SCCOR in Cardiac Dysfunction and Disease

描述（由申请人提供）： 心力衰竭（HF）影响> 470万人（美国），每年新发病例> 50万例。HF的原因包括冠状动脉疾病、糖尿病、高血压、瓣膜疾病、病毒性心肌炎和遗传/代谢紊乱。对于每种事件，最初代偿性的后遗症导致不同类型的左心室（LV）心肌重塑。 由于导致HF的致病机制显示出重要的差异，因此SCCOR提案的目标是阐明三种不同形式的心脏病-二尖瓣返流（MR）容量超负荷，原发性醛固酮增多症和糖尿病心肌病-对标准药物治疗有抵抗力的LV重塑机制。我们将研究交感神经系统和肥大细胞介导的基质金属蛋白酶激活和细胞外基质降解在二尖瓣返流患者和犬二尖瓣返流模型中进行性不良左室重构和衰竭中的作用。我们将研究膳食盐状态、炎症和肥大细胞在醛固酮诱导的心肌纤维化和左室重塑患者和/或肥大细胞缺乏症的遗传模型中的作用。我们将确定是否AT 1受体阻滞剂和黄嘌呤氧化酶抑制剂将减轻左心室重构和功能障碍，在该地区对糖尿病患者的梗死。这也将研究血液动力学应激后的糖尿病大鼠，该应激复制了人类心肌梗死远端区域的几何重构类型。行政部门将确保科学和临床职能的有效整合。 生物分析将提供支持假设检验的一致和响应性分析数据。 成像将为SCCOR提供LV功能和几何形状的体内测量。 生物统计将在数据管理和结果分析方面提供支持。总之，我们将确定HF的常见和独特的致病机制，并将根据临床研究和临床相关动物模型研究中获得的见解，在患者中采用新的治疗策略。

DESCRIPTION (provided by applicant): Heart failure (HF) affects > 4.7 million people (US), with > 500,000 new cases/yr. Causes of HF include coronary artery disease, diabetes mellitus, hypertension, valvular disease, viral myocarditis, and genetic/metabolic disorders. With each event, sequellae that are initially compensatory, result in distinct types of left ventricular (LV) myocardial remodeling. Since the pathogenic mechanisms leading to HF display important differences, the goal of this SCCOR proposal is to unravel mechanisms of LV remodeling in three disparate forms of heart disease--volume overload of mitral regurgitation (MR), primary aldosteronism, and diabetic cardiomyopathy--that are resistant to standard medical therapy. We will study the role of sympathetic nervous system- and mast cell-mediated matrix metalloproteinase activation and extracellular matrix degradation in progressive adverse LV remodeling and failure in patients with MR and dog models of this disease. We will study the role of dietary salt status, inflammation, and mast cells in aldosterone-induced myocardial fibrosis and LV remodeling in patients and/or in genetic models of mast cell deficiency. We will determine whether AT1 receptor blockade and xanthine oxdidase inhibition will attenuate LV remodeling and dysfunction in the area opposite the infarct in diabetic patients. This will also study diabetic rats following a hemodynamic stress that duplicates the type of geometric remodeling in the area remote to the myocardial infarction in humans. Administrative will assure an effective integration of scientific and clinical functions. Bioanalysis will provide consistent and responsive analytical data that supports the hypothesis-testing. Imaging will provide in vivo measurements of LV function and geometry for SCCOR. Biostatistics will support with respect to data management and analysis of results. In aggregate, we will identify common and unique pathogenic mechanisms for HF and will employ novel therapeutic strategies in patients based on insights gained from both clinical investigation and the study of clinically relevant animal models.