Biventricular Pacing in Heart Failure

描述（由申请人提供）： 心力衰竭（HF）是美国的一种流行病，影响超过500万人。据估计，明年将有近400，000例新病例被诊断，100万人将住院，300，000人将因HF死亡。大约一半的死亡将归因于泵功能恶化，而其余的将归因于心源性猝死。双心室（BIV）起搏最近已成为治疗心室传导异常并持续遭受严重HF症状的晚期HF患者的新模式（纽约心脏协会III-IV级）尽管包括血管紧张素转换酶抑制剂、b受体阻滞剂和保钾利尿剂在内的最佳药物治疗可以从BIV起搏中获益，其形式为改善最大耗氧量，运动耐量和生活质量，以及降低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联合终点方面具有获益。尽管如此，人们对BIV起搏获益的区域、细胞和分子机制知之甚少。本提案旨在利用兔HF模型更好地了解BIV起搏改善心脏的机制。冠状动脉结扎的家兔将接受右心室与BIV起搏1个月。将结果与右心室、BIV和无起搏的假手术家兔以及梗死家兔进行比较。本项目将1）检验BIV起搏在改善HF的超声心动图、血浆神经激素、细胞和分子标志物方面上级右心室起搏的假设，2）检验BIV起搏积极调节HF中脉冲的电传播和传导速度的假设，3）并检验BIV起搏防止HF中心肌细胞的细胞电生理学中的不良重构的假设。

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.