Intersection of Obesity and Heart Failure with Preserved Ejection Fraction

肥胖和心力衰竭与射血分数保留的交叉点

• 批准号: 10572620
• 负责人: David Alan Kass
• 金额: $ 73.65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-20 至 2029-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572620
• 关键词: Affect; African American; Animal Model; Benchmarking; Biological; Calcium; Cardiac; Cell physiology; Citrates; Citric Acid Cycle; Clinical; Contracts; Dedications; Depressed mood; Diabetes Mellitus; Disease; EFRAC; Epigenetic Process; Etiology; Female; Fibrosis; Fumarates; Gene Expression; Genes; Heart; Heart failure; Histone Acetylation; Human; Hypertension; Hypertrophy; Knowledge; Medical; Medicine; Metabolic; Metabolic syndrome; Metabolism; Microfilaments; Modeling; Molecular; Morbidity - disease rate; Motor; Muscle Cells; Myocardial; Myocardial tissue; Myocardium; Obesity; Organ; Oxidative Phosphorylation; Patients; Performance; Phenotype; Physiology; Polyamines; Prevalence; Prognosis; Proteins; Sarcomeres; Stress; Succinates; Syndrome; Testing; United States National Institutes of Health; effective therapy; flexibility; genetic regulatory protein; glucose metabolism; heart metabolism; hemodynamics; histone methylation; histone modification; improved; insight; interest; lipid metabolism; metabolic abnormality assessment; mortality; myocardial biopsy; novel; obese patients; preservation; programs

This project will elucidate the biological mechanisms by which obesity alters the myocardium in patients with heart failure and a preserved ejection fraction (HFpEF) to ultimately derive sorely needed precision- guided therapies. HFpEF currently represents more than half of all heart failure worldwide, its prevalence is rising, morbidity and mortality are substantial, and yet we still have very few effective therapies. It is a major unmet medical need and a disease priority for the NIH. One of the factors that has made it difficult to treat is a major transformation over the past two decades such that most patients are now obese, many severely, with diabetes and metabolic syndrome also very common. This obesity-metabolic syndrome (OMS-HFpEF) phenotype has altered disease manifestations and progression and worsened prognosis. Yet our knowledge of the underlying myocardial pathobiology effects from obesity are limited. Johns Hopkins has established a dedicated clinical HFpEF Center that obtains detailed phenotyping of HFpEF patients, the majority being OMS-HFpEF, African American, and female. The phenotyping includes obtaining myocardial biopsies that have already provided novel insights into cellular and molecular features. Our recent studies revealed less fibrosis than predicted, and that fat metabolism and glucose metabolism seem both to be depressed in OMS-HFpEF, pairing abnormalities found in HF with reduced EF and obesity/diabetes respectively, in essence a worst of both worlds that limits fuel flexibility. Yet unlike HFrEF, oxidative phosphorylation seems enhanced particularly in obese patients. We also find a strong inverse correlation between obesity and calcium-stimulated myofilament function – being very depressed in OMS-HFpEF ± diabetes, hypertension, or LV hypertrophy. Obesity is thus a major driver for fundamental changes in HFpEF. This R35 Program dissects metabolic and sarcomeric dysregulation in OMS-HFpEF, starting with analysis of human myocardial tissues, and testing abnormalities in animal models that have both marked OMS and cardiac hemodynamic stress. Models are benchmarked to pair with human molecular/cellular pathobiology, rather than only organ level physiology as historically done. Our metabolic studies will determine the fuel substrates used by OMS-HFpEF heart, where bottlenecks in fuel metabolism occur, how these maybe circumvented and what the impact is, which metabolites are formed that can impact epigenetics (histone modifications) to alter gene programs controlling metabolism and other key cellular functions. Major interest is on Krebs cycle intermediates such as citrate, succinate and fumarate and polyamines, that can impact histone methylation and acetylation. Our myocyte studies will determine how obesity depresses sarcomere function, find the protein(s) and structural changes involved, their causes, and prove causality. Lastly, we will test therapies to improve metabolic flexibility and sarcomere performance in OMS-HFpEF that can lead to precision-guided medicines for this common phenotype.

这个项目将阐明肥胖改变患者心肌的生物学机制 心力衰竭和射血分数保留（HFpEF），以最终获得急需的精度- 指导治疗。HFpEF目前占全球所有心力衰竭的一半以上，其患病率 发病率和死亡率都很高，但我们仍然很少有有效的治疗方法。这是一个 主要未满足的医疗需求和NIH的疾病优先事项。其中一个因素是， 在过去的二十年里，治疗是一个重大的转变，大多数患者现在都很肥胖， 严重者，合并糖尿病和代谢综合征也很常见。这种肥胖代谢综合征 （OMS-HFpEF）表型改变了疾病表现和进展，并使预后恶化。 然而，我们对肥胖潜在的心肌病理生物学影响的认识是有限的。约翰 霍普金斯建立了专门的临床HFpEF中心，获得HFpEF的详细表型 患者，大多数为OMS-HFpEF、非裔美国人和女性。表型分析包括 获得心肌活检已经提供了新的见解，细胞和分子 功能.我们最近的研究显示，纤维化比预期的要少，脂肪代谢和葡萄糖 代谢似乎在OMS-HFpEF中均受到抑制，在HF中发现配对异常伴EF降低 和肥胖/糖尿病，本质上是限制燃料灵活性的两个世界中最糟糕的一个。但不像 HFrEF，氧化磷酸化似乎增强，特别是在肥胖患者中。我们还发现一个强大的 肥胖和钙刺激肌丝功能之间的负相关性-在 OMS-HFpEF ±糖尿病、高血压或LV肥大。因此，肥胖是一个主要的驱动力， HFpEF的变化。该R35程序剖析了OMS-HFpEF中的代谢和肌节失调， 从分析人类心肌组织开始，并在动物模型中测试异常， 都有明显的OMS和心脏血流动力学应激。对模型进行基准测试， 分子/细胞病理生物学，而不仅仅是器官水平的生理学。我们的代谢 研究将确定OMS-HFpEF心脏使用的燃料底物，其中燃料代谢的瓶颈 发生，这些可能如何规避和影响是什么，哪些代谢物形成，可以 影响表观遗传学（组蛋白修饰），以改变控制代谢和其他关键的基因程序 细胞功能。主要关注的是克雷布斯循环中间体，如柠檬酸盐，琥珀酸盐和富马酸盐 和多胺，可以影响组蛋白甲基化和乙酰化。我们的肌细胞研究将决定 肥胖如何抑制肌节功能，发现蛋白质和结构变化， 原因，并证明因果关系。最后，我们将测试改善代谢灵活性和肌节的疗法。 OMS-HFpEF的性能，可以导致这种常见表型的精确指导药物。