Myocardial Metabolic Remodeling in Cardiac Hypertrophy

 描述(由申请人提供)：心力衰竭(HF)是全球发病率和死亡率的主要原因。高血压所致的左心室肥厚(LVH)是收缩和舒张性心衰的重要危险因素。最近，通过改善能量的产生和使用来预防肥厚，作为改善患者预后的治疗目标重新引起了人们的兴趣。在压力超负荷的情况下，心脏会从脂肪酸转换为葡萄糖代谢以产生能量。这种最初有益的代谢反应在持续时会变得不适应，并可能引发心脏的功能和结构重塑，导致左心室肥厚。我们实验室最新的FDG PET成像数据表明，糖代谢是一种可能的治疗靶点。我们假设，在压力超负荷的心脏中，葡萄糖代谢的改变先于心功能受损，最终导致左心室肥厚和心衰。然而，代谢重塑和心功能受损与左心室肥厚发展之间的时间和因果关系尚不清楚。TAC小鼠模型缺乏人类疾病的一些关键特征，最重要的是压力超负荷的缓慢渐进发展。这使得无法区分适应性不良和适应性代谢反应，也无法确定可用于改善人类高血压临床结果的积极治疗策略的窗口。因此，我们建议在自发性高血压大鼠(SHR)模型中表征心肌代谢变化及其对心脏结构和功能的影响。自发性高血压大鼠模型被广泛用作从稳定代偿性左心室肥厚向收缩期心衰过渡的模型。在这项提案中，我们将检验我们的中心假设，即心肌代谢的变化，特别是转向葡萄糖作为主要能量来源，尽管最初有利于维持心脏功能，但变得不适应，并在压力超负荷心脏收缩功能障碍的发展中发挥主要作用。为了验证这一假设，我们将在目标1下，通过体内系列FDG PET和MR成像、血流动力学测量以及体外分子和代谢分析，在20-24个月的大鼠生命周期中评估心肌糖代谢与疾病进展到LVH和HF之间的时间关系。在目标2下，我们将通过体内系列FDG PET和MR成像、血流动力学研究和体外分析来测试二甲双胍(一种FDA批准的改善葡萄糖代谢的药物)的干预是否可以防止SHR心脏收缩功能和心脏结构的损害。这些研究将为未来的转化性研究提供基础知识，使用人类FDG PET成像来定义用于预防LVH的代谢干预窗口，从而改善患者的预后。

 DESCRIPTION (provided by applicant): Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Left ventricular hypertrophy (LVH) due to hypertension is an important risk factor for the development of systolic and diastolic HF. Prevention of hypertrophy by improving energy generation and use has recently received renewed interest as a therapeutic target to improve patient outcomes. In response to pressure overload the heart switches from fatty-acid to glucose metabolism for energy production. This initially beneficial metabolic response becomes maladaptive when sustained and may trigger the onset of functional and structural remodeling of the heart leading to LVH. Recent FDG PET imaging data from our laboratory in transverse aortic constriction (TAC)-induced pressure overload LVH in mice and hypertension-induced LVH in humans have identified glucose metabolism as a possible therapeutic target. We hypothesize that alterations in glucose metabolism in the pressure-overloaded heart precede the development of impaired cardiac function that eventually lead to LVH and HF. The temporal and causal relationship between metabolic remodeling and impaired cardiac function and the development of LVH is, however, unknown. The TAC mouse model lacks some of the key features of the human disease, most importantly the slow progressive development of pressure overload. This makes it impossible to distinguish the maladaptive from the adaptive metabolic response and to identify the window for aggressive therapeutic strategies that could be used to improve clinical outcome in human hypertension. We thus propose to characterize the myocardial metabolic changes and consequences on cardiac structure and function in the spontaneously hypertensive rat (SHR) model that is widely used as a model for transition from stable compensated LVH to systolic HF. In this proposal, we will test our central hypothesis that changes in myocardial metabolism, specifically the switch to glucose as a major energy source, although initially beneficial to maintaining cardiac function, becomes maladaptive and plays a major role in the development of contractile dysfunction in the pressure overloaded heart. To test this hypothesis, we will under Aim 1 evaluate the temporal relationship between myocardial glucose metabolism and the progression of the disease to LVH and HF by serial FDG PET and MR imaging in vivo, hemodynamic measurements and ex vivo molecular and metabolic analysis of SHR and control Wistar-Kyoto (WKY) rat hearts over the 20-24 month life cycle of the rats. Under Aim 2 we will then test whether intervention with metformin, a FDA-approved drug that improves glucose metabolism, can prevent impairments in the contractile function and cardiac structure of the SHR heart using serial FDG PET and MR imaging in vivo, hemodynamic studies and ex vivo analysis. These studies will provide basic knowledge for future translational research using human FDG PET imaging to define a window for metabolic intervention for prevention of LVH and thus improve patient outcomes.