Myocardial Metabolic Remodeling in Cardiac Hypertrophy

心脏肥大中的心肌代谢重塑

• 批准号: 9281869
• 负责人: Bijoy K Kundu
• 金额: $ 53.79万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-07 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9281869
• 关键词: 5' -AMP-activated protein kinase; Acute; Affect; Animals; Cardiac; Clinical; Data; Development; Diagnostic; Diastolic heart failure; Disease Progression; Early Diagnosis; Energy Metabolism; Energy-Generating Resources; Enzymes; FDA approved; FRAP1 gene; Fatty Acids; Functional disorder; Future; Generations; Genes; Glucose; Heart; Heart Hypertrophy; Heart failure; Human; Hypertension; Hypertrophy; Image; Impairment; Inbred SHR Rats; Inbred WKY Rats; Intervention; Knowledge; Laboratories; Lead; Left Ventricular Hypertrophy; Left Ventricular Remodeling; Life Cycle Stages; Magnetic Resonance Imaging; Measurement; Measures; Medical; Metabolic; Metabolism; Metformin; Methodology; Methods; Mission; Modeling; Molecular; Molecular Analysis; Monitor; Morbidity - disease rate; Mus; Myocardial; Myocardial dysfunction; Myocardium; National Heart, Lung, and Blood Institute; Non-Invasive Cancer Detection; Nutrient; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Play; Population; Positron-Emission Tomography; Prevention; Preventive Intervention; Production; Public Health; Rattus; Research; Risk Factors; Role; Signal Transduction; Source; Structure; Systemic hypertension; Systolic heart failure; Testing; Therapeutic; Therapeutic Effect; Time; Toxic effect; Translating; Translational Research; Workload; aggressive therapy; clinical practice; constriction; fetal; glucose metabolism; glucose uptake; heart metabolism; hemodynamics; high risk; human disease; imaging modality; improved; improved outcome; in vivo; interest; intervention effect; metabolic imaging; mortality; mouse model; non-invasive imaging; oxidation; pressure; prevent; public health relevance; response; sensor; serial imaging; therapeutic target; tool; treatment strategy

 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.

 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。高血压引起的左心室肥厚（LVH）是收缩期和舒张期HF发生的重要危险因素。通过改善能量产生和使用来预防肥大最近作为改善患者结果的治疗靶点重新受到关注。作为对压力超负荷的反应，心脏从脂肪酸代谢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变得适应不良，并可能触发心脏的功能和结构重塑，导致LVH。最近的FDG PET成像数据，从我们的实验室在横向主动脉缩窄（TAC）诱导的压力超负荷LVH的小鼠和高血压诱导的LVH的人类已经确定葡萄糖代谢作为一个可能的治疗目标。我们推测，在压力超负荷心脏中葡萄糖代谢的改变先于最终导致LVH和HF的心功能受损的发展。然而，代谢重构和心功能受损与LVH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进行性发展。这使得它不可能区分适应不良的适应性代谢反应，并确定积极的治疗策略，可用于改善人类高血压的临床结果的窗口。因此，我们建议在自发性高血压大鼠（SHR）模型，被广泛用作从稳定的代偿性LVH到收缩期HF的过渡模型的心肌代谢变化和心脏结构和功能的后果。在这个提议中，我们将测试我们的中心假设，即心肌代谢的变化，特别是葡萄糖作为主要能量来源的转变，虽然最初有利于维持心脏功能，但变得适应不良，并在压力超负荷心脏收缩功能障碍的发展中起着重要作用。为了验证这一假设，我们将在目标1下，通过连续FDG PET和MR体内成像、血流动力学测量以及SHR和对照Wistar-Kyoto（WKY）大鼠心脏在20-24个月生命周期内的离体分子和代谢分析，评估心肌葡萄糖代谢与疾病进展为LVH和HF之间的时间关系。在目标2下，我们将使用体内连续FDG PET和MR成像、血流动力学研究和离体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）干预是否可以预防SHR心脏收缩功能和心脏结构的损伤。这些研究将为未来使用人体FDG PET成像的转化研究提供基础知识，以确定预防LVH的代谢干预窗口，从而改善患者结局。