Rate Control and Cardiac Energitics in heart Failure

心力衰竭（HF）是一个巨大的医疗、社会和经济负担。它是导致死亡的主要原因 和发病率在美国和竞争对手或超过许多癌症。寻找更好 HF的治疗是心脏病学的主要挑战之一。HF的高发病率是由 疾病的进行性，即受影响的患者的状态随时间推移而变化，尽管 无并发临床不良事件。因此，任何可以延缓这种情况的治疗方法， 无情的进步或逆转，它必然会对生存和生活质量产生重大影响。 HF患者。心脏衰竭的原因有很多。衰竭的心脏是“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话题的一个主要原因是 潜在的概念，即任何针对HF的能量节省治疗都可能改善心脏功能， 因此是长期结果。心脏能量代谢虽然复杂，但可以减少到基本上3 组分，即1）底物利用，2）氧化磷酸化和3）能量转移，以及 利用率在HF中，线粒体，心肌细胞ATP供应的来源，在结构和功能上是 导致氧化磷酸化异常。在该项目中，能源利用的调制将 以心率（HR）降低的形式及其对HF进展的影响进行探索。休息HR是 在HF中增加，并且是不良长期结局的决定因素。心率是心肌氧含量的决定因素 消耗，从而影响能源利用。我们的工作假设是，最佳的HR降低， HF的设置防止或逆转线粒体功能的恶化，维持或恢复正常 心脏底物代谢，并延缓或逆转进行性LV功能障碍和重塑。所有 将使用已建立的慢性HF犬冠状动脉微栓塞模型进行研究。 将实施三种明显不同的方法来降低慢性HR，即1）慢性HR 迷走神经电刺激降低，2）药理学选择性和 起搏器If电流的特异性抑制和3）传统β肾上腺素能慢性心率减慢 受体阻断剂。所有研究均在中度HF（LV射血分数约35%）犬中进行， 在晚期HF（LV射血分数<20%）犬中也是如此。

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%).