PROGRESSION OF HEART FAILURE

左心室(LV)功能障碍，一旦确立，会随着时间的推移而恶化，尽管没有并发的不良事件。这种左心室恶化通常最终导致充血性心力衰竭(HF)。对这一过程负责的机制还没有完全了解。我们和其他人推测，LV功能障碍的进展和随后过渡到过度心力衰竭的部分原因可能是由于进行性的全球LV重构，以及细胞水平，由于心肌细胞的持续丢失和/或残留心肌细胞内在收缩功能障碍的进行性恶化。在过去的资金周期中，我们第一次表明，进行性左心功能不全和扩张伴随着存活心肌的持续丧失。我们和其他人在心力衰竭犬身上所做的开创性研究，在晚期移植了衰竭的人心脏，诱发心肌细胞凋亡，作为心力衰竭患者存活心肌持续丧失的潜在原因。虽然这些发现对我们对心力衰竭的整体病理生理学知识至关重要，但这些发现的真正重要性是因为我们对心力衰竭状态固有的适应和/或适应不良的理解存在重大差距，这些适应和/或适应不良导致持续的心肌细胞死亡过程，最终导致顽固性心力衰竭。在本申请中，我们提出了旨在弥合这一知识鸿沟的新调查。在接下来的5年里，我们建议确定1)左心功能不全的严重程度与心肌细胞凋亡的程度；2)左心功能不全的进展与蛋白磷酸酶的活性和表达；已被认为促进细胞凋亡的酶，并已被我们证明在心力衰竭中升高；3)左心功能不全的严重程度与去甲肾上腺素、血管紧张素-II和低氧介导的心肌细胞凋亡的敏感性之间的关系；所有这些都是心力衰竭的典型特征。我们进一步建议检查体内应用血管内皮生长因子治疗心衰是否通过血管生成改善缺氧状态，从而防止缺氧介导的细胞凋亡，从而防止进展为显性心衰。最后，我们将讨论中枢适应在心衰中的作用，即渐进性左室扩张过程本身是否促进了心肌细胞的丢失，反之亦然。我们将通过在前一个资金周期中发现的关键发现的强度周围放置被动约束装置来测试这一点，并与我们的总体目标一致，即确定心功能进行性恶化的机制，这是心衰状态的特征。

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.