Biventricular Pacing in Heart Failure

描述(由申请人提供)： 心力衰竭(HF)在美国是一种流行病，影响着500多万人。据估计，明年将诊断出近40万例新病例，100万人将因心力衰竭住院，30万人将死于心力衰竭。大约一半的死亡将归因于泵功能恶化，其余的将归因于心源性猝死。双室(BIV)起搏最近已成为治疗晚期心力衰竭患者的一种新方法，这些患者仍有严重的心力衰竭症状(纽约心脏协会III-IV级)，尽管最佳的药物治疗包括血管紧张素转换酶抑制剂、b受体阻滞剂和节钾利尿剂，但BIV起搏可以改善最大耗氧量、运动耐量和生活质量，减少室性心律失常的发生率。新发表的报告还表明，BIV起搏在改善死亡和住院的综合终点方面有好处。尽管如此，人们对BIV起搏益处的区域、细胞和分子机制知之甚少。本提案旨在利用兔心衰模型更好地了解BIV起搏改善心脏功能的机制。冠状动脉结扎的兔接受1个月的右室起搏与BIV起搏。结果将与右室、BIV和没有起搏的假手术兔和梗死兔进行比较。本项目将1)检验BIV起搏在改善心衰超声心动图、血浆神经激素、细胞和分子标志物方面优于右室起搏的假说；2)检验BIV起搏正向调节心力衰竭时脉冲的电传播和传导速度的假说；3)检验BIV起搏预防心力衰竭心肌细胞电生理的不利重构的假说。

DESCRIPTION (provided by applicant): Heart Failure (HF) is a disease of epidemic proportion in the U.S. affecting over 5 million individuals. It is estimated that in the next year nearly 400,000 new cases will be diagnosed, 1 million individuals will be hospitalized and 300,000 deaths will occur because of HF. Approximately half of the deaths will be attributed to worsening pump function while the remainder will be attributable to sudden cardiac death. Biventricular (BIV) pacing has recently emerged as a new modality for the treatment of advanced HF Patients with ventricular conduction abnormalities who continue to suffer from severe HF symptoms (New York Heart Association Class III-IV) despite optimal pharmacologic therapy including angiotensin converting enzyme inhibitors, b-blockers, and potassium-sparing diuretics can extract benefits from BIV pacing in the form of improved maximum oxygen consumption, exercise tolerance, and quality of life, as well as reduced incidence of ventricular arrhythmias. New published reports also suggest a benefit from BIV pacing in improving the combined endpoint of death and hospitalization. Despite all this, little is known about the regional, cellular, and molecular mechanisms responsible for the benefits seen with BIV pacing. The present proposal aims at utilizing a rabbit model of HF to better understand the mechanisms of cardiac improvement with BIV pacing. Rabbits with coronary artery ligation will undergo right ventricular versus BIV pacing for 1 month. Results will be compared to sham-operated rabbits with right ventricular, BIV, and no pacing and to infarcted rabbits. The present project will 1) test the hypothesis that BIV pacing is superior to right ventricular pacing in improving echocardiographic, plasma neurohormonal, cellular and molecular markers of HF, 2) test the hypothesis that BIV pacing positively modulates electrical propagation and conduction velocity of impulses in HF, 3) and test the hypothesis that BIV pacing prevents adverse remodeling in the cellular electrophysiology of cardiac myocytes in HF.