PROGRESSION OF HEART FAILURE

截至1984年，估计有200万患者发生心力衰竭 仅在美国就有大约25万例新病例， 每年死亡。 这些数字稳步上升， 预期寿命和高危老年人口的扩大。 尽管出现了更有效的治疗方法，大多数，如果不是所有的病人， 继续死于这种疾病。 缺血性心脏病是迄今为止 导致心力衰竭的最常见病因。 严重丧失存活能力 左心室（LV）心肌发生在大面积梗死后，或 多个较小的梗死并导致相当大的LV功能障碍。 现在人们认识到，在一个国家与另一个国家之间的过渡时期， 代偿性LV功能障碍和心脏失代偿和显性心脏 失败后，尽管没有任何 其他并发临床事件。 造成这种情况的因素 LV功能进行性恶化未知。 现时的建议 检验了LV功能进行性恶化的假设， 在这个过渡期，由于功能的逐渐丧失， 心脏单位由残余的持续变性和坏死介导 存活的心肌细胞 拟议的研究还旨在测试 假设进行性退化和丧失 残余的存活心肌细胞的结果，从发展的反应性 间质性纤维化，其充当氧气扩散的屏障， 毛细血管和胶原包围心肌细胞。 最后，研究 被提出来检验血管紧张素转换酶 抑制剂预防或延缓LV功能的进行性恶化 通过预防或减轻间质纤维化的发展。 这些相互关联的假设将在犬慢性 多次序贯冠状动脉内灌注致心力衰竭 微栓塞 这只狗的准备表明 左室功能恶化和反应性间质纤维化 停止冠状动脉微栓塞，因此， 对所提出的假设进行详细的询问。 揭开 负责从补偿过渡到 失代偿性心力衰竭是发展有效的 和针对性的治疗，旨在预防，或者至少， 延缓了明显心力衰竭的进程

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.