Rate Control and Cardiac Energitics in heart Failure

心力衰竭是一个巨大的医疗、社会和经济负担。它是导致死亡的主要原因

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%).