Targeting Energetics to Improve Outcomes in Hypertrophic Cardiomyopathy

项目总结。尽管最近心血管遗传学领域的指数性增长导致了新的-- 数百个与肥厚型心肌病(HCM)有关的突变的鉴定，其机制与 肉瘤突变对临床表型的影响尚不清楚。肥厚性心肌病的临床特点是严重的左、左静脉曲张。 三尖瓣肥厚、心肌纤维化、舒张期功能障碍以及心律失常和心脏风险增加 失败了。由于没有可用的疾病修正疗法，肥厚性心肌炎仍然是猝发的最常见原因。 年轻人的心脏性死亡。这项提议将恶化的心肌能量学视为未知的共享 当被肌节突变触发时，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能力，导致几个- 将增加的ATP需求翻倍。线粒体最初满足增加的需求，并维持正常的ATP含量。 浓缩，尽管是以积累ATP水解产物ADP为代价的。ADP升高限制自由能 三磷酸腺苷的水解度(∆G~三磷酸腺苷)，这是三磷酸腺苷中的化学能，三磷酸腺苷酶可以用来执行 工作。∆G~ATP值降低抑制离子泵SERCA和Na+/K+ATPase导致舒张期钙升高 和细胞内[Na+]i，与舒张期功能障碍和心律失常有关。此外，[Na+]i进一步升高 损害线粒体ATP合成，增加活性氧(ROS)的产生。过量的ROS， 反过来，氧化抑制线粒体蛋白质和ATP的合成。因此，即使主要缺陷在 低效的肌节、线粒体的损伤随之而来，形成了能源短缺的恶性循环。这个 这一建议的中心假设是，改善能量平衡、改善功能、 肥厚性心肌肥大和纤维化。核心假设将通过两种机制进行检验，以改善 HCM中的能量学：1)减少ATP需求；2)促进线粒体ATP合成。钠和 磷磁共振波谱和成像将确定心肌之间的相互作用 [Na+]i、ROS、收缩功能、能量、肥大和纤维化 在最致命的突变中，肌球蛋白的R403Q和肌钙蛋白T的R92L将检验这一假设 用肌球蛋白ATPase抑制剂Myk-461治疗可以减少过量的ATP消耗以改善 ∆G~-ATP、[Na+]i、氧化应激与心功能《特定目标2》将检验这一假设 增加线粒体ATP合成的干预措施可改善∆G~ATP、舒缩功能和收缩功能 在胡志明医院服务。HCM小鼠的ATP合成将通过a)饱和线粒体和可访问的 底物，丁酸，b)通过过度表达线粒体过氧化氢酶抑制过量的线粒体ROS，以及 C)用钠/葡萄糖共转运(SGLT2)抑制剂依帕格列酮降低细胞内[Na+]i。这些结果 将提供可立即翻译的工具来修改HCM中的疾病过程。此外，他们还将指导药物 除HCM外，基于线粒体的心血管疾病的研究进展。

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.