cardiovascular-agents and Hypertrophy

Regardless of the type of arterial reconstruction, luminal narrowing (stenosis or restenosis) develops in approximately one third of the vessels. In the past, the focus of research has been on the mechanisms of stenosis (intimal hyperplasia, pathologic remodeling) and pharmacologic approaches to prevention. An alternative approach is to induce intimal atrophy after luminal narrowing has developed, thus limiting treatment to only those patients that develop a problem. This approach to treat established disease by reducing wall mass through induction of cell death and extracellular matrix removal would be particularly useful for treating stenosis in synthetic bypass grafts or stented vessels, in which intimal hyperplasia is the primary mechanism of stenosis. This approach may be applicable as well to other vascular proliferative disorders, such as pulmonary hypertension and chronic transplant arteriopathy. Proof of principle has been shown in experiments with antibodies to platelet-derived growth factor (PDGF) receptors that cause neointimal regression in baboon polytetrafluoroethylene (PTFE) grafts and with angiotensin-converting enzyme inhibitors that induce medial atrophy in hypertensive arteries. Possible molecular targets could include PDGF receptors, A20, and BMP4. Further studies are needed to determine the utility of such a therapeutic approach to vascular disease.

Topics: Animals; Arterial Occlusive Diseases; Atrophy; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Blood Vessels; Cardiovascular Agents; Cell Death; Cell Proliferation; Constriction, Pathologic; Coronary Disease; Disease Models, Animal; Heart Transplantation; Humans; Hyperplasia; Hypertension; Hypertrophy; Recurrence; Remission Induction; Signal Transduction; Stents

Myocardial recovery after left ventricular assist device (LVAD) support has been reported. The LVAD Working Group Recovery Study was a prospective multicenter trial to assess the incidence of myocardial recovery in patients bridged to cardiac transplantation.. After LVAD implantation, patients were evaluated with the use of rest echocardiograms with partial LVAD support and cardiopulmonary exercise testing. Dobutamine echocardiography with hemodynamic measurements was performed in those patients with left ventricular ejection fraction >40% during resting studies. Histological analysis was performed on myocardial samples taken at LVAD implantation and explantation. Sixty-seven LVAD patients with heart failure participated in the study. After 30 days, significant improvement occurred in left ventricular ejection fraction (17+/-7% versus 34+/-12%; P<0.001) and reductions in left ventricular end-diastolic diameter (7.1+/-1.2 versus 5.1+/-1.1 cm; P<0.001) and left ventricular mass (320+/-113 versus 194+/-79 g; P<0.001) compared with before LVAD. Thirty-four percent of patients had left ventricular ejection fraction >40% with partial device support. Left ventricular ejection fraction decreased over time to pre-LVAD measurement by 120 days. Peak VO2 improved with mechanical support (13.7+/-4.2 versus 18.9+/-5.5 mL/kg per minute, 30 versus 120 days; P<0.001). Tissue analysis revealed significant reductions in myocyte size, collagen content, and cardiac tumor necrosis factor-alpha. Six subjects (9%) underwent LVAD explantation for recovery.. Cardiac function improves significantly after device implantation. Although cellular recovery and improvement in ventricular function are observed, the degree of clinical recovery is insufficient for device explantation in most patients with chronic heart failure.

Topics: Cardiovascular Agents; Combined Modality Therapy; Cytokines; Dobutamine; Exercise Test; Exercise Tolerance; Female; Fibrosis; Heart Failure; Heart Function Tests; Heart Transplantation; Heart-Assist Devices; Humans; Hypertrophy; Male; Middle Aged; Myocardium; Myocytes, Cardiac; Prospective Studies; Single-Blind Method; Stroke Volume; Treatment Outcome; Ultrasonography

The renin-angiotensin system (RAS), which plays an important role in the progression of heart failure, is efficiently blocked by the inhibition of renin, the rate-limiting enzyme in the RAS cascade. In the present study, we investigated the cardioprotective effects of TAK-272 (SCO-272, imarikiren), a novel, orally effective direct renin inhibitor (DRI), and compared its efficacy with that of aliskiren, a DRI that is already available in the market. TAK-272 was administered to calsequestrin transgenic (CSQ-tg) heart failure mouse model that show severe symptoms and high mortality. The CSQ-tg mice treated with 300 mg/kg, the highest dose tested, of TAK-272 showed significantly reduced plasma renin activity (PRA), cardiac hypertrophy, and lung congestion. Further, TAK-272 reduced cardiomyocyte injury accompanied by an attenuation of the increase in NADPH oxidase 4 and nitric oxide synthase 3 expressions. TAK-272 also prolonged the survival of CSQ-tg mice in a dose-dependent manner (30 mg/kg: P = 0.42, 100 mg/kg: P = 0.12, 300 mg/kg: P < 0.01). Additionally, when compared at the same dose level (300 mg/kg), TAK-272 showed strong and sustained PRA inhibition and reduced the heart weight and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration, a heart failure biomarker, while aliskiren showed a significant weaker PRA inhibition and failed to demonstrate any cardioprotective effects. Our results showed that TAK-272 is an orally active and persistent renin inhibitor, which reduced the mortality of CSQ-tg mice and conferred protection against cardiac hypertrophy and injury. Thus, TAK-272 treatment could provide a new therapeutic approach for heart failure.

Topics: Amides; Animals; Benzimidazoles; Cardiovascular Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Fumarates; Heart; Heart Failure; Hypertrophy; Lung Diseases; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Transgenic; Morpholines; Piperidines; Protective Agents; Random Allocation; Renin

Defibrillation testing (DT) is considered a standard procedure during implantable cardioverter-defibrillator (ICD) implantation. However, little is known about the factors that are significantly related to patients with high defibrillation threshold (DFT) using the present triad system.. We examined 286 consecutive patients who underwent ICD implantation with a transvenous dual-coil lead and DT from December 2000 to December 2011. We defined patients who required 25 J or more by the implanted device as the high DFT group, and those who required less than 25 J as the normal DFT group. For each patient, assessment parameters included underlying disease, comorbidities, NYHA functional class, drugs, and echocardiographic measures. The high DFT group consisted of 12 patients (4.2%). Multivariate analysis identified 3 independent predictors for high DFT: atrial fibrillation (odds ratio (OR) 4.85, 95% confidence interval (CI) 1.24-22.33, P=0.023), hypertension (OR 4.01, 95% CI 1.08-15.96, P=0.039), thickness of interventricular septum (IVS) >12 mm (OR 4.82, 95% CI 1.17-20.31, P=0.030).. Atrial fibrillation, hypertension and IVS hypertrophy were significantly associated with high DFT. Identification of such patients could help to lower the risk of complications with DT.

Topics: Atrial Fibrillation; Cardiovascular Agents; Combined Modality Therapy; Defibrillators, Implantable; Electrodes; Equipment Design; Female; Heart Diseases; Heart Septum; Humans; Hypertension; Hypertrophy; Male; Middle Aged; Retrospective Studies; Risk Factors; Ventricular Fibrillation

The present study evaluated the antihypertrophic potential of the ethanolic extract of Boerhaavia diffusa (BDE), a well-known edible cardiotonic plant reported in Ayurveda against angiotensin II-induced hypertrophy in H9c2 cardiac myoblast cells. Markers of hypertrophy such as cell size, protein content and the concentrations of atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) were analysed for the confirmation of hypertrophy induction. Angiotensin II (100 nM) caused an increase in cell volume (69·26 (SD 1·21)%),protein content (48·48 (SD 1·64)%), ANP (81·90 (SD 1·22)%) and BNP (108·57 (SD 1·47)%). BDE treatment significantly reduced cell volume, protein content and the concentrations of ANP and BNP (P#0·05) in H9c2 cells. The activity of various antioxidant enzymes and the concentration of reduced glutathione, which was lowered due to hypertrophy, were increased in BDE-treated cells. The BDE treatment also reduced intracellular reactive oxygen species generation, lipid peroxidation and protein carbonyls in cells. In addition,the expression patterns of NF-kb and transforming growth factor b1 were found to be increased during hypertrophy, and their expressions were reduced on BDE treatment. In vitro chemical assays showed that BDE inhibits angiotensin-converting enzyme and xanthine oxidase in a dose-dependent manner with an estimated 50% effective concentration (EC50) value of 166·12 (SD 2·42) and 60·05 (SD 1·54) mg/ml,respectively. The overall results clearly indicate the therapeutic potential of B. diffusa against cardiac hypertrophy, in addition to its nutritional qualities.

Topics: Angiotensin II; Animals; Antioxidants; Biomarkers; Cardiovascular Agents; Cell Line; Down-Regulation; Glutathione; Hypertrophy; Lipid Peroxidation; Myoblasts, Cardiac; Myocardium; NF-kappa B; Nyctaginaceae; Oxidative Stress; Plant Extracts; Protein Carbonylation; Rats; Reactive Oxygen Species; Transforming Growth Factor beta1

We previously showed that omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The mechanisms underlying this effect are unknown.. The purpose of this study was to use a genome-wide approach to identify gene expression profiles involved in a new model of AF vulnerability and to determine whether they were altered by PUFA therapy.. Thirty-six dogs were randomized evenly into three groups. Two groups were paced using simultaneous atrioventricular pacing (SAVP) at 220 bpm for 14 days to induce atrial enlargement, fibrosis, and susceptibility to AF. One group was supplemented with oral PUFAs (850 mg/day) for 21 days, commencing 7 days before the start of pacing (SAVP-PUFAs). The second group received no PUFAs (SAVP-No PUFAs). The remaining dogs were unpaced, unsupplemented controls (CTRL). Atrial tissue was sampled at the end of the protocol. Gene expression was analyzed in four dogs randomly selected from each group (n = 12) via microarray. Results were confirmed with quantitative real-time polymerase chain reaction (RT-PCR) and histology on all 36 dogs.. Microarray or quantitative RT-PCR results showed that SAVP-No PUFAs dogs had significantly increased mRNA levels of protein kinase B (Akt), epidermal growth factor (EGF), JAM3, myosin heavy chain alpha (MHCalpha), and CD99 and significantly decreased levels of Smad6 compared with CTRL dogs. Quantitative RT-PCR showed that PUFA supplementation was associated with significant down-regulation of Akt, EGF, JAM3, MHCalpha, and CD99 levels compared with SAVP-No PUFAs dogs.. The effect of PUFAs on these fibrosis, hypertrophy, and inflammation related genes suggests that, in this model, PUFA-mediated prevention of AF may be due to attenuation of adverse remodeling at the genetic level in response to mechanical stress.

Topics: Animals; Atrial Fibrillation; Atrial Function; Cardiomyopathies; Cardiovascular Agents; Disease Models, Animal; Dogs; Fatty Acids, Omega-3; Fibrosis; Gene Expression; Heart Atria; Hypertrophy; Stress, Mechanical

Topics: Cardiovascular Agents; Drug Therapy; Humans; Hypertrophy; Infant; Infant, Newborn; Muscle Relaxants, Central; Pyloric Stenosis; Pyloric Stenosis, Hypertrophic; Surgical Procedures, Operative