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Subodh Verma

Publications and source records attributed to Subodh Verma.

At least 55 records · Page 3Linked to original sources
PubMed2005

Combined endothelial and myocardial protection by endothelin antagonism enhances transplant allograft preservation.

BACKGROUND: Endothelin is a potent inflammatory peptide associated with myocardial dysfunction, coronary vasculopathy, and reduced survival after cardiac transplantation. We hypothesized that endothelin antagonism during cardiac allograft storage would limit early endothelial dysfunction and improve myocardial performance after transplantation. METHODS: Porcine orthotopic transplantations (n = 16) were performed after 6 hours of ischemic storage. Intermittent donor blood perfusion (control, n = 8) was compared with donor blood perfusion enhanced with 100 micromol/L of an endothelin receptor blocker (n = 8). Left ventricular performance was assessed after caval occlusion with a Millar micromanometer and conductance catheter. Coronary endothelial function was assessed in vitro with a macrovascular tissue bath apparatus. Myocardial endothelin, tumor necrosis factor alpha, and transforming growth factor beta protein expression were determined. Oxidative stress was inferred on the basis of 8-isoprostane levels, and myocardial metabolism was inferred on the basis of the extraction or production of oxygen, acid, and lactate by the heart. RESULTS: Endothelial function was diminished 48 hours after transplantation but not earlier. Endothelin receptor blocker treatment during preservation limited coronary endothelial dysfunction 48 hours after reperfusion ( P = .001). Weaning from cardiopulmonary bypass and left ventricular performance after transplantation was improved in endothelin receptor blocker-treated hearts (P = .02). Myocardial endothelin expression was equivalent in both groups and increased during reperfusion after transplantation (P = .001). Tumor necrosis factor alpha levels decreased with endothelin receptor blocker treatment (P = .02), whereas transforming growth factor beta levels did not change (P = .86). 8-Isoprostane, oxygen, acid, and lactate levels were similar, suggesting that oxidative stress and metabolism were not important mechanisms of benefit. CONCLUSIONS: Endothelin accumulates during allograft storage and contributes to endothelial and myocardial dysfunction after transplantation. Endothelin blockade during allograft preservation limits endothelial injury and enhances ventricular recovery after transplantation.

Animals↗
PubMed2005

C-reactive protein comes of age.

Cardiovascular disease remains a leading cause of death throughout the world despite advances in its detection and treatment. Commonly used risk algorithms, such as the Framingham Risk Score fail to identify all affected individuals. Novel cardiovascular risk factors that identify these missed individuals would greatly improve overall care of patients. C-reactive protein (CRP), an inflammatory biomarker, has emerged as a leading candidate to fulfill this role. Based on the results of several prospective epidemiologic studies, CRP has emerged as one of the most powerful predictors of cardiovascular disease. This marker provides valuable information to clinicians in various clinical settings, ranging from overt cardiovascular disease, stable angina, presenting acute coronary syndromes and peripheral vascular disease, to the metabolic syndrome. Furthermore, CRP has been demonstrated to actively contribute to all stages of atherogenesis, participating in endothelial dysfunction, atherosclerotic-plaque formation, plaque maturation, plaque destabilization and eventual rupture. Thus, it might also serve as a therapeutic target. It is our contention that the future will see much wider use of CRP and CRP-driven therapies in clinical medicine, improving our ability to identify and manage cardiovascular disease.

Atherosclerosis↗
PubMed2005

C-reactive protein and statins: IL-8 as a molecular link?

CRP (C-reactive protein) has not only emerged as a useful biomarker for cardiovascular disease, but also as a mediator of atherosclerosis. CRP directly activates vascular endothelial cells, amplifying the inflammatory response underlying atherogenesis. The expression of IL (interleukin)-8 appears to serve as one of the downstream effects of CRP. Kibayashi and co-workers in this issue of Clinical Science confirm that CRP induces IL-8 production in human aortic endothelial cells in vitro, via the activation of MAPKs (mitogen-activated protein kinases), an effect that can be inhibited by pitavastatin.

Aorta↗
PubMed2005

Bicuspid aortic valve disease: recent insights in pathophysiology and treatment.

Bicuspid aortic valve is a common congenital cardiac malformation with a broad spectrum of clinical outcomes. Bicuspid aortic valve may go undetected throughout an individual's lifetime or, alternatively, they may have devastating clinical consequences, resulting in death. Both clinicians and medical scientists have taken a renewed interest in the development, pathophysiology and treatment options for this subtle but often substantial clinical entity. Evidence is mounting to suggest that an underlying disease of the aorta is inherited with bicuspid aortic valve, although considerable controversy surrounds this theory. Novel molecular mechanisms underlying the valve and vascular pathologies, as well as new surgical therapies for these patients have been proposed in the past 10 years.

Aortic Valve↗
PubMed2005

Canadian Cardiovascular Society Consensus Conference: peripheral arterial disease - executive summary.

This Consensus Conference has been supported by the Canadian Cardiovascular Society. The process is dynamic, with intentional structure that requires peer review and feedback from cardiovascular specialists across Canada. The writing and review panel encompassed a broad range of specialists caring for the patient with peripheral arterial disease (PAD). PAD is an often asymptomatic, underdiagnosed, under-recognized and undertreated condition. It is associated with significant morbidity and cardiac mortality. Until recently, little attention has focused on the evaluation and treatment of the disease process itself. The goal of the present paper is to ensure better treatment, to reduce both morbidity and mortality in the patient with vascular disease and, importantly, to serve as a guide to the busy clinician. Although the focus is PAD, there are chapters on thoracic and abdominal aortic disease, renal arterial disease and the evidence supporting management. Screening and diagnostic techniques including history and physical examination as well as noninvasive imaging techniques are reviewed. Medical management for patients with vascular disease including prevention and risk reduction is graded based on evidence, including both pharmacological and nonpharmacological management strategies, followed by an introduction to newer percutaneous techniques. Finally, surgical treatment for claudication including new concepts on the perioperative risk assessment for patients undergoing major vascular surgery is discussed.

Aortic Aneurysm↗
PubMed2004

TIMP-3 deficiency leads to dilated cardiomyopathy.

BACKGROUND: Despite the mounting clinical burden of heart failure, the biomolecules that control myocardial tissue remodeling are poorly understood. TIMP-3 is an endogenous inhibitor of matrix metalloproteinases (MMPs) that has been found to be deficient in failing human myocardium. We hypothesized that TIMP-3 expression prevents maladaptive tissue remodeling in the heart, and accordingly, its deficiency in mice would alone be sufficient to trigger progressive cardiac remodeling and dysfunction similar to human heart failure. METHODS AND RESULTS: Mice with a targeted timp-3 deficiency were evaluated with aging and compared with age-matched wild-type littermates. Loss of timp-3 function triggered spontaneous LV dilatation, cardiomyocyte hypertrophy, and contractile dysfunction at 21 months of age consistent with human dilated cardiomyopathy. Its absence also resulted in interstitial matrix disruption with elevated MMP-9 activity, and activation of the proinflammatory tumor necrosis factor-alpha cytokine system, molecular hallmarks of human myocardial remodeling. CONCLUSIONS: TIMP-3 deficiency disrupts matrix homeostasis and the balance of inflammatory mediators, eliciting the transition to cardiac dilation and dysfunction. Therapeutic restoration of myocardial TIMP-3 may provide a novel approach to limit cardiac remodeling and the progression to failure in patients with dilated cardiomyopathy.

ADAM Proteins↗
PubMed2004

Novel cardioprotective effects of pravastatin in human ventricular cardiomyocytes subjected to hypoxia and reoxygenation: beneficial effects of statins independent of endothelial cells.

Cardioprotective strategies are needed to prevent perioperative myocardial dysfunction in high-risk patients undergoing cardiac surgery. Despite accumulating evidence that statins exert lipid-independent cardioprotective effects, these have been ascribed primarily to improvements in endothelial function and neutrophil-endothelial interaction. The direct effects of statins on cardiomyocytes (independent of endothelial cells) remain unknown. Using a well-characterized model of low-volume hypoxia and reoxygenation, we studied the effects of pravastatin on human ventricular cardiomyocytes. Cardiomyocytes were subjected to 90 min of low-volume hypoxia and 30 min of reoxygenation in the presence and absence of pravastatin (1, 10, and 100 microm) (n = 10 per group). In some experiments, the effects of endothelin (ET) receptor blockade (with bosentan) and nitric oxide synthase (NOS) inhibition (with L-NAME) on pravastatin-mediated cardioprotection were evaluated. Cell survival, NO, and ET-1 production and protein kinase Akt activation were determined. Pravastatin treatment prevented cardiomyocyte cell death following simulated hypoxia and reoxygenation (P < 0.01). This effect was mediated via an increase in NO release, decrease in myocyte ET-1 production/action, and an increase in protein kinase Akt activation. We demonstrate, for the first time, novel protective effects of pravastatin in human ventricular cardiomyocytes independent of endothelial cells or other cell types. Statin therapy may restore ischemic hearts to full functional integrity during cardioplegic arrest through a direct effect on cardiomyocyte survival.

Acyl Coenzyme A↗
PubMed2004

C-reactive protein attenuates endothelial progenitor cell survival, differentiation, and function: further evidence of a mechanistic link between C-reactive protein and cardiovascular disease.

BACKGROUND: Myocardial ischemia provides a potent stimulus to angiogenesis, and the mobilization and differentiation of endothelial progenitor cells (EPCs) has been shown to be important in this process. An elevated level of C-reactive protein (CRP) has emerged as one of the most powerful predictors of cardiovascular disease. However, the impact of CRP on EPC biology is unknown. METHODS AND RESULTS: EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in endothelial cell basal medium-2 in the absence and presence of CRP (5 to 20 microg/mL), rosiglitazone (1 micromol/L), and/or vascular endothelial growth factor. EPC differentiation, survival, and function were assayed. CRP at concentrations > or =15 microg/mL significantly reduced EPC cell number, inhibited the expression of the endothelial cell-specific markers Tie-2, EC-lectin, and VE-cadherin, significantly increased EPC apoptosis, and impaired EPC-induced angiogenesis. EPC-induced angiogenesis was dependent on the presence of nitric oxide, and CRP treatment caused a decrease in endothelial nitric oxide synthase mRNA expression by EPCs. However, all of these detrimental CRP-mediated effects on EPCs were attenuated by pretreatment with rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist. CONCLUSIONS: Human recombinant CRP, at concentrations known to predict adverse vascular outcomes, directly inhibits EPC differentiation, survival, and function, key components of angiogenesis and the response to chronic ischemia. This occurs in part via an effect of CRP to reduce EPC eNOS expression. The PPARgamma agonist rosiglitazone inhibits the negative effects of CRP on EPC biology. The ability of CRP to inhibit EPC differentiation and survival may represent an important mechanism that further links inflammation to cardiovascular disease.

Apoptosis↗