PROGRESSION OF HEART FAILURE

心力衰竭的进展

• 批准号: 2668694
• 负责人: HANI N SABBAH
• 金额: $ 24.74万
• 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 2000-01-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2668694
• 关键词: ACE inhibitors; angiography; cellular respiration; disease /disorder model; dogs; enalapril; fibrosis; heart disorder; heart failure; heart function; heart ventricle; hemodynamics; longitudinal animal study; nonhuman therapy evaluation; pathology; peptidyl dipeptidase A; vasodilators

As of 1984, heart failure has been estimated to occur in 2 million patients in the United States alone with approximately 250,000 new cases and 200,000 deaths each year. These numbers have steadily increased with increasing life expectancy and expansion of the higher risk geriatric population. Despite the advent of more effective therapy, most, if not all patients, continue to succumb to this disease. Ischemic heart disease is by far the most common etiology leading to heart failure. Significant loss of viable left ventricular (LV) myocardium occurs after a large infarction or multiple smaller infarctions and results in considerable LV dysfunction. It is now recognized that during the transition period between a state of compensated LV dysfunction and cardiac decompensation and overt heart failure, lV function continues to deteriorate despite the absence of any additional concurrent clinical events. The factors responsible for this progressive worsening of LV function are not know. The present proposal tests the hypothesis that the progressive deterioration of LV function, during this transition period, results from progressive loss of functional cardiac units mediated by ongoing degeneration and necrosis of residual viable cardiomyocytes. The proposed studies are also designed to test the hypothesis that the hypothesis that the progressive degeneration and loss of residual viable cadiomyocytes result from the development of reactive interstitial fibrosis which acts as a barrier to oxygen diffusion between capillaries and the collagen encircled cardiomyocytes. Finally, studies are proposed to test the hypothesis that angiotensin converting enzyme inhibitors prevent or retard the progressive deterioration of LV function by preventing or attenuating the development of interstitial fibrosis. These interrelated hypotheses will be tested in a canine model of chronic heart failure produced by multiple sequential intracoronary microembolizations. This canine preparation manifests spontaneous deterioration of lV function and reactive interstitial fibrosis long-after cessation of coronary microembolizations and, therefore, is ideally suited for detailed interrogation of the proposed hypotheses. Uncovering the mechanism(s) responsible for the transition from compensated to decompensated heart failure is essential in the development of effective and target specific therapies aimed at preventing or, at the very least, retarding the progression toward overt heart failure.

截至1984年，估计心力衰竭发生在200万患者中 仅在美国，大约有25万个新案件和200,000个案件 每年死亡。 这些数字随着增加而稳步增加 预期寿命和较高风险的老年人口的扩大。 尽管出现了更有效的疗法，但大多数（即使不是所有患者） 继续屈服于这种疾病。 迄今为止，缺血性心脏病是 最常见的病因导致心力衰竭。 可行的重大损失 左心室（LV）心肌发生在大梗塞或 多个较小的梗塞，并导致相当大的LV功能障碍。 现在已经认识到，在一个状态之间的过渡期 补偿的LV功能障碍和心脏代表和明显的心脏 失败，尽管没有任何 其他并发临床事件。 为此负责的因素 LV功能的逐渐恶化。 目前的提议 检验以下假设：LV功能的进行性恶化， 在此过渡期间，功能的进行性丧失导致 持续变性和残留坏死介导的心脏单位 可行的心肌细胞。 拟议的研究还旨在测试 假设是进行性变性和损失的假设 剩余的可行的会计系数是由反应性的发展而产生的 间质纤维化，这是氧扩散的障碍 毛细血管和胶原蛋白包围的心肌细胞。 最后，研究 提出了用于检验血管紧张素转化酶的假设 抑制剂预防或阻碍LV功能的逐渐恶化 通过预防或衰减间质纤维化的发展。 这些相互关联的假设将在慢性的犬类模型中进行测试 由多个顺序冠状动脉室产生的心力衰竭 微栓塞。 这种犬的准备表现出自发的 LV功能和反应性间质纤维化的恶化长期 冠状动脉微栓塞的停止，因此非常适合 用于详细询问提议的假设。 揭开 负责从补偿到过渡到的机制 代偿性心力衰竭对于开发有效至关重要 并针对旨在预防或至少旨在预防的特定疗法 阻碍向明显心力衰竭的进展。