Rate Control and Cardiac Energitics in heart Failure

心力衰竭是巨大的医疗、社会和经济负担。它是导致死亡的主要原因。 而美国及其竞争对手的发病率甚至超过了许多癌症。对更好的追求 心力衰竭的治疗是心脏病学的主要挑战之一。心力衰竭的高发病率是由 疾病的进行性，受影响的患者的状态会随着时间的推移而恶化，尽管 没有并发的临床不良事件。因此，任何可以延缓这种情况的治疗方法 坚持不懈地前进或逆转，势必对人的生存和生活质量产生重大影响 心衰患者。心脏衰竭的原因有很多。心力衰竭是“能量”的概念 饥饿“是这个项目的核心。人们应该密切关注这个主题的一个主要原因是 心力衰竭的任何节能治疗都可能改善心功能和 因此，这是一个长期的结果。心脏能量代谢虽然复杂，但基本上可以减少到3 成分，即1)底物利用，2)氧化磷酸化和3)能量转移和 利用率。在线粒体HF中，心肌细胞的ATP供应来源在结构和功能上 异常导致氧化磷酸化异常。在这个项目中，能源利用的调节将 以心率(HR)减慢的形式进行探讨及其对心力衰竭进展的影响。休息期HR为 心力衰竭增加，是长期预后不良的决定因素。心率是心肌氧含量的决定因素 消耗，因此，能源利用。我们的工作假设是最优的人力资源削减 设置HF可防止或逆转线粒体功能恶化，维持或恢复正常 心脏底物代谢，并延缓或逆转进行性左心室功能障碍和重构。全 研究将使用已建立的慢性心衰犬冠脉微栓塞术模型进行。 将实施三种截然不同的慢性人力资源削减方法，即1)慢性人力资源 电刺激迷走神经减速，2)药物选择性慢性心率减慢。 起搏器IF电流和3)传统β-肾上腺素能慢性心率减慢的特异性抑制 受体阻滞剂。所有研究将在中度心力衰竭(左心室射血分数~35%)为AS的犬身上进行。 晚期心力衰竭(LV射血分数&lt；20%)犬也是如此。

Heart failure (HF) is an enormous medical, social and economic burden. It is a leading cause of mortality and morbidity in the United States and rivals or exceeds that of many cancers. The search for better treatments for HF is one of the major challenges in cardiology. The high morbidity in HF is fueled by the progressive nature of the disease whereby the status of the affected patient worsens over time despite the absence of concurrent clinically adverse events. Therefore, any therapeutic approach that can retard this relentless progression or reverse it is bound to have a major impact on survival and on the quality of life of patients with HF. There are many reasons why a heart can fail. The concept that the failing heart is "energy starved" is a centerpiece of this project. A major reason why one should pay close attention to this topic is the underlying concept that any energy-sparing treatment for HF is likely to improve cardiac function and hence long-term outcome. Cardiac energy metabolism, while complex, can be reduced to essentially 3 components namely, 1) substrate utilization, 2) oxidative phosphorylation and 3) energy transfer and utilization. In HF, mitochondria, the source of ATP supply to cardiomyocytes is structurally and functionally abnormal leading to abnormal oxidative phosphorylation. In this project, modulation of energy utilization will be explored in the form of heart rate (HR) reduction and its impact on the progression of HF. Resting HR is increased in HF and is a determinant of poor long-term outcome. HR is a determinant of myocardial oxygen consumption and, hence, energy utilization. Our working hypothesis is that optimal HR reduction in the setting of HF prevents or reverses deterioration of mitochondrial function, maintains or restores normal cardiac substrate metabolism, and retards or reverses progressive LV dysfunction and remodeling. All studies will be conducted using the well established canine coronary microembolization model of chronic HF. Three distinctly differing approaches to chronic HR reduction will be implemented, namely, 1) chronic HR reduction with electrical Vagus nerve stimulation, 2) chronic HR reduction with pharmacological selective and specific inhibition of the pacemaker If current and 3) chronic HR reduction with traditional beta-adrenergic receptor blockers. All studies will be performed in dogs with moderate HF (LV ejection fraction ~35%) as well as in dogs with advanced HF (LV ejection fraction <20%).