PROGRESSION OF HEART FAILURE

心力衰竭的进展

• 批准号: 6041462
• 负责人: HANI N SABBAH
• 金额: $ 32.25万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6041462
• 关键词: BCL2 gene /protein; angiography; angiotensin II; apoptosis; calcineurin; cardiac myocytes; cysteine endopeptidases; cytochrome c; disease /disorder model; dogs; flow cytometry; heart contraction; heart enlargement; heart failure; heart ventricle; hemodynamics; histopathology; immunocytochemistry; myocardial ischemia /hypoxia; norepinephrine; pathologic process; phosphoprotein phosphatase; retinoblastoma protein; terminal nick end labeling; vascular endothelial growth factors

Left ventricular (LV) dysfunction, once established, worsens over time, despite the absence of intercurrent adverse events. This LV deterioration often culminates in congestive heart failure (HF). The mechanisms responsible for this process are not fully understood. We and others have speculated that progression of LV dysfunction and subsequent transition to over HF may be due, in part, to progressive global LV remodeling, and the cellular level, to ongoing loss of cardiomyocytes and/or progressive worsening of intrinsic contractile dysfunction of residual myocytes. During the past funding cycle, we showed for the first time, that progressive LV dysfunction and dilation are accompanied by ongoing loss of viable myocardium. Pioneering studies by us in dogs with HF and by others, in end-stage, explanted failed human hearts, evoked cardiomyocyte apoptosis, as a potential cause of ongoing loss of viable myocardium in HF. While critical to our knowledge of the overall pathophysiology of HF, the true importance of these findings is tempered by the existence of a major gap in our understanding of the adaptations and/or maladaptations, inherent to the HF state, that drive the process of ongoing cardiac muscle cell death that ultimately leads to intractable HF. In this application, we propose new investigations intended to close this knowledge gap. Over the next 5 years, we propose to determine if a relationship exists between 1) the severity of LV dysfunction and the extent of cardiomyocyte apoptosis; 2) progression of LV dysfunction and the activity and expression of protein phosphatases; enzymes that have been suggested to promote apoptosis and have been shown by us to be elevated in HF; and 3) the severity of LV dysfunction and susceptibility of cardiomyocytes to undergo apoptosis mediated by norepinephrine, angiotensin-II and hypoxia; all of which are classic features of HF. We further propose to examine if in-vivo treatment of HF with vascular endothelial growth factor ameliorates the hypoxic state through angiogenesis and, in doing so, prevent hypoxia-mediated apoptosis and, consequently, prevent the progression to overt HF. Finally, we will address the role of a central adaptation in HF namely, whether the process of progressive LV dilation itself promotes cardiomyocyte loss or vice versa. We will test this by surgical placement of a passive constraining device around strengths of critical findings uncovered during the previous funding cycle and are in line with our overall objective of identifying the mechanisms of progressive deterioration of LV function that is characteristic of the HF state.

左心室（LV）功能障碍一旦建立，尽管没有发生互动的不良事件，但随着时间的流逝会恶化。这种LV恶化通常在充血性心力衰竭（HF）中达到顶点。负责此过程的机制尚未完全理解。我们和其他人推测，LV功能障碍的进展以及随后的过渡到过度的过渡可能部分归因于渐进的全球LV重塑和细胞水平，这是由于心肌细胞的持续丧失和/或进行性静脉内静脉内静脉内静脉内肌动力障碍的损失。在过去的资金周期中，我们首次表明，进行性LV功能障碍和扩张伴随着可行的心肌持续丧失。我们在HF和他人的狗中进行的开创性研究，在末期，植入了失败的人类心脏，唤起心肌细胞凋亡，这是HF中持续失去可行心肌的潜在原因。尽管对我们对HF的整体病理生理学的了解至关重要，但这些发现的真正重要性是由于我们对HF状态固有的适应和/或疾病的理解而存在一个主要差距，从而驱动了正在进行的心肌细胞死亡的过程，这最终导致了持续的HF。在此应用程序中，我们提出了旨在缩小这一知识差距的新调查。在接下来的5年中，我们建议确定是否存在1）LV功能障碍的严重程度和心肌细胞凋亡的程度； 2）LV功能障碍的进展以及蛋白质磷酸酶的活性和表达；建议促进凋亡的酶，并已证明我们在HF中升高。 3）LV功能障碍和心肌细胞的易感性严重程度，可通过去甲肾上腺素，血管紧张素II和缺氧介导的细胞凋亡；所有这些都是HF的经典功能。我们进一步建议检查血管内皮生长因子对HF的体内治疗是否通过血管生成来改善低氧状态，并防止缺氧介导的细胞凋亡，从而防止其发展为明显的HF。最后，我们将解决中心适应在HF中的作用，即进行性LV扩张的过程本身是否会促进心肌细胞损失，反之亦然。我们将通过将被动约束装置的外科手术围绕在上一个融资周期中发现的关键发现的强度进行手术放置，并符合我们确定LV功能的渐进性降低机制，这是HF状态的特征。