PROGRESSION OF HEART FAILURE

左心室（LV）功能障碍一旦确立，尽管没有并发的不良事件，但会随着时间的推移而恶化。这种LV恶化通常在充血性心力衰竭（HF）中达到高潮。负责这一过程的机制尚未完全了解。我们和其他人推测，LV功能障碍的进展和随后过渡到HF可能部分是由于进行性整体LV重构，以及细胞水平，心肌细胞的持续损失和/或残留肌细胞的固有收缩功能障碍的进行性恶化。在过去的资助周期中，我们首次发现，进行性LV功能障碍和扩张伴随着存活心肌的持续丧失。我们在患有HF的狗和其他人的开创性研究中，在终末期，恢复失败的人类心脏，诱发心肌细胞凋亡，作为HF中存活心肌持续丧失的潜在原因。虽然对我们了解HF的整体病理生理学至关重要，但这些发现的真正重要性受到我们对HF状态固有的适应和/或适应不良的理解存在重大差距的影响，这些适应和/或适应不良推动了持续心肌细胞死亡的过程，最终导致顽固性HF。在这个应用程序中，我们提出了新的调查旨在缩小这一知识差距。在接下来的5年里，我们计划确定1）左心室功能障碍的严重程度和心肌细胞凋亡的程度之间是否存在关系; 2）左心室功能障碍的进展和蛋白磷酸酶的活性和表达之间是否存在关系;这些酶被认为可以促进细胞凋亡，并且我们已经证明在HF中升高;和3）LV功能障碍的严重性和心肌细胞经历由去甲肾上腺素、血管紧张素-II和缺氧介导的细胞凋亡的易感性;所有这些都是HF的典型特征。我们进一步提出，如果在体内治疗HF与血管内皮生长因子改善缺氧状态，通过血管生成，并在这样做，防止缺氧介导的细胞凋亡，因此，防止进展到明显的HF。最后，我们将讨论心力衰竭中中枢适应的作用，即进行性左心室扩张过程本身是否促进心肌细胞损失，反之亦然。我们将通过手术放置被动限制装置来测试这一点，该装置围绕上一个资助周期中发现的关键发现的优势，并符合我们的总体目标，即确定HF状态特征性LV功能进行性恶化的机制。

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.