Targeting Energetics to Improve Outcomes in Hypertrophic Cardiomyopathy

靶向能量药物以改善肥厚型心肌病的预后

• 批准号: 10687401
• 负责人: Ivan Luptak
• 金额: $ 81.76万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-16 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10687401
• 关键词: ATP Hydrolysis; ATP Synthesis Pathway; ATP phosphohydrolase; Acute; Address; Affect; Age; American; Antidiabetic Drugs; Arrhythmia; Butyrates; Cardiac; Cardiology; Cardiovascular system; Chemicals; Clinical; Consumption; Data; Defect; Development; Diabetes Mellitus; Disease; Early Diagnosis; Echocardiography; Excision; Fibrosis; Free Energy; Functional disorder; Genes; Genetic; Glucose; Growth; Heart; Heart Hypertrophy; Heart failure; Hereditary Disease; Hypertrophic Cardiomyopathy; Hypertrophy; Image; Impairment; Intervention; Ion Pumps; Knowledge; Left Ventricular Hypertrophy; Link; Magnetic Resonance Spectroscopy; Measurement; Measures; Mitochondria; Mitochondrial Proteins; Mus; Muscle Cells; Mutation; Myocardial; Myocardium; Myosin ATPase; Na(+)-K(+)-Exchanging ATPase; Nonmuscle Myosin Type IIA; Outcome; Oxidative Stress; Pathogenicity; Pathway interactions; Perfusion; Persons; Phase; Phenotype; Phosphorus; Process; Production; Protein Biosynthesis; Reactive Oxygen Species; Relaxation; Risk; Sarcomeres; Sodium; Sodium Phosphorus; Structure; Testing; Troponin T; Work; base; catalase; clinical development; clinical phenotype; coronary fibrosis; cost; diabetic cardiomyopathy; drinking water; drug development; effective therapy; energy balance; heart function; hemodynamics; improved; improved functioning; improved outcome; in vivo magnetic resonance spectroscopy; inhibitor; interest; mouse model; overexpression; protein function; research clinical testing; small molecule; sudden cardiac death; tool

PROJECT SUMMARY. Despite recent exponential growth of the field of cardiovascular genetics leading to iden- tification of hundreds of mutations responsible for hypertrophic cardiomyopathy (HCM), the mechanism linking sarcomeric mutations to the clinical phenotype remains unknown. Clinical features of HCM are severe left ven- tricular hypertrophy, myocardial fibrosis, diastolic dysfunction, and an increased risk of arrhythmias and heart failure. As there is no disease-modifying therapy available, HCM remains the most common cause of sudden cardiac death in the young. This proposal considers worsened myocardial energetics as the unknown shared pathway that, when triggered by a sarcomeric mutation, leads to the development of the clinical phenotype. Mutations responsible for HCM increase power of contraction in extremely inefficient way, resulting in several- fold increased ATP demand. Mitochondria initially meet the increased demand and maintain normal ATP con- centration, albeit at a cost of accumulation of ADP, a product of ATP hydrolysis. Elevated ADP limits free energy of ATP hydrolysis (∆G~ATP), which is the amount of chemical energy in ATP that ATPases can use to perform work. Decreased ∆G~ATP inhibits ion pumps SERCA and Na+/K+ ATPase leading to increased diastolic Ca++ and intracellular [Na+]i, associated with diastolic dysfunction and arrhythmias. Moreover, elevated [Na+]i further impairs mitochondrial ATP synthesis and increases reactive oxygen species (ROS) production. Excessive ROS, in turn, oxidatively inhibit mitochondrial proteins and ATP synthesis. Thus, even though the primary defect is in the inefficient sarcomere, mitochondrial damage ensues, establishing a vicious cycle of energy shortage. The central hypothesis of this proposal is that interventions that improve energy balance, result in improved function, hypertrophy and fibrosis in HCM. The central hypothesis will be tested by pursuing two mechanisms to improve energetics in HCM: 1) decreasing ATP demand and 2) improving mitochondrial ATP synthesis. Sodium and phosphorus magnetic resonance spectroscopy and imaging will determine the interplay between myocardial [Na+]i, ROS, contractile function, energetics, hypertrophy and fibrosis in a murine models of HCM bearing two of the most lethal mutations, R403Q in myosin and R92L in troponin T. Specific Aim 1 will test the hypothesis that treatment with a myosin ATPase inhibitor, MYK-461, decreases excessive ATP consumption to improve ∆G~ATP, [Na+]i, oxidative stress and cardiac function in HCM mice. Specific Aim 2 will test the hypothesis that interventions that increase mitochondrial ATP synthesis improve ∆G~ATP, diastolic function and contractile re- serve in HCM. ATP synthesis in HCM mice will be increased by a) saturating mitochondria with an accessible substrate, butyrate, b) supressing excessive mitochondrial ROS by overexpressing mitochondrial catalase, and c) decreasing intracellular [Na+]i with empagliflozin, a Na+/glucose cotransport (SGLT2) inhibitor. These results will provide immediately translatable tools to modify the disease process in HCM. Moreover, they will guide drug development in spectrum of mitochondria-based cardiovascular conditions beyond HCM.

项目摘要。尽管最近心血管遗传学领域的指数增长导致了识别， 导致肥厚型心肌病（HCM）的数百种突变的确认， 肌节突变与临床表型的关系仍然未知。肥厚型心肌病的临床特征是严重的左心室肥厚， 三尖瓣肥大、心肌纤维化、舒张功能障碍以及心律失常和心脏病风险增加 失败由于没有可用的疾病修饰疗法，HCM仍然是突发性HCM的最常见原因。 年轻人的心源性死亡该建议认为心肌能量学恶化是未知的共享 当由肌节突变触发时，导致临床表型发展的途径。 导致HCM的突变以极其低效的方式增加收缩力，导致几种- 增加ATP需求。线粒体最初满足增加的需求并维持正常的ATP浓度， 浓缩，尽管以ATP水解产物ADP的积累为代价。ADP升高限制了自由能 ATP水解（ATP酶），这是ATP酶可以用来执行的ATP中的化学能的量 工作ATP酶活性降低，抑制离子泵SERCA和Na+/K+ ATP酶，导致舒张期Ca++升高 和细胞内[Na+]i，与舒张功能障碍和心律失常有关。此外，升高的[Na+]i进一步 损害线粒体ATP合成并增加活性氧（ROS）的产生。过量的ROS， 进而氧化抑制线粒体蛋白质和ATP合成。因此，即使主要缺陷是在 肌节效率低下，线粒体损伤加剧，形成能量短缺的恶性循环。的 该建议的中心假设是，改善能量平衡的干预措施，导致改善的功能， 肥厚和纤维化。中心假设将通过追求两种机制来测试，以改善 HCM中的能量学：1）减少ATP需求和2）改善线粒体ATP合成。钠和 磷磁共振波谱和成像将确定心肌 [Na+]i、ROS、收缩功能、能量学、肥大和纤维化 在最致命的突变中，肌球蛋白中的R403 Q和肌钙蛋白T中的R92 L。具体目标1将检验假设 用肌球蛋白ATP酶抑制剂MYK-461治疗，减少了过度的ATP消耗， 肥厚型心肌病小鼠心肌组织中ATP、[Na+]i、氧化应激与心功能的关系具体目标2将检验以下假设： 增加线粒体ATP合成的干预措施可改善线粒体ATP合成、舒张功能和收缩功能。 服务于HCM。HCM小鼠中的ATP合成将通过以下方式增加：a）用可接近的ATP饱和线粒体， 底物丁酸盐，B）通过过表达线粒体过氧化氢酶抑制过量的线粒体ROS，和 c）使用恩格列净（一种Na+/葡萄糖共转运（SGLT 2）抑制剂）降低细胞内[Na+]i。这些结果 将提供立即可翻译的工具来修改HCM中的疾病过程。此外，他们将指导药物 HCM以外的心血管疾病谱的发展。