular diseases. Toll like receptors (TLR) and nucleotide-binding oligomerization domain-like receptors (NLRs) are pattern recognition receptors that play an important role in the induction of innate immune and inflammatory responses. There is a line of evidence supporting that activation of TLRs contributes to the development and progression of cardiovascular diseases but less is known regarding the role of NLRs. Here we demonstrate the presence of the NLR member NOD1 (nucleotide-binding oligomerization domain containing 1) in the murine heart. Activation of NOD1 with the specific agonist C12-iEDAP, but not with the inactive analogue iE-Lys, induces a time- and dose-dependent cardiac dysfunction that occurs concomitantly with cardiac fibrosis and apoptosis. The administration of iEDAP promotes the activation of the NF-κB and TGF-β pathways and induces apoptosis in whole hearts. At the cellular level, both native cardiomyocytes and cardiac fibroblasts expressed NOD1. The NLR activation in cardiomyocytes was associated with NF-κB activation and induction of apoptosis. NOD1 stimulation in fibroblasts was linked to NF-κB activation and to increased expression of pro-fibrotic mediators. The down-regulation of NOD1 by specific siRNAs blunted the effect of iEDAP on the pro-fibrotic TGF-β pathway and cell apoptosis. In conclusion, our report uncovers a new pro-inflammatory target that is expressed in the heart, NOD1. The specific activation of this NLR induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis, pathological processes involved in several cardiac diseases such as heart failure. PMID:23028889

  1. Cardiac Arrhythmias and Abnormal Electrocardiograms After Acute Stroke.

    PubMed

    Ruthirago, Doungporn; Julayanont, Parunyou; Tantrachoti, Pakpoom; Kim, Jongyeol; Nugent, Kenneth

    2016-01-01

    Cardiac arrhythmias and electrocardiogram (ECG) abnormalities occur frequently but are often underrecognized after strokes. Acute ischemic and hemorrhagic strokes in some particular area of brain can disrupt central autonomic control of the heart, precipitating cardiac arrhythmias, ECG abnormalities, myocardial injury and sometimes sudden death. Identification of high-risk patients after acute stroke is important to arrange appropriate cardiac monitoring and effective management of arrhythmias, and to prevent cardiac morbidity and mortality. More studies are needed to better clarify pathogenesis, localization of areas associated with arrhythmias and practical management of arrhythmias and abnormal ECGs after acute stroke.

  2. Differential contribution of clinical amounts of acetaldehyde to skeletal and cardiac muscle dysfunction in alcoholic myopathy.

    PubMed

    Oba, Toshiharu; Maeno, Yoshitaka; Ishida, Kazuto

    2005-01-01

    Acute intoxication due to alcohol consumption has been known to elicit reversible skeletal and cardiac muscle dysfunction, or "alcoholic myopathy and cardiomyopathy". Sometimes, irreversible muscle damage can be induced after heavy alcohol drinking. Many researchers have proposed that acetaldehyde, the major oxidised product of alcohol, may be a primary factor underlying alcohol-induced muscle dysfunction. Because acetaldehyde is rapidly metabolised to acetate by aldehyde dehydrogenase (ALDH) mainly in the liver, blood concentration of acetaldehyde is maintained at a low level even after heavy alcohol intoxication. In alcoholics, blood acetaldehyde level is relatively high, probably due to hepatic inhibition of ALDH activity. Several mM of acetaldehyde have been used for studies of cardiac muscle contraction, the intracellular calcium transient, and the L-type calcium channel. In skeletal muscle, the calcium release channel/ryanodine receptor activity has been reported to be inhibited by exposure to 1 mM acetaldehyde. However, these observations were made using potentially lethal concentrations of acetaldehyde, so the hypothesis that acetaldehyde plays a crucial role on alcoholic myopathy is questionable. In this review, we will summarise the effect of alcohol and its major oxidised product, acetaldehyde, on skeletal and heart muscles and propose a toxic contribution of clinical concentrations of acetaldehyde to alcoholic myopathy. In addition, this review will include briefly the effect of acetaldehyde on diabetic cardiomyopathy.

  3. Mesenteric lymph duct ligation prevents trauma/hemorrhage shock-induced cardiac contractile dysfunction

    PubMed Central

    Sambol, Justin T.; Lee, Marlon A.; Caputo, Francis J.; Kawai, Kentaro; Badami, Chirag; Kawai, Tomoko; Deitch, Edwin A.; Yatani, Atsuko

    2009-01-01

    Clinical and experimental studies have shown that trauma combined with hemorrhage shock (T/HS) is associated with myocardial contractile dysfunction. However, the initial events triggering the cardiac dysfunction are not fully elucidated. Thus we tested the hypothesis that factors carried in intestinal (mesenteric) lymph contribute to negative inotropic effects in rats subjected to a laparotomy (T) plus hemorrhagic shock (HS; mean arterial blood pressure of 30–40 Torr for 90 min) using a Langendorff isolated heart preparation. Left ventricular (LV) function was assessed 24 h after trauma plus sham shock (T/SS) or T/HS by recording the LV developed pressure (LVDP) and the maximal rate of LVDP rise and fall ( ± dP/dtmax) in five groups of rats: 1) naive noninstrumented rats, 2) rats subjected to T/SS, 3) rats subjected to T/HS, 4) rats subjected to T/SS with mesenteric lymph duct ligation (T/SS+LDL), or 5) rats subjected to T/HS+LDL. Cardiac function was comparable in hearts from naive, T/SS, and T/SS+LDL rats. Both LVDP and ± dP/dtmax were significantly depressed after T/HS. The T/HS hearts also manifested a blunted responsiveness to increases in coronary flow rates and Ca2+, and this was prevented by LDL preceding T/HS. Although electrocardiograms were normal under physiological conditions, when the T/HS hearts were perfused with low Ca2+ levels (∼0.5 mM), prolonged P-R intervals and second-degree plus Wenckebach-type atrioventricular blocks were observed. No such changes occurred in the control or T/HS+LDL hearts. The effects of T/HS were similar to those of the Ca2+ channel antagonist diltiazem, indicating that an impairment of cellular Ca2+ handling contributes to T/HS-induced cardiac dysfunction. In conclusion, gut-derived factors carried in mesenteric lymph are responsible for acute T/HS-induced cardiac dysfunction. PMID:19008486

  4. Cardiac surgery-associated acute kidney injury

    PubMed Central

    Ortega-Loubon, Christian; Fernández-Molina, Manuel; Carrascal-Hinojal, Yolanda; Fulquet-Carreras, Enrique

    2016-01-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is a well-recognized complication resulting with the higher morbid-mortality after cardiac surgery. In its most severe form, it increases the odds ratio of operative mortality 3–8-fold, length of stay in the Intensive Care Unit and hospital, and costs of care. Early diagnosis is critical for an optimal treatment of this complication. Just as the identification and correction of preoperative risk factors, the use of prophylactic measures during and after surgery to optimize renal function is essential to improve postoperative morbidity and mortality of these patients. Cardiopulmonary bypass produces an increased in tubular damage markers. Their measurement may be the most sensitive means of early detection of AKI because serum creatinine changes occur 48 h to 7 days after the original insult. Tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 are most promising as an early diagnostic tool. However, the ideal noninvasive, specific, sensitive, reproducible biomarker for the detection of AKI within 24 h is still not found. This article provides a review of the different perspectives of the CSA-AKI, including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment. We searched the electronic databases, MEDLINE, PubMed, EMBASE using search terms relevant including pathogenesis, risk factors, diagnosis, biomarkers, classification, postoperative management, and treatment, in order to provide an exhaustive review of the different perspectives of the CSA-AKI. PMID:27716701

  5. Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction.

    PubMed

    Wood, David M; Dargan, Paul I; Hoffman, Robert S

    2009-01-01

    Cocaine use is common in many areas of the world, particularly the United States and Western Europe. Toxicity following the use of cocaine is associated with a wide range of clinical features. In this review, we will focus on the cocaine-associated cardiac arrhythmias and, in particular, some of the controversies in their etiology and management. Cocaine can produce arrhythmias either through the production of myocardial ischemia or as a direct result of ion channel alterations. Excessive catecholamines, combined with sodium and potassium channel blockades, give rise to a wide variety of supra-ventricular and ventricular rhythms. The animal and human evidence for ion channel dysfunction is reviewed, and the effects of catecholamines are followed from the cardiac action potential to the development of arrhythmias. Finally, theoretical constructs are combined with existing evidence to develop a rational treatment strategy for patients with cocaine-induced cardiac arrhythmias. In particular, we review the evidence concerning the controversies relating to the use of lidocaine in comparison with sodium bicarbonate, in terms of QRS prolongation secondary to sodium channel blockade.

  6. Cardiac BMIPP imaging in acute myocardial infarction.

    PubMed

    Nakata, T; Hashimoto, A; Eguchi, M

    1999-02-01

    Fatty acid metabolism functions as a major energy-producing system under aerobic conditions, but it is impaired immediately after myocardial ischaemia. This imaging can provide intracellular information which cannot be obtained by angiographical, perfusional or functional analysis. 123I-BMIPP and perfusion imagings in patients with acute myocardial infarction have demonstrated three different correlations between myocardial perfusion and fatty acid metabolism: concordant defects of perfusion and BMIPP which represent scar or non-viable tissue; lower BMIPP uptake relative to perfusion (perfusion-BMIPP mismatch) which implicates metabolically damaged, often dysynergic, but viable myocardium; and equivalently normal uptakes of perfusion and BMIPP in completely salvaged myocardium. Identification of these perfusion-metabolism correlations contributes to the detection of ischaemia-related myocardial injury in viable and non-viable myocardium, to the prediction of post-ischaemic or post-interventional functional recovery and to the identification of patients who have myocardium at ischaemic risk. Further clinical investigations might reveal more clearly the pathophysiological and prognostic implications of cardiac BMIPP imaging in patients with acute myocardial infarction.

  7. Acute dysfunction of Starr-Edwards mitral prostheses

    PubMed Central

    Gunstensen, John

    1971-01-01

    Four cases of acute dysfunction of Starr-Edwards mitral prostheses are recorded. The patients presented with sudden dysponea 4 to 18 months after apparently successful mitral valve replacement. The prosthetic valve dysfunction was caused by thrombus on the bare metal cage of the prosthesis. No warning thromboembolic phenomena had been recorded. Urgent replacement of the valve resulted in the survival of one patient. Images PMID:5576532

  8. Hydrogen Sulfide Attenuates High Fat Diet-Induced Cardiac Dysfunction via the Suppression of Endoplasmic Reticulum Stress

    PubMed Central

    Barr, Larry A.; Shimizu, Yuuki; Lambert, Jonathan P.; Nicholson, Chad K.; Calvert, John W.

    2015-01-01

    Diabetic cardiomyopathy is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. However, the underlying molecular mechanisms that lead to its development have not been fully elucidated. Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that is critical for the regulation of cardiovascular homeostasis. Recently, therapeutic strategies aimed at increasing its levels have proven cardioprotective in models of acute myocardial ischemia-reperfusion injury and heart failure. The precise role of H2S in the pathogenesis of diabetic cardiomyopathy has not yet been established. Therefore, the goal of the present study was to evaluate circulating and cardiac H2S levels in a murine model of high fat diet (HFD)-induced cardiomyopathy. Diabetic cardiomyopathy was produced by feeding mice HFD (60% fat) chow for 24 weeks. HFD feeding reduced both circulating and cardiac H2S and induced hallmark features of type-2 diabetes. We also observed marked cardiac dysfunction, evidence of cardiac enlargement, cardiac hypertrophy, and fibrosis. H2S therapy (SG-1002, an orally active H2S donor) restored sulfide levels, improved some of the metabolic perturbations stemming from HFD feeding, and attenuated HFD-induced cardiac dysfunction. Additional analysis revealed that H2S therapy restored adiponectin levels and suppressed cardiac ER stress stemming from HFD feeding. These results suggest that diminished circulating and cardiac H2S levels play a role in the pathophysiology of HFD-induced cardiomyopathy. Additionally, these results suggest that H2S therapy may be of clinical importance in the treatment of cardiovascular complications stemming from diabetes. PMID:25575644

  9. The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction

    EPA Science Inventory

    Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease and cardiac dysfunction ha...

  10. Diminazene Aceturate Improves Cardiac Fibrosis and Diastolic Dysfunction in Rats with Kidney Disease

    PubMed Central

    Velkoska, Elena; Patel, Sheila K.; Griggs, Karen

    2016-01-01

    Angiotensin converting enzyme (ACE) 2 is a negative regulator of the renin angiotensin system (RAS) through its role to degrade angiotensin II. In rats with subtotal nephrectomy (STNx), adverse cardiac remodelling occurs despite elevated cardiac ACE2 activity. We hypothesised that diminazene aceturate (DIZE), which has been described as having an off-target effect to activate ACE2, would have beneficial cardiac effects in STNx rats. STNx led to hypertension, diastolic dysfunction, left ventricular hypertrophy, cardiac fibrosis, and increased cardiac ACE, ACE2, Ang II and Ang 1–7 levels. Cardiac gene expression of ADAM17 was also increased. In STNx, two-weeks of subcutaneous DIZE (15mg/kg/d) had no effect on blood pressure but improved diastolic dysfunction and cardiac fibrosis, reduced ADAM17 mRNA and shifted the cardiac RAS balance to a cardioprotective profile with reduced ACE and Ang II. There was no change in cardiac ACE2 activity or in cardiac Ang 1–7 levels with DIZE. In conclusion, our results suggest that DIZE exerts a protective effect on the heart under the pathological condition of kidney injury. This effect was not due to improved kidney function, a fall in blood pressure or a reduction in LVH but was associated with a reduction in cardiac ACE and cardiac Ang II levels. As in vitro studies showed no direct effect of DIZE on ACE2 or ACE activity, the precise mechanism of action of DIZE remains to be determined. PMID:27571511

  11. Diminazene Aceturate Improves Cardiac Fibrosis and Diastolic Dysfunction in Rats with Kidney Disease.

    PubMed

    Velkoska, Elena; Patel, Sheila K; Griggs, Karen; Burrell, Louise M

    2016-01-01

    Angiotensin converting enzyme (ACE) 2 is a negative regulator of the renin angiotensin system (RAS) through its role to degrade angiotensin II. In rats with subtotal nephrectomy (STNx), adverse cardiac remodelling occurs despite elevated cardiac ACE2 activity. We hypothesised that diminazene aceturate (DIZE), which has been described as having an off-target effect to activate ACE2, would have beneficial cardiac effects in STNx rats. STNx led to hypertension, diastolic dysfunction, left ventricular hypertrophy, cardiac fibrosis, and increased cardiac ACE, ACE2, Ang II and Ang 1-7 levels. Cardiac gene expression of ADAM17 was also increased. In STNx, two-weeks of subcutaneous DIZE (15mg/kg/d) had no effect on blood pressure but improved diastolic dysfunction and cardiac fibrosis, reduced ADAM17 mRNA and shifted the cardiac RAS balance to a cardioprotective profile with reduced ACE and Ang II. There was no change in cardiac ACE2 activity or in cardiac Ang 1-7 levels with DIZE. In conclusion, our results suggest that DIZE exerts a protective effect on the heart under the pathological condition of kidney injury. This effect was not due to improved kidney function, a fall in blood pressure or a reduction in LVH but was associated with a reduction in cardiac ACE and cardiac Ang II levels. As in vitro studies showed no direct effect of DIZE on ACE2 or ACE activity, the precise mechanism of action of DIZE remains to be determined. PMID:27571511

  12. Cardiac Autonomic Dysfunction from Occupational Exposure to Polycyclic Aromatic Hydrocarbons

    PubMed Central

    Lee, Mi-Sun; Magari, Shannon; Christiani, David C.

    2013-01-01

    Objectives Polycyclic aromatic hydrocarbons (PAHs) exposures have been associated with cardiopulmonary mortality and cardiovascular events. This study investigated the association between a biological marker of PAHs exposure, assessed by urinary 1-hydroxypyrene (1-OHP), and heart rate variability (HRV) in an occupational cohort of boilermakers. Methods Continuous 24-hour monitoring of the ambulatory electrocardiogram (ECG) and pre and post shift urinary 1-OHP were repeated over extended periods of the work week. Mixed effects models were fit for the 5-minute standard deviation of normal-to-normal intervals (SDNN) in relation to urinary 1-OHP levels pre and post workshift on the day they wore the monitor, controlling for potential confounders. Results We found a significant decrease in 5-min SDNN during work of −13.6% (95% confidence interval, −17.2% to −9.8%) for every standard deviation (0.53 microgram/gram [μg/g] creatinine) increase in the next-morning pre-shift 1-OHP levels. The magnitude of reduction in 5-min SDNN were largest during the late night period after work and increased with every standard deviation (0.46 μg/g creatinine) increase in post-shift 1-OHP levels. Conclusion This is the first report providing evidence that occupational exposure to PAHs is associated with altered cardiac autonomic function. Acute exposure to PAHs may be an important predictor of cardiovascular disease risk in the work environment. PMID:21172795

  13. The heart as an extravascular target of endothelin-1 in particulate matter-induced cardiac dysfunction.

    PubMed

    Chan, Elizabeth A W; Buckley, Barbara; Farraj, Aimen K; Thompson, Leslie C

    2016-09-01

    Exposure to particulate matter air pollution has been causally linked to cardiovascular disease in humans. Several broad and overlapping hypotheses describing the biological mechanisms by which particulate matter exposure leads to cardiovascular disease have been explored, although linkage with specific factors or genes remains limited. These hypotheses may or may not also lead to particulate matter-induced cardiac dysfunction. Evidence pointing to autocrine/paracrine signaling systems as modulators of cardiac dysfunction has increased interest in the emerging role of endothelins as mediators of cardiac function following particulate matter exposure. Endothelin-1, a well-described small peptide expressed in the pulmonary and cardiovascular systems, is best known for its ability to constrict blood vessels, although it can also induce extravascular effects. Research on the role of endothelins in the context of air pollution has largely focused on vascular effects, with limited investigation of responses resulting from the direct effects of endothelins on cardiac tissue. This represents a significant knowledge gap in air pollution health effects research, given the abundance of endothelin receptors found on cardiac tissue and the ability of endothelin-1 to modulate cardiac contractility, heart rate, and rhythm. The plausibility of endothelin-1 as a mediator of particulate matter-induced cardiac dysfunction is further supported by the therapeutic utility of certain endothelin receptor antagonists. The present review examines the possibility that endothelin-1 release caused by exposure to PM directly modulates extravascular effects on the heart, deleteriously altering cardiac function.

  14. Acute and Chronic Allograft Dysfunction in Kidney Transplant Recipients.

    PubMed

    Goldberg, Ryan J; Weng, Francis L; Kandula, Praveen

    2016-05-01

    Allograft dysfunction after a kidney transplant is often clinically asymptomatic and is usually detected as an increase in serum creatinine level with corresponding decrease in glomerular filtration rate. The diagnostic evaluation may include blood tests, urinalysis, transplant ultrasonography, radionuclide imaging, and allograft biopsy. Whether it occurs early or later after transplant, allograft dysfunction requires prompt evaluation to determine its cause and subsequent management. Acute rejection, medication toxicity from calcineurin inhibitors, and BK virus nephropathy can occur early or later. Other later causes include transplant glomerulopathy, recurrent glomerulonephritis, and renal artery stenosis.

  15. Endothelial cells overexpressing IL-8 receptor reduce cardiac remodeling and dysfunction following myocardial infarction.

    PubMed

    Zhao, Xiangmin; Zhang, Wei; Xing, Dongqi; Li, Peng; Fu, Jinyan; Gong, Kaizheng; Hage, Fadi G; Oparil, Suzanne; Chen, Yiu-Fai

    2013-08-15

    The endothelium is a dynamic component of the cardiovascular system that plays an important role in health and disease. This study tested the hypothesis that targeted delivery of endothelial cells (ECs) overexpressing neutrophil membrane IL-8 receptors IL8RA and IL8RB reduces acute myocardial infarction (MI)-induced left ventricular (LV) remodeling and dysfunction and increases neovascularization in the area at risk surrounding the infarcted tissue. MI was created by ligating the left anterior descending coronary artery in 12-wk-old male Sprague-Dawley rats. Four groups of rats were studied: group 1: sham-operated rats without MI or EC transfusion; group 2: MI rats with intravenous vehicle; group 3: MI rats with transfused ECs transduced with empty adenoviral vector (Null-EC); and group 4: MI rats with transfused ECs overexpressing IL8RA/RB (1.5 × 10⁶ cells post-MI). Two weeks after MI, LV function was assessed by echocardiography; infarct size was assessed by triphenyltetrazolium chloride (live tissue) and picrosirus red (collagen) staining, and capillary density and neutrophil infiltration in the area at risk were measured by CD31 and MPO immunohistochemical staining, respectively. When compared with the MI + vehicle and MI-Null-EC groups, transfusion of IL8RA/RB-ECs decreased neutrophil infiltration and pro-inflammatory cytokine expression and increased capillary density in the area at risk, decreased infarct size, and reduced MI-induced LV dysfunction. These findings provide proof of principle that targeted delivery of ECs is effective in repairing injured cardiac tissue. Targeted delivery of ECs to infarcted hearts provides a potential novel strategy for the treatment of acute MI in humans.

  16. Neuroanatomical correlates of severe cardiac arrhythmias in acute ischemic stroke.

    PubMed

    Seifert, Frank; Kallmünzer, Bernd; Gutjahr, Isabell; Breuer, Lorenz; Winder, Klemens; Kaschka, Iris; Kloska, Stephan; Doerfler, Arnd; Hilz, Max-Josef; Schwab, Stefan; Köhrmann, Martin

    2015-05-01

    Neurocardiological interactions can cause severe cardiac arrhythmias in patients with acute ischemic stroke. The relationship between the lesion location in the brain and the occurrence of cardiac arrhythmias is still discussed controversially. The aim of the present study was to correlate the lesion location with the occurrence of cardiac arrhythmias in patients with acute ischemic stroke. Cardiac arrhythmias were systematically assessed in patients with acute ischemic stroke during the first 72 h after admission to a monitored stroke unit. Voxel-based lesion-symptom mapping (VLSM) was used to correlate the lesion location with the occurrence of clinically relevant severe arrhythmias. Overall 150 patients, 56 with right-hemispheric and 94 patients with a left-hemispheric lesion, were eligible to be included in the VLSM study. Severe cardiac arrhythmias were present in 49 of these 150 patients (32.7%). We found a significant association (FDR correction, q < 0.05) between lesions in the right insular, right frontal and right parietal cortex as well as the right amygdala, basal ganglia and thalamus and the occurrence of cardiac arrhythmias. Because left- and right-hemispheric lesions were analyzed separately, the significant findings rely on the 56 patients with right-hemispheric lesions. The data indicate that these areas are involved in central autonomic processing and that right-hemispheric lesions located to these areas are associated with an elevated risk for severe cardiac arrhythmias.

  17. Disruption of Sarcoendoplasmic Reticulum Calcium ATPase Function in Drosophila Leads to Cardiac Dysfunction

    PubMed Central

    Abraham, Dennis M.; Wolf, Matthew J.

    2013-01-01

    Abnormal sarcoendoplasmic reticulum Calcium ATPase (SERCA) function has been associated with poor cardiac function in humans. While modifiers of SERCA function have been identified and studied using animal models, further investigation has been limited by the absence of a model system that is amenable to large-scale genetic screens. Drosophila melanogaster is an ideal model system for the investigation of SERCA function due to the significant homology to human SERCA and the availability of versatile genetic screening tools. To further the use of Drosophila as a model for examining the role of SERCA in cardiac function, we examined cardiac function in adult flies. Using optical coherence tomography (OCT) imaging in awake, adult Drosophila, we have been able to characterize cardiac chamber dimensions in flies with disrupted in Drosophila SERCA (CaP60A). We found that the best studied CaP60A mutant, the conditional paralytic mutant CaP60Akum170, develops marked bradycardia and chamber enlargement that is closely linked to the onset of paralysis and dependent on extra cardiac CaP60A. In contrast to prior work, we show that disruption of CaP60A in a cardiac specific manner results in cardiac dilation and dysfunction rather than alteration in heart rate. In addition, the co-expression of a calcium release channel mutation with CaP60A kum170 is sufficient to rescue the cardiac phenotype but not paralysis. Finally, we show that CaP60A overexpression is able to rescue cardiac function in a model of Drosophila cardiac dysfunction similar to what is observed in mammals. Thus, we present a cardiac phenotype associated with Drosophila SERCA dysfunction that would serve as additional phenotyping for further large-scale genetic screens for novel modifiers of SERCA function. PMID:24098595

  18. Dysfunctional cognitive appraisal and psychophysiological reactivity in acute stress disorder.

    PubMed

    Elsesser, Karin; Freyth, Claudia; Lohrmann, Thomas; Sartory, Gudrun

    2009-10-01

    The present study investigated the extent of dysfunctional appraisal as measured with the Posttraumatic Cognitions Inventory (PTCI) and physiological responses to trauma-related material in patients with acute stress disorder (ASD; N=44) in comparison to participants without trauma exposure (N=27). Heart-rate (HR), skin conductance responses (SCR), and viewing time were recorded in response to - for trauma victims - idiosyncratically trauma-relevant and control pictures. ASD patients evidenced greater dysfunctional appraisal than control participants with regard to the PTCI scales Self and World and also an accelerative HR reaction and greater SCRs to trauma-relevant pictures. Among patients, PTCI was highly correlated with ASD severity while PTCI World was positively correlated with resting HR and depression. Amplitude of the HR reaction to trauma-related pictures was negatively correlated with viewing time. Results suggest that dysfunctional appraisal and autonomic reactivity are only loosely related in ASD.

  19. Cardiac overexpression of monocyte chemoattractant protein-1 in transgenic mice prevents cardiac dysfunction and remodeling after myocardial infarction.

    PubMed

    Morimoto, Hajime; Takahashi, Masafumi; Izawa, Atsushi; Ise, Hirohiko; Hongo, Minoru; Kolattukudy, Pappachan E; Ikeda, Uichi

    2006-10-13

    Myocardial infarction (MI) is accompanied by inflammatory responses that lead to the recruitment of leukocytes and subsequent myocardial damage, healing, and scar formation. Because monocyte chemoattractant protein-1 (MCP-1) (also known as CCL2) regulates monocytic inflammatory responses, we investigated the effect of cardiac MCP-1 overexpression on left ventricular (LV) dysfunction and remodeling in a murine MI model. Transgenic mice expressing the mouse JE-MCP-1 gene under the control of the alpha-cardiac myosin heavy chain promoter (MHC/MCP-1 mice) were used for this purpose. MHC/MCP-1 mice had reduced infarct area and scar formation and improved LV dysfunction after MI. These mice also showed induction of macrophage infiltration and neovascularization; however, few bone marrow-derived endothelial cells were detected in MHC/MCP-1 mice whose bone marrow was replaced with that of Tie2/LacZ transgenic mice. Flow cytometry analysis showed no increase in endothelial progenitor cells (CD34+/Flk-1+ cells) in MHC/MCP-1 mice. Marked myocardial interleukin (IL)-6 secretion, STAT3 activation, and LV hypertrophy were observed after MI in MHC/MCP-1 mice. Furthermore, cardiac myofibroblasts accumulated after MI in MHC/MCP-1 mice. In vitro experiments revealed that a combination of IL-6 with MCP-1 synergistically stimulated and sustained STAT3 activation in cardiomyocytes. MCP-1, IL-6, and hypoxia directly promoted the differentiation of cardiac fibroblasts into myofibroblasts. Our results suggest that cardiac overexpression of MCP-1 induced macrophage infiltration, neovascularization, myocardial IL-6 secretion, and accumulation of cardiac myofibroblasts, thereby resulting in the prevention of LV dysfunction and remodeling after MI. They also provide a new insight into the role of cardiac MCP-1 in the pathophysiology of MI. PMID:16990567

  20. Maternal Cardiac Diastolic Dysfunction by Doppler Echocardiography in Women with Preeclampsia

    PubMed Central

    Muthyala, Tanuja; Mehrotra, Saurabh; Suri, Vanita

    2016-01-01

    Introduction Preeclampsia may lead to heart failure in late pregnancy and early puerperium. Diastolic dysfunction may be the cause of heart failure in these patients. There is paucity of data on diastolic dysfunction in patients with preeclampsia. Aim To assess cardiac diastolic dysfunction in women with preeclampsia by Doppler echocardiography and to correlate severity of dysfunction with severity of preeclampsia. Materials and Methods One hundred and fifty nulliparous women in age group of 20-35 years were recruited for the study. Among these, 120 women with preeclampsia were taken as cases and 30 normotensive women as controls. Doppler echocardiography was carried out between 28-36 weeks of gestation in both groups to assess and grade severity of diastolic dysfunction. Results Of 120 women with preeclampsia, 61 had mild preeclampsia and 59 had severe preeclampsia. Diastolic dysfunction was seen in 25(20.8%) cases. Among these, grade I diastolic dysfunction was seen in 40% and the rest 60% had grade II diastolic dysfunction. In the mild preeclampsia group, only 2(3.3%) patients had diastolic dysfunction. Both had grade I dysfunction. Of severe preeclampsia patients, 8(13.6%) had grade I and 15(25.4%) had grade II diastolic dysfunction (p=0.001). None of these progressed to heart failure or pulmonary oedema. Systolic function assessed by left ventricular ejection fraction was normal in all cases. All controls had normal systolic and diastolic functions. Conclusion Cardiac diastolic dysfunction occurred in one-fifth of women with preeclampsia. Grade of diastolic dysfunction correlated with the severity of preeclampsia. PMID:27656506

  1. Influence of renal dysfunction on clinical outcomes in patients with congestive heart failure complicating acute myocardial infarction.

    PubMed

    Kim, Chang Seong; Kim, Min Jee; Kang, Yong Un; Choi, Joon Seok; Bae, Eun Hui; Ma, Seong Kwon; Ahn, Young-Keun; Jeong, Myung Ho; Kim, Young Jo; Cho, Myeong Chan; Kim, Chong Jin; Kim, Soo Wan

    2013-01-01

    The clinical course and medical treatment of patients with congestive heart failure (CHF) complicating acute myocardial infarction (AMI) are not well established, especially in patients with concomitant renal dysfunction. We performed a retrospective analysis of the prospective Korean Acute Myocardial Infarction Registry to assess the medical treatments and clinical outcomes of patients with CHF (Killip classes II or III) complicated by AMI, in the presence or absence of renal dysfunction. Of 13,498 patients with AMI, 2769 (20.5%) had CHF on admission. Compared to CHF patients with preserved renal function, in-hospital mortality and major adverse cardiac events were increased both at 1 month and at 1 year after discharge in patients with renal dysfunction (1154; 41.7%). Postdischarge use of aspirin, betablockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers and statins significantly reduced the 1-year mortality rate for CHF patients with renal dysfunction; such reduction was not observed for those without renal dysfunction, except in the case of aspirin. Patients with CHF complicating AMI, which is accompanied by renal dysfunction, are at higher risk for adverse cardiovascular outcomes than patients without renal dysfunction. However, they receive fewer medications proven to reduce mortality rates.

  2. Early life exposure to air pollution induces adult cardiac dysfunction.

    PubMed

    Gorr, Matthew W; Velten, Markus; Nelin, Timothy D; Youtz, Dane J; Sun, Qinghua; Wold, Loren E

    2014-11-01

    diseases and the potential for PM2.5 to induce persistent cardiac dysfunction at adulthood.

  3. Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias

    NASA Technical Reports Server (NTRS)

    Levine, Benjamin D.; Bungo, Michael W.; Platts, Steven H.; Hamilton, Douglas R.; Johnston, Smith L.

    2009-01-01

    Cardiac Atrophy and Diastolic Dysfunction During and After Long Duration Spaceflight: Functional Consequences for Orthostatic Intolerance, Exercise Capability and Risk for Cardiac Arrhythmias (Integrated Cardiovascular) will quantify the extent of long-duration space flightassociated cardiac atrophy (deterioration) on the International Space Station crewmembers.

  4. Increased Age-Related Cardiac Dysfunction in Bradykinin B2 Receptor-Deficient Mice.

    PubMed

    Feng, Wenjing; Xu, Xizhen; Zhao, Gang; Zhao, Junjie; Dong, Ruolan; Ma, Ben; Zhang, Yanjun; Long, Guangwen; Wang, Dao Wen; Tu, Ling

    2016-02-01

    Experimental evidence indicates that the kinin peptide binds to bradykinin B2 receptor (B2R) to trigger various beneficial effects on the cardiovascular system. However, the effects and underlying mechanisms of B2R in cardiac aging remain unknown. A significant age-dependent decrease in B2R expression in the myocardium was observed in C57BL/6J mice. Echocardiographic measurements showed that aging caused a significant cardiac dysfunction in C57BL/6J mice, and importantly B2R deficiency augmented this dysfunction in aging mice. The deficiency of B2R expression in the aging heart repressed p53-pGC-1α-induced mitochondria renewal, increased reactive oxygen species production, and destroyed mitochondrial ultrastructure. Age-related decrease or lack of B2R increased oxidative stress, macrophage infiltration, and inflammatory cytokine expression and compromised antioxidant enzyme expression. Moreover, the inflammatory signals were mainly mediated by the activation of p38 MAPK, JNK, and subsequent translocation of nuclear factor-kappa B to the nucleus. In summary, our data provide evidence that B2R deficiency contributes to the aging-induced cardiac dysfunction, which is likely mediated by increased mitochondrial dysfunction, oxidative stress, and inflammation. This study indicates that preventing the loss of cardioprotective B2R expression may be a novel approach for the prevention and treatment of age-related cardiac dysfunction.

  5. Effects of acute and chronic sunitinib treatment on cardiac function and calcium/calmodulin-dependent protein kinase II

    PubMed Central

    Mooney, L; Skinner, M; Coker, S J; Currie, S

    2015-01-01

    Background and Purpose Calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac contractile function and dysfunction and may be an unwanted secondary target for anti-cancer drugs such as sunitinib and imatinib that have been reported to alter cardiac performance. This study aimed to determine whether anti-cancer kinase inhibitors may affect CaMKII activity and expression when administered in vivo. Experimental Approach Cardiovascular haemodynamics in response to acute and chronic sunitinib treatment, and chronic imatinib treatment, were assessed in guinea pigs and the effects compared with those of the known positive and negative inotropes, isoprenaline and verapamil. Parallel studies from the same animals assessed CaMKIIδ expression and CaMKII activity following drug treatments. Key Results Acute administration of sunitinib decreased left ventricular (LV) dP/dtmax. Acute administration of isoprenaline increased LVdP/dtmax dose-dependently, while LVdP/dtmax was decreased by verapamil. CaMKII activity was decreased by acute administration of sunitinib and was increased by acute administration of isoprenaline, and decreased by acute administration of verapamil. CaMKIIδ expression following all acute treatments remained unchanged. Chronic imatinib and sunitinib treatments did not alter fractional shortening; however, both CaMKIIδ expression and CaMKII activity were significantly increased. Chronic administration of isoprenaline and verapamil decreased LV fractional shortening with parallel increases in CaMKIIδ expression and CaMKII activity. Conclusions and Implications Chronic sunitinib and imatinib treatment increased CaMKIIδ expression and CaMKII activity. As these compounds are associated with cardiac dysfunction, increased CaMKII expression could be an early indication of cellular cardiotoxicity marking potential progression of cardiac contractile dysfunction. PMID:26040813

  6. Low-dose enalapril reduces angiotensin II and attenuates diabetic-induced cardiac and autonomic dysfunctions.

    PubMed

    Malfitano, Christiane; De Angelis, Kátia; Fernandes, Tiago; Wichi, Rogério Brandão; Rosa, Kaleizu; Pazzine, Mariana; Mostarda, Cristiano; Ronchi, Fernanda Aparecida; Oliveira, Edilamar Menezes; de Oliveira, Edilamar Menezes; Casarini, Dulce Elena; Irigoyen, Maria-Claudia

    2012-01-01

    Activation of renin-angiotensin system has been linked to cardiovascular and autonomic dysfunctions in diabetes. Experiments were performed to investigate the effects of angiotensin-converting enzyme inhibitor (ACEI), enalapril, on cardiac and autonomic functions in diabetic rats. Diabetes was induced by streptozotocin (50 mg/kg), and rats were treated with enalapril (1 mg · kg(-1) · d(-1)). After 30 days, evaluations were performed in control, diabetic, and enalapril-treated groups. Cardiac function was evaluated by echocardiography and through cannulation of the left ventricle (at baseline and in response to volume overload). Heart rate and systolic blood pressure variabilities were evaluated in the time and frequency domains. Streptozotocin rats had left ventricular systolic and diastolic dysfunctions, expressed by reduced ejection fraction and increased isovolumic relaxation time. The ACEI prevented these changes, improved diastolic cardiac responses to volume overload and total power of heart rate variability, reduced the ACE1 activity and protein expression and cardiac angiotensin (Ang) II levels, and increased angiotensin-converting enzyme 2 activity, despite unchanged blood pressure. Correlations were obtained between Ang II content with systolic and diastolic functions and heart rate variability. These findings provide evidence that the low-dose ACEI prevents autonomic and cardiac dysfunctions induced by diabetes without changing blood pressure and associated with reduced cardiac Ang II and increased angiotensin-converting enzyme 2 activity. PMID:21921804

  7. Acute effects of firefighting on cardiac performance.

    PubMed

    Fernhall, Bo; Fahs, Christopher A; Horn, Gavin; Rowland, Thomas; Smith, Denise

    2012-02-01

    This study examined standard echocardiographic measures of cardiac size and performance in response to a 3-h firefighting training exercise. Forty experienced male personnel completed a standardized 3 h live firefighting exercise. Before and after the firefighting activities, participants were weighed, height, heart rate, blood pressure and blood samples were obtained, and echocardiographic measurements were made. Firefighting produced significant decreases in left ventricular diastolic dimension, stroke volume, fractional shortening, and mitral E velocity, tachycardia, a rise in core temperature, and a reduction in calculated plasma volume. On tissue Doppler imaging, there were no changes in systolic contractile function, but a decreased lateral wall diastolic velocity was observed. These findings show that 3 h of live firefighting produced cardiac changes consistent with cardiac fatigue, coupled with a decrease in systemic arterial compliance. These data show that live firefighting produces significant cardiovascular changes and future work is needed to evaluate if these changes are related to the increase in cardiovascular risk during live firefighting.

  8. High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker.

    PubMed

    Choi, He Yun; Park, Ji Hye; Jang, Woong Bi; Ji, Seung Taek; Jung, Seok Yun; Kim, Da Yeon; Kang, Songhwa; Kim, Yeon Ju; Yun, Jisoo; Kim, Jae Ho; Baek, Sang Hong; Kwon, Sang-Mo

    2016-07-01

    Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes. PMID:27350339

  9. High Glucose Causes Human Cardiac Progenitor Cell Dysfunction by Promoting Mitochondrial Fission: Role of a GLUT1 Blocker

    PubMed Central

    Choi, He Yun; Park, Ji Hye; Jang, Woong Bi; Ji, Seung Taek; Jung, Seok Yun; Kim, Da Yeon; Kang, Songhwa; Kim, Yeon Ju; Yun, Jisoo; Kim, Jae Ho; Baek, Sang Hong; Kwon, Sang-Mo

    2016-01-01

    Cardiovascular disease is the most common cause of death in diabetic patients. Hyperglycemia is the primary characteristic of diabetes and is associated with many complications. The role of hyperglycemia in the dysfunction of human cardiac progenitor cells that can regenerate damaged cardiac tissue has been investigated, but the exact mechanism underlying this association is not clear. Thus, we examined whether hyperglycemia could regulate mitochondrial dynamics and lead to cardiac progenitor cell dysfunction, and whether blocking glucose uptake could rescue this dysfunction. High glucose in cardiac progenitor cells results in reduced cell viability and decreased expression of cell cycle-related molecules, including CDK2 and cyclin E. A tube formation assay revealed that hyperglycemia led to a significant decrease in the tube-forming ability of cardiac progenitor cells. Fluorescent labeling of cardiac progenitor cell mitochondria revealed that hyperglycemia alters mitochondrial dynamics and increases expression of fission-related proteins, including Fis1 and Drp1. Moreover, we showed that specific blockage of GLUT1 improved cell viability, tube formation, and regulation of mitochondrial dynamics in cardiac progenitor cells. To our knowledge, this study is the first to demonstrate that high glucose leads to cardiac progenitor cell dysfunction through an increase in mitochondrial fission, and that a GLUT1 blocker can rescue cardiac progenitor cell dysfunction and downregulation of mitochondrial fission. Combined therapy with cardiac progenitor cells and a GLUT1 blocker may provide a novel strategy for cardiac progenitor cell therapy in cardiovascular disease patients with diabetes. PMID:27350339

  10. 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. PMID:26578366

  11. 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.

  12. Exertional heat stroke and acute liver failure: a late dysfunction.

    PubMed

    Carvalho, Ana Sofia; Rodeia, Simão C; Silvestre, Joana; Póvoa, Pedro

    2016-01-01

    Heat stroke (HS) is defined as a severe elevation of core body temperature along with central nervous system dysfunction. Exertional heat stroke (EHS) with acute liver failure (ALF) is a rare condition. The authors report the case of a 25-year-old man with a history of cognitive enhancers' intake who developed hyperthermia and neurological impairment while running an outdoor marathon. The patient was cooled and returned to normal body temperature after 6 h. He subsequently developed ALF and was transferred to the intensive care unit. Over-the-counter drug intake may have been related to heat intolerance and contributed to the event. The patient was successfully treated with conservative measures. In the presence of EHS, it is crucial to act promptly with aggressive total body cooling, in order to prevent progression of the clinical syndrome. Liver function must also be monitored, since it can be a late organ dysfunction. PMID:26969359

  13. Role of Telomere Dysfunction in Cardiac Failure in Duchenne Muscular Dystrophy

    PubMed Central

    Mourkioti, Foteini; Kustan, Jackie; Kraft, Peggy; Day, John W.; Zhao, Ming-Ming; Kost-Alimova, Maria; Protopopov, Alexei; DePinho, Ronald A.; Bernstein, Daniel; Meeker, Alan K.; Blau, Helen M.

    2013-01-01

    Duchenne Muscular Dystrophy (DMD), the most common inherited muscular dystrophy of childhood, leads to death due to cardiorespiratory failure. Paradoxically, mdx mice with the same genetic deficiency of dystrophin, exhibit minimal cardiac dysfunction, impeding the development of therapies. We postulated that the difference between mdx and DMD might result from differences in telomere lengths in mice and humans. We show here that, like DMD patients, mice that lack dystrophin and have shortened telomeres (mdx/mTRKO) develop severe functional cardiac deficits including ventricular dilation, contractile and conductance dysfunction, and accelerated mortality. These cardiac defects are accompanied by telomere erosion, mitochondrial fragmentation, and increased oxidative stress. Treatment with anti-oxidants significantly retards the onset of cardiac dysfunction and death of mdx/mTRKO mice. In corroboration, of four DMD patients analyzed, all had 45% shorter telomeres in their cardiomyocytes relative to age- and sex-matched controls. We propose that the demands of contraction in the absence of dystrophin coupled with increased oxidative stress conspire to accelerate telomere erosion culminating in cardiac failure and death. These findings provide strong support for a link between telomere length and dystrophin deficiency in the etiology of dilated cardiomyopathy in DMD and suggest preventive interventions. PMID:23831727

  14. Lipasuria in acute pancreatitis: result of tubular dysfunction?

    PubMed

    Muench, R; Buehler, H; Kehl, O; Ammann, R

    1987-01-01

    Lipase, in contrast to amylase, is completely reabsorbed by the proximal tubules after glomerular filtration. Therefore, no lipase is detectable in the unconcentrated urine according to the current opinion. The handling of lipase (detected with an enzyme-immunoassay) by the kidney was investigated in comparison with creatinine, amylase, and beta-2-microglobulin by clearance studies in acute pancreatitis (n = 10), burn injury (n = 4), glomerular proteinuria (n = 8), and controls without evidence of pancreatic or renal diseases (n = 5). In initial stages of acute pancreatitis a measurable clearance of lipase (mean: 49.6 microliters/min, range: 0.5-234) was found in association with corresponding increased clearances of beta-2-microglobulin (mean: 10.5 ml/min, range: 0.02-58.9) and of amylase (mean: 8.9 ml/min, range: 2.4-22.6) in nine of ten patients. This finding is consistent with a defect of tubular function. However, regression analysis failed to show a significant correlation between lipase and beta-2-microglobulin clearance. Repeated measurements during the course of pancreatitis in seven patients showed reversibility of tubular dysfunction. In patients with burn injury a similar elevation of clearances of beta-2-microglobulin and of amylase was found, but tubular dysfunction in this condition was not associated with lipasuria. In glomerular proteinuria a lipase clearance was found in two of five cases with moderate, and in the other three cases with severe impairment of creatinine clearance. beta-2-microglobulin clearance was normal in the former and only slightly elevated in the latter group. In conclusion lipase is measurable in the urine of most patients with acute pancreatitis as a result of a reversible tubular dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

  15. Evidence of exercise-induced cardiac dysfunction and elevated cTnT in separate cohorts competing in an ultra-endurance mountain marathon race.

    PubMed

    Shave, R E; Dawson, E; Whyte, G; George, K; Ball, D; Gaze, D C; Collinson, P O

    2002-10-01

    Cardiac damage has recently been implicated in the aetiology of "exercise induced cardiac dysfunction". The humoral markers of cardiac damage that have been utilised to date are not sufficiently cardio-specific to investigate this hypothesis. The aim of the present study was to examine cardiac function following prolonged exercise, and investigate the contention of cardiac damage utilising a new highly cardio-specific marker. Thirty-seven competitors in the 2-day Lowe Alpine Mountain Marathon 2000 volunteered for the study. Competitors were sub-divided into 2 groups. Group 1 (n = 11) were examined using echocardiography pre and post the event, examining left ventricular diastolic and systolic function. Group 2 (n = 26) had venous blood samples drawn prior to the event and immediately following day-1 and day-2. Blood samples were analysed for total creatine kinase activity (CK), creatine kinase isoenzyme MB(mass) (CK-MB(mass)), and cardiac troponin T. Echocardiographic results indicated left ventricular diastolic and systolic dysfunction following cessation of exercise. CK and CK-MB(mass) were both elevated following day-1, and immediately following race completion. Cardiac troponin T levels were below the 99th percentile (0.01 microg/L) in all subjects prior to the event, following day-1 cTnT was elevated above 0.01 microg/L in 13 subjects, but returned to below 0.01 microg/L following race completion on day-2. However, no individual data reached clinical cut-off levels for acute myocardial infarction (AMI) (0.1 microg/L). Two days arduous exercise over mountainous terrain resulted in cardiac dysfunction, and significant skeletal muscular degradation. The elevation of cTnT above the 99th percentile in the present study is suggestive of minimal myocardial damage. The clinical significance of and exact mechanism responsible for such damage remains to be elucidated.

  16. Cardiac dysfunction among soft tissue sarcoma patients in Denmark

    PubMed Central

    Shantakumar, Sumitra; Olsen, Morten; Vo, Thao T; Nørgaard, Mette; Pedersen, Lars

    2016-01-01

    Purpose Soft tissue sarcoma (STS) patients may experience post-treatment cardiotoxicity, yet no population-based data exist. We examined the incidence of left ventricular ejection fraction (LVEF) decline, heart failure, and cardiac death following STS diagnosis among adults, using Danish patient registries and medical record review. Patients and methods LVEF decline was examined in a regional cohort of STS patients diagnosed during 1997–2011 in Western Denmark for whom cardiac imaging data were available. LVEF decline was defined as an absolute decline from baseline to follow-up of 10% or more, or, where baseline imaging was not available, a decline below the lower limit of normal (or 40%) for a follow-up LVEF. Heart failure and cardiac death were investigated in a national Danish cohort of all STS patients diagnosed from 2000 to 2009. We followed patients from STS diagnosis until heart failure, cardiac death, emigration or December 31, 2012 (whichever occurred first). Results The incidence rate of LVEF decline for the regional cohort with follow-up data (N=100, five events) or baseline and follow-up measurements (N=75, 19 events) was 16.8 (95% confidence interval [CI]: 7.0–40.3) and 108 (95% CI: 69–170), respectively, per 1,000 person-years. In the national cohort (N=1,187), the incidence of heart failure (40 events) and cardiac death (15 events) was 7.3 (95% CI: 5.4–10.0) and 2.7 (95% CI: 1.6–4.5), respectively, per 1,000 person-years. The strongest predictors of heart failure were doxorubicin treatment (hazard ratio [HR] =2.2, 95% CI: 0.5–10.2) and pre-existing cardiovascular disease (HR=6.3, 95% CI: 0.98–40.6). Conclusion LVEF decline occurred more frequently compared to heart failure or cardiac death in a nationally representative cohort of Danish STS patients. PMID:27186077

  17. Clinical significance of automatic warning function of cardiac remote monitoring systems in preventing acute cardiac episodes

    PubMed Central

    Chen, Shou-Qiang; Xing, Shan-Shan; Gao, Hai-Qing

    2014-01-01

    Objective: In addition to ambulatory Holter electrocardiographic recording and transtelephonic electrocardiographic monitoring (TTM), a cardiac remote monitoring system can provide an automatic warning function through the general packet radio service (GPRS) network, enabling earlier diagnosis, treatment and improved outcome of cardiac diseases. The purpose of this study was to estimate its clinical significance in preventing acute cardiac episodes. Methods: Using 2 leads (V1 and V5 leads) and the automatic warning mode, 7160 patients were tested with a cardiac remote monitoring system from October 2004 to September 2007. If malignant arrhythmias or obvious ST-T changes appeared in the electrocardiogram records was automatically transferred to the monitoring center, the patient and his family members were informed, and the corresponding precautionary or therapeutic measures were implemented immediately. Results: In our study, 274 cases of malignant arrhythmia, including sinus standstill and ventricular tachycardia, and 43 cases of obvious ST-segment elevation were detected and treated. Because of early detection, there was no death or deformity. Conclusions: A cardiac remote monitoring system providing an automatic warning function can play an important role in preventing acute cardiac episodes. PMID:25674124

  18. Endothelial Mineralocorticoid Receptor Deletion Prevents Diet-Induced Cardiac Diastolic Dysfunction in Females.

    PubMed

    Jia, Guanghong; Habibi, Javad; DeMarco, Vincent G; Martinez-Lemus, Luis A; Ma, Lixin; Whaley-Connell, Adam T; Aroor, Annayya R; Domeier, Timothy L; Zhu, Yi; Meininger, Gerald A; Barrett Mueller, Katelee; Jaffe, Iris Z; Sowers, James R

    2015-12-01

    Overnutrition and insulin resistance are especially prominent risk factors for the development of cardiac diastolic dysfunction in females. We recently reported that consumption of a Western diet (WD) containing excess fat (46%), sucrose (17.5%), and high fructose corn syrup (17.5%) for 16 weeks resulted in cardiac diastolic dysfunction and aortic stiffening in young female mice and that these abnormalities were prevented by mineralocorticoid receptor blockade. Herein, we extend those studies by testing whether WD-induced diastolic dysfunction and factors contributing to diastolic impairment, such as cardiac fibrosis, hypertrophy, inflammation, and impaired insulin signaling, are modulated by excess endothelial cell mineralocorticoid receptor signaling. Four-week-old female endothelial cell mineralocorticoid receptor knockout and wild-type mice were fed mouse chow or WD for 4 months. WD feeding resulted in prolonged relaxation time, impaired diastolic septal wall motion, and increased left ventricular filling pressure indicative of diastolic dysfunction. This occurred in concert with myocardial interstitial fibrosis and cardiomyocyte hypertrophy that were associated with enhanced profibrotic (transforming growth factor β1/Smad) and progrowth (S6 kinase-1) signaling, as well as myocardial oxidative stress and a proinflammatory immune response. WD also induced cardiomyocyte stiffening, assessed ex vivo using atomic force microscopy. Conversely, endothelial cell mineralocorticoid receptor deficiency prevented WD-induced diastolic dysfunction, profibrotic, and progrowth signaling, in conjunction with reductions in macrophage proinflammatory polarization and improvements in insulin metabolic signaling. Therefore, our findings indicate that increased endothelial cell mineralocorticoid receptor signaling associated with consumption of a WD plays a key role in the activation of cardiac profibrotic, inflammatory, and growth pathways that lead to diastolic dysfunction in

  19. Nrf2-Mediated Cardiac Maladaptive Remodeling and Dysfunction in a Setting of Autophagy Insufficiency.

    PubMed

    Qin, Qingyun; Qu, Chen; Niu, Ting; Zang, Huimei; Qi, Lei; Lyu, Linmao; Wang, Xuejun; Nagarkatti, Mitzi; Nagarkatti, Prakash; Janicki, Joseph S; Wang, Xing Li; Cui, Taixing

    2016-01-01

    Nuclear factor erythroid-2-related factor 2 (Nrf2) appears to exert either a protective or detrimental effect on the heart; however, the underlying mechanism remains poorly understood. Herein, we uncovered a novel mechanism for turning off the Nrf2-mediated cardioprotection and switching on Nrf2-mediated cardiac dysfunction. In a murine model of pressure overload-induced cardiac remodeling and dysfunction via transverse aortic arch constriction, knockout of Nrf2 enhanced myocardial necrosis and death rate during an initial stage of cardiac adaptation when myocardial autophagy function is intact. However, knockout of Nrf2 turned out to be cardioprotective throughout the later stage of cardiac maladaptive remodeling when myocardial autophagy function became insufficient. Transverse aortic arch constriction -induced activation of Nrf2 was dramatically enhanced in the heart with impaired autophagy, which is induced by cardiomyocyte-specific knockout of autophagy-related gene (Atg)5. Notably, Nrf2 activation coincided with the upregulation of angiotensinogen (Agt) only in the autophagy-impaired heart after transverse aortic arch constriction. Agt5 and Nrf2 gene loss-of-function approaches in combination with Jak2 and Fyn kinase inhibitors revealed that suppression of autophagy inactivated Jak2 and Fyn and nuclear translocation of Fyn, while enhancing nuclear translocation of Nrf2 and Nrf2-driven Agt expression in cardiomyocytes. Taken together, these results indicate that the pathophysiological consequences of Nrf2 activation are closely linked with the functional integrity of myocardial autophagy during cardiac remodeling. When autophagy is intact, Nrf2 is required for cardiac adaptive responses; however, autophagy impairment most likely turns off Fyn-operated Nrf2 nuclear export thus activating Nrf2-driven Agt transcription, which exacerbates cardiac maladaptation leading to dysfunction. PMID:26573705

  20. Two-dimensional speckle strain imaging: in the management of paraganglioma, acute junctional tachycardia, and myocardial dysfunction in a child.

    PubMed

    Pignatelli, Ricardo; Law, Mark A; Martinez, Hugo; Altman, Carolyn; Ayres, Nancy; Jefferies, John L; Ganame, Javier

    2012-01-01

    Two-dimensional speckle-tracking strain imaging (speckle strain imaging) is useful for evaluating left ventricular myocardial function in patients with ischemic heart disease and cardiomyopathy, including hypertrophic and dilated phenotypes. The usefulness of speckle strain imaging in patients with pheochromocytoma who are undergoing adrenal surgery has been described, but we found no reports of the use of this method to evaluate ventricular dysfunction longitudinally in children. Herein, we describe the case of a 10-year-old girl with a paraganglioma, acute junctional tachycardia, and myocardial dysfunction. After control of the tachycardia and partial resection of the tumor, speckle strain imaging enabled clinical management that led to substantial improvement in the patient's initially diffuse myocardial dysfunction. Because conventional echocardiographic methods alone may be inadequate to guide the management of pediatric patients with partially resected neuroendocrine tumors, we recommend speckle strain imaging as an additional noninvasive option for treatment guidance and monitoring of cardiac tissue response.

  1. Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism.

    PubMed

    Neto-Neves, Evandro M; Sousa-Santos, Ozelia; Ferraz, Karina C; Rizzi, Elen; Ceron, Carla S; Romano, Minna M D; Gali, Luis G; Maciel, Benedito C; Schulz, Richard; Gerlach, Raquel F; Tanus-Santos, Jose E

    2013-12-01

    Activated matrix metalloproteinases (MMPs) cause cardiomyocyte injury during acute pulmonary thromboembolism (APT). However, the functional consequences of this alteration are not known. We examined whether doxycycline (a MMP inhibitor) improves right ventricle function and the cardiac responses to dobutamine during APT. APT was induced with autologous blood clots (350 mg/kg) in anaesthetized male lambs pre-treated with doxycycline (Doxy, 10 mg/kg/day, intravenously) or saline. Non-embolized control lambs received doxycycline pre-treatment or saline. The responses to intravenous dobutamine (Dob, 1, 5, 10 μg/kg/min.) or saline infusions at 30 and 120 min. after APT induction were evaluated by echocardiography. APT increased mean pulmonary artery pressure and pulmonary vascular resistance index by ~185%. Doxycycline partially prevented APT-induced pulmonary hypertension (P < 0.05). RV diameter increased in the APT group (from 10.7 ± 0.8 to 18.3 ± 1.6 mm, P < 0.05), but not in the Doxy+APT group (from 13.3 ± 0.9 to 14.4 ± 1.0 mm, P > 0.05). RV dysfunction on stress echocardiography was observed in embolized lambs (APT+Dob group) but not in embolized animals pre-treated with doxycycline (Doxy+APT+Dob). APT increased MMP-9 activity, oxidative stress and gelatinolytic activity in the RV. Although doxycycline had no effects on RV MMP-9 activity, it prevented the increases in RV oxidative stress and gelatinolytic activity (P < 0.05). APT increased serum cardiac troponin I concentrations (P < 0.05), doxycycline partially prevented this alteration (P < 0.05). We found evidence to support that doxycycline prevents RV dysfunction and improves the cardiac responses to dobutamine during APT. PMID:24199964

  2. Nobiletin attenuates cardiac dysfunction, oxidative stress, and inflammatory in streptozotocin: induced diabetic cardiomyopathy.

    PubMed

    Zhang, Ning; Yang, Zheng; Xiang, Shi-Zhao; Jin, Ya-Ge; Wei, Wen-Ying; Bian, Zhou-Yan; Deng, Wei; Tang, Qi-Zhu

    2016-06-01

    Diabetic cardiomyopathy, characterized by the presence of diastolic and/or systolic myocardial dysfunction, is one of the major causes of heart failure. Nobiletin, which is extracted from the fruit peel of citrus, is reported to possess anti-inflammatory, anti-oxidative, and hypolipidemic properties. The purpose of this study was to investigate whether nobiletin exerts the therapeutic effect on streptozotocin-induced diabetic cardiomyopathy (DCM) in mice. 80 experimental male C57BL mice were randomly assigned into four groups: sham + vehicle (VEH/SH), sham + nobiletin (NOB/SH), DCM + vehicle (VEH/DM), and DCM + nobiletin (NOB/DM). Nobiletin treatment ameliorated cardiac dysfunction in the DCM group, as shown by the result of echocardiography and hemodynamic measurements. Nobiletin treatment also blunted the mRNA expression of NADPH oxidase isoforms p67(phox), p22(phox), and p91(phox), and abated oxidative stress. Although administration of diabetic mice with nobiletin did not significantly effect the level of blood glucose, it decreased the TGF-β1, CTGF, fibronectin, and collagen Iα expressions and blunted cardiac fibrosis. In addition, nobiletin inhibited the activation of c-Jun NH2-terminal kinase (JNK), P38, and NF-κB in the cardiac tissue of diabetic mice. Collectively, our study indicates that treatment with nobiletin mitigates cardiac dysfunction and interstitial fibrosis, and these beneficial of nobiletin may belong to the suppression of JNK, P38, and NF-κB signaling pathways.

  3. Myocardial Fibrosis and Left Ventricular Dysfunction in Duchenne Muscular Dystrophy Carriers Using Cardiac Magnetic Resonance Imaging.

    PubMed

    Lang, Sean M; Shugh, Svetlana; Mazur, Wojciech; Sticka, Joshua J; Rattan, Mantosh S; Jefferies, John L; Taylor, Michael D

    2015-10-01

    The goal of our study was to characterize the degree of myocardial fibrosis and left ventricular dysfunction in our cohort of Duchenne muscular dystrophy (DMD) carriers using cardiac magnetic resonance imaging (CMR). Seventy percent of males with DMD have mothers who are carriers of the Xp21 mutation. Carrier phenotypic characteristics range from asymptomatic to left ventricular (LV) dysfunction and cardiomyopathy. The true prevalence of cardiac involvement in DMD carriers is unknown. We performed a retrospective observational study. All female DMD carriers who underwent clinical CMR studies at Cincinnati Children's Hospital Medical Center from December 6, 2006, to August 28, 2013, were evaluated. Patients underwent standard CMR assessment with LV function assessment and late gadolinium enhancement (LGE). In addition, offline feature tracking strain analysis was performed on the basal, mid, and apical short axis. Twenty-two patients were studied, of which 20 underwent adequate testing for myocardial LGE. Four of 22 patients (18 %) were found to have LV dysfunction (ejection fraction <55 %). Seven of 20 DMD carriers (35 %) were found to have LGE. The patients with evidence of LGE had an overall trend to lower absolute deformation parameters; however, this did not meet statistical significance when correcting for multiple comparisons. Our study demonstrates a high rate of LGE as well as LV dysfunction in DMD carriers. Cardiovascular and musculoskeletal symptoms were not statistically different between those with and without cardiac involvement. This study demonstrates the importance of surveillance CMR evaluation of DMD carriers. PMID:25976773

  4. Cardiac, renal, and neurological benefits of preoperative levosimendan administration in patients with right ventricular dysfunction and pulmonary hypertension undergoing cardiac surgery: evaluation with two biomarkers neutrophil gelatinase-associated lipocalin and neuronal enolase

    PubMed Central

    Guerrero-Orriach, José Luis; Ariza-Villanueva, Daniel; Florez-Vela, Ana; Garrido-Sánchez, Lourdes; Moreno-Cortés, María Isabel; Galán-Ortega, Manuel; Ramírez-Fernández, Alicia; Alcaide Torres, Juan; Fernandez, Concepción Santiago; Navarro Arce, Isabel; Melero-Tejedor, José María; Rubio-Navarro, Manuel; Cruz-Mañas, José

    2016-01-01

    Purpose To evaluate if the preoperative administration of levosimendan in patients with right ventricular (RV) dysfunction, pulmonary hypertension, and high perioperative risk would improve cardiac function and would also have a protective effect on renal and neurological functions, assessed using two biomarkers neutrophil gelatinase-associated lipocalin (N-GAL) and neuronal enolase. Methods This is an observational study. Twenty-seven high-risk cardiac patients with RV dysfunction and pulmonary hypertension, scheduled for cardiac valve surgery, were prospectively followed after preoperative administration of levosimendan. Levosimendan was administered preoperatively on the day before surgery. All patients were considered high risk of cardiac and perioperative renal complications. Cardiac function was assessed by echocardiography, renal function by urinary N-GAL levels, and the acute kidney injury scale. Neuronal damage was assessed by neuron-specific enolase levels. Results After surgery, no significant variations were found in mean and SE levels of N-GAL (14.31 [28.34] ng/mL vs 13.41 [38.24] ng/mL), neuron-specific enolase (5.40 [0.41] ng/mL vs 4.32 [0.61] ng/mL), or mean ± SD creatinine (1.06±0.24 mg/dL vs 1.25±0.37 mg/dL at 48 hours). RV dilatation decreased from 4.23±0.7 mm to 3.45±0.6 mm and pulmonary artery pressure from 58±18 mmHg to 42±19 mmHg at 48 hours. Conclusion Preoperative administration of levosimendan has shown a protective role against cardiac, renal, and neurological damage in patients with a high risk of multiple organ dysfunctions undergoing cardiac surgery. PMID:27143905

  5. Cardiac autonomic dysfunction in obese normotensive children and adolescents

    PubMed Central

    Freitas, Isabelle Magalhães G.; Miranda, Josiane Aparecida; Mira, Pedro Augusto C.; Lanna, Carla Marcia M.; Lima, Jorge Roberto P.; Laterza, Mateus Camaroti

    2014-01-01

    OBJECTIVE: To test the hypothesis that obese normotensive children and adolescents present impaired cardiac autonomic control compared to non-obese normotensive ones. METHODS: For this cross-sectional study, 66 children and adolescents were divided into the following groups: Obese (n=31, 12±3 years old) and Non-Obese (n=35, 13±3 years old). Obesity was defined as body mass index greater than the 95th percentile for age and gender. Blood pressure was measured by oscillometric method after 15 minutes of rest in supine position. The heart rate was continuously registered during ten minutes in the supine position with spontaneous breathing. The cardiac autonomic control was assessed by heart rate variability, which was calculated from the five-minute minor variance of the signal. The derivations were the index that indicates the proportion of the number of times in which normal adjacent R-R intervals present differences >50 miliseconds (pNN50), for the time domain, and, for the spectral analysis, low (LF) and high frequency (HF) bands, besides the low and high frequencies ratio (LF/HF). The results were expressed as mean±standard deviation and compared by Student's t-test or Mann-Whitney's U-test. RESULTS: Systolic blood pressure (116±14 versus 114±13mmHg, p=0.693) and diastolic blood pressure (59±8 versus 60±11mmHg, p=0.458) were similar between the Obese and Non-Obese groups. The pNN50 index (29±21 versus 43±23, p=0.015) and HF band (54±20 versus 64±14 normalized units - n.u., p=0.023) were lower in the Obese Group. The LF band (46±20 versus 36±14 n.u., p=0.023) and LF/HF ratio (1.3±1.6 versus 0.7±0.4, p=0.044) were higher in Obese Group. CONCLUSIONS: Obese normotensive children and adolescents present impairment of cardiac autonomic control. PMID:25119757

  6. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities.

    PubMed

    Cavalera, Michele; Wang, Junhong; Frangogiannis, Nikolaos G

    2014-10-01

    Cardiac fibrosis is strongly associated with obesity and metabolic dysfunction and may contribute to the increased incidence of heart failure, atrial arrhythmias, and sudden cardiac death in obese subjects. This review discusses the evidence linking obesity and myocardial fibrosis in animal models and human patients, focusing on the fundamental pathophysiological alterations that may trigger fibrogenic signaling, the cellular effectors of fibrosis, and the molecular signals that may regulate the fibrotic response. Obesity is associated with a wide range of pathophysiological alterations (such as pressure and volume overload, metabolic dysregulation, neurohumoral activation, and systemic inflammation); their relative role in mediating cardiac fibrosis is poorly defined. Activation of fibroblasts likely plays a major role in obesity-associated fibrosis; however, inflammatory cells, cardiomyocytes, and vascular cells may also contribute to fibrogenic signaling. Several molecular processes have been implicated in regulation of the fibrotic response in obesity. Activation of the renin-angiotensin-aldosterone system, induction of transforming growth factor β, oxidative stress, advanced glycation end-products, endothelin 1, Rho-kinase signaling, leptin-mediated actions, and upregulation of matricellular proteins (such as thrombospondin 1) may play a role in the development of fibrosis in models of obesity and metabolic dysfunction. Moreover, experimental evidence suggests that obesity and insulin resistance profoundly affect the fibrotic and remodeling response after cardiac injury. Understanding the pathways implicated in obesity-associated fibrosis may lead to the development of novel therapies to prevent heart failure and attenuate postinfarction cardiac remodeling in patients with obesity.

  7. Cardiac myocyte dysfunction induced by streptolysin O is membrane pore and calcium dependent

    PubMed Central

    Bolz, Devin D.; Li, Zhi; McIndoo, Eric R.; Tweten, Rodney K.; Bryant, Amy E.; Stevens, Dennis L.

    2014-01-01

    Septic cardiomyopathy is a severe complication among some patients who develop group A streptococcal toxic shock syndrome (StrepTSS). Despite the importance of cardiac dysfunction in determining prognosis, very little is known about mechanisms that reduce cardiac output in association with streptococcal infection. Here, we investigated the effects of streptococcal extracellular toxins on mechanical contractility of electrically paced primary murine cardiomyocytes. Our data demonstrate that Streptolysin O (SLO) is the major streptococcal toxin responsible for cardiomyocyte contractile dysfunction. SLO dose-dependently affected cardiac myocyte function in discrete stages. Exposure to SLO caused a failure of cardiac cells to respond to electrical pacing, followed by spontaneous dysregulated contractions and augmented strength of contraction. Central to these SLO-mediated effects is a marked influx of calcium into the cytosol through SLO-mediated pores in the cytoplasmic membrane. Such calcium mobilization in response to SLO correlated temporally with hypercontractility and unpaced contractions. During continued exposure to SLO, cardiomyocytes exhibited periods of reversion to normal electrical pacing suggestive of membrane lesion repair and restoration of calcium handling. Together, these observations are consistent with the clinical observation that septic cardiomyopathy is a reversible condition in patients that survive StrepTSS. These data provide strong evidence that streptococcal exotoxins, specifically SLO, can directly impact cardiac mechanical function. PMID:25243426

  8. Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation.

    PubMed

    Lopez-Fernandez, Silvia; Manito-Lorite, Nicolas; Gómez-Hospital, Joan Antoni; Roca, Josep; Fontanillas, Carles; Melgares-Moreno, Rafael; Azpitarte-Almagro, José; Cequier-Fillat, Angel

    2014-12-01

    Cardiac allograft vasculopathy remains one of the major causes of death post-heart transplantation. Its etiology is multifactorial and prevention is challenging. The aim of this study was to prospectively determine factors related to cardiac allograft vasculopathy after heart transplantation. This research was planned on 179 patients submitted to heart transplant. Performance of an early coronary angiography with endothelial function evaluation was scheduled at three-month post-transplant. Patients underwent a second coronary angiography after five-yr follow-up. At the 5- ± 2-yr follow-up, 43% of the patients had developed cardiac allograft vasculopathy (severe in 26% of them). Three independent predictors of cardiac allograft vasculopathy were identified: cardiogenic shock at the time of the transplant operation (OR: 6.49; 95% CI: 1.86-22.7, p = 0.003); early coronary endothelial dysfunction (OR: 3.9; 95% CI: 1.49-10.2, p = 0.006), and older donor age (OR: 1.05; 95% CI: 1.00-1.10, p = 0.044). Besides early endothelial coronary dysfunction and older donor age, a new predictor for development of cardiac allograft vasculopathy was identified: cardiogenic shock at the time of transplantation. In these high-risk patient subgroups, preventive measures (treatment of cardiovascular risk factors, use of novel immunosuppressive agents such as mTOR inhibitors) should be earlier and much more aggressive.

  9. Artificial aortic valve dysfunction due to pannus and thrombus – different methods of cardiac surgical management

    PubMed Central

    Marcinkiewicz, Anna; Kośmider, Anna; Walczak, Andrzej; Zwoliński, Radosław; Jaszewski, Ryszard

    2015-01-01

    Introduction Approximately 60 000 prosthetic valves are implanted annually in the USA. The risk of prosthesis dysfunction ranges from 0.1% to 4% per year. Prosthesis valve dysfunction is usually caused by a thrombus obstructing the prosthetic discs. However, 10% of prosthetic valves are dysfunctional due to pannus formation, and 12% of prostheses are damaged by both fibrinous and thrombotic components. The authors present two patients with dysfunctional aortic prostheses who were referred for cardiac surgery. Different surgical solutions were used in the treatment of each case. Case study 1 The first patient was a 71-year-old woman whose medical history included arterial hypertension, stable coronary artery disease, diabetes mellitus, chronic obstructive pulmonary disease (COPD), and hypercholesterolemia; she had previously undergone left-sided mastectomy and radiotherapy. The patient was admitted to the Cardiac Surgery Department due to aortic prosthesis dysfunction. Transthoracic echocardiography revealed complete obstruction of one disc and a severe reduction in the mobility of the second. The mean transvalvular gradient was very high. During the operation, pannus covering the discs’ surface was found. A biological aortic prosthesis was reimplanted without complications. Case study 2 The second patient was an 87-year-old woman with arterial hypertension, persistent atrial fibrillation, and COPD, whose past medical history included gastric ulcer disease and ischemic stroke. As in the case of the first patient, she was admitted due to valvular prosthesis dysfunction. Preoperative transthoracic echocardiography revealed an obstruction of the posterior prosthetic disc and significant aortic regurgitation. Transesophageal echocardiography and fluoroscopy confirmed the prosthetic dysfunction. During the operation, a thrombus growing around a minor pannus was found. The thrombus and pannus were removed, and normal functionality of the prosthetic valve was restored

  10. Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation.

    PubMed

    Bernardo, Bianca C; Sapra, Geeta; Patterson, Natalie L; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A; McMullen, Julie R

    2015-01-01

    Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions. PMID:26660322

  11. Long-Term Overexpression of Hsp70 Does Not Protect against Cardiac Dysfunction and Adverse Remodeling in a MURC Transgenic Mouse Model with Chronic Heart Failure and Atrial Fibrillation

    PubMed Central

    Bernardo, Bianca C.; Sapra, Geeta; Patterson, Natalie L.; Cemerlang, Nelly; Kiriazis, Helen; Ueyama, Tomomi; Febbraio, Mark A.; McMullen, Julie R.

    2015-01-01

    Previous animal studies had shown that increasing heat shock protein 70 (Hsp70) using a transgenic, gene therapy or pharmacological approach provided cardiac protection in models of acute cardiac stress. Furthermore, clinical studies had reported associations between Hsp70 levels and protection against atrial fibrillation (AF). AF is the most common cardiac arrhythmia presenting in cardiology clinics and is associated with increased rates of heart failure and stroke. Improved therapies for AF and heart failure are urgently required. Despite promising observations in animal studies which targeted Hsp70, we recently reported that increasing Hsp70 was unable to attenuate cardiac dysfunction and pathology in a mouse model which develops heart failure and intermittent AF. Given our somewhat unexpected finding and the extensive literature suggesting Hsp70 provides cardiac protection, it was considered important to assess whether Hsp70 could provide protection in another mouse model of heart failure and AF. The aim of the current study was to determine whether increasing Hsp70 could attenuate adverse cardiac remodeling, cardiac dysfunction and episodes of arrhythmia in a mouse model of heart failure and AF due to overexpression of Muscle-Restricted Coiled-Coil (MURC). Cardiac function and pathology were assessed in mice at approximately 12 months of age. We report here, that chronic overexpression of Hsp70 was unable to provide protection against cardiac dysfunction, conduction abnormalities, fibrosis or characteristic molecular markers of the failing heart. In summary, elevated Hsp70 may provide protection in acute cardiac stress settings, but appears insufficient to protect the heart under chronic cardiac disease conditions. PMID:26660322

  12. Pentoxifylline alleviates cardiac ischemia and dysfunction following experimental angina in insulin resistance.

    PubMed

    Azhar, Ahmad; El-Bassossy, Hany M

    2014-01-01

    We have previously shown that pentoxifylline (PTX) protects from vascular complications associated with insulin resistance (IR). Here, we investigated the protective effect of PTX against cardiac ischemia and dysfunction following experimental angina in IR. IR, along with its accompanying cardiac dysfunction, was induced in rats by a high-fructose (10% in drinking water) high-fat diet for 12 weeks. PTX was administered daily (30 mg⋅kg(-1)) during the last 4 weeks of the study. Experimental angina was induced by isoproterenol (10 µg⋅kg(-1)) administered by intravenous injection. Both before (baseline) and after the experimental angina, cardiac contractility was assessed by continuous recording in anesthetized rats via a microtip catheter inserted in the left ventricle, and cardiac conductivity was determined by a surface electrocardiograph. Serum glucose, insulin, tumor necrosis factor-α (TNFα), and adiponectin levels and lipid profile were also determined. Feeding the rats a high-fructose high-fat diet produced IR, as evidenced by significant hyperinsulinemia and hyperglycemia, and PTX administration did not affect this IR. When subjected to experimental angina, IR hearts were less resistant to the ischemia following induction of angina (reflected by the large ST height depression) compared with controls, and PTX completely prevented the excessive ST height depression in IR animals. In addition, left ventricular pressure development was largely attenuated during and after induction of angina in IR animals compared with controls. PTX administration prevented the excessive attenuation in ventricular pressure development in IR animals. IR was associated with elevated levels of the inflammatory cytokine TNFα, whereas PTX treatment elevated the serum level of the anti-inflammatory cytokine adiponectin. PTX alleviates cardiac ischemia and dysfunction following experimental angina in IR directly through inhibition of the low-grade inflammation that accompanies IR.

  13. Cardiac-Specific Overexpression of Catalase Attenuates Lipopolysaccharide-Induced Myocardial Contractile Dysfunction: Role of Autophagy

    PubMed Central

    Turdi, Subat; Han, Xuefeng; Huff, Anna F.; Roe, Nathan D.; Hu, Nan; Gao, Feng; Ren, Jun

    2012-01-01

    Lipopolysaccharide (LPS) from Gram-negative bacteria is a major initiator of sepsis, leading to cardiovascular collapse. Accumulating evidence has indicated a role of reactive oxygen species (ROS) in cardiovascular complication in sepsis. This study was designed to examine the effect of cardiac-specific overexpression of catalase in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Catalase transgenic and wild-type FVB mice were challenged with LPS (6 mg/kg) and cardiac function was evaluated. Levels of oxidative stress, autophagy, apoptosis and protein damage were examined using fluorescence microscopy, Western blot, TUNEL assay, caspase-3 activity and carbonyl formation. Kaplan-Meier curve was constructed for survival following LPS treatment. Our results revealed a lower mortality in catalase mice compared with FVB mice following LPS challenge. LPS injection led to depressed cardiac contractile capacity as evidenced by echocardiography and cardiomyocyte contractile function, the effect of which was ablated by catalase overexpression. LPS treatment induced elevated TNF-α level, autophagy, apoptosis (TUNEL, caspase-3 activation, cleaved caspase-3), production of ROS and O2−, and protein carbonyl formation, the effects of which were significantly attenuated by catalase overexpression. Electron microscopy revealed focal myocardial damage characterized by mitochondrial injury following LPS treatment, which was less severe in catalase mice. Interestingly, LPS-induced cardiomyocyte contractile dysfunction was prevented by antioxidant NAC and the autophagy inhibitor 3-methyladenine. Taken together, our data revealed that catalase protects against LPS-induced cardiac dysfunction and mortality, which may be associated with inhibition of oxidative stress and autophagy. PMID:22902401

  14. Reactive Oxygen Species, Endoplasmic Reticulum Stress and Mitochondrial Dysfunction: The Link with Cardiac Arrhythmogenesis

    PubMed Central

    Tse, Gary; Yan, Bryan P.; Chan, Yin W. F.; Tian, Xiao Yu; Huang, Yu

    2016-01-01

    Background: Cardiac arrhythmias represent a significant problem globally, leading to cerebrovascular accidents, myocardial infarction, and sudden cardiac death. There is increasing evidence to suggest that increased oxidative stress from reactive oxygen species (ROS), which is elevated in conditions such as diabetes and hypertension, can lead to arrhythmogenesis. Method: A literature review was undertaken to screen for articles that investigated the effects of ROS on cardiac ion channel function, remodeling and arrhythmogenesis. Results: Prolonged endoplasmic reticulum stress is observed in heart failure, leading to increased production of ROS. Mitochondrial ROS, which is elevated in diabetes and hypertension, can stimulate its own production in a positive feedback loop, termed ROS-induced ROS release. Together with activation of mitochondrial inner membrane anion channels, it leads to mitochondrial depolarization. Abnormal function of these organelles can then activate downstream signaling pathways, ultimately culminating in altered function or expression of cardiac ion channels responsible for generating the cardiac action potential (AP). Vascular and cardiac endothelial cells become dysfunctional, leading to altered paracrine signaling to influence the electrophysiology of adjacent cardiomyocytes. All of these changes can in turn produce abnormalities in AP repolarization or conduction, thereby increasing likelihood of triggered activity and reentry. Conclusion: ROS plays a significant role in producing arrhythmic substrate. Therapeutic strategies targeting upstream events include production of a strong reducing environment or the use of pharmacological agents that target organelle-specific proteins and ion channels. These may relieve oxidative stress and in turn prevent arrhythmic complications in patients with diabetes, hypertension, and heart failure. PMID:27536244

  15. Ecstasy (MDMA) Alters Cardiac Gene Expression and DNA Methylation: Implications for Circadian Rhythm Dysfunction in the Heart.

    PubMed

    Koczor, Christopher A; Ludlow, Ivan; Hight, Robert S; Jiao, Zhe; Fields, Earl; Ludaway, Tomika; Russ, Rodney; Torres, Rebecca A; Lewis, William

    2015-11-01

    MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMA's acute cardiotoxicity includes tachycardia and arrhythmia which are associated with cardiomyopathy. MDMA acute cardiotoxicity has been explored, but neither long-term MDMA cardiac pathological changes nor epigenetic changes have been evaluated. Microarray analyses were employed to identify cardiac gene expression changes and epigenetic DNA methylation changes. To identify permanent MDMA-induced pathogenetic changes, mice received daily 10- or 35-day MDMA, or daily 10-day MDMA followed by 25-day saline washout (10 + 25 days). MDMA treatment caused differential gene expression (p < .05, fold change >1.5) in 752 genes following 10 days, 558 genes following 35 days, and 113 genes following 10-day MDMA + 25-day saline washout. Changes in MAPK and circadian rhythm gene expression were identified as early as 10 days. After 35 days, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) persisted to be differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was found to be 71% at 10 days, 68% at 35 days, and 91% at 10 + 25 days washout. Differential gene expression paralleled DNA methylation in 22% of genes at 10-day treatment, 17% at 35 days, and 48% at 10 + 25 days washout. We show here that MDMA induced cardiac epigenetic changes in DNA methylation where hypermethylation predominated. Moreover, MDMA induced gene expression of key elements of circadian rhythm regulatory genes. This suggests a fundamental organism-level event to explain some of the etiologies of MDMA dysfunction in the heart.

  16. Measures of endothelial dysfunction predict response to cardiac resynchronisation therapy

    PubMed Central

    Warriner, David R; Lawford, Patricia; Sheridan, Paul J

    2016-01-01

    Objectives Cardiac resynchronisation therapy (CRT) improves morbidity and mortality in heart failure (HF). Impaired endothelial function, as measured by flow-mediated dilation (FMD) is associated with increased morbidity and mortality in HF and may help to differentiate responders from non-responders. Methods 19 patients were recruited, comprising 94% men, mean age 69±8 years, New York Heart Association functional classes II–IV, QRSd 161±21 ms and mean left ventricular ejection fraction 26±8%. Markers of response and FMD were measured at baseline, 6 and 12 months following CRT. Results 14 patients were responders to CRT. Responders had significant improvements in VO2 (12.6±1.7 to 14.7±1.5 mL/kg/min, p<0.05), quality of life score (44.4±22.9–24.1±21.3, p<0.01), left ventricular end diastolic volume (201.5±72.5 mL–121.3±72.0 mL, p<0.01) and 6-min walk distance (374.0±112.8 m at baseline to 418.1±105.3 m, p<0.05). Baseline FMD in responders was 2.9±1.9% and 7.4±3.73% in non-responders (p<0.05). Conclusions Response to CRT at 6 and 12 months is predicted by baseline FMD. This study confirms that FMD identifies responders to CRT, due to endothelium-dependent mechanisms alone. PMID:27335654

  17. Endothelial RAGE exacerbates acute postischaemic cardiac inflammation.

    PubMed

    Ziegler, Tilman; Horstkotte, Melanie; Lange, Philipp; Ng, Judy; Bongiovanni, Dario; Hinkel, Rabea; Laugwitz, Karl-Ludwig; Sperandio, Markus; Horstkotte, Jan; Kupatt, Christian

    2016-08-01

    Advanced glycation end-products (AGEs) interact with their receptor RAGE, leading to an inflammatory state. We investigated the role of RAGE in postischaemic leukocyte adhesion after myocardial infarction and its effect on postischaemic myocardial function. Wildtype (WT), ICAM-1-/-, RAGE-/- or ICAM-1/RAGE-/- mice underwent 20 minutes (min) of LAD-occlusion followed by 15 min of reperfusion. We applied in vivo fluorescence microscopy visualising Rhodamine-6G labelled leukocytes. To differentiate between endothelial and leukocyte RAGE, we generated bone marrow chimeric mice. Invasive hemodynamic measurements were performed in mice undergoing 45 min of myocardial ischaemia (via LAD-occlusion) followed by 24 hours of reperfusion. Left-ventricular developed pressure (LVDP) was assessed by insertion of a millar-tip catheter into the left ventricle. In the acute model of myocardial ischaemia, leukocyte retention (WT 68 ± 4 cells/hpf) was significantly reduced in ICAM-1-/- (40 ± 3 cells/hpf) and RAGE-/- mice (38 ± 4 cells/hpf). ICAM-1/RAGE-/- mice displayed an additive reduction of leukocyte retention (ICAM-1/RAGE-/- 15 ± 3 cells/hpf). Ly-6G+ neutrophil were predominantly reduced in ICAM-1/RAGE-/- hearts (28 %), whereas Ly-6C+ proinflammatory monocytes decreased to a lesser extent (55 %). Interestingly, PMN recruitment was not affected in chimeric mice with RAGE deficiency in BM cells (WT mice reconstituted with ICAM-1/RAGE-/- BM: 55 ± 4 cells/hpf) while in mice with global RAGE deficiency (ICAM-1/RAGE-/- mice reconstituted with ICAM-1/RAGE-/- BM) leucocyte retention was significantly reduced (13 ± 1 cells/hpf), similar to non-transplanted ICAM/RAGE-/- mice. Furthermore, postischaemic LVDP increased in ICAM-1/RAGE-/- animals (98 ± 4 mmHg vs 86 ± 4 mmHg in WT mice). In conclusion, combined deficiency of ICAM-1 and RAGE reduces leukocyte influx into infarcted myocardium and improves LV function during the acute phase after myocardial ischaemia and reperfusion

  18. Modulation of Cardiac Autonomic Dysfunction in Ischemic Stroke following Ayurveda (Indian System of Medicine) Treatment

    PubMed Central

    Jaideep, Sriranjini Sitaram; Nagaraja, Dindagur; Pal, Pramod Kumar; Sudhakara, D.; Talakad, Sathyaprabha N.

    2014-01-01

    Objectives. Cardiac autonomic dysfunction in stroke has implications on morbidity and mortality. Ayurveda (Indian system of medicine) describes stroke as pakshaghata. We intended to study the effect of Ayurveda therapies on the cardiac autonomic dysfunction. Methods. Fifty patients of ischemic stroke (middle cerebral artery territory) (mean age 39.26 ± 9.88 years; male 43, female 7) were recruited within one month of ictus. All patients received standard allopathic medications as advised by neurologist. In addition, patients were randomized to receive physiotherapy (Group I) or Ayurveda treatment (Group II) for 14 days. Continuous electrocardiogram and finger arterial pressure were recorded for 15 min before and after treatments and analyzed offline to obtain heart rate and blood pressure variability and baroreflex sensitivity (BRS). Results were analysed by RMANOVA. Results. Patients in Group II showed statistically significant improvement in cardiac autonomic parameters. The standard deviation of normal to normal intervals,and total and low frequency powers were significantly enhanced (F = 8.16, P = 0.007, F = 9.73, P = 0.004, F = 13.51, and P = 0.001, resp.). The BRS too increased following the treatment period (F = 10.129, P = 0.004). Conclusions. The current study is the first to report a positive modulation of cardiac autonomic activity after adjuvant Ayurveda treatment in ischemic stroke. Further long term studies are warranted. PMID:24971149

  19. Cardiac CT: atherosclerosis to acute coronary syndrome

    PubMed Central

    Munnur, Ravi Kiran; Cameron, James D.; Ko, Brian S.; Meredith, Ian T.

    2014-01-01

    Coronary computed tomographic angiography (CCTA) is a robust non-invasive method to assess coronary artery disease (CAD). Qualitative and quantitative assessment of atherosclerotic coronary stenosis with CCTA has been favourably compared with invasive coronary angiography (ICA) and intravascular ultrasound (IVUS). Importantly, it allows the study of preclinical stages of atherosclerotic disease, may help improve risk stratification and monitor the progressive course of the disease. The diagnostic accuracy of CCTA in the assessment of coronary artery bypass grafts (CABG) is excellent and the constantly improving technology is making the evaluation of stents feasible. Novel techniques are being developed to assess the functional significance of coronary stenosis. The excellent negative predictive value of CCTA in ruling out disease enables early and safe discharge of patients with suspected acute coronary syndromes (ACS) in the Emergency Department (ED). In addition, CCTA is useful in predicting clinical outcomes based on the extent of coronary atherosclerosis and also based on individual plaque characteristics such as low attenuation plaque (LAP), positive remodelling and spotty calcification. In this article, we review the role of CCTA in the detection of coronary atherosclerosis in native vessels, stented vessels, calcified arteries and grafts; the assessment of plaque progression, evaluation of chest pain in the ED, assessment of functional significance of stenosis and the prognostic significance of CCTA. PMID:25610801

  20. Recent Advances on Pathophysiology, Diagnostic and Therapeutic Insights in Cardiac Dysfunction Induced by Antineoplastic Drugs

    PubMed Central

    Molinaro, Marilisa; Ameri, Pietro; Marone, Giancarlo; Petretta, Mario; Abete, Pasquale; Di Lisa, Fabio; De Placido, Sabino; Bonaduce, Domenico; Tocchetti, Carlo G.

    2015-01-01

    Along with the improvement of survival after cancer, cardiotoxicity due to antineoplastic treatments has emerged as a clinically relevant problem. Potential cardiovascular toxicities due to anticancer agents include QT prolongation and arrhythmias, myocardial ischemia and infarction, hypertension and/or thromboembolism, left ventricular (LV) dysfunction, and heart failure (HF). The latter is variable in severity, may be reversible or irreversible, and can occur soon after or as a delayed consequence of anticancer treatments. In the last decade recent advances have emerged in clinical and pathophysiological aspects of LV dysfunction induced by the most widely used anticancer drugs. In particular, early, sensitive markers of cardiac dysfunction that can predict this form of cardiomyopathy before ejection fraction (EF) is reduced are becoming increasingly important, along with novel therapeutic and cardioprotective strategies, in the attempt of protecting cardiooncologic patients from the development of congestive heart failure. PMID:26583088

  1. A Pre-clinical Animal Model of Trypanosoma brucei Infection Demonstrating Cardiac Dysfunction.

    PubMed

    McCarroll, Charlotte S; Rossor, Charlotte L; Morrison, Linda R; Morrison, Liam J; Loughrey, Christopher M

    2015-05-01

    African trypanosomiasis (AT), caused by Trypanosoma brucei species, results in both neurological and cardiac dysfunction and can be fatal if untreated. Research on the pathogenesis and treatment of the disease has centred to date on the characteristic neurological symptoms, whereas cardiac dysfunction (e.g. ventricular arrhythmias) in AT remains largely unstudied. Animal models of AT demonstrating cardiac dysfunction similar to that described in field cases of AT are critically required to transform our understanding of AT-induced cardiac pathophysiology and identify future treatment strategies. We have previously shown that T. brucei can interact with heart muscle cells (cardiomyocytes) to induce ventricular arrhythmias in ex vivo adult rat hearts. However, it is unknown whether the arrhythmias observed ex vivo are also present during in vivo infection in experimental animal models. Here we show for the first time the characterisation of ventricular arrhythmias in vivo in two animal models of AT infection using electrocardiographic (ECG) monitoring. The first model utilised a commonly used monomorphic laboratory strain, Trypanosoma brucei brucei Lister 427, whilst the second model used a pleomorphic laboratory strain, T. b. brucei TREU 927, which demonstrates a similar chronic infection profile to clinical cases. The frequency of ventricular arrhythmias and heart rate (HR) was significantly increased at the endpoint of infection in the TREU 927 infection model, but not in the Lister 427 infection model. At the end of infection, hearts from both models were isolated and Langendorff perfused ex vivo with increasing concentrations of the β-adrenergic agonist isoproterenol (ISO). Interestingly, the increased frequency of arrhythmias observed in vivo in the TREU 927 infection model was lost upon isolation of the heart ex vivo, but re-emerged with the addition of ISO. Our results demonstrate that TREU 927 infection modifies the substrate of the myocardium in such a way

  2. Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration.

    PubMed

    Wang, E R; Jarrah, A A; Benard, L; Chen, J; Schwarzkopf, M; Hadri, L; Tarzami, S T

    2014-05-01

    Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its downstream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor-induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases whereas fibrosis increases. In addition, CXCR4 expression was rescued with the use of cardiotropic adeno-associated viral-9 vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo. PMID:24646609

  3. Deletion of CXCR4 in cardiomyocytes exacerbates cardiac dysfunction following isoproterenol administration

    PubMed Central

    Wang, ER; Jarrah, AA; Benard, L; Chen, J; Schwarzkopf, M; Hadri, L; Tarzami, ST

    2014-01-01

    Altered alpha- and beta-adrenergic receptor signaling is associated with cardiac hypertrophy and failure. Stromal cell-derived factor-1α (SDF-1α) and its cognate receptor CXCR4 have been reported to mediate cardioprotection after injury through the mobilization of stem cells into injured tissue. However, little is known regarding whether SDF-1/CXCR4 induces acute protection following pathological hypertrophy and if so, by what molecular mechanism. We have previously reported that CXCR4 physically interacts with the beta-2 adrenergic receptor and modulates its down stream signaling. Here we have shown that CXCR4 expression prevents beta-adrenergic receptor induced hypertrophy. Cardiac beta-adrenergic receptors were stimulated with the implantation of a subcutaneous osmotic pump administrating isoproterenol and CXCR4 expression was selectively abrogated in cardiomyocytes using Cre-loxP-mediated gene recombination. CXCR4 knockout mice showed worsened fractional shortening and ejection fraction. CXCR4 ablation increased susceptibility to isoproterenol-induced heart failure, by upregulating apoptotic markers and reducing mitochondrial function; cardiac function decreases while fibrosis increases. Additionally, CXCR4 expression was rescued with the use of cardiotropic Adeno-associated viral-9 (AAV9) vectors. CXCR4 gene transfer reduced cardiac apoptotic signaling, improved mitochondrial function and resulted in a recovered cardiac function. Our results represent the first evidence that SDF-1/CXCR4 signaling mediates acute cardioprotection through modulating beta-adrenergic receptor signaling in vivo. PMID:24646609

  4. Metabonomics of acute kidney injury in children after cardiac surgery.

    PubMed

    Beger, Richard D; Holland, Ricky D; Sun, Jinchun; Schnackenberg, Laura K; Moore, Page C; Dent, Catherine L; Devarajan, Prasad; Portilla, Didier

    2008-06-01

    Acute kidney injury (AKI) is a major complication in children who undergo cardiopulmonary bypass surgery. We performed metabonomic analyses of urine samples obtained from 40 children that underwent cardiac surgery for correction of congenital cardiac defects. Serial urine samples were obtained from each patient prior to surgery and at 4 h and 12 h after surgery. AKI, defined as a 50% or greater rise in baseline level of serum creatinine, was noted in 21 children at 48-72 h after cardiac surgery. The principal component analysis of liquid chromatography/mass spectrometry (LC/MS) negative ionization data of the urine samples obtained 4 h and 12 h after surgery from patients who develop AKI clustered away from patients who did not develop AKI. The LC/MS peak with mass-to-charge ratio (m/z) 261.01 and retention time (tR) 4.92 min was further analyzed by tandem mass spectrometry (MS/MS) and identified as homovanillic acid sulfate (HVA-SO4), a dopamine metabolite. By MS single-reaction monitoring, the sensitivity was 0.90 and specificity was 0.95 for a cut-off value of 24 ng/microl for HVA-SO4 at 12 h after surgery. We concluded that urinary HVA-SO4 represents a novel, sensitive, and predictive early biomarker of AKI after pediatric cardiac surgery.

  5. Early detection of acute kidney injury after pediatric cardiac surgery

    PubMed Central

    Jefferies, John Lynn; Devarajan, Prasad

    2016-01-01

    Acute kidney injury (AKI) is increasingly recognized as a common problem in children undergoing cardiac surgery, with well documented increases in morbidity and mortality in both the short and the long term. Traditional approaches to the identification of AKI such as changes in serum creatinine have revealed a large incidence in this population with significant negative impact on clinical outcomes. However, the traditional diagnostic approaches to AKI diagnosis have inherent limitations that may lead to under-diagnosis of this pathologic process. There is a dearth of randomized controlled trials for the prevention and treatment of AKI associated with cardiac surgery, at least in part due to the paucity of early predictive biomarkers. Novel non-invasive biomarkers have ushered in a new era that allows for earlier detection of AKI. With these new diagnostic tools, a more consistent approach can be employed across centers that may facilitate a more accurate representation of the actual prevalence of AKI and more importantly, clinical investigation that may minimize the occurrence of AKI following pediatric cardiac surgery. A thoughtful management approach is necessary to mitigate the effects of AKI after cardiac surgery, which is best accomplished in close collaboration with pediatric nephrologists. Long-term surveillance for improvement in kidney function and potential development of chronic kidney disease should also be a part of the comprehensive management strategy. PMID:27429538

  6. Nobiletin attenuates cardiac dysfunction, oxidative stress, and inflammatory in streptozotocin: induced diabetic cardiomyopathy.

    PubMed

    Zhang, Ning; Yang, Zheng; Xiang, Shi-Zhao; Jin, Ya-Ge; Wei, Wen-Ying; Bian, Zhou-Yan; Deng, Wei; Tang, Qi-Zhu

    2016-06-01

    Diabetic cardiomyopathy, characterized by the presence of diastolic and/or systolic myocardial dysfunction, is one of the major causes of heart failure. Nobiletin, which is extracted from the fruit peel of citrus, is reported to possess anti-inflammatory, anti-oxidative, and hypolipidemic properties. The purpose of this study was to investigate whether nobiletin exerts the therapeutic effect on streptozotocin-induced diabetic cardiomyopathy (DCM) in mice. 80 experimental male C57BL mice were randomly assigned into four groups: sham + vehicle (VEH/SH), sham + nobiletin (NOB/SH), DCM + vehicle (VEH/DM), and DCM + nobiletin (NOB/DM). Nobiletin treatment ameliorated cardiac dysfunction in the DCM group, as shown by the result of echocardiography and hemodynamic measurements. Nobiletin treatment also blunted the mRNA expression of NADPH oxidase isoforms p67(phox), p22(phox), and p91(phox), and abated oxidative stress. Although administration of diabetic mice with nobiletin did not significantly effect the level of blood glucose, it decreased the TGF-β1, CTGF, fibronectin, and collagen Iα expressions and blunted cardiac fibrosis. In addition, nobiletin inhibited the activation of c-Jun NH2-terminal kinase (JNK), P38, and NF-κB in the cardiac tissue of diabetic mice. Collectively, our study indicates that treatment with nobiletin mitigates cardiac dysfunction and interstitial fibrosis, and these beneficial of nobiletin may belong to the suppression of JNK, P38, and NF-κB signaling pathways. PMID:27160937

  7. High fat feeding in mice is insufficient to induce cardiac dysfunction and does not exacerbate heart failure.

    PubMed

    Brainard, Robert E; Watson, Lewis J; Demartino, Angelica M; Brittian, Kenneth R; Readnower, Ryan D; Boakye, Adjoa Agyemang; Zhang, Deqing; Hoetker, Joseph David; Bhatnagar, Aruni; Baba, Shahid Pervez; Jones, Steven P

    2013-01-01

    Preclinical studies of animals with risk factors, and how those risk factors contribute to the development of cardiovascular disease and cardiac dysfunction, are clearly needed. One such approach is to feed mice a diet rich in fat (i.e. 60%). Here, we determined whether a high fat diet was sufficient to induce cardiac dysfunction in mice. We subjected mice to two different high fat diets (lard or milk as fat source) and followed them for over six months and found no significant decrement in cardiac function (via echocardiography), despite robust adiposity and impaired glucose disposal. We next determined whether antecedent and concomitant exposure to high fat diet (lard) altered the murine heart's response to infarct-induced heart failure; high fat feeding during, or before and during, heart failure did not significantly exacerbate cardiac dysfunction. Given the lack of a robust effect on cardiac dysfunction with high fat feeding, we then examined a commonly used mouse model of overt diabetes, hyperglycemia, and obesity (db/db mice). db/db mice (or STZ treated wild-type mice) subjected to pressure overload exhibited no significant exacerbation of cardiac dysfunction; however, ischemia-reperfusion injury significantly depressed cardiac function in db/db mice compared to their non-diabetic littermates. Thus, we were able to document a negative influence of a risk factor in a relevant cardiovascular disease model; however, this did not involve exposure to a high fat diet. High fat diet, obesity, or hyperglycemia does not necessarily induce cardiac dysfunction in mice. Although many investigators use such diabetes/obesity models to understand cardiac defects related to risk factors, this study, along with those from several other groups, serves as a cautionary note regarding the use of murine models of diabetes and obesity in the context of heart failure.

  8. Increased LDL electronegativity in chronic kidney disease disrupts calcium homeostasis resulting in cardiac dysfunction.

    PubMed

    Chang, Kuan-Cheng; Lee, An-Sheng; Chen, Wei-Yu; Lin, Yen-Nien; Hsu, Jing-Fang; Chan, Hua-Chen; Chang, Chia-Ming; Chang, Shih-Sheng; Pan, Chia-Chi; Sawamura, Tatsuya; Chang, Chi-Tzong; Su, Ming-Jai; Chen, Chu-Huang

    2015-07-01

    Chronic kidney disease (CKD), an independent risk factor for cardiovascular disease, is associated with abnormal lipoprotein metabolism. We examined whether electronegative low-density lipoprotein (LDL) is mechanistically linked to cardiac dysfunction in patients with early CKD. We compared echocardiographic parameters between patients with stage 2 CKD (n = 88) and normal controls (n = 89) and found that impaired relaxation was more common in CKD patients. Reduction in estimated glomerular filtration rate was an independent predictor of left ventricular relaxation dysfunction. We then examined cardiac function in a rat model of early CKD induced by unilateral nephrectomy (UNx) by analyzing pressure-volume loop data. The time constant of isovolumic pressure decay was longer and the maximal velocity of pressure fall was slower in UNx rats than in controls. When we investigated the mechanisms underlying relaxation dysfunction, we found that LDL from CKD patients and UNx rats was more electronegative than LDL from their respective controls and that LDL from UNx rats induced intracellular calcium overload in H9c2 cardiomyocytes in vitro. Furthermore, chronic administration of electronegative LDL, which signals through lectin-like oxidized LDL receptor-1 (LOX-1), induced relaxation dysfunction in wild-type but not LOX-1(-/-) mice. In in vitro and in vivo experiments, impaired cardiac relaxation was associated with increased calcium transient resulting from nitric oxide (NO)-dependent nitrosylation of SERCA2a due to increases in inducible NO synthase expression and endothelial NO synthase uncoupling. In conclusion, LDL becomes more electronegative in early CKD. This change disrupts SERCA2a-regulated calcium homeostasis, which may be the mechanism underlying cardiorenal syndrome.

  9. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction.

    PubMed

    Heger, Jacqueline; Gödecke, Axel; Flögel, Ulrich; Merx, Marc W; Molojavyi, Andrei; Kühn-Velten, W Nikolaus; Schrader, Jürgen

    2002-01-11

    Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific alpha-myosin heavy chain (alpha-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO(x) levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated. PMID:11786524

  10. Cardiac-specific overexpression of inducible nitric oxide synthase does not result in severe cardiac dysfunction.

    PubMed

    Heger, Jacqueline; Gödecke, Axel; Flögel, Ulrich; Merx, Marc W; Molojavyi, Andrei; Kühn-Velten, W Nikolaus; Schrader, Jürgen

    2002-01-11

    Nitric oxide (NO), a potent regulator of myocardial contractility, has been implicated in the development of heart failure; however, no study exists describing the relation between expression of inducible nitric oxide synthase (iNOS), formation of NO in vivo, and cardiac contractility. We have therefore generated transgenic (TG) mice overexpressing iNOS under the cardiospecific alpha-myosin heavy chain (alpha-MHC) promoter. In vitro, iNOS activity in hearts of two transgenic lines was 260- to 400-fold above controls (wild type [WT]), but TG mice were viable and appeared normal. Ventricular mass/body weight ratio did not differ; heart rate and cardiac output as well as mean arterial blood pressure were decreased by 10%. NO(x) levels of hearts and blood of TG mice were 2.5- and 2-fold above WT controls, respectively. In the isolated heart, release of the NO oxidation products nitrate and nitrite, an index of in vivo NOS activity, was 40-fold over WT. However, cardiac hemodynamics and levels of ATP and phosphocreatine were unaltered. The high iNOS activity was associated with reduced cardiac L-arginine in TG hearts to only 15% of the WT, indicating limited substrate availability, whereas L-citrulline was 20-fold elevated. Our findings demonstrate that the heart can tolerate high levels of iNOS activity without detrimental functional consequences. The concept that iNOS-derived NO is the triggering factor in the pathomechanism leading to heart failure therefore needs to be reevaluated.

  11. Intermittent cardiac overload results in adaptive hypertrophy and provides protection against left ventricular acute pressure overload insult.

    PubMed

    Moreira-Gonçalves, Daniel; Henriques-Coelho, Tiago; Fonseca, Hélder; Ferreira, Rita; Padrão, Ana Isabel; Santa, Cátia; Vieira, Sara; Silva, Ana Filipa; Amado, Francisco; Leite-Moreira, Adelino; Duarte, José Alberto

    2015-09-01

    The present study aimed to test whether a chronic intermittent workload could induce an adaptive cardiac phenotype Chronic intermittent workload induced features of adaptive hypertrophy This was paralleled by protection against acute pressure overload insult The heart may adapt favourably to balanced demands, regardless of the nature of the stimuli. The present study aimed to test whether submitting the healthy heart to intermittent and tolerable amounts of workload, independently of its nature, could result in an adaptive cardiac phenotype. Male Wistar rats were subjected to treadmill running (Ex) (n = 20), intermittent cardiac overload with dobutamine (ITO) (2 mg kg(-1) , s.c.; n = 20) or placebo administration (Cont) (n = 20) for 5 days week(-1) for 8 weeks. Animals were then killed for histological and biochemical analysis or subjected to left ventricular haemodynamic evaluation under baseline conditions, in response to isovolumetric contractions and to sustained LV acute pressure overload (35% increase in peak systolic pressure maintained for 2 h). Baseline cardiac function was enhanced only in Ex, whereas the response to isovolumetric heartbeats was improved in both ITO and Ex. By contrast to the Cont group, in which rats developed diastolic dysfunction with sustained acute pressure overload, ITO and Ex showed increased tolerance to this stress test. Both ITO and Ex developed cardiomyocyte hypertrophy without fibrosis, no overexpression of osteopontin-1 or β-myosin heavy chain, and increased expression of sarcoplasmic reticulum Ca(2+) protein. Regarding hypertrophic pathways, ITO and Ex showed activation of the protein kinase B/mammalian target of rapamycin pathway but not calcineurin. Mitochondrial complex IV and V activities were also increased in ITO and Ex. Chronic submission to controlled intermittent cardiac overload, independently of its nature, results in an adaptive cardiac phenotype. Features of the cardiac overload, such as the duration and

  12. Cardiac computed tomography in patients with acute chest pain.

    PubMed

    Nieman, Koen; Hoffmann, Udo

    2015-04-14

    The efficient and reliable evaluation of patients with acute chest pain is one of the most challenging tasks in the emergency department. Coronary computed tomography (CT) angiography may play a major role, since it permits ruling out coronary artery disease with high accuracy if performed with expertise in properly selected and prepared patients. Several randomized trials have established early cardiac CT as a viable safe and potentially more efficient alternative to functional testing in the evaluation of acute chest pain. Ongoing investigations explore whether advanced anatomic and functional assessments such as high-risk coronary plaque, resting myocardial perfusion, and left ventricular function, or the simulation of the fractional coronary flow reserve will add information to the anatomic assessment for stenosis, which would allow expanding the benefits of cardiac CT from triage to treatment decisions. Especially, the combination of high-sensitive troponins and coronary computed tomography angiography may play a valuable role in future strategies for the management of patients presenting with acute chest pain.

  13. Thrombolytic therapy in acute cerebral infarction complicating diagnostic cardiac catheterization.

    PubMed

    Chen, Yu-Wei; Sim, Ming-Ming; Smith, Eric E

    2006-10-01

    Diagnostic and interventional percutaneous coronary catheterization is associated with stroke. Many of such strokes are asymptomatic, but some are devastating. Once the diagnosis of acute cerebral infarction is confirmed, thrombolytic therapy should be administrated within the time window of 3 hours. We report a 61-year-old woman who suffered from an acute cerebral infarction during diagnostic cardiac catheterization for unstable angina, which manifested as sudden onset of global aphasia, right hemiplegia and gaze preponderance to the left side. Computed tomography of the head performed immediately after recognition of the symptoms showed a hyperdense middle cerebral artery (MCA) sign. Following prompt recognition and diagnosis, intravenous thrombolytic therapy was administered 2 hours after symptom onset. The patient had a favorable outcome. Initially, National Institutes of Health Stroke Scale score was 21, and 24 hours later it improved to 9. The hyperdense MCA lesion had resolved on the 24-hour follow-up scan. This case illustrates the clinical benefit of thrombolytic therapy in the setting of acute stroke associated with cardiac catheterization.

  14. Acute cardiac sympathetic disruption in the pathogenesis of the takotsubo syndrome: a systematic review of the literature to date.

    PubMed

    Y-Hassan, Shams

    2014-01-01

    Takotsubo syndrome (TS), also known as broken heart syndrome and neurogenic stunned myocardium, is an acute cardiac disease entity characterized by a clinical picture mimicking that of an acute coronary syndrome. The pathogenesis of TS has not been established yet. Among the most often debated pathologic mechanisms of TS are as follows: first, multi-vessel coronary spasm; second, myocardial microvascular dysfunction; third, aborted myocardial infarction caused by transient thrombotic occlusion of a long wrap-around left anterior descending artery; fourth, left ventricular outflow tract obstruction; fifth, blood-borne catecholamine cardiac toxicity; and sixth, cardiac sympathetic disruption and norepinephrine seethe and spillover. The aim of this review is to provide a thorough analysis of the literature data coming mainly from the neurological literature and dealing with the pathogenesis of TS. Substantial evidence challenging the first five hypotheses and arguing in favor of the hypothesis that acute cardiac sympathetic eruption and norepinephrine seethe and spillover is causing TS in predisposed patients is presented. PMID:24140050

  15. Percutaneous coronary intervention for acute myocardial infarction in elderly patients with renal dysfunction: results from the Korea Acute Myocardial Infarction Registry.

    PubMed

    Lim, Sang Yup; Bae, Eun Hui; Choi, Joon Seok; Kim, Chang Seong; Ma, Seong Kwon; Ahn, Youngkeun; Jeong, Myung Ho; Kim, Weon; Woo, Jong Shin; Kim, Young Jo; Cho, Myeong Chan; Kim, Chong Jin; Kim, Soo Wan

    2013-07-01

    This study aimed to evaluate the effects of percutaneous coronary intervention (PCI) on short- and long-term major adverse cardiac events (MACE) in elderly (>75 yr old) acute myocardial infarction (AMI) patients with renal dysfunction. As part of Korea AMI Registry (KAMIR), elderly patients with AMI and renal dysfunction (GFR<60 mL/min) received either medical (n=439) or PCI (n=1,019) therapy. Primary end point was in-hospital death. Secondary end point was MACE during a 1 month and 1 yr follow-up. PCI group showed a significantly lower incidence of in-hospital death (20.0% vs 14.3%, P=0.006). Short-term and long-term MACE rates were higher in medical therapy group (31.9% vs 19.0%; 57.7% vs 31.3%, P<0.001), and this difference was mainly attributed to cardiac death (29.3% vs 17.6%; 51.9% vs 25.0%, P<0.001). MACE-free survival time after adjustment was also higher in PCI group on short-term (hazard ratio, 0.67; confidence interval, 0.45-0.98; P=0.037) and long-term follow-up (hazard ratio, 0.61, confidence interval, 0.45-0.83; P=0.002). In elderly AMI patients with renal dysfunction, PCI therapy yields favorable in-hospital and short-term and long-term MACE-free survival.

  16. Endothelial cell dysfunction and cardiac hypertrophy in the STOX1 model of preeclampsia

    PubMed Central

    Ducat, Aurélien; Doridot, Ludivine; Calicchio, Rosamaria; Méhats, Celine; Vilotte, Jean-Luc; Castille, Johann; Barbaux, Sandrine; Couderc, Betty; Jacques, Sébastien; Letourneur, Franck; Buffat, Christophe; Le Grand, Fabien; Laissue, Paul; Miralles, Francisco; Vaiman, Daniel

    2016-01-01

    Preeclampsia is a disease of pregnancy involving systemic endothelial dysfunction. However, cardiovascular consequences of preeclampsia are difficult to analyze in humans. The objective of the present study is to evaluate the cardiovascular dysfunction induced by preeclampsia by examining the endothelium of mice suffering of severe preeclampsia induced by STOX1 overexpression. Using Next Generation Sequencing on endothelial cells of mice carrying either transgenic or control embryos, we discovered significant alterations of gene networks involved in inflammation, cell cycle, and cardiac hypertrophy. In addition, the heart of the preeclamptic mice revealed cardiac hypertrophy associated with histological anomalies. Bioinformatics comparison of the networks of modified genes in the endothelial cells of the preeclamptic mice and HUVECs exposed to plasma from preeclamptic women identified striking similarities. The cardiovascular alterations in the pregnant mice are comparable to those endured by the cardiovascular system of preeclamptic women. The STOX1 mice could help to better understand the endothelial dysfunction in the context of preeclampsia, and guide the search for efficient therapies able to protect the maternal endothelium during the disease and its aftermath. PMID:26758611

  17. PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis.

    PubMed

    Taniguchi, Takuya; Maruyama, Naoki; Ogata, Takehiro; Kasahara, Takeru; Nakanishi, Naohiko; Miyagawa, Kotaro; Naito, Daisuke; Hamaoka, Tetsuro; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi

    2016-01-01

    Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF-/-) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF-/- mice. PTRF-/- mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF-/- mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF-/- hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF-/- hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF-/- hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart. PMID:27612189

  18. PTRF/Cavin-1 Deficiency Causes Cardiac Dysfunction Accompanied by Cardiomyocyte Hypertrophy and Cardiac Fibrosis

    PubMed Central

    Ogata, Takehiro; Kasahara, Takeru; Nakanishi, Naohiko; Miyagawa, Kotaro; Naito, Daisuke; Hamaoka, Tetsuro; Nishi, Masahiro; Matoba, Satoaki; Ueyama, Tomomi

    2016-01-01

    Mutations in the PTRF/Cavin-1 gene cause congenital generalized lipodystrophy type 4 (CGL4) associated with myopathy. Additionally, long-QT syndrome and fatal cardiac arrhythmia are observed in patients with CGL4 who have homozygous PTRF/Cavin-1 mutations. PTRF/Cavin-1 deficiency shows reductions of caveolae and caveolin-3 (Cav3) protein expression in skeletal muscle, and Cav3 deficiency in the heart causes cardiac hypertrophy with loss of caveolae. However, it remains unknown how loss of PTRF/Cavin-1 affects cardiac morphology and function. Here, we present a characterization of the hearts of PTRF/Cavin-1-null (PTRF−/−) mice. Electron microscopy revealed the reduction of caveolae in cardiomyocytes of PTRF−/− mice. PTRF−/− mice at 16 weeks of age developed a progressive cardiomyopathic phenotype with wall thickening of left ventricles and reduced fractional shortening evaluated by echocardiography. Electrocardiography revealed that PTRF−/− mice at 24 weeks of age had low voltages and wide QRS complexes in limb leads. Histological analysis showed cardiomyocyte hypertrophy accompanied by progressive interstitial/perivascular fibrosis. Hypertrophy-related fetal gene expression was also induced in PTRF−/− hearts. Western blotting analysis and quantitative RT-PCR revealed that Cav3 expression was suppressed in PTRF−/− hearts compared with that in wild-type (WT) ones. ERK1/2 was activated in PTRF−/− hearts compared with that in WT ones. These results suggest that loss of PTRF/Cavin-1 protein expression is sufficient to induce a molecular program leading to cardiomyocyte hypertrophy and cardiomyopathy, which is partly attributable to Cav3 reduction in the heart. PMID:27612189

  19. Paneth cell-mediated multiorgan dysfunction after acute kidney injury

    PubMed Central

    Park, Sang Won; Kim, Mihwa; Kim, Joo Yun; Ham, Ahrom; Brown, Kevin M.; Mori-Akiyama, Yuko; Ouellette, André J.; D’Agati, Vivette D.; Lee, H. Thomas

    2012-01-01

    Acute kidney injury (AKI) is frequently complicated by extra-renal multi-organ injury including intestinal and hepatic dysfunction. In this study, we hypothesized that a discrete intestinal source of pro-inflammatory mediators drives multi-organ injury in response to AKI. After induction of AKI in mice by renal ischemia-reperfusion or bilateral nephrectomy, small intestinal Paneth cells increased the synthesis and release of IL-17A in conjunction with severe intestinal apoptosis and inflammation. We also detected significantly increased IL-17A in portal and systemic circulation after AKI. Intestinal macrophages appear to transport released Paneth cell granule constituents induced by AKI, away from the base of the crypts into the liver. Genetic or pharmacologic depletion of Paneth cells decreased small intestinal IL-17A secretion and plasma IL-17A levels significantly and attenuated intestinal, hepatic, and renal injury after AKI. Similarly, portal delivery of IL-17A in macrophage depleted mice decreased markedly, and intestinal, hepatic, and renal injury following AKI was attenuated without affecting intestinal IL-17A generation. In conclusion, AKI induces IL-17A synthesis and secretion by Paneth cells to initiate intestinal and hepatic injury by hepatic and systemic delivery of IL-17A by macrophages. Modulation of Paneth cell dysregulation may have therapeutic implications by reducing systemic complications arising from AKI. PMID:23109723

  20. MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats.

    PubMed

    Shintani-ishida, Kaori; Saka, Kanju; Yamaguchi, Koji; Hayashida, Makiko; Nagai, Hisashi; Takemura, Genzou; Yoshida, Ken-ichi

    2014-05-01

    The underlying mechanisms of cardiotoxicity of 3,4-methylenedioxymethylamphetamine (MDMA, "ecstasy") abuse are unclear. Autophagy exerts either adaptive or maladaptive effects on cardiac function in various pathological settings, but nothing is known on the role of autophagy in the MDMA cardiotoxicity. Here, we investigated the mechanism through which autophagy may be involved in MDMA-induced cardiac contractile dysfunction. Rats were injected intraperitoneally with MDMA (20mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24h after MDMA administration. Western blot analysis showed a time-dependent increase in the levels of microtubule-associated protein light chain 3-II (LC3-II) and cathepsin-D after MDMA administration. Electron microscopy showed the presence of autophagic vacuoles in cardiomyocytes. MDMA upregulated phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) at Thr172, mammalian target of rapamycin (mTOR) at Thr2446, Raptor at Ser792, and Unc51-like kinase (ULK1) at Ser555, suggesting activation of autophagy through the AMPK-mTOR pathway. The effects of autophagic inhibitors 3-methyladenine (3-MA) and chloroquine (CQ) on LC3-II levels indicated that MDMA enhanced autophagosome formation, but attenuated autophagosome clearance. MDMA also induced release of cathepsins into cytosol, and western blotting and electron microscopy showed cardiac troponin I (cTnI) degradation and myofibril damage, respectively. 3-MA, CQ, and a lysosomal inhibitor, E64c, inhibited cTnI proteolysis and improved contractile dysfunction after MDMA administration. In conclusion, MDMA causes lysosome destabilization following activation of the autophagy-lysosomal pathway, through which released lysosomal proteases damage myofibrils and induce LV systolic dysfunction in rat heart.

  1. Insulin-like growth factor 1 treatment of MSCs attenuates inflammation and cardiac dysfunction following MI.

    PubMed

    Guo, Jun; Zheng, Dong; Li, Wen-feng; Li, Hai-rui; Zhang, Ai-dong; Li, Zi-cheng

    2014-12-01

    It has been reported that insulin-like growth factor 1 (IGF-1) promoted migration of endothelial cells and cardiac resident progenitor cells. In the previous study, we found the time-dependent and dose-dependent effects of IGF-1 treatment on the CXCR4 expression in MSCs in vitro, but it is still not clear whether IGF-1 pretreatment of MSCs may play anti-apoptotic and anti-inflammation role in myocardial infarction. In this study, we demonstrated that IGF-1-treated MSCs' transplantation attenuate cardiac dysfunction, increase the survival of engrafted cells in the ischemic heart, decrease myocardium cells apoptosis, and inhibit protein production and gene expression of inflammation cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6. IGF-1 pretreatment of MSCs may play anti-apoptotic and anti-inflammation roles in post-myocardial infarction.

  2. Normalisation of plasma growth hormone levels improved cardiac dysfunction due to acromegalic cardiomyopathy with severe fibrosis.

    PubMed

    Yokota, Fumiko; Arima, Hiroshi; Hirano, Miho; Uchikawa, Tomohiro; Inden, Yasuya; Nagatani, Tetsuya; Oiso, Yutaka

    2010-09-19

    A 51-year-old man was referred to the Department of Cardiology in our hospital due to severe congestive heart failure and ventricular arrhythmias in March 2008. He had repeated ventricular tachycardia for years and the left ventricular ejection fraction (EF) was 11% on admission. A myocardial biopsy revealed that over 50% cardiomyocytes were replaced by fibrosis. Due to the typical acromegalic features, he was referred to the endocrinology department and diagnosed as acromegaly. He was treated with octreotide for 8 months followed by trans-sphenoidal surgery. The plasma levels of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) decreased by octreotide and normalised by surgery after which the cardiac function improved drastically. The current case demonstrates that cardiac dysfunction in acromegaly could be recovered by normalisation of GH and IGF-1 even in the presence of severe fibrosis in the myocardium.

  3. Cardiac-Autonomic Imbalance and Baroreflex Dysfunction in the Renovascular Angiotensin-Dependent Hypertensive Mouse

    PubMed Central

    Campagnaro, Bianca P.; Gava, Agata L.; Meyrelles, Silvana S.; Vasquez, Elisardo C.

    2012-01-01

    Mouse models provide powerful tools for studying the mechanisms underlying the dysfunction of the autonomic reflex control of cardiovascular function and those involved in cardiovascular diseases. The established murine model of two-kidney, one-clip (2K1C) angiotensin II-dependent hypertension represents a useful tool for studying the neural control of cardiovascular function. In this paper, we discuss the main contributions from our laboratory and others regarding cardiac-autonomic imbalance and baroreflex dysfunction. We show recent data from the angiotensin-dependent hypertensive mouse demonstrating DNA damage and oxidative stress using the comet assay and flow cytometry, respectively. Finally, we highlight the relationships between angiotensin and peripheral and central nervous system areas of cardiovascular control and oxidative stress in the 2K1C hypertensive mouse. PMID:23193440

  4. Blockade of Exosome Generation with GW4869 Dampens the Sepsis-Induced Inflammation and Cardiac Dysfunction

    PubMed Central

    Essandoh, Kobina; Yang, Liwang; Wang, Xiaohong; Huang, Wei; Qin, Dongze; Hao, Jiukuan; Wang, Yigang; Zingarelli, Basilia; Peng, Tianqing; Fan, Guo-Chang

    2015-01-01

    Sepsis is an infection-induced severe inflammatory disorder that leads to multiple organ failure. Amongst organs affected, myocardial depression is believed to be a major contributor to septic death. While it has been identified that large amounts of circulating pro-inflammatory cytokines are culprit for triggering cardiac dysfunction in sepsis, the underlying mechanisms remain obscure. Additionally, recent studies have shown that exosomes released from bacteria-infected macrophages are pro-inflammatory. Hence, we examined in this study whether blocking the generation of exosomes would be protective against sepsis-induced inflammatory response and cardiac dysfunction. To this end, we pre-treated RAW264.7 macrophages with GW4869, an inhibitor of exosome biogenesis/release, followed by endotoxin (LPS) challenge. In vivo, we injected wild-type (WT) mice with GW4869 for 1 h prior to endotoxin treatment or cecal ligation/puncture (CLP) surgery. We observed that pre-treatment with GW4869 significantly impaired release of both exosomes and pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) in RAW264.7 macrophages. At 12 h after LPS treatment or CLP surgery, WT mice pretreated with GW4869 displayed lower amounts of exosomes and pro-inflammatory cytokines in the serum than control PBS-injected mice. Accordingly, GW4869 treatment diminished the sepsis-induced cardiac inflammation, attenuated myocardial depression and prolonged survival. Together, our findings indicate that blockade of exosome generation in sepsis dampens the sepsis-triggered inflammatory response and thereby, improves cardiac function and survival. PMID:26300484

  5. Acute effects of carbon monoxide on cardiac electrical stability

    SciTech Connect

    Verrier, R.L.; Mills, A.K.; Skornik, W.A. )

    1990-10-01

    The objective of this project was to determine the effects of acute carbon monoxide exposure on cardiac electrical stability. To obtain a comprehensive assessment, diverse biological models were employed. These involved cardiac electrical testing in the normal and ischemic heart in anesthetized and conscious dogs. The experimental plan was designed both to examine the direct effects of carbon monoxide exposure on the myocardium and to evaluate possible indirect influences through alterations in platelet aggregability or changes in central nervous system activity in the conscious animal. Our results indicate that exposure to relatively high levels of carbon monoxide, leading to carboxyhemoglobin concentrations of up to 20 percent, is without significant effect on ventricular electrical stability. This appears to be the case in the acutely ischemic heart as well as in the normal heart. It is important to note that the total exposure period was in the range of 90 to 124 minutes. The possibility that longer periods of exposure or exacerbation from nicotine in cigarette smoke could have a deleterious effect cannot be excluded. We also examined whether or not alterations in platelet aggregability due to carbon monoxide exposure could be a predisposing factor for cardiac arrhythmias. A model involving partial coronary artery stenosis was used to simulate the conditions under which platelet plugs could lead to myocardial ischemia and life-threatening arrhythmias. We found no changes either in the cycle frequency of coronary blood flow oscillations or in platelet aggregability during carbon monoxide exposure. Thus, carbon monoxide exposure does not appear to alter platelet aggregability or its effect on coronary blood flow during stenosis. In the final series of experiments, we examined the effects of carbon monoxide exposure in the conscious state.

  6. Activation of the Cardiac Renin-Angiotensin System in High Oxygen-Exposed Newborn Rats: Angiotensin Receptor Blockade Prevents the Developmental Programming of Cardiac Dysfunction.

    PubMed

    Bertagnolli, Mariane; Dios, Anne; Béland-Bonenfant, Sarah; Gascon, Gabrielle; Sutherland, Megan; Lukaszewski, Marie-Amélie; Cloutier, Anik; Paradis, Pierre; Schiffrin, Ernesto L; Nuyt, Anne Monique

    2016-04-01

    Newborn rats exposed to high oxygen (O2), mimicking preterm birth-related neonatal stress, develop later in life cardiac hypertrophy, dysfunction, fibrosis, and activation of the renin-angiotensin system. Cardiac renin-angiotensin system activation in O2-exposed adult rats is characterized by an imbalance in angiotensin (Ang) receptors type 1/2 (AT1/2), with prevailing AT1 expression. To study the role of renin-angiotensin system in the developmental programming of cardiac dysfunction, we assessed Ang receptor expression during neonatal high O2 exposure and whether AT1 receptor blockade prevents cardiac alterations in early adulthood. Sprague-Dawley newborn rats were kept with their mother in 80% O2 or room air (control) from days 3 to 10 (P3-P10) of life. Losartan or water was administered by gavage from P8 to P10 (n=9/group). Rats were studied at P3 (before O2 exposure), P5, P10 (end of O2), and P28. Losartan treatment had no impact on growth or kidney development. AT1 and Ang type 2 receptors were upregulated in the left ventricle by high O2 exposure (P5 and P10), which was prevented by Losartan treatment at P10. Losartan prevented the cardiac AT1/2 imbalance at P28. Losartan decreased cardiac hypertrophy and fibrosis and improved left ventricle fraction of shortening in P28 O2-exposed rats, which was associated with decreased oxidation of calcium/calmodulin-dependent protein kinase II, inhibition of the transforming growth factor-β/SMAD3 pathway, and upregulation of cardiac angiotensin-converting enzyme 2. In conclusion, short-term Ang II blockade during neonatal high O2 prevents the development of cardiac alterations later in life in rats. These findings highlight the key role of neonatal renin-angiotensin system activation in the developmental programming of cardiac dysfunction induced by deleterious neonatal conditions.

  7. Optimal Cutoff Levels of More Sensitive Cardiac Troponin Assays for the Early Diagnosis of Myocardial Infarction in Patients With Renal Dysfunction

    PubMed Central

    Twerenbold, Raphael; Wildi, Karin; Jaeger, Cedric; Gimenez, Maria Rubini; Reiter, Miriam; Reichlin, Tobias; Walukiewicz, Astrid; Gugala, Mathias; Krivoshei, Lian; Marti, Nadine; Moreno Weidmann, Zoraida; Hillinger, Petra; Puelacher, Christian; Rentsch, Katharina; Honegger, Ursina; Schumacher, Carmela; Zurbriggen, Felicitas; Freese, Michael; Stelzig, Claudia; Campodarve, Isabel; Bassetti, Stefano; Osswald, Stefan

    2015-01-01

    Background— It is unknown whether more sensitive cardiac troponin (cTn) assays maintain their clinical utility in patients with renal dysfunction. Moreover, their optimal cutoff levels in this vulnerable patient population have not previously been defined. Methods and Results— In this multicenter study, we examined the clinical utility of 7 more sensitive cTn assays (3 sensitive and 4 high-sensitivity cTn assays) in patients presenting with symptoms suggestive of acute myocardial infarction. Among 2813 unselected patients, 447 (16%) had renal dysfunction (defined as Modification of Diet in Renal Disease–estimated glomerular filtration rate <60 mL·min−1·1.73 m−2). The final diagnosis was centrally adjudicated by 2 independent cardiologists using all available information, including coronary angiography and serial levels of high-sensitivity cTnT. Acute myocardial infarction was the final diagnosis in 36% of all patients with renal dysfunction. Among patients with renal dysfunction and elevated baseline cTn levels (≥99th percentile), acute myocardial infarction was the most common diagnosis for all assays (range, 45%–80%). In patients with renal dysfunction, diagnostic accuracy at presentation, quantified by the area under the receiver-operator characteristic curve, was 0.87 to 0.89 with no significant differences between the 7 more sensitive cTn assays and further increased to 0.91 to 0.95 at 3 hours. Overall, the area under the receiver-operator characteristic curve in patients with renal dysfunction was only slightly lower than in patients with normal renal function. The optimal receiver-operator characteristic curve–derived cTn cutoff levels in patients with renal dysfunction were significantly higher compared with those in patients with normal renal function (factor, 1.9–3.4). Conclusions— More sensitive cTn assays maintain high diagnostic accuracy in patients with renal dysfunction. To ensure the best possible clinical use, assay

  8. miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2.

    PubMed

    Wang, Hui; Bei, Yihua; Shen, Shutong; Huang, Peipei; Shi, Jing; Zhang, Jialiang; Sun, Qi; Chen, Yuanyuan; Yang, Yun; Xu, Tianzhao; Kong, Xiangqing; Xiao, Junjie

    2016-05-01

    Cardiac dysfunction with sepsis is a major cause of death in intensive care units. Several lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting sepsis, though direct evidence of their functional roles in septic cardiac dysfunction is still lacking. In this study, C57BL/6 mice were exposed to lipopolysaccharide (LPS) to induce sepsis-associated cardiac dysfunction, as evidenced by reduced fractional shortening (FS) and ejection fraction (EF) and detrimental changes in cardiac contractility, inflammation, and energy metabolism. Microarray analysis and qRT-PCRs revealed that miR-21-3p was significantly induced in heart samples challenged with LPS. Impressively, pharmacological inhibition of miR-21-3p using antagomiR was able to preserve FS and EF and prevent mitochondria ultrastructural damage and autophagy in LPS-treated mice, while forced expression of miR-21-3p using agomiR aggravated that. Besides that, miR-21-3p antagomiR improved the survival of mice treated with LPS. Meanwhile, our data showed that SH3 domain-containing protein 2 (SORBS2) was inversely correlated with miR-21-3p expression level in mice hearts, and was repressed in hearts challenged with LPS, suggesting SORBS2 as a target gene of miR-21-3p. Additionally, plasma miR-21-3p was markedly elevated in septic patients with cardiac dysfunction as compared to septic patients without cardiac dysfunction. The ROC curve showed that plasma miR-21-3p could be a specific predictor of septic patients developing cardiac dysfunction with an area under the curve of 0.939. Collectively, the present study provides strong evidence that miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2. Inhibition of miR-21-3p might be a protective strategy to treat sepsis-induced cardiac dysfunction.

  9. miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2.

    PubMed

    Wang, Hui; Bei, Yihua; Shen, Shutong; Huang, Peipei; Shi, Jing; Zhang, Jialiang; Sun, Qi; Chen, Yuanyuan; Yang, Yun; Xu, Tianzhao; Kong, Xiangqing; Xiao, Junjie

    2016-05-01

    Cardiac dysfunction with sepsis is a major cause of death in intensive care units. Several lines of evidence have revealed the potential of microRNAs (miRNAs, miRs) as biomarkers for detecting sepsis, though direct evidence of their functional roles in septic cardiac dysfunction is still lacking. In this study, C57BL/6 mice were exposed to lipopolysaccharide (LPS) to induce sepsis-associated cardiac dysfunction, as evidenced by reduced fractional shortening (FS) and ejection fraction (EF) and detrimental changes in cardiac contractility, inflammation, and energy metabolism. Microarray analysis and qRT-PCRs revealed that miR-21-3p was significantly induced in heart samples challenged with LPS. Impressively, pharmacological inhibition of miR-21-3p using antagomiR was able to preserve FS and EF and prevent mitochondria ultrastructural damage and autophagy in LPS-treated mice, while forced expression of miR-21-3p using agomiR aggravated that. Besides that, miR-21-3p antagomiR improved the survival of mice treated with LPS. Meanwhile, our data showed that SH3 domain-containing protein 2 (SORBS2) was inversely correlated with miR-21-3p expression level in mice hearts, and was repressed in hearts challenged with LPS, suggesting SORBS2 as a target gene of miR-21-3p. Additionally, plasma miR-21-3p was markedly elevated in septic patients with cardiac dysfunction as compared to septic patients without cardiac dysfunction. The ROC curve showed that plasma miR-21-3p could be a specific predictor of septic patients developing cardiac dysfunction with an area under the curve of 0.939. Collectively, the present study provides strong evidence that miR-21-3p controls sepsis-associated cardiac dysfunction via regulating SORBS2. Inhibition of miR-21-3p might be a protective strategy to treat sepsis-induced cardiac dysfunction. PMID:27033308

  10. Mesenteric lymph from rats with trauma-hemorrhagic shock causes abnormal cardiac myocyte function and induces myocardial contractile dysfunction.

    PubMed

    Sambol, Justin T; Lee, Marlon A; Jiang, Mingshan; Dosi, Garima; Dong, Wei; Deitch, Edwin A; Yatani, Atsuko

    2011-09-01

    Myocardial contractile dysfunction develops following trauma-hemorrhagic shock (T/HS). We have previously shown that, in a rat fixed pressure model of T/HS (mean arterial pressure of 30-35 mmHg for 90 min), mesenteric lymph duct ligation before T/HS prevented T/HS-induced myocardial contractile depression. To determine whether T/HS lymph directly alters myocardial contractility, we examined the functional effects of physiologically relevant concentrations of mesenteric lymph collected from rats undergoing trauma-sham shock (T/SS) or T/HS on both isolated cardiac myocytes and Langendorff-perfused whole hearts. Acute application of T/HS lymph (0.1-2%), but not T/SS lymph, induced dual inotropic effects on myocytes with an immediate increase in the amplitude of cell shortening (1.4 ± 0.1-fold) followed by a complete block of contraction. Similarly, T/HS lymph caused dual, positive and negative effects on cellular Ca²⁺ transients. These effects were associated with changes in the electrophysiological properties of cardiac myocytes; T/HS lymph initially prolonged the action potential duration (action potential duration at 90% repolarization, 3.3 ± 0.4-fold), and this was followed by a decrease in the plateau potential and membrane depolarization. Furthermore, intravenous infusion of T/HS lymph, but not T/SS lymph, caused myocardial contractile dysfunction at 24 h after injection, which mimicked actual T/HS-induced changes; left ventricular developed pressure (LVDP) and the maximal rate of LVDP rise and fall (±dP/dt(max)) were decreased and inotropic response to Ca²⁺ was blunted. However, the contractile responsiveness to β-adrenergic receptor stimulation in the T/HS lymph-infused hearts remained unchanged. These results suggest that T/HS lymph directly causes negative inotropic effects on the myocardium and that T/HS lymph-induced changes in myocyte function are likely to contribute to the development of T/HS-induced myocardial dysfunction.

  11. Mesenteric lymph from rats with trauma-hemorrhagic shock causes abnormal cardiac myocyte function and induces myocardial contractile dysfunction

    PubMed Central

    Sambol, Justin T.; Lee, Marlon A.; Jiang, Mingshan; Dosi, Garima; Dong, Wei; Deitch, Edwin A.

    2011-01-01

    Myocardial contractile dysfunction develops following trauma-hemorrhagic shock (T/HS). We have previously shown that, in a rat fixed pressure model of T/HS (mean arterial pressure of 30–35 mmHg for 90 min), mesenteric lymph duct ligation before T/HS prevented T/HS-induced myocardial contractile depression. To determine whether T/HS lymph directly alters myocardial contractility, we examined the functional effects of physiologically relevant concentrations of mesenteric lymph collected from rats undergoing trauma-sham shock (T/SS) or T/HS on both isolated cardiac myocytes and Langendorff-perfused whole hearts. Acute application of T/HS lymph (0.1–2%), but not T/SS lymph, induced dual inotropic effects on myocytes with an immediate increase in the amplitude of cell shortening (1.4 ± 0.1-fold) followed by a complete block of contraction. Similarly, T/HS lymph caused dual, positive and negative effects on cellular Ca2+ transients. These effects were associated with changes in the electrophysiological properties of cardiac myocytes; T/HS lymph initially prolonged the action potential duration (action potential duration at 90% repolarization, 3.3 ± 0.4-fold), and this was followed by a decrease in the plateau potential and membrane depolarization. Furthermore, intravenous infusion of T/HS lymph, but not T/SS lymph, caused myocardial contractile dysfunction at 24 h after injection, which mimicked actual T/HS-induced changes; left ventricular developed pressure (LVDP) and the maximal rate of LVDP rise and fall (±dP/dtmax) were decreased and inotropic response to Ca2+ was blunted. However, the contractile responsiveness to β-adrenergic receptor stimulation in the T/HS lymph-infused hearts remained unchanged. These results suggest that T/HS lymph directly causes negative inotropic effects on the myocardium and that T/HS lymph-induced changes in myocyte function are likely to contribute to the development of T/HS-induced myocardial dysfunction. PMID:21700891

  12. [Non-cardiac causes of acute ischemia in the arms].

    PubMed

    d'Addato, M; Pedrini, L

    1996-01-01

    Among a series of 286 cases of acute ischemia of the upper limb, we analyzed the files of 176 patients (61.5%) with noncardiac ischemia in order to identify the causes and treatment. Trauma was the most frequent cause (126 cases) including trauma of the forearm especially due to stab wounds. Lesions with a subclavian-axillary localization were predominantly due to tear wounds or blunt trauma. We analyzed two groups among the trauma cases: iatrogenic lesions (9 cases) usually resulted from orthopedic surgery (5 cases) or vascular catheterization (3 cases) as well as near-total limb amputations (13) cases. Thrombosis of the subclavian artery occurred in 33 patients; 9 had acute ischemia including 3 due to a cervical rib and 6 due to compression by the rib and the clavicle. Only 4 of these 33 patients suffered ischemia of the hand due to embolization. Acute ischemia was caused by arteriopathy of the hand in 8 patients including 2 volley ball players, 1 baseball player and 3 subjects with occupational microtrauma and 1 with thrombosis of the palmar arch. Finally 1 patient had thrombosis after intravenous drug injection. These files demonstrated the variety of non-cardiac causes of acute ischemia of the upper limb. During the acute phase, we propose locoregional thrombolysis in case of thrombosis and embolectomy for emboli followed by treatment of the casual lesion. An arteriography is essential for correct diagnosis and should include the subclavian artery in the hyperabduction position and the hand. Duplex scanning of the subclavian artery is indicated in case of ischemia of the hand using the Adson, McGowan and Wright maneuvers in order to guide the radiologist for invasive radiography before initiating appropriate treatment.

  13. Exercise training reduces cardiac dysfunction and remodeling in ovariectomized rats submitted to myocardial infarction.

    PubMed

    Almeida, Simone Alves de; Claudio, Erick Roberto Gonçalves; Mengal, Vinícius; Mengal, Vinícius Franskoviaky; Oliveira, Suelen Guedes de; Merlo, Eduardo; Podratz, Priscila Lang; Gouvêa, Sônia Alves; Graceli, Jones Bernardes; de Abreu, Gláucia Rodrigues

    2014-01-01

    The aim of this study was to evaluate whether exercise training (ET) prevents or minimizes cardiac dysfunction and pathological ventricular remodeling in ovariectomized rats subjected to myocardial infarction (MI) and to examine the possible mechanisms involved in this process. Ovariectomized Wistar rats were subjected to either MI or fictitious surgery (Sham) and randomly divided into the following groups: Control, OVX+SHAMSED, OVX+SHAMET, OVX+MISED and OVX+MIET. ET was performed on a motorized treadmill (5x/wk, 60 min/day, 8 weeks). Cardiac function was assessed by ventricular catheterization and Dihydroethidium fluorescence (DHE) was evaluated to analyze cardiac oxidative stress. Histological analyses were made to assess collagen deposition, myocyte hypertrophy and infarct size. Western Blotting was performed to analyze the protein expression of catalase and SOD-2, as well as Gp91phox and AT1 receptor (AT1R). MI-trained rats had significantly increased in +dP/dt and decreased left ventricular end-diastolic pressure compared with MI-sedentary rats. Moreover, oxidative stress and collagen deposition was reduced, as was myocyte hypertrophy. These effects occurred in parallel with a reduction in both AT1R and Gp91phox expression and an increase in catalase expression. SOD-2 expression was not altered. These results indicate that ET improves the functional cardiac parameters associated with attenuation of cardiac remodeling in ovariectomized rats subjected to MI. The mechanism seems to be related to a reduction in the expression of both the AT1 receptor and Gp91phox as well as an increase in the antioxidant enzyme catalase, which contributes to a reduction in oxidative stress. Therefore, ET may be an important therapeutic target for the prevention of heart failure in postmenopausal women affected by MI. PMID:25551214

  14. Difference in molecular pathology of natriuretic peptides in the myocardium between acute asphyxial and cardiac deaths.

    PubMed

    Chen, Jian-Hua; Michiue, Tomomi; Ishikawa, Takaki; Maeda, Hitoshi

    2012-07-01

    In investigating death due to mechanical asphyxiation and drowning, a cardiac attack is important for discriminating between possible causes of death and as a contributory factor in death processes; however, general pathologies involving visceral congestion are often similar. The present study compared terminal cardiac dysfunction in these fatalities using the molecular pathology of atrial and brain natriuretic peptides (ANP and BNP) in the myocardium as markers of cardiac strain. Both mechanical asphyxiation (n=27) and drowning (n=23) showed significantly lower ANP and BNP mRNA expressions in bilateral ventricular walls than sudden cardiac deaths (n=36). In addition, right atrial wall BNP mRNA expression was lower in asphyxiation; however, immunostaining did not demonstrate any difference among these fatalities. Differences among the subtypes of asphyxiation or between fresh- and saltwater drowning were insignificant. These observations suggest a difference between primary heart failure in sudden cardiac death and terminal cardiac dysfunction secondary to fatal asphyxiation or drowning.

  15. Pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction in dogs.

    PubMed

    Stepien, Rebecca L

    2009-09-01

    Pulmonary arterial hypertension is a description of a physiological finding rather than a diagnosis. Pulmonary arterial pressure is the result of interactions among pulmonary blood flow (right ventricular cardiac output), pulmonary vascular impedance and post-capillary pressure (typically reflecting left atrial pressure). When elevations in pulmonary arterial pressure (systolic/diastolic pulmonary arterial pressure > approximately 30/19 mmHg at rest) are accompanied by increased left atrial pressure, pulmonary arterial hypertension may be considered secondary to left-heart failure. Introduction of Doppler methods to diagnose pulmonary arterial hypertension has increased the awareness of the prevalence and importance of pulmonary arterial hypertension dogs with left-heart failure. Increasing understanding of the mechanism of development of pulmonary venous hypertension and reactive pulmonary arterial hypertension in dogs with left-heart disease has led to the development of successful additive therapies for progressive clinical signs in the setting of chronic therapy for congestive heart failure due to left-sided valvular and myocardial dysfunction. Because effective therapies for pulmonary arterial hypertension secondary to chronic left-sided cardiac dysfunction are now available, screening for pulmonary arterial hypertension should be a regular part of the Doppler echocardiographic examination in a clinical setting of chronic therapy for left-sided congestive heart failure due to valvular or myocardial disease.

  16. Matrix Metalloproteinase-9 Production following Cardiopulmonary Bypass Was Not Associated with Pulmonary Dysfunction after Cardiac Surgery

    PubMed Central

    Lin, Tso-Chou; Lin, Feng-Yen; Lin, Yi-Wen; Hsu, Che-Hao; Huang, Go-Shine; Wu, Zhi-Fu; Tsai, Yi-Ting; Lin, Chih-Yuan; Li, Chi-Yuan; Tsai, Chien-Sung

    2015-01-01

    Background. Cardiopulmonary bypass (CPB) causes release of matrix metalloproteinase- (MMP-) 9, contributing to pulmonary infiltration and dysfunction. The aims were to investigate MMP-9 production and associated perioperative variables and oxygenation following CPB. Methods. Thirty patients undergoing elective cardiac surgery were included. Arterial blood was sampled at 6 sequential points (before anesthesia induction, before CPB and at 2, 4, 6, and 24 h after beginning CPB) for plasma MMP-9 concentrations by ELISA. The perioperative laboratory data and variables, including bypass time, PaO2/FiO2, and extubation time, were also recorded. Results. The plasma MMP-9 concentrations significantly elevated at 2–6 h after beginning CPB (P < 0.001) and returned to the preanesthesia level at 24 h (P = 0.23), with predominant neutrophil counts after surgery (P < 0.001). The plasma MMP-9 levels at 4 and 6 h were not correlated with prolonged CPB time and displayed no association with postoperative PaO2/FiO2, regardless of reduced ratio from preoperative 342.9 ± 81.2 to postoperative 207.3 ± 121.3 mmHg (P < 0.001). Conclusion. Elective cardiac surgery with CPB induced short-term elevation of plasma MMP-9 concentrations within 24 hours, however, without significant correlation with CPB time and postoperative pulmonary dysfunction, despite predominantly increased neutrophils and reduced oxygenation. PMID:26273135

  17. Renal sympathetic denervation prevents the development of pulmonary arterial hypertension and cardiac dysfunction in dogs.

    PubMed

    Hu, Wei; Yu, Sheng-Bo; Chen, Liao; Guo, Rui-Qiang; Zhao, Qing-Yan

    2015-08-01

    The renin-angiotensin-aldosterone system is activated in pulmonary arterial hypertension (PAH) patients, and this activation may have long-term negative effects on the progression of PAH. The purpose of this study was to evaluate the effects of transcatheter renal sympathetic denervation (RSD) on the development of pulmonary arterial hypertension and cardiac dysfunction in dogs using two-dimensional speckle tracking imaging. Twenty-two dogs were randomly divided into three groups: control group (n = 7), PAH group (n = 8), and PAH + RSD group (n = 7). All dogs were assessed using two-dimensional speckle tracking imaging. The ventricular strain, ventricular synchrony, left ventricular (LV) twist, and torsion rate were analyzed to evaluate cardiac function. After 8 weeks, the right ventricular lateral longitudinal strain and the septum longitudinal strain were reduced in the PAH group compared with the control group (p < 0.001). However, these values were significantly restored in the PAH + RSD group compared with the PAH group (p < 0.01). The degree of LV and RV dyssynchrony was significantly higher in the PAH group compared with the control group (p < 0.001), but the degree of LV and RV dyssynchrony was significantly lower in the PAH + RSD group compared to the PAH group (p < 0.01). The LV twist was significantly restored in the PAH + RSD group compared to the PAH group (p < 0.01). Similarly, the rotation rate was markedly decreased in the PAH group, and strikingly improved in the PAH + RSD group (p < 0.01). These results indicate that RSD prevents the development of PAH and cardiac dysfunction in dogs.

  18. Western diet, but not high fat diet, causes maladaptation of cardiac fatty acid metabolism and cardiac dysfunction in the Wistar rat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity and diabetes are associated with increased fatty acid availability in excess of fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction. We tested the hypothesis that a "western" or a high fat diet will lead to maladaptation of cardia...

  19. "Western" diet, but not high fat diet, causes maladaptation of cardiac fatty acid metabolism and cardiac dysfunction in the Wistar rat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Obesity and diabetes are associated with increased fatty acid availability in excess of fatty acid oxidation capacity. This mismatch is implicated in the pathogenesis of cardiac contractile dysfunction. We tested the hypothesis that a "western" or a high fat diet will lead to maladaptation of cardia...

  20. Gestational hypertension and the developmental origins of cardiac hypertrophy and diastolic dysfunction.

    PubMed

    Armstrong, David W J; Tse, M Yat; Wong, Philip G; Ventura, Nicole M; Meens, Jalna A; Johri, Amer M; Matangi, Murray F; Pang, Stephen C

    2014-06-01

    The developmental origins of health and disease refer to the theory that adverse maternal environments influence fetal development and the risk of cardiovascular disease in adulthood. We used the chronically hypertensive atrial natriuretic peptide knockout (ANP-/-) mouse as a model of gestational hypertension, and attempted to determine the effect of gestational hypertension on left ventricular (LV) structure and function in adult offspring. We crossed normotensive ANP+/+ females with ANP-/- males (yielding ANP+/-(WT) offspring) and hypertensive ANP-/- females with ANP+/+ males (yielding ANP+/-(KO) offspring). Cardiac gene expression was measured using real-time quantitative PCR. Cardiac function was assessed using echocardiography. Daily injections of isoproterenol (ISO) were used to induce cardiac stress. Collagen deposition was assessed using picrosirius red staining. All mice were 10 weeks of age. Gestational hypertension resulted in significant LV hypertrophy in offspring, with no change in LV function. Treatment with ISO resulted in significant LV diastolic dysfunction with a restrictive filling pattern (increased E/A ratio and E/e') and interstitial myocardial fibrosis only in ANP+/-(KO) and not ANP+/-(WT) offspring. Gestational hypertension programs adverse LV structural and functional remodeling in offspring. These data suggest that adverse maternal environments may increase the risk of heart failure in offspring later in life.

  1. Neonatal cardiac dysfunction and transcriptome changes caused by the absence of Celf1

    PubMed Central

    Giudice, Jimena; Xia, Zheng; Li, Wei; Cooper, Thomas A.

    2016-01-01

    The RNA binding protein Celf1 regulates alternative splicing in the nucleus and mRNA stability and translation in the cytoplasm. Celf1 is strongly down-regulated during mouse postnatal heart development. Its re-induction in adults induced severe heart failure and reversion to fetal splicing and gene expression patterns. However, the impact of Celf1 depletion on cardiac transcriptional and posttranscriptional dynamics in neonates has not been addressed. We found that homozygous Celf1 knock-out neonates exhibited cardiac dysfunction not observed in older homozygous animals, although homozygous mice are smaller than wild type littermates throughout development. RNA-sequencing of mRNA from homozygous neonatal hearts identified a network of cell cycle genes significantly up-regulated and down-regulation of ion transport and circadian genes. Cell cycle genes are enriched for Celf1 binding sites supporting a regulatory role in mRNA stability of these transcripts. We also identified a cardiac splicing network coordinated by Celf1 depletion. Target events contain multiple Celf1 binding sites and enrichment in GU-rich motifs. Identification of direct Celf1 targets will advance our knowledge in the mechanisms behind developmental networks regulated by Celf1 and diseases where Celf1 is mis-regulated. PMID:27759042

  2. Cardiac dysfunction following brain death after severe pediatric traumatic brain injury: A preliminary study of 32 children

    PubMed Central

    Krishnamoorthy, Vijay; Prathep, Sumidtra; Sharma, Deepak; Fujita, Yasuki; Armstead, William; Vavilala, Monica S.

    2015-01-01

    Background: Cardiac dysfunction after brain death has been described in a variety of brain injury paradigms but is not well understood after severe pediatric traumatic brain injury (TBI). Cardiac dysfunction may have implications for organ donation in this patient population. Materials and Methods: We conducted a retrospective cohort study of pediatric patients with severe TBI, both with and without a diagnosis of brain death, who underwent echocardiography during the first 2 weeks after TBI, between the period of 2003–2011. We examined cardiac dysfunction in patients with and without a diagnosis of brain death. Results: In all, 32 (2.3%) of 1,413 severe pediatric TBI patients underwent echocardiogram evaluation. Most patients had head abbreviated injury score 5 (range 2–6) and subdural hematoma (34.4%). Ten patients with TBI had brain death compared with 22 severe TBI patients who did not have brain death. Four (40%) of 10 pediatric TBI patients with brain death had a low ejection fraction (EF) compared with 1 (4.5%) of 22 pediatric TBI patients without brain death who had low EF (OR = 14, P = 0.024). Conclusions: The incidence of cardiac dysfunction is higher among pediatric severe TBI patients with a diagnosis of brain death, as compared to patients without brain death. This finding may have implications for cardiac organ donation from this population and deserves further study. PMID:26157654

  3. 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

  4. Bronchogenic Carcinoma with Cardiac Invasion Simulating Acute Myocardial Infarction

    PubMed Central

    Das, Anirban; Das, Sibes K.; Pandit, Sudipta; Karmakar, Rathindra Nath

    2016-01-01

    Cardiac metastases in bronchogenic carcinoma may occur due to retrograde lymphatic spread or by hematogenous dissemination of tumour cells, but direct invasion of heart by adjacent malignant lung mass is very uncommon. Pericardium is frequently involved in direct cardiac invasion by adjacent lung cancer. Pericardial effusion, pericarditis, and tamponade are common and life threatening presentation in such cases. But direct invasion of myocardium and endocardium is very uncommon. Left atrial endocardium is most commonly involved in such cases due to anatomical contiguity with pulmonary hilum through pulmonary veins, and in most cases left atrial involvement is asymptomatic. But myocardial compression and invasion by adjacent lung mass may result in myocardial ischemia and may present with retrosternal, oppressive chest pain which clinically may simulate with the acute myocardial infarction (AMI). As a result, it leads to misdiagnosis and delayed diagnosis of lung cancer. Here we report a case of non-small-cell carcinoma of right lung which was presented with asymptomatic invasion in left atrium and retrosternal chest pain simulating AMI due to myocardial compression by adjacent lung mass, in a seventy-four-year-old male smoker. PMID:27042370

  5. Acute exercise modifies titin phosphorylation and increases cardiac myofilament stiffness

    PubMed Central

    Müller, Anna E.; Kreiner, Matthias; Kötter, Sebastian; Lassak, Philipp; Bloch, Wilhelm; Suhr, Frank; Krüger, Martina

    2014-01-01

    Titin-based myofilament stiffness is largely modulated by phosphorylation of its elastic I-band regions N2-Bus (decreases passive stiffness, PT) and PEVK (increases PT). Here, we tested the hypothesis that acute exercise changes titin phosphorylation and modifies myofilament stiffness. Adult rats were exercised on a treadmill for 15 min, untrained animals served as controls. Titin phosphorylation was determined by Western blot analysis using phosphospecific antibodies to Ser4099 and Ser4010 in the N2-Bus region (PKG and PKA-dependent. respectively), and to Ser11878 and Ser 12022 in the PEVK region (PKCα and CaMKIIδ-dependent, respectively). Passive tension was determined by step-wise stretching of isolated skinned cardiomyocytes to sarcomere length (SL) ranging from 1.9 to 2.4 μm and showed a significantly increased PT from exercised samples, compared to controls. In cardiac samples titin N2-Bus phosphorylation was significantly decreased by 40% at Ser4099, however, no significant changes were observed at Ser4010. PEVK phosphorylation at Ser11878 was significantly increased, which is probably mediated by the observed exercise-induced increase in PKCα activity. Interestingly, relative phosphorylation of Ser12022 was substantially decreased in the exercised samples. Surprisingly, in skeletal samples from acutely exercised animals we detected a significant decrease in PEVK phosphorylation at Ser11878 and an increase in Ser12022 phosphorylation; however, PKCα activity remained unchanged. In summary, our data show that a single exercise bout of 15 min affects titin domain phosphorylation and titin-based myocyte stiffness with obviously divergent effects in cardiac and skeletal muscle tissues. The observed changes in titin stiffness could play an important role in adapting the passive and active properties of the myocardium and the skeletal muscle to increased physical activity. PMID:25477822

  6. Screening for cardiac dysfunction in anthracycline-exposed childhood cancer survivors

    PubMed Central

    Armenian, Saro H.; Gelehrter, Sarah K.; Vase, Tabitha; Venkatramani, Rajkumar; Landier, Wendy; WilsonM, Karla D.; Herrera, Claudia; Reichman, Leah; Menteer, John-David; Mascarenhas, Leo; Freyer, David R.; Venkataraman, Kalyanasundaram; Bhatia, Smita

    2014-01-01

    Purpose To examine the utility and reliability of obtaining early echocardiographic measurements of left ventricular (LV) remodeling as well as blood biomarkers of cardiac injury in asymptomatic childhood cancer survivors at risk for LV dysfunction and congestive heart failure due to past exposure to anthracycline chemotherapy. Experimental Design Using a cross-sectional design, anthracycline-exposed childhood cancer survivors with preserved EF (≥50%) were evaluated using early echocardiographic indices and blood biomarkers of LV dysfunction. Survivors treated with ≥300mg/m2 anthracyclines (high-risk [HR]: n=100) were compared with: i) those treated with <300 mg/m2 anthracyclines (low-risk [LR]: n=50) and matched healthy controls (HC: n=50). All echocardiograms were interpreted by an institutional cardiologist and a study cardiologist blinded to risk status. Results Time from diagnosis was comparable for HR (12.0y) and LR (13.2y, p=0.8) survivors. Echocardiograms: HR had lower LV thickness-dimension ratio (Z-score: HR: −0.62, LR: −0.03, HC: −0.02; p<0.001), increased LV wall stress (HR: 66.7 g/cm2, LR: 56.6 g/cm2, HC: 54.2 g/cm2; p<0.01) and higher myocardial performance index (HR: 0.51, LR: 0.46, HC: 0.46; P<0.01). Inter-observer correlation (clinical/blinded reading) for all echocardiographic indices was excellent (range: R=0.76-0.97, p<0.001). Blood biomarkers: With the exception of NT-proBNP (r=0.28, p<0.01), there was no correlation between blood biomarkers (BNP, Troponin-T, ST-2, Galectin-3) and LV dysfunction. Conclusion Childhood cancer survivors with preserved EF 10+years from anthracycline exposure had dose-dependent changes in echocardiographic markers of LV dysfunction. PMID:24947931

  7. Enhanced cardiac inflammation and fibrosis in ovariectomized hypertensive rats: a possible mechanism of diastolic dysfunction in postmenopausal women.

    PubMed

    Mori, Takahiro; Kai, Hisashi; Kajimoto, Hidemi; Koga, Mitsuhisa; Kudo, Hiroshi; Takayama, Narimasa; Yasuoka, Suguru; Anegawa, Takahiro; Kai, Mamiko; Imaizumi, Tsutomu

    2011-04-01

    Diastolic dysfunction is more prevalent in individuals with hypertension, particularly postmenopausal women; however, the pathogenesis of diastolic dysfunction remains unknown. Pressure overload activates cardiac inflammation, which induces myocardial fibrosis and diastolic dysfunction in rats with a suprarenal aortic constriction (AC). Therefore, we examined the effects of bilateral ovariectomy (OVX) on left ventricle (LV) remodeling, diastolic dysfunction and cardiac inflammation in hypertensive female rats. Rats were randomized to OVX+AC, OVX and AC groups as well as a Control group receiving sham operations for both the procedures. Rats underwent OVX at 6 weeks and AC at 10 weeks (Day 0). At Day 28, OVX did not appear to affect arterial pressure, cardiac hypertrophy or LV fractional shortening in AC rats. However, OVX increased myocardial fibrosis, elevated LV end-diastolic pressure and reduced the transmitral Doppler spectra early to late filling velocity ratio in AC rats. AC-induced transient myocardial monocyte chemoattractant protein-1 expression and macrophage infiltration, both of which peaked at Day 3 and were augmented and prolonged by OVX. At Day 28, dihydroethidium staining revealed superoxide generation in the intramyocardial arterioles in the OVX+AC group but not in the AC group. NOX1, a functional subunit of nicotinamide adenine dinucleotide phosphate oxidase, was upregulated only in the OVX+AC group at Day 28. Chronic 17β-estradiol replacement prevented the increases in macrophage infiltration, NOX1 upregulation, myocardial fibrosis and diastolic dysfunction in OVX+AC rats. In conclusion, we suggest that estrogen deficiency augments cardiac inflammation and oxidative stress and thereby aggravates myocardial fibrosis and diastolic dysfunction in hypertensive female rats. The findings provide insight into the mechanism underlying diastolic dysfunction in hypertensive postmenopausal women.

  8. BATF inhibition prevent acute allograft rejection after cardiac transplantation

    PubMed Central

    Yang, Bo; He, Fan; Dai, Chen; Tan, Rumeng; Ma, Dongxia; Wang, Zhimin; Zhang, Bo; Feng, Jincheng; Wei, Lai; Zhu, Hua; Chen, Zhishui

    2016-01-01

    Acute allograft rejection is a serious and life-threatening complication of organ transplantation. Th17 cells induced inflammation has been described to play an important role in allograft rejection. Since there is a plenty of evidence indicating that transcriptional factor BATF regulates the differentiation of Th17 and follicular T helper cells both in vitro and in vivo, we investigated whether is BATF involved in acute rejection and allograft survival by injecting lentivirus containing BATF shRNA through tail vein before the cardiac transplantation operation. We found that the allograft survival time of the mice treated with BATF shRNA was significantly prolonged compared with that of negative shRNA treated group and the control group. Further pathological analysis revealed that the BATF shRNA treatment group had significantly lower rejection degree than the negative shRNA group, while there was no significant difference between the negative shRNA group and the control group. Furthermore, flow cytometry analysis and quantitative polymerase chain reaction and enzyme-linked immuno sorbent assay were used to determine the proportion of T helper cells, the expression of specific transcription factor and the inflammatory cytokines respectively. Data showed that BATF regulated Th17 and Treg responses during allograft rejection. And BATF inhibition led to reduction of the expression level of Rorγ-t and enhancement of the Foxp-3. In addition, cytokines IL-17A and IL-4 were found decreased. This may indicate BATF as a novel therapy target for treatment of acute allograft rejection. PMID:27648151

  9. BATF inhibition prevent acute allograft rejection after cardiac transplantation.

    PubMed

    Yang, Bo; He, Fan; Dai, Chen; Tan, Rumeng; Ma, Dongxia; Wang, Zhimin; Zhang, Bo; Feng, Jincheng; Wei, Lai; Zhu, Hua; Chen, Zhishui

    2016-01-01

    Acute allograft rejection is a serious and life-threatening complication of organ transplantation. Th17 cells induced inflammation has been described to play an important role in allograft rejection. Since there is a plenty of evidence indicating that transcriptional factor BATF regulates the differentiation of Th17 and follicular T helper cells both in vitro and in vivo, we investigated whether is BATF involved in acute rejection and allograft survival by injecting lentivirus containing BATF shRNA through tail vein before the cardiac transplantation operation. We found that the allograft survival time of the mice treated with BATF shRNA was significantly prolonged compared with that of negative shRNA treated group and the control group. Further pathological analysis revealed that the BATF shRNA treatment group had significantly lower rejection degree than the negative shRNA group, while there was no significant difference between the negative shRNA group and the control group. Furthermore, flow cytometry analysis and quantitative polymerase chain reaction and enzyme-linked immuno sorbent assay were used to determine the proportion of T helper cells, the expression of specific transcription factor and the inflammatory cytokines respectively. Data showed that BATF regulated Th17 and Treg responses during allograft rejection. And BATF inhibition led to reduction of the expression level of Rorγ-t and enhancement of the Foxp-3. In addition, cytokines IL-17A and IL-4 were found decreased. This may indicate BATF as a novel therapy target for treatment of acute allograft rejection. PMID:27648151

  10. BATF inhibition prevent acute allograft rejection after cardiac transplantation

    PubMed Central

    Yang, Bo; He, Fan; Dai, Chen; Tan, Rumeng; Ma, Dongxia; Wang, Zhimin; Zhang, Bo; Feng, Jincheng; Wei, Lai; Zhu, Hua; Chen, Zhishui

    2016-01-01

    Acute allograft rejection is a serious and life-threatening complication of organ transplantation. Th17 cells induced inflammation has been described to play an important role in allograft rejection. Since there is a plenty of evidence indicating that transcriptional factor BATF regulates the differentiation of Th17 and follicular T helper cells both in vitro and in vivo, we investigated whether is BATF involved in acute rejection and allograft survival by injecting lentivirus containing BATF shRNA through tail vein before the cardiac transplantation operation. We found that the allograft survival time of the mice treated with BATF shRNA was significantly prolonged compared with that of negative shRNA treated group and the control group. Further pathological analysis revealed that the BATF shRNA treatment group had significantly lower rejection degree than the negative shRNA group, while there was no significant difference between the negative shRNA group and the control group. Furthermore, flow cytometry analysis and quantitative polymerase chain reaction and enzyme-linked immuno sorbent assay were used to determine the proportion of T helper cells, the expression of specific transcription factor and the inflammatory cytokines respectively. Data showed that BATF regulated Th17 and Treg responses during allograft rejection. And BATF inhibition led to reduction of the expression level of Rorγ-t and enhancement of the Foxp-3. In addition, cytokines IL-17A and IL-4 were found decreased. This may indicate BATF as a novel therapy target for treatment of acute allograft rejection.

  11. Silent left ventricular dysfunction during routine activity after thrombolytic therapy for acute myocardial infarction

    SciTech Connect

    Kayden, D.S.; Wackers, F.J.; Zaret, B.L. )

    1990-06-01

    To investigate prospectively the occurrence and significance of postinfarction transient left ventricular dysfunction, 33 ambulatory patients who underwent thrombolytic therapy after myocardial infarction were monitored continuously for 187 +/- 56 min during normal activity with a radionuclide left ventricular function detector at the time of hospital discharge. Twelve patients demonstrated 19 episodes of transient left ventricular dysfunction (greater than 0.05 decrease in ejection fraction, lasting greater than or equal to 1 min), with no change in heart rate. Only two episodes in one patient were associated with chest pain and electrocardiographic changes. The baseline ejection fraction was 0.52 +/- 0.12 in patients with transient left ventricular dysfunction and 0.51 +/- 0.13 in patients without dysfunction (p = NS). At follow-up study (19.2 +/- 5.4 months), cardiac events (unstable angina, myocardial infarction or death) occurred in 8 of 12 patients with but in only 3 of 21 patients without transient left ventricular dysfunction (p less than 0.01). During submaximal supine bicycle exercise, only two patients demonstrated a decrease in ejection fraction greater than or equal to 0.05 at peak exercise; neither had a subsequent cardiac event. These data suggest that transient episodes of silent left ventricular dysfunction at hospital discharge in patients treated with thrombolysis after myocardial infarction are common and associated with a poor outcome. Continuous left ventricular function monitoring during normal activity may provide prognostic information not available from submaximal exercise test results.

  12. Postpartum Acute Liver Dysfunction: A Case of Acute Fatty Liver of Pregnancy Developing Massive Intrahepatic Calcification

    PubMed Central

    Bhat, Khalid Javid; Shovkat, Rabia; Samoon, Hamad Jeelani

    2015-01-01

    The function of the liver is particularly affected by the unique physiologic milieu of the pregnancy. Pregnancy-related liver diseases encompass a spectrum of different etiologies that are related to gestation or one of its complications. Hepatic calcification, a rare entity, is usually associated with infectious, vascular, or neoplastic lesions in the liver. To the best of our knowledge, only one case of rapidly occurring pregnancy-related intrahepatic calcification has been documented in a patient with severe eclampsia or hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome. Here we present a case of immediate “postpartum” acute fatty liver of pregnancy (AFLP) in a 23-year-old hypertensive primigravida, complicated by acute renal dysfunction who developed dense intrahepatic calcification in less than a month after the initial diagnosis. A multidisciplinary approach for the management was used, to which the patient responded aptly. This case illustrates the first description of intrahepatic calcification in AFLP syndrome and highlights some of the challenges met in making the final diagnosis.

  13. DJ-1 protects against cell death following acute cardiac ischemia–reperfusion injury

    PubMed Central

    Dongworth, R K; Mukherjee, U A; Hall, A R; Astin, R; Ong, S-B; Yao, Z; Dyson, A; Szabadkai, G; Davidson, S M; Yellon, D M; Hausenloy, D J

    2014-01-01

    Novel therapeutic targets are required to protect the heart against cell death from acute ischemia–reperfusion injury (IRI). Mutations in the DJ-1 (PARK7) gene in dopaminergic neurons induce mitochondrial dysfunction and a genetic form of Parkinson's disease. Genetic ablation of DJ-1 renders the brain more susceptible to cell death following ischemia–reperfusion in a model of stroke. Although DJ-1 is present in the heart, its role there is currently unclear. We sought to investigate whether mitochondrial DJ-1 may protect the heart against cell death from acute IRI by preventing mitochondrial dysfunction. Overexpression of DJ-1 in HL-1 cardiac cells conferred the following beneficial effects: reduced cell death following simulated IRI (30.4±4.7% with DJ-1 versus 52.9±4.7% in control; n=5, P<0.05); delayed mitochondrial permeability transition pore (MPTP) opening (a critical mediator of cell death) (260±33 s with DJ-1 versus 121±12 s in control; n=6, P<0.05); and induction of mitochondrial elongation (81.3±2.5% with DJ-1 versus 62.0±2.8% in control; n=6 cells, P<0.05). These beneficial effects of DJ-1 were absent in cells expressing the non-functional DJ-1L166P and DJ-1Cys106A mutants. Adult mice devoid of DJ-1 (KO) were found to be more susceptible to cell death from in vivo IRI with larger myocardial infarct sizes (50.9±3.5% DJ-1 KO versus 41.1±2.5% in DJ-1 WT; n≥7, P<0.05) and resistant to cardioprotection by ischemic preconditioning. DJ-1 KO hearts showed increased mitochondrial fragmentation on electron microscopy, although there were no differences in calcium-induced MPTP opening, mitochondrial respiratory function or myocardial ATP levels. We demonstrate that loss of DJ-1 protects the heart from acute IRI cell death by preventing mitochondrial dysfunction. We propose that DJ-1 may represent a novel therapeutic target for cardioprotection. PMID:24577080

  14. Colchicine Acutely Suppresses Local Cardiac Production of Inflammatory Cytokines in Patients With an Acute Coronary Syndrome

    PubMed Central

    Martínez, Gonzalo J; Robertson, Stacy; Barraclough, Jennifer; Xia, Qiong; Mallat, Ziad; Bursill, Christina; Celermajer, David S; Patel, Sanjay

    2015-01-01

    Background Interleukin (IL)-1β, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1β and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production. Methods and Results Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1β, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1β, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1β, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1β, IL-18, and IL-6, respectively). Conclusions ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines. PMID:26304941

  15. Monoamine Oxidase B Prompts Mitochondrial and Cardiac Dysfunction in Pressure Overloaded Hearts

    PubMed Central

    Kaludercic, Nina; Carpi, Andrea; Nagayama, Takahiro; Sivakumaran, Vidhya; Zhu, Guangshuo; Lai, Edwin W.; Bedja, Djahida; De Mario, Agnese; Chen, Kevin; Gabrielson, Kathleen L.; Lindsey, Merry L.; Pacak, Karel; Takimoto, Eiki; Shih, Jean C.; Kass, David A.; Di Lisa, Fabio

    2014-01-01

    Abstract Aims: Monoamine oxidases (MAOs) are mitochondrial flavoenzymes responsible for neurotransmitter and biogenic amines catabolism. MAO-A contributes to heart failure progression via enhanced norepinephrine catabolism and oxidative stress. The potential pathogenetic role of the isoenzyme MAO-B in cardiac diseases is currently unknown. Moreover, it is has not been determined yet whether MAO activation can directly affect mitochondrial function. Results: In wild type mice, pressure overload induced by transverse aortic constriction (TAC) resulted in enhanced dopamine catabolism, left ventricular (LV) remodeling, and dysfunction. Conversely, mice lacking MAO-B (MAO-B−/−) subjected to TAC maintained concentric hypertrophy accompanied by extracellular signal regulated kinase (ERK)1/2 activation, and preserved LV function, both at early (3 weeks) and late stages (9 weeks). Enhanced MAO activation triggered oxidative stress, and dropped mitochondrial membrane potential in the presence of ATP synthase inhibitor oligomycin both in neonatal and adult cardiomyocytes. The MAO-B inhibitor pargyline completely offset this change, suggesting that MAO activation induces a latent mitochondrial dysfunction, causing these organelles to hydrolyze ATP. Moreover, MAO-dependent aldehyde formation due to inhibition of aldehyde dehydrogenase 2 activity also contributed to alter mitochondrial bioenergetics. Innovation: Our study unravels a novel role for MAO-B in the pathogenesis of heart failure, showing that both MAO-driven reactive oxygen species production and impaired aldehyde metabolism affect mitochondrial function. Conclusion: Under conditions of chronic hemodynamic stress, enhanced MAO-B activity is a major determinant of cardiac structural and functional disarrangement. Both increased oxidative stress and the accumulation of aldehyde intermediates are likely liable for these adverse morphological and mechanical changes by directly targeting mitochondria. Antioxid. Redox

  16. Fractal Dimension in Quantifying Experimental-Pulmonary-Hypertension-Induced Cardiac Dysfunction in Rats

    PubMed Central

    Pacagnelli, Francis Lopes; Sabela, Ana Karênina Dias de Almeida; Mariano, Thaoan Bruno; Ozaki, Guilherme Akio Tamura; Castoldi, Robson Chacon; do Carmo, Edna Maria; Carvalho, Robson Francisco; Tomasi, Loreta Casquel; Okoshi, Katashi; Vanderlei, Luiz Carlos Marques

    2016-01-01

    Background Right-sided heart failure has high morbidity and mortality, and may be caused by pulmonary arterial hypertension. Fractal dimension is a differentiated and innovative method used in histological evaluations that allows the characterization of irregular and complex structures and the quantification of structural tissue changes. Objective To assess the use of fractal dimension in cardiomyocytes of rats with monocrotaline-induced pulmonary arterial hypertension, in addition to providing histological and functional analysis. Methods Male Wistar rats were divided into 2 groups: control (C; n = 8) and monocrotaline-induced pulmonary arterial hypertension (M; n = 8). Five weeks after pulmonary arterial hypertension induction with monocrotaline, echocardiography was performed and the animals were euthanized. The heart was dissected, the ventricles weighed to assess anatomical parameters, and histological slides were prepared and stained with hematoxylin/eosin for fractal dimension analysis, performed using box-counting method. Data normality was tested (Shapiro-Wilk test), and the groups were compared with non-paired Student t test or Mann Whitney test (p < 0.05). Results Higher fractal dimension values were observed in group M as compared to group C (1.39 ± 0.05 vs. 1.37 ± 0.04; p < 0.05). Echocardiography showed lower pulmonary artery flow velocity, pulmonary acceleration time and ejection time values in group M, suggesting function worsening in those animals. Conclusion The changes observed confirm pulmonary-arterial-hypertension-induced cardiac dysfunction, and point to fractal dimension as an effective method to evaluate cardiac morphological changes induced by ventricular dysfunction. PMID:27223643

  17. Targeted deletion of titin N2B region leads to diastolic dysfunction and cardiac atrophy

    PubMed Central

    Radke, Michael H.; Peng, Jun; Wu, Yiming; McNabb, Mark; Nelson, O. Lynne; Granzier, Henk; Gotthardt, Michael

    2007-01-01

    Titin is a giant protein that is in charge of the assembly and passive mechanical properties of the sarcomere. Cardiac titin contains a unique N2B region, which has been proposed to modulate elasticity of the titin filament and to be important for hypertrophy signaling and the ischemic stress response through its binding proteins FHL2 and αB-crystallin, respectively. To study the role of the titin N2B region in systole and diastole of the heart, we generated a knockout (KO) mouse deleting only the N2B exon 49 and leaving the remainder of the titin gene intact. The resulting mice survived to adulthood and were fertile. Although KO hearts were small, they produced normal ejection volumes because of an increased ejection fraction. FHL2 protein levels were significantly reduced in the KO mice, a finding consistent with the reduced size of KO hearts. Ultrastructural analysis revealed an increased extension of the remaining spring elements of titin (tandem Ig segments and the PEVK region), which, together with the reduced sarcomere length and increased passive tension derived from skinned cardiomyocyte experiments, translates to diastolic dysfunction as documented by echocardiography. We conclude from our work that the titin N2B region is dispensable for cardiac development and systolic properties but is important to integrate trophic and elastic functions of the heart. The N2B-KO mouse is the first titin-based model of diastolic dysfunction and, considering the high prevalence of diastolic heart failure, it could provide future mechanistic insights into the disease process. PMID:17360664

  18. Subclinical cardiac dysfunction in acromegaly: evidence for a specific disease of heart muscle.

    PubMed

    Rodrigues, E A; Caruana, M P; Lahiri, A; Nabarro, J D; Jacobs, H S; Raftery, E B

    1989-09-01

    Acromegaly is associated with an increased cardiac morbidity and mortality, but it is not clear whether this is the result of increased incidence of hypertension and coronary heart disease or of a specific disease of heart muscle. Thirty four acromegalic patients were studied by non-invasive techniques. Seven of these patients had raised plasma concentrations of growth hormone at the time of study; three were newly diagnosed and had not received any treatment. Hypertension was present in nine (26%) but only three (9%) had electrocardiographic left ventricular hypertrophy. Echocardiography showed ventricular hypertrophy in 12 (48%) and increased left ventricular mass in 17 (68%) patients. Holter monitoring detected important ventricular arrhythmias in 14 patients. Thallium-201 scanning showed evidence for coronary heart disease in eight patients. Systolic time intervals were normal except when there was coexistent ischaemic heart disease. A comparison between 19 acromegalic patients with no other detectable cause of heart disease and 22 age matched controls showed appreciably abnormal left ventricular diastolic function in the group with acromegaly. The abnormalities shown did not correlate with left ventricular mass or wall thickness. There was no difference in diastolic function between patients with active acromegaly and those with treated acromegaly. Hypertensive acromegalic patients had worse diastolic function than hypertensive controls, suggesting that hypertension may further impair the left ventricular diastolic abnormality in acromegaly. This is the first study to find evidence of subclinical cardiac diastolic dysfunction in acromegaly and it supports the suggestion that there is a specific disease of heart muscle in acromegaly.

  19. Cardiac magnetic resonance determinants of functional mitral regurgitation in ischemic and non ischemic left ventricular dysfunction.

    PubMed

    Fernández-Golfín, Covadonga; De Agustin, Alberto; Manzano, M Carmen; Bustos, Ana; Sánchez, Tibisay; Pérez de Isla, Leopoldo; Fuentes, Manuel; Macaya, Carlos; Zamorano, José

    2011-04-01

    Functional mitral regurgitation (FMR) is frequent in left ventricular (LV) dilatation/dysfunction. Echocardiographic predictors of FMR are known. However, cardiac magnetic resonance (CMR) predictors of FMR have not been fully addressed. The aim of the study was to evaluate CMR mitral valve (MV) parameters associated with FMR in ischemic and non ischemic LV dysfunction. 80 patients with LV ejection fraction below 45% and/or left ventricular dilatation of ischemic and non ischemic etiology were included. Cine-MR images (steady state free-precession) were acquired in a short-axis and 4 chambers views where MV evaluation was performed. Delayed enhancement was performed as well. Significant FMR was established as more than mild MR according to the echocardiographic report. Mean age was 59 years, males 79%. FMR was detected in 20 patients (25%) Significant differences were noted in LV functional parameters and in most MV parameters according to the presence of significant FMR. However, differences were noted between ischemic and non ischemic groups. In the first, differences in most MV parameters remained significant while in the non ischemic, only systolic and diastolic interpapillary muscle distance (1.60 vs. 2.19 cm, P = 0.001; 2. 51 vs. 3.04, P = 0.008) were predictors of FMR. FMR is associated with a more severe LV dilatation/dysfunction in the overall population. CMR MV parameters are associated with the presence of significant FMR and are different between ischemic and non ischemic patients. CMR evaluation of these patients may help in risk stratification as well as in surgical candidate selection.

  20. Relationship between post-cardiac arrest myocardial oxidative stress and myocardial dysfunction in the rat

    PubMed Central

    2014-01-01

    Background Reperfusion after resuscitation from cardiac arrest (CA) is an event that increases reactive oxygen species production leading to oxidative stress. More specifically, myocardial oxidative stress may play a role in the severity of post-CA myocardial dysfunction. This study investigated the relationship between myocardial oxidative stress and post-CA myocardial injury and dysfunction in a rat model of CA and cardiopulmonary resuscitation (CPR). Ventricular fibrillation was induced in 26 rats and was untreated for 6 min. CPR, including mechanical chest compression, ventilation, and epinephrine, was then initiated and continued for additional 6 min prior to defibrillations. Resuscitated animals were sacrificed at two h (n = 9), 4 h (n = 6) and 72 h (n = 8) following resuscitation, and plasma collected for assessment of: high sensitivity cardiac troponin T (hs-cTnT), as marker of myocardial injury; isoprostanes (IsoP), as marker of lipid peroxidation; and 8-hydroxyguanosine (8-OHG), as marker of DNA oxidative damage. Hearts were also harvested for measurement of tissue IsoP and 8-OHG. Myocardial function was assessed by echocardiography at the corresponding time points. Additional 8 rats were not subjected to CA and served as baseline controls. Results Compared to baseline, left ventricular ejection fraction (LVEF) was reduced at 2 and 4 h following resuscitation (p < 0.01), while it was similar at 72 h. Inversely, plasma hs-cTnT increased, compared to baseline, at 2 and 4 h post-CA (p < 0.01), and then recovered at 72 h. Similarly, plasma and myocardial tissue IsoP and 8-OHG levels increased at 2 and 4 h post-resuscitation (p < 0.01 vs. baseline), while returned to baseline 72 h later. Myocardial IsoP were directly related to hs-cTnT levels (r = 0.760, p < 0.01) and inversely related to LVEF (r = -0.770, p < 0.01). Myocardial 8-OHG were also directly related to hs-cTnT levels (r = 0.409, p < 0.05) and

  1. INHALATION OF OZONE AND DIESEL EXHAUST PARTICLES (DEP) INDUCES ACUTE AND REVERSIBLE CARDIAC GENE EXPRESSION CHANGES

    EPA Science Inventory

    We have recently shown that episodic but not acute exposure to ozone or DEP induces vascular effects that are associated with the loss of cardiac mitochondrial phospholipid fatty acids (DEP 2.0 mg/m3 > ozone, 0.4 ppm). In this study we determined ozone and DEP-induced cardiac gen...

  2. MOEMS-based cardiac enzymes detector for acute myocardial infarction

    NASA Astrophysics Data System (ADS)

    Amritsar, Jeetender; Stiharu, Ion G.; Packirisamy, Muthukumaran; Balagopal, Ganesharam; Li, Xing

    2004-10-01

    Biomedical applications of MOEMS are limited only by the mankind imagination. Precision measurements on minute amounts of biological material could be performed by optical means with a remarkable accuracy. Although available in medical laboratories for general purposes, such analyzers are making their way directly to the users in the form of dedicated equipment. Such an example is a test kit to detect the existence of cardiac enzymes in the blood stream. Apart from the direct users, the medical personnel will make use of such tools given the practicality of the kit. In a large proportion of patients admitted to the hospital suspected of Acute Myocardial Infarction (AMI), the symptoms and electrocardiographic changes are inconclusive. This necessitates the use of biochemical markers of myocardial damage for correct exclusion or conformation of AMI. In this study the concept of MOEMS is applied for the detection of enzyme reaction, in which glass spectrums are scanned optically when enzyme molecules adsorb on their surface. This paper presents the optical behavior of glass spectrums under Horseradish Peroxide (HRP) enzyme reaction. The reported experimental results provide valuable information that will be useful in the development of biosensors for enzymatic detection. This paper also reports the dynamic behavior of different glass spectrums.

  3. Evaluation of early cardiac dysfunction in patients with systemic lupus erythematosus with or without anticardiolipin antibodies.

    PubMed

    Barutcu, A; Aksu, F; Ozcelik, F; Barutcu, C A E; Umit, G E; Pamuk, O N; Altun, A

    2015-09-01

    The aim of this study was to use transthoracic Doppler echocardiographic (TTE) imaging methods to identify cardiac dysfunction, an indicator of subclinical atherosclerosis in asymptomatic systemic lupus erythematosus (SLE) patients in terms of cardiac effects. This study involved 80 patients: a study group (n = 50) and control group (n = 30). They were categorized into four subgroups: anticardiolipin antibodies (aCL) (+) (n = 14) and aCL (-) (n = 36); systemic lupus erythematosus disease activity index (SLEDAI) ≥ 6 (n = 15) and SLEDAI < 6 (n = 35); disease period ≥ 5 years (n = 21) and disease period < 5 years (n = 29); major organ involvement (+) (n = 19), major organ involvement (-) (n = 31). The ratio of mitral peak velocity of early filling to early diastolic mitral annular velocity (E/E') for the study group was found to be higher than the control (p < 0.01). Systolic septal motion velocity (Ssm) was lower in the study group compared with the control (p < 0.01). Left atrium (LA) dimension was greater in the study group than the control (p < 0.01). Ssm was found to be lower in the aCL (+) patients compared with the control and aCL (-) groups (p < 0.01, p < 0.05, respectively). LA dimension was greater in the aCL (+) and (-) groups compared with the control, (p < 0.01, p < 0.05, respectively) and aCL groups compared with each other (p < 0.05). The E/E' ratio for the aCL (+) and (-) groups was found to be greater than the control (p < 0.05). In the study, both the Ssm and the late diastolic septal velocity (sA') was found to be lower in the SLEDAI ≥ 6 group compared with SLEDAI<6 group, (p < 0.001, p < 0.05, respectively). LA dimension was statistically greater in the SLEDAI ≥ 6 group compared with the SLEDAI <6 group (p < 0.001). E' and early diastolic septal velocity (sE') were statistically lower in the disease period >5 years group compared with the disease period <5 years group (p < 0.01, p < 0.05, respectively). Carrying out regular scans with TTE

  4. Use of a Simply Modified Drainage Catheter for Peritoneal Dialysis Treatment of Acute Renal Failure Associated With Cardiac Surgery in Infants

    PubMed Central

    Chen, Qiang; Cao, Hua; Hu, Yun-Nan; Chen, Liang-Wan; He, Jia-jun

    2014-01-01

    Abstract Acute renal failure (ARF) is a common complication in infants who undergo cardiac surgery in the intensive care unit. We report on a modified drainage catheter used in peritoneal dialysis (PD) for the treatment of ARF associated with cardiac surgery in infants. Thirty-nine infants with congenital heart disease undergoing cardiac surgery who developed ARF at our center between January 2009 and January 2012 were assessed. A modified drainage catheter for PD was used in these infants. Their demographic, clinical, and surgical data were analyzed. Thirty infants with ARF were cured by PD, and the other 9 died in the first 48 hours because of the severity of the acute cardiac dysfunction. All these infants were dependent upon mechanical ventilation during the postoperative period and used vasoactive drugs. In the survival group, the interval between the procedure and initiation of PD was 13.6 ± 6.5 (range, 6–30) hours. PD duration was 3.9 ± 0.9 (3–6) days. Minor complications were encountered in some patients (asymptomatic hypokalemia, hyperglycemia, and thrombocytopenia). These complications were readily treated by drugs or resolved spontaneously. Hemodynamics, cardiac function, and renal function improved significantly during PD. These data suggest that PD using a modified drainage catheter for ARF after cardiac surgery in infants is safe, feasible, inexpensive, and yields good results. PMID:25255020

  5. Tanshinone IIA attenuates cardiac dysfunction in endotoxin-induced septic mice via inhibition of NADPH oxidase 2-related signaling pathway.

    PubMed

    Huang, Libing; Zheng, Man; Zhou, Yudi; Zhu, Juan; Zhu, Minghui; Zhao, Feng; Cui, Suyang

    2015-09-01

    Cardiac dysfunction is a critical event during sepsis/septic shock. Tanshinone IIA (TIIA), a compound extracted from herb medicine Danshen, has been shown possessing anti-inflammatory and anti-oxidative properties. It is possible, therefore, that treatment with TIIA may attenuate cardiac dysfunction during sepsis/septic shock through inhibition of inflammation. To test this possibility, we preadministrated C57BL/6 mice with TIIA prior to lipopolysaccharide (LPS) challenge. LPS significantly suppressed left ventricular function as evidenced by decreases in EF% and FS% in mice. However, TIIA pretreatment significantly attenuated cardiac dysfunction following LPS challenge. Furthermore, TIIA markedly attenuated the LPS-induced upregulation of circulating tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) levels. Meanwhile, LPS challenge significantly increased myocardial reactive oxygen species (ROS) production, which was attenuated by TIIA. Moreover, TIIA treatment dramatically decreased the level of the Nox2, reduced phosphorylation levels of extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) expression. In conclusion, TIIA effectively improves cardiac function during endotoxemia in mice. This is attributed to TIIA reducing inflammatory cytokines release and inhibiting the Nox2 signaling during endotoxemia. PMID:26202805

  6. Cardiac Mitochondrial Respiratory Dysfunction and Tissue Damage in Chronic Hyperglycemia Correlate with Reduced Aldehyde Dehydrogenase-2 Activity

    PubMed Central

    Deshpande, Mandar; Thandavarayan, Rajarajan A.; Xu, Jiang; Yang, Xiao-Ping; Palaniyandi, Suresh S.

    2016-01-01

    Aldehyde dehydrogenase (ALDH) 2 is a mitochondrial isozyme of the heart involved in the metabolism of toxic aldehydes produced from oxidative stress. We hypothesized that hyperglycemia-mediated decrease in ALDH2 activity may impair mitochondrial respiration and ultimately result in cardiac damage. A single dose (65 mg/kg; i.p.) streptozotocin injection to rats resulted in hyperglycemia with blood glucose levels of 443 ± 9 mg/dl versus 121 ± 7 mg/dl in control animals, p<0.0001, N = 7–11. After 6 months of diabetes mellitus (DM) induction, the rats were sacrificed after recording the functionality of their hearts. Increase in the cardiomyocyte cross sectional area (446 ± 32 μm2 Vs 221 ± 10 μm2; p<0.0001) indicated cardiac hypertrophy in DM rats. Both diastolic and systolic dysfunctions were observed with DM rats compared to controls. Most importantly, myocardial ALDH2 activity and levels were reduced, and immunostaining for 4HNE protein adducts was increased in DM hearts compared to controls. The mitochondrial oxygen consumption rate (OCR), an index of mitochondrial respiration, was decreased in mitochondria isolated from DM hearts compared to controls (p<0.0001). Furthermore, the rate of mitochondrial respiration and the increase in carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP)-induced maximal respiration were also decreased with chronic hyperglycemia. Chronic hyperglycemia reduced mitochondrial OXPHOS proteins. Reduced ALDH2 activity was correlated with mitochondrial dysfunction, pathological remodeling and cardiac dysfunction, respectively. Our results suggest that chronic hyperglycemia reduces ALDH2 activity, leading to mitochondrial respiratory dysfunction and consequently cardiac damage and dysfunction. PMID:27736868

  7. Chronic pharmacologic inhibition of EGFR leads to cardiac dysfunction in C57BL/6J mice

    SciTech Connect

    Barrick, Cordelia J.; Yu Ming; Chao, H.-H.; Threadgill, David W.

    2008-05-01

    Molecule-targeted therapies like those against the epidermal growth factor receptor (EGFR) are becoming widely used in the oncology clinic. With improvements in treatment efficacy, many cancers are being treated as chronic diseases, with patients having prolonged exposure to several therapies that were previously only given acutely. The consequence of chronic suppression of EGFR activity may lead to unexpected toxicities like altered cardiac physiology, a common organ site for adverse drug effects. To explore this possibility, we treated C57BL/6J (B6) mice with two EGFR small molecule tyrosine kinase inhibitors (TKIs), irreversible EKB-569 and reversible AG-1478, orally for 3 months. In B6 female mice, chronic exposure to both TKIs depressed body weight gain and caused significant changes in left ventricular (LV) wall thickness and cardiac function. No significant differences were observed in heart weight or cardiomyocyte size but histological analysis revealed an increase in fibrosis and in the numbers of TUNEL-positive cells in the hearts from treated female mice. Consistent with histological results, LV apoptotic gene expression was altered, with significant downregulation of the anti-apoptotic gene Bcl2l1. Although there were no significant differences in any of these endpoints in treated male mice, suggesting sex may influence susceptibility to TKI mediated toxicity, the LVs of treated male mice had significant upregulation of Egf, Erbb2 and Nppb over controls. Taken together, these data suggest that chronic dietary exposure to TKIs may result in pathological and physiological changes in the heart.

  8. Transgenic overexpression of mitofilin attenuates diabetes mellitus-associated cardiac and mitochondria dysfunction

    PubMed Central

    Thapa, Dharendra; Nichols, Cody E.; Lewis, Sara E.; Shepherd, Danielle L.; Jagannathan, Rajaganapathi; Croston, Tara L.; Tveter, Kevin J.; Holden, Anthony A.; Baseler, Walter A.; Hollander, John M.

    2014-01-01

    cardiac contractile dysfunction in the diabetic heart. PMID:25463274

  9. Aldehyde Dehydrogenase-2 Deficiency Aggravates Cardiac Dysfunction Elicited by Endoplasmic Reticulum Stress Induction

    PubMed Central

    Liao, Jianquan; Sun, Aijun; Xie, Yeqing; Isse, Toyoshi; Kawamoto, Toshihiro; Zou, Yunzeng; Ge, Junbo

    2012-01-01

    Mitochondrial aldehyde dehydrogenase-2 (ALDH2) has been characterized as an important mediator of endogenous cytoprotection in the heart. This study was designed to examine the role of ALDH2 knockout (KO) in the regulation of cardiac function after endoplasmic reticulum (ER) stress. Wild-type (WT) and ALDH2 KO mice were subjected to a tunicamycin challenge, and the echocardiographic property was examined. Protein levels of six items—78 kDa glucose-regulated protein (GRP78), phosphorylation of eukaryotic initiation factor 2 subunit α (p-eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP), phosphorylation of Akt, p47phox nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and 4-hydroxynonenal—were determined by using Western blot analysis. Cytotoxicity and apoptosis were estimated using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium bromide (MTT) assay and caspase-3 activity, respectively. ALDH2 deficiency exacerbated cardiac contractile dysfunction and promoted ER stress after ER stress induction, manifested by the changes of ejection fraction and fractional shortening. In vitro study revealed that tunicamycin significantly upregulated the levels of GRP78, p-eIF2α, CHOP, p47phox NADPH oxidase and 4-hydroxynonenal, which was exacerbated by ALDH2 knockdown and abolished by ALDH2 overexpression, respectively. Overexpression of ALDH2 abrogated tunicamycin-induced dephosphorylation Akt. Inhibition of phosphatidylinositol 3-kinase using LY294002 did not affect ALDH2-conferred protection against ER stress, although LY294002 reversed the antiapoptotic action of ALDH2 associated with p47phox NADPH oxidase. These results suggest a pivotal role of ALDH2 in the regulation of ER stress and ER stress–induced apoptosis. The protective role of ALDH2 against ER stress–induced cell death was probably mediated by Akt via a p47phox NADPH oxidase-dependent manner. These findings indicate the critical role of ALDH2 in the pathogenesis of ER stress

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

    PubMed Central

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

    2014-01-01

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

  11. Acute expanded perlite exposure with persistent reactive airway dysfunction syndrome.

    PubMed

    Du, Chung-Li; Wang, Jung-Der; Chu, Po-Chin; Guo, Yue-Liang Leon

    2010-01-01

    Expanded perlite has been assumed as simple nuisance, however during an accidental spill out in Taiwan, among 24 exposed workers followed for more than 6 months, three developed persisted respiratory symptoms and positive provocation tests were compatible with reactive airway dysfunction syndrome. During simulation experiment expanded perlite is shown to be very dusty and greatly exceed current exposure permission level. Review of literature and evidence, though exposure of expanded perlite below permission level may be generally safe, precautionary protection of short term heavy exposure is warranted.

  12. Cardiomyocyte-Specific Deletion of Endothelin Receptor A Rescues Ageing-Associated Cardiac Hypertrophy and Contractile Dysfunction: Role of Autophagy

    PubMed Central

    Ceylan-Isik, Asli F.; Dong, Maolong; Zhang, Yingmei; Dong, Feng; Turdi, Subat; Nair, Sreejayan; Yanagisawa, Masashi; Ren, Jun

    2013-01-01

    Cardiac ageing is manifested as cardiac remodeling and contractile dysfunction although precise mechanisms remain elusive. This study was designed to examine the role of endothelin-1 (ET-1) in ageing-associated myocardial morphological and contractile defects. Echocardiographic and cardiomyocyte contractile properties were evaluated in young (5–6 mo) and old (26–28 mo) C57BL/6 wild-type and cardiomyocyte-specific ETA receptor knockout (ETAKO) mice. Cardiac ROS production and histology were examined. Our data revealed that ETAKO mice displayed an improved survival. Ageing increased plasma levels of ET-1 and Ang II, compromised cardiac function (fractional shortening, cardiomyocyte peak shortening, maximal velocity of shortening/ relengthening and prolonged relengthening) and intracellular Ca2+ handling (reduced intracellular Ca2+ release and decay), the effects of which with the exception of ET-1 and Ang II levels was improved by ETAKO. Histological examination displayed cardiomyocyte hypertrophy and interstitial fibrosis associated with cardiac remodeling in aged C57 mice, which were alleviated in ETAKO mice. Ageing promoted ROS generation, protein damage, ER stress, upregulated GATA4, ANP, NFATc3, and the autophagosome cargo protein p62, downregulated intracellular Ca2+ regulatory proteins SERCA2a and phospholamban as well as the autophagic markers Beclin-1, Atg7, Atg5 and LC3BII, which were ablated by ETAKO. ET-1 triggered a decrease in autophagy and increased hypertrophic markers in vitrothe effect of which were reversed by the ETA receptor antagonist BQ123 and the autophagy inducer rapamycin. Antagonism of ETA but not ETB receptor rescued cardiac ageing, which was negated by autophagy inhibition. Taken together, our data suggest that cardiac ETA receptor ablation protects against ageing-associated myocardial remodeling and contractile dysfunction possibly through autophagy regulation. PMID:23381122

  13. On the Utility of MIBG SPECT/CT in Evaluating Cardiac Sympathetic Dysfunction in Lewy Body Diseases

    PubMed Central

    Odagiri, Hayato; Baba, Toru; Nishio, Yoshiyuki; Iizuka, Osamu; Matsuda, Minoru; Inoue, Kentaro; Kikuchi, Akio; Hasegawa, Takafumi; Aoki, Masashi; Takeda, Atsushi; Taki, Yasuyuki; Mori, Etsuro

    2016-01-01

    Background Abnormal cardiac uptake of 123I-metaiodobenzylguanidine (123I-MIBG) is a diagnostic marker of Lewy body diseases (LBDs), e.g., Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). Planar imaging is generally used to assess cardiac sympathetic dysfunction in 123I-MIBG scintigraphy; however, its clinical utility requires further improvement. We hypothesized that the co-registration of single-photon emission tomography (SPECT) and computed tomography (CT) images would improve the diagnostic accuracy of 123I-MIBG cardiac scintigraphy for LBDs. This study sought to evaluate the effects of SPECT/CT imaging on 123I-MIBG cardiac scintigraphy for diagnosing LBDs. Methods We retrospectively investigated data of 54 patients (consecutive 18 patients in each PD, DLB, and idiopathic normal pressure hydrocephalus [iNPH] groups) who underwent 123I-MIBG cardiac scintigraphy (planar and SPECT/CT) because of suspected LBDs at the Tohoku University hospital from June 2012 to June 2015. We compared the diagnostic accuracies of the conventional planar 123I-MIBG method and SPECT/CT methods (manual and semi-automatic). Results In the conventional planar analysis, 123I-MIBG uptake decreased only in the DLB group compared with the iNPH group. In contrast, the SPECT/CT analysis revealed significantly lower 123I-MIBG uptake in both the PD and DLB groups compared with the iNPH group. Furthermore, a receiver operating characteristic analysis revealed that both the manual and semi-automatic SPECT/CT methods were superior to the conventional planar method in differentiating the 3 disorders. Conclusions SPECT/CT 123I-MIBG cardiac scintigraphy can detect mild cardiac sympathetic dysfunction in LDBs. Our results suggest that the SPECT/CT technique improves diagnostic accuracy for LBDs. PMID:27055151

  14. Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome[S

    PubMed Central

    Kiebish, Michael A.; Yang, Kui; Liu, Xinping; Mancuso, David J.; Guan, Shaoping; Zhao, Zhongdan; Sims, Harold F.; Cerqua, Rebekah; Cade, W. Todd; Han, Xianlin; Gross, Richard W.

    2013-01-01

    Barth syndrome is a complex metabolic disorder caused by mutations in the mitochondrial transacylase tafazzin. Recently, an inducible tafazzin shRNA knockdown mouse model was generated to deconvolute the complex bioenergetic phenotype of this disease. To investigate the underlying cause of hemodynamic dysfunction in Barth syndrome, we interrogated the cardiac structural and signaling lipidome of this mouse model as well as its myocardial bioenergetic phenotype. A decrease in the distribution of cardiolipin molecular species and robust increases in monolysocardiolipin and dilysocardiolipin were demonstrated. Additionally, the contents of choline and ethanolamine glycerophospholipid molecular species containing precursors for lipid signaling at the sn-2 position were altered. Lipidomic analyses revealed specific dysregulation of HETEs and prostanoids, as well as oxidized linoleic and docosahexaenoic metabolites. Bioenergetic interrogation uncovered differential substrate utilization as well as decreases in Complex III and V activities. Transgenic expression of cardiolipin synthase or iPLA2γ ablation in tafazzin-deficient mice did not rescue the observed phenotype. These results underscore the complex nature of alterations in cardiolipin metabolism mediated by tafazzin loss of function. Collectively, we identified specific lipidomic, bioenergetic, and signaling alterations in a murine model that parallel those of Barth syndrome thereby providing novel insights into the pathophysiology of this debilitating disease. PMID:23410936

  15. Oxidized CaMKII causes cardiac sinus node dysfunction in mice

    PubMed Central

    Swaminathan, Paari Dominic; Purohit, Anil; Soni, Siddarth; Voigt, Niels; Singh, Madhu V.; Glukhov, Alexey V.; Gao, Zhan; He, B. Julie; Luczak, Elizabeth D.; Joiner, Mei-ling A.; Kutschke, William; Yang, Jinying; Donahue, J. Kevin; Weiss, Robert M.; Grumbach, Isabella M.; Ogawa, Masahiro; Chen, Peng-Sheng; Efimov, Igor; Dobrev, Dobromir; Mohler, Peter J.; Hund, Thomas J.; Anderson, Mark E.

    2011-01-01

    Sinus node dysfunction (SND) is a major public health problem that is associated with sudden cardiac death and requires surgical implantation of artificial pacemakers. However, little is known about the molecular and cellular mechanisms that cause SND. Most SND occurs in the setting of heart failure and hypertension, conditions that are marked by elevated circulating angiotensin II (Ang II) and increased oxidant stress. Here, we show that oxidized calmodulin kinase II (ox-CaMKII) is a biomarker for SND in patients and dogs and a disease determinant in mice. In wild-type mice, Ang II infusion caused sinoatrial nodal (SAN) cell oxidation by activating NADPH oxidase, leading to increased ox-CaMKII, SAN cell apoptosis, and SND. p47–/– mice lacking functional NADPH oxidase and mice with myocardial or SAN-targeted CaMKII inhibition were highly resistant to SAN apoptosis and SND, suggesting that ox-CaMKII–triggered SAN cell death contributed to SND. We developed a computational model of the sinoatrial node that showed that a loss of SAN cells below a critical threshold caused SND by preventing normal impulse formation and propagation. These data provide novel molecular and mechanistic information to understand SND and suggest that targeted CaMKII inhibition may be useful for preventing SND in high-risk patients. PMID:21785215

  16. Serum from Diesel Exhaust-Exposed Rats with Cardiac Dysfunction Alters Aortic Endothelial Cell Function In Vitro: Circulating Mediators as Causative Factors?

    EPA Science Inventory

    Although circulating inflammatory mediators are strongly associated with adverse cardiovascular outcomes triggered by inhaled air pollution, direct cause-effect linkage has not been established. Given that endothelial toxicity often precedes and precipitates cardiac dysfunction, ...

  17. Acute heart failure with low cardiac output: can we develop a short-term inotropic agent that does not increase adverse events?

    PubMed

    Campia, Umberto; Nodari, Savina; Gheorghiade, Mihai

    2010-09-01

    Acute heart failure represents an increasingly common cause of hospitalization, and may require the use of inotropic drugs in patients with low cardiac output and evidence of organ hypoperfusion. However, currently available therapies may have deleterious effects and increase mortality. An ideal inotropic drug should restore effective tissue perfusion by enhancing myocardial contractility without causing adverse effects. Such a drug is not available yet. New agents with different biological targets are under clinical development. In particular, istaroxime seems to dissociate the inotropic effect exerted by digitalis (inhibition of the membrane sodium/potassium adenosine triphosphatase) from the arrhythmic effect and to ameliorate diastolic dysfunction (via sarcoendoplasmic reticulum calcium adenosine triphosphatase activation). Additionally, the myosin activator omecamtiv mecarbil appears to have promising characteristics, while genetic therapy has been explored in animal studies only. Further investigations are needed to confirm and expand the effectiveness and safety of these agents in patients with acute heart failure and low cardiac output.

  18. Overexpression of myeloid differentiation protein 88 in mice induces mild cardiac dysfunction, but no deficit in heart morphology

    PubMed Central

    Chen, W.; Huang, Z.; Jiang, X.; Li, C.; Gao, X.

    2015-01-01

    Cardiac remodeling involves changes in heart shape, size, structure, and function after injury to the myocardium. The proinflammatory adaptor protein myeloid differentiation protein 88 (MyD88) contributes to cardiac remodeling. To investigate whether excessive MyD88 levels initiate spontaneous cardiac remodeling at the whole-organism level, we generated a transgenic MyD88 mouse model with a cardiac-specific promoter. MyD88 mice (male, 20-30 g, n=∼80) were born at the expected Mendelian ratio and demonstrated similar morphology of the heart and cardiomyocytes with that of wild-type controls. Although heart weight was unaffected, cardiac contractility of MyD88 hearts was mildly reduced, as shown by echocardiographic examination, compared with wild-type controls. Moreover, the cardiac dysfunction phenotype was associated with elevation of ANF and BNP expression. Collectively, our data provide novel evidence of the critical role of balanced MyD88 signaling in maintaining physiological function in the adult heart. PMID:26628395

  19. Detection of Left Ventricular Regional Dysfunction and Myocardial Abnormalities Using Complementary Cardiac Magnetic Resonance Imaging in Patients with Systemic Sclerosis without Cardiac Symptoms: A Pilot Study.

    PubMed

    Kobayashi, Yasuyuki; Kobayashi, Hitomi; T Giles, Jon; Yokoe, Isamu; Hirano, Masaharu; Nakajima, Yasuo; Takei, Masami

    2016-01-01

    Objective We sought to detect the presence of left ventricular regional dysfunction and myocardial abnormalities in systemic sclerosis (SSc) patients without cardiac symptoms using a complementary cardiac magnetic resonance (CMR) imaging approach. Methods Consecutive patients with SSc without cardiac symptoms and healthy controls underwent CMR on a 1.5 T scanner. The peak systolic regional function in the circumferential and radial strain (Ecc, % and Err, %) were calculated using a feature tracking analysis on the mid-left ventricular slices obtained with cine MRI. In addition, we investigated the myocardial characteristics by contrast MRI. Pharmacological stress and rest perfusion scans were performed to assess perfusion defect (PD) due to micro- or macrovascular impairment, and late gadolinium enhancement (LGE) images were obtained for the assessment of myocarditis and/or fibrosis. Results We compared 15 SSc patients with 10 healthy controls. No statistically significant differences were observed in the baseline characteristics between the patients and healthy controls. The mean peak Err and Ecc of all segments was significantly lower in the patients than the controls (p=0.011 and p=0.003, respectively). Four patients with LGE (28.6%) and seven patients with PD (50.0%) were observed. PD was significantly associated with digital ulcers (p=0.005). Utilizing a linear regression model, the presence of myocardial LGE was significantly associated with the peak Ecc (p=0.024). After adjusting for age, the association between myocardial LGE and the peak Ecc was strengthened. Conclusion A subclinical myocardial involvement, as detected by CMR, was prevalent in the SSc patients without cardiac symptoms. Regional dysfunction might predict the myocardial abnormalities observed in SSc patients without cardiac symptoms.

  20. Total Flavones of Choerospondias axillaris Attenuate Cardiac Dysfunction and Myocardial Interstitial Fibrosis by Modulating NF-κB Signaling Pathway.

    PubMed

    Sun, Bei; Xia, Qiumei; Gao, Zhiyong

    2015-07-01

    This study aimed to investigate the effect of total flavonoids of Choerospondias axillaris (TFC) on myocardial infarction (MI)-induced cardiac dysfunction, interstitial fibrosis and inflammatory reaction and further to clarify the potential signaling pathway involved. Rats were subjected to MI via coronary artery occlusion. The model establishment was confirmed by the occurrence of ST-segment elevation in electrocardiogram. Then, TFC was administrated at doses of 75, 150 and 300 mg/kg for 28 consecutive days (gavage). Body weight and heart weight were recorded. Hemodynamics, infarct size and myocardial fibrosis were examined. Blood samples were collected to determine tumor necrosis factor-α (TNF-α) and interleukin 6, 10 (IL-6, IL-10) levels. The expressions of matrix metalloproteinases-2, 9 (MMP-2, 9), phosphor-IKBα (p-IKBα) and transforming growth factor-β1 (TGF-β1) were assayed by Western blot. The results indicated that TFC significantly improved cardiac dysfunction, the heart coefficient and myocardial fibrosis in MI rat. TFC also decreased the levels of TNF-α and IL-6, but increased IL-10 content. Moreover, treatment with TFC protected the heart from chronic MI injury by decreasing the expressions of MMP-2, 9, TGF-β1 and p-IKBα. The results suggested that TFC attenuated cardiac dysfunction and myocardial interstitial fibrosis by modulating nuclear factor-kappa B (NF-κB) signaling pathway.

  1. Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story.

    PubMed

    Elnakish, Mohammad T; Ahmed, Amany A E; Mohler, Peter J; Janssen, Paul M L

    2015-01-01

    Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models. PMID:26146529

  2. Role of Oxidative Stress in Thyroid Hormone-Induced Cardiomyocyte Hypertrophy and Associated Cardiac Dysfunction: An Undisclosed Story

    PubMed Central

    Elnakish, Mohammad T.; Ahmed, Amany A. E.; Mohler, Peter J.; Janssen, Paul M. L.

    2015-01-01

    Cardiac hypertrophy is the most documented cardiomyopathy following hyperthyroidism in experimental animals. Thyroid hormone-induced cardiac hypertrophy is described as a relative ventricular hypertrophy that encompasses the whole heart and is linked with contractile abnormalities in both right and left ventricles. The increase in oxidative stress that takes place in experimental hyperthyroidism proposes that reactive oxygen species are key players in the cardiomyopathy frequently reported in this endocrine disorder. The goal of this review is to shed light on the effects of thyroid hormones on the development of oxidative stress in the heart along with the subsequent cellular and molecular changes. In particular, we will review the role of thyroid hormone-induced oxidative stress in the development of cardiomyocyte hypertrophy and associated cardiac dysfunction, as well as the potential effectiveness of antioxidant treatments in attenuating these hyperthyroidism-induced abnormalities in experimental animal models. PMID:26146529

  3. Deficiency of cardiac Acyl-CoA synthetase-1 induces diastolic dysfunction, but pathologic hypertrophy is reversed by rapamycin.

    PubMed

    Paul, David S; Grevengoed, Trisha J; Pascual, Florencia; Ellis, Jessica M; Willis, Monte S; Coleman, Rosalind A

    2014-06-01

    In mice with temporally-induced cardiac-specific deficiency of acyl-CoA synthetase-1 (Acsl1(H-/-)), the heart is unable to oxidize long-chain fatty acids and relies primarily on glucose for energy. These metabolic changes result in the development of both a spontaneous cardiac hypertrophy and increased phosphorylated S6 kinase (S6K), a substrate of the mechanistic target of rapamycin, mTOR. Doppler echocardiography revealed evidence of significant diastolic dysfunction, indicated by a reduced E/A ratio and increased mean performance index, although the deceleration time and the expression of sarco/endoplasmic reticulum calcium ATPase and phospholamban showed no difference between genotypes. To determine the role of mTOR in the development of cardiac hypertrophy, we treated Acsl1(H-/-) mice with rapamycin. Six to eight week old Acsl1(H-/-) mice and their littermate controls were given i.p. tamoxifen to eliminate cardiac Acsl1, then concomitantly treated for 10weeks with i.p. rapamycin or vehicle alone. Rapamycin completely blocked the enhanced ventricular S6K phosphorylation and cardiac hypertrophy and attenuated the expression of hypertrophy-associated fetal genes, including α-skeletal actin and B-type natriuretic peptide. mTOR activation of the related Acsl3 gene, usually associated with pathologic hypertrophy, was also attenuated in the Acsl1(H-/-) hearts, indicating that alternative pathways of fatty acid activation did not compensate for the loss of Acsl1. Compared to controls, Acsl1(H-/-) hearts exhibited an 8-fold higher uptake of 2-deoxy[1-(14)C]glucose and a 35% lower uptake of the fatty acid analog 2-bromo[1-(14)C]palmitate. These data indicate that Acsl1-deficiency causes diastolic dysfunction and that mTOR activation is linked to the development of cardiac hypertrophy in Acsl1(H-/-) mice. PMID:24631848

  4. Prospective investigation of pituitary functions in patients with acute infectious meningitis: is acute meningitis induced pituitary dysfunction associated with autoimmunity?

    PubMed

    Tanriverdi, F; De Bellis, A; Teksahin, H; Alp, E; Bizzarro, A; Sinisi, A A; Bellastella, G; Paglionico, V A; Bellastella, A; Unluhizarci, K; Doganay, M; Kelestimur, F

    2012-12-01

    Previous case reports and retrospective studies suggest that pituitary dysfunction may occur after acute bacterial or viral meningitis. In this prospective study we assessed the pituitary functions, lipid profile and anthropometric measures in adults with acute bacterial or viral meningitis. Moreover, in order to investigate whether autoimmune mechanisms could play a role in the pathogenesis of acute meningitis-induced hypopituitarism we also investigated the anti-pituitary antibodies (APA) and anti-hypothalamus antibodies (AHA) prospectively. Sixteen patients (10 males, 6 females; mean ± SD age 40.9 ± 15.9) with acute infectious meningitis were included and the patients were evaluated in the acute phase, and at 6 and 12 months after the acute meningitis. In the acute phase 18.7% of the patients had GH deficiency, 12.5% had ACTH and FSH/LH deficiencies. At 12 months after acute meningitis 6 of 14 patients (42.8%) had GH deficiency, 1 of 14 patients (7.1%) had ACTH and FSH/LH deficiencies. Two of 14 patients (14.3%) had combined hormone deficiencies and four patients (28.6%) had isolated hormone deficiencies at 12 months. Four of 9 (44.4%) hormone deficiencies at 6 months were recovered at 12 months, and 3 of 8 (37.5%) hormone deficiencies at 12 months were new-onset hormone deficiencies. At 12 months there were significant negative correlations between IGF-I level vs. LDL-C, and IGF-I level vs. total cholesterol. The frequency of AHA and APA positivity was substantially high, ranging from 35 to 50% of the patients throughout the 12 months period. However there were no significant correlations between AHA or APA positivity and hypopituitarism. The risk of hypopituitarism, GH deficiency in particular, is substantially high in the acute phase, after 6 and 12 months of the acute infectious meningitis. Moreover we found that 6th month after meningitis is too early to make a decision for pituitary dysfunction and these patients should be screened for at least 12 months

  5. Targeted deletion of PTEN in cardiomyocytes renders cardiac contractile dysfunction through interruption of Pink1-AMPK signaling and autophagy.

    PubMed

    Roe, Nathan D; Xu, Xihui; Kandadi, Machender R; Hu, Nan; Pang, Jiaojiao; Weiser-Evans, Mary C M; Ren, Jun

    2015-02-01

    Phosphatase and tensin homolog (PTEN) deleted from chromosome 10 has been implicated in the maintenance of cardiac homeostasis although the underlying mechanism(s) remains elusive. We generated a murine model of cardiomyocyte-specific knockout of PTEN to evaluate cardiac geometry and contractile function, as well as the effect of metformin on PTEN deficiency-induced cardiac anomalies, if any. Cardiac histology, autophagy and related signaling molecules were evaluated. Cardiomyocyte-specific PTEN deletion elicited cardiac hypertrophy and contractile anomalies (echocardiographic and cardiomyocyte contractile dysfunction) associated with compromised intracellular Ca(2+) handling. PTEN deletion-induced cardiac hypertrophy and contractile anomalies were associated with dampened phosphorylation of PTEN-inducible kinase 1 (Pink1) and AMPK. Interestingly, administration of AMPK activator metformin (200mg/kg/d, in drinking H2O for 4weeks) rescued against PTEN deletion-induced geometric and functional defects as well as interrupted autophagy and autophagic flux in the heart. Moreover, metformin administration partially although significantly attenuated PTEN deletion-induced accumulation of superoxide. RNA interference against Pink1 in H9C2 myoblasts overtly increased intracellular ATP levels and suppressed AMPK phosphorylation, confirming the role of AMPK as a downstream target for PTEN-Pink1. Further scrutiny revealed that activation of AMPK and autophagy using metformin and rapamycin, respectively, rescued against PTEN deletion-induced mechanical anomalies with little additive effect. These data demonstrated that cardiomyocyte-specific deletion of PTEN leads to the loss of Pink1-AMPK signaling, development of cardiac hypertrophy and contractile defect. Activation of AMPK rescued against PTEN deletion-induced cardiac anomalies associated with restoration of autophagy and autophagic flux. This article is part of a Special Issue entitled: Autophagy and protein quality control

  6. Elevation of CXCR3-binding chemokines in urine indicates acute renal-allograft dysfunction.

    PubMed

    Hu, Huaizhong; Aizenstein, Brian D; Puchalski, Alice; Burmania, Jeanine A; Hamawy, Majed M; Knechtle, Stuart J

    2004-03-01

    A noninvasive urinary test that diagnoses acute renal allograft dysfunction would benefit renal transplant patients. We aimed to develop a rapid urinary diagnostic test by detecting chemokines. Seventy-three patients with renal allograft dysfunction prompting biopsy and 26 patients with stable graft function were recruited. Urinary levels of CXCR3-binding chemokines, monokine induced by IFN-gamma (Mig/CXCL9), IFN-gamma-induced protein of 10 kDa (IP-10/CXCL10), and IFN-inducible T-cell chemoattractant (I-TAC/CXCL11), were determined by a particle-based triplex assay. IP-10, Mig and I-TAC were significantly elevated in renal graft recipients with acute rejection, acute tubular injury and BK virus nephritis. Using 100 pg/mL as the threshold level, both IP-10 and Mig had diagnostic value (sensitivity 86.4%; specificity 91.3%) in differentiating acute graft dysfunction from other clinical conditions. In terms of monitoring the response to antirejection therapy, this urinary test is more sensitive and predictive than serum creatinine. These results indicate that this rapid test is clinically useful.

  7. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J.; Llanos-Gómez, Juan M.; Cabello-Rodríguez, Ana I.; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called “sanctuaries,” are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass.

  8. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

    PubMed Central

    Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J.; Llanos-Gómez, Juan M.; Cabello-Rodríguez, Ana I.; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called “sanctuaries,” are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass. PMID:27642531

  9. Cardiac Relapse of Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation.

    PubMed

    Facenda-Lorenzo, María; Sánchez-Quintana, Ana; Quijada-Fumero, Alejandro; Laynez-Carnicero, Ana; Breña-Atienza, Joaquín; Poncela-Mireles, Francisco J; Llanos-Gómez, Juan M; Cabello-Rodríguez, Ana I; Ramos-López, María

    2016-01-01

    Secondary or metastatic cardiac tumors are much more common than primary benign or malignant cardiac tumors. Any tumor can cause myocardial or pericardial metastasis, although isolated or combined tumor invasion of the pericardium is more common. Types of neoplasia with the highest rates of cardiac or pericardial involvement are melanoma, lung cancer, and breast and mediastinal carcinomas. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Initial treatment involves chemotherapy followed by consolidation treatment to reduce the risk of relapse. In high-risk patients, the treatment of choice for consolidation is hematopoietic stem cell transplantation (HSCT). Relapse of AML is the most common cause of HSCT failure. Extramedullary relapse is rare. The organs most frequently affected, called "sanctuaries," are the testes, ovaries, and central nervous system. We present a case with extramedullary relapse in the form of a solid cardiac mass. PMID:27642531

  10. SPR detection of cardiac troponin T for acute myocardial infarction.

    PubMed

    Pawula, Maria; Altintas, Zeynep; Tothill, Ibtisam E

    2016-01-01

    A surface plasmon resonance (SPR) sensor developed for the rapid, sensitive and specific detection of cardiac troponin T (cTnT) in serum samples is reported in this work. An extensive optimisation of assay parameters was conducted to achieve optimal detection strategy. Both direct and sandwich immunoassay formats were investigated and optimised. The response obtained was enhanced further by the use of gold nanoparticles (AuNPs) conjugated to the anti-cTnT detection antibody. A regeneration method was developed to enable the reuse of the SPR sensor for multiple sample application. The SPR immunosensor showed good reproducibility for cTnT detection in the concentration range of 25-1000 ng mL(-1) and 5-400 ng mL(-1) for the direct and sandwich assays in buffer, respectively. The linear regression analysis was performed and R(2) value was found as 0.99 for both assays. In order to optimise the sensor for serum analysis, nonspecific binding of serum proteins was reduced through the use of additives in the dilution buffer. To achieve greater sensitivity, the performance of the cTnT immunosensor sandwich assay in human serum was evaluated using non-modified and AuNP modified detector antibodies. A detection limit (LOD) for the immunosensor in 50% serum was assessed as 5 ng mL(-1) cTnT for the standard sandwich assay and 0.5 ng mL(-1) cTnT when using AuNP conjugated detector antibodies with a linear dynamic range of 0.5-40 ng mL(-1). The dissociation constant was found as 3.28 × 10(-9) M using Langmuir binding model which indicates high affinity between cTnT and its antibody. The proposed SPR immunosensor has a promising potential to be developed for point-of-care testing for the early diagnosis of acute myocardial infarction (AMI). This method can also be used for the rapid detection of biomarkers in central nervous system diseases. PMID:26695335

  11. SPR detection of cardiac troponin T for acute myocardial infarction.

    PubMed

    Pawula, Maria; Altintas, Zeynep; Tothill, Ibtisam E

    2016-01-01

    A surface plasmon resonance (SPR) sensor developed for the rapid, sensitive and specific detection of cardiac troponin T (cTnT) in serum samples is reported in this work. An extensive optimisation of assay parameters was conducted to achieve optimal detection strategy. Both direct and sandwich immunoassay formats were investigated and optimised. The response obtained was enhanced further by the use of gold nanoparticles (AuNPs) conjugated to the anti-cTnT detection antibody. A regeneration method was developed to enable the reuse of the SPR sensor for multiple sample application. The SPR immunosensor showed good reproducibility for cTnT detection in the concentration range of 25-1000 ng mL(-1) and 5-400 ng mL(-1) for the direct and sandwich assays in buffer, respectively. The linear regression analysis was performed and R(2) value was found as 0.99 for both assays. In order to optimise the sensor for serum analysis, nonspecific binding of serum proteins was reduced through the use of additives in the dilution buffer. To achieve greater sensitivity, the performance of the cTnT immunosensor sandwich assay in human serum was evaluated using non-modified and AuNP modified detector antibodies. A detection limit (LOD) for the immunosensor in 50% serum was assessed as 5 ng mL(-1) cTnT for the standard sandwich assay and 0.5 ng mL(-1) cTnT when using AuNP conjugated detector antibodies with a linear dynamic range of 0.5-40 ng mL(-1). The dissociation constant was found as 3.28 × 10(-9) M using Langmuir binding model which indicates high affinity between cTnT and its antibody. The proposed SPR immunosensor has a promising potential to be developed for point-of-care testing for the early diagnosis of acute myocardial infarction (AMI). This method can also be used for the rapid detection of biomarkers in central nervous system diseases.

  12. Persistent Maternal Cardiac Dysfunction After Preeclampsia Identifies Patients at Risk for Recurrent Preeclampsia.

    PubMed

    Valensise, Herbert; Lo Presti, Damiano; Gagliardi, Giulia; Tiralongo, Grazia Maria; Pisani, Ilaria; Novelli, Gian Paolo; Vasapollo, Barbara

    2016-04-01

    The purpose of our study was to assess cardiac function in nonpregnant women with previous early preeclampsia before a second pregnancy to highlight the cardiovascular pattern, which may take a risk for recurrent preeclampsia. Seventy-five normotensive patients with previous preeclampsia and 147 controls with a previous uneventful pregnancy were enrolled in a case-control study and submitted to echocardiographic examination in the nonpregnant state 12 to 18 months after the first delivery. All patients included in the study had pregnancy within 24 months from the echocardiographic examination and were followed until term. Twenty-two (29%) of the 75 patients developed recurrent preeclampsia. In the nonpregnant state, patients with recurrent preeclampsia compared with controls and nonrecurrent preeclampsia had lower stroke volume (63 ± 14 mL versus 73 ± 12 mL and 70 ± 11 mL, P<0.05), cardiac output (4.6 ± 1.2 L versus 5.3 ± 0.9 L and 5.2 ± 1.0 L, P<0.05), higher E/E' ratio (11.02 ± 3.43 versus 7.34 ± 2.11 versus 9.03 ± 3.43, P<0.05), and higher total vascular resistance (1638 ± 261 dyne · s(-1) · cm(-5) versus 1341 ± 270 dyne · s(-1) · cm(-5) and 1383 ± 261 dyne · s(-1) · cm(-5), P<0.05). Left ventricular mass index was higher in both recurrent and nonrecurrent preeclampsia compared with controls (30.0 ± 6.3 g/m(2.7) and 30.4 ± 6.8 g/m(2.7) versus 24.8 ± 5.0 g/m(2.7), P<0.05). Signs of diastolic dysfunction and different left ventricular characteristics are present in the nonpregnant state before a second pregnancy with recurrent preeclampsia. Previous preeclamptic patients with nonrecurrent preeclampsia show left ventricular structural and functional features intermediate with respect to controls and recurrent preeclampsia.

  13. Acute cardiac arrhythmias following surgery for congenital heart disease: mechanisms, diagnostic tools, and management.

    PubMed

    Payne, Linda; Zeigler, Vicki L; Gillette, Paul C

    2011-06-01

    This article focuses on the management of those cardiac arrhythmias most commonly seen in the immediate postoperative period. They include ventricular tachycardia, ventricular fibrillation, atrial flutter, junctional ectopic tachycardia, bradycardia, and atrioventricular block. The mechanisms of cardiac arrhythmias are reviewed followed by a brief overview of the predominant acute arrhythmias, tools used for the diagnostic evaluation of these arrhythmias, management strategies, and, finally, nursing considerations.

  14. Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction.

    PubMed

    Wang, Qingjie; Yang, Hui; Bai, Aobing; Jiang, Wei; Li, Xiuya; Wang, Xinhong; Mao, Yishen; Lu, Chao; Qian, Ruizhe; Guo, Feng; Ding, Tianling; Chen, Haiyan; Chen, Sifeng; Zhang, Jianyi; Liu, Chen; Sun, Ning

    2016-10-01

    With the advent of induced pluripotent stem cells and directed differentiation techniques, it is now feasible to derive individual-specific cardiac cells for human heart tissue engineering. Here we report the generation of functional engineered human cardiac patches using human induced pluripotent stem cells-derived cardiac cells and decellularized natural heart ECM as scaffolds. The engineered human cardiac patches can be tailored to any desired size and shape and exhibited normal contractile and electrical physiology in vitro. Further, when patching on the infarct area, these patches improved heart function of rats with acute myocardial infarction in vivo. These engineered human cardiac patches can be of great value for normal and disease-specific heart tissue engineering, drug screening, and meet the demands for individual-specific heart tissues for personalized regenerative therapy of myocardial damages in the future. PMID:27509303

  15. Functional engineered human cardiac patches prepared from nature's platform improve heart function after acute myocardial infarction.

    PubMed

    Wang, Qingjie; Yang, Hui; Bai, Aobing; Jiang, Wei; Li, Xiuya; Wang, Xinhong; Mao, Yishen; Lu, Chao; Qian, Ruizhe; Guo, Feng; Ding, Tianling; Chen, Haiyan; Chen, Sifeng; Zhang, Jianyi; Liu, Chen; Sun, Ning

    2016-10-01

    With the advent of induced pluripotent stem cells and directed differentiation techniques, it is now feasible to derive individual-specific cardiac cells for human heart tissue engineering. Here we report the generation of functional engineered human cardiac patches using human induced pluripotent stem cells-derived cardiac cells and decellularized natural heart ECM as scaffolds. The engineered human cardiac patches can be tailored to any desired size and shape and exhibited normal contractile and electrical physiology in vitro. Further, when patching on the infarct area, these patches improved heart function of rats with acute myocardial infarction in vivo. These engineered human cardiac patches can be of great value for normal and disease-specific heart tissue engineering, drug screening, and meet the demands for individual-specific heart tissues for personalized regenerative therapy of myocardial damages in the future.

  16. Low Intensity Physical Exercise Attenuates Cardiac Remodeling and Myocardial Oxidative Stress and Dysfunction in Diabetic Rats

    PubMed Central

    Gimenes, C.; Gimenes, R.; Rosa, C. M.; Xavier, N. P.; Campos, D. H. S.; Fernandes, A. A. H.; Cezar, M. D. M.; Guirado, G. N.; Cicogna, A. C.; Takamoto, A. H. R.; Okoshi, M. P.; Okoshi, K.

    2015-01-01

    We evaluated the effects of a low intensity aerobic exercise protocol on cardiac remodeling and myocardial function in diabetic rats. Wistar rats were assigned into four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary diabetes (DM-Sed), and exercised diabetes (DM-Ex). Diabetes was induced by intraperitoneal injection of streptozotocin. Rats exercised for 9 weeks in treadmill at 11 m/min, 18 min/day. Myocardial function was evaluated in left ventricular (LV) papillary muscles and oxidative stress in LV tissue. Statistical analysis was given by ANOVA or Kruskal-Wallis. Echocardiogram showed diabetic groups with higher LV diastolic diameter-to-body weight ratio and lower posterior wall shortening velocity than controls. Left atrium diameter was lower in DM-Ex than DM-Sed (C-Sed: 5.73 ± 0.49; C-Ex: 5.67 ± 0.53; DM-Sed: 6.41 ± 0.54; DM-Ex: 5.81 ± 0.50 mm; P < 0.05 DM-Sed vs C-Sed and DM-Ex). Papillary muscle function was depressed in DM-Sed compared to C-Sed. Exercise attenuated this change in DM-Ex. Lipid hydroperoxide concentration was higher in DM-Sed than C-Sed and DM-Ex. Catalase and superoxide dismutase activities were lower in diabetics than controls and higher in DM-Ex than DM-Sed. Glutathione peroxidase activity was lower in DM-Sed than C-Sed and DM-Ex. Conclusion. Low intensity exercise attenuates left atrium dilation and myocardial oxidative stress and dysfunction in type 1 diabetic rats. PMID:26509175

  17. Early allograft dysfunction in liver transplantation with donation after cardiac death donors results in inferior survival.

    PubMed

    Lee, David D; Singh, Amandeep; Burns, Justin M; Perry, Dana K; Nguyen, Justin H; Taner, C Burcin

    2014-12-01

    Donation after cardiac death (DCD) liver allografts have been associated with increased morbidity from primary nonfunction, biliary complications, early allograft failure, cost, and mortality. Early allograft dysfunction (EAD) after liver transplantation has been found to be associated with inferior patient and graft survival. In a cohort of 205 consecutive liver-only transplant patients with allografts from DCD donors at a single center, the incidence of EAD was found to be 39.5%. The patient survival rates for those with no EAD and those with EAD at 1, 3, and 5 years were 97% and 89%, 79% and 79%, and 61% and 54%, respectively (P = 0.009). Allograft survival rates for recipients with no EAD and those with EAD at 1, 3, and 5 years were 90% and 75%, 72% and 64%, and 53% and 43%, respectively (P = 0.003). A multivariate analysis demonstrated a significant association between the development of EAD and the cold ischemia time [odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.01-1.56, P = 0.037] and hepatocellular cancer as a secondary diagnosis in recipients (OR = 2.26, 95% CI = 1.11-4.58, P = 0.025). There was no correlation between EAD and the development of ischemic cholangiopathy. In conclusion, EAD results in inferior patient and graft survival in recipients of DCD liver allografts. Understanding the events that cause EAD and developing preventive or early therapeutic approaches should be the focus of future investigations. PMID:25179581

  18. Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction.

    PubMed

    Huang, Chien-Hua; Tsai, Min-Shan; Chiang, Chih-Yen; Su, Yu-Jen; Wang, Tzung-Dau; Chang, Wei-Tien; Chen, Huei-Wen; Chen, Wen-Jone

    2015-11-01

    While therapeutic hypothermia improves the outcomes of individuals in cardiac arrest, the hemodynamic responses and mechanisms which underlie hypothermia-induced cardioprotection are not fully understood. Therefore, we investigated the mechanism by which induced hypothermia preserves cardiac function and protects against mitochondrial damage following cardiac arrest. Cardiac arrest was induced in adult male Wistar rats by asphyxiation for 8.5 min. Following resuscitation, the animals were randomly assigned to a hypothermia (32 °C) or normothermia (37 °C) group. Monitoring results showed that cardiac output at the fourth hour after resuscitation was significantly better in rats treated with hypothermia when compared to rats treated with normothermia (P < 0.01). Examinations by transmission electron microscopy showed that mitochondria in the left ventricle of rats in the hypothermia group were significantly less swollen compared to such mitochondria in the normothermia group (P < 0.001). Additionally, opening of mitochondrial permeability transition pores occurred less frequently in the hypothermic group. While complex I/III activity in the electron transport reaction was damaged after cardiac arrest and resuscitation, the degree of injury was ameliorated by hypothermia treatment (P < 0.05). The amount of STAT-3 phosphorylated at tyrosine 705 and its expression in mitochondria were significantly higher under hypothermia treatment compared to normothermia treatment. In vitro studies showed that inhibition STAT-3 activation abolished the ability of hypothermia to protect H9C2 cardiomyocytes against injury produced by simulated ischemia and reperfusion. Therapeutic hypothermia treatment can ameliorate cardiac dysfunction and help preserve both mitochondrial integrity and electron transport activity. PMID:26471891

  19. Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction.

    PubMed

    Huang, Chien-Hua; Tsai, Min-Shan; Chiang, Chih-Yen; Su, Yu-Jen; Wang, Tzung-Dau; Chang, Wei-Tien; Chen, Huei-Wen; Chen, Wen-Jone

    2015-11-01

    While therapeutic hypothermia improves the outcomes of individuals in cardiac arrest, the hemodynamic responses and mechanisms which underlie hypothermia-induced cardioprotection are not fully understood. Therefore, we investigated the mechanism by which induced hypothermia preserves cardiac function and protects against mitochondrial damage following cardiac arrest. Cardiac arrest was induced in adult male Wistar rats by asphyxiation for 8.5 min. Following resuscitation, the animals were randomly assigned to a hypothermia (32 °C) or normothermia (37 °C) group. Monitoring results showed that cardiac output at the fourth hour after resuscitation was significantly better in rats treated with hypothermia when compared to rats treated with normothermia (P < 0.01). Examinations by transmission electron microscopy showed that mitochondria in the left ventricle of rats in the hypothermia group were significantly less swollen compared to such mitochondria in the normothermia group (P < 0.001). Additionally, opening of mitochondrial permeability transition pores occurred less frequently in the hypothermic group. While complex I/III activity in the electron transport reaction was damaged after cardiac arrest and resuscitation, the degree of injury was ameliorated by hypothermia treatment (P < 0.05). The amount of STAT-3 phosphorylated at tyrosine 705 and its expression in mitochondria were significantly higher under hypothermia treatment compared to normothermia treatment. In vitro studies showed that inhibition STAT-3 activation abolished the ability of hypothermia to protect H9C2 cardiomyocytes against injury produced by simulated ischemia and reperfusion. Therapeutic hypothermia treatment can ameliorate cardiac dysfunction and help preserve both mitochondrial integrity and electron transport activity.

  20. Activation of Retinoid Receptor-Mediated Signaling Ameliorates Diabetes-Induced Cardiac Dysfunction in Zucker Diabetic Rats

    PubMed Central

    Guleria, Rakeshwar S.; Singh, Amar B.; Nizamutdinova, Irina T.; Souslova, Tatiana; Mohammad, Amin A.; Kendall, Jonathan A.; Baker, Kenneth M.; Pan, Jing

    2013-01-01

    Diabetic cardiomyopathy (DCM) is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. Retinoids, through activation of retinoic acid receptor (RAR) and retinoid×receptor (RXR), have been linked to control of glucose and lipid homeostasis, with effects on obesity and diabetes. However, the functional role of RAR and RXR in the development of DCM remains unclear. Zucker diabetic fatty (ZDF) and lean rats were treated with Am580 (RARα agonist) or LGD1069 (RXR agonist) for 16 weeks, and cardiac function and metabolic alterations were determined. Hyperglycemia, hyperlipidemia and insulin resistance were observed in ZDF rats. Diabetic cardiomyopathy was characterized in ZDF rats by increased oxidative stress, apoptosis, fibrosis, inflammation, activation of MAP kinases and NF-κB signaling and diminished Akt phosphorylation, along with decreased glucose transport and increased cardiac lipid accumulation, and ultimately diastolic dysfunction. Am580 and LGD1069 attenuated diabetes-induced cardiac dysfunction and the pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signaling pathways. Am580 inhibited body weight gain, attenuated the increased cardiac fatty acid uptake, β-oxidation and lipid accumulation in the hearts of ZDF rats. However, LGD1069 promoted body weight gain, hyperlipidemia and cardiac lipid accumulation. In conclusion, our data suggest that activation of RAR and RXR may have therapeutic potential in the treatment of diabetic cardiomyopathy. However, further studies are necessary to clarify the role of RAR and RXR in the regulation of lipid metabolism and homeostasis. PMID:23395853

  1. Activation of retinoid receptor-mediated signaling ameliorates diabetes-induced cardiac dysfunction in Zucker diabetic rats.

    PubMed

    Guleria, Rakeshwar S; Singh, Amar B; Nizamutdinova, Irina T; Souslova, Tatiana; Mohammad, Amin A; Kendall, Jonathan A; Baker, Kenneth M; Pan, Jing

    2013-04-01

    Diabetic cardiomyopathy (DCM) is a significant contributor to the morbidity and mortality associated with diabetes and metabolic syndrome. Retinoids, through activation of retinoic acid receptor (RAR) and retinoid x receptor (RXR), have been linked to control glucose and lipid homeostasis, with effects on obesity and diabetes. However, the functional role of RAR and RXR in the development of DCM remains unclear. Zucker diabetic fatty (ZDF) and lean rats were treated with Am580 (RARα agonist) or LGD1069 (RXR agonist) for 16 weeks, and cardiac function and metabolic alterations were determined. Hyperglycemia, hyperlipidemia and insulin resistance were observed in ZDF rats. Diabetic cardiomyopathy was characterized in ZDF rats by increased oxidative stress, apoptosis, fibrosis, inflammation, activation of MAP kinases and NF-κB signaling and diminished Akt phosphorylation, along with decreased glucose transport and increased cardiac lipid accumulation, and ultimately diastolic dysfunction. Am580 and LGD1069 attenuated diabetes-induced cardiac dysfunction and the pathological alterations, by improving glucose tolerance and insulin resistance; facilitating Akt activation and glucose utilization, and attenuating oxidative stress and interrelated MAP kinase and NF-κB signaling pathways. Am580 inhibited body weight gain, attenuated the increased cardiac fatty acid uptake, β-oxidation and lipid accumulation in the hearts of ZDF rats. However, LGD1069 promoted body weight gain, hyperlipidemia and cardiac lipid accumulation. In conclusion, our data suggest that activation of RAR and RXR may have therapeutic potential in the treatment of diabetic cardiomyopathy. However, further studies are necessary to clarify the role of RAR and RXR in the regulation of lipid metabolism and homeostasis.

  2. Galectin-3 level and the severity of cardiac diastolic dysfunction using cellular and animal models and clinical indices

    PubMed Central

    Wu, Cho-Kai; Su, Mao-Yuan; Lee, Jen-Kuang; Chiang, Fu-Tien; Hwang, Juey-Jen; Lin, Jiunn-Lee; Chen, Jin-Jer; Liu, Fu-Tong; Tsai, Chia-Ti

    2015-01-01

    Heart failure with preserved ejection fraction (HFPEF) is characterized by myocardial interstitial fibrosis. A total of 146 patients with HFPEF, were recruited. HFPEF severity was determined using Doppler imaging (E/Em) and also cardiac magnetic resonance imaging (CMRI). Canine modeling of HFPEF was induced by aortic banding. Hemodynamic and echocardiographic data were obtained before and after pressure loading and myocardial Galectin-3 was determined. Mechanical stretch of cultured cardiomyocytes served as the cellular model of HFPEF. Patients with severe HFPEF had significantly higher plasma Galectin-3 levels. Significant correlation between plasma Galectin-3 and E/Em in advanced HFPEF patients was noted. After 2 weeks of pressure overload in canine models, the protein expression of Galectin-3 from LV myocardial tissue was significantly increased (p < 0.01) compared with controls. Galectin-3 expression paralleled the severity of LV diastolic dysfunction by evaluation of CMRI (r = −0.58, p = 0.003) and tissue fibrosis (r = 0.59, p = 0.002). After adjusting for confounders for diastolic dysfunction, Galectin-3 levels were still associated with diastolic parameters both in humans (p < 0.001) and canine model (p = 0.041). Mechanical stretch increased Galectin-3 secretion in cultured cardiomyocytes. Both plasma and myocardial Galectin-3 levels correlated with severity of cardiac diastolic dysfunction. PMID:26582585

  3. Nitric Oxide Bioavailability and Adiponectin Production in Chronic Systolic Heart Failure: Relation to Severity of Cardiac Dysfunction

    PubMed Central

    Tang, W.H. Wilson; Shrestha, Kevin; Tong, Wilson; Wang, Zeneng; Troughton, Richard W.; Borowski, Allen G.; Klein, Allan L.; Hazen, Stanley L.

    2013-01-01

    Adiponectin is an anti-inflammatory, anti-atherogenic adipokine elevated in heart failure (HF) that may protect against endothelial dysfunction by influencing underlying nitric oxide bioavailablity. In this study, we examine the relationship between plasma adiponectin levels and measures of nitric oxide bioavailability and myocardial performance in patients with chronic systolic HF. In 139 ambulatory patients with stable, chronic systolic HF (left ventricular [LV] ejection fraction ≤40%, New York Heart Association [NYHA] class I to IV), we measured plasma levels of adiponectin, asymmetric dimethylarginine (ADMA) and global arginine bioavailability (GABR), and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse events (all-cause mortality or cardiac transplantation) were prospectively tracked for a median of 39 months. Plasma adiponectin levels directly correlated with plasma ADMA levels (Spearman’s r=0.41, p<0.001) and NT-proBNP levels (r=0.55, p<0.001), inversely correlated with GABR (r= −0.39, p<0.001), and were not associated with hsCRP (p=0.81) or MPO (p=0.07). Interestingly, increased plasma adiponectin levels remained positively correlated with plasma ADMA levels only in patients with elevated NT-proBNP levels (r= 0.33, p=0.009). Higher plasma adiponectin levels were associated with worse LV diastolic dysfunction (rank sums p=0.002), RV systolic dysfunction (rank sums p=0.002), and RV diastolic dysfunction (rank sums p=0.011), but not after adjustment for plasma ADMA and NT-proBNP levels. Plasma adiponectin levels predicted increased risk of adverse clinical events (HR [95% CI]: 1.45 [1.02–2.07], p=0.038) but not after adjustment for plasma ADMA and NT-proBNP levels, or echocardiographic indices of diastolic or RV systolic dysfunction. In patients with chronic systolic HF, adiponectin production is more closely linked with nitric oxide bioavailability than inflammation, and appears to be more robust

  4. Sudden cardiac death after acute ST elevation myocardial infarction: insight from a developing country

    PubMed Central

    Rao, Hygriv B; Sastry, B K S; Korabathina, Radhika; Raju, Krishnam P

    2012-01-01

    Background There is no data concerning sudden cardiac death (SCD) following acute ST elevation myocardial infarction (STEMI) in India. We assessed the incidence and factors influencing SCD following STEMI. Methods Patients with STEMI admitted in our hospital from 2006 to 2009 were prospectively entered into a database. In the period 2010–2011, patients or their kin were periodically contacted and administered a questionnaire to ascertain their survival, and mode of death if applicable. Results Study population comprised of 929 patients with STEMI (mean age 55±17 years) having a mean follow-up of 41±16 months. The total number of deaths was 159, of which 78 were SCD (mean age 62.2±10 years). The cumulative incidence of total deaths and SCD at 1 month, 1, 2, 3 years and at conclusion of the study was 10.1%, 13.2%, 14.6%, 15.8%, 17.3% and 4.9%, 6.5%, 8.0%, 8.9% and 9.7%, respectively. The temporal distribution of SCD was 53.9% at first month, 19.2% at 1 month to 1 year, 15.4% in 1–2 years, 7.6% in 2–3 years and 3.8% beyond 3 years. Comparison between SCD and survivor cohorts by multivariate analysis showed five variables were found to be associated with SCD (age p=0.0163, female gender p=0.0042, severe LV dysfunction p=0.0292, absence of both reperfusion and revascularisation p=0.0373 and lack of compliance with medications p <0.0001). Conclusions SCD following STEMI accounts for about half of the total deaths. It involves younger population and most of these occur within the first month. This data has relevance in prioritising healthcare strategies in India. PMID:27326036

  5. Cardiac manifestations of acute carbamate and organophosphate poisoning.

    PubMed Central

    Saadeh, A. M.; Farsakh, N. A.; al-Ali, M. K.

    1997-01-01

    OBJECTIVE: To study the frequency, extent, and pathogenesis of the cardiac complications accompanying organophosphate and carbamate poisoning. DESIGN: Retrospective study. SETTING: A medical intensive care unit (MICU) of a general hospital. SUBJECTS: 46 adult patients admitted over a five year period with a diagnosis of organophosphate or carbamate poisoning. RESULTS: Cardiac complications developed in 31 patients (67%). These were: non-cardiogenic pulmonary oedema, 20 (43%); cardiac arrhythmias, 11 (24%); electrocardiographic abnormalities including prolonged Q-Tc interval, 31 (67%); ST-T changes, 19 (41%); and conduction defects, 4 (9%). Sinus tachycardia occurred in 16 patients (35%) and sinus bradycardia in 13 (28%). Hypertension developed in 10 patients (22%) and hypotension in eight (17%). Eight patients (17%) needed respiratory support because of respiratory depression. Although more than two thirds of the patients (67%) had a prolonged Q-Tc interval, none had polymorphic ventricular tachycardia of the torsade de pointes type. Two patients died from ventricular fibrillation, an in hospital mortality of 4%. CONCLUSIONS: Cardiac complications often accompany poisoning with these compounds, particularly during the first few hours. Hypoxaemia, acidosis, and electrolyte derangements are major predisposing factors. Intensive supportive treatment in intensive or coronary care facilities with administration of atropine in adequate doses early in the course of the illness will reduce the mortality. PMID:9196418

  6. Bupivacaine induced cardiac toxicity mimicking an acute non-ST segment elevation myocardial infarction.

    PubMed

    Ryu, Ho Yoel; Kim, Jang-Young; Lim, Hyun Kyo; Yoon, Junghan; Yoo, Byung-Su; Choe, Kyung-Hoon; Lee, Seung-Hwan

    2007-04-30

    Bupivacaine is widely used as a local anesthetic. Central nervous system (CNS) and cardiovascular toxicity are well known side effects. However, there has been no report of bupivacaine-induced myocardial injury. We present a case of bupivacaine cardiac toxicity mimicking an acute non-ST segment elevation myocardial infarction, which was eventually diagnosed as bupivacaine-induced cardiac toxicity without CNS toxicity. As soon as a healthy young woman at a private clinic was given a spinal anesthesia of 6mg bupivacaine for hemorrhoidectomy, she developed arrhythmia and hypotension. She was transferred to our emergency room. There was an accelerated idioventricular rhythm with ST segment depression on electrocardiogram, coarse breathing sounds with rales on whole lung field and a butterfly sign on the chest radiograph. 2D transthoracic echocardiography (TTE) revealed reduced left ventricle systolic ejection fraction (approximately 27%). There was regional wall motion abnormality of the left ventricle on 2D TTE and the cardiac marker was increased. We diagnosed the patient as having acute non-ST segment elevation myocardial infarction but her impaired cardiac function improved gradually. On the seventh day from admission, there was a complete spontaneous recovery of cardiac function, and coronary angiography revealed a normal coronary artery. Therefore, we firmly believe that bupivacaine directly injures the cardiac cell.

  7. PULMONARY AND CARDIAC GENE EXPRESSION FOLLOWING ACUTE ULTRAFINE CARBON PARTICLE INHALATION IN HYPERTENSIVE RATS

    EPA Science Inventory

    Inhalation of ultrafine carbon particles (ufCP) causes cardiac physiological changes without marked pulmonary injury or inflammation. We hypothesized that acute ufCP exposure of 13 months old Spontaneously Hypertensive (SH) rats will cause differential effects on the lung and hea...

  8. Study of Aetiology and Outcome in Acute Febrile Illness Patients with Multiple Organ Dysfunction Syndrome

    PubMed Central

    Muthaiah, Bhanukumar; Kondareddy, Srinivas; Chikkegowda, Prathima

    2016-01-01

    Introduction Acute febrile illness with Multi Organ Dysfunction Syndrome (MODS) carries significant morbidity and mortality despite standard therapy in intensive care settings. Infections are the most common cause of MODS followed by polytrauma. Present study was undertaken in medical intensive care units of a tertiary hospital to study the aetiology and outcome among patients with acute febrile illness developing MODS. Aim 1) To study the aetiology of acute febrile illness in patients developing MODS. 2) To study the final outcome among these patients. Materials and Methods The present study was conducted at a tertiary care hospital in Mysuru, Karnataka, India, over a period of 6 months from July 2013 to December 2013. The Institutional Ethics Committee Approval (IEC) was obtained before the commencement of the study. A total of 213 cases admitted in intensive care unit with acute febrile illness with two or more organ dysfunction were screened for the inclusion and exclusion criterias. Results A total of 213 cases of acute febrile illness with one or more organ dysfunction were screened. Of the screened patients 75 patients were finally included in the study out of which 46 (61.3%) patients were males and 29 (38.7%) patients were females. Aetiology for acute febrile illness with MODS could be established in 49 (65.3%) patients and it was obscure in 26 (34.7%) patients despite repeated investigations. Dengue infection (29.3%) was the commonest cause of febrile illness with MODS followed by leptospirosis (22.7%). Majority of these patients had haematological derangements (78.7%) and liver function test abnormalities (68%). Out of these 75 cases, 54 (72%) patients recovered completely and 21 (28%) patients died. Among males (N=46), 35 (76.1%) patients recovered and 11 (23.9%) patients died where as among females (N=29), 19 (65.5%) patients recovered and 10 (34.5%) patients died. Mortality was proportionate with the number of organ dysfunction, especially Central

  9. ACE2 Deficiency Worsens Epicardial Adipose Tissue Inflammation and Cardiac Dysfunction in Response to Diet-Induced Obesity.

    PubMed

    Patel, Vaibhav B; Mori, Jun; McLean, Brent A; Basu, Ratnadeep; Das, Subhash K; Ramprasath, Tharmarajan; Parajuli, Nirmal; Penninger, Josef M; Grant, Maria B; Lopaschuk, Gary D; Oudit, Gavin Y

    2016-01-01

    Obesity is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; angiotensin (Ang)-converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. We studied the role of ACE2 in obesity-mediated cardiac dysfunction. ACE2 null (ACE2KO) and wild-type (WT) mice were fed a high-fat diet (HFD) or a control diet and studied at 6 months of age. Loss of ACE2 resulted in decreased weight gain but increased glucose intolerance, epicardial adipose tissue (EAT) inflammation, and polarization of macrophages into a proinflammatory phenotype in response to HFD. Similarly, human EAT in patients with obesity and heart failure displayed a proinflammatory macrophage phenotype. Exacerbated EAT inflammation in ACE2KO-HFD mice was associated with decreased myocardial adiponectin, decreased phosphorylation of AMPK, increased cardiac steatosis and lipotoxicity, and myocardial insulin resistance, which worsened heart function. Ang 1-7 (24 µg/kg/h) administered to ACE2KO-HFD mice resulted in ameliorated EAT inflammation and reduced cardiac steatosis and lipotoxicity, resulting in normalization of heart failure. In conclusion, ACE2 plays a novel role in heart disease associated with obesity wherein ACE2 negatively regulates obesity-induced EAT inflammation and cardiac insulin resistance.

  10. Early detection of cardiac dysfunction in the type 1 diabetic heart using speckle-tracking based strain imaging.

    PubMed

    Shepherd, Danielle L; Nichols, Cody E; Croston, Tara L; McLaughlin, Sarah L; Petrone, Ashley B; Lewis, Sara E; Thapa, Dharendra; Long, Dustin M; Dick, Gregory M; Hollander, John M

    2016-01-01

    Enhanced sensitivity in echocardiographic analyses may allow for early detection of changes in cardiac function beyond the detection limits of conventional echocardiographic analyses, particularly in a small animal model. The goal of this study was to compare conventional echocardiographic measurements and speckle-tracking based strain imaging analyses in a small animal model of type 1 diabetes mellitus. Conventional analyses revealed differences in ejection fraction, fractional shortening, cardiac output, and stroke volume in diabetic animals relative to controls at 6-weeks post-diabetic onset. In contrast, when assessing short- and long-axis speckle-tracking based strain analyses, diabetic mice showed changes in average systolic radial strain, radial strain rate, radial displacement, and radial velocity, as well as decreased circumferential and longitudinal strain rate, as early as 1-week post-diabetic onset and persisting throughout the diabetic study. Further, we performed regional analyses for the LV and found that the free wall region was affected in both the short- and long-axis when assessing radial dimension parameters. These changes began 1-week post-diabetic onset and remained throughout the progression of the disease. These findings demonstrate the use of speckle-tracking based strain as an approach to elucidate cardiac dysfunction from a global perspective, identifying left ventricular cardiac regions affected during the progression of type 1 diabetes mellitus earlier than contractile changes detected by conventional echocardiographic measurements.

  11. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age☆

    PubMed Central

    Sikka, Gautam; Miller, Karen L.; Steppan, Jochen; Pandey, Deepesh; Jung, Sung M.; Fraser, Charles D.; Ellis, Carla; Ross, Daniel; Vandegaer, Koenraad; Bedja, Djahida; Gabrielson, Kathleen; Walston, Jeremy D.; Berkowitz, Dan E.; Barouch, Lili A.

    2013-01-01

    Cardiovascular dysfunction is a primary independent predictor of age-related morbidity and mortality. Frailty is associated with activation of inflammatory pathways and fatigue that commonly presents and progresses with age. Interleukin 10 (IL-10), the cytokine synthesis inhibitory factor, is an anti-inflammatory cytokine produced by immune and non-immune cells. Homozygous deletion of IL-10 in mice yields a phenotype that is consistent with human frailty, including age-related increases in serum inflammatory mediators, muscular weakness, higher levels of IGF-1 at midlife, and early mortality. While emerging evidence suggests a role for IL-10 in vascular protection, a clear mechanism has not yet been elucidated. Methods In order to evaluate the role of IL-10 in maintenance of vascular function, force tension myography was utilized to access ex-vivo endothelium dependent vasorelaxation in vessels isolated from IL-10 knockout IL-10(tm/tm) and control mice. Pulse wave velocity ((PWV), index of stiffness) of vasculature was measured using ultrasound and blood pressure was measured using the tail cuff method. Echocardiography was used to elucidated structure and functional changes in the heart. Results Mean arterial pressures were significantly higher in IL-10(tm/tm) mice as compared to C57BL6/wild type (WT) controls. PWV was increased in IL-10(tm/tm) indicating stiffer vasculature. Endothelial intact aortic rings isolated from IL-10(tm/tm) mice demonstrated impaired vasodilation at low acetylcholine doses and vasoconstriction at higher doses whereas vasorelaxation responses were preserved in rings from WT mice. Cyclo-oxygenase (COX-2)/thromboxane A2 inhibitors improved endothelial dependent vasorelaxation and reversed vasoconstriction. Left ventricular end systolic diameter, left ventricular mass, isovolumic relaxation time, fractional shortening and ejection fraction were all significantly different in the aged IL-10(tm/tm) mice compared to WT mice. Conclusion Aged IL

  12. Maternal hyperglycemia leads to fetal cardiac hyperplasia and dysfunction in a rat model.

    PubMed

    Lehtoranta, Lara; Vuolteenaho, Olli; Laine, V Jukka; Koskinen, Anna; Soukka, Hanna; Kytö, Ville; Määttä, Jorma; Haapsamo, Mervi; Ekholm, Eeva; Räsänen, Juha

    2013-09-01

    Accelerated fetal myocardial growth with altered cardiac function is a well-documented complication of human diabetic pregnancy, but its pathophysiology is still largely unknown. Our aim was to explore the mechanisms of fetal cardiac remodeling and cardiovascular hemodynamics in a rat model of maternal pregestational streptozotocin-induced hyperglycemia. The hyperglycemic group comprised 107 fetuses (10 dams) and the control group 219 fetuses (20 dams). Fetal cardiac function was assessed serially by Doppler ultrasonography. Fetal cardiac to thoracic area ratio, newborn heart weight, myocardial cell proliferative and apoptotic activities, and cardiac gene expression patterns were determined. Maternal hyperglycemia was associated with increased cardiac size, proliferative, apoptotic and mitotic activities, upregulation of genes encoding A- and B-type natriuretic peptides, myosin heavy chain types 2 and 3, uncoupling proteins 2 and 3, and the angiogenetic tumor necrosis factor receptor superfamily member 12A. The genes encoding Kv channel-interacting protein 2, a regulator of electrical cardiac phenotype, and the insulin-regulated glucose transporter 4 were downregulated. The heart rate was lower in fetuses of hyperglycemic dams. At 13-14 gestational days, 98% of fetuses of hyperglycemic dams had holosystolic atrioventricular valve regurgitation and decreased outflow mean velocity, indicating diminished cardiac output. Maternal hyperglycemia may lead to accelerated fetal myocardial growth by cardiomyocyte hyperplasia. In fetuses of hyperglycemic dams, expression of key genes that control and regulate cardiomyocyte electrophysiological properties, contractility, and metabolism are altered and may lead to major functional and clinical implications on the fetal heart. PMID:23839525

  13. Acute myocarditis in dengue hemorrhagic fever: a case report and review of cardiac complications in dengue-affected patients.

    PubMed

    Lee, Ing-Kit; Lee, Wen-Huei; Liu, Jien-Wei; Yang, Kuender D

    2010-10-01

    We report a case of dengue hemorrhagic fever (DHF) complicated by acute myocarditis and review the literature. A 65-year-old woman experienced DHF due to dengue virus serotype 3, complicated with acute myocarditis and acute pulmonary edema. Clinically this masqueraded as acute myocardial infarction, with an electrocardiographically depressed ST segment in precordial leads and elevated serum cardiac-specific troponin I level. Under supportive management, the patient recovered 3 days later. A total of 18 pertinent articles involving 339 dengue-affected patients with cardiac complications were found by PubMed search. Clinical manifestations of cardiac complications varied considerably, from self-limiting tachy-brady arrhythmia to severe myocardial damage, leading to hypotension and pulmonary edema. Although rare, a fatal outcome was reported in some cases of dengue with cardiac complications. To avoid otherwise preventable morbidity and mortality, physicians should have a high index of suspicion for cardiac complications in patients with dengue illness and should manage this accordingly.

  14. Saturated hydrogen saline attenuates endotoxin-induced acute liver dysfunction in rats.

    PubMed

    Xu, X-F; Zhang, J

    2013-01-01

    To determine the effect of saturated hydrogen saline on lipopolysaccharide (LPS)-induced acute liver dysfunction, rats were divided into control, LPS, and LPS plus saturated hydrogen saline (LPS+H(2)) groups. Treatment with saturated hydrogen saline prolonged the median survival time and reduced liver dysfunction. Moreover, saturated hydrogen saline significantly reduced pathological alterations in liver tissues, the number of ballooned hepatocytes, serum tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 levels, and myeloperoxidase (MPO) and malondialdehyde (MDA) levels in liver tissues (P<0.05). Cell apoptosis was detected in liver tissues after LPS treatment, and attenuated by saturated hydrogen saline treatment. Saturated hydrogen saline also decreased phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated Jun kinase (p-JNK), nuclear factor-kappa B (NF-kappaB), and second mitochondria-derived activator of caspase (Smac) levels, and increased p38 activation (P<0.05). Thus, saturated hydrogen saline may attenuate LPS-induced acute liver dysfunction in rats, possibly by reducing inflammation and cell apoptosis. Mitogen-activated protein kinase (MAPK), NF-kappaB, and Smac may contribute to saturated hydrogen saline-mediated liver protection.

  15. Strategies for prevention of acute kidney injury in cardiac surgery: an integrative review

    PubMed Central

    Santana-Santos, Eduesley; Marcusso, Marila Eduara Fátima; Rodrigues, Amanda Oliveira; de Queiroz, Fernanda Gomes; de Oliveira, Larissa Bertacchini; Rodrigues, Adriano Rogério Baldacin; Palomo, Jurema da Silva Herbas

    2014-01-01

    Acute kidney injury is a common complication after cardiac surgery and is associated with increased morbidity and mortality and increased length of stay in the intensive care unit. Considering the high prevalence of acute kidney injury and its association with worsened prognosis, the development of strategies for renal protection in hospitals is essential to reduce the associated high morbidity and mortality, especially for patients at high risk of developing acute kidney injury, such as patients who undergo cardiac surgery. This integrative review sought to assess the evidence available in the literature regarding the most effective interventions for the prevention of acute kidney injury in patients undergoing cardiac surgery. To select the articles, we used the CINAHL and MedLine databases. The sample of this review consisted of 16 articles. After analyzing the articles included in the review, the results of the studies showed that only hydration with saline has noteworthy results in the prevention of acute kidney injury. The other strategies are controversial and require further research to prove their effectiveness. PMID:25028954

  16. [Stunned myocardium after acute ischemic stroke].

    PubMed

    Varela, Daniel; Díaz, Fernanda; Hlavnicka, Alejandro; Wainsztein, Néstor; Leiguarda, Ramón

    2006-01-01

    The so-called stunned myocardium, defined as transitory myocardial contractile dysfunction, has been clearly demonstrated in diverse clinical situations. However, stunned myocardium related to ischemic stroke has been poorly identified. We describe two patients with diagnosis of acute ischemic stroke who developed eletrocardiographic changes, cardiac enzyme increasing levels and myocardial dysfunction secondary to abnormal cardiac wall motion. At the same time the patients developed acute lung injury with rapid resolution, perhaps as a consequence of neurocardiogenic components.

  17. Dose-Reduced Trastuzumab Emtansine: Active and Safe in Acute Hepatic Dysfunction

    PubMed Central

    Sharp, Adam; Johnston, Stephen R.D.

    2015-01-01

    Breast cancer is the most common cancer in women worldwide. The majority of deaths attributed to breast cancer are a result of metastatic disease, and 30% of early breast cancers (EBC) will develop distant disease. The 5-year survival of patients with metastatic disease is estimated at 23%. Breast cancer subtypes continue to be stratified histologically on oestrogen, progesterone and human epidermal growth factor-2 (HER2) receptor expression. HER2-positive breast cancers represent 25% of all breast cancer diagnoses. The therapies available for metastatic breast cancer (MBC) are expanding, in particular within the field of HER2-positive disease, with the approval of trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (TDM-1). Recently, TDM-1 has been shown to improve progression-free survival in HER2 MBC when compared to capecitabine and lapatinib in clinical studies. Its main toxicities are deranged liver function tests and thrombocytopenia. There have also been cases of acute liver failure. Therefore, its use in acute hepatic dysfunction, to our knowledge, has been neither studied nor reported. We report a patient with progressive HER2-positive MBC who had previously responded to multiple HER2-targeted therapies that presented with acute hepatic dysfunction. She was treated with dose-reduced TDM-1 safely, with clear evidence of rapid biochemical, clinical and radiological response. This allowed dose escalation of TDM-1, and the patient maintains an ongoing response. PMID:25873876

  18. Expanding the pool of kidney donors: use of kidneys with acute renal dysfunction

    PubMed Central

    de Matos, Ana Cristina Carvalho; Requião-Moura, Lúcio Roberto; Clarizia, Gabriela; Durão, Marcelino de Souza; Tonato, Eduardo José; Chinen, Rogério; de Arruda, Érika Ferraz; Filiponi, Thiago Corsi; Pires, Luciana Mello de Mello Barros; Bertocchi, Ana Paula Fernandes; Pacheco-Silva, Alvaro

    2015-01-01

    ABSTRACT Given the shortage of organs transplantation, some strategies have been adopted by the transplant community to increase the supply of organs. One strategy is the use of expanded criteria for donors, that is, donors aged >60 years or 50 and 59 years, and meeting two or more of the following criteria: history of hypertension, terminal serum creatinine >1.5mg/dL, and stroke as the donor´s cause of death. In this review, emphasis was placed on the use of donors with acute renal failure, a condition considered by many as a contraindication for organ acceptance and therefore one of the main causes for kidney discard. Since these are well-selected donors and with no chronic diseases, such as hypertension, renal disease, or diabetes, many studies showed that the use of donors with acute renal failure should be encouraged, because, in general, acute renal dysfunction is reversible. Although most studies demonstrated these grafts have more delayed function, the results of graft and patient survival after transplant are very similar to those with the use of standard donors. Clinical and morphological findings of donors, the use of machine perfusion, and analysis of its parameters, especially intrarenal resistance, are important tools to support decision-making when considering the supply of organs with renal dysfunction. PMID:26154553

  19. Pseudo-acute myocardial infarction due to transient apical ventricular dysfunction syndrome (Takotsubo syndrome)

    PubMed Central

    Maciel, Bruno Araújo; Cidrão, Alan Alves de Lima; Sousa, Ítalo Bruno dos Santos; Ferreira, José Adailson da Silva; Messias Neto, Valdevino Pedro

    2013-01-01

    Takotsubo syndrome is characterized by predominantly medial-apical transient left ventricular dysfunction, which is typically triggered by physical or emotional stress. The present article reports the case of a 61-year-old female patient presenting with dizziness, excessive sweating, and sudden state of ill feeling following an episode involving intense emotional stress. The physical examination and electrocardiogram were normal upon admission, but the troponin I and creatine kinase-MB concentrations were increased. Acute myocardial infarction without ST segment elevation was suspected, and coronary angiography was immediately performed, which showed severe diffuse left ventricular hypokinesia, medial-apical systolic ballooning, and a lack of significant coronary injury. The patient was referred to the intensive care unit and was successfully treated with supportive therapy. As this case shows, Takotsubo syndrome might simulate the clinical manifestations of acute myocardial infarction, and coronary angiography is necessary to distinguish between both myocardial infarction and myocardial infarction in the acute stage. The present patient progressed with spontaneous resolution of the ventricular dysfunction without any sequelae. PMID:23887762

  20. Expanding the pool of kidney donors: use of kidneys with acute renal dysfunction.

    PubMed

    Matos, Ana Cristina Carvalho de; Requião-Moura, Lúcio Roberto; Clarizia, Gabriela; Durão Junior, Marcelino de Souza; Tonato, Eduardo José; Chinen, Rogério; Arruda, Érika Ferraz de; Filiponi, Thiago Corsi; Pires, Luciana Mello de Mello Barros; Bertocchi, Ana Paula Fernandes; Pacheco-Silva, Alvaro

    2015-01-01

    Given the shortage of organs transplantation, some strategies have been adopted by the transplant community to increase the supply of organs. One strategy is the use of expanded criteria for donors, that is, donors aged >60 years or 50 and 59 years, and meeting two or more of the following criteria: history of hypertension, terminal serum creatinine >1.5mg/dL, and stroke as the donor´s cause of death. In this review, emphasis was placed on the use of donors with acute renal failure, a condition considered by many as a contraindication for organ acceptance and therefore one of the main causes for kidney discard. Since these are well-selected donors and with no chronic diseases, such as hypertension, renal disease, or diabetes, many studies showed that the use of donors with acute renal failure should be encouraged, because, in general, acute renal dysfunction is reversible. Although most studies demonstrated these grafts have more delayed function, the results of graft and patient survival after transplant are very similar to those with the use of standard donors. Clinical and morphological findings of donors, the use of machine perfusion, and analysis of its parameters, especially intrarenal resistance, are important tools to support decision-making when considering the supply of organs with renal dysfunction.

  1. Reactive airways dysfunction syndrome from acute inhalation of a dishwasher detergent powder.

    PubMed

    Hannu, Timo J; Riihimäki, Vesa E; Piirilä, Päivi L

    2012-01-01

    Reactive airway dysfunction syndrome, a type of occupational asthma without a latency period, is induced by irritating vapour, fumes or smoke. The present report is the first to describe a case of reactive airway dysfunction syndrome caused by acute exposure to dishwater detergent containing sodium metasilicate and sodium dichloroisocyanurate. The diagnosis was based on exposure data, clinical symptoms and signs, as well as respiratory function tests. A 43-year-old nonatopic male apprentice cook developed respiratory symptoms immediately after exposure to a cloud of detergent powder that was made airborne by vigorous shaking of the package. In spirometry, combined obstructive and restrictive ventilatory impairment developed, and the histamine challenge test revealed bronchial hyper-responsiveness. Even routine handling of a strongly caustic detergent, such as filling a dishwasher container, is not entirely risk free and should be performed with caution. PMID:22679618

  2. Reactive airways dysfunction syndrome from acute inhalation of dishwasher detergent powder

    PubMed Central

    Hannu, Timo J; Riihimäki, Vesa E; Piirilä, Päivi L

    2012-01-01

    Reactive airway dysfunction syndrome, a type of occupational asthma without a latency period, is induced by irritating vapour, fumes or smoke. The present report is the first to describe a case of reactive airway dysfunction syndrome caused by acute exposure to dishwater detergent containing sodium metasilicate and sodium dichloroisocyanurate. The diagnosis was based on exposure data, clinical symptoms and signs, as well as respiratory function tests. A 43-year-old nonatopic male apprentice cook developed respiratory symptoms immediately after exposure to a cloud of detergent powder that was made airborne by vigorous shaking of the package. In spirometry, combined obstructive and restrictive ventilatory impairment developed, and the histamine challenge test revealed bronchial hyper-responsiveness. Even routine handling of a strongly caustic detergent, such as filling a dishwasher container, is not entirely risk free and should be performed with caution. PMID:22679618

  3. ACE2/Ang 1-7 axis: A critical regulator of epicardial adipose tissue inflammation and cardiac dysfunction in obesity.

    PubMed

    Patel, Vaibhav B; Basu, Ratnadeep; Oudit, Gavin Y

    2016-01-01

    Obesity is characterized by an excessive fat accumulation in adipose tissues leading to weight gain and is increasing in prevalence and is strongly associated with metabolic and cardiovascular disorders. The renin-angiotensin system (RAS) has emerged as a key pathogenic mechanism for these disorders; activated RAS and angiotensin (Ang) II production results in worsening of cardiovascular diseases and angiotensin converting enzyme 2 (ACE2) negatively regulates RAS by metabolizing Ang II into Ang 1-7. ACE2 is expressed in the adipocytes and its expression is upregulated in response to high fat diet induced obesity in mice. Loss of ACE2 results in heart failure with preserved ejection fraction which is mediated in part by epicardial adipose tissue inflammation. Angiotensin 1-7 reduces the obesity associated cardiac dysfunction predominantly via its role in adiponectin expression and attenuation of epicardial adipose tissue inflammation. Human heart disease is also linked with inflammed epicardial adipose tissue. Here, we discuss the important interpretation of the novel of ACE2/Ang 1-7 pathway in obesity associated cardiac dysfunction. PMID:27617176

  4. Dysfunctional Hyperpolarization-Activated Cyclic Nucleotide-gated Ion Channels in Cardiac Diseases

    PubMed Central

    Zhao, Xiaoqi; Gu, Tianxiang

    2016-01-01

    Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are reverse voltage-dependent, and their activation depends on the hyperpolarization of the membrane and may be directly or indirectly regulated by the cyclic adenosine monophosphate (cAMP) or other signal-transduction cascades. The distribution, quantity and activation states of HCN channels differ in tissues throughout the body. Evidence exhibits that HCN channels play critical roles in the generation and conduction of the electrical impulse and the physiopathological process of some cardiac diseases. They may constitute promising drug targets in the treatment of these cardiac diseases. Pharmacological treatment targeting HCN channels is of benefit to these cardiac conditions. PMID:27556324

  5. β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury.

    PubMed

    Kim, Ki-Seok; Abraham, Dennis; Williams, Barbara; Violin, Jonathan D; Mao, Lan; Rockman, Howard A

    2012-10-15

    Pharmacological blockade of the ANG II type 1 receptor (AT1R) is a common therapy for treatment of congestive heart failure and hypertension. Increasing evidence suggests that selective engagement of β-arrestin-mediated AT1R signaling, referred to as biased signaling, promotes cardioprotective signaling. Here, we tested the hypothesis that a β-arrestin-biased AT1R ligand TRV120023 would confer cardioprotection in response to acute cardiac injury compared with the traditional AT1R blocker (ARB), losartan. TRV120023 promotes cardiac contractility, assessed by pressure-volume loop analyses, while blocking the effects of endogenous ANG II. Compared with losartan, TRV120023 significantly activates MAPK and Akt signaling pathways. These hemodynamic and biochemical effects were lost in β-arrestin-2 knockout (KO) mice. In response to cardiac injury induced by ischemia reperfusion injury or mechanical stretch, pretreatment with TRV120023 significantly diminishes cell death compared with losartan, which did not appear to be cardioprotective. This cytoprotective effect was lost in β-arrestin-2 KO mice. The β-arrestin-biased AT1R ligand, TRV120023, has cardioprotective and functional properties in vivo, which are distinct from losartan. Our data suggest that this novel class of drugs may provide an advantage over conventional ARBs by supporting cardiac function and reducing cellular injury during acute cardiac injury.

  6. Electrocardiographic abnormalities in very young Duchenne muscular dystrophy patients precede the onset of cardiac dysfunction.

    PubMed

    James, Jeanne; Kinnett, Kathleen; Wang, Yu; Ittenbach, Richard F; Benson, D Woodrow; Cripe, Linda

    2011-07-01

    Overt cardiac involvement in Duchenne muscular dystrophy (DMD) typically occurs later in the disease. The primary aim was to estimate the proportion of young (<6 years of age) DMD patients with manifestations of cardiac disease by electrocardiography (ECG). Secondary aims were to assess associations between ECG abnormalities and evidence of cardiac disease by echocardiography, as well as to estimate the relationship between dystrophin mutation site and an abnormal ECG. Seventy eight steroid-naive DMD patients <6 years of age were identified. ECG abnormalities were identified in 78%, with LV pathology being the most commonly identified pattern. Only one echocardiogram was abnormal. There was no statistically significant relationship identified between ECG abnormalities and dystrophin genotype. ECG abnormalities are common in very young DMD patients, signaling cardiac involvement well before the onset of clinical symptoms.

  7. Cardiac Dysfunction Induced by Obesity Is Not Related to β-Adrenergic System Impairment at the Receptor-Signalling Pathway.

    PubMed

    Ferron, Artur Junio Togneri; Jacobsen, Bruno Barcellos; Sant'Ana, Paula Grippa; de Campos, Dijon Henrique Salomé; de Tomasi, Loreta Casquel; Luvizotto, Renata de Azevedo Mello; Cicogna, Antonio Carlos; Leopoldo, André Soares; Lima-Leopoldo, Ana Paula

    2015-01-01

    Obesity has been shown to impair myocardial performance. Some factors have been suggested as responsible for possible cardiac abnormalities in models of obesity, among them beta-adrenergic (βA) system, an important mechanism of regulation of myocardial contraction and relaxation. The objective of present study was to evaluate the involvement of βA system components in myocardial dysfunction induced by obesity. Thirty-day-old male Wistar rats were distributed in control (C, n = 25) and obese (Ob, n = 25) groups. The C group was fed a standard diet and Ob group was fed four unsaturated high-fat diets for 15 weeks. Cardiac function was evaluated by isolated papillary muscle preparation and βA system evaluated by using cumulative concentrations of isoproterenol and Western blot. After 15 weeks, the Ob rats developed higher adiposity index than C rats and several comorbidities; however, were not associated with changes in systolic blood pressure. Obesity caused structural changes and the myocardial responsiveness to post-rest contraction stimulus and increased extracellular calcium (Ca2+) was compromised. There were no changes in cardiac function between groups after βA stimulation. The obesity was not accompanied by changes in protein expression of G protein subunit alpha (Gsα) and βA receptors (β1AR and β2AR). In conclusion, the myocardial dysfunction caused by unsaturated high-fat diet-induced obesity, after 15 weeks, is not related to βAR system impairment at the receptor-signalling pathway. PMID:26390297

  8. Cardiac Dysfunction Induced by Obesity Is Not Related to β-Adrenergic System Impairment at the Receptor-Signalling Pathway

    PubMed Central

    Sant’Ana, Paula Grippa; de Campos, Dijon Henrique Salomé; de Tomasi, Loreta Casquel; Luvizotto, Renata de Azevedo Mello; Cicogna, Antonio Carlos; Leopoldo, André Soares; Lima-Leopoldo, Ana Paula

    2015-01-01

    Obesity has been shown to impair myocardial performance. Some factors have been suggested as responsible for possible cardiac abnormalities in models of obesity, among them beta-adrenergic (βA) system, an important mechanism of regulation of myocardial contraction and relaxation. The objective of present study was to evaluate the involvement of βA system components in myocardial dysfunction induced by obesity. Thirty-day-old male Wistar rats were distributed in control (C, n = 25) and obese (Ob, n = 25) groups. The C group was fed a standard diet and Ob group was fed four unsaturated high-fat diets for 15 weeks. Cardiac function was evaluated by isolated papillary muscle preparation and βA system evaluated by using cumulative concentrations of isoproterenol and Western blot. After 15 weeks, the Ob rats developed higher adiposity index than C rats and several comorbidities; however, were not associated with changes in systolic blood pressure. Obesity caused structural changes and the myocardial responsiveness to post-rest contraction stimulus and increased extracellular calcium (Ca2+) was compromised. There were no changes in cardiac function between groups after βA stimulation. The obesity was not accompanied by changes in protein expression of G protein subunit alpha (Gsα) and βA receptors (β1AR and β2AR). In conclusion, the myocardial dysfunction caused by unsaturated high-fat diet-induced obesity, after 15 weeks, is not related to βAR system impairment at the receptor-signalling pathway. PMID:26390297

  9. Acute and Chronic Hyperglycemia Elicit JIP1/JNK-Mediated Endothelial Vasodilator Dysfunction of Retinal Arterioles

    PubMed Central

    Hein, Travis W.; Xu, Wenjuan; Xu, Xin; Kuo, Lih

    2016-01-01

    Purpose Hyperglycemia, a hallmark of diabetes mellitus, is associated with retinal inflammation and impairment of endothelium-dependent nitric oxide (NO)–mediated dilation of retinal arterioles. However, molecular mechanisms involved in this diminished endothelial vasodilator function remain unclear. We examined whether inflammatory stress-activated kinases, c-Jun N-terminal kinase (JNK) and p38, contribute to retinal arteriolar dysfunction during exposure to acute and chronic hyperglycemia. Methods Retinal arterioles were isolated from streptozocin-induced diabetic pigs (2 weeks; chronic hyperglycemia, 471 ± 23 mg/dL) or age-matched control pigs (euglycemia, 79 ± 5 mg/dL), and then cannulated and pressurized for vasoreactivity study. For acute hyperglycemia study, vessels from nondiabetic pigs were exposed intraluminally to high glucose (25 mM ≈ 450 mg/dL) for 2 hours, and normal glucose (5 mM ≈ 90 mg/dL) served as the control. Results Endothelium-dependent vasodilation to bradykinin was reduced in a similar manner after exposure to acute or chronic hyperglycemia. Administration of NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) nearly abolished vasodilations either in control (euglycemia and normal glucose) or hyperglycemic (acute and chronic) vessels. Treatment of either acute or chronic hyperglycemic vessels with JNK inhibitor SP600125 or JNK-interacting protein-1 (JIP1) inhibitor BI-78D3, but not p38 inhibitor SB203580, preserved bradykinin-induced dilation in an L-NAME–sensitive manner. By contrast, endothelium-independent vasodilation to sodium nitroprusside was unaffected by acute or chronic hyperglycemia. Conclusions Activation of JIP1/JNK signaling in retinal arterioles during exposure to acute or chronic hyperglycemia leads to selective impairment of endothelium-dependent NO-mediated dilation. Therapeutic targeting of the vascular JNK pathway may improve retinal endothelial vasodilator function during early diabetes. PMID

  10. [Nitrid oxide, levosimendan and sildenafile in a patient with right ventricle dysfunction and severe pulmonary hypertension after cardiac surgery].

    PubMed

    Aleixandre, L; Cortell, J; Vicente, R; Herrera, P; Loro, J M; Valera, F

    2014-11-01

    Pulmonary hypertension (PHT) and the resulting right ventricle dysfunction are important risk factors in patients who undergo cardiac surgery. The treatment of PHT and right ventricle dysfunction should be focused on maintaining the correct right ventricle after load, improving right ventricle function and reducing the right ventricle pre-load and therefore reducing pulmonary vascular resistance by means of vasodilators. A combined therapy of vasodilators and medicines which have different mechanisms of action, is becoming an option for the treatment of PHT. We present a 65 year old woman that suffered from mitral regurgitation, aortic valve disease, tricuspid and ascending aortic dilation with 115mmHg of pulmonary artery pressure (by ultrasound evaluation). The patient was operated on of mitral, aortic valve and tricuspid plastia and proximal aortic artery plastia as well. Previosly to surgery the patient suffered right ventricle dysfunction and PHT and was treated with nitric oxide, intravenous sildenafil and levosimendan. Subsequent evolution was satisfactory, PHT being controlled, without arterial hypotension nor respiratory alterations.

  11. BMIPP imaging to assess functional outcome in patients with acute and chronic left ventricular dysfunction.

    PubMed

    Franken, P R; Hambÿe, A S; De Geeter, F W

    1999-02-01

    Assessment of myocardial viability is an important clinical issue for patient management during the acute and chronic stages of myocardial infarction. BMIPP (15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid) is a free fatty acid analogue which is trapped in the myocardium, thus permitting for metabolic imaging with single photon emission computerized tomography (SPECT). Less BMIPP than flow tracers that may be observed in the areas of infarction, may reflect the metabolic shift from fatty acid to glucose utilization in ischaemic myocardium. In this sense, the combined imaging of BMIPP and a flow tracer with SPECT may provide similar and important information as fluoro-18 deoxyglucose (FDG) and positron emission tomography (PET) regarding the assessment of myocardial viability. The purpose of this article is to review the clinical impact of BMIPP in patients with acute and with chronic left ventricular dysfunction for the identification of jeopardized but viable myocardium and the prediction of the functional outcome.

  12. Renal dysfunction and thrombolytic therapy in patients with acute ischemic stroke: a systematic review and meta-analysis.

    PubMed

    Hao, Zilong; Yang, Chunsong; Liu, Ming; Wu, Bo

    2014-12-01

    Renal dysfunction is a prevalent comorbidity in acute ischemic stroke patients requiring thrombolytic therapy. However, the effect of renal dysfunction on the clinical outcome of this population remains controversial. This study aimed to evaluate the safety and effectiveness of thrombolytic therapy in acute stroke patients with renal dysfunction using a meta-analysis. We systematically searched PubMed and EMBASE for studies that evaluated the relationship between renal dysfunction and intravenous tissue plasminogen activator (tPA) in patients with acute ischemic stroke. Poor outcome (modified Rankin Scale≥2), mortality, and symptomatic intracranial hemorrhage (ICH) and any ICH were analyzed. Fourteen studies were included (N=53,553 patients). The mean age ranged from 66 to 75 years. The proportion of male participants was 49% to 74%. The proportion of renal dysfunction varied from 21.9% to 83% according to different definitions. Based on 9 studies with a total of 7796 patients, the meta-analysis did not identify a significant difference in the odds of poor outcome (odds ratio [OR]=1.06; 95% confidence interval [CI]: 0.96-1.16; I=44.5) between patients with renal dysfunction and those without renal dysfunction. Patients with renal dysfunction were more likely to die after intravenous thrombolysis (OR=1.13; 95% CI: 1.05-1.21; I=70.3). No association was observed between symptomatic ICH (OR=1.02; 95% CI: 0.94-1.10; I=0) and any ICH (OR=1.07; 95% CI: 0.96-1.18; I=25.8). Renal dysfunction does not increase the risk of poor outcome and ICH after stroke thrombolysis. Renal dysfunction should not be a contraindication for administration of intravenous thrombolysis to eligible patients. PMID:25526464

  13. Hepatic Dysfunction in Hospitalized Patients with Acute Thyrotoxicosis: A Decade of Experience

    PubMed Central

    Elias, Richard M.; Dean, Diana S.; Barsness, Gregory W.

    2012-01-01

    Thyroid disease is a common condition, and thyroid hormone excess or deficiency is known to have wide-ranging effects on a variety of organ systems. Our objective is to describe the magnitude, biochemical features, and clinical characteristics of hepatic abnormalities in patients with acute thyrotoxicosis. We performed a retrospective review of all patients admitted to our institution between January 1, 1998 and December 31, 2008 with a discharge diagnosis of acute thyrotoxicosis excluding iatrogenic causes. The records of these patients were reviewed and data extracted regarding demographic, biochemical, and clinical data particularly relevant to liver function. Fourteen patients were identified of which eleven had liver studies performed. The majority (90.9%) had Graves disease. Nine of eleven patients (81.8%) had some degree of hepatic abnormality. Seven patients (63.6%) had an elevation in one or both transaminases, and two (18.2%) had isolated synthetic dysfunction as manifested as an elevated INR and/or decreased albumin without transaminitis. The mean magnitude of deviation from the normal range was greater in the transaminases as compared to bilirubin, INR, or albumin. Definitive treatment was radioiodine ablation in six cases (54.5%) and surgical thyroidectomy in two cases (18.2%). Noniatrogenic acute thyrotoxicosis requiring hospitalization is a rare condition which is most frequently caused by Graves disease. The majority of patients have disordered liver tests of a highly variable nature, making the recognition of this association important in the care of patients presenting with acute thyrotoxicosis. PMID:23251814

  14. Ablation of C/EBP homologous protein increases the acute phase mortality and doesn't attenuate cardiac remodeling in mice with myocardial infarction.

    PubMed

    Luo, Guangjin; Li, Qingman; Zhang, Xiajun; Shen, Liang; Xie, Jiahe; Zhang, Jingwen; Kitakaze, Masafumi; Huang, Xiaobo; Liao, Yulin

    2015-08-14

    Endoplasmic reticulum stress is a proapoptotic and profibrotic stimulus. Ablation of C/EBP homologous protein (CHOP) is reported to reverse cardiac dysfunction by attenuating cardiac endoplasmic reticulum stress in mice with pressure overload or ischemia/reperfusion, but it is unclear whether loss of CHOP also inhibits cardiac remodeling induced by permanent-infarction. In mice with permanent ligation of left coronary artery, we found that ablation of CHOP increased the acute phase mortality. For the mice survived to 4 weeks, left ventricular anterior (LV) wall thickness was larger in CHOP knockout mice than in the wildtype littermates, while no difference was noted on posterior wall thickness, LV dimensions, LV fractional shortening and ejection fraction. Similarly, invasive assessment of LV hemodynamics, morphological analysis of heart and lung weight indexes, myocardial fibrosis and TUNEL-assessed apoptosis showed no significant differences between CHOP knockout mice and their wildtype ones, while in mice with ischemia for 45 min and reperfusion for 1 week, myocardial fibrosis and apoptosis in the infarct area were significantly attenuated in CHOP knockout mice. These findings indicate that ablation of CHOP doesn't ameliorate cardiac remodeling induced by permanent-myocardial infarction, which implicates that early reperfusion is a prerequisite for ischemic myocardium to benefit from CHOP inhibition.

  15. National Heart Attack Alert Program position paper: chest pain centers and programs for the evaluation of acute cardiac ischemia.

    PubMed

    Zalenski, R J; Selker, H P; Cannon, C P; Farin, H M; Gibler, W B; Goldberg, R J; Lambrew, C T; Ornato, J P; Rydman, R J; Steele, P

    2000-05-01

    The National Heart Attack Alert Program (NHAAP), which is coordinated by the National Heart, Lung, and Blood Institute (NHLBI), promotes the early detection and optimal treatment of patients with acute myocardial infarction and other acute coronary ischemic syndromes. The NHAAP, having observed the development and growth of chest pain centers in emergency departments with special interest, created a task force to evaluate such centers and make recommendations pertaining to the management of patients with acute cardiac ischemia. This position paper offers recommendations to assist emergency physicians in EDs, including those with chest pain centers, in providing comprehensive care for patients with acute cardiac ischemia. PMID:10783408

  16. Acute dissociation and cardiac reactivity to script-driven imagery in trauma-related disorders

    PubMed Central

    Sack, Martin; Cillien, Melanie; Hopper, James W.

    2012-01-01

    Background Potential acute protective functions of dissociation include modulation of stress-induced psychophysiological arousal. This study was designed to explore whether acute dissociative reactions during a stress experiment would override the effects of reexperiencing. Methods Psychophysiological reactions during exposure to script-driven trauma imagery were studied in relation to acute responses of reexperiencing and dissociative symptoms in 61 patients with histories of exposure to a variety of traumas. Acute symptomatic responses were assessed with the Responses to Script-Driven Imagery Scale (RSDI), and participants were divided into four groups by median splits of RSDI reexperiencing and dissociation subscale scores. Results In a comparison of the high RSDI reexperiencing groups with low versus high acute dissociative symptoms, the high dissociators exhibited significantly lower heart rate (HR) during trauma script and a significantly smaller script-induced decrease in parasympathetic cardiac activity. HR reactivity to the trauma script was negatively correlated with acute dissociative symptom severity. Conclusions Acute dissociative reactions are a potential moderator of response to experimental paradigms investigating psychologically traumatized populations. We therefore suggest that future research on psychophysiological stress reactions in traumatized samples should routinely assess for acute dissociative symptoms. PMID:23198029

  17. Acute effects of carbon monoxide on cardiac electrical stability. Research report, Sep 85-Jul 88

    SciTech Connect

    Verrier, R.L.; Mills, A.K.; Skornik, W.A.

    1990-01-01

    The objective of the project was to determine the effects of acute carbon monoxide exposure on cardiac electrical stability in the normal and ischemic heart of anesthetized and conscious dogs. Exposure (90 to 120 minutes) to relatively high levels of carbon monoxide, leading to carboxyhemoglobin concentrations of up to 20 percent, was without significant effect on ventricular electrical stability in laboratory dogs. This appears to be the case in the acutely ischemic heart as well as in the normal heart. Using a model involving partial coronary artery stenosis, no changes were found in either the cycle frequency of coronary blood flow oscillations or in platelet aggregability during carbon monoxide exposure. Also examined were the effects of carbon monoxide exposure in the conscious state in order to take into consideration possible adverse consequences mediated by the central nervous system. The study found no adverse effects on the cardiac-excitable properties in response to either a 2-hour- or 24-hour-exposure paradigm.

  18. Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring

    PubMed Central

    Beauchamp, Brittany; Thrush, A. Brianne; Quizi, Jessica; Antoun, Ghadi; McIntosh, Nathan; Al-Dirbashi, Osama Y.; Patti, Mary-Elizabeth; Harper, Mary-Ellen

    2015-01-01

    Intrauterine growth restriction (IUGR) is associated with an increased risk of developing obesity, insulin resistance and cardiovascular disease. However, its effect on energetics in heart remains unknown. In the present study, we examined respiration in cardiac muscle and liver from adult mice that were undernourished in utero. We report that in utero undernutrition is associated with impaired cardiac muscle energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate and decreased proton leak respiration. No differences in oxidative characteristics were detected in liver. We also measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased with in utero undernutrition. Results reveal the negative impact of suboptimal maternal nutrition on adult offspring cardiac energy metabolism, which may have life-long implications for cardiovascular function and disease risk. PMID:26182362

  19. Novel biomarkers for early diagnosis of acute kidney injury after cardiac surgery in adults

    PubMed Central

    Kališnik, Jurij Matija

    2016-01-01

    Acute kidney injury after cardiac surgery with cardiopulmonary bypass is a common and serious complication and it is associated with increased morbidity and mortality. Diagnosis of acute kidney injury is based on the serum creatinine levels which rise several hours to days after the initial injury. Thus, novel biomarkers that will enable faster diagnosis are needed in clinical practice. There are numerous urine and serum proteins that indicate kidney injury and are under extensive research. Despite promising basic research results and assembled data, which indicate superiority of some biomarkers to creatinine, we are still awaiting clinical application. PMID:27212976

  20. Postoperative Neurocognitive Dysfunction in Patients Undergoing Cardiac Surgery after Remote Ischemic Preconditioning: A Double-Blind Randomized Controlled Pilot Study

    PubMed Central

    Meybohm, Patrick; Renner, Jochen; Broch, Ole; Caliebe, Dorothee; Albrecht, Martin; Cremer, Jochen; Haake, Nils; Scholz, Jens; Zacharowski, Kai; Bein, Berthold

    2013-01-01

    Background Remote ischemic preconditioning (RIPC) has been shown to enhance the tolerance of remote organs to cope with a subsequent ischemic event. We hypothesized that RIPC reduces postoperative neurocognitive dysfunction (POCD) in patients undergoing complex cardiac surgery. Methods We conducted a prospective, randomized, double-blind, controlled trial including 180 adult patients undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomized either to RIPC or to control group. Primary endpoint was postoperative neurocognitive dysfunction 5–7 days after surgery assessed by a comprehensive test battery. Cognitive change was assumed if the preoperative to postoperative difference in 2 or more tasks assessing different cognitive domains exceeded more than one SD (1 SD criterion) or if the combined Z score was 1.96 or greater (Z score criterion). Results According to 1 SD criterion, 52% of control and 46% of RIPC patients had cognitive deterioration 5–7 days after surgery (p = 0.753). The summarized Z score showed a trend to more cognitive decline in the control group (2.16±5.30) compared to the RIPC group (1.14±4.02; p = 0.228). Three months after surgery, incidence and severity of neurocognitive dysfunction did not differ between control and RIPC. RIPC tended to decrease postoperative troponin T release at both 12 hours [0.60 (0.19–1.94) µg/L vs. 0.48 (0.07–1.84) µg/L] and 24 hours after surgery [0.36 (0.14–1.89) µg/L vs. 0.26 (0.07–0.90) µg/L]. Conclusions We failed to demonstrate efficacy of a RIPC protocol with respect to incidence and severity of POCD and secondary outcome variables in patients undergoing a wide range of cardiac surgery. Therefore, definitive large-scale multicenter trials are needed. Trial Registration ClinicalTrials.gov NCT00877305 PMID:23741380

  1. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines

    PubMed Central

    Lauriol, Jessica; Cabrera, Janel R.; Roy, Ashbeel; Keith, Kimberly; Hough, Sara M.; Damilano, Federico; Wang, Bonnie; Segarra, Gabriel C.; Flessa, Meaghan E.; Miller, Lauren E.; Das, Saumya; Bronson, Roderick; Lee, Kyu-Ho; Kontaridis, Maria I.

    2016-01-01

    Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium. Trabeculation and valvular hyperplasia were diminished in hearts of embryonic mice expressing a human NSML-associated variant of SHP2, and these defects were recapitulated in mice expressing NSML-associated SHP2 specifically in endothelial, but not myocardial or neural crest, cells. In contrast, mice with myocardial- but not endothelial-specific NSML SHP2 expression developed ventricular septal defects, suggesting that NSML-associated mutations have both cell-autonomous and nonautonomous functions in cardiac development. However, only endothelial-specific expression of NSML-associated SHP2 induced adult-onset cardiac hypertrophy. Further, embryos expressing the NSML-associated SHP2 mutation exhibited aberrant AKT activity and decreased downstream forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling, indicating that SHP2 is required for regulating reciprocal crosstalk between developing endocardium and myocardium. Together, our data provide functional and disease-based evidence that aberrant SHP2 signaling during cardiac development leads to CHD and adult-onset heart hypertrophy. PMID:27348588

  2. Developmental SHP2 dysfunction underlies cardiac hypertrophy in Noonan syndrome with multiple lentigines.

    PubMed

    Lauriol, Jessica; Cabrera, Janel R; Roy, Ashbeel; Keith, Kimberly; Hough, Sara M; Damilano, Federico; Wang, Bonnie; Segarra, Gabriel C; Flessa, Meaghan E; Miller, Lauren E; Das, Saumya; Bronson, Roderick; Lee, Kyu-Ho; Kontaridis, Maria I

    2016-08-01

    Hypertrophic cardiomyopathy is a common cause of mortality in congenital heart disease (CHD). Many gene abnormalities are associated with cardiac hypertrophy, but their function in cardiac development is not well understood. Loss-of-function mutations in PTPN11, which encodes the protein tyrosine phosphatase (PTP) SHP2, are implicated in CHD and cause Noonan syndrome with multiple lentigines (NSML), a condition that often presents with cardiac hypertrophic defects. Here, we found that NSML-associated hypertrophy stems from aberrant signaling mechanisms originating in developing endocardium. Trabeculation and valvular hyperplasia were diminished in hearts of embryonic mice expressing a human NSML-associated variant of SHP2, and these defects were recapitulated in mice expressing NSML-associated SHP2 specifically in endothelial, but not myocardial or neural crest, cells. In contrast, mice with myocardial- but not endothelial-specific NSML SHP2 expression developed ventricular septal defects, suggesting that NSML-associated mutations have both cell-autonomous and nonautonomous functions in cardiac development. However, only endothelial-specific expression of NSML-associated SHP2 induced adult-onset cardiac hypertrophy. Further, embryos expressing the NSML-associated SHP2 mutation exhibited aberrant AKT activity and decreased downstream forkhead box P1 (FOXP1)/FGF and NOTCH1/EPHB2 signaling, indicating that SHP2 is required for regulating reciprocal crosstalk between developing endocardium and myocardium. Together, our data provide functional and disease-based evidence that aberrant SHP2 signaling during cardiac development leads to CHD and adult-onset heart hypertrophy. PMID:27348588

  3. Acute effect of rheopheresis on peripheral endothelial dysfunction in patients suffering from sudden hearing loss.

    PubMed

    Balletshofer, Bernd M; Stock, Jan; Rittig, Kilian; Lehn-Stefan, Angela; Braun, Norbert; Burkart, Frank; Plontke, Stefan; Klingel, Reinhard; Häring, Hans-Ulrich

    2005-10-01

    Single low density lipoprotein (LDL) fibrinogen apheresis has shown beneficial effects in the treatment of patients with sudden sensorineural hearing loss (SSHL). Pathophysiologically, a microcirculatory disorder of the inner ear, probably caused by disturbed endothelial function, is discussed as a final common pathway of a variety of SSHL etiologies. Thus, we carried out a prospective pilot study on the efficacy of Rheopheresis on vascular function in these patients, embedded into an ongoing randomized controlled multicenter trial investigating the efficacy of Rheopheresis for the treatment of SSHL. Potential modulation of systemic endothelial dysfunction by Rheopheresis was examined by measuring flow-associated vasodilatation of the brachial artery (according to the criteria of the American College of Cardiology) in a small group of patients suffering from SSHL (N=6, 5m/1f, mean age 56+/-11 years) within the last 3 days. At baseline, five of the six patients with acute hearing loss showed endothelial dysfunction as evidenced by diminished flow-mediated vasodilatation (FMD<5%). After a single Rheopheresis treatment, flow-mediated vasodilatation improved significantly (from 3.9+/-3.6% to 7.2+/-2.4%, P=0.05, mean+/-SD, two-sided paired T-test). This was paralleled by a reduction in fibrinogen (364+/-216 mg/dL to 142+/-96 mg/dL, P=0.03), total cholesterol (228+/-23 to 98+/-10, P<0.0001) and LDL cholesterol levels (153+/-8 mg/dL to 83+/-23 mg/dL, P<0.01). Based on this case series we conclude that single Rheopheresis treatment might have an acute beneficial effect on endothelial dysfunction in patients suffering from SSHL.

  4. Sick sinus syndrome in a patient with extensive cardiac lipomatosis (sinus node dysfunction in lipomatosis).

    PubMed

    Kadmon, Ehud; Paz, Rami; Kusniec, Jairo; Strasberg, Boris

    2010-04-01

    We present a case of a 45-year-old man with an incidental and longstanding diagnosis of extensive mediastinal and cardiac lipomatosis. Along the years, he had experienced various arrhythmias, mainly bradyarrhythmias, mostly asymptomatic. Recently after documenting a sinus pause of 6 seconds and runs of nonsustained ventricular tachycardias, he underwent an implantation of a cardioverter-defibrillator. There are many reports of cardiac lipomatosis in the literature, including reports of related ventricular arrhythmias, some of which are fatal. (PACE 2010; 513-515).

  5. Risk prediction of acute kidney injury in cardiac surgery and prevention using aminophylline.

    PubMed

    Mahaldar, A R; Sampathkumar, K; Raghuram, A R; Kumar, S; Ramakrishnan, M; Mahaldar, D A C

    2012-05-01

    The incidence of acute kidney injury (AKI) after cardiac surgery remains high. The nonspecific adenosine receptor antagonist aminophylline has been shown to confer benefit in experimental and clinical acute renal failure (ARF) due to ischemia, contrast media, and various nephrotoxic agents. We conducted a prospective open label trial to assess the effectiveness of aminophylline for prevention of renal impairment after cardiac surgery. One hundred and thirty-eight patients undergoing cardiac surgery were risk stratified as per Cleveland score to assess for prediction of AKI. Sixty-three patients received a bolus aminophylline of 5 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/h for up to 72 h, while 75 patients received usual postoperative care. Serum creatinine concentrations were measured preoperatively and daily until day 5 after surgery and the glomerular filtration rate estimated using Cockcroft and Gault formula. Hourly urine output was recorded and patients assigned to respective RIFLE stage of AKI. Cleveland score ≥6 was associated with higher incidence of AKI: I and F (P<0.005). Number needed to treat, an insight into the clinical relevance of a specific treatment, is 8. These results suggest that the perioperative use of aminophylline infusion is associated with lower incidence of deterioration in renal function following cardiac surgery in high-risk patients. PMID:23087551

  6. Risk prediction of acute kidney injury in cardiac surgery and prevention using aminophylline

    PubMed Central

    Mahaldar, A. R.; Sampathkumar, K.; Raghuram, A. R.; Kumar, S.; Ramakrishnan, M.; Mahaldar, D. A. C.

    2012-01-01

    The incidence of acute kidney injury (AKI) after cardiac surgery remains high. The nonspecific adenosine receptor antagonist aminophylline has been shown to confer benefit in experimental and clinical acute renal failure (ARF) due to ischemia, contrast media, and various nephrotoxic agents. We conducted a prospective open label trial to assess the effectiveness of aminophylline for prevention of renal impairment after cardiac surgery. One hundred and thirty-eight patients undergoing cardiac surgery were risk stratified as per Cleveland score to assess for prediction of AKI. Sixty-three patients received a bolus aminophylline of 5 mg/kg and a subsequent continuous infusion of 0.25 mg/kg/h for up to 72 h, while 75 patients received usual postoperative care. Serum creatinine concentrations were measured preoperatively and daily until day 5 after surgery and the glomerular filtration rate estimated using Cockcroft and Gault formula. Hourly urine output was recorded and patients assigned to respective RIFLE stage of AKI. Cleveland score ≥6 was associated with higher incidence of AKI: I and F (P<0.005). Number needed to treat, an insight into the clinical relevance of a specific treatment, is 8. These results suggest that the perioperative use of aminophylline infusion is associated with lower incidence of deterioration in renal function following cardiac surgery in high-risk patients. PMID:23087551

  7. The Complex Role of iNOS in Acutely-Rejecting Cardiac Transplants

    PubMed Central

    Pieper, Galen M.; Roza, Allan M.

    2008-01-01

    This review summarizes the evidence for a detrimental role of nitric oxide (NO) derived from inducible NO synthase (iNOS) and/or reactive nitrogen species such as peroxynitrite in acutely-rejecting cardiac transplants. In chronic cardiac transplant rejection, iNOS may have an opposing beneficial component. The purpose of this review is primarily to address issues related to acute rejection which is a recognized risk factor for chronic rejection. The evidence for a detrimental role is based upon strategies involving non-selective NOS inhibitors, NO neutralizers, selective iNOS inhibitors and iNOS gene deletion in rodent models of cardiac rejection. The review is discussed in the context of the impact on various components including graft survival, histological rejection and cardiac function which may contribute in toto to the process of graft rejection. Possible limitations of each strategy are discussed in order to understand better the variance in published findings including issues related to the potential importance of cell localization of iNOS expression. Finally, the concept of a dual role of NO and its down-stream product, peroxynitrite, in rejection vs. immune regulation is discussed. PMID:18291116

  8. A new model to predict acute kidney injury requiring renal replacement therapy after cardiac surgery

    PubMed Central

    Pannu, Neesh; Graham, Michelle; Klarenbach, Scott; Meyer, Steven; Kieser, Teresa; Hemmelgarn, Brenda; Ye, Feng; James, Matthew

    2016-01-01

    Background: Acute kidney injury after cardiac surgery is associated with adverse in-hospital and long-term outcomes. Novel risk factors for acute kidney injury have been identified, but it is unknown whether their incorporation into risk models substantially improves prediction of postoperative acute kidney injury requiring renal replacement therapy. Methods: We developed and validated a risk prediction model for acute kidney injury requiring renal replacement therapy within 14 days after cardiac surgery. We used demographic, and preoperative clinical and laboratory data from 2 independent cohorts of adults who underwent cardiac surgery (excluding transplantation) between Jan. 1, 2004, and Mar. 31, 2009. We developed the risk prediction model using multivariable logistic regression and compared it with existing models based on the C statistic, Hosmer–Lemeshow goodness-of-fit test and Net Reclassification Improvement index. Results: We identified 8 independent predictors of acute kidney injury requiring renal replacement therapy in the derivation model (adjusted odds ratio, 95% confidence interval [CI]): congestive heart failure (3.03, 2.00–4.58), Canadian Cardiovascular Society angina class III or higher (1.66, 1.15–2.40), diabetes mellitus (1.61, 1.12–2.31), baseline estimated glomerular filtration rate (0.96, 0.95–0.97), increasing hemoglobin concentration (0.85, 0.77–0.93), proteinuria (1.65, 1.07–2.54), coronary artery bypass graft (CABG) plus valve surgery (v. CABG only, 1.25, 0.64–2.43), other cardiac procedure (v. CABG only, 3.11, 2.12–4.58) and emergent status for surgery booking (4.63, 2.61–8.21). The 8-variable risk prediction model had excellent performance characteristics in the validation cohort (C statistic 0.83, 95% CI 0.79–0.86). The net reclassification improvement with the prediction model was 13.9% (p < 0.001) compared with the best existing risk prediction model (Cleveland Clinic Score). Interpretation: We have developed

  9. Acute Targeting of General Transcription Factor IIB Restricts Cardiac Hypertrophy via Selective Inhibition of Gene Transcription

    PubMed Central

    Sayed, Danish; Yang, Zhi; He, Minzhen; Pfleger, Jessica M.; Abdellatif, Maha

    2014-01-01

    Background We previously reported that specialized and housekeeping genes are differentially regulated via de novo recruitment and pause-release of RNA polymerase II (pol II), respectively, during cardiac hypertrophy. However, the significance of this finding remains to be examined. Therefore, the purpose of this study was to determine the mechanisms that differentially regulate these gene groups and exploit them for therapeutic targeting. Methods and Results Here we show that general transcription factor IIB (TFIIB) and cyclin-dependent kinase 9 are upregulated during hypertrophy, both targeted by miR-1, and play preferential roles in regulating those two groups of genes. Chromatin immunoprecipitation-sequencing reveals that TFIIB is constitutively bound to all paused, housekeeping, promoters, whereas, de novo recruitment of TFIIB and pol II is required for specialized genes that are induced during hypertrophy. We exploited this dichotomy to acutely inhibit induction of the latter set, which encompasses cardiomyopathy, immune reaction, and extracellular matrix genes, using locked nucleic acid (LNA)-modified antisense TFIIB oligonucleotide treatment. This resulted in suppression of all specialized genes, while sparing the housekeeping ones, and, thus, attenuated pathological hypertrophy. Conclusions The data for the first time reveal distinct general transcription factor IIB dynamics that regulate specialized vs. housekeeping genes during cardiac hypertrophy. Thus, by acutely targeting TFIIB we were able to selectively inhibit the former set of genes and ameliorate pressure overload hypertrophy. We also demonstrate the feasibility of acutely and reversibly targeting cardiac mRNA for therapeutic purposes using LNA-modified antisense oligonucleotides. PMID:25398966

  10. Galectin-1 controls cardiac inflammation and ventricular remodeling during acute myocardial infarction.

    PubMed

    Seropian, Ignacio M; Cerliani, Juan P; Toldo, Stefano; Van Tassell, Benjamín W; Ilarregui, Juan M; González, Germán E; Matoso, Mirian; Salloum, Fadi N; Melchior, Ryan; Gelpi, Ricardo J; Stupirski, Juan C; Benatar, Alejandro; Gómez, Karina A; Morales, Celina; Abbate, Antonio; Rabinovich, Gabriel A

    2013-01-01

    Galectin-1 (Gal-1), an evolutionarily conserved β-galactoside-binding lectin, plays essential roles in the control of inflammation and neovascularization. Although identified as a major component of the contractile apparatus of cardiomyocytes, the potential role of Gal-1 in modulating heart pathophysiology is uncertain. Here, we aimed to characterize Gal-1 expression and function in the infarcted heart. Expression of Gal-1 was substantially increased in the mouse heart 7 days after acute myocardial infarction (AMI) and in hearts from patients with end-stage chronic heart failure. This lectin was localized mainly in cardiomyocytes and inflammatory infiltrates in peri-infarct areas, but not in remote areas. Both simulated hypoxia and proinflammatory cytokines selectively up-regulated Gal-1 expression in mouse cardiomyocytes, whereas anti-inflammatory cytokines inhibited expression of this lectin or had no considerable effect. Compared with their wild-type counterpart, Gal-1-deficient (Lgals1(-/-)) mice showed enhanced cardiac inflammation, characterized by increased numbers of macrophages, natural killer cells, and total T cells, but reduced frequency of regulatory T cells, leading to impaired cardiac function at baseline and impaired ventricular remodeling 7 days after nonreperfused AMI. Treatment of mice with recombinant Gal-1 attenuated cardiac damage in reperfused AMI. Taken together, our results indicate a protective role for Gal-1 in normal cardiac homeostasis and postinfarction remodeling by preventing cardiac inflammation. Thus, Gal-1 treatment represents a potential novel strategy to attenuate heart failure in AMI.

  11. Acute kidney injury after using contrast during cardiac catheterization in children with heart disease.

    PubMed

    Hwang, Young Ju; Hyun, Myung Chul; Choi, Bong Seok; Chun, So Young; Cho, Min Hyun

    2014-08-01

    Acute kidney injury (AKI) is closely associated with the mortality of hospitalized patients and long-term development of chronic kidney disease, especially in children. The purpose of our study was to assess the evidence of contrast-induced AKI after cardiac catheterization in children with heart disease and evaluate the clinical usefulness of candidate biomarkers in AKI. A total of 26 children undergoing cardiac catheterization due to various heart diseases were selected and urine and blood samples were taken at 0 hr, 6 hr, 24 hr, and 48 hr after cardiac catheterization. Until 48 hr after cardiac catheterization, there was no significant increase in serum creatinine level in all patients. Unlike urine kidney injury molecule-1, IL-18 and neutrophil gelatinase-associated lipocalin, urine liver-type fatty acid-binding protein (L-FABP) level showed biphasic pattern and the significant difference in the levels of urine L-FABP between 24 and 48 hr. We suggest that urine L-FABP can be one of the useful biomarkers to detect subclinical AKI developed by the contrast before cardiac surgery.

  12. Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving.

    PubMed

    Shiels, H A; Galli, G L J; Block, B A

    2015-02-01

    Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation-contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28°C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca(2+) transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation-contraction coupling across an acute 20°C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range.

  13. Cardiac function in an endothermic fish: cellular mechanisms for overcoming acute thermal challenges during diving

    PubMed Central

    Shiels, H. A.; Galli, G. L. J.; Block, B. A.

    2015-01-01

    Understanding the physiology of vertebrate thermal tolerance is critical for predicting how animals respond to climate change. Pacific bluefin tuna experience a wide range of ambient sea temperatures and occupy the largest geographical niche of all tunas. Their capacity to endure thermal challenge is due in part to enhanced expression and activity of key proteins involved in cardiac excitation–contraction coupling, which improve cardiomyocyte function and whole animal performance during temperature change. To define the cellular mechanisms that enable bluefin tuna hearts to function during acute temperature change, we investigated the performance of freshly isolated ventricular myocytes using confocal microscopy and electrophysiology. We demonstrate that acute cooling and warming (between 8 and 28°C) modulates the excitability of the cardiomyocyte by altering the action potential (AP) duration and the amplitude and kinetics of the cellular Ca2+ transient. We then explored the interactions between temperature, adrenergic stimulation and contraction frequency, and show that when these stressors are combined in a physiologically relevant way, they alter AP characteristics to stabilize excitation–contraction coupling across an acute 20°C temperature range. This allows the tuna heart to maintain consistent contraction and relaxation cycles during acute thermal challenges. We hypothesize that this cardiac capacity plays a key role in the bluefin tunas' niche expansion across a broad thermal and geographical range. PMID:25540278

  14. Antihypertensive therapy with prazosin in patients with left ventricular dysfunction. Improvement in cardiac performance and exercise tolerance.

    PubMed

    Massie, B M; Chan, S

    1981-12-01

    Although the relationship between blood pressure and cardiac performance has been widely recognized, there are few published clinical observations concerning the effect of blood pressure control on cardiac function. We evaluated the effect of prazosin, an antihypertensive agent which also improves hemodynamic measurements in normotensive patients with heart failure, in 16 patients with moderate hypertension and reduced ejection fractions. Therapy with digoxin and diuretics was continued throughout the study, but other antihypertensive agents were withdrawn at least one week prior to the initiation of the study. Measurements of ejection fraction, cardiothoracic ratio and the duration of maximal treadmill exercise were made before and after two months of antihypertensive therapy with prazosin. On prazosin, blood pressure fell from a mean of 169/103 to 141/84. Excellent control was achieved in 13/16 patients and significant reductions were noted in the remaining three. Concomitantly, ejection fraction rose from .38 +/- .02 (SEM) to .43 +/- .03 (P less than .02), cardiothoracic ratio decreased from .55 +/- .02 to .53 +/- .02 (P less than .05) and exercise capacity increased from 9.2 +/- 0.9 to 11.9 +/- 1.1 minutes (P less than .005). Prazosin was well tolerated except in one patient who experienced worsening angina. These findings emphasize the importance of rigorous blood pressure control in hypertensive patients with left ventricular dysfunction and indicate that prazosin is effective in this setting.

  15. Liver dysfunction as an important predicting risk factor in patients undergoing cardiac surgery: a systematic review and meta-analysis

    PubMed Central

    Hsieh, Wan Chin; Chen, Po Chen; Corciova, Flavia-Catalina; Tinica, Grigore

    2015-01-01

    Liver function is not considered as a risk factor by current risk scores, such as EUROSCORE II or STS-Score for cardiac surgery. The aim of this study was to review the role of liver dysfunction, classified by the Child-Turcotte-Pugh classification or model for end-stage liver disease scores, as a risk factor for mortality and morbidity of patients following cardiac surgery. The Pubmed referencing library was searched. The rates of mortality and morbidity were calculated using SPSS software. The mortality rates in patients of Child class A, Child class B, and Child class C were pairwise compared respectively. A total of 22 reports including 939 patients from eight countries were reviewed. The mortality rate of patients increased in accordance with increased CTP classification. The lowest mortality rate was recorded in Child class A patients, followed by Child class B patients and the highest mortality rate was observed in Child class C patients. The mean complication rate ranged from 3.82% to 22.15%. Child class C patients should be considered unacceptable for cardiovascular surgery. As two studies revealed, patients with a higher MELD score had significantly higher mortality rates. Liver function should be viewed as an important risk factor for cardiovascular surgery, based on its strong association with mortality and morbidity. PMID:26884994

  16. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery.

    PubMed

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-03-01

    Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a protective

  17. Differences in Left Versus Right Ventricular Electrophysiological Properties in Cardiac Dysfunction and Arrhythmogenesis

    PubMed Central

    Molina, Cristina E; Heijman, Jordi; Dobrev, Dobromir

    2016-01-01

    A wide range of ion channels, transporters, signaling pathways and tissue structure at a microscopic and macroscopic scale regulate the electrophysiological activity of the heart. Each region of the heart has optimised these properties based on its specific role during the cardiac cycle, leading to well-established differences in electrophysiology, Ca2+ handling and tissue structure between atria and ventricles and between different layers of the ventricular wall. Similarly, the right ventricle (RV) and left ventricle (LV) have different embryological, structural, metabolic and electrophysiological features, but whether interventricular differences promote differential remodeling leading to arrhythmias is not well understood. In this article, we will summarise the available data on intrinsic differences between LV and RV electrophysiology and indicate how these differences affect cardiac function. Furthermore, we will discuss the differential remodeling of both chambers in pathological conditions and its potential impact on arrhythmogenesis. PMID:27403288

  18. Cardiac arrhythmias the first month after acute traumatic spinal cord injury

    PubMed Central

    Bartholdy, Kim; Biering-Sørensen, Tor; Malmqvist, Lasse; Ballegaard, Martin; Krassioukov, Andrei; Hansen, Birgitte; Svendsen, Jesper Hastrup; Kruse, Anders; Welling, Karen-Lise; Biering-Sørensen, Fin

    2014-01-01

    Objective Cardiovascular complications including cardiac arrest and arrhythmias remain a clinical challenge in the management of acute traumatic spinal cord injury (SCI). Still, there is a lack of knowledge regarding the characteristics of arrhythmias in patients with acute traumatic SCI. The aim of this prospective observational study was to investigate the occurrence of cardiac arrhythmias and cardiac arrests in patients with acute traumatic SCI. Methods As early as possible after SCI 24-hour Holter monitoring was performed. Additional Holter recordings were performed 1, 2, 3, and 4 weeks after SCI. Furthermore, 12-lead electrocardiograms (ECGs) were obtained shortly after SCI and at 4 weeks. Results Thirty patients were included. Bradycardia (heart rate (HR) <50 b.p.m.) was present in 17–35% of the patients with cervical (C1–C8) SCI (n = 24) within the first 14 days. In the following 14 days, the occurrence was 22–32%. Bradycardia in the thoracic (Th1–Th12) SCI group (n = 6) was present in 17–33% during the observation period. The differences between the two groups were not statistically significant. The mean minimum HR was significantly lower in the cervical group compared with the thoracic group both on 12-lead ECGs obtained shortly after SCI (P = 0.030) and at 4 weeks (P = 0.041). Conclusion Many patients with cervical SCI experience arrhythmias such as bradycardia, sinus node arrest, supraventricular tachycardia, and more rarely cardiac arrest the first month after SCI. Apart from sinus node arrests and limited bradycardia, no arrhythmias were seen in patients with thoracic SCI. Standard 12-lead ECGs will often miss the high prevalence these arrhythmias have. PMID:24559419

  19. Resveratrol attenuated estrogen-deficient-induced cardiac dysfunction: role of AMPK, SIRT1, and mitochondrial function

    PubMed Central

    Meng, Zijun; Jing, Hongjiang; Gan, Lu; Li, Hua; Luo, Bingde

    2016-01-01

    Large epidemiological studies suggest that there are important differences in the incidence and severity of a wide variety of cardiac diseases, between premenopausal and menopausal women. Recently, it has been demonstrated that resveratrol may has similar function as estrogen. However, whether resveratrol replacement could mimic estrogen to protect heart in ovariectomized mice remains completely unknown. Firstly, the present study has used OVX/CAL model to investigate the effect of RSV on ischemic heart. Echocardiography analysis revealed that RSV administration significantly improved cardiac contractile function in estrogen-deficient mice. RSV also significantly reduced CK and LDH release, and heart infarct size in OVX/CAL group. Secondly, mitochondrial functions, including MRC activities, MDA level, and mitochondrial swelling, were evaluated in OVX mice. It was found that supplementation with RSV could restore mitochondrial function dampened by OVX. Thirdly, these protective functions mediated by RSV were mainly attributed to the enhancement of SIRT1/AMPK activity. In summary, the results support a potential role of resveratrol in the protection of cardiac functions under estrogen depletion status. PMID:27398147

  20. Effects of Mineralocorticoid Receptor Antagonists on the Risk of Sudden Cardiac Death in Patients With Left Ventricular Systolic Dysfunction

    PubMed Central

    Bapoje, Srinivas R.; Bahia, Amit; Hokanson, John E.; Peterson, Pamela N.; Heidenreich, Paul A.; Lindenfeld, JoAnn; Allen, Larry A.; Masoudi, Frederick A.

    2013-01-01

    Background Sudden cardiac death (SCD) is an important cause of death in patients with left ventricular systolic dysfunction. Mineralocorticoid receptor antagonists (MRAs) may attenuate this risk. The objective of this meta-analysis was to assess the impact of MRAs on SCD in patients with left ventricular systolic dysfunction. Methods and Results We systematically searched PubMed, EMBASE, Cochrane, and other databases through March 30, 2012, without language restrictions. We included trials that enrolled patients with left ventricular ejection fraction of ≤45%, randomized subjects to MRAs versus control and reported outcomes on SCD, total and cardiovascular mortality. Eight published trials that enrolled 11875 patients met inclusion criteria. Of these, 6 reported data on SCD and cardiovascular mortality, and 7 reported data on total mortality. No heterogeneity was observed among the trials. Patients treated with MRAs had 23% lower odds of experiencing SCD compared with controls (odds ratio, 0.77; 95% confidence interval, 0.66–0.89; P=0.001). Similar reductions were observed in cardiovascular (0.75; 95% confidence interval, 0.68– 0.84; P<0.001) and total mortality (odds ratio, 0.74; 95% confidence interval, 0.63–0.86; P<0.001). Although publication bias was observed, the results did not change after a trim and fill test, suggesting that the impact of this bias was likely insignificant. Conclusions MRAs reduce the risk of SCD in patients with left ventricular systolic dysfunction. Comparative effectiveness studies of MRAs on SCD in usual care as well as studies evaluating the efficacy of other therapies to prevent SCD in patients receiving optimal MRA therapy are needed to guide clinical decision-making. PMID:23403436

  1. Obesity-associated cardiac dysfunction in starvation-selected Drosophila melanogaster.

    PubMed

    Hardy, Christopher M; Birse, Ryan T; Wolf, Matthew J; Yu, Lin; Bodmer, Rolf; Gibbs, Allen G

    2015-09-15

    There is a clear link between obesity and cardiovascular disease, but the complexity of this interaction in mammals makes it difficult to study. Among the animal models used to investigate obesity-associated diseases, Drosophila melanogaster has emerged as an important platform of discovery. In the laboratory, Drosophila can be made obese through lipogenic diets, genetic manipulations, and adaptation to evolutionary stress. While dietary and genetic changes that cause obesity in flies have been demonstrated to induce heart dysfunction, there have been no reports investigating how obesity affects the heart in laboratory-evolved populations. Here, we studied replicated populations of Drosophila that had been selected for starvation resistance for over 65 generations. These populations evolved characteristics that closely resemble hallmarks of metabolic syndrome in mammals. We demonstrate that starvation-selected Drosophila have dilated hearts with impaired contractility. This phenotype appears to be correlated with large fat deposits along the dorsal cuticle, which alter the anatomical position of the heart. We demonstrate a strong relationship between fat storage and heart dysfunction, as dilation and reduced contractility can be rescued through prolonged fasting. Unlike other Drosophila obesity models, the starvation-selected lines do not exhibit excessive intracellular lipid deposition within the myocardium and rather store excess triglycerides in large lipid droplets within the fat body. Our findings provide a new model to investigate obesity-associated heart dysfunction.

  2. Blood-brain barrier dysfunction in acute lead encephalopathy: a reappraisal.

    PubMed

    Bouldin, T W; Mushak, P; O'Tuama, L A; Krigman, M R

    1975-12-01

    Acute lead encephalopathy was induced in adult guinea pigs by administering daily oral doses of lead carbonate. During the development of the encephalopathy, the structural and functional integrity of the blood-brain barrier was evaluated with electron microscopy and tracer probes. Blood, cerebral gray matter, liver, and kidney were analyzed for lead, calcium, and magnesium content. The animals regularly developed an encephalopathy after four doses of lead. There were no discernible pathomorphologic alterations in the cerebral capillaries or perivascular glial sheaths. Furthermore, no evidence of blood-brain barrier dysfunction was demonstrated with Evans blue-albumin complex or horseradish peroxidase. Blood-brain barrier permeability to radiolead was not increased in the intoxicated animals. During the development of the encephalopathy there was a progressive rise in the lead concentration in all tissues. Concurrently, there was a significant rise in brain calcium. These results suggest that the encephalopathic effects of lead may be mediated directly at the neuronal level.

  3. New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.

    PubMed

    Carvalho, Nélson R; da Rosa, Edovando F; da Silva, Michele H; Tassi, Cintia C; Dalla Corte, Cristiane L; Carbajo-Pescador, Sara; Mauriz, Jose L; González-Gallego, Javier; Soares, Félix A

    2013-01-01

    The acute liver failure (ALF) induced by acetaminophen (APAP) is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe)2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe)2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe)2 to the N-acetylcysteine (NAC) during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg), (PhSe)2 (15.6 mg/kg), NAC (1200 mg/kg), APAP+(PhSe)2 or APAP+NAC, where the (PhSe)2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation) and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe)2. The effectiveness of (PhSe)2 was similar at a lower dose than NAC. In summary, (PhSe)2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced. PMID:24349162

  4. Acute restraint stress induces endothelial dysfunction: role of vasoconstrictor prostanoids and oxidative stress.

    PubMed

    Carda, Ana P P; Marchi, Katia C; Rizzi, Elen; Mecawi, André S; Antunes-Rodrigues, José; Padovan, Claudia M; Tirapelli, Carlos R

    2015-01-01

    We hypothesized that acute stress would induce endothelial dysfunction. Male Wistar rats were restrained for 2 h within wire mesh. Functional and biochemical analyses were conducted 24 h after the 2-h period of restraint. Stressed rats showed decreased exploration on the open arms of an elevated-plus maze (EPM) and increased plasma corticosterone concentration. Acute restraint stress did not alter systolic blood pressure, whereas it increased the in vitro contractile response to phenylephrine and serotonin in endothelium-intact rat aortas. NG-nitro-l-arginine methyl ester (l-NAME; nitric oxide synthase, NOS, inhibitor) did not alter the contraction induced by phenylephrine in aortic rings from stressed rats. Tiron, indomethacin and SQ29548 reversed the increase in the contractile response to phenylephrine induced by restraint stress. Increased systemic and vascular oxidative stress was evident in stressed rats. Restraint stress decreased plasma and vascular nitrate/nitrite (NOx) concentration and increased aortic expression of inducible (i) NOS, but not endothelial (e) NOS. Reduced expression of cyclooxygenase (COX)-1, but not COX-2, was observed in aortas from stressed rats. Restraint stress increased thromboxane (TX)B(2) (stable TXA(2) metabolite) concentration but did not affect prostaglandin (PG)F2α concentration in the aorta. Restraint reduced superoxide dismutase (SOD) activity, whereas concentrations of hydrogen peroxide (H(2)O(2)) and reduced glutathione (GSH) were not affected. The major new finding of our study is that restraint stress increases vascular contraction by an endothelium-dependent mechanism that involves increased oxidative stress and the generation of COX-derived vasoconstrictor prostanoids. Such stress-induced endothelial dysfunction could predispose to the development of cardiovascular diseases.

  5. Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin.

    PubMed

    Kao, Shang-Jyh; Liu, Demeral David; Su, Chain-Fa; Chen, Hsing I

    2007-09-01

    Poly (ADP-ribose) synthabse (PARS) or polymerase (PARP) is a cytotoxic enzyme causing cellular damage. Niacinamide inhibits PARS or PARP. The present experiment tests the effects of niacinamide (NCA) on organ dysfunction and acute lung injury (ALI) following lipopolysaccharide (LPS). LPS was administered to anesthetized rats and to isolated rat lungs. In anesthetized rats, LPS caused systemic hypotension and increased biochemical factors, nitrate/nitrite (NOx), methyl guanidine (MG), tumor necrosis factoralpha (TNFalpha), and interleukin-1beta (IL-1beta). In isolated lungs, LPS increased lung weight (LW) to body weight ratio, LW gain, protein and dye tracer leakage, and capillary permeability. The insult also increased NOx, MG, TNFalpha, and IL-1beta in lung perfusate, while decreased adenosine triphosphate (ATP) content with an increase in PARP activity in lung tissue. Pathological examination revealed pulmonary edema with inflammatory cell infiltration. These changes were abrogated by posttreatment (30 min after LPS) with NCA. Following LPS, the inducible NO synthase (iNOS) mRNA expression was increased. NCA reduced the iNOS expression. Niacinamide exerts protective effects on the organ dysfunction and ALI caused by endotoxin. The mechanisms may be mediated through the inhibition on the PARP activity, iNOS expression and the subsequent suppression of NO, free radicals, and proinflammatory cytokines with restoration of ATP.

  6. [Assessment of renal function, iatrogenic hyperkalemia and acute renal dysfunction in cardiology. Contrast-induced nephropathy].

    PubMed

    Górriz Teruel, José Luis; Beltrán Catalán, Sandra

    2011-12-01

    Renal impairment influences the prognosis of patients with cardiovascular disease and increases cardiovascular risk. Renal dysfunction is a marker of lesions in other parts of the vascular tree and detection facilitates early identification of individuals at high risk of cardiovascular events. In patients with cardiovascular disease, renal function is assessed by measuring albuminuria in a spot urine sample and by estimating the glomerular filtration rate using creatinine-derived predictive formulas or equations. We recommend the Chronic Kidney Disease Epidemiology Collaboration or the Modification of Diet in Renal Disease formulas. The Cockcroft-Gault formula is a possible alternative. The administration of drugs that block the angiotensin-renin system can, on occasion, be associated with acute renal dysfunction or hyperkalemia. We need to know when risk of these complications exists so as to provide the best possible treatment: prevention. Given the growing number of diagnostic and therapeutic procedures in the field of cardiology that use intravenous contrast media, contrast-induced nephrotoxicity represents a significant problem. We should identify the risk factors and patients at greatest risk, and prevent it from appearing.

  7. Mechanisms of vascular dysfunction in acute phase of Trypanosoma cruzi infection in mice.

    PubMed

    Silva, Josiane F; Capettini, Luciano S A; da Silva, José F P; Sales-Junior, Policarpo; Cruz, Jader Santos; Cortes, Steyner F; Lemos, Virginia S

    2016-07-01

    Vascular disorders have a direct link to mortality in the acute phase of Trypanosoma cruzi infection. However, the underlying mechanisms of vascular dysfunction in this phase are largely unknown. We hypothesize that T. cruzi invades endothelial cells causing dysfunction in contractility and relaxation of the mouse aorta. Immunodetection of T. cruzi antigen TcRBP28 was observed in endothelial cells. There was a decreased endothelial nitric oxide synthase (eNOS)-derived NO-dependent vascular relaxation, and increased vascular contractility accompanied by augmented superoxide anions production. Endothelial removal, inhibition of cyclooxygenase 2 (COX-2), blockade of thromboxane A2 (TXA2) TP receptors, and scavenger of superoxide normalized the contractile response. COX-2, thromboxane synthase, inducible nitric oxide synthase (iNOS), p65 NFκB subunit and p22(phox) of NAD(P)H oxidase (NOX) subunit expressions were increased in vessels of chagasic animals. Serum TNF-α was augmented. Basal NO production, and nitrotyrosine residue expression were increased. It is concluded that T. cruzi invades mice aorta endothelial cells and increases TXA2/TP receptor/NOX-derived superoxide formation. Alongside, T. cruzi promotes systemic TNF-α increase, which stimulates iNOS expression in vessels and nitrosative stress. In light of the heart failure that develops in the chronic phase of the disease, to understand the mechanism involved in the increased contractility of the aorta is crucial.

  8. Evaluation of the acute cardiac and central nervous system effects of the fluorocarbon trifluoromethane in baboons

    SciTech Connect

    Branch, C.A.; Goldberg, D.A.; Ewing, J.R.; Butt, S.S.; Gayner, J.; Fagan, S.C.

    1994-12-31

    The gaseous fluorocarbon trifluoromethane has recently been investigated for its potential as an in vivo gaseous indicator for nuclear magnetic resonance studies of brain perfusion. Trifluoromethane may also have significant value as a replacement for chlorofluorocarbon fire retardants. Because of possible species-specific cardiotoxic and anesthetic properties, the toxicological evaluation of trifluoromethane in primates (Papio anubis) is necessary prior to its evaluation in humans. We report the acute cardiac and central nervous system effects of trifluoromethane in eight anesthetized baboons. A dose-response effect was established for respiratory rate, electroencephalogram, and cardiac sinus rate, which exhibited a stepwise decrease from 10% trifluoromethane. No spontaneous arrhythmias were noted, and arterial blood pressure remained unchanged at any inspired level. Intravenous epinephrine infusions (1 {mu}g/kg) induced transient cardiac arrhythmia in 1 animal only at 70% FC-23 (v/v) trifluoromethane. Trifluoromethane appears to induce mild dose-related physiological changes at inspired levels of 30% or more, indicative of an anesthetic effect. These data suggest that trifluoromethane may be safe to use in humans, without significant adverse acute effects, at an inspired level of 30%. 23 refs., 3 figs., 3 tabs.

  9. An efficacy and mechanism evaluation study of Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS): protocol for a randomized controlled trial

    PubMed Central

    2014-01-01

    Background Organ dysfunction consequent to infection (‘severe sepsis’) is the leading cause of admission to an intensive care unit (ICU). In both animal models and early clinical studies the calcium channel sensitizer levosimendan has been demonstrated to have potentially beneficial effects on organ function. The aims of the Levosimendan for the Prevention of Acute oRgan Dysfunction in Sepsis (LeoPARDS) trial are to identify whether a 24-hour infusion of levosimendan will improve organ dysfunction in adults who have septic shock and to establish the safety profile of levosimendan in this group of patients. Methods/Design This is a multicenter, randomized, double-blind, parallel group, placebo-controlled trial. Adults fulfilling the criteria for systemic inflammatory response syndrome due to infection, and requiring vasopressor therapy, will be eligible for inclusion in the trial. Within 24 hours of meeting these inclusion criteria, patients will be randomized in a 1:1 ratio stratified by the ICU to receive either levosimendan (0.05 to 0.2 μg.kg-1.min-1 or placebo for 24 hours in addition to standard care. The primary outcome measure is the mean Sequential Organ Failure Assessment (SOFA) score while in the ICU. Secondary outcomes include: central venous oxygen saturations and cardiac output; incidence and severity of renal failure using the Acute Kidney Injury Network criteria; duration of renal replacement therapy; serum bilirubin; time to liberation from mechanical ventilation; 28-day, hospital, 3 and 6 month survival; ICU and hospital length-of-stay; and days free from catecholamine therapy. Blood and urine samples will be collected on the day of inclusion, at 24 hours, and on days 4 and 6 post-inclusion for investigation of the mechanisms by which levosimendan might improve organ function. Eighty patients will have additional blood samples taken to measure levels of levosimendan and its active metabolites OR-1896 and OR-1855. A total of 516 patients

  10. Acute kidney injury following cardiac surgery: current understanding and future directions.

    PubMed

    O'Neal, Jason B; Shaw, Andrew D; Billings, Frederic T

    2016-07-04

    Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI.

  11. Acute kidney injury following cardiac surgery: current understanding and future directions.

    PubMed

    O'Neal, Jason B; Shaw, Andrew D; Billings, Frederic T

    2016-01-01

    Acute kidney injury (AKI) complicates recovery from cardiac surgery in up to 30 % of patients, injures and impairs the function of the brain, lungs, and gut, and places patients at a 5-fold increased risk of death during hospitalization. Renal ischemia, reperfusion, inflammation, hemolysis, oxidative stress, cholesterol emboli, and toxins contribute to the development and progression of AKI. Preventive strategies are limited, but current evidence supports maintenance of renal perfusion and intravascular volume while avoiding venous congestion, administration of balanced salt as opposed to high-chloride intravenous fluids, and the avoidance or limitation of cardiopulmonary bypass exposure. AKI that requires renal replacement therapy occurs in 2-5 % of patients following cardiac surgery and is associated with 50 % mortality. For those who recover from renal replacement therapy or even mild AKI, progression to chronic kidney disease in the ensuing months and years is more likely than for those who do not develop AKI. Cardiac surgery continues to be a popular clinical model to evaluate novel therapeutics, off-label use of existing medications, and nonpharmacologic treatments for AKI, since cardiac surgery is fairly common, typically elective, provides a relatively standardized insult, and patients remain hospitalized and monitored following surgery. More efficient and time-sensitive methods to diagnose AKI are imperative to reduce this negative outcome. The discovery and validation of renal damage biomarkers should in time supplant creatinine-based criteria for the clinical diagnosis of AKI. PMID:27373799

  12. Adiponectin ameliorates hyperglycemia-induced cardiac hypertrophy and dysfunction by concomitantly activating Nrf2 and Brg1.

    PubMed

    Li, Haobo; Yao, Weifeng; Irwin, Michael G; Wang, Tingting; Wang, Shuang; Zhang, Liangqing; Xia, Zhengyuan

    2015-07-01

    attenuated cellular oxidative stress, myocyte size, and apoptotic cells. Inhibition of HO-1 by ZnPP (10μM) or small interfering RNA (siRNA) canceled all the above gAd beneficial effects. Moreover, inhibition of Nrf2 (either by the Nrf2 inhibitor luteolin or siRNA) or Brg1 (by siRNA) canceled gAd-induced HO-1 induction and cellular protection in CMs and in H9C2 cells incubated with HG. In summary, our present study demonstrated that APN reduced cardiac oxidative stress, ameliorated cardiomyocyte hypertrophy, and prevented left ventricular dysfunction in diabetes by concomitantly activating Nrf2 and Brg1 to facilitate HO-1 induction. PMID:25795513

  13. Subclinical Cardiac Dysfunction in Children with Coeliac Disease: Is the Gluten-Free Diet Effective?

    PubMed Central

    Saylan, Berna; Cevik, Ayhan; Kirsaclioglu, Ceyda Tuna; Ekici, Filiz; Tosun, Ozgur; Ustundag, Gonca

    2012-01-01

    Objectives. The aim of this study is to investigate the effects of coeliac disease on cardiac function in children using conventional transthoracic echocardiography (TTE) and tissue Doppler echocardiography (TDE). Methods. Coeliac disease patients were evaluated in two different groups based on serum endomysial antibody (EmA) titers (EmA (+) and EmA (−)), and the data obtained by conventional and TDE studies were compared between the patient groups and healthy controls. Results. There was no significant difference between EmA (+) and EmA (−) groups in terms of the conventional TTE parameters, including ejection fraction (EF), fractional shortening (FS), and left ventricle end diastolic diameter (LVEDD), that show the left ventricular systolic function (P = 0.727, P = 0.317, P = 0.118). TDE showed a significant difference in left ventricle (LV) isovolumic relaxation time (LV IVRT) and LV myocardial performance index (LV MPI) parameters between EmA (+) and EmA (−) patient groups (P < 0.0001). Conclusion. The measurement of LV MPI and LV IVRT parameters by TDE would be beneficial in early determination of the cardiac involvement and establishing appropriate treatment and followup of patients with coeliac disease as well as in making distinction between EmA (+) and EmA (−) patients. PMID:23209919

  14. Acute cardiac sympathetic disruption and left ventricular wall motion abnormality in takotsubo syndrome.

    PubMed

    Y-Hassan, Shams

    2015-03-01

    Takotsubo syndrome (TS) is characterized by a unique pattern of transient circumferential left ventricular wall motion abnormality (LVWMA). The LVWMA in TS may be localized to the apical, mid-apical, mid-ventricular, mid-basal or basal regions of the left ventricle. Focal and generialized (global) LVWMA have also been reported. In the acute phase of TS, the hyperkinetic valve-like motion of the basal segments and/or the hyperkinetic slingshot-like motion of the apical segments combined with the firm stunned a-, hypokinetic segments result in a conspicuous left ventricular ballooning during systole. The LVWMA in TS follows most probably the local cardiac sympathetic nerve distribution and caused by local cardiac sympathetic disruption and noradrenaline spillover. PMID:25535745

  15. Inflammatory Cytokines as Risk Factors for Mortality After Acute Cardiac Events

    PubMed Central

    Hamzic-Mehmedbasic, Aida

    2016-01-01

    Introduction: Inflammatory markers have been identified as potential indicators of future adverse outcome after acute cardiac events. Aim: This study aimed to analyze baseline inflammatory cytokines levels in patients with acute heart failure (AHF) and/or acute coronary syndrome (ACS) according to survival. The main objective was to identify risk factors for mortality after an episode of AHF and/or ACS. Methods: In this prospective longitudinal study 75 patients with the diagnosis of AHF and/or ACS were enrolled. Baseline laboratory and clinical data were retrieved. Serum and urine interleukin-6 (IL-6) and interleukin-18 (IL-18) levels, plasma B-type natriuretic peptide (BNP) and serum cystatin C values were determined. The primary outcome was in-hospital mortality while secondary outcome was six-month mortality. Results: Median serum and urine IL-6 levels, serum and urine IL-18 levels, as well as median concentrations of plasma BNP and serum cystatin C, were significantly increased in deceased in comparison to surviving AHF and/or ACS patients. Univariate Cox regression analysis identified serum IL-6, serum IL-18, urine IL-6, urine IL-18 as well as serum cystatin C and Acute Physiology and Chronic Health Evaluation (APACHE) II score as risk factors for mortality after an episode of AHF and/or ACS. Multivariate Cox regression analysis revealed that only serum IL-6 is the independent risk factor for mortality after acute cardiac events (HR 61.7, 95% CI 2.1-1851.0; p=0.018). Conclusion: Present study demonstrated the strong prognostic value of serum IL-6 in predicting mortality of patients with AHF and/or ACS. PMID:27703283

  16. Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction.

    PubMed

    Das, Anindita; Durrant, David; Mitchell, Clint; Mayton, Eric; Hoke, Nicholas N; Salloum, Fadi N; Park, Margaret A; Qureshi, Ian; Lee, Ray; Dent, Paul; Kukreja, Rakesh C

    2010-10-19

    We have shown that the potent phosphodiesterase-5 (PDE-5) inhibitor sildenafil (Viagra) induces a powerful effect on reduction of infarct size following ischemia/reperfusion injury and improvement of left ventricular dysfunction in the failing heart after myocardial infarction or doxorubicin (DOX) treatment. In the present study, we further investigated the potential effects of sildenafil on improving antitumor efficacy of DOX in prostate cancer. Cotreatment with sildenafil enhanced DOX-induced apoptosis in PC-3 and DU145 prostate cancer cells, which was mediated by enhanced generation of reactive oxygen species, up-regulation of caspase-3 and caspase-9 activities, reduced expression of Bcl-xL, and phosphorylation of Bad. Overexpression of Bcl-xL or dominant negative caspase 9 attenuated the synergistic effect of sildenafil and DOX on prostate cancer cell killing. Furthermore, treatment with sildenafil and DOX in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. The reduced tumor size was associated with amplified apoptotic cell death and increased expression of activated caspase 3. Doppler echocardiography showed that sildenafil treatment ameliorated DOX-induced left ventricular dysfunction. In conclusion, these results provide provocative evidence that sildenafil is both a powerful sensitizer of DOX-induced killing of prostate cancer while providing concurrent cardioprotective benefit. PMID:20884855

  17. Cardiac Oxidative Stress and Dysfunction by Fine Concentrated Ambient Particles (CAPs) are Mediated by Angiotensin-II

    PubMed Central

    Ghelfi, Elisa; Wellenius, Gregory A.; Lawrence, Joy; Millet, Emil; Gonzalez-Flecha, Beatriz

    2013-01-01

    Inhalation exposure to fine Concentrated Ambient Particles (CAPs) increases cardiac oxidants by mechanisms involving modulation of the sympathovagal tone on the heart. Angiotensin-II is a potent vasoconstrictor and a sympatho-excitatory peptide involved in the regulation of blood pressure. We hypothesized that increases in angiotensin-II after fine PM exposure could be involved in the development of cardiac oxidative stress. Adult rats were treated with an angiotensin converting enzyme (ACE) inhibitor (Benazepril ®), or an angiotensin receptor blocker (ARB, Valsartan ®) before exposure to fine PM aerosols or filtered air. Exposures were carried out for 5 hours in the chamber of the Harvard Fine Particle Concentrator (fine PM mass concentration: 440 ± 80 μg/m3). At the end of the exposure the animals were tested for in situ chemiluminescence (CL) of the heart, TBARS and for plasma levels of angiotensin-II. Also, continuous ECG measurements were collected on a subgroup of exposed animals. PM exposure was associated with statistically significant increases in plasma angiotensin concentrations. Pretreatment with the ACE inhibitor effectively lowered angiotensin concentration, whereas ARB treatment led to increases in angiotensin above the PM-only level. PM exposure also led to significant increases in heart oxidative stress (CL, TBARs), and a shortening of the T-end to T-peak interval on the ECG that were prevented by treatment with both the ACE inhibitor and ARB. These results show that ambient fine particles can increase plasma levels of angiotensin-II and suggest a role of the renin-angiotensin system in the development of particle-related acute cardiac events. PMID:20718632

  18. Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.

    PubMed

    Taniyama, Yoshiaki; Katsuragi, Naruto; Sanada, Fumihiro; Azuma, Junya; Iekushi, Kazuma; Koibuchi, Nobutaka; Okayama, Keita; Ikeda-Iwabu, Yuka; Muratsu, Jun; Otsu, Rei; Rakugi, Hiromi; Morishita, Ryuichi

    2016-02-01

    We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other periostin variants might offer a new class of medication for the treatment of acute myocardial infarction patients.

  19. Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function.

    PubMed

    Erkens, Ralf; Kramer, Christian M; Lückstädt, Wiebke; Panknin, Christina; Krause, Lisann; Weidenbach, Mathias; Dirzka, Jennifer; Krenz, Thomas; Mergia, Evanthia; Suvorava, Tatsiana; Kelm, Malte; Cortese-Krott, Miriam M

    2015-12-01

    Increased production of reactive oxygen species and failure of the antioxidant defense system are considered to play a central role in the pathogenesis of cardiovascular disease. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key master switch controlling the expression of antioxidant and protective enzymes, and was proposed to participate in protection of vascular and cardiac function. This study was undertaken to analyze cardiac and vascular phenotype of mice lacking Nrf2. We found that Nrf2 knock out (Nrf2 KO) mice have a left ventricular (LV) diastolic dysfunction, characterized by prolonged E wave deceleration time, relaxation time and total diastolic time, increased E/A ratio and myocardial performance index, as assessed by echocardiography. LV dysfunction in Nrf2 KO mice was associated with cardiac hypertrophy, and a downregulation of the sarcoplasmic reticulum Ca(2+)-ATPase (SERCA2a) in the myocardium. Accordingly, cardiac relaxation was impaired, as demonstrated by decreased responses to β-adrenergic stimulation by isoproterenol ex vivo, and to the cardiac glycoside ouabain in vivo. Surprisingly, we found that vascular endothelial function and endothelial nitric oxide synthase (eNOS)-mediated vascular responses were fully preserved, blood pressure was decreased, and eNOS was upregulated in the aorta and the heart of Nrf2 KO mice. Taken together, these results show that LV dysfunction in Nrf2 KO mice is mainly associated with cardiac hypertrophy and downregulation of SERCA2a, and is independent from changes in coronary vascular function or systemic hemodynamics, which are preserved by a compensatory upregulation of eNOS. These data provide new insights into how Nrf2 expression/function impacts the cardiovascular system.

  20. Myocardial Galectin-3 Expression Is Associated with Remodeling of the Pressure-Overloaded Heart and May Delay the Hypertrophic Response without Affecting Survival, Dysfunction, and Cardiac Fibrosis.

    PubMed

    Frunza, Olga; Russo, Ilaria; Saxena, Amit; Shinde, Arti V; Humeres, Claudio; Hanif, Waqas; Rai, Vikrant; Su, Ya; Frangogiannis, Nikolaos G

    2016-05-01

    The β-galactoside-binding animal lectin galectin-3 is predominantly expressed by activated macrophages and is a promising biomarker for patients with heart failure. Galectin-3 regulates inflammatory and fibrotic responses; however, its role in cardiac remodeling remains unclear. We hypothesized that galectin-3 may be up-regulated in the pressure-overloaded myocardium and regulate hypertrophy and fibrosis. In normal mouse myocardium, galectin-3 was constitutively expressed in macrophages and was localized in atrial but not ventricular cardiomyocytes. In a mouse model of transverse aortic constriction, galectin-3 expression was markedly up-regulated in the pressure-overloaded myocardium. Early up-regulation of galectin-3 was localized in subpopulations of macrophages and myofibroblasts; however, after 7 to 28 days of transverse aortic constriction, a subset of cardiomyocytes in fibrotic areas contained large amounts of galectin-3. In vitro, cytokine stimulation suppressed galectin-3 synthesis by macrophages and cardiac fibroblasts. Correlation studies revealed that cardiomyocyte- but not macrophage-specific galectin-3 localization was associated with adverse remodeling and dysfunction. Galectin-3 knockout mice exhibited accelerated cardiac hypertrophy after 7 days of pressure overload, whereas female galectin-3 knockouts had delayed dilation after 28 days of transverse aortic constriction. However, galectin-3 loss did not affect survival, systolic and diastolic dysfunction, cardiac fibrosis, and cardiomyocyte hypertrophy in the pressure-overloaded heart. Despite its potential role as a prognostic biomarker, galectin-3 is not a critical modulator of cardiac fibrosis but may delay the hypertrophic response. PMID:26948424

  1. Serum and salivary cardiac analytes in acute myocardial infarction related to oral health status

    NASA Astrophysics Data System (ADS)

    Ebersole, Jeffrey L.; Kryscio, Richard J.; Campbell, Charles; Kinane, Denis F.; McDevitt, John T.; Christodoulides, Nicolaos; Floriano, Pierre N.; Miller, Craig S.

    2014-06-01

    With the advent of an increased emphasis on the potential to utilize biomarkers in saliva for systemic diseases, the issue of existing oral disease is an important consideration that could adversely affect the interpretation of diagnostic results obtained from saliva. We addressed the question does a patient's oral inflammation status confound biomarker levels used in diagnosis of acute myocardial infarction (AMI). The results demonstrated that multiple serum biomarkers and a few salivary biomarkers reflected the cardiac event. Importantly, oral health of the individual had minimal impact on the validity of the serum or salivary biomarker effectiveness.

  2. Long-term methionine-diet induced mild hyperhomocysteinemia associated cardiac metabolic dysfunction in multiparous rats

    PubMed Central

    Song, Su; Kertowidjojo, Elizabeth; Ojaimi, Caroline; Martin-Fernandez, Beatriz; Kandhi, Sharath; Wolin, Michael; Hintze, Thomas H

    2015-01-01

    Mild hyperhomocysteinemia (HHcy, clinically defined as less than 30 μmol/L) is an independent cardiovascular disease (CVD) risk factor, and is associated with many complications during pregnancy, such as preeclampsia (PE). The aim of this study was to assess the effect of long-term mild HHcy on cardiac metabolic function of multiparous rats. Female rats were mated 3 to 4 times and were fed with methionine in drinking water to increase plasma Hcy (2.9 ± 0.3 to 10.5 ± 2.3 μmol/L) until termination. This caused significant increase of heart weight/body weight (0.24 ± 0.01 to 0.27 ± 0.01 g/100 g) and left ventricle weight (0.69 ± 0.03 to 0.78 ± 0.01 g). Superoxide production was increased by 2.5-fold in HHcy hearts using lucigenin chemiluminescence. The ability of bradykinin and carbachol to regulate myocardial oxygen consumption (MVO2) in vitro was impaired by 59% and 66% in HHcy heart, and it was restored by ascorbic acid (AA), tempol, or apocynin (Apo). Protein expression of p22phox subunit of NAD(P)H oxidase was increased by 2.6-fold, but there were no changes in other NAD(P)H oxidase subunits, NOSs or SODs. Microarray revealed 1518 genes to be differentially regulated (P < 0.05). The mRNA level of NAD(P)H oxidase subunits, NOSs or SODs remained unchanged. In conclusion, long-term mild HHcy increases cardiac superoxide mainly through regulation of p22phox component of the NAD(P)H oxidase and impairs the ability of NO to regulate MVO2 in heart of multiparous mothers. PMID:26009634

  3. Approaches to Improving Cardiac Structure and Function During and After an Acute Myocardial Infarction: Acute and Chronic Phases.

    PubMed

    Kloner, Robert A; Dai, Wangde; Hale, Sharon L; Shi, Jianru

    2016-07-01

    While progress has been made in improving survival following myocardial infarction, this injury remains a major source of mortality and morbidity despite modern reperfusion therapy. While one approach has been to develop therapies to reduce lethal myocardial cell reperfusion injury, this concept has not translated to the clinics, and several recent negative clinical trials raise the question of whether reperfusion injury is important in humans undergoing reperfusion for acute ST segment elevation myocardial infarction. Therapy aimed at reducing myocardial cell death while the myocytes are still ischemic is more likely to further reduce myocardial infarct size. Developing new therapies to further reduce left ventricular remodeling after the acute event is another approach to preserving structure and function of the heart after infarction. Such therapy may include chronic administration of pharmacologic agents and/or therapies developed from the field of regenerative cardiology, including cellular or non-cellular materials such as extracellular matrix. The optimal therapy will be to administer agents that both reduce myocardial infarct size in the acute phase of infarction as well as reduce adverse left ventricular remodeling during the chronic or healing phase of myocardial infarction. Such a dual approach will help optimize the preservation of both cardiac structure and function.

  4. Caffeic acid phenethyl amide ameliorates ischemia/reperfusion injury and cardiac dysfunction in streptozotocin-induced diabetic rats

    PubMed Central

    2014-01-01

    Background Caffeic acid phenethyl ester (CAPE) has been shown to protect the heart against ischemia/reperfusion (I/R) injury by various mechanisms including its antioxidant effect. In this study, we evaluated the protective effects of a CAPE analog with more structural stability in plasma, caffeic acid phenethyl amide (CAPA), on I/R injury in streptozotocin (STZ)-induced type 1 diabetic rats. Methods Type 1 diabetes mellitus was induced in Sprague–Dawley rats by a single intravenous injection of 60 mg/kg STZ. To produce the I/R injury, the left anterior descending coronary artery was occluded for 45 minutes, followed by 2 hours of reperfusion. CAPA was pretreated intraperitoneally 30 minutes before reperfusion. An analog devoid of the antioxidant property of CAPA, dimethoxyl CAPA (dmCAPA), and a nitric oxide synthase (NOS) inhibitor (Nω-nitro-l-arginine methyl ester [l-NAME]) were used to evaluate the mechanism involved in the reduction of the infarct size following CAPA-treatment. Finally, the cardioprotective effect of chronic treatment of CAPA was analyzed in diabetic rats. Results Compared to the control group, CAPA administration (3 and 15 mg/kg) significantly reduced the myocardial infarct size after I/R, while dmCAPA (15 mg/kg) had no cardioprotective effect. Interestingly, pretreatment with a NOS inhibitor, (l-NAME, 3 mg/kg) eliminated the effect of CAPA on myocardial infarction. Additionally, a 4-week CAPA treatment (1 mg/kg, orally, once daily) started 4 weeks after STZ-induction could effectively decrease the infarct size and ameliorate the cardiac dysfunction by pressure-volume loop analysis in STZ-induced diabetic animals. Conclusions CAPA, which is structurally similar to CAPE, exerts cardioprotective activity in I/R injury through its antioxidant property and by preserving nitric oxide levels. On the other hand, chronic CAPA treatment could also ameliorate cardiac dysfunction in diabetic animals. PMID:24923878

  5. Depletion of Tip60 from In Vivo Cardiomyocytes Increases Myocyte Density, Followed by Cardiac Dysfunction, Myocyte Fallout and Lethality

    PubMed Central

    Fisher, Joseph B.; Horst, Audrey; Wan, Tina; Kim, Min-Su; Auchampach, John; Lough, John

    2016-01-01

    Tat-interactive protein 60 (Tip60), encoded by the Kat5 gene, is a member of the MYST family of acetyltransferases. Cancer biology studies have shown that Tip60 induces the DNA damage response, apoptosis, and cell-cycle inhibition. Although Tip60 is expressed in the myocardium, its role in cardiomyocytes (CMs) is unclear. Earlier studies here showed that application of cardiac stress to globally targeted Kat5+/—haploinsufficient mice resulted in inhibition of apoptosis and activation of the CM cell-cycle, despite only modest reduction of Tip60 protein levels. It was therefore of interest to ascertain the effects of specifically and substantially depleting Tip60 from CMs using Kat5LoxP/-;Myh6-Cre mice in the absence of stress. We report initial findings using this model, in which the effects of specifically depleting Tip60 protein from ventricular CMs, beginning at early neonatal stages, were assessed in 2–12 week-old mice. Although 5’-bromodeoxyuridine immunostaining indicated that CM proliferation was not altered at any of these stages, CM density was increased in 2 week-old ventricles, which persisted in 4 week-old hearts when TUNEL staining revealed inhibition of apoptosis. By week 4, levels of connexin-43 were depleted, and its patterning was dysmorphic, concomitant with an increase in cardiac hypertrophy marker expression and interstitial fibrosis. This was followed by systolic dysfunction at 8 weeks, after which extensive apoptosis and CM fallout occurred, followed by lethality as mice approached 12 weeks of age. In summary, chronic depletion of Tip60 from the ventricular myocardium beginning at early stages of neonatal heart development causes CM death after 8 weeks; hence, Tip60 protein has a crucial function in the heart. PMID:27768769

  6. Post-Acute Care Services Received by Older Adults Following a Cardiac Event: A Population-Based Analysis

    PubMed Central

    Xu, Fang; Zullo, Melissa; Shishehbor, Mehdi; Moore, Shirley M.; Rimm, Alfred A.

    2010-01-01

    Background Post-acute care (PAC) is available for older adults who need additional services after hospitalization for acute cardiac events. With the aging population and an increase in the prevalence of cardiac disease, it is important to determine current PAC use for cardiac patients to assist health care workers to meet the needs of older cardiac patients. The purpose of this study was to determine the current PAC use and factors associated with PAC use for older adults following hospitalization for a cardiac event that includes coronary artery bypass graph (CABG) and valve surgeries, myocardial infarction (MI), percutaneous coronary intervention (PCI), and heart failure (HF). Methods and Results A cross-sectional design and the 2003 Medicare Part A database were used for this study. The sample (n=1,493,521) consisted of patients aged 65 years and older discharged after their first cardiac event. Multinomial logistic regression was used to examine factors associated with PAC use. Overall, PAC use was 55% for cardiac valve surgery, 50% for MI, 45% for HF, 44% for CABG, and 5% for PCI. Medical patients use more skilled nursing facility care and surgical patients use more home health care. Only 0.1–3.4% of the cardiac patients use intermediate rehabilitation facilities. Compared to those who do not use PAC, those who use home health care and skilled nursing facility care are older, female, have a longer hospital length of stay, and more comorbidity. Asians, Hispanics and Native Americans were less likely to use PAC after hospitalization for an MI or HF. Conclusions The current rate of PAC use indicates that almost half of non-disabled Medicare patients discharged from the hospital following a cardiac event use one of these services. Healthcare professionals can increase PAC use for Asians, Hispanics and Native Americans by including culturally targeted communication. Optimizing recovery for cardiac patients who use PAC may require focused cardiac rehabilitation

  7. Prognostic implications of cardiac scintigraphic parameters obtained in the early phase of acute myocardial infarction

    SciTech Connect

    Suzuki, A.; Matsushima, H.; Satoh, A.; Hayashi, H.; Sotobata, I.

    1988-06-01

    A cohort of 76 patients with acute myocardial infarction was studied with infarct-avid scan, radionuclide ventriculography, and thallium-201 myocardial perfusion scintigraphy. Infarct area, left ventricular ejection fraction, and defect score were calculated as radionuclide indices of the extent of myocardial infarction. The correlation was studied between these indices and cardiac events (death, congestive heart failure, postinfarction angina, and recurrence of myocardial infarction) in the first postinfarction year. High-risk patients (nonsurvivors and patients who developed heart failure) had a larger infarct area, a lower left ventricular ejection fraction, and a larger defect score than the others. Univariate linear discriminant analysis was done to determine the optimal threshold of these parameters for distinguishing high-risk patients from others. Radionuclide parameters obtained in the early phase of acute myocardial infarction were useful for detecting both patients with grave complications and those with poor late prognosis during a mean follow-up period of 2.6 years.

  8. [Cardiac Angiosarcoma with Acute Myocardial Infarction due to Tumor Embolism;Report of a Case].

    PubMed

    Date, Yusuke; Miyazu, Katsuyuki; Ikeda, Masahiro

    2016-09-01

    We report the case of a 28-year-old man with a rare angiosarcoma complicated by acute myocardial infarction secondary to tumor embolism. He was transported to our emergency unit because of sudden onset of chest pain. The echocardiography showed a 42×60 mm mass in the left ventricle, and the coronary angiography showed embolic occlusion of the proximal left anterior descending and circumflex arteries. Emergent surgical removal of the mass was attempted under cardiopulmonary bypass, concomitant with double coronary artery bypass grafting and mitral valve replacement with a mechanical prosthesis. However, complete tumor excision was impossible. The postoperative pathological examination revealed undifferentiated angiosarcoma. Twenty days after the operation, the patient suffered acute cerebral hemorrhage from a metastatic tumor in the brain. He died at 37 days after the initial cardiac surgery. PMID:27586319

  9. [Preventive antifibrillatory treatment of sudden cardiac death in acute myocardial infarct].

    PubMed

    Thale, J; Gülker, H; Hindricks, G; Haverkamp, W; Pollock, B; Buchwalsky, R

    1988-01-01

    The pathophysiological basis of sudden cardiac death due to ventricular arrhythmias in acute myocardial infarction has been extensively investigated in experimental as well as in some clinical studies. Numerous clinical studies have been performed with the aim to establish the feasibility of antifibrillatory prophylaxis of sudden cardiac death by pretreatment with antiarrhythmic drugs. Using class I-antiarrhythmic drugs the reported findings were contradictory. While the antiarrhythmic efficacy of Lidocaine and other, newer class I-antiarrhythmic drugs is well established, the antifibrillatory effects of these drugs in the early phase of acute myocardial infarction remain uncertain. In clinical studies with the endpoint of mortality in patients at risk, longterm administration of orally effective class I-antiarrhythmic drugs did not prove to be superior to placebo. However, beta-sympatholytic agents have been shown to reduce mortality in patients at risk in several large clinical studies. The basic mechanism seems to be primarily a reduction in sudden cardiac death which is caused predominantly by ventricular fibrillation. The antifibrillatory properties of beta-blockers was demonstrated as well by a reduction in the number of episodes of ventricular fibrillation. The recognition of patients at risk who profit most from chronic beta-blocker therapy remains the main problem when treatment of numerous low-risk patients is avoided. In the ISIS I-study with Atenolol intravenous administration of a beta-blocker in the early phase of acute myocardial infarction has been shown to be beneficial if hemodynamic monitoring, for example using flow-directed heart catherization is performed. In general this does not apply to the treatment with calciumantagonists, especially with Verapamil and Nifedipine. These drugs do not improve prognosis of acute myocardial ischemia, obviously because of hemodynamic side effects. The antifibrillatory efficacy of Verapamil

  10. Nongenomic effects of estrogen mediate the dose-related myocardial oxidative stress and dysfunction caused by acute ethanol in female rats

    PubMed Central

    El-Mas, Mahmoud M.

    2013-01-01

    Acute ethanol lowers blood pressure (BP) and cardiac output in proestrus and after chronic estrogen (E2) replacement in ovariectomized (OVX) female rats. However, whether rapid nongenomic effects of estrogen mediate these hemodynamic effects of ethanol remains unanswered. To test this hypothesis, we investigated the effect of ethanol (0.5 or 1.5 g/kg iv) on left ventricular (LV) function and oxidative markers in OVX rats pretreated 30 min earlier with 1 μg/kg E2 (OVXE2) or vehicle (OVX) and in proestrus sham-operated (SO) rats. In SO rats, ethanol caused significant and dose-related reductions in BP, rate of rise in LV pressure (LV dP/dtmax), and LV developed pressure (LVDP). These effects of ethanol disappeared in OVX rats and were restored in OVXE2 rats, suggesting rapid estrogen receptor signaling mediates the detrimental effects of ethanol on LV function. Ex vivo studies revealed that the estrogen-dependent myocardial dysfunction caused by ethanol was coupled with higher LV 1) generation of reactive oxygen species (ROS), 2) expression of malondialdehyde and 4-hydroxynonenal protein adducts, 3) phosphorylation of protein kinase B (Akt) and extracellular signal-regulated kinases (ERK1/2), and 4) catalase activity. ERK1/2 inhibition by PD-98059 (1 mg/kg iv) abrogated the myocardial dysfunction, hypotension, and the elevation in myocardial ROS generation caused by ethanol. We conclude that rapid estrogen receptor signaling is implicated in cellular events that lead to the generation of aldehyde protein adducts and Akt/ERK1/2 phosphorylation, which ultimately mediate the estrogen-dependent LV oxidative stress and dysfunction caused by ethanol in female rats. PMID:24368668

  11. Practical nonlinear method for detection of respiratory and cardiac dysfunction in human subjects

    NASA Astrophysics Data System (ADS)

    Katz, Richard A.; Lawee, Michael S.; Newman, Anthony K.; Weiss, J. Woodrow; Chandra, Shalabh; Grimm, Richard A.; Thomas, James D.

    1995-12-01

    This research applies novel nonlinear signal detection techniques in studies of human subjects with respiratory and cardiac diseases. One of the studies concerns a breathing disorder during sleep, a disease called Obstructive Sleep Apnea (OSA). In a second study we investigate a disease of the heart, Atrial Fibrillation (AF). The former study involves nonlinear processing of the time sequences of sleep apnea recordings (cardio-respirograms) collected from patients with known obstructive sleep apnea, and from a normal control. In the latter study, we apply similar nonlinear metrics to Doppler flow measurements obtained by transesophageal echocardiography (TEE). One of our metrics, the 'chaotic radius' is used for tracking the position of points in phase space relative to some reference position. A second metric, the 'differential radius' provides a measure of the separation rate of contiguous (evolving) points in phase space. A third metric, the 'chaotic frequency' gives angular position of the phase space orbit as a function of time. All are useful for identifying change of physiologic condition that is not always apparent using conventional methods.

  12. Deficiency in adiponectin exaggerates cigarette smoking exposure-induced cardiac contractile dysfunction: Role of autophagy.

    PubMed

    Hu, Nan; Yang, Lifang; Dong, Maolong; Ren, Jun; Zhang, Yingmei

    2015-10-01

    Second hand smoke is an independent risk factor for cardiovascular disease. Adiponectin (APN), an adipose-derived adipokine, has been shown to offer cardioprotective effect through an AMPK-dependent manner. This study was designed to evaluate the impact of adiponectin deficiency on second hand smoke-induced cardiac pathology and underlying mechanisms using a mouse model of side-stream smoke exposure. Adult wild-type (WT) and adiponectin knockout (APNKO) mice were placed in a chamber exposed to cigarette smoke for 1 hour daily for 40 days. Echocardiographic, cardiomyocyte function, and intracellular Ca2+ handling were evaluated. Autophagy and apoptosis were examined using western blot. 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA) staining was used to evaluate reactive oxygen species (ROS) generation. Masson trichrome staining was employed to measure interstitial fibrosis. Our data revealed that adiponectin deficiency provoked smoke exposure-induced cardiomyopathy (compromised fractional shortening, disrupted cardiomyocyte function and intracellular Ca2+ homeostasis, apoptosis and ROS generation). In addition, these detrimental effects of side-stream smoke were accompanied by defective autophagolysosome formation, the effect of which was exacerbated by adiponectin deficiency. Blocking autophagolysosome formation using bafilomycin A1 (BafA1) negated the cardioprotective effect of rapamycin against smoke extract. Induction of autophagy using rapamycin and AMPKα activation using AICAR rescued against smoke extract-induced myopathic anomalies in APNKO mice. Our data suggest that adiponectin serves as an indispensable cardioprotective factor against side-stream smoke exposure-induced myopathic changes possibly through facilitating autophagolysosome formation. PMID:26276084

  13. Ataxin-10 is part of a cachexokine cocktail triggering cardiac metabolic dysfunction in cancer cachexia

    PubMed Central

    Schäfer, Michaela; Oeing, Christian U.; Rohm, Maria; Baysal-Temel, Ezgi; Lehmann, Lorenz H.; Bauer, Ralf; Volz, H. Christian; Boutros, Michael; Sohn, Daniela; Sticht, Carsten; Gretz, Norbert; Eichelbaum, Katrin; Werner, Tessa; Hirt, Marc N.; Eschenhagen, Thomas; Müller-Decker, Karin; Strobel, Oliver; Hackert, Thilo; Krijgsveld, Jeroen; Katus, Hugo A.; Berriel Diaz, Mauricio; Backs, Johannes; Herzig, Stephan

    2015-01-01

    Objectives Cancer cachexia affects the majority of tumor patients and significantly contributes to high mortality rates in these subjects. Despite its clinical importance, the identity of tumor-borne signals and their impact on specific peripheral organ systems, particularly the heart, remain mostly unknown. Methods and results By combining differential colon cancer cell secretome profiling with large-scale cardiomyocyte phenotyping, we identified a signature panel of seven “cachexokines”, including Bridging integrator 1, Syntaxin 7, Multiple inositol-polyphosphate phosphatase 1, Glucosidase alpha acid, Chemokine ligand 2, Adamts like 4, and Ataxin-10, which were both sufficient and necessary to trigger cardiac atrophy and aberrant fatty acid metabolism in cardiomyocytes. As a prototypical example, engineered secretion of Ataxin-10 from non-cachexia-inducing cells was sufficient to induce cachexia phenotypes in cardiomyocytes, correlating with elevated Ataxin-10 serum levels in murine and human cancer cachexia models. Conclusions As Ataxin-10 serum levels were also found to be elevated in human cachectic cancer patients, the identification of Ataxin-10 as part of a cachexokine cocktail now provides a rational approach towards personalized predictive, diagnostic and therapeutic measures in cancer cachexia. PMID:26909315

  14. Cardiac Dysfunction in the BACHD Mouse Model of Huntington’s Disease

    PubMed Central

    Schroeder, Analyne M.; Wang, Huei Bin; Park, Saemi; Jordan, Maria C.; Gao, Fuying; Coppola, Giovanni; Fishbein, Michael C.; Roos, Kenneth P.; Ghiani, Cristina A.; Colwell, Christopher S.

    2016-01-01

    While Huntington’s disease (HD) is classified as a neurological disorder, HD patients exhibit a high incidence of cardiovascular events leading to heart failure and death. In this study, we sought to better understand the cardiovascular phenotype of HD using the BACHD mouse model. The age-related decline in cardiovascular function was assessed by echocardiograms, electrocardiograms, histological and microarray analysis. We found that structural and functional differences between WT and BACHD hearts start at 3 months of age and continue throughout life. The aged BACHD mice develop cardiac fibrosis and ultimately apoptosis. The BACHD mice exhibited adaptive physiological changes to chronic isoproterenol treatment; however, the medication exacerbated fibrotic lesions in the heart. Gene expression analysis indicated a strong tilt toward apoptosis in the young mutant heart as well as changes in genes involved in cellular metabolism and proliferation. With age, the number of genes with altered expression increased with the large changes occurring in the cardiovascular disease, cellular metabolism, and cellular transport clusters. The BACHD model of HD exhibits a number of changes in cardiovascular function that start early in the disease progress and may provide an explanation for the higher cardiovascular risk in HD. PMID:26807590

  15. Impact of cardiac magnet resonance imaging on management of ventricular septal rupture after acute myocardial infarction

    PubMed Central

    Gassenmaier, Tobias; Gorski, Armin; Aleksic, Ivan; Deubner, Nikolas; Weidemann, Frank; Beer, Meinrad

    2013-01-01

    A 74-year-old man was admitted to the cardiac catheterization laboratory with acute myocardial infarction. After successful angioplasty and stent implantation into the right coronary artery, he developed cardiogenic shock the following day. Echocardiography showed ventricular septal rupture. Cardiac magnet resonance imaging (MRI) was performed on the critically ill patient and provided detailed information on size and localization of the ruptured septum by the use of fast MRI sequences. Moreover, the MRI revealed that the ventricular septal rupture was within the myocardial infarction area, which was substantially larger than the rupture. As the patient’s condition worsened, he was intubated and had intra-aortic balloon pump implanted, and extracorporeal membrane oxygenation was initiated. During the following days, the patient’s situation improved, and surgical correction of the ventricular septal defect could successfully be performed. To the best of our knowledge, this case report is the first description of postinfarction ventricular septal rupture by the use of cardiac MRI in an intensive care patient with cardiogenic shock and subsequent successful surgical repair. PMID:23710303

  16. Acute Vhl gene inactivation induces cardiac HIF-dependent erythropoietin gene expression.

    PubMed

    Miró-Murillo, Marta; Elorza, Ainara; Soro-Arnáiz, Inés; Albacete-Albacete, Lucas; Ordoñez, Angel; Balsa, Eduardo; Vara-Vega, Alicia; Vázquez, Silvia; Fuertes, Esther; Fernández-Criado, Carmen; Landázuri, Manuel O; Aragonés, Julián

    2011-01-01

    Von Hippel Lindau (Vhl) gene inactivation results in embryonic lethality. The consequences of its inactivation in adult mice, and of the ensuing activation of the hypoxia-inducible factors (HIFs), have been explored mainly in a tissue-specific manner. This mid-gestation lethality can be also circumvented by using a floxed Vhl allele in combination with an ubiquitous tamoxifen-inducible recombinase Cre-ER(T2). Here, we characterize a widespread reduction in Vhl gene expression in Vhl(floxed)-UBC-Cre-ER(T2) adult mice after dietary tamoxifen administration, a convenient route of administration that has yet to be fully characterized for global gene inactivation. Vhl gene inactivation rapidly resulted in a marked splenomegaly and skin erythema, accompanied by renal and hepatic induction of the erythropoietin (Epo) gene, indicative of the in vivo activation of the oxygen sensing HIF pathway. We show that acute Vhl gene inactivation also induced Epo gene expression in the heart, revealing cardiac tissue to be an extra-renal source of EPO. Indeed, primary cardiomyocytes and HL-1 cardiac cells both induce Epo gene expression when exposed to low O(2) tension in a HIF-dependent manner. Thus, as well as demonstrating the potential of dietary tamoxifen administration for gene inactivation studies in UBC-Cre-ER(T2) mouse lines, this data provides evidence of a cardiac oxygen-sensing VHL/HIF/EPO pathway in adult mice.

  17. Acute Mesenteric Ischemia after Cardiac Surgery: An Analysis of 52 Patients

    PubMed Central

    Gucu, Arif; Toktas, Faruk; Erdolu, Burak; Ozyazıcıoglu, Ahmet

    2013-01-01

    Objective. Acute mesenteric ischemia (AMI) is a rare but serious complication after cardiac surgery. The aim of this retrospective study was to evaluate the incidence, outcome, and perioperative risk factors of AMI in the patients undergoing elective cardiac surgery. Methods. From January 2005 to May 2013, all patients who underwent cardiac surgery were screened for participation, and patients with registered gastrointestinal complications were retrospectively reviewed. Univariate analyses were performed. Results. The study included 6013 patients, of which 52 (0.86%) patients suffered from AMI, 35 (67%) of whom died. The control group (150 patients) was randomly chosen from among cases undergoing cardiopulmonary bypass (CPB). Preoperative parameters including age (P = 0.03), renal insufficiency (P = 0.004), peripheral vascular disease (P = 0.04), preoperative inotropic support (P < 0.001), poor left ventricular ejection fraction (P = 0.002), cardiogenic shock (P = 0.003), and preoperative intra-aortic balloon pump (IABP) support (P = 0.05) revealed significantly higher levels in the AMI group. Among intra- and postoperative parameters, CPB time (P < 0.001), dialysis (P = 0.04), inotropic support (P = 0.007), prolonged ventilator time (P < 0.001), and IABP support (P = 0.007) appeared significantly higher in the AMI group than the control group. Conclusions. Prompt diagnosis and early treatment should be initiated as early as possible in any patient suspected of AMI, leading to dramatic reduction in the mortality rate. PMID:24288499

  18. Advances in acute kidney injury associated with cardiac surgery: the unfolding revolution in early detection.

    PubMed

    Wyckoff, Tygh; Augoustides, John G T

    2012-04-01

    Cardiac surgery-associated acute kidney injury (CSA-AKI) is important because it remains common and serious. A major limitation in the management of CSA-AKI has been ongoing delayed diagnosis by standard clinical approaches, including serum creatinine and calculated glomerular filtration rate. Recent advances in the understanding of CSA-AKI have highlighted the utility of novel biomarkers that diagnose CSA-AKI within the first 24 hours. The biomarkers that have been evaluated in clinical trials include neutrophil gelatinase-associated lipocalin (NGAL), cystatin C, kidney injury molecule 1 and interleukin-18. The biomarker with the greatest clinical promise is NGAL. Although it has multiple advantages over serum creatinine, it is still not the ideal biomarker for CSA-AKI. It is likely that a panel of early biomarkers will be developed to facilitate rapid and reliable detection of CSA-AKI, combining their different characteristics to optimize patient management. Future clinical trials likely will focus on whether these biomarkers predict adverse outcomes independent of serum creatinine fluctuations and whether therapies guided by biomarker profiles improve renal salvage and overall clinical outcomes. Given their clinical utility, these novel biomarkers have been evaluated beyond cardiac surgery for AKI in multiple clinical environments, including the emergency department, the operating room, the cardiac catheterization laboratory, and the intensive care unit. Their integration into clinical practice seems likely in the near future.

  19. Dipyridamole-thallium-201 scintigraphy in the prediction of future cardiac events after acute myocardial infarction

    SciTech Connect

    Leppo, J.A.; O'Brien, J.; Rothendler, J.A.; Getchell, J.D.; Lee, V.W.

    1984-04-19

    To evaluate the safety and usefulness of serial thallium scanning immediately after intravenous dipyridamole, we studied 51 patients recovering from acute myocardial infarction. Eight patients experienced angina during the procedure, but there were no serious complications. Patients were followed for a mean period of 19 months after hospital discharge. Eleven of 12 patients who died during follow-up or had another infarction had shown transient defects (redistribution) on their predischarge scan, as had 22 of the 24 patients who needed readmission for management of angina. Among all the other clinical or scintigraphic criteria tested, the presence of redistribution on the dipyridamole-thallium scan was the only significant predictor of these serious cardiac events. Twenty-six patients were also given a submaximal exercise test before discharge, of whom 13 subsequently had serious cardiac events. The exercise test had been positive in only 6 of these 13 patients, whereas the dipyridamole-thallium scan had shown a redistribution pattern in 12 (P less than 0.001). We conclude from this preliminary study that dipyridamole-thallium scintigraphy after myocardial infraction is relatively safe. It appears to be a more sensitive predictor of subsequent cardiac events than a submaximal exercise test and may therefore prove useful in evaluating patients after recovery from a myocardial infarction.

  20. Role and importance of ultrasound lung comets in acute cardiac care.

    PubMed

    Ricci, Fabrizio; Aquilani, Roberta; Radico, Francesco; Bianco, Francesco; Dipace, Gioacchino Giuseppe; Miniero, Ester; De Caterina, Raffaele; Gallina, Sabina

    2015-04-01

    Lung ultrasonography is an emerging, user-friendly and easy-to-use technique that can be performed quickly at the patient's bedside to evaluate several pathologic conditions affecting the lung. Ultrasound lung comets (ULCs) are an echographic sign of uncertain biophysical characterisation mostly attributed to water-thickened subpleural interlobular septa, but invariably associated with increased extravascular lung water. ULCs have thus been proposed as a complementary tool for the assessment and monitoring of acute heart failure and are now entering into statements in international recommendation documents. Adding lung ultrasonography to conventional echocardiography allows for performing an integrated cardiopulmonary ultrasound examination, and this is an important opportunity for the cardiologist. The technique allows the simultaneous gathering of considerable information about the heart and the lungs to investigate acute and chronic cardio-pulmonary conditions within a non-invasive, radiation-free, single-probe, all-in-one examination. We have here reviewed the pertinent literature on the physical origin of ULCs and on their role and importance in intensive and acute cardiac care settings. We also here propose a new algorithm aimed at implementing evaluation in the diagnostic work-up of patients with suspected acute heart failure. PMID:25267879

  1. Preoperative Low Serum Bicarbonate Levels Predict Acute Kidney Injury After Cardiac Surgery

    PubMed Central

    Jung, Su-Young; Park, Jung Tak; Kwon, Young Eun; Kim, Hyung Woo; Ryu, Geun Woo; Lee, Sul A.; Park, Seohyun; Jhee, Jong Hyun; Oh, Hyung Jung; Han, Seung Hyeok; Yoo, Tae-Hyun; Kang, Shin-Wook

    2016-01-01

    Abstract Acute kidney injury (AKI) after cardiac surgery is a common and serious complication. Although lower than normal serum bicarbonate levels are known to be associated with consecutive renal function deterioration in patients with chronic kidney injury, it is not well-known whether preoperative low serum bicarbonate levels are associated with the development of AKI in patients who undergo cardiac surgery. Therefore, the clinical implication of preoperative serum bicarbonate levels on AKI occurrence after cardiac surgery was investigated. Patients who underwent coronary artery bypass or valve surgery at Yonsei University Health System from January 2013 to December 2014 were enrolled. The patients were divided into 3 groups based on preoperative serum bicarbonate levels, which represented group 1 (below normal levels) <23 mEq/L; group 2 (normal levels) 23 to 24 mEq/L; and group 3 (elevated levels) >24 mEq/L. The primary outcome was the predicated incidence of AKI 48 hours after cardiac surgery. AKI was defined according to Acute Kidney Injury Network criteria. Among 875 patients, 228 (26.1%) developed AKI within 48 hours after cardiac surgery. The incidence of AKI was higher in group 1 (40.9%) than in group 2 (26.5%) and group 3 (19.5%) (P < 0.001). In addition, the duration of postoperative stay in a hospital intensive care unit (ICU) was longer for AKI patients and for those in the low-preoperative-serum-bicarbonate-level groups. A multivariate logistic regression analysis showed that low preoperative serum bicarbonate levels were significantly associated with AKI even after adjustment for age, sex, hypertension, diabetes mellitus, operation type, preoperative hemoglobin, and estimated glomerular filtration rate. In conclusion, low serum bicarbonate levels were associated with higher incidence of AKI and prolonged ICU stay. Further studies are needed to clarify whether strict correction of bicarbonate levels close to normal limits may have a

  2. Cardiac Autonomic Effects of Acute Exposures to Airborne Particulates in Men and Women

    NASA Technical Reports Server (NTRS)

    Howarth, M. S.; Schlegel, T. T.; Knapp, C. F.; Patwardhan, A. R.; Jenkins, R. A.; Ilgner, R. H.; Evans, J. M.

    2007-01-01

    The aim of this research was to investigate cardiac autonomic changes associated with acute exposures to airborne particulates. Methods: High fidelity 12-lead ECG (CardioSoft, Houston, TX) was acquired from 19 (10 male / 9 female) non-smoking volunteers (age 33.6 +/- 6.6 yrs) during 10 minutes pre-exposure, exposure and post-exposure to environmental tobacco smoke (ETS), cooking oil fumes, wood smoke and sham (water vapor). To control exposure levels, noise, subject activity, and temperature, all studies were conducted inside an environmental chamber. Results: The short-term fractal scaling exponent (Alpha-1) and the ratio of low frequency to high frequency Heart Rate Variability (HRV) powers (LF/HF, a purported sympathetic index) were both higher in males (p<0.017 and p<0.05, respectively) whereas approximate entropy (ApEn) and HF/(LF+HF) (a purported parasympathetic index) were both lower in males (p<0.036, and p<0.044, respectively). Compared to pre-exposure (p<0.0002) and sham exposure (p<0.047), male heart rates were elevated during early ETS post-exposure. Our data suggest that, in addition to tonic HRV gender differences, cardiac responses to some acute airborne particulates are gender related.

  3. Cardiac progenitor-derived exosomes protect ischemic myocardium from acute ischemia/reperfusion injury

    SciTech Connect

    Chen, Lijuan; Wang, Yingjie; Pan, Yaohua; Zhang, Lan; Shen, Chengxing; Qin, Gangjian; Ashraf, Muhammad; Weintraub, Neal; Ma, Genshan; Tang, Yaoliang

    2013-02-15

    Highlights: ► Cardiac progenitor-derived (CPC) Exosomes protect H9C2 from apoptosis in vitro. ► CPC-exosomes protect cardiomyoyctes from MI/R induced apoptosis in vivo. ► CPC-exosomes were taken up by H9C2 with high efficiency using PKH26 labeling. ► miR-451, one of GATA4-responsive miRNA cluster, is enriched in CPC-exosomes. -- Abstract: Background: Cardiac progenitors (CPC) mediate cardioprotection via paracrine effects. To date, most of studies focused on secreted paracrine proteins. Here we investigated the CPC-derived-exosomes on protecting myocardium from acute ischemia/reperfusion (MI/R) injury. Methods and results: CPC were isolated from mouse heart using two-step protocol. Exosomes were purified from conditional medium, and confirmed by electron micrograph and Western blot using CD63 as a marker. qRT-PCR shows that CPC-exosomes have high level expression of GATA4-responsive-miR-451. Exosomes were ex vivo labeled with PKH26, We observed exosomes can be uptaken by H9C2 cardiomyoblasts with high efficiency after 12 h incubation. CPC-exosomes protect H9C2 from oxidative stress by inhibiting caspase 3/7 activation invitro. In vivo delivery of CPC-exosomes in an acute mouse myocardial ischemia/reperfusion model inhibited cardiomyocyte apoptosis by about 53% in comparison with PBS control (p < 0.05). Conclusion: Our results suggest, for the first time, the CPC-exosomes can be used as a therapeutic vehicle for cardioprotection, and highlights a new perspective for using non-cell exosomes for cardiac disease.

  4. Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection

    PubMed Central

    Agrati, C; Castilletti, C; Casetti, R; Sacchi, A; Falasca, L; Turchi, F; Tumino, N; Bordoni, V; Cimini, E; Viola, D; Lalle, E; Bordi, L; Lanini, S; Martini, F; Nicastri, E; Petrosillo, N; Puro, V; Piacentini, M; Di Caro, A; Kobinger, G P; Zumla, A; Ippolito, G; Capobianchi, M R

    2016-01-01

    Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells. PMID:27031961

  5. Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection.

    PubMed

    Agrati, C; Castilletti, C; Casetti, R; Sacchi, A; Falasca, L; Turchi, F; Tumino, N; Bordoni, V; Cimini, E; Viola, D; Lalle, E; Bordi, L; Lanini, S; Martini, F; Nicastri, E; Petrosillo, N; Puro, V; Piacentini, M; Di Caro, A; Kobinger, G P; Zumla, A; Ippolito, G; Capobianchi, M R

    2016-01-01

    Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells.

  6. Arginase 1: An Unexpected Mediator of Pulmonary Capillary Barrier Dysfunction in Models of Acute Lung Injury

    PubMed Central

    Lucas, Rudolf; Czikora, Istvàn; Sridhar, Supriya; Zemskov, Evgeny A.; Oseghale, Aluya; Circo, Sebastian; Cederbaum, Stephen D.; Chakraborty, Trinad; Fulton, David J.; Caldwell, Robert W.; Romero, Maritza J.

    2013-01-01

    The integrity of epithelial and endothelial barriers in the lower airspaces of the lungs has to be tightly regulated, in order to prevent leakage and to assure efficient gas exchange between the alveoli and capillaries. Both G− and G+ bacterial toxins, such as lipopolysaccharide and pneumolysin, respectively, can be released in high concentrations within the pulmonary compartments upon antibiotic treatment of patients suffering from acute respiratory distress syndrome (ARDS) or severe pneumonia. These toxins are able to impair endothelial barrier function, either directly, or indirectly, by induction of pro-inflammatory mediators and neutrophil sequestration. Toxin-induced endothelial hyperpermeability can involve myosin light chain phosphorylation and/or microtubule rearrangement. Endothelial nitric oxide synthase (eNOS) was proposed to be a guardian of basal barrier function, since eNOS knock-out mice display an impaired expression of inter-endothelial junction proteins and as such an increased vascular permeability, as compared to wild type mice. The enzyme arginase, the activity of which can be regulated by the redox status of the cell, exists in two isoforms – arginase 1 (cytosolic) and arginase 2 (mitochondrial) – both of which can be expressed in lung microvascular endothelial cells. Upon activation, arginase competes with eNOS for the substrate l-arginine, as such impairing eNOS-dependent NO generation and promoting reactive oxygen species generation by the enzyme. This mini-review will discuss recent findings regarding the interaction between bacterial toxins and arginase during acute lung injury and will as such address the role of arginase in bacterial toxin-induced pulmonary endothelial barrier dysfunction. PMID:23966993

  7. Longitudinal characterization of dysfunctional T cell-activation during human acute Ebola infection.

    PubMed

    Agrati, C; Castilletti, C; Casetti, R; Sacchi, A; Falasca, L; Turchi, F; Tumino, N; Bordoni, V; Cimini, E; Viola, D; Lalle, E; Bordi, L; Lanini, S; Martini, F; Nicastri, E; Petrosillo, N; Puro, V; Piacentini, M; Di Caro, A; Kobinger, G P; Zumla, A; Ippolito, G; Capobianchi, M R

    2016-01-01

    Data on immune responses during human Ebola virus disease (EVD) are scanty, due to limitations imposed by biosafety requirements and logistics. A sustained activation of T-cells was recently described but functional studies during the acute phase of human EVD are still missing. Aim of this work was to evaluate the kinetics and functionality of T-cell subsets, as well as the expression of activation, autophagy, apoptosis and exhaustion markers during the acute phase of EVD until recovery. Two EVD patients admitted to the Italian National Institute for Infectious Diseases, Lazzaro Spallanzani, were sampled sequentially from soon after symptom onset until recovery and analyzed by flow cytometry and ELISpot assay. An early and sustained decrease of CD4 T-cells was seen in both patients, with an inversion of the CD4/CD8 ratio that was reverted during the recovery period. In parallel with the CD4 T-cell depletion, a massive T-cell activation occurred and was associated with autophagic/apoptotic phenotype, enhanced expression of the exhaustion marker PD-1 and impaired IFN-gamma production. The immunological impairment was accompanied by EBV reactivation. The association of an early and sustained dysfunctional T-cell activation in parallel to an overall CD4 T-cell decline may represent a previously unknown critical point of Ebola virus (EBOV)-induced immune subversion. The recent observation of late occurrence of EBOV-associated neurological disease highlights the importance to monitor the immuno-competence recovery at discharge as a tool to evaluate the risk of late sequelae associated with resumption of EBOV replication. Further studies are required to define the molecular mechanisms of EVD-driven activation/exhaustion and depletion of T-cells. PMID:27031961

  8. Distinctive cardiac autonomic dysfunction following stress exposure in both sexes in an animal model of PTSD.

    PubMed

    Koresh, Ori; Kaplan, Zeev; Zohar, Joseph; Matar, Michael A; Geva, Amir B; Cohen, Hagit

    2016-07-15

    It is unclear whether the poor autonomic flexibility or dysregulation observed in patients with posttraumatic stress disorder (PTSD) represents a pre-trauma vulnerability factor or results from exposure to trauma. We used an animal model of PTSD to assess the association between the behavioral response to predator scent stress (PSS) and the cardiac autonomic modulation in male and female rats. The rats were surgically implanted with radiotelemetry devices to measure their electrocardiograms and locomotor activity (LMA). Following baseline telemetric monitoring, the animals were exposed to PSS or sham-PSS. Continuous telemetric monitoring (24h/day sampling) was performed over the course of 7days. The electrocardiographic recordings were analyzed using the time- and frequency-domain indexes of heart rate variability (HRV). The behavioral response patterns were assessed using the elevated plus maze and acoustic startle response paradigms for the retrospective classification of individuals according to the PTSD-related cut-off behavioral criteria. During resting conditions, the male rats had significantly higher heart rates (HR) and lower HRV parameters than the female rats during both the active and inactive phases of the daily cycle. Immediately after PSS exposure, both the female and male rats demonstrated a robust increase in HR and a marked drop in HRV parameters, with a shift of sympathovagal balance towards sympathetic predominance. In both sexes, autonomic system habituation and recovery were selectively inhibited in the rats whose behavior was extremely disrupted after exposure to PSS. However, in the female rats, exposure to the PSS produced fewer EBR rats, with a more rapid recovery curve than that of the male rats. PSS did not induce changes to the circadian rhythm of the LMA. According to our results, PTSD can be conceptualized as a disorder that is related to failure-of-recovery mechanisms that impede the restitution of physiological homeostasis. PMID

  9. Cellular basis of burn-induced cardiac dysfunction and prevention by mesenteric lymph duct ligation

    PubMed Central

    Sambol, Justin; Deitch, Edwin A.; Takimoto, Koichi; Dosi, Garima; Yatani, Atsuko

    2013-01-01

    Background Myocardial contractile depression develops 4–24 hrs after major burn injury. We have reported previously that in a rat burn injury model (≈40% of total body surface area burn), mesenteric lymph duct ligation (LDL) prior to burn prevented myocardial dysfunction. However, the underlying cellular and molecular mechanisms are not well understood. Materials and Methods Left ventricular myocytes were isolated from sham burn (control), sham burn with LDL (sham+LDL), burn, and burn with LDL (burn+LDL) rats at 4 and 24 hrs after burn or sham burn. Electrophysiological techniques were used to study myocyte size, contractility and L-type Ca2+ channel current (ICa). Further studies examined changes in the mRNA expression levels of pore-forming subunit of the L-type Ca2+ channel, α1C and its auxiliary subunits, β1, β2, β3 and α2δ1 which modulate the abundance of the ICa in post burn hearts Results Depressed myocyte contractility (≈20%) developed during 4–24 hrs post-burn compared with control, sham+LDL or burn+LDL groups, a pattern of changes consistent with whole heart studies. There was no significant alteration in myocyte size. The ICa density was significantly decreased (≈30%) at 24 hrs post-burn whereas the mRNA expression levels of Ca2+ channel gene were not significantly altered at 4 and 24 hrs after burn injury. Conclusions These results suggest that the post-burn contractile phenotype in vivo was also present in isolated myocytes in vitro, but cellular remodeling was not a major factor. The results also suggest that changes in ICa regulation, but not from Ca2+ channel gene modification may be a key element involved in post-burn contractile depression and the beneficial effects of LDL. PMID:23465433

  10. Prostaglandins attenuate cardiac contractile dysfunction produced by free radical generation but not by hydrogen peroxide.

    PubMed

    Zimmer, K M; Karmazyn, M

    1997-11-01

    The aim of this study was to examine and compare the potential influence of cyclooxygenase or lipoxygenase derived metabolites of arachidonic acid on myocardial injury produced either by a free radical generating system consisting of purine plus xanthine oxidase or that produced by hydrogen peroxide. A free radical generating system consisting of purine (2.3 mM) and xanthine oxidase (10 U/L) as well as hydrogen peroxide (75 microM) produced significant functional changes in the absence of either significant deficits in high energy phosphates or ultrastructural damage. Prostaglandin F2 alpha (30 nM) significantly attenuated both the negative inotropic effect of purine plus xanthine oxidase as well as the ability of the free radical generator to elevate diastolic pressure. An identical concentration of prostaglandin 12 (prostacyclin) significantly reduced diastolic pressure elevation only and had no effect on contractile depression. The salutary effects of the two PGs occurred in the absence of any inhibitory influence on superoxide anion generation produced by the purine and xanthine oxidase reaction. None of prostaglandins modulated the response to hydrogen peroxide. In addition, neither prostaglandin E2 nor leukotrienes exerted any effect on changes produced by either type of oxidative stress. A 5 fold elevation in the concentrations of free radical generators or hydrogen peroxide produced extensive injury as characterized by a virtual total loss in contractility, 400% elevation in diastolic pressure, ultrastructural damage and significant depletions in high energy phosphate content. None of these effects were modulated by eicosanoid treatment. Our results therefore demonstrate a selective ability of both prostaglandin F2 alpha and to a lesser extent prostacyclin, to attenuate dysfunction produced by purine plus xanthine oxidase but not hydrogen peroxide. It is possible that these eicosanoids may represent endogenous protective factors under conditions of enhanced

  11. Vasopressin, renin, and cortisol responses to hemorrhage during acute blockade of cardiac nerves in conscious dogs

    NASA Technical Reports Server (NTRS)

    O'Donnell, C. P.; Keil, L. C.; Thrasher, T. N.

    1993-01-01

    The effect of acute cardiac nerve blockade (CNB) on the increases in plasma renin activity (PRA), arginine vasopressin (AVP), and cortisol in response to a 30 ml/kg hemorrhage was determined in conscious dogs (n = 9). Procaine was infused into the pericardial space to produce acute reversible CNB, or saline was infused in the control hemorrhage. Blood was removed from the inferior vena cava at a rate of 1 ml.kg-1.min-1. In the control hemorrhage, plasma AVP increased from 1.8 +/- 0.3 to 219 +/- 66 pg/ml, PRA increased from 0.63 +/- 0.20 to 3.08 +/- 0.91 ng angiotensin I (ANG I).ml-1.3 h-1, and cortisol increased from 1.4 +/- 0.2 to 4.0 +/- 0.7 micrograms/dl. When the hemorrhage was repeated during acute CNB, plasma AVP increased from 2.8 +/- 1.6 to 185 +/- 59 pg/ml, PRA increased from 0.44 +/- 0.14 to 2.24 +/- 0.27 ng ANG I.ml-1.3 h-1, and cortisol increased from 1.9 +/- 0.3 to 5.4 +/- 0.6 micrograms/dl, and none of the increases differed significantly from the responses during the control hemorrhage. Left atrial pressure fell significantly after removal of 6 ml/kg of blood, but mean arterial pressure was maintained at control levels until blood loss reached 20 ml/kg during pericardial infusion of either saline or procaine. The declines in MAP at the 30 ml/kg level of hemorrhage in both treatments were similar. These results demonstrate that acutely blocking input from cardiac receptors does not reduce the increases in plasma AVP, cortisol, and PRA in response to a 30 ml/kg hemorrhage. The results of this study do not support the hypothesis that input from cardiac receptors is required for a normal AVP response to hemorrhage and suggest that other receptors, presumably arterial baroreceptors, can stimulate AVP and cortisol secretion in the absence of signals from the heart.

  12. Greater Volume of Acute Normovolemic Hemodilution May Aid in Reducing Blood Transfusions After Cardiac Surgery

    PubMed Central

    Goldberg, Joshua; Paugh, Paugh; Dickinson, Timothy A.; Fuller, John; Paone, Gaetano; Theurer, Patty F.; Shann, Kenneth G.; Sundt, Thoralf M.; Prager, Richard L.; Likosky, Donald S.

    2016-01-01

    Background Perioperative red blood cell transfusions (RBC) are associated with increased morbidity and mortality after cardiac surgery. Acute normovolemic hemodilution (ANH) is recommended to reduce perioperative transfusions; however, supporting data are limited and conflicting. We describe the relationship between ANH and RBC transfusions after cardiac surgery using a multi-center registry. Methods We analyzed 13,534 patients undergoing cardiac surgery between 2010 and 2014 at any of the 26 hospitals participating in a prospective cardiovascular perfusion database. The volume of ANH (no ANH, <400mL, 400–799mL, ≥800mL) was recorded and linked to each center’s surgical data. We report adjusted relative risks reflecting the association between the use and amount of ANH and the risk of perioperative RBC transfusion. Results were adjusted for preoperative risk factors, procedure, BSA, preoperative HCT, and center. Results ANH was used in 17% of the patients. ANH was associated with a reduction in RBC transfusions (RRadj 0.74, p <0.001). Patients having ≥800mL of ANH had the most profound reduction in RBC transfusions (RRadj 0.57, p<0.001). Platelet and plasma transfusions were also significantly lower with ANH. The ANH population had superior postoperative morbidity and mortality compared to the no ANH population. Conclusions There is a significant association between ANH and reduced perioperative RBC transfusion in cardiac surgery. Transfusion reduction is most profound with larger volumes of ANH. Our findings suggest the volume of ANH, rather than just its use, may be an important feature of a center’s blood conservation strategy. PMID:26206721

  13. A novel role for epidermal growth factor receptor tyrosine kinase and its downstream endoplasmic reticulum stress in cardiac damage and microvascular dysfunction in type 1 diabetes mellitus.

    PubMed

    Galán, Maria; Kassan, Modar; Choi, Soo-Kyoung; Partyka, Megan; Trebak, Mohamed; Henrion, Daniel; Matrougui, Khalid

    2012-07-01

    Epidermal growth factor receptor tyrosine kinase (EGFRtk) and endoplasmic reticulum (ER) stress are important factors in cardiovascular complications. Understanding whether enhanced EGFRtk activity and ER stress induction are involved in cardiac damage, and microvascular dysfunction in type 1 diabetes mellitus is an important question that has remained unanswered. Cardiac fibrosis and microvascular function were determined in C57BL/6J mice injected with streptozotocin only or in combination with EGFRtk inhibitor (AG1478), ER stress inhibitor (Tudca), or insulin for 2 weeks. In diabetic mice, we observed an increase in EGFRtk phosphorylation and ER stress marker expression (CHOP, ATF4, ATF6, and phosphorylated-eIF2α) in heart and mesenteric resistance arteries, which were reduced with AG1478, Tudca, and insulin. Cardiac fibrosis, enhanced collagen type I, and plasminogen activator inhibitor 1 were decreased with AG1478, Tudca, and insulin treatments. The impaired endothelium-dependent relaxation and -independent relaxation responses were also restored after treatments. The inhibition of NO synthesis reduced endothelium-dependent relaxation in control and treated streptozotocin mice, whereas the inhibition of NADPH oxidase improved endothelium-dependent relaxation only in streptozotocin mice. Moreover, in mesenteric resistance arteries, the mRNA levels of Nox2 and Nox4 and the NADPH oxidase activity were augmented in streptozotocin mice and reduced with treatments. This study unveiled novel roles for enhanced EGFRtk phosphorylation and its downstream ER stress in cardiac fibrosis and microvascular endothelial dysfunction in type 1 diabetes mellitus.

  14. Improvement of vestibular compensation by Levo-sulpiride in acute unilateral labyrinthine dysfunction.

    PubMed

    Zanetti, D; Civiero, N; Balzanelli, C; Tonini, M; Antonelli, A R

    2004-04-01

    L-sulpiride is the levorotatory enantiomer of sulpiride, a neuroleptic of the family of benzamide derivatives; it has a characteristic antagonist effect on central DA2 dopaminergic receptors and dopamine DA1 "autoreceptors". Its efficacy in the symptomatic control of acute vertigo spells has been recognized, apart from its well-known antiemetic, antidyspeptic and anti-depressant properties, at high dosages. To establish objective parameters of the results of its clinical application, a randomized prospective study was started comparing the effects of the drug in a group of 87 patients with vertigo of peripheral origin, with those in a control group treated with other vestibular suppressants. The drug was administered via the intravenous route, 25 mg t.i.d., for the first 3 days, then by oral administration, with the same schedule and dosage, for a further 7 days. After clinical evaluation of vestibular signs and symptoms, electronystagmographic recordings of rotatory tests were obtained, at admission and were then controlled after 6 months. A subjective Visual Analogue Scale was also delivered daily to the patients in order to monitor symptomatic improvements. When compared to conventional treatments, L-sulpiride appeared to induce a statistically significant faster recovery in unilateral vestibular lesions. An unexpected favourable outcome of treatment was the facilitation of spontaneous vestibular compensation, in terms of lesser residual labyrinthine dysfunction and reduction of recurrent vertigo attacks during the 6 months follow-up. The mechanisms of action of the drug and its interaction with the vestibular system are discussed.

  15. Obesity-Related Alterations in Cardiac Lipid Profile and Nondipping Blood Pressure Pattern during Transition to Diastolic Dysfunction in Male db/db Mice

    PubMed Central

    Ford, David A.; Henriksen, Erik J.; Aroor, Annayya R.; Johnson, Megan S.; Habibi, Javad; Ma, Lixin; Yang, Ming; Albert, Carolyn J.; Lally, John W.; Ford, Caleb A.; Prasannarong, Mujalin; Hayden, Melvin R.; Whaley-Connell, Adam T.; Sowers, James R.

    2013-01-01

    Obesity and a nondipping circadian blood pressure (BP) pattern are associated with diastolic dysfunction. Ectopic lipid accumulation is increasingly recognized as an important metabolic abnormality contributing to diastolic dysfunction. However, little is known about the contribution of different lipids and the composition of lipid analytes to diastolic dysfunction. We have performed functional and structural studies and analyzed cardiac lipid profile at two time points during progression to diastolic dysfunction in a genetic model of obesity. Serial cardiac magnetic resonance imaging and telemetric measures of BP between 12 and 15 wk of age in obese male db/db mice indicated a nondipping circadian BP pattern and normal diastolic function at 12 wk that progressed to a deteriorating nondipping pattern and onset of diastolic dysfunction at 15 wk of age. Lipidomic analysis demonstrated elevated fatty acids and ceramides in db/db at 12 wk, but their levels were decreased at 15 wk, and this was accompanied by persistent mitochondrial ultrastructural abnormalities in concert with evidence of increased fatty acid oxidation and enhanced production of reactive oxygen species. Triacylglyceride and diacylglyceride levels were elevated at both 12 and 15 wk, but their composition changed to consist of more saturated and less unsaturated fatty acyl at 15 wk. An increase in the lipid droplets was apparent at both time points, and this was associated with increases in phosphatidycholine. In conclusion, a distinct pattern of myocardial lipid remodeling, accompanied by oxidative stress, is associated with the onset of diastolic dysfunction in obese, insulin-resistant db/db mice. PMID:23142808

  16. Particles Alter Diesel Exhaust Gases-Induced Hypotension, Cardiac Arrhythmia,Conduction Disturbance, and Autonomic Imbalance in Heart Failure-Prone Rats

    EPA Science Inventory

    Epidemiologic studies indicate that acute exposures to vehicular traffic and particulate matter (PM) air pollution are key causes of fatal cardiac arrhythmia, especially in those with preexisting cardiovascular disease. Researchers point to electrophysiologic dysfunction and auto...

  17. SOD1 overexpression prevents acute hyperglycemia-induced cerebral myogenic dysfunction: relevance to contralateral hemisphere and stroke outcomes

    PubMed Central

    Coucha, Maha; Li, Weiguo; Hafez, Sherif; Abdelsaid, Mohammed; Johnson, Maribeth H.; Fagan, Susan C.

    2014-01-01

    Admission hyperglycemia (HG) amplifies vascular injury and neurological deficits in acute ischemic stroke, but the mechanisms remain controversial. We recently reported that ischemia-reperfusion (I/R) injury impairs the myogenic response in both hemispheres via increased nitration. However, whether HG amplifies contralateral myogenic dysfunction and whether loss of tone in the contralateral hemisphere contributes to stroke outcomes remain to be determined. Our hypothesis was that contralateral myogenic dysfunction worsens stroke outcomes after acute hyperglycemic stroke in an oxidative stress-dependent manner. Male wild-type or SOD1 transgenic rats were injected with saline or 40% glucose solution 10 min before surgery and then subjected to 30 min of ischemia/45 min or 24 h of reperfusion. In another set of animals (n = 5), SOD1 was overexpressed only in the contralateral hemisphere by stereotaxic adenovirus injection 2–3 wk before I/R. Myogenic tone and neurovascular outcomes were determined. HG exacerbated myogenic dysfunction in contralateral side only, which was associated with infarct size expansion, increased edema, and more pronounced neurological deficit. Global and selective SOD1 overexpression restored myogenic reactivity in ipsilateral and contralateral sides, respectively, and enhanced neurovascular outcomes. In conclusion, our results show that SOD1 overexpression nullified the detrimental effects of HG on myogenic tone and stroke outcomes and that the contralateral hemisphere may be a novel target for the management of acute hyperglycemic stroke. PMID:25552308

  18. Bariatric Surgery Restores Cardiac and Sudomotor Autonomic C-Fiber Dysfunction towards Normal in Obese Subjects with Type 2 Diabetes

    PubMed Central

    Lieb, David C.; Wohlgemuth, Stephen D.

    2016-01-01

    baseline. Conclusion This study shows that bariatric surgery can restore both cardiac and sudomotor autonomic C-fiber dysfunction in subjects with diabetes, potentially impacting morbidity and mortality. PMID:27137224

  19. Combined venoarterial extracorporeal membrane oxygenation and transcatheter aortic valve implantation for the treatment of acute aortic prosthesis dysfunction in a high-risk patient.

    PubMed

    Pergolini, Amedeo; Zampi, Giordano; Tinti, Maria Denitza; Polizzi, Vincenzo; Pino, Paolo Giuseppe; Pontillo, Daniele; Musumeci, Francesco; Luzi, Giampaolo

    2016-01-01

    We describe the case of a patient with acute bioprosthesis dysfunction in cardiogenic shock, in whom hemodynamic support was provided by venoarterial extracorporeal membrane oxygenation, and successfully treated by transcatheter aortic valve implantation.

  20. Combined venoarterial extracorporeal membrane oxygenation and transcatheter aortic valve implantation for the treatment of acute aortic prosthesis dysfunction in a high-risk patient.

    PubMed

    Pergolini, Amedeo; Zampi, Giordano; Tinti, Maria Denitza; Polizzi, Vincenzo; Pino, Paolo Giuseppe; Pontillo, Daniele; Musumeci, Francesco; Luzi, Giampaolo

    2016-01-01

    We describe the case of a patient with acute bioprosthesis dysfunction in cardiogenic shock, in whom hemodynamic support was provided by venoarterial extracorporeal membrane oxygenation, and successfully treated by transcatheter aortic valve implantation. PMID:27402446

  1. Acute renal failure after cardiac transplantation: a case report and review of the literature.

    PubMed Central

    Cruz, D. N.; Perazella, M. A.

    1996-01-01

    Acute renal failure (ARF) is a relatively frequent complication associated with heart transplantation. It develops in the first few days postoperatively and is characterized by oliguria with laboratory and urinary indices typical of pre-renal azotemia. Cyclosporine, especially with higher doses, is one of the many factors which play an integral part in the nephrotoxicity following cardiac transplant. Poor preoperative renal function and perioperative hemodynamic compromise may also contribute to ARF. The actual incidence of ARF now encountered by transplant centers may be lower than previously reported, the result of lower cyclosporine doses. Currently, management is entirely supportive, but novel therapeutic approaches with atrial natriuretic peptide-like substances are being explored. A case illustrating the typical clinical presentation of ARF after heart transplant will be presented and the clinical features will be reviewed. PMID:9381741

  2. The Effect of Glucose-Insulin-Potassium on Cardiac Ultrastructure Following Acute Experimental Coronary Occlusion

    PubMed Central

    Sybers, H. D.; Maroko, P. R.; Ashraf, M.; Libby, P.; Braunwald, E.

    1973-01-01

    The effects of glucose-insulin-potassium (GIK) on cardiac ultrastructure following acute experimental coronary occlusion were studied in dogs. Epicardial ST segment elevations at multiple sites on the anterior surface of the left ventricle 15 minutes after ligation of the left anterior descending coronary artery were used to predict infarct development. Biopsies removed from sites of known ST segment elevation were examined with the electron microscope, and the degree of injury was correlated with the ST segment elevation. The animals receiving GIK showed significantly less necrosis than was seen in dogs with occlusion alone at corresponding levels of ST segment elevation. Other evidence suggesting a beneficial effect of GIK was the presence of a fibrillar material in several biopsies from the treated animals, which may indicate the regeneration of myofilaments. ImagesFig 3Fig 4Fig 8Fig 9Fig 5Fig 6Fig 10Fig 7p[417]-aFig 1Fig 2 PMID:4570076

  3. In Emergency Department Patients with Acute Chest Pain, Stress Cardiac MRI Observation Unit Care Reduces 1- year Cardiac-Related Health Care Expenditures: A Randomized Trial

    PubMed Central

    Miller, Chadwick D.; Hwang, Wenke; Case, Doug; Hoekstra, James W.; Lefebvre, Cedric; Blumstein, Howard; Hamilton, Craig A.; Harper, Erin N.; Hundley, W. Gregory

    2013-01-01

    Objective To compare the direct cost of medical care and clinical events during the first year after patients with intermediate risk acute chest pain were randomized to stress cardiovascular magnetic resonance (CMR) observation unit (OU) testing, versus inpatient care. Background In a recent study, randomization to OU-CMR reduced median index hospitalization cost compared to inpatient care in patients presenting to the emergency department with intermediate risk acute chest pain. Methods Emergency department patients with intermediate risk chest pain were randomized to OU-CMR (OU care, cardiac markers, stress CMR) or inpatient care (admission, care per admitting provider). This analysis reports the direct cost of cardiac-related care and clinical outcomes (MI, revascularization, cardiovascular death) during the first year of follow-up subsequent to discharge. Consistent with health economics literature, provider cost was calculated from work-related relative value units using the Medicare conversion factor; facility charges were converted to cost using departmental specific cost-to-charge ratios. Linear models were used to compare cost accumulation among study groups. Results One-hundred nine (109) randomized subjects were included in this analysis (52 OU-CMR, 57 inpatient care). The median age was 56 years; baseline characteristics were similar in both groups. At 1 year, 6% of OU-CMR and 9% of inpatient care participants experienced a major cardiac event (p=0.72) with 1 patient in each group experiencing a cardiac event after discharge. First-year cardiac-related costs were significantly lower for participants randomized to OU-CMR compared to participants receiving inpatient care (geometric mean = $3101 vs $4742 including the index visit (p = .004) and $29 vs $152 following discharge (p = .012)). During the year following randomization, 6% of OU-CMR and 9% of inpatient care participants experienced a major cardiac event (p=0.72). Conclusions An OU-CMR strategy

  4. Critical role of extracellular heat shock cognate protein 70 in the myocardial inflammatory response and cardiac dysfunction after global ischemia-reperfusion

    PubMed Central

    Zou, Ning; Ao, Lihua; Cleveland, Joseph C.; Yang, Xiaoping; Su, Xin; Cai, Guang-Yun; Banerjee, Anirban; Fullerton, David A.; Meng, Xianzhong

    2010-01-01

    Previous studies showed that Toll-like receptor 4 (TLR4) modulates the myocardial inflammatory response to ischemia-reperfusion injury, and we recently found that cytokines link TLR4 to postischemic cardiac dysfunction. Although TLR4 can be activated in cultured cells by endogenous agents including heat shock protein 70, how it is activated during myocardial ischemia-reperfusion is unknown. In the present study, we examined 1) whether heat shock cognate protein 70 (HSC70), which is constitutively expressed in the myocardium, is released during ischemia-reperfusion; 2) whether extracellular HSC70 induces the myocardial inflammatory response and modulates cardiac function; and 3) whether HSC70 exerts these effects via TLR4. We subjected isolated mouse hearts to global ischemia-reperfusion via the Langendorff technique. Immunoblotting and immunostaining detected the release of HSC70 from the myocardium during reperfusion. Treatment with an antibody specific to HSC70 suppressed myocardial cytokine expression and improved cardiac functional recovery after ischemia-reperfusion. Recombinant HSC70 induced NF-κB activation and cytokine expression and depressed myocardial contractility in a TLR4-dependent manner. These effects required the substrate-binding domain of HSC70. Fluorescence resonance energy transfer analysis of isolated macrophages demonstrated that extracellular HSC70 interacts with TLR4. Therefore, this study demonstrates for the first time that 1) the myocardium releases HSC70 during ischemia-reperfusion, 2) extracellular HSC70 contributes to the postischemic myocardial inflammatory response and to cardiac dysfunction, 3) HSC70 exerts these effects through a TLR4-dependent mechanism, and 4) the substrate-binding domain of HSC70 is required to induce these effects. Thus extracellular HSC70 plays a critical role in regulating the myocardial innate immune response and cardiac function after ischemia-reperfusion. PMID:18441202

  5. Predictive Value of Beat-to-Beat QT Variability Index across the Continuum of Left Ventricular Dysfunction: Competing Risks of Non-cardiac or Cardiovascular Death, and Sudden or Non-Sudden Cardiac Death

    PubMed Central

    Tereshchenko, Larisa G.; Cygankiewicz, Iwona; McNitt, Scott; Vazquez, Rafael; Bayes-Genis, Antoni; Han, Lichy; Sur, Sanjoli; Couderc, Jean-Philippe; Berger, Ronald D.; de Luna, Antoni Bayes; Zareba, Wojciech

    2012-01-01

    Background The goal of this study was to determine the predictive value of beat-to-beat QT variability in heart failure (HF) patients across the continuum of left ventricular dysfunction. Methods and Results Beat-to-beat QT variability index (QTVI), heart rate variance (LogHRV), normalized QT variance (QTVN), and coherence between heart rate variability and QT variability have been measured at rest during sinus rhythm in 533 participants of the Muerte Subita en Insuficiencia Cardiaca (MUSIC) HF study (mean age 63.1±11.7; males 70.6%; LVEF >35% in 254 [48%]) and in 181 healthy participants from the Intercity Digital Electrocardiogram Alliance (IDEAL) database. During a median of 3.7 years of follow-up, 116 patients died, 52 from sudden cardiac death (SCD). In multivariate competing risk analyses, the highest QTVI quartile was associated with cardiovascular death [hazard ratio (HR) 1.67(95%CI 1.14-2.47), P=0.009] and in particular with non-sudden cardiac death [HR 2.91(1.69-5.01), P<0.001]. Elevated QTVI separated 97.5% of healthy individuals from subjects at risk for cardiovascular [HR 1.57(1.04-2.35), P=0.031], and non-sudden cardiac death in multivariate competing risk model [HR 2.58(1.13-3.78), P=0.001]. No interaction between QTVI and LVEF was found. QTVI predicted neither non-cardiac death (P=0.546) nor SCD (P=0.945). Decreased heart rate variability (HRV) rather than increased QT variability was the reason for increased QTVI in this study. Conclusions Increased QTVI due to depressed HRV predicts cardiovascular mortality and non-sudden cardiac death, but neither SCD nor excracardiac mortality in HF across the continuum of left ventricular dysfunction. Abnormally augmented QTVI separates 97.5% of healthy individuals from HF patients at risk. PMID:22730411

  6. Prolongation of heart rate-corrected QT interval is a predictor of cardiac autonomic dysfunction in patients with systemic lupus erythematosus.

    PubMed

    Nomura, Atsushi; Kishimoto, Mitsumasa; Takahashi, Osamu; Deshpande, Gautam A; Yamaguchi, Kenichi; Okada, Masato

    2014-05-01

    Heart rate-corrected QT interval duration (QTc) has been shown to be related to cardiac autonomic dysfunction in patients with diabetes mellitus, although this association has not been previously described in patients with systemic lupus erythematosus (SLE). We retrospectively reviewed the medical records of 91 SLE patients and 144 non-SLE connective tissue disease patients visiting our clinic from November 2010 to April 2011. We compared ambulatory heart rate identified by pulse measured by automated machine in an outpatient waiting area versus resting heart rate identified on prior screening electrocardiogram. Heart rate differences were analyzed in relation to QTc interval and other characteristics. Ambulatory and resting heart rate differences were larger among SLE patients with QTc prolongation (QTc > 430 ms) than those without QTc prolongation (mean difference, 15.9 vs. 9.6, p = 0.001). In multivariate analysis, differences in heart rate were associated with QTc prolongation (OR 1.10, 95 % CI 1.01-1.21; p = 0.038), independent of age, duration of disease, immunosuppressant use, hydroxychloroquine use, diabetes mellitus, cardiac abnormality, anti-Ro/SS-A antibody positivity, or resting heart rate. Cardiac autonomic dysfunction is a common manifestation of SLE and may be related to QTc prolongation.

  7. Utility of 3-dimensional echocardiography, global longitudinal strain, and exercise stress echocardiography to detect cardiac dysfunction in breast cancer patients treated with doxorubicin-containing adjuvant therapy

    PubMed Central

    Khouri, Michel G.; Hornsby, Whitney E.; Risum, Niels; Velazquez, Eric J.; Thomas, Samantha; Lane, Amy; Scott, Jessica M.; Koelwyn, Graeme J.; Herndon, James E.; Mackey, John R.; Douglas, Pamela S.

    2015-01-01

    Conventional resting left ventricular ejection fraction (LVEF) assessments have limitations for detecting doxorubicin (DOX)-related cardiac dysfunction. Novel resting echocardiographic parameters, including 3-dimen-sional echocardiography (3DE) and global longitudinal strain (GLS), have potential for early identification of chemotherapy-related myocardial injury. Exercise “stress” is an established method to uncover impairments in cardiac function but has received limited attention in the adult oncology setting. We evaluated the utility of an integrated approach using 3DE, GLS, and exercise stress echocardiography for detecting subclinical cardiac dysfunction in early breast cancer patients treated with DOX-containing chemotherapy. Fifty-seven asymptomatic women with early breast cancer (mean 26 ± 22 months post-chemotherapy) and 20 sex-matched controls were studied. Resting left ventricular (LV) function was assessed by LVEF using 2-dimensional echocardiography (2DE) and 3DE and by GLS using 2-dimensional speckle-tracking echocardiography (2D-STE). After resting assessments, subjects completed cardiopulmonary exercise testing with stress 2DE. Resting LVEF was lower in patients than controls by 3DE (55 ± 4 vs. 59 ± 5 %; p = 0.005) but not 2DE (56 ± 4 vs. 58 ± 3 %; p = 0.169). 10 of 51 (20 %) patients had GLS greater than or equal to −17 %, which was below the calculated lower limit of normal (control mean 2SD); this patient subgroup had a mean 20 % impairment in GLS (−16.1 ± 0.9 vs. −20.1 ± 1.5 %; p < 0.001), despite similar LVEF by 2DE and 3DE compared to controls (p > 0.05). Cardiopulmonary function (VO2peak) was 20 % lower in patients than controls (p < 0.001). Exercise stress 2DE assessments of stroke volume (61 ± 11 vs. 69 ± 15 ml; p = 0.018) and cardiac index (2.3 ± 0.9 vs. 3.1 ± 0.8 1 min−1 m−2 mean increase; p = 0.003) were lower in patients than controls. Post-exercise increase in cardiac index predicted VO2peak (r = 0.429, p = 0

  8. Epicardial delivery of VEGF and cardiac stem cells guided by 3-dimensional PLLA mat enhancing cardiac regeneration and angiogenesis in acute myocardial infarction.

    PubMed

    Chung, Hye-Jin; Kim, Jong-Tae; Kim, Hee-Jung; Kyung, Hei-Won; Katila, Pramila; Lee, Jeong-Han; Yang, Tae-Hyun; Yang, Young-Il; Lee, Seung-Jin

    2015-05-10

    Congestive heart failure is mostly resulted in a consequence of the limited myocardial regeneration capacity after acute myocardial infarction. Targeted delivery of proangiogenic factors and/or stem cells to the ischemic myocardium is a promising strategy for enhancing their local and sustained therapeutic effects. Herein, we designed an epicardial delivery system of vascular endothelial growth factor (VEGF) and cardiac stem cells (CSCs) using poly(l-lactic acid) (PLLA) mat applied to the acutely infarcted myocardium. The fibrous VEGF-loaded PLLA mat was fabricated by an electrospinning method using PLLA solution emulsified VEGF. This mat not only allowed for sustained release of VEGF for 4weeks but boosted migration and proliferation of both endothelial cells and CSCs in vitro. Furthermore, sustained release of VEGF showed a positive effect on in vitro capillary-like network formation of endothelial cells compared with bolus treatment of VEGF. PLLA mat provided a permissive 3-dimensional (3D) substratum that led to spontaneous cardiomyogenic differentiation of CSCs in vitro. Notably, sustained stimulation by VEGF-loaded PLLA mat resulted in a substantial increase in the expression of proangiogenic mRNAs of CSCs in vitro. The epicardially implanted VEGF-loaded PLLA mat showed modest effects on angiogenesis and cardiomyogenesis in the acutely infarcted hearts. However, co-implantation of VEGF and CSCs using the PLLA mat showed meaningful therapeutic effects on angiogenesis and cardiomyogenesis compared with controls, leading to reduced cardiac remodeling and enhanced global cardiac function. Collectively, the PLLA mat allowed a smart cargo that enabled the sustained release of VEGF and the delivery of CSCs, thereby synergistically inducing angiogenesis and cardiomyogenesis in acute myocardial infarction.

  9. Postoperative blood transfusion is an independent predictor of acute kidney injury in cardiac surgery patients

    PubMed Central

    Freeland, Kristofer; Hamidian Jahromi, Alireza; Duvall, Lucas Maier; Mancini, Mary Catherine

    2015-01-01

    Background: Acute kidney injury (AKI) is a serious complication of cardiac surgery with cardiopulmonary bypass (CPB) which increases postoperative morbidity and mortality. Objectives: The study was designed to assess the incidence of AKI and associated risk factors in patients undergoing CPB ancillary to coronary artery bypass grafting (CABG), valve surgery, and combined CABG and valve surgery. Patients and Methods: This Intuitional Review Board (IRB) approved retrospective study included patients with normal preoperative kidney function (Serum creatinine [sCr] <2.0 mg/dl) who underwent cardiac surgery with CPB between 2012 and 2014. Patients were divided into 2 groups: group I: Patients with cardiac surgery associated AKI (CS-AKI) (postoperative sCr >2 mg/dl with a minimal doubling of baseline sCr) and group II: Patients with a normal postoperative kidney function. Demographic data, body mass index (BMI), co-morbidities, hematologic/biochemical profiles, preoperative ejection fraction (%EF), blood transfusion history, and operative data were compared between the groups. Mean arterial pressure (MAP) was recorded during the operation and in the postoperative period. Δ-MAP was defined as the difference between pre-CPB-MAP and the CPB-MAP. Results: 241 patients matched the inclusion criteria (CS-AKI incidence = 8.29%). Age, gender, BMI, %EF, and co-morbidities were not predictors of CS-AKI (P > 0.05). High preoperative sCr (P = 0.047), type of procedure (P = 0.04), clamp time (P = 0.003), pump time (P = 0.005) and history of blood transfusion within 14 days postsurgery (P = 0.0004) were associated with risk of CS-AKI. Pre-CPB-MAP, CPB-MAP, Δ-MAP, and ICU-MAP were not significantly different between the 2 groups. Male gender (OR: 5.53; P = 0.048), age>60 (OR: 4.54; P = 0.027) and blood transfusion after surgery (OR: 5.25; P = 0.0054) were independent predictors for postoperative AKI. Conclusions: Age, gender and blood transfusion were independent predictors of

  10. Exercise prevents Western diet-associated erectile dysfunction and coronary artery endothelial dysfunction: response to acute apocynin and sepiapterin treatment.

    PubMed

    La Favor, Justin D; Anderson, Ethan J; Dawkins, Jillian T; Hickner, Robert C; Wingard, Christopher J

    2013-08-15

    The aim of this study was to investigate aerobic exercise training as a means to prevent erectile dysfunction (ED) and coronary artery disease (CAD) development associated with inactivity and diet-induced obesity. Male Sprague-Dawley rats were fed a Western diet (WD) or a control diet (CD) for 12 wk. Subgroups within each diet remained sedentary (Sed) or participated in aerobic interval treadmill running throughout the dietary intervention. Erectile function was evaluated under anesthesia by measuring the mean arterial pressure and intracavernosal pressure in response to electrical field stimulation of the cavernosal nerve, in the absence or presence of either apocynin, an NADPH oxidase inhibitor, or sepiapterin, a tetrahydrobiopterin precursor. Coronary artery endothelial function (CAEF) was evaluated ex vivo with cumulative doses of ACh applied to preconstricted segments of the left anterior descending coronary artery. CAEF was assessed in the absence or presence of apocynin or sepiapterin. Erectile function (P < 0.0001) and CAEF (P < 0.001) were attenuated in WD-Sed. Exercise preserved erectile function (P < 0.0001) and CAEF (P < 0.05) within the WD. Erectile function (P < 0.01) and CAEF (P < 0.05) were augmented by apocynin only in WD-Sed, while sepiapterin (P < 0.05) only augmented erectile function in WD-Sed. These data demonstrate that a chronic WD induces impairment in erectile function and CAEF that are commonly partially reversible by apocynin, whereas sepiapterin treatment exerted differential functional effects between the two vascular beds. Furthermore, exercise training may be a practical means of preventing diet-induced ED and CAD development.

  11. Role of cardiac volume receptors in the control of ADH release during acute simulated weightlessness in man

    NASA Technical Reports Server (NTRS)

    Convertino, V. A.; Benjamin, B. A.; Keil, L. C.; Sandler, H.

    1984-01-01

    Hemodynamic responses and antidiuretic hormone (ADH) were measured during body position changes, designed to induce central blood volume shifts in ten cardiac and one heart-lung transplant recipients, to assess the contribution of cardiac volume receptors in the control of ADH release during the initial acute phase of exposure to weightlessness. Each subject underwent 15 min of a sitting-control period (C) followed by 30 min of 6 deg headdown tilt (T) and 30 min of resumed sitting (S). Venous blood samples and cardiac dimensions were taken at 0 and 15 min of C; 5, 15, and 30 min of T; and 5, 15, and 30 min of S. Blood samples were analyzed for hematocrit, plasma osmolality, plasma renin activity (PRA), and ADH. Heart rate and blood pressure were recorded every two min. Plasma osmolality was not altered by posture changes. Mean left ventricular end-diastolic volume increased (P less than 0.05) from 90 ml in C to 106 ml in T and returned to 87 ml in S. Plasma ADH was reduced by 20 percent (P less than 0.05) with T, and returned to control levels with S. These responses were similar in six normal cardiac-innervated control subjects. These data may suggest that cardiac volume receptors are not the primary mechanism for the control of ADH release during acute central volume shifts in man.

  12. Diagnostic and Prognostic Properties of Osteoprotegerin in Patients with Acute Dyspnoea: Observations from the Akershus Cardiac Examination (ACE) 2 Study

    PubMed Central

    Pervez, Mohammed Osman; Pedersen, Marit Holmefjord; Brynildsen, Jon; Høiseth, Arne Didrik; Hagve, Tor-Arne; Røsjø, Helge; Omland, Torbjørn

    2016-01-01

    Background Circulating osteoprotegerin (OPG) levels are increased in patients with chronic heart failure (HF). The diagnostic and prognostic merit of OPG measurement in patients admitted with acute dyspnoea is unknown. Objectives To evaluate the diagnostic and prognostic value of measuring OPG in patients admitted to hospital with acute dyspnoea. Methods OPG was analysed by ELISA in 308 patients admitted due to acute dyspnoea. Investigators blinded to OPG results adjudicated the diagnosis for the index hospitalization. Clinical outcomes were obtained from hospital records. Results In total, 139 patients (45%) were hospitalized with acute HF. OPG levels on hospital admission were higher in patients with acute HF vs. no acute HF, 7.8 (5.5–10.4) vs. 5.4 (3.8–7.2) pmol/L, p<0.001. The area under the receiver operator characteristic curve (ROC AUC) of OPG to discriminate between HF vs. non-HF was 0.695 [95% CI 0.636–0.754]. OPG did not provide incremental information to the ED physician’s prediction or N-terminal pro-B-type natriuretic peptide regarding the diagnosis of acute HF. OPG levels (log transformed) were associated with mortality in crude analysis (HR (95% CI) 1.87 (1.34 to 2.61), p<0.001), but this association was attenuated and no longer significant after including established cardiac biomarkers into the model. Conclusion In patients admitted to hospital with acute dyspnoea, OPG levels are higher in patients with acute HF than in those with dyspnoea from other causes. However, OPG does not provide incremental information beyond ED physician assessment for the diagnosis of acute HF or beyond clinical risk variables and established cardiac biomarkers concerning prognosis. PMID:27463973

  13. Cardiac oxygen limitation during an acute thermal challenge in the European perch: effects of chronic environmental warming and experimental hyperoxia.

    PubMed

    Ekström, Andreas; Brijs, Jeroen; Clark, Timothy D; Gräns, Albin; Jutfelt, Fredrik; Sandblom, Erik

    2016-08-01

    Oxygen supply to the heart has been hypothesized to limit cardiac performance and whole animal acute thermal tolerance (CTmax) in fish. We tested these hypotheses by continuously measuring venous oxygen tension (Pvo2) and cardiovascular variables in vivo during acute warming in European perch (Perca fluviatilis) from a reference area during summer (18°C) and a chronically heated area (Biotest enclosure) that receives warm effluent water from a nuclear power plant and is normally 5-10°C above ambient (24°C at the time of experiments). While CTmax was 2.2°C higher in Biotest compared with reference perch, the peaks in cardiac output and heart rate prior to CTmax occurred at statistically similar Pvo2 values (2.3-4.0 kPa), suggesting that cardiac failure occurred at a common critical Pvo2 threshold. Environmental hyperoxia (200% air saturation) increased Pvo2 across temperatures in reference fish, but heart rate still declined at a similar temperature. CTmax of reference fish increased slightly (by 0.9°C) in hyperoxia, but remained significantly lower than in Biotest fish despite an improved cardiac output due to an elevated stroke volume. Thus, while cardiac oxygen supply appears critical to elevate stroke volume at high temperatures, oxygen limitation may not explain the bradycardia and arrhythmia that occur prior to CTmax Acute thermal tolerance and its thermal plasticity can, therefore, only be partially attributed to cardiac failure from myocardial oxygen limitations, and likely involves limiting factors on multiple organizational levels. PMID:27280433

  14. Acute Auditory Stimulation with Different Styles of Music Influences Cardiac Autonomic Regulation in Men

    PubMed Central

    da Silva, Sheila Ap. F.; Guida, Heraldo L.; dos Santos Antonio, Ana Marcia; de Abreu, Luiz Carlos; Monteiro, Carlos B. M.; Ferreira, Celso; Ribeiro, Vivian F.; Barnabe, Viviani; Silva, Sidney B.; Fonseca, Fernando L. A.; Adami, Fernando; Petenusso, Marcio; Raimundo, Rodrigo D.; Valenti, Vitor E.

    2014-01-01

    Background: No clear evidence is available in the literature regarding the acute effect of different styles of music on cardiac autonomic control. Objectives: The present study aimed to evaluate the acute effects of classical baroque and heavy metal musical auditory stimulation on Heart Rate Variability (HRV) in healthy men. Patients and Methods: In this study, HRV was analyzed regarding time (SDNN, RMSSD, NN50, and pNN50) and frequency domain (LF, HF, and LF / HF) in 12 healthy men. HRV was recorded at seated rest for 10 minutes. Subsequently, the participants were exposed to classical baroque or heavy metal music for five minutes through an earphone at seated rest. After exposure to the first song, they remained at rest for five minutes and they were again exposed to classical baroque or heavy metal music. The music sequence was random for each individual. Standard statistical methods were used for calculation of means and standard deviations. Besides, ANOVA and Friedman test were used for parametric and non-parametric distributions, respectively. Results: While listening to heavy metal music, SDNN was reduced compared to the baseline (P = 0.023). In addition, the LF index (ms2 and nu) was reduced during exposure to both heavy metal and classical baroque musical auditory stimulation compared to the control condition (P = 0.010 and P = 0.048, respectively). However, the HF index (ms2) was reduced only during auditory stimulation with music heavy metal (P = 0.01). The LF/HF ratio on the other hand decreased during auditory stimulation with classical baroque music (P = 0.019). Conclusions: Acute auditory stimulation with the selected heavy metal musical auditory stimulation decreased the sympathetic and parasympathetic modulation on the heart, while exposure to a selected classical baroque music reduced sympathetic regulation on the heart. PMID:25177673

  15. Proteotoxicity and Cardiac Dysfunction

    PubMed Central

    McLendon, Patrick M.; Robbins, Jeffrey

    2015-01-01

    Baseline physiological function of the mammalian heart is under the constant threat of environmental or intrinsic pathological insults. Cardiomyocyte proteins are thus subject to unremitting pressure to function optimally and this depends upon them assuming and maintaining proper conformation. This review explores the multiple defenses a cell may employ for its proteins to assume and maintain correct protein folding and conformation. There are multiple quality control mechanisms to ensure that nascent polypeptides are properly folded and mature proteins maintain their functional conformation. When proteins do misfold, either in the face of normal or pathologic stimuli or because of intrinsic mutations or post-translational modifications, they must either be refolded correctly or recycled. In the absence of these corrective processes, they may become toxic to the cell. Herein, we explore some of the underlying mechanisms that lead to proteotoxicity. The continued presence and chronic accumulation of misfolded or unfolded proteins can be disastrous in cardiomyocytes as these misfolded proteins can lead to aggregation or the formation of soluble peptides that are proteotoxic. This in turn leads to compromised protein quality control and precipitating a downward spiral of the cell's ability to maintain protein homeostasis. Some underlying mechanisms are discussed and the therapeutic potential of interfering with proteotoxicity in the heart is explored. PMID:25999425

  16. Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein

    PubMed Central

    Wang, Lei; Zhang, Tian-Peng; Zhang, Yuan; Bi, Hai-Lian; Guan, Xu-Min; Wang, Hong-Xia; Wang, Xia; Du, Jie; Xia, Yun-Long; Li, Hui-Hua

    2016-01-01

    Carboxyl terminus of Hsp70-interacting protein (CHIP) is a critical ubiquitin ligase/cochaperone to reduce cardiac oxidative stress, inflammation, cardiomyocyte apoptosis and autophage etc. However, it is unclear whether overexpression of CHIP in the heart would exert protective effects against DOX-induced cardiomyopathy. Cardiac-specific CHIP transgenic (CHIP-TG) mice and the wild-type (WT) littermates were treated with DOX or saline. DOX-induced cardiac atrophy, dysfunction, inflammation, oxidative stress and cardiomyocyte apoptosis were significantly attenuated in CHIP-TG mice. CHIP-TG mice also showed higher survival rate than that of WT mice (40% versus 10%) after 10-day administration of DOX. In contrast, knockdown of CHIP by siRNA in vitro further enhanced DOX-induced cardiotoxic effects. Global gene microarray assay revealed that after DOX-treatment, differentially expressed genes between WT and CHIP-TG mice were mainly involved in apoptosis, atrophy, immune/inflammation and oxidative stress. Mechanistically, CHIP directly promotes ubiquitin-mediated degradation of p53 and SHP-1, which results in activation of ERK1/2 and STAT3 pathways thereby ameliorating DOX-induced cardiac toxicity. PMID:27323684

  17. [Assessment and evaluation of cardiac function].

    PubMed

    Yazaki, Y

    1993-05-01

    Assessment and evaluation of cardiac function have become commonplace in the care of cardiac patients with acute or chronic disorders, since therapy of most cardiac diseases is designed specifically to improve ventricular function. Now, various techniques are available for quantitative measurements of the size, shape and motion of the ventricle. Ventricular dysfunction is defined with two components, systolic and diastolic dysfunction, and can be described hemodynamically in terms of the ventricular pressure-volume diagram. Pure systolic dysfunction is associated with a depression in the end-systolic pressure-volume relation, using the Frank-Starling relation to restore cardiac output toward normal. In contrast, pure diastolic dysfunction is associated with preservation of the end-systolic pressure-volume relation but distortion of the diastolic relation, showing higher diastolic pressure at any given volume. However, in patients presenting clinically with heart failure, both systolic and diastolic dysfunction are usually observed. In this context, factors and disorders that influence ventricular dysfunction are described, considering extrinsic or intrinsic to the ventricular chambers.

  18. Mechanism of programmed cell death factor 4/nuclear factor-κB signaling pathway in porcine coronary micro-embolization-induced cardiac dysfunction

    PubMed Central

    Su, Qiang; Wang, Jiangyou; Zhou, You; Liu, Yangchun

    2015-01-01

    The aim of this study was to investigate the role of the programmed cell death factor 4 (PDCD4)/nuclear factor-κB (NF-κB) signaling pathway in coronary micro-embolism (CME)-induced inflammatory responses and cardiac dysfunction in a porcine model. Bama miniature pigs were randomly divided into four groups (n = 5 per group). Micro-embolization balls or saline were infused through a microcatheter in the left anterior descending (LAD) artery in the CME and Sham groups, respectively. PDCD4 siRNA or control siRNA mixed with transfection reagent was infused via the LAD artery 72 h before CME induction in the CME + siRNA-PDCD4 and siRNA-control groups, respectively. Cardiac function was evaluated with ultrasound. Tissue biopsy was stained with hematoxylin–eosin (HE) and hematoxylin basic fuchsin picric acid (HBFP) to measure infarction area. Myocardial PDCD4 and tumor necrosis factor-α (TNF-α) mRNA and protein expression were analyzed by quantitative PCR and Western blotting. NF-κB activity was evaluated in gel electrophoretic mobility shift assay. Echocardiographic parameters showed that compared with the sham group, the CME group had impaired heart function, manifested as systolic dysfunction and left ventricular dilatation (reduced left ventricular ejection fraction [LVEF], left ventricular fractional shortening [FS], and cardiac output [CO] [P < 0.05] and increased left ventricular end-diastolic diameter [LVEDd] [P < 0.05]). Compared with the CME group, the CME + siRNA-PDCD4 group had attenuated CME-induced cardiac function damage (increased LVEF, FS and CO [P < 0.05] and reduced LVEDd [P < 0.05]). Compared with the sham group, the CME group had significantly increased PDCD4 and TNF-α mRNA and protein expression and increased NF-κB activity (P < 0.05). These effects were significantly inhibited in the CME + siRNA-PDCD4 group (P < 0.05). In conclusion, PDCD4/NF-κB signaling pathway activation is an important mechanism for CME

  19. Diesel Exhaust-Induced Cardiac Dysfunction Is Mediated by Sympathetic Dominance in Heart Failure-Prone Rats

    EPA Science Inventory

    Short-term exposure to vehicular emissions is associated with adverse cardiac events. Diesel exhaust (DE) may provoke cardiac events through defective co-ordination of the two main autonomic nervous system (ANS) branches. We exposed heart failure-prone rats once to DE (500 g/m3 ...

  20. Berberine ameliorates severe acute pancreatitis‑induced intestinal barrier dysfunction via a myosin light chain phosphorylation‑dependent pathway.

    PubMed

    Liang, Hong-Yin; Chen, Tao; Yan, Hong-Tao; Huang, Zhu; Tang, Li-Jun

    2014-05-01

    Berberine is a traditional drug used to treat gastrointestinal disorders in China and has been demonstrated to attenuate intestinal barrier dysfunction in certain animal models. However, the effects of berberine on pancreatitis-induced intestinal barrier dysfunction are yet to be fully elucidated. This study aimed to investigate the effect of berberine pretreatment on the attenuation of intestinal barrier dysfunction induced by severe acute pancreatitis (SAP). A total of 36 rats were randomly divided into Sham, SAP and SAP plus berberine groups. Pancreatitis was induced using retrograde injection of 3% Na-taurocholate into the pancreatic duct. Histological examinations of the pancreas were performed and intestinal barrier dysfunction was characterized by histological measurements and the assessment of serum diamine oxidase activity and endotoxin levels. Zonula occludens-1 and occludin mRNA and protein expression, as well as myosin light chain (MLC) phosphorylation, were assessed. SAP rat models were successfully established. Berberine treatment was found to have no significant effect on the histological changes in the pancreas, but was observed to ameliorate the intestinal mucosal barrier damage and membrane permeability associated with SAP. Although berberine exerted minimal effects on tight junction proteins in the ilea of SAP rats, it was observed to significantly inhibit SAP-induced MLC phosphorylation. To the best of our knowledge, this is the first study to demonstrate that berberine attenuates SAP‑induced intestinal barrier dysfunction in vivo. In addition, this study shows that the effect of berberine on intestinal barrier function may be associated with the inhibition of SAP‑induced upregulation of MLC phosphorylation.

  1. Cardiac Rhythm Monitoring After Acute Decompensation for Heart Failure: Results from the CARRYING ON for HF Pilot Study

    PubMed Central

    Mortara, Andrea; Diotallevi, Paolo; Gallone, Giuseppe; Mariconti, Barbara; Gronda, Edoardo; Gentili, Alessandra; Bisetti, Silvia; Botto, Giovanni Luca

    2016-01-01

    Background There’s scarce evidence about cardiovascular events (CV) in patients with hospitalization for acute heart failure (HF) and no indication for immediate device implant. Objective The CARdiac RhYthm monitorING after acute decompensatiON for Heart Failure study was designed to assess the incidence of prespecified clinical and arrhythmic events in this patient population. Methods In this pilot study, 18 patients (12 (67%) male; age 72±10; 16 (89%) NYHA II-III), who were hospitalized for HF with low left ventricular ejection fraction (LVEF) (<40%) and no immediate indication for device implant received an implantable loop recorder (ILR) before hospital discharge. Follow-up visits were scheduled at 3 and 6 months, and at every 6 months until study closure; device data were remotely reviewed monthly. CV mortality, unplanned CV hospitalization, and major arrhythmic events during follow-up were analyzed. Results During a median follow-up of 593 days, major CV occurred in 13 patients (72%); of those, 7 patients had at least 1 cardiac arrhythmic event, 2 had at least a clinical event (CV hospitalization or CV death), and 4 had both an arrhythmic and a CV event. Six (33%) patients experienced 10 major clinical events, 5 of them (50%) were HF related. During follow-up, 2 (11%) patients died due to a CV cause and 3 (16%) patients received a permanent cardiac device. Conclusions After an acute HF hospitalization, patients with LVEF<40% and who are not readily eligible for permanent cardiac device implant have a known high incidence of major CV event. In these patients, ILR allows early detection of major cardiac arrhythmias and the ability to react appropriately in a timely manner. Trial Registration ClinicalTrials.gov NCT01216670; https://clinicaltrials.gov/ct2/show/NCT01216670 PMID:27118481

  2. Peri-operative heart-type fatty acid binding protein is associated with acute kidney injury after cardiac surgery

    PubMed Central

    Schaub, Jennifer A.; Garg, Amit X.; Coca, Steven G.; Testani, Jeffrey M.; Shlipak, Michael G.; Eikelboom, John; Kavsak, Peter; McArthur, Eric; Shortt, Colleen; Whitlock, Richard; Parikh, Chirag R.

    2015-01-01

    Acute Kidney Injury (AKI) is a common complication after cardiac surgery and is associated with worse outcomes. Since heart fatty acid binding protein (H-FABP) is a myocardial protein that detects cardiac injury, we sought to determine if plasma H-FABP was associated with AKI in the TRIBE-AKI cohort; a multi-center cohort of 1219 patients at high risk for AKI who underwent cardiac surgery. The primary outcomes of interest were any AKI (Acute Kidney Injury Network (AKIN) stage 1 or higher) and severe AKI (AKIN stage 2 or higher). The secondary outcome was long-term mortality after discharge. Patients who developed AKI had higher levels of H-FABP pre- and post-operatively than patients who did not have AKI. In analyses adjusted for known AKI risk factors, first post-operative log(H-FABP) was associated with severe AKI (adjusted OR 5.39 [95% CI, 2.87-10.11] per unit increase), while pre-operative log(H-FABP) was associated with any AKI (2.07 [1.48-2.89]) and mortality (1.67 [1.17-2.37]). These relationships persisted after adjustment for change in serum creatinine (for first postoperative log(H-FABP)) and biomarkers of cardiac and kidney injury, including brain natriuretic peptide, cardiac troponin-I, interleukin-18, liver fatty acid binding protein, kidney injury molecule-1, and neutrophil gelatinase associated lipocalin. Thus, peri-operative plasma H-FABP levels may be used for risk-stratification of AKI and mortality following cardiac surgery. PMID:25830762

  3. SYSTEMIC IMBALANCE OF ESSENTIAL METALS AND CARDIAC GENE EXPRESSION IN RATS FOLLOWING ACUTE PULMONARY ZINC EXPOSURE

    EPA Science Inventory

    We have recently demonstrated that PM containing water-soluble zinc may cause cardiac injury following pulmonary exposure. To investigate if pulmonary zinc exposure causes systemic metal imbalance and direct cardiac effects, we intratracheally (IT) instilled male Wistar Kyoto (WK...

  4. Acute nicotine treatment attenuates lipopolysaccharide-induced cognitive dysfunction by increasing BDNF expression and inhibiting neuroinflammation in the rat hippocampus.

    PubMed

    Wei, Penghui; Liu, Qingshen; Li, Dong; Zheng, Qiang; Zhou, Jinfeng; Li, Jianjun

    2015-09-14

    Although nicotine has been shown to improve cognitive function in various studies, the mechanisms underlying acute nicotine treatment-induced neuroprotection remain incompletely understood. In this study, we evaluated the effect of acute nicotine treatment on the cognitive impairment induced by lipopolysaccharide (LPS) and explored the underlying mechanism. We found that acute nicotine injection markedly attenuated LPS-elicited cognitive deficits and suppressed the strong LPS-induced release of IL-1β, IL-6, and TNF-α into serum and the dorsal hippocampus at 4 and 24h after LPS injection. Western blot analysis indicated a clear increase in the levels of cleaved caspase-3 in LPS-treated animals but not in nicotine- or saline-treated animals. Furthermore, nicotine administration led to a significant increase in BDNF mRNA expression at 4 and 24h and in BDNF protein expression at 24h after LPS injection in the dorsal hippocampus. Taken together, acute nicotine administration attenuated LPS-induced cognitive dysfunction, and this neuroprotective effect may be related to the up-regulation of BDNF and the inhibition of neuroinflammation and apoptosis-related proteins in the dorsal hippocampus. PMID:26259694

  5. Acute nicotine treatment attenuates lipopolysaccharide-induced cognitive dysfunction by increasing BDNF expression and inhibiting neuroinflammation in the rat hippocampus.

    PubMed

    Wei, Penghui; Liu, Qingshen; Li, Dong; Zheng, Qiang; Zhou, Jinfeng; Li, Jianjun

    2015-09-14

    Although nicotine has been shown to improve cognitive function in various studies, the mechanisms underlying acute nicotine treatment-induced neuroprotection remain incompletely understood. In this study, we evaluated the effect of acute nicotine treatment on the cognitive impairment induced by lipopolysaccharide (LPS) and explored the underlying mechanism. We found that acute nicotine injection markedly attenuated LPS-elicited cognitive deficits and suppressed the strong LPS-induced release of IL-1β, IL-6, and TNF-α into serum and the dorsal hippocampus at 4 and 24h after LPS injection. Western blot analysis indicated a clear increase in the levels of cleaved caspase-3 in LPS-treated animals but not in nicotine- or saline-treated animals. Furthermore, nicotine administration led to a significant increase in BDNF mRNA expression at 4 and 24h and in BDNF protein expression at 24h after LPS injection in the dorsal hippocampus. Taken together, acute nicotine administration attenuated LPS-induced cognitive dysfunction, and this neuroprotective effect may be related to the up-regulation of BDNF and the inhibition of neuroinflammation and apoptosis-related proteins in the dorsal hippocampus.

  6. Heparin-binding epidermal growth factor–like growth factor attenuates acute lung injury and multiorgan dysfunction after scald burn

    PubMed Central

    Lutmer, Jeffrey; Watkins, Daniel; Chen, Chun-Liang; Velten, Markus; Besner, Gail

    2013-01-01

    Background Impaired gut barrier function and acute lung injury (ALI) are significant components of the multiorgan dysfunction syndrome that accompanies severe burns. Heparin-binding epidermal growth factor–like growth factor (HB-EGF) has been shown to reduce inflammation, preserve gut barrier function, and protect the lungs from acute injury in several models of intestinal injury; however, comparable effects of HB-EGF after burn injury have never been investigated. The present studies were based on the hypothesis that HB-EGF would reduce the severity of ALI and multiorgan dysfunction after scald burns in mice. Materials and methods Mice were randomized to sham, burn (25% of total body surface area with full thickness dorsal scald), and burn + HB-EGF groups. The HB-EGF group was pre-treated with two enteral doses of HB-EGF (1200 μg/kg/dose). Mice were resuscitated after injury and sacrificed at 8 h later. Their lungs were harvested for determination of pulmonary myeloperoxidase activity, wet:dry ratios, and terminal deoxynucleotidyl transferase dUTP nick end label and cleaved caspase 3 immunohistochemistry. Lung function was assessed using the SCIREQ Flexivent. Splenic apoptosis was quantified by Western blot for cleaved caspase 3, and intestinal permeability was measured using the everted gut sac method. Results Mice subjected to scald burn injury had increased lung myeloperoxidase levels, increased pulmonary and splenic apoptosis, elevated airway resistance and bronchial reactivity, and increased intestinal permeability compared with sham mice. These abnormalities were significantly attenuated in mice that were subjected to scald burn injury but treated with enteral HB-EGF. Conclusions These data suggest that HB-EGF protects mice from ALI after scald burn and attenuates the severity of postburn multiorgan dysfunction. PMID:23777985

  7. Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction

    PubMed Central

    Lecarpentier, Yves; Claes, Victor; Duthoit, Guillaume; Hébert, Jean-Louis

    2014-01-01

    Circadian clock mechanisms are far-from-equilibrium dissipative structures. Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta, and gamma) play a key role in metabolic regulatory processes, particularly in heart muscle. Links between circadian rhythms (CRs) and PPARs have been established. Mammalian CRs involve at least two critical transcription factors, CLOCK and BMAL1 (Gekakis et al., 1998; Hogenesch et al., 1998). PPAR gamma plays a major role in both glucose and lipid metabolisms and presents circadian properties which coordinate the interplay between metabolism and CRs. PPAR gamma is a major component of the vascular clock. Vascular PPAR gamma is a peripheral regulator of cardiovascular rhythms controlling circadian variations in blood pressure and heart rate through BMAL1. We focused our review on diseases with abnormalities of CRs and with primary or secondary cardiac dysfunction. Moreover, these diseases presented changes in the Wnt/beta-catenin pathway and PPARs, according to two opposed profiles. Profile 1 was defined as follows: inactivation of the Wnt/beta-catenin pathway with increased expression of PPAR gamma. Profile 2 was defined as follows: activation of the Wnt/beta-catenin pathway with decreased expression of PPAR gamma. A typical profile 1 disease is arrhythmogenic right ventricular cardiomyopathy, a genetic cardiac disease which presents mutations of the desmosomal proteins and is mainly characterized by fatty acid accumulation in adult cardiomyocytes mainly in the right ventricle. The link between PPAR gamma dysfunction and desmosomal genetic mutations occurs via inactivation of the Wnt/beta-catenin pathway presenting oscillatory properties. A typical profile 2 disease is type 2 diabetes, with activation of the Wnt/beta-catenin pathway and decreased expression of PPAR gamma. CRs abnormalities are present in numerous pathologies such as cardiovascular diseases, sympathetic/parasympathetic dysfunction, hypertension, diabetes

  8. The antioxidant edaravone prevents cardiac dysfunction by suppressing oxidative stress in type 1 diabetic rats and in high-glucose-induced injured H9c2 cardiomyoblasts.

    PubMed

    Ji, Lei; Liu, Yingying; Zhang, Ying; Chang, Wenguang; Gong, Junli; Wei, Shengnan; Li, Xudong; Qin, Ling

    2016-09-01

    Edaravone, a radical scavenger, has been recognized as a potential protective agent for cardiovascular diseases. However, little is known about the effect of edaravone in cardiac complications associated with diabetes. Here, we have demonstrated that edaravone prevents cardiac dysfunction and apoptosis in the streptozotocin-induced type 1 diabetic rat heart. Mechanistic studies revealed that edaravone treatment improved cardiac function and restored superoxide dismutase levels. In addition, treatment of diabetic animals by edaravone increased protein expressions of sirtuin-1 (SIRT-1), peroxisome proliferator activated receptor γ coactivator α (PGC-1α), nuclear factor like-2 (NRF-2), and B cell lymphoma 2 (Bcl-2), and reduced protein expressions of Bax and Caspase-3 compared to the control group. High glucose incubation resulted in the production of reactive oxygen species (ROS) and cell death. Treatment of high-glucose-incubated H9c2 cells by edaravone reduced ROS production and cell death. In addition, the treatment of high-glucose-incubated H9c2 cells by edaravone increased the activity of antioxidative stress by increasing SIRT-1, PGC-1α, and NRF-2, and this treatment also reduced apoptosis by increasing Bcl-2 expression and reducing Bax and Caspase-3 expressions. Knockdown SIRT-1 with small interferer RNA abolished the effects of edaravone. Overall, our data demonstrated that edaravone may be an effective agent against the development of diabetic cardiomyopathy. PMID:27376621

  9. Ambulatory and Challenge-Associated Heart Rate Variability Measures Predict Cardiac Responses to “Real-World” Acute Emotional Stress

    PubMed Central

    Dikecligil, GN; Mujica-Parodi, LR

    2010-01-01

    Background Heart rate variability (HRV) measures homeostatic regulation of the autonomic nervous system in response to perturbation, and has been previously shown to quantify risk for cardiac events. In spite of known interactions between stress vulnerability, psychiatric illness, and cardiac health, however, to our knowledge this is the first study to directly compare the value of laboratory HRV in predicting autonomic modulation of “real-world” emotional stress. Methods We recorded ECG on 56 subjects: first, within the laboratory, and then during an acute emotional stressor: a first-time skydive. Laboratory sessions included two five-minute ECG recordings separated by one ambulatory 24-hour recording. To test the efficacy of introducing a mild emotional challenge, during each of the five-minute laboratory recordings subjects viewed either aversive or benign images. Following the laboratory session, subjects participated in the acute stressor wearing a holter ECG. Artifact-free ECGs (N=33) were analyzed for HRV, then statistically compared across laboratory and acute stress sessions. Results There were robust correlations (r=0.7-0.8) between the laboratory and acute stress HRV, indicating that the two most useful paradigms (long-term wake, followed by short-term challenge) also were most sensitive to distinct components of the acute stressor: the former correlated with the fine-tuned regulatory modulation occurring immediately prior and following the acute stressor, while the latter correlated with gross amplitude and recovery. Conclusions Our results confirmed the efficacy of laboratory-acquired HRV in predicting autonomic response to acute emotional stress, and suggest that ambulatory and challenge protocols enhance predictive value. PMID:20299007

  10. Time-dependent changes in the expression of thyroid hormone receptor alpha 1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling.

    PubMed

    Pantos, Constantinos; Mourouzis, Iordanis; Xinaris, Christodoulos; Kokkinos, Alexandros D; Markakis, Konstantinos; Dimopoulos, Antonios; Panagiotou, Matthew; Saranteas, Theodosios; Kostopanagiotou, Georgia; Cokkinos, Dennis V

    2007-04-01

    The present study investigated whether changes in thyroid hormone (TH) signalling can occur after acute myocardial infarction (AMI) with possible physiological consequences on myocardial performance. TH may regulate several genes encoding important structural and regulatory proteins particularly through the TR alpha 1 receptor which is predominant in the myocardium. AMI was induced in rats by ligating the left coronary artery while sham-operated animals served as controls. This resulted in impaired cardiac function in AMI animals after 2 and 13 weeks accompanied by a shift in myosin isoforms expression towards a fetal phenotype in the non-infarcted area. Cardiac hypertrophy was evident in AMI hearts after 13 weeks but not at 2 weeks. This response was associated with a differential pattern of TH changes at 2 and 13 weeks; T(3) and T(4) levels in plasma were not changed at 2 weeks but T(3) was significantly lower and T(4) remained unchanged at 13 weeks. A twofold increase in TR alpha 1 expression was observed after 13 weeks in the non-infarcted area, P<0.05 versus sham operated, while TR alpha 1 expression remained unchanged at 2 weeks. A 2.2-fold decrease in TR beta 1 expression was found in the non-infarcted area at 13 weeks, P<0.05, while no change in TR beta 1 expression was seen at 2 weeks. Parallel studies with neonatal cardiomyocytes showed that phenylephrine (PE) administration resulted in 4.5-fold increase in the expression of TR alpha 1 and 1.6-fold decrease in TR beta 1 expression versus untreated, P<0.05. In conclusion, cardiac dysfunction which occurs at late stages after AMI is associated with increased expression of TR alpha 1 receptor and lower circulating tri-iodothyronine levels. Thus, apo-TR alpha 1 receptor state may prevail contributing to cardiac fetal phenotype. Furthermore, down-regulation of TR beta 1 also contributes to fetal phenotypic changes. alpha1-adrenergic signalling is, at least in part, involved in this response.

  11. Erectile dysfunction.

    PubMed

    Shamloul, Rany; Ghanem, Hussein

    2013-01-12

    Erectile dysfunction is a common clinical entity that affects mainly men older than 40 years. In addition to the classical causes of erectile dysfunction, such as diabetes mellitus and hypertension, several common lifestyle factors, such as obesity, limited or an absence of physical exercise, and lower urinary tract symptoms, have been linked to the development of erectile dysfunction. Substantial steps have been taken in the study of the association between erectile dysfunction and cardiovascular disease. Erectile dysfunction is a strong predictor for coronary artery disease, and cardiovascular assessment of a non-cardiac patient presenting with erectile dysfunction is now recommended. Substantial advances have occurred in the understanding of the pathophysiology of erectile dysfunction that ultimately led to the development of successful oral therapies, namely the phosphodiesterase type 5 inhibitors. However, oral phosphodiesterase type 5 inhibitors have limitations, and present research is thus investigating cutting-edge therapeutic strategies including gene and cell-based technologies with the aim of discovering a cure for erectile dysfunction.

  12. Role of endothelin in microvascular dysfunction following percutaneous coronary intervention for non-ST elevation acute coronary syndromes: a single-centre randomised controlled trial

    PubMed Central

    Guddeti, Raviteja R; Prasad, Abhiram; Matsuzawa, Yasushi; Aoki, Tatsuo; Rihal, Charanjit; Holmes, David; Best, Patricia; Lennon, Ryan J; Lerman, Lilach O; Lerman, Amir

    2016-01-01

    Objectives Percutaneous coronary intervention (PCI) for acute coronary syndromes frequently fails to restore myocardial perfusion despite establishing epicardial vessel patency. Endothelin-1 (ET-1) is a potent vasoconstrictor, and its expression is increased in atherosclerosis and after PCI. In this study, we aim to define the role of endothelin in regulating coronary microvascular blood flow and myocardial perfusion following PCI in patients with non-ST elevation acute coronary syndromes (NSTACS), by assessing whether adjunctive therapy with a selective endothelin A (ETA) receptor antagonist acutely improves postprocedural coronary microvascular blood flow. Methods In a randomised, double-blinded, placebo-controlled trial, 23 NSTACS patients were enrolled to receive an intracoronary infusion of placebo (n=11) or BQ-123 (n=12) immediately before PCI. Post-PCI coronary microvascular blood flow and myocardial perfusion were assessed by measuring Doppler-derived average peak velocity (APV), and cardiac biomarker levels were quantified. Results Compared with the placebo group, APV was significantly higher in the drug group immediately after PCI (30 (20, 37) vs 19 (9, 26) cm/s; p=0.03). Hyperaemic APV, measured post-adenosine administration, was higher in the BQ-123 group, but the difference did not achieve statistical significance (56 (48, 72) vs 46 (34, 64) cm/s; p=0.090). Maximum coronary flow reserve postprocedure was not different between the two groups (2.1 (1.6, 2.3) vs 2.5 (1.8, 3.0)). Per cent change in creatine kinase isoenzyme MB from the time of PCI to 8 and 16 hours post-PCI was significantly lower in the drug group compared with the placebo group (−17 (−26, −10) vs 26 (−15, 134); p=0.02 and −17 (−38, 14) vs 107 (2, 446); p=0.007, respectively). Conclusions Endothelin is a mediator of microvascular dysfunction during PCI in NSTACS, and adjunctive selective ETA antagonist may augment myocardial perfusion during PCI. Trial registration number

  13. Referrals in Acute Coronary Events for CARdiac Catheterization: The RACE CAR trial

    PubMed Central

    Kreatsoulas, Catherine; Sloane, Debi; Pogue, Janice; Velianou, James L; Anand, Sonia S

    2010-01-01

    BACKGROUND: Women with acute coronary syndromes have lower rates of cardiac catheterization (CC) than men. OBJECTIVE: To determine whether sex/gender, age, risk level and patient preference influence physician decision making to refer patients for CC. METHODS: Twelve clinical scenarios controlling for sex/gender, age (55 or 75 years of age), Thrombolysis in Myocardial Infarction risk score (low, moderate or high) and patient preference for CC (agreeable or refused/no preference expressed) were designed. Scenarios were administered to specialists across Canada using a web-based computerized survey instrument. Questions were standardized using a five-point Likert scale ranging from 1 (very unlikely to benefit from CC) to 5 (very likely to benefit from CC). Outcomes were assessed using a two-tailed mixed linear regression model. RESULTS: Of 237 scenarios, physicians rated men as more likely to benefit from CC than women (mean [± SE] 4.44±0.07 versus 4.25±0.07, P=0.03), adjusted for age, risk and patient preference. Low-risk men were perceived to benefit more than low-risk women (4.20±0.13 versus 3.54±0.14, P<0.01), and low-risk younger patients were perceived to benefit more than low-risk older patients (4.52±0.17 versus 3.22±0.16, P<0.01). Regardless of risk, patients who agreed to CC were perceived as more likely to benefit from CC than patients who were disagreeable or made no comment at all (5.0±0.23, 3.67±0.21, 2.95±0.14, respectively, P<0.01). CONCLUSION: Canadian specialists’ decisions to refer patients for CC appear to be influenced by sex/gender, age and patient preference in clinical scenarios in which cardiac risk is held constant. Future investigation of possible age and sex/gender biases as proxies for risk is warranted. PMID:20931097

  14. Myocardin-related transcription factor-A-overexpressing bone marrow stem cells protect cardiomyocytes and alleviate cardiac damage in a rat model of acute myocardial infarction.

    PubMed

    Zhong, Ze; Hu, Jia-Qing; Wu, Xin-Dong; Sun, Yong; Jiang, Jun

    2015-09-01

    Myocardin-related transcription factor-A (MRTF-A) can transduce biomechanical and humoral signals, which can positively modulate cardiac damage induced by acute myocardial infarction (AMI). In the clinic, bone marrow stem cell (BMSC) therapy is being increasingly utilized for AMI; however, the effects of BMSC transplantation remain to be optimized. Therefore, a novel strategy to enhance BMSC‑directed myocardial repair is particularly important. The present study was performed to assess the efficacy of MRTF‑A-overexpressing BMSCs in a rat model of AMI. Primary cardiomyocytes were prepared from neonatal Sprague-Dawley rats and BMSCs were isolated from male Sprague-Dawley rats (aged 8-12 weeks). Annexin V-phycoerythrin/7-actinomycin D staining was used to evaluate BMSC and cardiomyocyte survival after exposure to hydrogen peroxide in vitro. B-cell lymphoma 2 (Bcl-2) protein expression was measured by flow cytometric and western blot analyses. The effects of MRTF-A‑overexpressing BMSCs in a rat model of AMI were investigated by hematoxylin and eosin staining and western blot analysis of Bcl-2 expression in myocardial tissue sections. MRTF-A enhanced the migration of BMSCs, and overexpression of MRTF-A in BMSCs prevented hydrogen peroxide-induced apoptosis in primary cardiomyocytes ex vivo. In addition, co-culture of cardiomyocytes with MRTF‑A-overexpressing BMSCs inhibited hydrogen peroxide-induced apoptosis and the enhanced expression of Bcl-2. Furthermore, in vivo, enhanced cell survival was observed in the MRTF-A-modified BMSC group compared with that in the control group. These observations indicated that MRTF-A-overexpressing BMSCs have the potential to exert cardioprotective effects against hydrogen peroxide-induced injury and that treatment with MRTF‑A‑modified BMSCs is able to reverse cardiac dysfunction after AMI.

  15. Role of cardiac output and the autonomic nervous system in the antinatriuretic response to acute constriction of the thoracic superior vena cava.

    NASA Technical Reports Server (NTRS)

    Schrier, R. W.; Humphreys, M. H.; Ufferman, R. C.

    1971-01-01

    Study of the differential characteristics of hepatic congestion and decreased cardiac output in terms of potential afferent stimuli in the antinatriuretic effect of acute thoracic inferior vena cava (TIVC) constriction. An attempt is made to see if the autonomic nervous system is involved in the antinatriuretic effect of acute TIVC or thoracic superior vena cava constriction.

  16. Assessment of microembolization associated with revascularization in acute myocardial infarction: MDCT cardiac perfusion and function study.

    PubMed

    Saeed, Maythem; Hetts, Steven W; Do, Loi; Wilson, Mark W

    2013-12-01

    To use multi-detector computed tomography (MDCT) for assessing the effects of coronary microemboli on pre-existing acute myocardial infarct (AMI) and to compare this pathology to LAD microembolization and occlusion/reperfusion. An angioplasty balloon catheter was placed in the LAD coronary artery of pigs under X-ray guidance. Four animals served as controls without intervention (group A) and an additional 24 animals (8/group) were subjected to microembolization (group B), occlusion/reperfusion (group C) or combination of the two insults (group D). MDCT was used to assess perfusion, LV function and viability. At postmortem, the LV sections were stained with hematoxylin/eosin and triphenyltetrazolium chloride (TTC). Dynamic perfusion and helical cine MDCT demonstrated decline in regional LV perfusion and function, respectively, after all interventions. MDCT showed significant differences in ejection fraction between groups: A = 57.5 ± 4.7%, B = 40.3 ± 0.5% P < 0.05, C = 34.9 ± 1.3% P < 0.05 and D = 30.7 ± 1.2% P < 0.05, while viability MDCT demonstrated differences in enhancement patterns and extents of damage between the groups (B = 9.1 ± 0.4% LV mass, C = 11.9 ± 0.7% and D = 16.2 ± 1.2%, P < 0.05) and extent of microvascular obstruction (MVO) (group C = 3.2 ± 1.0% LV mass versus D = 5.2 ± 0.7%, P < 0.01). DE-MDCT overestimated all types of myocardial damage compared with TTC, but showed a close correlation (r > 0.7). Microscopic examination confirmed the presence of patchy and contiguous necrosis, MVO, edema and calcium deposits. Dynamic and helical cine MDCT imaging can grade LV dysfunction and perfusion deficit, respectively. DE-MDCT demonstrated a large and persistent MVO zone after microembolization of pre-existing AMI. Furthermore, it has the potential to visualize patchy microinfarct, detect perfusion deficits and dysfunction at the border zone after microembolization of pre-existing AMI.

  17. Chagas cardiomyopathy: The potential effect of benznidazole treatment on diastolic dysfunction and cardiac damage in dogs chronically infected with Trypanosoma cruzi.

    PubMed

    Santos, Fabiane M; Mazzeti, Ana L; Caldas, Sérgio; Gonçalves, Karolina R; Lima, Wanderson G; Torres, Rosália M; Bahia, Maria Terezinha

    2016-09-01

    Cardiac involvement represents the main cause of mortality among patients with Chagas disease, and the relevance of trypanocidal treatment to improving diastolic dysfunction is still doubtful. In the present study, we used a canine model infected with the benznidazole-sensitive Berenice-78 Trypanosoma cruzi strain to verify the efficacy of an etiologic treatment in reducing the parasite load and ameliorating cardiac muscle tissue damage and left ventricular diastolic dysfunction in the chronic phase of the infection. The effect of the treatment on reducing the parasite load was monitored by blood PCR and blood culture assays, and the effect of the treatment on the outcome of heart tissue damage and on diastolic function was evaluated by histopathology and echo Doppler cardiogram. The benefit of the benznidazole-treatment in reducing the parasite burden was demonstrated by a marked decrease in positive blood culture and PCR assay results until 30days post-treatment. At this time, the PCR and blood culture assays yielded negative results for 82% of the treated animals, compared with only 36% of the untreated dogs. However, a progressive increase in the parasite load could be detected in the peripheral blood for one year post-treatment, as evidenced by a progressive increase in positive results for both the PCR and the blood culture assays at follow-up. The parasite load reduction induced by treatment was compatible with the lower degree of tissue damage among animals euthanized in the first month after treatment and with the increased cardiac damage after this period, reaching levels similar to those in untreated animals at the one-year follow-up. The two infected groups also presented similar, significantly smaller values for early tissue septal velocity (E' SIV) than the non-infected dogs did at this later time. Moreover, in the treated animals, an increase in the E/E' septal tissue filling pressure ratio was observed when compared with basal values as well as with

  18. Rat Adipose Tissue-Derived Stem Cells Transplantation Attenuates Cardiac Dysfunction Post Infarction and Biopolymers Enhance Cell Retention

    PubMed Central

    Danoviz, Maria E.; Nakamuta, Juliana S.; Marques, Fabio L. N.; dos Santos, Leonardo; Alvarenga, Erica C.; dos Santos, Alexandra A.; Antonio, Ednei L.; Schettert, Isolmar T.; Tucci, Paulo J.; Krieger, Jose E.

    2010-01-01

    Background Cardiac cell transplantation is compromised by low cell retention and poor graft viability. Here, the effects of co-injecting adipose tissue-derived stem cells (ASCs) with biopolymers on cell cardiac retention, ventricular morphometry and performance were evaluated in a rat model of myocardial infarction (MI). Methodology/Principal Findings 99mTc-labeled ASCs (1×106 cells) isolated from isogenic Lewis rats were injected 24 hours post-MI using fibrin a, collagen (ASC/C), or culture medium (ASC/M) as vehicle, and cell body distribution was assessed 24 hours later by γ-emission counting of harvested organs. ASC/F and ASC/C groups retained significantly more cells in the myocardium than ASC/M (13.8±2.0 and 26.8±2.4% vs. 4.8±0.7%, respectively). Then, morphometric and direct cardiac functional parameters were evaluated 4 weeks post-MI cell injection. Left ventricle (LV) perimeter and percentage of interstitial collagen in the spare myocardium were significantly attenuated in all ASC-treated groups compared to the non-treated (NT) and control groups (culture medium, fibrin, or collagen alone). Direct hemodynamic assessment under pharmacological stress showed that stroke volume (SV) and left ventricle end-diastolic pressure were preserved in ASC-treated groups regardless of the vehicle used to deliver ASCs. Stroke work (SW), a global index of cardiac function, improved in ASC/M while it normalized when biopolymers were co-injected with ASCs. A positive correlation was observed between cardiac ASCs retention and preservation of SV and improvement in SW post-MI under hemodynamic stress. Conclusions We provided direct evidence that intramyocardial injection of ASCs mitigates the negative cardiac remodeling and preserves ventricular function post-MI in rats and these beneficial effects can be further enhanced by administrating co-injection of ASCs with biopolymers. PMID:20711471

  19. Acute chlorine gas exposure produces transient inflammation and a progressive alteration in surfactant composition with accompanying mechanical dysfunction

    SciTech Connect

    Massa, Christopher B.; Scott, Pamela; Abramova, Elena; Gardner, Carol; Laskin, Debra L.; Gow, Andrew J.

    2014-07-01

    Acute Cl{sub 2} exposure following industrial accidents or military/terrorist activity causes pulmonary injury and severe acute respiratory distress. Prior studies suggest that antioxidant depletion is important in producing dysfunction, however a pathophysiologic mechanism has not been elucidated. We propose that acute Cl{sub 2} inhalation leads to oxidative modification of lung lining fluid, producing surfactant inactivation, inflammation and mechanical respiratory dysfunction at the organ level. C57BL/6J mice underwent whole-body exposure to an effective 60 ppm-hour Cl{sub 2} dose, and were euthanized 3, 24 and 48 h later. Whereas pulmonary architecture and endothelial barrier function were preserved, transient neutrophilia, peaking at 24 h, was noted. Increased expression of ARG1, CCL2, RETLNA, IL-1b, and PTGS2 genes was observed in bronchoalveolar lavage (BAL) cells with peak change in all genes at 24 h. Cl{sub 2} exposure had no effect on NOS2 mRNA or iNOS protein expression, nor on BAL NO{sub 3}{sup −} or NO{sub 2}{sup −}. Expression of the alternative macrophage activation markers, Relm-α and mannose receptor was increased in alveolar macrophages and pulmonary epithelium. Capillary surfactometry demonstrated impaired surfactant function, and altered BAL phospholipid and surfactant protein content following exposure. Organ level respiratory function was assessed by forced oscillation technique at 5 end expiratory pressures. Cl{sub 2} exposure had no significant effect on either airway or tissue resistance. Pulmonary elastance was elevated with time following exposure and demonstrated PEEP refractory derecruitment at 48 h, despite waning inflammation. These data support a role for surfactant inactivation as a physiologic mechanism underlying respiratory dysfunction following Cl{sub 2} inhalation. - Highlights: • Effect of 60 ppm*hr Cl{sub 2} gas on lung inflammation and mechanical function examined. • Pulmonary inflammation is transient and minor.

  20. Use of intra-aortic balloon pump support for oozing-type cardiac rupture after acute myocardial infarction.

    PubMed

    Zhang, Zhi-Ping; Su, Xi; Liu, Cheng-Wei; Song, Dan; Peng, Jian; Wu, Ming-Xiang; Yang, Yu-Chun; Liu, Bo; Xu, Cheng-Yi; Wang, Fang

    2016-01-01

    Left ventricular free wall rupture usually leads to acute hemopericardium and sudden cardiac death resulting in cardiac tamponade. Rarely, only a few patients with subacute free wall rupture such as oozing-type ventricular rupture or left ventricular false aneurysm may permit time for pericardiocentesis and surgery. We report a 63-year-old man with ST-elevation myocardial infarction who underwent primary percutaneous coronary intervention about 12 hours from the onset, and cardiac tamponade occurred on the second day. An intra-aortic balloon pump (IABP) was immediately inserted for hemodynamic support. After 100 mL of pericardial fresh blood was drained from the percardial cavity, his hemodynamic collapse was promptly improved with IABP support. In the following 24 hours, about 600 mL of hemorrhagic pericardial fluid was drained. The most likely diagnosis was concerning for oozing-type ventricular rupture, and a conservative approach was decided. The patient survived to the acute phase under IABP support and was discharged with complete recovery. PMID:26145582

  1. Interleukin-6 and Interleukin-10 as Acute Kidney Injury Biomarkers after Pediatric Cardiac Surgery

    PubMed Central

    Greenberg, Jason H.; Whitlock, Richard; Zhang, William R.; Thiessen-Philbrook, Heather R.; Zappitelli, Michael; Devarajan, Prasad; Eikelboom, John; Kavsak, Peter A.; Devereaux, PJ; Shortt, Colleen; Garg, Amit X.; Parikh, Chirag R.

    2015-01-01

    Background Children undergoing cardiac surgery may exhibit a pronounced inflammatory response to cardiopulmonary bypass (CPB). Inflammation is recognized as an important pathophysiologic process leading to acute kidney injury (AKI). The aim of this study was to evaluate the association of two inflammatory cytokines interleukin (IL)-6 and IL-10 with AKI and other adverse outcomes in children after CPB surgery. Methods This is a sub-study of the Translational Research Investigating Biomarker Endpoints in AKI (TRIBE-AKI) cohort, including 106 children from 1 month to 18 years old undergoing CPB. Plasma IL-6 and IL-10 were measured preoperatively and postoperatively on days 1 (within 6 hours after surgery) and 3. Results Stage 2/3 AKI, defined by atleast a doubling of baseline serum creatinine or dialysis, was diagnosed in 24 (23%) patients. Preoperative IL-6 was significantly higher in patients with stage 2/3 AKI vs. without stage 2/3 AKI (median (IQR), 2.6 (0.6-4.9) vs. 0.6 (0.6-2.2), p=0.03). After adjustment for clinical and demographic variables, the highest preoperative IL-6 tertile was associated with a six-fold increased risk for stage 2/3 AKI compared with the lowest tertile (adjusted OR 6.41 (CI: 1.16-35.35)). IL-6 and IL-10 increased significantly after surgery, peaking postoperatively on day 1. First postoperative IL-6 and IL-10 did not significantly differ between patients with vs. without stage 2/3 AKI. Elevated IL-6 on day 3 was associated with longer hospital stay (p=0.0001). Conclusions Preoperative plasma IL-6 is associated with development of stage 2/3 AKI and may be prognostic of resource utilization. PMID:25877915

  2. The clinical challenge of preventing sudden cardiac death immediately after acute ST-elevation myocardial infarction.

    PubMed

    Manolis, Antonis S

    2014-12-01

    Unfortunately, of all patients experiencing acute myocardial infarction (MI), usually in the form of ST-elevation MI, 25-35% will die of sudden cardiac death (SCD) before receiving medical attention, most often from ventricular fibrillation. For patients who reach the hospital, prognosis is considerably better and has improved over the years. Reperfusion therapy, best attained with primary percutaneous coronary intervention compared to thrombolysis, has made a big difference in reducing the risk of SCD early and late after ST-elevation MI. In-hospital SCD due to ventricular tachyarrhythmias is manageable, with either preventive measures or drugs or electrical cardioversion. There is general agreement for secondary prevention of SCD post-MI with implantation of a cardioverter defibrillator (ICD) when malignant ventricular arrhythmias occur late (>48 h) after an MI, and are not due to reversible or correctable causes. The major challenge remains that of primary prevention, that is, how to prevent SCD during the first 1-3 months after ST-elevation MI for patients who have low left ventricular ejection fraction and are not candidates for an ICD according to current guidelines, due to the results of two studies, which did not show any benefits of early (<40 days after an MI) ICD implantation. Two recent documents may provide direction as to how to bridge the gap for this early post-MI period. Both recommend an electrophysiology study to guide implantation of an ICD, at least for those developing syncope or non-sustained ventricular tachycardia, who have an inducible sustained ventricular tachycardia at the electrophysiology study. An ICD is also recommended for patients with indication for a permanent pacemaker due to bradyarrhythmias, who also meet primary prevention criteria for SCD.

  3. Regional cardiac adrenergic function using I-123 meta-iodobenzylguanidine tomographic imaging after acute myocardial infarction

    SciTech Connect

    McGhie, A.I.; Corbett, J.R.; Akers, M.S.; Kulkarni, P.; Sills, M.N.; Kremers, M.; Buja, L.M.; Durant-Reville, M.; Parkey, R.W.; Willerson, J.T. )

    1991-02-01

    The effect of acute myocardial infarction (AMI) on regional cardiac adrenergic function was studied in 27 patients mean +/- standard deviation 10 +/- 4 days after AMI. Regional adrenergic function was evaluated noninvasively with I-123 meta-iodobenzylguanidine (MIBG) using a dedicated 3-detector tomograph. Four hours after its administration, there was reduced MIBG uptake in the region of infarction, 0.38 +/- 0.31 counts/pixel/mCi x 103 compared with 0.60 +/- 0.30 counts/pixel/mCi x 103 and 0.92 +/- 0.35 counts/pixel/mCi x 103 in the zones bordering and distant from the infarct area, respectively, p less than 0.001. In all patients, the area of reduced MIBG uptake after 4 hours was more extensive that the associated thallium-201 perfusion defect with defect scores of 52 +/- 22 and 23 +/- 18%, respectively, p less than 0.001. After anterior wall AMI, the 4-hour MIBG defect score was 70 +/- 13% and the degree of mismatch between myocardial perfusion and MIBG uptake was 30 +/- 9% compared with 39 +/- 17 and 21 +/- 17% after inferior AMI, p less than 0.001 and p = 0.016, respectively. The 4-hour MIBG defect score correlated inversely with the predischarge left ventricular ejection fraction, r = -0.73, p less than 0.001. Patients with ventricular arrhythmia of greater than or equal to 1 ventricular premature complexes per hour, paired ventricular premature complexes or ventricular tachycardia detected during the late hospital phase had higher 4-hour MIBG defect scores, 62.5 +/- 15.0%, than patients with no detectable complex ventricular ectopic activity and a ventricular premature complex frequency of less than 1 per hour, 44.6 +/- 23.4%, p = 0.036.

  4. Obesity negatively impacts aerobic capacity improvements both acutely and 1-year following cardiac rehabilitation.

    PubMed

    Martin, Billie-Jean; Aggarwal, Sandeep G; Stone, James A; Hauer, Trina; Austford, Leslie D; Knudtson, Merril; Arena, Ross

    2012-12-01

    Cardiac rehabilitation (CR) produces a host of health benefits related to modifiable cardiovascular risk factors. The purpose of the present investigation was to determine the influence of body weight, assessed through BMI, on acute and long-term improvements in aerobic capacity following completion of CR. Three thousand nine hundred and ninety seven subjects with coronary artery disease (CAD) participated in a 12-week multidisciplinary CR program. Subjects underwent an exercise test to determine peak estimated metabolic equivalents (eMETs) and BMI assessment at baseline, immediately following CR completion and at 1-year follow-up. Normal weight subjects at 1-year follow-up demonstrated the greatest improvement in aerobic fitness and best retention of those gains (gain in peak METs: 0.95 ± 1.1, P < 0.001). Although the improvement was significant (P < 0.001), subjects who were initially classified as obese had the lowest aerobic capacity and poorest retention in CR fitness gains at 1-year follow-up (gain in peak eMETs: 0.69 ± 1.2). Subjects initially classified as overweight by BMI had a peak eMET improvement that was also significantly better (P < 0.05) than obese subjects at 1-year follow-up (gain in peak eMETs: 0.82 ± 1.1). Significant fitness gains, one of the primary beneficial outcomes of CR, can be obtained by all subjects irrespective of BMI classification. However, obese patients have poorer baseline fitness and are more likely to "give back" fitness gains in the long term. Obese CAD patients may therefore benefit from additional interventions to enhance the positive adaptations facilitated by CR.

  5. Cardiac complications in thalassemia major.

    PubMed

    Auger, Dominique; Pennell, Dudley J

    2016-03-01

    The myocardium is particularly susceptible to complications from iron loading in thalassemia major. In the first years of life, severe anemia leads to high-output cardiac failure and death if not treated. The necessary supportive blood transfusions create loading of iron that cannot be naturally excreted, and this iron accumulates within tissues, including the heart. Free unbound iron catalyzes the formation of toxic hydroxyl radicals, which damage cells and cause cardiac dysfunction. Significant cardiac siderosis may present by the age of 10 and may lead to acute clinical heart failure, which must be treated urgently. Atrial fibrillation is the most frequently encountered iron-related arrhythmia. Iron chelation is effective at removing iron from the myocardium, at the expense of side effects that hamper compliance to therapy. Monitoring of myocardial iron content is mandatory for clinical management of cardiac risk. T2* cardiac magnetic resonance measures myocardial iron and is the strongest biomarker for prediction of heart failure and arrhythmic events. It has been calibrated to human myocardial tissue iron concentration and is highly reproducible across all magnetic resonance scanner vendors. As survival and patient age increases, endothelial dysfunction and diabetes may become new factors in the cardiovascular health of thalassemia patients. Promising new imaging technology and therapies could ameliorate the long-term prognosis.

  6. Comparison of isoflurane and α-chloralose in an anesthetized swine model of acute pulmonary embolism producing right ventricular dysfunction.

    PubMed

    Beam, Daren M; Neto-Neves, Evandro M; Stubblefield, William B; Alves, Nathan J; Tune, Johnathan D; Kline, Jeffrey A

    2015-02-01

    Pulmonary embolism (PE) is a leading cause of sudden cardiac death, and a model is needed for testing potential treatments. In developing a model, we compared the hemodynamic effects of isoflurane and α-chloralose in an acute swine model of PE because the choice of anesthesia will likely affect the cardiovascular responses of an animal to PE. At baseline, swine that received α-chloralose (n = 6) had a lower heart rate and cardiac output and higher SpO2, end-tidal CO2, and mean arterial pressure than did those given isoflurane (n = 9). After PE induction, swine given α-chloralose compared with isoflurane exhibited a lower heart rate (63 ± 10 compared with 116 ± 15 bpm) and peripheral arterial pressure (52 ± 12 compared with 61 ± 12 mm Hg); higher SpO2 (98% ± 3% compared with 95% ± 1%), end-tidal CO2 (35 ± 4 compared with 32 ± 5), and systolic blood pressure (121 ± 8 compared with 104 ± 20 mm Hg); and equivalent right ventricular:left ventricular ratios (1.32 ± 0.50 compared with 1.23 ± 0.19) and troponin I mean values (0.09 ± 0.07 ng/mL compared with 0.09 ± 0.06 ng/mL). Isoflurane was associated with widely variable fibrinogen and activated partial thromboplastin time. Intraexperiment mortality was 0 of 6 animals for α-chloralose and 2 of 9 swine for isoflurane. All swine anesthetized with α-chloralose survived with sustained pulmonary hypertension, RV-dilation-associated cardiac injury without the confounding vasodilatory or coagulatory effects of isoflurane. These data demonstrate the physiologic advantages of α-chloralose over isoflurane for anesthesia in a swine model of severe submassive PE. PMID:25730758

  7. Chronic Testosterone Replacement Exerts Cardioprotection against Cardiac Ischemia-Reperfusion Injury by Attenuating Mitochondrial Dysfunction in Testosterone-Deprived Rats

    PubMed Central

    Pongkan, Wanpitak; Chattipakorn, Siriporn C.; Chattipakorn, Nipon

    2015-01-01

    Background Although testosterone deficiency is associated with increased risks of heart disease, the benefits of testosterone therapy are controversial. Moreover, current understanding on the cardiac effect of testosterone during cardiac ischemia-reperfusion (I/R) periods is unclear. We tested the hypothesis that testosterone replacement attenuates the impairment of left ventricular (LV) function and heart rate variability (HRV), and reduces the infarct size and arrhythmias caused by I/R injury in orchiectomized (ORX) rats. Methodology ORX or sham-operated male Wistar rats (n = 24) were randomly divided and received either testosterone (2 mg/kg, subcutaneously administered) or the vehicle for 8 weeks. The ejection fraction (EF) and HRV were determined at baseline and the 4th and 8th week. I/R was performed by left anterior descending coronary artery ligation for 30 minutes, followed by a 120-minute reperfusion. LV pressure, arrhythmia scores, infarct size and cardiac mitochondrial function were determined. Results Prior to I/R, EF and HRV were impaired in the ORX group, but were restored in the testosterone-treated group. During I/R, arrhythmia scores and the infarct size were greater, and cardiac mitochondrial function was impaired, whereas the time to 1st VT/VF onset and the LV end-systolic pressure were decreased in the ORX group when compared to the sham group. Testosterone replacement attenuated the impairment of these parameters in ORX rats during I/R injury, but did not show any benefit or adverse effect in non-ORX rats. Conclusions Testosterone replacement restores cardiac function and autonomic regulation, and exerts cardioprotective effects during the I/R period via mitochondrial protection in ORX rats. PMID:25822979

  8. Angiotensin type 1a receptor-deficient mice develop diabetes-induced cardiac dysfunction, which is prevented by renin-angiotensin system inhibitors

    PubMed Central

    2013-01-01

    Background Diabetes-induced organ damage is significantly associated with the activation of the renin-angiotensin system (RAS). Recently, several studies have demonstrated a change in the RAS from an extracellular to an intracellular system, in several cell types, in response to high ambient glucose levels. In cardiac myocytes, intracellular angiotensin (ANG) II synthesis and actions are ACE and AT1 independent, respectively. However, a role of this system in diabetes-induced organ damage is not clear. Methods To determine a role of the intracellular ANG II in diabetic cardiomyopathy, we induced diabetes using streptozotocin in AT1a receptor deficient (AT1a-KO) mice to exclude any effects of extracellular ANG II. Further, diabetic animals were treated with a renin inhibitor aliskiren, an ACE inhibitor benazeprilat, and an AT1 receptor blocker valsartan. Results AT1a-KO mice developed significant diastolic and systolic dysfunction following 10 wks of diabetes, as determined by echocardiography. All three drugs prevented the development of cardiac dysfunction in these animals, without affecting blood pressure or glucose levels. A significant down regulation of components of the kallikrein-kinin system (KKS) was observed in diabetic animals, which was largely prevented by benazeprilat and valsartan, while aliskiren normalized kininogen expression. Conclusions These data indicated that the AT1a receptor, thus extracellular ANG II, are not required for the development of diabetic cardiomyopathy. The KKS might contribute to the beneficial effects of benazeprilat and valsartan in diabetic cardiomyopathy. A role of intracellular ANG II is suggested by the inhibitory effects of aliskiren, which needs confirmation in future studies. PMID:24215514

  9. Netrin-1 Abrogates Ischemia Reperfusion-induced Cardiac Mitochondrial Dysfunction via Nitric Oxide-dependent Attenuation of NOX4 Activation and Recoupling of NOS

    PubMed Central

    Siu, Kin Lung; Lotz, Christopher; Ping, Peipei; Cai, Hua

    2014-01-01

    Despite an established role of mitochondrial dysfunction in cardiac ischemia reperfusion (I/R) injury, the upstream activators have remained incompletely defined. We have recently identified an innovative role of exogenously applied netrin-1 in cardioprotection, which is mediated by increased nitric oxide (NO) bioavailability. Here, we tested the hypothesis that this “pharmacological” treatment of netrin-1 preserves mitochondrial function via novel mechanisms that are NO dependent. Freshly isolated C57BL6 mouse hearts were perfused using a Langendorff system, and subjected to a 20 min global ischemia/60 min reperfusion, in the presence or absence of netrin-1. I/R induced marked increases in infarct size, total superoxide and hydrogen peroxide production, activity and protein abundance of NADPH oxidase (NOX) isoform 4 (NOX4), as well as impaired mitochondrial integrity and function, all of which were attenuated by netrin-1. This protective effect of netrin-1 is attributed to cGMP, a downstream effector of NO. The protein levels of NOX1 and NOX2 were however unaffected, and infarct size from NOX1 and NOX2 knockouts were not different from wild type animals. Scavenging of NO with PTIO reversed inhibitory effects of netrin-1 on NOX4, while NO donor attenuated NOX4 protein abundance. In vivo NOX4 RNAi, or sepiapterin perfusion, resulted in recoupling of NOS, decreased infarct size, and blockade of dysfunctional mitochondrial swelling and mitochondrial superoxide production. These data demonstrate that netrin-1 induces cardioprotection through inhibition of NOX4 activity, which leads to recoupling of NOS, augmented NO bioavailability, reduction in oxidative stress, and ultimately preservation of mitochondrial function. The NO-dependent NOX4 inhibition connects with our previously established pathway of DCC/ERK1/2/eNOS/NO/DCC feed-forward mechanism, to maintain NOS in the coupling state to attenuate oxidative stress to preserve mitochondrial function. These findings

  10. Increased 4-hydroxy-2-nonenal-induced proteasome dysfunction is correlated with cardiac damage in streptozotocin-injected rats with isoproterenol infusion.

    PubMed

    Deshpande, Mandar; Mali, Vishal R; Pan, Guodong; Xu, Jiang; Yang, Xiao-Ping; Thandavarayan, Rajarajan A; Palaniyandi, Suresh Selvaraj

    2016-07-01

    Increase in 4-hydroxy-2-nonenal (4HNE) due to oxidative stress has been observed in a variety of cardiac diseases such as diabetic cardiomyopathy. 4HNE exerts a damaging effect in the myocardium by interfering with subcellular organelles like mitochondria by forming adducts. Therefore, we hypothesized that increased 4HNE adduct formation in the heart results in proteasome inactivation in isoproterenol (ISO)-infused type 1 diabetes mellitus (DM) rats. Eight-week-old male Sprague Dawley rats were injected with streptozotocin (STZ, 65 mg kg(-1) ). The rats were infused with ISO (5 mg kg(-1) ) for 2 weeks by mini pumps, after 8 weeks of STZ injection. We studied normal control (n = 8) and DM + ISO (n = 10) groups. Cardiac performance was assessed by echocardiography and Millar catheter at the end of the protocol at 20 weeks. Initially, we found an increase in 4HNE adducts in the hearts of the DM + ISO group. There was also a decrease in myocardial proteasomal peptidase (chymotrypsin and trypsin-like) activity. Increases in cardiomyocyte area (446 ± 32·7 vs 221 ± 10·83) (µm(2) ), per cent area of cardiac fibrosis (7·4 ± 0·7 vs 2·7 ± 0·5) and cardiac dysfunction were also found in DM + ISO (P < 0·05) relative to controls. We also found increased 4HNE adduct formation on proteasomal subunits. Furthermore, reduced aldehyde dehydrogenase 2 activity was observed in the myocardium of the DM + ISO group. Treatment with 4HNE (100 μM) for 4 h on cultured H9c2 cardiomyocytes attenuated proteasome activity. Therefore, we conclude that the 4HNE-induced decrease in proteasome activity may be involved in the cardiac pathology in STZ-injected rats infused with ISO. Copyright © 2016 John Wiley & Sons, Ltd. PMID:27273517

  11. Mitochondrial Ultrastructural Alterations and Declined M2 Receptor Density Were Involved in Cardiac Dysfunction in Rats after Long Term Treatment with Autoantibodies against M2 Muscarinic Receptor

    PubMed Central

    Wang, Jin; Wang, Li; Wu, Ye; Wang, Jie; Lv, Tingting; Liu, Huirong

    2015-01-01

    Background Previous studies showed that autoantibodies (M2-AA) against the second extracellular loop of M2 muscarinic receptor (M2AChR-el2) from dilated cardiomyopathy (DCM) serum could induce DCM-like morphological changes in mice hearts. However, the effects of M2-AA on the cardiac function during the process of DCM and the potential mechanisms are not fully known. The present study was designed to dynamically observe the cardiac function, mitochondrial changes, and M2 receptor binding characteristics in rats long-term stimulated with M2-AA in vivo. Methods M2-AA-positive model was established by actively immunizing healthy male Wistar rats with synthetic M2AChR-el2 peptide for 18 months. Meanwhile, vehicle group rats were administrated with physiological saline. The change of mitochondrial membrane potential (ΔΨm) was detected by radionuclide imaging. The ultrastructure of mitochondria was observed under electron microscopy. The M2 receptor binding characteristics were determined by radioactive ligand binding assay. Results After immunization for 12 months, compared with vehicle group, M2AChR-el2-immunized rats showed decreased myocardial contractility and cardiac diastolic function evidenced by declined maximal rate of rise of ventricular pressure and increased left ventricular end-diastolic pressure, respectively. Additionally, mitochondrial swelling and vacuolation were observed. At 18 months, M2AChR-el2-immunized rats manifested significant decreased cardiac systolic and diastolic function and pathological changes such as enlargement of right ventricular cavity and wall thinning; and the mitochondrial damage was aggravated. Furthermore, the M2 receptor maximum binding capacity (Bmax) of the M2AChR-el2-immunized rats significantly decreased, while the M2 receptor dissociation constant (Kd) was increased. Conclusions Our study suggested that long-term stimulation with M2-AA leaded to the ventricular dilatation and gradual deterioration of cardiac dysfunction

  12. Acute Cardiac Failure in a Pregnant Woman due to Thyrotoxic Crisis

    PubMed Central

    Okuda, Nao; Onodera, Mutsuo; Tsunano, Yumiko; Nakataki, Emiko; Oto, Jun; Imanaka, Hideaki; Nishimura, Masaji

    2012-01-01

    Introduction. Cardiac failure during pregnancy is usually related to preeclampsia/eclampsia, rarely to hyperthyroidism. While hyperthyroidism can easily lead to hypertensive cardiac failure and may harm the fetus, it is sometimes difficult to distinguish hyperthyroidism from normal pregnancy. Case Presentation. We encountered a case of 41-year-old pregnant woman with hypertensive cardiac failure. Because we initially diagnosed as pre-eclampsia/eclampsia, Caesarian section was performed. However, her symptoms still persisted after delivery. After thyroid function test results taken on the day of admission were obtained on the fourth day, we could diagnose that her cardiac failure was caused by thyrotoxic crisis. Conclusions. Hypertensive cardiac failure due to hyperthyroidism during pregnancy is rare and difficult to diagnose because of similar presentation of normal pregnancy. However, physicians should be aware of the risks posed by hyperthyroidism during pregnancy. PMID:24804110

  13. An Altered Pattern of Myocardial Histopathological and Molecular Changes Underlies the Different Characteristics of Type-1 and Type-2 Diabetic Cardiac Dysfunction

    PubMed Central

    Radovits, Tamás; Korkmaz, Sevil; Mátyás, Csaba; Oláh, Attila; Páli, Szabolcs; Zubarevich, Alina; Gwanmesia, Patricia Neh; Li, Shiliang; Loganathan, Sivakkanan; Barnucz, Enikő; Merkely, Béla; Szabó, Gábor

    2015-01-01

    Increasing evidence suggests that both types of diabetes mellitus (DM) lead to cardiac structural and functional changes. In this study we investigated and compared functional characteristics and underlying subcellular pathological features in rat models of type-1 and type-2 diabetic cardiomyopathy. Type-1 DM was induced by streptozotocin. For type-2 DM, Zucker Diabetic Fatty (ZDF) rats were used. Left ventricular pressure-volume analysis was performed to assess cardiac function. Myocardial nitrotyrosine immunohistochemistry, TUNEL assay, hematoxylin-eosin, and Masson's trichrome staining were performed. mRNA and protein expression were quantified by qRT-PCR and Western blot. Marked systolic dysfunction in type-1 DM was associated with severe nitrooxidative stress, apoptosis, and fibrosis. These pathological features were less pronounced or absent, while cardiomyocyte hypertrophy was comparable in type-2 DM, which was associated with unaltered systolic function and increased diastolic stiffness. mRNA-expression of hypertrophy markers c-fos, c-jun, and β-MHC, as well as pro-apoptotic caspase-12, was elevated in type-1, while it remained unaltered or only slightly increased in type-2 DM. Expression of the profibrotic TGF-β1 was upregulated in type-1 and showed a decrease in type-2 DM. We compared type-1 and type-2 diabetic cardiomyopathy in standard rat models and described an altered pattern of key pathophysiological features in the diabetic heart and corresponding functional consequences. PMID:25629059

  14. Continuous angiotensin-(1-7) infusion improves myocardial calcium transient and calcium transient alternans in ischemia-induced cardiac dysfunction rats.

    PubMed

    Luo, Duan; Zhuang, Xiaodong; Luo, Chufan; Long, Ming; Deng, Chunyu; Liao, Xinxue; Wang, Lichun

    2015-11-27

    The aim of this study was to evaluate the impact of Ang-(1-7) on calcium transient (CaT) in cardiomyocytes during the pathogenesis of heart failure. Cardiac dysfunction was induced by ligation of left anterior descending coronary artery in adult SD rats. Randomly selected rats were ligated and continuously infused with Ang-(1-7) [HF + Ang-(1-7) group] or saline (HF + saline group) via osmotic minipumps. After 28 days, hemodynamic parameters, the CaT, and the heart rate threshold of CaT alternans (CaT-Alt) were measured. Continuous Ang-(1-7) treatment could attenuate the impairment of cardiac function following LAD ligation. The amplitudes (F/F0) and 50%/90% recovery time of CaT were significantly different among HF + saline, HF + Ang-(1-7) and Sham-operated group. Compared to the Sham-operated group, the HF + saline group showed decreased CaT amplitude, and a prolonged 50%/90% CaT recovery time; Ang-(1-7) significantly improved these abnormalities. Compared with Sham-operated group, heart rate thresholds of CaT-Alt significantly reduced in HF + saline group, and Ang-(1-7) partly restored it. These findings indicate that Ang-(1-7) attenuates the CaT disturbance and increases the heart rate threshold of CaT-Alt during the pathogenesis of ischemic heart failure.

  15. Monoamine oxidase-A is an important source of oxidative stress and promotes cardiac dysfunction, apoptosis, and fibrosis in diabetic cardiomyopathy.

    PubMed

    Umbarkar, Prachi; Singh, Sarojini; Arkat, Silpa; Bodhankar, S L; Lohidasan, Sathiyanarayanan; Sitasawad, Sandhya L

    2015-10-01

    Oxidative stress is closely associated with the pathophysiology of diabetic cardiomyopathy (DCM). The mitochondrial flavoenzyme monoamine oxidase A (MAO-A) is an important source of oxidative stress in the myocardium. We sought to determine whether MAO-A plays a major role in modulating DCM. Diabetes was induced in Wistar rats by single intraperitoneal injection of streptozotocin (STZ). To investigate the role of MAO-A in the development of pathophysiological features of DCM, hyperglycemic and age-matched control rats were treated with or without the MAO-A-specific inhibitor clorgyline (CLG) at 1 mg/kg/day for 8 weeks. Diabetes upregulated MAO-A activity; elevated markers of oxidative stress such as cardiac lipid peroxidation, superoxide dismutase activity, and UCP3 protein expression; enhanced apoptotic cell death; and increased fibrosis. All these parameters were significantly attenuated by CLG treatment. In addition, treatment with CLG substantially prevented diabetes-induced cardiac contractile dysfunction as evidenced by decreased QRS, QT, and corrected QT intervals, measured by ECG, and LV systolic and LV end-diastolic pressure measured by microtip pressure transducer. These beneficial effects of CLG were seen despite the persistent hyperglycemic and hyperlipidemic environments in STZ-induced experimental diabetes. In summary, this study provides strong evidence that MAO-A is an important source of oxidative stress in the heart and that MAO-A-derived reactive oxygen species contribute to DCM.

  16. High-dose perioperative atorvastatin and acute kidney injury following cardiac surgery: a randomized clinical trial

    PubMed Central

    Billings, Frederic T.; Hendricks, Patricia A.; Schildcrout, Jonathan S.; Shi, Yaping; Petracek, Michael R.; Byrne, John G.; Brown, Nancy J.

    2016-01-01

    Importance Hydroxy-methylglutaryl-coenzyme A reductase inhibitors affect several mechanisms underlying acute kidney injury (AKI). Objective To test the hypothesis that short-term high-dose perioperative atorvastatin would reduce AKI following cardiac surgery Design, Setting, Participants Double-blinded, placebo-controlled, randomized trial of adult cardiac surgery patients conducted November 2009 to October 2014 at Vanderbilt University Medical Center Intervention Statin-naïve patients (n=199) were randomly assigned 80mg atorvastatin the day before surgery, 40mg the morning of surgery, and 40mg daily following surgery (n=102) or matching placebo (n=97). Patients using statins prior to study enrollment (n=416) continued their pre-enrollment statin until the day of surgery, were randomly assigned 80mg atorvastatin the morning of surgery and 40mg the morning after (n=206) or matching placebo (n=210), and resumed their statin on postoperative day 2. Main Outcome AKI, defined as 0.3 mg/dl rise in serum creatinine within 48 hours of surgery (AKIN criteria) Results The DSMB recommended stopping the statin-naïve group due to increased AKI among statin-naïve participants with chronic kidney disease (CKD, estimated glomerular filtration rate <60 ml/min/1.73 m2) receiving atorvastatin and then recommended stopping for futility after 615 participants (median age, 67 years; 188 [30.6%] women, and 202 [32.8%] diabetic) completed the study. Among all participants (n=615), AKI occurred in 64 of 308 participants (20.8%) randomized to atorvastatin versus 60 of 307 participants (19.5%) randomized to placebo (risk ratio [RR], 1.06 [95% CI, 0.78–1.46]; P=0.75). Among statin-naïve participants (n=199), AKI occurred in 22 of 102 (21.6%) receiving atorvastatin versus 13 of 97 (13.4%) receiving placebo (RR, 1.61 [0.86–3.01]; P=0.15), and serum creatinine increased 0.11mg/dl (−0.11 to 0.56) (median [10th to 90th percentile]) in those randomized to atorvastatin versus 0.05 (−0

  17. Antioxidant catalase rescues against high fat diet-induced cardiac dysfunction via an IKKβ-AMPK-dependent regulation of autophagy.

    PubMed

    Liang, Lei; Shou, Xi-Ling; Zhao, Hai-Kang; Ren, Gu-Qun; Wang, Jian-Bang; Wang, Xi-Hui; Ai, Wen-Ting; Maris, Jackie R; Hueckstaedt, Lindsay K; Ma, Ai-Qun; Zhang, Yingmei

    2015-02-01

    Autophagy, a conservative degradation process for long-lived and damaged proteins, participates in a variety of biological processes including obesity. However, the precise mechanism of action behind obesity-induced changes in autophagy still remains elusive. This study was designed to examine the role of the antioxidant catalase in high fat diet-induced changes in cardiac geometry and function as well as the underlying mechanism of action involved with a focus on autophagy. Wild-type (WT) and transgenic mice with cardiac overexpression of catalase were fed low or high fat diet for 20 weeks prior to assessment of myocardial geometry and function. High fat diet intake triggered obesity, hyperinsulinemia, and hypertriglyceridemia, the effects of which were unaffected by catalase transgene. Myocardial geometry and function were compromised with fat diet intake as manifested by cardiac hypertrophy, enlarged left ventricular end systolic and diastolic diameters, fractional shortening, cardiomyocyte contractile capacity and intracellular Ca²⁺ mishandling, the effects of which were ameliorated by catalase. High fat diet intake promoted reactive oxygen species production and suppressed autophagy in the heart, the effects of which were attenuated by catalase. High fat diet intake dampened phosphorylation of inhibitor kappa B kinase β(IKKβ), AMP-activated protein kinase (AMPK) and tuberous sclerosis 2 (TSC2) while promoting phosphorylation of mTOR, the effects of which were ablated by catalase. In vitro study revealed that palmitic acid compromised cardiomyocyte autophagy and contractile function in a manner reminiscent of fat diet intake, the effect of which was significantly alleviated by inhibition of IKKβ, activation of AMPK and induction of autophagy. Taken together, our data revealed that the antioxidant catalase counteracts against high fat diet-induced cardiac geometric and functional anomalies possibly via an IKKβ-AMPK-dependent restoration of myocardial

  18. Thymosin-β4 prevents cardiac rupture and improves cardiac function in mice with myocardial infarction.

    PubMed

    Peng, Hongmei; Xu, Jiang; Yang, Xiao-Ping; Dai, Xiangguo; Peterson, Edward L; Carretero, Oscar A; Rhaleb, Nour-Eddine

    2014-09-01

    Thymosin-β4 (Tβ4) promotes cell survival, angiogenesis, and tissue regeneration and reduces inflammation. Cardiac rupture after myocardial infarction (MI) is mainly the consequence of excessive regional inflammation, whereas cardiac dysfunction after MI results from a massive cardiomyocyte loss and cardiac fibrosis. It is possible that Tβ4 reduces the incidence of cardiac rupture post-MI via anti-inflammatory actions and that it decreases adverse cardiac remodeling and improves cardiac function by promoting cardiac cell survival and cardiac repair. C57BL/6 mice were subjected to MI and treated with either vehicle or Tβ4 (1.6 mg·kg(-1)·day(-1) ip via osmotic minipump) for 7 days or 5 wk. Mice were assessed for 1) cardiac remodeling and function by echocardiography; 2) inflammatory cell infiltration, capillary density, myocyte apoptosis, and interstitial collagen fraction histopathologically; 3) gelatinolytic activity by in situ zymography; and 4) expression of ICAM-1 and p53 by immunoblot analysis. Tβ4 reduced cardiac rupture that was associated with a decrease in the numbers of infiltrating inflammatory cells and apoptotic myocytes, a decrease in gelatinolytic activity and ICAM-1 and p53 expression, and an increase in the numbers of CD31-positive cells. Five-week treatment with Tβ4 ameliorated left ventricular dilation, improved cardiac function, markedly reduced interstitial collagen fraction, and increased capillary density. In a murine model of acute MI, Tβ4 not only decreased mortality rate as a result of cardiac rupture but also significantly improved cardiac function after MI. Thus, the use of Tβ4 could be explored as an alternative therapy in preventing cardiac rupture and restoring cardiac function in patients with MI.

  19. Glucose modulates respiratory complex I activity in response to acute mitochondrial dysfunction.

    PubMed

    Cannino, Giuseppe; El-Khoury, Riyad; Pirinen, Marja; Hutz, Bettina; Rustin, Pierre; Jacobs, Howard T; Dufour, Eric

    2012-11-01

    Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an "emergency shutdown" system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases.

  20. Stress Mediators and Immune Dysfunction in Patients with Acute Cerebrovascular Diseases

    PubMed Central

    Liesz, Arthur; Rüger, Holger; Purrucker, Jan; Zorn, Markus; Dalpke, Alexander; Möhlenbruch, Markus; Englert, Stefan; Nawroth, Peter P.; Veltkamp, Roland

    2013-01-01

    Background Post-stroke immune depression contributes to the development of infections which are major complications after stroke. Previous experimental and clinical studies suggested that humoral stress mediators induce immune dysfunction. However, prospective clinical studies testing this concept are missing and no data exists for other cerebrovascular diseases including intracerebral hemorrhage (ICH) and TIA. Methods We performed a prospective clinical study investigating 166 patients with TIA, ischemic and hemorrhagic stroke. We measured a broad panel of stress mediators, leukocyte subpopulations, cytokines and infection markers from hospital admission to day 7 and on follow-up after 2–3 months. Multivariate regression analyses detected independent predictors of immune dysfunction and bacterial infections. ROC curves were used to test the diagnostic value of these parameters. Results Only severe ischemic strokes and ICH increased some catecholamine metabolites, ACTH and cortisol levels. Immunodysfunction was eminent already on hospital admission after large brain lesions with lymphocytopenia as a key feature. None of the stress mediators was an independent predictor of lymphocytopenia or infections. However, lymphocytopenia on hospital admission was detected as an independent explanatory variable of later infections. NIHSSS and lymphocytopenia on admission were excellent predictors of infection. Conclusions Our results question the present pathophysiological concept of stress-hormone mediated immunodysfunction after stroke. Early lymphocytopenia was identified as an early independent predictor of post-stroke infections. Absence of lymphocytopenia may serve as a negative predictive marker for stratification for early antibiotic treatment. PMID:24069356

  1. Glucose modulates respiratory complex I activity in response to acute mitochondrial dysfunction.

    PubMed

    Cannino, Giuseppe; El-Khoury, Riyad; Pirinen, Marja; Hutz, Bettina; Rustin, Pierre; Jacobs, Howard T; Dufour, Eric

    2012-11-01

    Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an "emergency shutdown" system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases. PMID:23007390

  2. Acute Cardiac Impairment Associated With Concurrent Chemoradiotherapy for Esophageal Cancer: Magnetic Resonance Evaluation

    SciTech Connect

    Hatakenaka, Masamitsu; Yonezawa, Masato; Nonoshita, Takeshi; Nakamura, Katsumasa; Yabuuchi, Hidetake; Shioyama, Yoshiyuki; Nagao, Michinobu; Matsuo, Yoshio; Kamitani, Takeshi; Higo, Taiki; Nishikawa, Kei; Setoguchi, Taro; Honda, Hiroshi

    2012-05-01

    Purpose: To evaluate acute cardiac effects of concurrent chemoradiotherapy (CCRT) for esophageal cancer. Methods and Materials: This prospective study was approved by the institutional review board, and written informed consent was obtained from all participants. The left ventricular function (LVF) of 31 patients with esophageal cancer who received cisplatin and 5-fluorouracil-based CCRT was evaluated using cardiac cine magnetic resonance imaging. The patients were classified into two groups according to mean LV dose. The parameters related to LVF were compared between before and during (40 Gy) or between before and after CCRT using a Wilcoxon matched-pairs single rank test, and parameter ratios (during/before CCRT, after/before CCRT) were also compared between the groups with a t test. Data were expressed as mean {+-} SE. Results: In the low LV-dose group (n = 10; mean LV dose <0.6 Gy), LV ejection fraction decreased significantly (before vs. during vs. after CCRT; 62.7% {+-} 2.98% vs. 59.8% {+-} 2.56% vs. 60.6% {+-} 3.89%; p < 0.05). In the high LV-dose group (n = 21; mean LV dose of 3.6-41.2 Gy), LV end-diastolic volume index (before vs. after CCRT; 69.1 {+-} 2.93 vs. 57.0 {+-} 3.23 mL/m{sup 2}), LV stroke volume index (38.6 {+-} 1.56 vs. 29.9 {+-} 1.60 mL/m{sup 2}), and LV ejection fraction (56.9% {+-} 1.79% vs. 52.8% {+-} 1.15%) decreased significantly (p < 0.05) after CCRT. Heart rate increased significantly (before vs. during vs. after CCRT; 66.8 {+-} 3.05 vs. 72.4 {+-} 4.04 vs. 85.4 {+-} 3.75 beats per minute, p < 0.01). Left ventricle wall motion decreased significantly (p < 0.05) in segments 8 (before vs. during vs. after CCRT; 6.64 {+-} 0.54 vs. 4.78 {+-} 0.43 vs. 4.79 {+-} 0.50 mm), 9 (6.88 {+-} 0.45 vs. 5.04 {+-} 0.38 vs. 5.27 {+-} 0.47 mm), and 10 (9.22 {+-} 0.48 vs. 8.08 {+-} 0.34 vs. 8.19 {+-} 0.56 mm). The parameter ratios of LV end-diastolic volume index, stroke volume index, wall motion in segment 9, and heart rate showed significant difference

  3. Acute cerebellar dysfunction with neuromuscular manifestations after scorpionism presumably caused by Tityus obscurus in Santarém, Pará / Brazil.

    PubMed

    Torrez, Pasesa P Q; Quiroga, Mariana M M; Abati, Paulo A M; Mascheretti, Melissa; Costa, Walter Silva; Campos, Luciana P; França, Francisco O S

    2015-03-01

    Scorpionism is a public health problem in many tropical countries, especially in North Africa, South India, Latin America and the Middle East. In Brazil, patients with severe scorpion envenoming have mainly cardiovascular events, including acute heart failure, acute respiratory distress syndrome and shock, death is rare. We described 58 accidents presumably caused by Tityus obscurus in Brazilian Amazonia. Patients reported a sensation of "electric shocks" which could last hours. The vast majority of patients presented a clinical picture compatible with acute cerebellar dysfunction, beginning minutes and lasting up to 2 days after the accident. They presented cerebellar ataxia, dysdiadochokinesia, dysmetry, dysarthria, dyslalia, nausea and vomiting. Besides, some patients presented myoclonus and fasciculation which can also be attributed to cerebellar dysfunction or maybe the result of direct action on skeletal muscle. Two patients had evidence of intense rhabdomyolysis and acute kidney injury. The clinical picture in this scorpion envenoming is mainly characterized by an acute dysfunction of cerebellar activities and abnormal neuromuscular manifestations and in some cases muscle injury which are not described in any other region of the world. This work presents clinical, epidemiologic, laboratory and treatment aspects of this unmatched scorpion envenoming in the state of Pará, northern Brazil. PMID:25549940

  4. Deficiency of adipocyte fatty-acid-binding protein alleviates myocardial ischaemia/reperfusion injury and diabetes-induced cardiac dysfunction.

    PubMed

    Zhou, Mi; Bao, Yuqian; Li, Haobo; Pan, Yong; Shu, Lingling; Xia, Zhengyuan; Wu, Donghai; Lam, Karen S L; Vanhoutte, Paul M; Xu, Aimin; Jia, Weiping; Hoo, Ruby L-C

    2015-10-01

    Clinical evidence shows that circulating levels of adipocyte fatty-acid-binding protein (A-FABP) are elevated in patients with diabetes and closely associated with ischaemic heart disease. Patients with diabetes are more susceptible to myocardial ischaemia/reperfusion (MI/R) injury. The experiments in the present study investigated the role of A-FABP in MI/R injury with or without diabetes. Non-diabetic and diabetic (streptozotocin-induced) A-FABP knockout and wild-type mice were subjected to MI/R or sham intervention. After MI/R, A-FABP knockout mice exhibited reductions in myocardial infarct size, apoptotic index, oxidative and nitrative stress, and inflammation. These reductions were accompanied by an improved left ventricular function compared with the relative controls under non-diabetic or diabetic conditions. After diabetes induction, A-FABP knockout mice exhibited a preserved cardiac function compared with that in wild-type mice. Endothelial cells, but not cardiomyocytes, were identified as the most likely source of cardiac A-FABP. Cardiac and circulating A-FABP levels were significantly increased in mice with diabetes or MI/R. Diabetes-induced superoxide anion production was significantly elevated in wild-type mice, but diminished in A-FABP knockout mice, and this elevation contributed to the exaggeration of MI/R-induced cardiac injury. Phosphorylation of endothelial nitric oxide synthase (eNOS) and production of nitric oxide (NO) were enhanced in both diabetic and non-diabetic A-FABP knockout mice after MI/R injury, but diminished in wild-type mice. The beneficial effects of A-FABP deficiency on MI/R injury were abolished by the NOS inhibitor N(G)-nitro-L-arginine methyl ester. Thus, A-FABP deficiency protects mice against MI/R-induced and/or diabetes-induced cardiac injury at least partially through activation of the eNOS/NO pathway and reduction in superoxide anion production.

  5. Mineralocorticoid and AT1 receptors in the paraventricular nucleus contribute to sympathetic hyperactivity and cardiac dysfunction in rats post myocardial infarct.

    PubMed

    Huang, Bing S; Chen, Aidong; Ahmad, Monir; Wang, Hong-Wei; Leenen, Frans H H

    2014-08-01

    Intracerebroventricular infusion of a mineralocorticoid receptor (MR) or angiotensin II type 1 receptor (AT1R) blocker in rats attenuates sympathetic hyperactivity and progressive left ventricular (LV) dysfunction post myocardial infarction (MI). The present study examined whether knockdown of MRs or AT1Rs specifically in the paraventricular nucleus (PVN) contributes to these effects, and compared cardiac effects with those of systemic treatment with the β1-adrenergic receptor blocker metoprolol. The PVN of rats was infused with adeno-associated virus carrying small interfering RNA against either MR (AAV-MR-siRNA) or AT1R (AAV-AT1R-siRNA), or as control scrambled siRNA. At 4 weeks post MI, AT1R but not MR expression was increased in the PVN, excitatory renal sympathetic nerve activity and pressor responses to air stress were enhanced, and arterial baroreflex function was impaired; LV end-diastolic pressure (LVEDP) was increased and LV peak systolic pressure (LVPSP), ejection fraction (EF) and dP/dtmax decreased. AAV-MR-siRNA and AAV-AT1R-siRNA both normalized AT1R expression in the PVN, similarly ameliorated sympathetic and pressor responses to air stress, largely prevented baroreflex desensitization, and improved LVEDP, EF and dP/dtmax as well as cardiac interstitial (but not perivascular) fibrosis. In a second set of rats, metoprolol at 70 or 250 mg kg(-1) day(-1) in the drinking water for 4 weeks post MI did not improve LV function except for a decrease in LVEDP at the lower dose. These results suggest that in rats MR-dependent upregulation of AT1Rs in the PVN contributes to sympathetic hyperactivity, and LV dysfunction and remodelling post MI. In rats, normalizing MR-AT1R signalling in the PVN is a more effective strategy to improve LV dysfunction post MI than systemic β1 blockade.

  6. [Mitochondrial dysfunction and compensatory mechanisms in liver cells during acute carbon tetrachloride-induced rat intoxication].

    PubMed

    Zavodnik, I B

    2015-01-01

    Electron-transport chain and redox-balance of mitochondria are important targets that are damaged during intoxication. The aim of the present work was to estimate the role of impairments in cellular bioenergetic function in the development of liver damage during acute carbon tetrachloride intoxication in rats and to elucidate possible compensatory mechanisms. Acute CCl4-induced rat intoxication (0.8 g/kg or 4 g/kg) resulted in considerable impairments of respiratory and synthetic mitochondrial functions; their manifestations depended on the dose of the toxic agent and the duration of the intoxication increased and accompanied by complete uncoupling of oxidation and phosphorylation processes in liver mitochondria. The intoxication induced considerable liver damage and accumulation of NO in blood plasma and liver tissue. The changes of some parameters of liver mitochondrial functional activity demonstrate an oscillative pattern, reflecting compensatory mechanisms during intoxication that involved increased reduced glutathione level and enhanced succinate dehydrogenase activity. PMID:26716745

  7. [Mitochondrial dysfunction and compensatory mechanisms in liver cells during acute carbon tetrachloride-induced rat intoxication].

    PubMed

    Zavodnik, I B

    2015-01-01

    Electron-transport chain and redox-balance of mitochondria are important targets that are damaged during intoxication. The aim of the present work was to estimate the role of impairments in cellular bioenergetic function in the development of liver damage during acute carbon tetrachloride intoxication in rats and to elucidate possible compensatory mechanisms. Acute CCl4-induced rat intoxication (0.8 g/kg or 4 g/kg) resulted in considerable impairments of respiratory and synthetic mitochondrial functions; their manifestations depended on the dose of the toxic agent and the duration of the intoxication increased and accompanied by complete uncoupling of oxidation and phosphorylation processes in liver mitochondria. The intoxication induced considerable liver damage and accumulation of NO in blood plasma and liver tissue. The changes of some parameters of liver mitochondrial functional activity demonstrate an oscillative pattern, reflecting compensatory mechanisms during intoxication that involved increased reduced glutathione level and enhanced succinate dehydrogenase activity.

  8. Sensitivity Analysis of Vagus Nerve Stimulation Parameters on Acute Cardiac Autonomic Responses: Chronotropic, Inotropic and Dromotropic Effects

    PubMed Central

    Ojeda, David; Le Rolle, Virginie; Romero-Ugalde, Hector M.; Gallet, Clément; Bonnet, Jean-Luc; Henry, Christine; Bel, Alain; Mabo, Philippe; Carrault, Guy; Hernández, Alfredo I.

    2016-01-01

    Although the therapeutic effects of Vagus Nerve Stimulation (VNS) have been recognized in pre-clinical and pilot clinical studies, the effect of different stimulation configurations on the cardiovascular response is still an open question, especially in the case of VNS delivered synchronously with cardiac activity. In this paper, we propose a formal mathematical methodology to analyze the acute cardiac response to different VNS configurations, jointly considering the chronotropic, dromotropic and inotropic cardiac effects. A latin hypercube sampling method was chosen to design a uniform experimental plan, composed of 75 different VNS configurations, with different values for the main parameters (current amplitude, number of delivered pulses, pulse width, interpulse period and the delay between the detected cardiac event and VNS onset). These VNS configurations were applied to 6 healthy, anesthetized sheep, while acquiring the associated cardiovascular response. Unobserved VNS configurations were estimated using a Gaussian process regression (GPR) model. In order to quantitatively analyze the effect of each parameter and their combinations on the cardiac response, the Sobol sensitivity method was applied to the obtained GPR model and inter-individual sensitivity markers were estimated using a bootstrap approach. Results highlight the dominant effect of pulse current, pulse width and number of pulses, which explain respectively 49.4%, 19.7% and 6.0% of the mean global cardiovascular variability provoked by VNS. More interestingly, results also quantify the effect of the interactions between VNS parameters. In particular, the interactions between current and pulse width provoke higher cardiac effects than the changes on the number of pulses alone (between 6 and 25% of the variability). Although the sensitivity of individual VNS parameters seems similar for chronotropic, dromotropic and inotropic responses, the interacting effects of VNS parameters provoke

  9. Acute Cardiac Rejection Requires Directly Cytotoxic CD4 T cells: A Parallel Pathway between Fas and Perforin1

    PubMed Central

    Grazia, Todd J.; Plenter, Robert J.; Weber, Sarah M.; Lepper, Helen M.; Victorino, Francisco; Zamora, Martin R.; Pietra, Biagio A.; Gill, Ronald G.

    2009-01-01

    Background CD4 T cells can suffice as effector cells to mediate primary acute cardiac allograft rejection. While CD4 T cells can readily kill appropriate target cells in vitro, the corresponding role of such cytolytic activity for mediating allograft rejection in vivo is unknown. Therefore, we determined whether the cytolytic effector molecules perforin and/or FasL (CD95L) were necessary for CD4 T cell-mediated rejection in vivo. Methods Wild type C3H(H-2k) or Fas (CD95)-deficient C3Hlpr (H-2k) hearts were transplanted into immune-deficient C57B6rag−/− (H-2b) mice. Recipients then were reconstituted with naïve purified CD4 T cells from either wild-type, perforin (pfp)-deficient, or FasL (gld)-deficient T cell donors. Results In vitro, alloreactive CD4 T cells were competent to lyse donor MHC class II+ target cells, largely by a Fas-dependent mechanism. In vivo, the individual disruption of either donor Fas expression (lpr) or CD4 T cell-derived perforin had no signifcant impact on acute rejection. However, FasL-deficient (gld) CD4 T cells demonstrated delayed allograft rejection. Importantly, the simultaneous removal of both donor Fas expression and CD4 T cell perforin completely abrograted acute rejection, despite the persistence of CD4 T cells within the graft. Conclusions Results demonstrate that the direct rejection of cardiac allografts by CD4 effector T cells requires the alternative contribution of graft Fas expression and T cell perforin expression. To our knowledge, this is the first demonstration that cytolytic activity by CD4 T cells can play an obligate role for primary acute allograft rejection in vivo. PMID:20061916

  10. The impact of beat-to-beat variability in optimising the acute hemodynamic response in cardiac resynchronisation therapy

    PubMed Central

    Niederer, Steven; Walker, Cameron; Crozier, Andrew; Hyde, Eoin R.; Blazevic, Bojan; Behar, Jonathan M.; Claridge, Simon; Sohal, Manav; Shetty, Anoop; Jackson, Tom; Rinaldi, Christopher

    2015-01-01

    Background Acute indicators of response to cardiac resynchronisation therapy (CRT) are critical for developing lead optimisation algorithms and evaluating novel multi-polar, multi-lead and endocardial pacing protocols. Accounting for beat-to-beat variability in measures of acute haemodynamic response (AHR) may help clinicians understand the link between acute measurements of cardiac function and long term clinical outcome. Methods and results A retrospective study of invasive pressure tracings from 38 patients receiving an acute pacing and electrophysiological study was performed. 602 pacing protocols for left ventricle (LV) (n = 38), atria–ventricle (AV) (n = 9), ventricle–ventricle (VV) (n = 12) and endocardial (ENDO) (n = 8) optimisation were performed. AHR was measured as the maximal rate of LV pressure development (dP/dtMx) for each beat. The range of the 95% confidence interval (CI) of mean AHR was ~ 7% across all optimisation protocols compared with the reported CRT response cut off value of 10%. A single clear optimal protocol was identifiable in 61%, 22%, 25% and 50% for LV, AV, VV and ENDO optimisation cases, respectively. A level of service (LOS) optimisation that aimed to maximise the expected AHR 5th percentile, minimising variability and maximising AHR, led to distinct optimal protocols from conventional mean AHR optimisation in 34%, 78%, 67% and 12.5% of LV, AV, VV and ENDO optimisation cases, respectively. Conclusion The beat-to-beat variation in AHR is significant in the context of CRT cut off values. A LOS optimisation offers a novel index to identify the optimal pacing site that accounts for both the mean and variation of the baseline measurement and pacing protocol. PMID:26844303

  11. PEDF improves cardiac function in rats with acute myocardial infarction via inhibiting vascular permeability and cardiomyocyte apoptosis.

    PubMed

    Zhang, Hao; Wang, Zheng; Feng, Shou-Jie; Xu, Lei; Shi, He-Xian; Chen, Li-Li; Yuan, Guang-Da; Yan, Wei; Zhuang, Wei; Zhang, Yi-Qian; Zhang, Zhong-Ming; Dong, Hong-Yan

    2015-03-11

    Pigment epithelium-derived factor (PEDF) is a pleiotropic gene with anti-inflammatory, antioxidant and anti-angiogenic properties. However, recent reports about the effects of PEDF on cardiomyocytes are controversial, and it is not known whether and how PEDF acts to inhibit hypoxic or ischemic endothelial injury in the heart. In the present study, adult Sprague-Dawley rat models of acute myocardial infarction (AMI) were surgically established. PEDF-small interfering RNA (siRNA)-lentivirus (PEDF-RNAi-LV) or PEDF-LV was delivered into the myocardium along the infarct border to knockdown or overexpress PEDF, respectively. Vascular permeability, cardiomyocyte apoptosis, myocardial infarct size and animal cardiac function were analyzed. We also evaluated PEDF's effect on the suppression of the endothelial permeability and cardiomyocyte apoptosis under hypoxia in vitro. The results indicated that PEDF significantly suppressed the vascular permeability and inhibited hypoxia-induced endothelial permeability through PPARγ-dependent tight junction (TJ) production. PEDF protected cardiomyocytes against ischemia or hypoxia-induced cell apoptosis both in vivo and in vitro via preventing the activation of caspase-3. We also found that PEDF significantly reduced myocardial infarct size and enhanced cardiac function in rats with AMI. These data suggest that PEDF could protect cardiac function from ischemic injury, at least by means of reducing vascular permeability, cardiomyocyte apoptosis and myocardial infarct size.

  12. Cardiac peroxisome proliferator-activated receptor-γ expression is modulated by oxidative stress in acutely infrasound-exposed cardiomyocytes.

    PubMed

    Pei, Zhaohui; Meng, Rongsen; Zhuang, Zhiqiang; Zhao, Yiqiao; Liu, Fangpeng; Zhu, Miao-Zhang; Li, Ruiman

    2013-12-01

    The aim of the present study was to examine the effects of acute infrasound exposure on oxidative damage and investigate the underlying mechanisms in rat cardiomyocytes. Neonatal rat cardiomyocytes were cultured and exposed to infrasound for several days. In the study, the expression of CAT, GPx, SOD1, and SOD2 and their activities in rat cardiomyocytes in infrasound exposure groups were significantly decreased compared to those in the various time controls, along with significantly higher levels of O2 (-) and H2O2. Decreased cardiac cell viability was not observed in various time controls. A significant reduction in cardiac cell viability was observed in the infrasound group compared to the control, while significantly increased cardiac cell viability was observed in the infrasound exposure and rosiglitazone pretreatment group. Compared to the control, rosiglitazone significantly upregulated CAT, GPx, SOD1, and SOD2 expression and their activities in rat cardiomyocytes exposed to infrasound, while the levels of O2 (-) or H2O2 were significantly decreased. A potential link between a significant downregulation of PPAR-γ expression in rat cardiomyocytes in the infrasound group was compared to the control and infrasound-induced oxidative stress. These findings indicate that infrasound can induce oxidative damage in rat cardiomyocytes by inactivating PPAR-γ. PMID:23632742

  13. Infection related renal impairment: a major cause of acute allograft dysfunction.

    PubMed

    Nampoory, Mangalathillam R N; Johny, Kaivilayil V; Costandy, Jamal N; Nair, Madhavan P; Said, Tarek; Homoud, Hani; Al-Muzairai, Ibrahim; Samhan, Mohmoud; Al-Moussawi, Mustafa

    2003-06-01

    We prospectively analyzed the impact of post-transplant infections on the renal function in 532 stable renal transplant recipients (M=340; F=192) over a period of 5 years. Their age ranged from 3-75 years (40+14 years). During the follow-up period, 52 patients expired and 64 lost on followup. We defined renal impairment (RI) as a persistent rise in serum creatinine above 20% from baseline value. 495 episodes of RI occurred in 269 recipients. This included 180-36% episodes of acute rejection, 53-10.7% Cyclosporine toxicity, 236-47.7% infection related renal impairment [IRRI] and 26-5.3% others. The severity of renal failure is less in IRRI (100+90.2) than that of acute rejection (166+127.1), but was more than that in cyclosporine toxicity (50+42.2). Sites of infection in IRRI were urinary (33%), respiratory (26.3%), septicemia (15.7%) and others (25.4%). Episode of IRRI occurred more frequently in LURD (159-67.4%) compared to LRD-RTR (50-21.2%). Occurrence of IRRI is more significantly higher in patients on triple drug immunosuppression (IS) (34.3%) than those on two drug IS (13.2%) (P=or<0.01). Ecoli (23.1%), Pseudomonas (11.1%), Salmonella (8.8%), Klebsiella (8.8%) and Staphylococai (8.3%) were the major organisms producing IRRI. IRRI is frequent (27.8%) during the first six months. Present study denotes that IRRI is a major cause of acute failure in RTR. PMID:15859909

  14. High-sensitivity cardiac troponin I at presentation in patients with suspected acute coronary syndrome: a cohort study

    PubMed Central

    Shah, Anoop S V; Anand, Atul; Sandoval, Yader; Lee, Kuan Ken; Smith, Stephen W; Adamson, Philip D; Chapman, Andrew R; Langdon, Timothy; Sandeman, Dennis; Vaswani, Amar; Strachan, Fiona E; Ferry, Amy; Stirzaker, Alexandra G; Reid, Alan; Gray, Alasdair J; Collinson, Paul O; McAllister, David A; Apple, Fred S; Newby, David E; Mills, Nicholas L

    2015-01-01

    Summary Background Suspected acute coronary syndrome is the commonest reason for emergency admission to hospital and is a large burden on health-care resources. Strategies to identify low-risk patients suitable for immediate discharge would have major benefits. Methods We did a prospective cohort study of 6304 consecutively enrolled patients with suspected acute coronary syndrome presenting to four secondary and tertiary care hospitals in Scotland. We measured plasma troponin concentrations at presentation using a high-sensitivity cardiac troponin I assay. In derivation and validation cohorts, we evaluated the negative predictive value of a range of troponin concentrations for the primary outcome of index myocardial infarction, or subsequent myocardial infarction or cardiac death at 30 days. This trial is registered with ClinicalTrials.gov (number NCT01852123). Findings 782 (16%) of 4870 patients in the derivation cohort had index myocardial infarction, with a further 32 (1%) re-presenting with myocardial infarction and 75 (2%) cardiac deaths at 30 days. In patients without myocardial infarction at presentation, troponin concentrations were less than 5 ng/L in 2311 (61%) of 3799 patients, with a negative predictive value of 99·6% (95% CI 99·3–99·8) for the primary outcome. The negative predictive value was consistent across groups stratified by age, sex, risk factors, and previous cardiovascular disease. In two independent validation cohorts, troponin concentrations were less than 5 ng/L in 594 (56%) of 1061 patients, with an overall negative predictive value of 99·4% (98·8–99·9). At 1 year, these patients had a lower risk of myocardial infarction and cardiac death than did those with a troponin concentration of 5 ng/L or more (0·6% vs 3·3%; adjusted hazard ratio 0·41, 95% CI 0·21–0·80; p<0·0001). Interpretation Low plasma troponin concentrations identify two-thirds of patients at very low risk of cardiac events who could be discharged from

  15. Combined ECG, Echocardiographic, and Biomarker Criteria for Diagnosing Acute Myocardial Infarction in Out-of-Hospital Cardiac Arrest Patients

    PubMed Central

    Lee, Sang-Eun; Uhm, Jae-Sun; Kim, Jong-Youn; Pak, Hui-Nam; Lee, Moon-Hyoung

    2015-01-01

    Purpose Acute coronary lesions commonly trigger out-of-hospital cardiac arrest (OHCA). However, the prevalence of coronary artery disease (CAD) in Asian patients with OHCA and whether electrocardiogram (ECG) and other findings might predict acute myocardial infarction (AMI) have not been fully elucidated. Materials and Methods Of 284 consecutive resuscitated OHCA patients seen between January 2006 and July 2013, we enrolled 135 patients who had undergone coronary evaluation. ECGs, echocardiography, and biomarkers were compared between patients with or without CAD. Results We included 135 consecutive patients aged 54 years (interquartile range 45-65) with sustained return of spontaneous circulation after OHCA between 2006 and 2012. Sixty six (45%) patients had CAD. The initial rhythm was shockable and non-shockable in 110 (81%) and 25 (19%) patients, respectively. ST-segment elevation predicted CAD with 42% sensitivity, 87% specificity, and 65% accuracy. ST elevation and/or regional wall motion abnormality (RWMA) showed 68% sensitivity, 52% specificity, and 70% accuracy in the prediction of CAD. Finally, a combination of ST elevation and/or RWMA and/or troponin T elevation predicted CAD with 94% sensitivity, 17% specificity, and 55% accuracy. Conclusion In patients with OHCA without obvious non-cardiac causes, selection for coronary angiogram based on the combined criterion could detect 94% of CADs. However, compared with ECG only criteria, the combined criterion failed to improve diagnostic accuracy with a lower specificity. PMID:26069108

  16. Safe Oral Triiodo-L-Thyronine Therapy Protects from Post-Infarct Cardiac Dysfunction and Arrhythmias without Cardiovascular Adverse Effects

    PubMed Central

    Rajagopalan, Viswanathan; Zhang, Youhua; Ojamaa, Kaie; Chen, Yue-feng; Pingitore, Alessandro; Pol, Christine J.; Saunders, Debra; Balasubramanian, Krithika; Towner, Rheal A.; Gerdes, A. Martin

    2016-01-01

    Background A large body of evidence suggests that thyroid hormones (THs) are beneficial for the treatment of cardiovascular disorders. We have shown that 3 days of triiodo-L-thyronine (T3) treatment in myocardial infarction (MI) rats increased left ventricular (LV) contractility and decreased myocyte apoptosis. However, no clinically translatable protocol is established for T3 treatment of ischemic heart disease. We hypothesized that low-dose oral T3 will offer safe therapeutic benefits in MI. Methods and Results Adult female rats underwent left coronary artery ligation or sham surgeries. T3 (~6 μg/kg/day) was available in drinking water ad libitum immediately following MI and continuing for 2 month(s) (mo). Compared to vehicle-treated MI, the oral T3-treated MI group at 2 mo had markedly improved anesthetized Magnetic Resonance Imaging-based LV ejection fraction and volumes without significant negative changes in heart rate, serum TH levels or heart weight, indicating safe therapy. Remarkably, T3 decreased the incidence of inducible atrial tachyarrhythmias by 88% and improved remodeling. These were accompanied by restoration of gene expression involving several key pathways including thyroid, ion channels, fibrosis, sympathetic, mitochondria and autophagy. Conclusions Low-dose oral T3 dramatically improved post-MI cardiac performance, decreased atrial arrhythmias and cardiac remodeling, and reversed many adverse changes in gene expression with no observable negative effects. This study also provides a safe and effective treatment/monitoring protocol that should readily translate to humans. PMID:26981865

  17. Corticosteroids prevent acute lung dysfunction caused by thoracic irradiation in unanesthetized sheep

    SciTech Connect

    Loyd, J.E.; Bolds, J.M.; Wickersham, N.; Malcolm, A.W.; Brigham, K.L.

    1988-11-01

    We sought to determine the effect of corticosteroid therapy in a new acute model of oxidant lung injury, thoracic irradiation in awake sheep. Sheep were irradiated with 1,500 rads to the whole chest except for blocking the heart and adjacent ventral lung. Seven experimental sheep were given methylprednisolone (1 g intravenously every 6 h for four doses) and thoracic irradiation; control sheep received only irradiation. In irradiated control sheep, lung lymph flow increased from baseline (7.6 ml/h) to peak at 3 h (13.2), and lung lymph protein clearance increased from 5.1 to 9.7 ml/h. Mean pulmonary artery pressure increased in the irradiated control sheep from 19 to 32.4 cm H/sub 2/O, whereas the lung lymph thromboxane concentration increased from 0.09 to 6.51 ng/ml at 3 h. Arterial oxygen tension in irradiated control sheep fell gradually from 86 mm Hg at baseline to 65 mm Hg at 8 h. Methylprednisolone administration significantly prevented the increase in lung lymph protein clearance, mean pulmonary artery pressure, and lung lymph thromboxane concentration. Methylprednisolone also prevented the fall in arterial oxygen tension after thoracic irradiation, but did not prevent a further decrease in lymphocytes in blood or lung lymph after radiation. We conclude that corticosteroid therapy prevents most of the acute physiologic changes caused by thoracic irradiation in awake sheep.

  18. Probiotics Prevent Intestinal Barrier Dysfunction in Acute Pancreatitis in Rats via Induction of Ileal Mucosal Glutathione Biosynthesis

    PubMed Central

    Lutgendorff, Femke; Nijmeijer, Rian M.; Sandström, Per A.; Trulsson, Lena M.; Magnusson, Karl-Eric; Timmerman, Harro M.; van Minnen, L. Paul; Rijkers, Ger T.; Gooszen, Hein G.; Akkermans, Louis M. A.; Söderholm, Johan D.

    2009-01-01

    Background During acute pancreatitis (AP), oxidative stress contributes to intestinal barrier failure. We studied actions of multispecies probiotics on barrier dysfunction and oxidative stress in experimental AP. Methodology/Principal Findings Fifty-three male Spraque-Dawley rats were randomly allocated into five groups: 1) controls, non-operated, 2) sham-operated, 3) AP, 4) AP and probiotics and 5) AP and placebo. AP was induced by intraductal glycodeoxycholate infusion and intravenous cerulein (6 h). Daily probiotics or placebo were administered intragastrically, starting five days prior to AP. After cerulein infusion, ileal mucosa was collected for measurements of E. coli K12 and 51Cr-EDTA passage in Ussing chambers. Tight junction proteins were investigated by confocal immunofluorescence imaging. Ileal mucosal apoptosis, lipid peroxidation, and glutathione levels were determined and glutamate-cysteine-ligase activity and expression were quantified. AP-induced barrier dysfunction was characterized by epithelial cell apoptosis and alterations of tight junction proteins (i.e. disruption of occludin and claudin-1 and up-regulation of claudin-2) and correlated with lipid peroxidation (r>0.8). Probiotic pre-treatment diminished the AP-induced increase in E. coli passage (probiotics 57.4±33.5 vs. placebo 223.7±93.7 a.u.; P<0.001), 51Cr-EDTA flux (16.7±10.1 vs. 32.1±10.0 cm/s10−6; P<0.005), apoptosis, lipid peroxidation (0.42±0.13 vs. 1.62±0.53 pmol MDA/mg protein; P<0.001), and prevented tight junction protein disruption. AP-induced decline in glutathione was not only prevented (14.33±1.47 vs. 8.82±1.30 nmol/mg protein, P<0.001), but probiotics even increased mucosal glutathione compared with sham rats (14.33±1.47 vs. 10.70±1.74 nmol/mg protein, P<0.001). Glutamate-cysteine-ligase activity, which is rate-limiting in glutathione biosynthesis, was enhanced in probiotic pre-treated animals (probiotics 2.88±1.21 vs. placebo 1.94±0.55 nmol/min/mg protein; P<0

  19. Silencing MicroRNA-155 Attenuates Cardiac Injury and Dysfunction in Viral Myocarditis via Promotion of M2 Phenotype Polarization of Macrophages

    PubMed Central

    Zhang, Yingying; Zhang, Mengying; Li, Xueqin; Tang, Zongsheng; Wang, Xiangmin; Zhong, Min; Suo, Qifeng; Zhang, Yao; Lv, Kun

    2016-01-01

    Macrophage infiltration is a hallmark feature of viral myocarditis. As studies have shown that microRNA-155 regulates the differentiation of macrophages, we aimed to investigate the role of microRNA-155 in VM. We report that silencing microRNA-155 protects mice from coxsackievirus B3 induced myocarditis. We found that microRNA-155 expression was upregulated and localized primarily in heart-infiltrating macrophages and CD4+ T lymphocytes during acute myocarditis. In contrast with wildtype (WT) mice, microRNA-155−/− mice developed attenuated viral myocarditis, which was characterized by decreased cardiac inflammation and decreased intracardiac CD45+ leukocytes. Hearts of microRNA-155−/− mice expressed decreased levels of the IFN-γ and increased levels of the cytokines IL-4 and IL-13. Although total CD4+ and regulatory T cells were unchanged in miR-155−/− spleen proportionally, the activation of T cells and CD4+ T cell proliferation in miR-155−/− mice were significantly decreased. Beyond the acute phase, microRNA-155−/− mice had reduced mortality and improved cardiac function during 5 weeks of follow-up. Moreover, silencing microRNA-155 led to increased levels of alternatively-activated macrophages (M2) and decreased levels of classically-activated macrophages (M1) in the heart. Combined, our studies suggest that microRNA-155 confers susceptibility to viral myocarditis by affecting macrophage polarization, and thus may be a potential therapeutic target for viral myocarditis. PMID:26931072

  20. Renal and Cardiac Endothelial Heterogeneity Impact Acute Vascular Rejection in Pig-to-Baboon Xenotransplantation

    PubMed Central

    Knosalla, C.; Yazawa, K.; Behdad, A.; Bodyak, N.; Shang, H.; Bühler, L.; Houser, S.; Gollackner, B.; Griesemer, A.; Schmitt-Knosalla, I.; Schuurman, H.-J.; Awwad, M.; Sachs, D. H.; Cooper, D. K. C.; Yamada, K.; Usheva, A.; Robson, S. C.

    2010-01-01

    Xenograft outcomes are dictated by xenoantigen expression, for example, Gal α 1, 3Gal (Gal), but might also depend on differing vascular responses. We investigated whether differential vascular gene expression in kidney and cardiac xenografts correlate with development of thrombotic microangiopathy (TM) and consumptive coagulation (CC). Immunosuppressed baboons underwent miniswine or hDAF pig kidney (n = 6) or heart (n = 7), or Gal-transferase gene-knockout (GalT-KO) (thymo)kidney transplantation (n = 14). Porcine cDNA miniarrays determined donor proinflammatory, apoptosis-related and vascular coagulant/fibrinolytic gene expression at defined time points; validated by mRNA, protein levels and immunopathology. hDAF-transgenic and GalT-KO xenografts, (particularly thymokidneys) exhibited prolonged survival. CC was seen with Gal-expressing porcine kidneys (3 of 6), only 1 of 7 baboons post-cardiac xenotransplantation and was infrequent following GalT-KO grafts (1 of 14). Protective-type genes (heme oxygenase-I, superoxide dismutases and CD39) together with von Willebrand factor and P-selectin were upregulated in all renal grafts. Transcriptional responses in Gal-expressing xenografts were comparable to those seen in the infrequent GalT-KO rejection. In cardiac xenografts, fibrin deposition was associated with increased plasminogen activator inhibitor-1 expression establishing that gene expression profiles in renal and cardiac xenografts differ in a quantitative manner. These findings suggest that therapeutic targets may differ for renal and cardiac xenotransplants. PMID:19422330

  1. The implication of tissue Doppler echocardiography and cardiopulmonary exercise in early detection of cardiac dysfunction in systemic lupus erythematosus patients

    PubMed Central

    Elnady, Basant M.; Abdelghafar, Ayman Saeed Mohamed; Khalik, El Shazly Abdul; Algethami, Mohammed Mesfer; Basiony, A.S.; Al-otaibi, Mona Dhaif Allah; Al-otaibi, Maram Eidhah

    2016-01-01

    Objective Systemic lupus erythematosus (SLE) can present limitations to exercise capacity and quality of life (QoL) because of various clinical conditions, such as pulmonary disease or heart disease. Tissue Doppler echocardiography (TDE) offers the promise of an objective measurement to quantify regional and global ventricular function through the assessment of myocardial velocity data. This study aimed to assess the intensity of left ventricular (LV) and right ventricular (RV) systolic and diastolic dysfunction in SLE patients by means of TDE and cardiopulmonary exercise (CPX) testing to determine their impact on QoL. Material and Methods Overall, 56 SLE patients within two tertiary healthcare centers as well as 50 healthy controls were examined with TDE after the exclusion of cardiovascular risk factors. TDE was performed for maximal systolic (S), early diastolic (E′), and late diastolic (A′) velocities of the mitral and tricuspid annulus. Pulsed wave (PW) Doppler of mitral and tricuspid valve inflow was performed in addition to the estimation of the left ventricle ejection fraction and assessment of right ventricle systolic function by tricuspid annular plane systolic excursion (TAPSE). Disease activity was assessed by the Systemic Lupus Activity Measure (SLAM), and the damage index was assessed by the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) Damage Index (SDI). CPX tests according to the modified Bruce protocol were performed. Results SLE patients in both subgroups had more or less similar laboratory data and statistically higher values of ESR, CRP, and anticardiolipin (aCL) antibodies compared to the control group. LV function showed statistically insignificant EF compared to the control group, being lower in the patient group. Tissue Doppler image revealed that E′ and A′ of the mitral annulus were lower in the patient group than in the control group. Concerning RV, TAPSE in the patient group was

  2. Amisulpride-induced acute akathisia in OCD: an example of dysfunctional dopamine–serotonin interactions?

    PubMed Central

    Ersche, Karen D; Cumming, Paul; Craig, Kevin J; Müller, Ulrich; Fineberg, Naomi A; Bullmore, Edward T; Robbins, Trevor W

    2013-01-01

    We report about a clinical observation in a well-characterized group of patients with obsessive–compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D2/3 antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive–compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that individual differences in dopamine–serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies. PMID:21746752

  3. Amisulpride-induced acute akathisia in OCD: an example of dysfunctional dopamine-serotonin interactions?

    PubMed

    Ersche, Karen D; Cumming, Paul; Craig, Kevin J; Müller, Ulrich; Fineberg, Naomi A; Bullmore, Edward T; Robbins, Trevor W

    2012-06-01

    We report about a clinical observation in a well-characterized group of patients with obsessive-compulsive disorder (OCD) during an experimental medicine study in which a single dose of amisulpride (a selective D₂/₃ antagonist) was administered. Almost half of the OCD patients, in particular those with less severe obsessive-compulsive symptoms, experienced acute akathisia in response to the amisulpride challenge. This unexpectedly high incidence of akathisia in the selective serotonin reuptake inhibitor (SSRI)-treated patients with OCD suggests that individual differences in dopamine-serotonin interactions underlie the clinical heterogeneity of OCD, and may thus explain the insufficiency of SSRI monotherapy in those patients not experiencing a satisfactory outcome in symptom reduction. We further speculate about the neuropathology possibly underlying this clinical observation and outline a testable hypothesis for future molecular imaging studies.

  4. Renal Sympathetic Denervation in Rats Ameliorates Cardiac Dysfunction and Fibrosis Post-Myocardial Infarction Involving MicroRNAs

    PubMed Central

    Zheng, Xiaoxin; Li, Xiaoyan; Lyu, Yongnan; He, Yiyu; Wan, Weiguo; Jiang, Xuejun

    2016-01-01

    Background The role of renal sympathetic denervation (RSD) in ameliorating post-myocardial infarction (MI) left ventricular (LV) fibrosis via microRNA-dependent regulation of connective tissue growth factor (CTGF) remains unknown. Material/Methods MI and RSD were induced in Sprague–Dawley rats by ligating the left coronary artery and denervating the bilateral renal nerves, respectively. Norepinephrine, renin, angiotensin II and aldosterone in plasma, collagen, microRNA21, microRNA 101a, microRNA 133a and CTGF in heart tissue, as well as cardiac function were evaluated six weeks post-MI. Results In the RSD group, parameters of cardiac function were significantly improved as evidenced by increased LV ejection fraction (p<0.01), LV end-systolic diameter (p<0.01), end-diastolic diameter (p<0.05), LV systolic pressure (p<0.05), maximal rate of pressure rise and decline (dP/dtmax and dP/dtmin, p<0.05), and decreased LV end-diastolic pressure (p<0.05) when compared with MI rats. Further, reduced collagen deposition in peri-infarct myocardium was observed in RSD-treated rats along with higher microRNA101a and microRNA133a (p<0.05) and lower microRNA21 expression (p<0.01) than in MI rats. CTGF mRNA and protein levels were decreased in LV following RSD (p<0.01), accompanied by decreased expression of norepinephrine, renin, angiotensin II and aldosterone in plasma (p<0.05) compared with untreated MI rats. Conclusions The potential therapeutic effects of RSD on post-MI LV fibrosis may be partly mediated by inhibition of CTGF expression via upregulation of microRNA 101a and microRNA 133a and downregulation of microRNA21. PMID:27490896

  5. Oral glutamine supplementation improves intestinal permeability dysfunction in a murine acute graft-vs.-host disease model.

    PubMed

    Noth, Rainer; Häsler, Robert; Stüber, Eckhard; Ellrichmann, Mark; Schäfer, Heiner; Geismann, Claudia; Hampe, Jochen; Bewig, Burkhard; Wedel, Thilo; Böttner, Martina; Schreiber, Stefan; Rosenstiel, Philip; Arlt, Alexander

    2013-04-01

    Although a profound barrier dysfunction has been reported, little is known about the pathophysiological mechanism evoking gastrointestinal graft-vs.-host disease (GI-GvHD) and apparent therapeutic options. The aim of this study was to evaluate the influence of oral glutamine on the course of GI-GvHD in an acute semiallogenic graft-vs.-host disease (GvHD) in irradiated B6D2F1 mice. An acute semiallogenic GvHD was induced by intraperitoneal injection of lymphocytes from C57BL/6 mice to irradiated B6D2F1 mice. Half of the GvHD animals received oral glutamine supplementation for 6 days started at the time of lymphocyte transfer. Six days after induction of the semiallogenic GvHD, jejunum specimens were prepared. The expression of the proinflammatory cytokine TNF-α and the tight junction protein occludin was investigated by PCR. Histological changes along with the apoptotic response were evaluated and intestinal permeability was assessed. Animals with GvHD showed a strong increase in paracellular permeability as a sign of the disturbed barrier function. TNF-α expression was significantly increased and the expression of the tight junction protein occludin decreased. GvHD led to mucosal atrophy, crypt hyperplasia, crypt apoptosis, and a disintegration of the tight junctions. Glutamine-treated mice showed reduced expression of TNF-α, increased occludin expression, fewer histological changes in the jejunum, smaller number of apoptotic cells in the crypt, and reduced gastrointestinal permeability. In conclusion, oral glutamine seems to have beneficial effects on the severity of inflammatory changes in the course of GvHD and might be a therapeutic option.

  6. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol

    PubMed Central

    Gulati, Geeta; Heck, Siri Lagethon; Ree, Anne Hansen; Hoffmann, Pavel; Schulz-Menger, Jeanette; Fagerland, Morten W.; Gravdehaug, Berit; von Knobelsdorff-Brenkenhoff, Florian; Bratland, Åse; Storås, Tryggve H.; Hagve, Tor-Arne; Røsjø, Helge; Steine, Kjetil; Geisler, Jürgen; Omland, Torbjørn

    2016-01-01

    Aims Contemporary adjuvant treatment for early breast cancer is associated with improved survival but at the cost of increased risk of cardiotoxicity and cardiac dysfunction. We tested the hypothesis that concomitant therapy with the angiotensin receptor blocker candesartan or the β-blocker metoprolol will alleviate the decline in left ventricular ejection fraction (LVEF) associated with adjuvant, anthracycline-containing regimens with or without trastuzumab and radiation. Methods and results In a 2 × 2 factorial, randomized, placebo-controlled, double-blind trial, we assigned 130 adult women with early breast cancer and no serious co-morbidity to the angiotensin receptor blocker candesartan cilexetil, the β-blocker metoprolol succinate, or matching placebos in parallel with adjuvant anticancer therapy. The primary outcome measure was change in LVEF by cardiac magnetic resonance imaging. A priori, a change of 5 percentage points was considered clinically important. There was no interaction between candesartan and metoprolol treatments (P = 0.530). The overall decline in LVEF was 2.6 (95% CI 1.5, 3.8) percentage points in the placebo group and 0.8 (95% CI −0.4, 1.9) in the candesartan group in the intention-to-treat analysis (P-value for between-group difference: 0.026). No effect of metoprolol on the overall decline in LVEF was observed. Conclusion In patients treated for early breast cancer with adjuvant anthracycline-containing regimens with or without trastuzumab and radiation, concomitant treatment with candesartan provides protection against early decline in global left ventricular function. PMID:26903532

  7. The integration of depressive behaviors and cardiac dysfunction during an operational measure of depression: investigating the role of negative social experiences using an animal model

    PubMed Central

    Grippo, Angela J.; Moffitt, Julia A.; Sgoifo, Andrea; Jepson, Amanda J.; Bates, Suzanne L.; Chandler, Danielle L.; McNeal, Neal; Preihs, Kristin

    2012-01-01

    Objective There is a bidirectional association between depression and cardiovascular disease. The neurobiological mechanisms underlying this association may involve an inability to cope with disrupted social bonds. This study investigated in an animal model the integration of depressive behaviors and cardiac dysfunction following a disrupted social bond and during an operational measure of depression, relative to the protective effects of intact social bonds. Methods Depressive behaviors in the forced swim test and continuous electrocardiographic parameters were measured in 14 adult, female socially monogamous prairie voles (rodents), following 4 weeks of social pairing or isolation. Results Following social isolation, animals exhibited (all values are mean ± standard error of the mean, isolated vs. paired respectively) increased heart rate (416±14bpm vs. 370±14bpm, P<0.05) and reduced heart rate variability [3.3±0.2ln(ms2) vs. 3.9±0.2ln(ms2)]. During the forced swim test, isolated animals exhibited greater helpless behavior (immobility, 106±11sec vs. 63±11sec, P<0.05), increased heart rate (530±22bpm vs. 447±15bpm, P<0.05), reduced heart rate variability [1.8±0.4ln(ms2) vs. 2.7±0.2ln(ms2), P<0.05), and increased arrhythmias (arrhythmic burden score, 181±46 vs. 28±12, P<0.05). Conclusions The display of depressive behaviors during an operational measure of depression is coupled with increased heart rate, reduced heart rate variability, and increased arrhythmias, indicative of dysfunctional behavioral and physiological stress-coping abilities as a function of social isolation. In contrast, social pairing with a sibling is behaviorally- and cardioprotective. The present results can provide insight into a possible social mechanism underlying the association of depression and cardiovascular disease in humans. PMID:22753634

  8. The role of thyroid hormone therapy in acutely ill cardiac patients

    PubMed Central

    Wyne, Kathleen L

    2005-01-01

    The presence of a 'low T3 syndrome' in the setting of nonthyroidal illness has long been recognized as the 'euthyroid sick syndrome', with the recommendation to observe and not treat with thyroid hormone replacement therapy. That approach has recently been challenged in the setting of critical cardiac illness. Research demonstrating that thyroid hormone therapy may improve hemodynamic parameters has rekindled interest in the use of thyroid hormone therapy in critical illness. Continued improvements in survival after critical cardiac illness provokes the question of whether thyroid hormone therapy would provide further incremental benefit. PMID:16137376

  9. The Association of Acute Kidney Injury and Atrial Fibrillation after Cardiac Surgery in an Asian Prospective Cohort Study.

    PubMed

    Ng, Roderica Rui Ge; Tan, Gabriel Hong Jie; Liu, Weiling; Ti, Lian Kah; Chew, Sophia Tsong Huey

    2016-03-01

    Acute kidney injury (AKI) and atrial fibrillation (AF) after cardiac surgery are common occurrences and increase patient morbidity and mortality. Inflammation plays a role in increased incidence of AF in patients with chronic kidney disease (CKD); reactive oxygen species and inflammatory markers which are increased in patients with CKD were found to affect the proper functioning of the intracellular ion channels, connexions (transmembrane proteins found in intercellular gap junctions), and electrical homogeneity of the extracellular matrix which are essential for electrical stability and proper conduction of electrical impulses in the atrium. However, it is not known if similar mechanisms are also involved in AKI. We tested the hypothesis that patients with AKI after cardiac surgery have a higher incidence of postoperative AF.Data from 2885 patients, who had undergone cardiac surgery between August 2008 and July 2012 from the Singapore's 2 major heart centers, were obtained prospectively. Postoperative AKI was defined using the Acute Kidney Injury Network criteria. The primary outcome was postoperative AF, and subjects were considered to have postoperative AF if the AF lasted more than an hour, affected hemodynamics, or required medical treatment.The incidence of AKI was 29.7% and the incidence of postoperative AF was 16.8%. A total of 27.7% of AKI patients developed AF. Patients with AKI had a 2-fold increased risk of developing AF (relative risk [RR], 1.716; 95% confidence interval [CI], 1.433-2.055; P < 0.001). The following factors were found to independently increase the risk of AF in patients with AKI: age (RR, 1.011; 95% CI, 1.000-1.022; P = 0.04), low preoperative hemoglobin (RR, 0.942; 95% CI, 0.888-1.000; P = 0.05), low preoperative estimated glomerular filtration rate (eGFR) (RR, 0.987; 95% CI, 0.980-0.994; P < 0.001), and lowest hematocrit during bypass (RR, 0.943; 95% CI, 0.910-0.978; P < 0.001).Patients with AKI are more likely to

  10. Acute Physiological Responses to Short- and Long-Stage High-Intensity Interval Exercise in Cardiac Rehabilitation: A Pilot Study.

    PubMed

    Tschakert, Gerhard; Kroepfl, Julia M; Mueller, Alexander; Harpf, Hanns; Harpf, Leonhard; Traninger, Heimo; Wallner-Liebmann, Sandra; Stojakovic, Tatjana; Scharnagl, Hubert; Meinitzer, Andreas; Pichlhoefer, Patriz; Hofmann, Peter

    2016-03-01

    Despite described benefits of aerobic high-intensity interval exercise (HIIE), the acute responses during different HIIE modes and associated health risks have only been sparsely discovered in heart disease patients. Therefore, the aim of this study was to investigate the acute responses for physiological parameters, cardiovascular and inflammatory biomarkers, and catecholamines yielded by two different aerobic HIIE protocols compared to continuous exercise (CE) in phase III cardiac rehabilitation. Eight cardiac patients (7 with coronary heart disease, 1 with myocarditis; 7 males, 1 female; age: 63.0 ± 9.4 years; height: 1.74 ± 0.05 m; weight: 83.6 ± 8.7 kg), all but one treated with ß-blocking agents, performed a maximal symptom-limited incremental exercise test (IET) and three different exercise tests matched for mean load (Pmean) and total duration: 1) short HIIE with a peak workload duration (tpeak) of 20 s and a peak workload (Ppeak) equal to the maximum power output (Pmax) from IET; 2) long HIIE with a tpeak of 4 min, Ppeak was corresponding to the power output at 85 % of maximal heart rate (HRmax) from IET; 3) CE with a target workload equal to Pmean of both HIIE modes. Acute metabolic and peak cardiorespiratory responses were significantly higher during long HIIE compared to short HIIE and CE (p < 0.05) except HRpeak which tended to be higher in long HIIE than in short HIIE (p = 0.08). Between short HIIE and CE, no significant difference was found for any parameter. Acute responses of cardiovascular and inflammatory biomarkers and catecholamines didn't show any significant difference between tests (p > 0.05). All health-related variables remained in a normal range in any test except NT-proBNP, which was already elevated at baseline. Despite a high Ppeak particularly in short HIIE, both HIIE modes were as safe and as well tolerated as moderate CE in cardiac patients by using our methodological approach. Key pointsHigh-intensity interval exercise (HIIE

  11. Acute Physiological Responses to Short- and Long-Stage High-Intensity Interval Exercise in Cardiac Rehabilitation: A Pilot Study

    PubMed Central

    Tschakert, Gerhard; Kroepfl, Julia M.; Mueller, Alexander; Harpf, Hanns; Harpf, Leonhard; Traninger, Heimo; Wallner-Liebmann, Sandra; Stojakovic, Tatjana; Scharnagl, Hubert; Meinitzer, Andreas; Pichlhoefer, Patriz; Hofmann, Peter

    2016-01-01

    Despite described benefits of aerobic high-intensity interval exercise (HIIE), the acute responses during different HIIE modes and associated health risks have only been sparsely discovered in heart disease patients. Therefore, the aim of this study was to investigate the acute responses for physiological parameters, cardiovascular and inflammatory biomarkers, and catecholamines yielded by two different aerobic HIIE protocols compared to continuous exercise (CE) in phase III cardiac rehabilitation. Eight cardiac patients (7 with coronary heart disease, 1 with myocarditis; 7 males, 1 female; age: 63.0 ± 9.4 years; height: 1.74 ± 0.05 m; weight: 83.6 ± 8.7 kg), all but one treated with ß-blocking agents, performed a maximal symptom-limited incremental exercise test (IET) and three different exercise tests matched for mean load (Pmean) and total duration: 1) short HIIE with a peak workload duration (tpeak) of 20 s and a peak workload (Ppeak) equal to the maximum power output (Pmax) from IET; 2) long HIIE with a tpeak of 4 min, Ppeak was corresponding to the power output at 85 % of maximal heart rate (HRmax) from IET; 3) CE with a target workload equal to Pmean of both HIIE modes. Acute metabolic and peak cardiorespiratory responses were significantly higher during long HIIE compared to short HIIE and CE (p < 0.05) except HRpeak which tended to be higher in long HIIE than in short HIIE (p = 0.08). Between short HIIE and CE, no significant difference was found for any parameter. Acute responses of cardiovascular and inflammatory biomarkers and catecholamines didn’t show any significant difference between tests (p > 0.05). All health-related variables remained in a normal range in any test except NT-proBNP, which was already elevated at baseline. Despite a high Ppeak particularly in short HIIE, both HIIE modes were as safe and as well tolerated as moderate CE in cardiac patients by using our methodological approach. Key points High-intensity interval exercise (HIIE

  12. Adrenoceptor hyporeactivity is responsible for Escherichia coli endotoxin-induced acute vascular dysfunction in humans.

    PubMed

    Pleiner, Johannes; Heere-Ress, Elisabeth; Langenberger, Herbert; Sieder, Anna E; Bayerle-Eder, Michaela; Mittermayer, Fritz; Fuchsjäger-Mayrl, Gabriele; Böhm, Johannes; Jansen, Burkhard; Wolzt, Michael

    2002-01-01

    Impaired response to catecholamines contributes to the altered hemodynamics in sepsis, which has been attributed to excessive NO formation. We have studied the systemic hemodynamic and local forearm responses and inducible NO synthase (iNOS) expression during experimental endotoxemia in humans. Escherichia coli endotoxin (lipopolysaccharide [LPS]) was administered at doses of 1 or 2 ng/kg to healthy volunteers. In 10 subjects, the systemic pressor effect of phenylephrine was assessed before and after the administration of LPS. In 9 further subjects, forearm blood flow responses to intra-arterial noradrenaline, acetylcholine, glyceryl trinitrate, and N(G)-monomethyl-L-arginine (L-NMMA) were studied at baseline and after LPS administration. Peripheral blood was collected and analyzed for iNOS mRNA and protein. Four hours after LPS, the response of systolic blood pressure (P<0.0005) and heart rate (P<0.05) to phenylephrine was significantly reduced. In the forearm, noradrenaline-induced vasoconstriction was also reduced by approximately 50% (P<0.01), but L-NMMA responsiveness was unchanged. iNOS mRNA or protein was not increased. Marked vascular adrenoceptor hyporeactivity is detectable in the absence of increased NO activity or iNOS expression in endotoxemia, arguing against major involvement of vascular iNOS activity in the acute systemic vasodilation to LPS.

  13. Subclinical Cardiac Dysfunction Detected by Strain Imaging During Breast Irradiation With Persistent Changes 6 Weeks After Treatment

    SciTech Connect

    Lo, Queenie; Hee, Leia; Batumalai, Vikneswary; Allman, Christine; MacDonald, Peter; Delaney, Geoff P.; Lonergan, Denise; Thomas, Liza

    2015-06-01

    Purpose: To evaluate 2-dimensional strain imaging (SI) for the detection of subclinical myocardial dysfunction during and after radiation therapy (RT). Methods and Materials: Forty women with left-sided breast cancer, undergoing only adjuvant RT to the left chest, were prospectively recruited. Standard echocardiography and SI were performed at baseline, during RT, and 6 weeks after RT. Strain (S) and strain rate (Sr) parameters were measured in the longitudinal, circumferential, and radial planes. Correlation of change in global longitudinal strain (GLS % and Δ change) and the volume of heart receiving 30 Gy (V30) and mean heart dose (MHD) were examined. Results: Left ventricular ejection fraction was unchanged; however, longitudinal systolic S and Sr and radial S were significantly reduced during RT and remained reduced at 6 weeks after treatment [longitudinal S (%) −20.44 ± 2.66 baseline vs −18.60 ± 2.70* during RT vs −18.34 ± 2.86* at 6 weeks after RT; longitudinal Sr (s{sup −1}) −1.19 ± 0.21 vs −1.06 ± 0.18* vs −1.06 ± 0.16*; radial S (%) 56.66 ± 18.57 vs 46.93 ± 14.56* vs 49.22 ± 15.81*; *P<.05 vs baseline]. Diastolic Sr were only reduced 6 weeks after RT [longitudinal E Sr (s{sup −1}) 1.47 ± 0.32 vs 1.29 ± 0.27*; longitudinal A Sr (s{sup −1}) 1.19 ± 0.31 vs 1.03 ± 0.24*; *P<.05 vs baseline], whereas circumferential strain was preserved throughout. A modest correlation between S and Sr and V30 and MHD was observed (GLS Δ change and V30 ρ = 0.314, P=.05; GLS % change and V30 ρ = 0.288, P=.076; GLS Δ change and MHD ρ = 0.348, P=.03; GLS % change and MHD ρ = 0.346, P=.031). Conclusions: Subclinical myocardial dysfunction was detected by 2-dimensional SI during RT, with changes persisting 6 weeks after treatment, though long-term effects remain unknown. Additionally, a modest correlation between strain reduction and radiation dose was observed.

  14. A pilot study of prognostic value of non-invasive cardiac parameters for major adverse cardiac events in patients with acute coronary syndrome treated with percutaneous coronary intervention

    PubMed Central

    Yuan, Min-Jie; Pan, Ye-Sheng; Hu, Wei-Guo; Lu, Zhi-Gang; Zhang, Qing-Yong; Huang, Dong; Huang, Xiao-Li; Wei, Meng; Li, Jing-Bo

    2015-01-01

    The objective of this study was to determine the combination of left ventricular ejection fraction (LVEF) and individual electrocardiographic parameters related to abnormal depolarization/repolarization or baroreceptor sensitivity that had the best predictive value for major adverse cardiac events (MACE) in patients with acute coronary syndrome (ACS). Patients with ACS who underwent coronary angiography and percutaneous coronary intervention (PCI) were included in this prospective study. Ventricular late potential (VLP), heart rate turbulence (HRT), heart rate variability (HRV), and T wave alternans (TWA) parameters were measured using 24 h Holter monitoring 2-4 weeks after onset of ACS. Initial and follow-up LVEF was measured by ultrasound. Patients were followed for at least 6 months to record the occurrence of MACE. Models using combinations of the individual independent prognostic factors found by multivariate analysis were then constructed to use for estimation of risk of MACE. In multivariate analysis, VLP measured as QRS duration, HRV measured as standard deviation of normal RR intervals, and followup LVEF, but none of the other parameters studied, were independent risk factors for MACE. Areas under ROC curve (AUCs) for combinations of 2 or all 3 factors ranged from 0.73 to 0.76. Combinations of any of the three independent risk factors for MACE in ACS patients with PCI improved prediction and, because these risk factors were obtained non-invasively, may have future clinical usefulness. PMID:26885226

  15. Oxidative stress predicts progression of peripheral and cardiac autonomic nerve dysfunction over 6 years in diabetic patients.

    PubMed

    Ziegler, Dan; Buchholz, Stefanie; Sohr, Christoph; Nourooz-Zadeh, Jaffar; Roden, Michael

    2015-02-01

    Oxidative stress is implicated in the pathogenesis of experimental diabetic neuropathy, but prospective studies in diabetic patients are lacking. We aimed to evaluate whether the plasma levels of various biomarkers of oxidative stress predict the progression of diabetic neuropathy and mortality over 6 years. We followed 89 diabetic patients aged 54 ± 14 years (59 % with polyneuropathy), 72 of whom underwent nerve function reassessment after 6.2 ± 0.8 years, whereas 17 died after 4.2 ± 1.0 years. Plasma markers of oxidative stress at baseline included superoxide anion, hypochlorous acid, peroxynitrite, 8-iso-prostaglandin F2α, vitamin E/lipid ratio, and vitamin C. Neuropathy was assessed by symptoms and deficits, motor and sensory nerve conduction velocity (MNCV, SNCV), vibration perception thresholds (VPT), thermal detection thresholds, and heart rate variability (HRV). Despite a reduction in HbA1c by 1.4 ± 1.6 % (p < 0.001), median SNCV, sural SNCV, peroneal MNCV, malleolar VPT, and warm TDT deteriorated after 6 years (all p < 0.05). In multivariate models, increased superoxide generation was associated with a decline in median SNCV (β = -0.997; p = 0.036) and deterioration in HRV at rest (OR 1.63 [95 % CI 1.09-2.44]; p = 0.017) over 6 years. Low vitamin E/lipid ratio tended to predict a decrease in peroneal MNCV (β = 0.781; p = 0.057) and an increase in malleolar VPT (β = -0.725; p = 0.077). Plasma superoxide generation was associated with an increased risk of mortality (HR 23.2 [95 % CI 1.05-513]; p = 0.047). In conclusion, increased plasma superoxide generation predicted the decline in sensory and cardiac autonomic nerve function and mortality over 6 years in diabetic patients, but larger studies are required for confirmation.

  16. Tissue-Specific B-Cell Dysfunction and Generalized Memory B-Cell Loss during Acute SIV Infection

    PubMed Central

    Peruchon, Sandrine; Chaoul, Nada; Burelout, Chantal; Delache, Benoit; Brochard, Patricia; Laurent, Pascale; Cognasse, Fabrice; Prévot, Sophie; Garraud, Olivier; Le Grand, Roger; Richard, Yolande

    2009-01-01

    Background Primary HIV-infected patients display severe and irreversible damage to different blood B-cell subsets which is not restored by highly efficient anti-retroviral therapy (HAART). Because longitudinal investigations of primary HIV-infection is limited by the availability of lymphoid organs, we studied the tissue-specific B-cell dysfunctions in acutely simian immunodeficiency virus (SIV) mac251-infected Cynomolgus macaques. Methods and Findings Experiments were performed on three groups of macaques infected for 14, 21 or 28 days and on three groups of animals treated with HAART for two-weeks either initiated at 4 h, 7 or 14 days post-infection (p.i.). We have simultaneously compared changes in B-cell phenotypes and functions and tissue organization of B-cell areas in various lymphoid organs. We showed that SIV induced a steady decline in SIgG-expressing memory (SIgD−CD27+) B-cells in spleen and lymph nodes during the first 4 weeks of infection, concomitant to selective homing/sequestration of B-cells to the small intestine and spleen. SIV non-specific Ig production was transiently increased before D14p.i., whereas SIV-specific Ig production was only detectable after D14p.i., coinciding with the presence of CD8+ T-cells and IgG-expressing plasma cells within germinal centres. Transient B-cell apoptosis on D14p.i. and commitment to terminal differentiation contributed to memory B-cell loss. HAART abrogated B-cell apoptosis, homing to the small intestine and SIV-specific Ig production but had minimal effect on early Ig production, increased B-cell proportions in spleen and loss of memory B-cells. Therefore, virus–B-cell interactions and SIV-induced inflammatory cytokines may differently contribute to early B-cell dysfunction and impaired SIV/HIV-specific antibody response. Conclusions These data establish tissue-specific impairments in B-cell trafficking and functions and a generalized and steady memory B-cell loss in secondary lymphoid organs

  17. Mood disturbance and depression in Arab women following hospitalisation from acute cardiac conditions: a cross-sectional study from Qatar

    PubMed Central

    Donnelly, Tam Truong; Al Suwaidi, Jassim Mohd; Al-Qahtani, Awad; Asaad, Nidal; Fung, Tak; Singh, Rajvir; Qader, Najlaa Abdul

    2016-01-01

    Objectives Depression is associated with increased morbidity and mortality rates among cardiovascular patients. Depressed patients have three times higher risk of death than those who are not. We sought to determine the presence of depressive symptoms, and whether gender and age are associated with depression among Arab patients hospitalised with cardiac conditions in a Middle Eastern country. Setting Using a non-probability convenient sampling technique, a cross-sectional survey was conducted with 1000 Arab patients ≥20 years who were admitted to cardiology units between 2013 and 2014 at the Heart Hospital in Qatar. Patients were interviewed 3 days after admission following the cardiac event. Surveys included demographic and clinical characteristics, and the Arabic version of the Beck Depression Inventory Second Edition (BDI-II). Depression was assessed by BDI-II clinical classification scale. Results 15% of the patients had mild mood disturbance and 5% had symptoms of clinical depression. Twice as many females than males suffered from mild mood disturbance and clinical depression symptoms, the majority of females were in the age group 50 years and above, whereas males were in the age group 40–49 years. χ2 Tests and multivariate logistic regression analyses indicated that gender and age were statistically significantly related to depression (p<0.001 for all). Conclusions Older Arab women are more likely to develop mood disturbance and depression after being hospitalised with acute cardiac condition. Gender and age differences approach, and routine screening for depression should be conducted with all cardiovascular patients, especially for females in the older age groups. Mental health counselling should be available for all cardiovascular patients who exhibit depressive symptoms. PMID:27388362

  18. Outcome of veno-venous extracorporeal membrane oxygenation use in acute respiratory distress syndrome after cardiac surgery with cardiopulmonary bypass

    PubMed Central

    Song, Joo Han; Woo, Won Ki; Song, Seung Hwan; Kim, Hyo Hyun; Kim, Bong Joon; Kim, Ha Eun; Kim, Do Jung; Suh, Jee Won; Shin, Yu Rim; Park, Han Ki; Lee, Seung Hyun; Joo, Hyun Chel; Lee, Sak; Chang, Byung Chul; Yoo, Kyung Jong; Kim, Young Sam

    2016-01-01

    Background Cardiac surgery with cardiopulmonary bypass (CPB) is a known risk factor for acute respiratory distress syndrome (ARDS). We aimed to analyze the treatment outcome in patients who required veno-venous extracorporeal membrane oxygenation (VV-ECMO) for postcardiotomy ARDS despite other rescue modalities. Methods We retrospectively reviewed the outcomes in 13 patients (mean age, 54.7±5.9 years) who received VV-ECMO support for refractory ARDS after cardiac surgery between March 2013 and February 2016 at Severance Hospital, Yonsei University (Seoul, Korea). Results At the start of VV-ECMO, the average lung injury score was 3.0±0.2, and the Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score was −4±1.1. Although 7 patients initiated VV-ECMO support within 24 h from operation, the remaining 6 started at a median of 8.5 days (range, 5−16 days). Nine (69.3%) patients were successfully weaned from VV-ECMO. After a median follow-up duration of 14.5 months (range, 1.0−33.0 months) for survivors, the 1-year overall survival was 58.6%±14.4%. The differences in the overall survival from VV-ECMO according to the RESP score risk classes were borderline significant (100% in class III, 50%±25% in class IV, and 20%±17.9% in class V; P=0.088). Conclusions VV-ECMO support can be a feasible rescue strategy for adult patients who develop refractory ARDS after a cardiac surgery. Additionally, the RESP score seems a valuable prognostic tool for post-ECMO survival outcome in this patient population as well. PMID:27499972

  19. Enhanced carotid-cardiac baroreflex response and elimination of orthostatic hypotension 24 hours after acute exercise in paraplegics

    NASA Technical Reports Server (NTRS)

    Engelke, K. A.; Shea, J. D.; Doerr, D. F.; Convertino, V. A.

    1992-01-01

    To test the hypothesis that an acute bout of maximal exercise can ameliorate orthostatic hypotension consequent to prolonged wheelchair confinement, we evaluated heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure responses during 15 minutes of 70 degrees head-up tilt (HUT) in 10 paraplegic subjects 24 hours after arm crank exercise designed to elicit maximal effort, and during a control (no exercise) conditions. Additionally, the carotid baroreceptor stimulus-cardiac response relationship was determined by measurement of R-R interval during external application of graded pressures to the carotid sinuses. One week separated the treatment conditions. The maximum slope of the carotid-cardiac baroreflex response was increased (p = 0.049) by exercise (6.2 +/- 1.7 msec/mmHg) compared to control (3.3 +/- 0.6). During control HUT, HR increased from 61 +/- 1 to 90 +/- 7 bpm (p = 0.001) while SBP decreased from 118 +/- 5 to 106 +/- 9 mmHg (p = 0.025). During HUT 24 hours after exercise, HR increased from 60 +/- 2 to 90 +/- 4 bpm (p = 0.001), but the reduction in SBP was essentially eliminated (116 +/- 5 to 113 +/- 5 mmHg).

  20. Intravenous administration of atorvastatin-pretreated mesenchymal stem cells improves cardiac performance after acute myocardial infarction: role of CXCR4

    PubMed Central

    Li, Na; Yang, Yue-Jin; Qian, Hai-Yan; Li, Qing; Zhang, Qian; Li, Xiang-Dong; Dong, Qiu-Ting; Xu, Hui; Song, Lei; Zhang, Hao

    2015-01-01

    Background: The interaction between stromal cell-derived factor 1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) plays an important role in mesenchymal stem cells (MSCs) migration and engraftment. Statins can increase the survival of MSCs. However, whether statins could enhance MSCs migration and engraftment is still unknown. Therefore, we designed the study to investigate whether atorvastatin (ATV) could enhance CXCR4 expression of MSCs and promote them homing toward the injured myocardium. Methods and results: Expression of CXCR4 was evaluated by flow cytometry and real time PCR. A transwell system was used to assess MSCs migration ability. Recruitment of systematically delivered MSCs to the infarcted heart was evaluated in Sprague-Dawley rats with acute myocardial infarction (AMI). ATV pretreatment enhanced the expression of CXCR4 and stimulated MSCs migration in vitro. However, the effect was largely abolished by CXCR4 neutralizing antibody. In AMI models, we found much more ATV-pretreated MSCs homing toward the infarcted myocardium than non-treated cells and this was accompanied by improved cardiac performance. Conclusions: ATV increases the migration ability of MSCs and improves cardiac performance due to up-regulated expression of CXCR4. These results suggest that ATV pretreatment of donor MSCs is an effective way to promote cell therapeutic potential for AMI. PMID:26279750

  1. Lipopolysaccharide Binding Protein and sCD14 are Not Produced as Acute Phase Proteins in Cardiac Surgery

    PubMed Central

    Kudlova, Manuela; Kunes, Pavel; Kolackova, Martina; Lonsky, Vladimir; Mandak, Jiri; Andrys, Ctirad; Jankovicova, Karolina; Krejsek, Jan

    2007-01-01

    Objectives. The changes in the serum levels of lipopolysaccharide binding protein (LBP) and sCD14 during cardiac surgery were followed in this study. Design. Thirty-four patients, 17 in each group, were randomly assigned to coronary artery bypass grafting surgery performed either with (“on-pump”) or without (“off-pump”) cardiopulmonary bypass. LBP and sCD14 were evaluated by ELISA. Results. The serum levels of LBP were gradually increased from the 1st postoperative day and reached their maximum on the 3rd postoperative day in both “on-pump” and “off-pump” patients (30.33±9.96 μg/mL; 37.99±16.58 μg/mL), respectively. There were no significant differences between “on-pump” and “off-pump” patients regarding LBP. The significantly increased levels of sCD14 from the 1st up to the 7th postoperative day in both “on-pump” and “off-pump” patients were found with no significant differences between these groups. No correlations between LBP and sCD14 and IL-6, CRP and long pentraxin PTX3 levels were found. Conclusions. The levels of LBP and sCD14 are elevated in cardiac surgical patients being similar in both groups. These molecules are not produced as acute phase proteins in these patients. PMID:18288274

  2. Influence of microvascular dysfunction on regional myocardial deformation post-acute myocardial infarction: insights from a novel angiographic index for assessing myocardial tissue-level reperfusion.

    PubMed

    He, Ben; Ding, Song; Qiao, Zhiqing; Gao, Lincheng; Wang, Wei; Ge, Heng; Shen, Xuedong; Pu, Jun

    2016-05-01

    To investigate the impact of microvascular dysfunction assessed by angiography on myocardial deformation assessed by two-dimensional speckle-tracking echocardiography in ST-segment elevation myocardial infarction (STEMI). A total of 121 STEMI patients who received primary percutaneous coronary intervention were included. Thrombolysis in myocardial infarction, Myocardial Perfusion Frame Count (TMPFC), a novel angiographic method to assess myocardial perfusion, was used to evaluate microvascular dysfunction. Two-dimensional speckle-tracking echocardiography was performed at 3-7 days after reperfusion. The infarction related regional longitudinal (RLS) strains as well as circumferential (RCS) and radial (RRS) ones, along with global longitudinal, circumferential (GCS), and radial (GRS) strains were measured. Patients with microvascular dysfunction had decreased peak amplitude of RLS (p = 0.012), RCS (p < 0.001), RRS (p = 0.012) at the regional level and decreased peak amplitude of GCS (p = 0.005), GRS (p = 0.012) at the global level. The RCS to RLS and RCS to RRS ratios were significantly different between patients without than with microvascular dysfunction (1.28 ± 0.31 vs. 1.07 ± 0.47, p = 0.027 and 0.69 ± 0.33 vs. 0.56 ± 0.28, p = 0.047). Receiver operator characteristics curves identified a cutoff value of 94 frames for TMPFC to differentiate between normal and abnormal wall motion score index in the sub-acute phase of STEMI (AUC = 0.72; p < 0.001). In the sub-acute phase of STEMI, the presence of microvascular dysfunction in infarcted tissue relates to reduced global and regional myocardial deformation. RCS alterations were more significant than RLS and RRS between patients with than without microvascular dysfunction. TMPFC was useful to predict left ventricular systolic dysfunction in the sub-acute phase of STEMI.

  3. Ultra-rapid manufacturing of engineered epicardial substitute to regenerate cardiac tissue following acute ischemic injury.

    PubMed

    Serpooshan, Vahid; Ruiz-Lozano, Pilar

    2014-01-01

    Considering the impaired regenerative capacity of adult mammalian heart tissue, cardiovascular tissue engineering aims to create functional substitutes that can restore the structure and function of the damaged cardiac tissue. The success of cardiac regenerative therapies has been limited mainly due to poor control on the structure and properties of the tissue substitute, lack of vascularization, and immunogenicity. In this study we introduce a new approach to rapidly engineer dense biomimetic scaffolds consisting of type I collagen, to protect the heart against severe ischemic injury. Scaffold biomechanical properties are adjusted to mimic embryonic epicardium which is shown to be optimal to support cardiomyocyte contractile work. Moreover, the designed patch can serve as a delivery device for targeted, controlled release of cells or therapeutic macromolecules into the lesion area.

  4. The role of acute hyperinsulinemia in the development of cardiac arrhythmias.

    PubMed

    Drimba, László; Döbrönte, Róbert; Hegedüs, Csaba; Sári, Réka; Di, Yin; Németh, Joseph; Szilvássy, Zoltán; Peitl, Barna

    2013-05-01

    Patients with perturbed metabolic control are more prone to develop cardiac rhythm disturbances. The main purpose of the present preclinical study was to investigate the possible role of euglycemic hyperinsulinemia in development of cardiac arrhythmias. Euglycemic hyperinsulinemia was induced in conscious rabbits equipped with a right ventricular pacemaker electrode catheter by hyperinsulinemic euglycemic glucose clamp (HEGC) applying two different rates of insulin infusion (5 and 10 mIU/kg/min) and variable rate of glucose infusion to maintain euglycemia (5.5 ± 0.5 mmol/l). The effect of hyperinsulinemia on cardiac electrophysiological parameters was continuously monitored by means of 12-lead surface ECG recording. Arrhythmia incidence was determined by means of programmed electrical stimulation (PES). The possible role of adrenergic activation was investigated by determination of plasma catecholamine levels and intravenous administration of a beta adrenergic blocking agent, metoprolol. All of the measurements were performed during the steady-state period of HEGC and subsequent to metoprolol administration. Both 5 and 10 mIU/kg/min insulin infusion prolonged significantly QTend, QTc, and Tpeak-Tend intervals. The incidence of ventricular arrhythmias generated by PES was increased significantly by euglycemic hyperinsulinemia and exhibited linear relationship to plasma levels of insulin. No alteration on plasma catecholamine levels could be observed; however, metoprolol treatment restored the prolonged QTend, QTc, and Tpeak-Tend intervals and significantly reduced the hyperinsulinemia-induced increase of arrhythmia incidence. Euglycemic hyperinsulinemia can exert proarrhythmic effect presumably due to the enhancement of transmural dispersion of repolarization. Metoprolol treatment may be of benefit in hyperinsulinemia associated with increased incidence of cardiac arrhythmias.

  5. mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces Cardiac Dysfunction with the Increased Number of Small Mitochondria Mediated through the Down-Regulation of Autophagy.

    PubMed

    Taneike, Manabu; Nishida, Kazuhiko; Omiya, Shigemiki; Zarrinpashneh, Elham; Misaka, Tomofumi; Kitazume-Taneike, Rika; Austin, Ruth; Takaoka, Minoru; Yamaguchi, Osamu; Gambello, Michael J; Shah, Ajay M; Otsu, Kinya

    2016-01-01

    Mammalian target of rapamycin complex 1 (mTORC1) is a key regulator of cell growth, proliferation and metabolism. mTORC1 regulates protein synthesis positively and autophagy negatively. Autophagy is a major system to manage bulk degradation and recycling of cytoplasmic components and organelles. Tuberous sclerosis complex (TSC) 1 and 2 form a heterodimeric complex and inactivate Ras homolog enriched in brain, resulting in inhibition of mTORC1. Here, we investigated the effects of hyperactivation of mTORC1 on cardiac function and structure using cardiac-specific TSC2-deficient (TSC2-/-) mice. TSC2-/- mice were born normally at the expected Mendelian ratio. However, the median life span of TSC2-/- mice was approximately 10 months and significantly shorter than that of control mice. TSC2-/- mice showed cardiac dysfunction and cardiomyocyte hypertrophy without considerable fibrosis, cell infiltration or apoptotic cardiomyocyte death. Ultrastructural analysis of TSC2-/- hearts revealed misalignment, aggregation and a decrease in the size and an increase in the number of mitochondria, but the mitochondrial function was maintained. Autophagic flux was inhibited, while the phosphorylation level of S6 or eukaryotic initiation factor 4E -binding protein 1, downstream of mTORC1, was increased. The upregulation of autophagic flux by trehalose treatment attenuated the cardiac phenotypes such as cardiac dysfunction and structural abnormalities of mitochondria in TSC2-/- hearts. The results suggest that autophagy via the TSC2-mTORC1 signaling pathway plays an important role in maintenance of cardiac function and mitochondrial quantity and size in the heart and could be a therapeutic target to maintain mitochondrial homeostasis in failing hearts.

  6. mTOR Hyperactivation by Ablation of Tuberous Sclerosis Complex 2 in the Mouse Heart Induces