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.

该项目将阐明肥胖改变患者心肌的生物学机制 具有心力衰竭和保留的射血分数（HFPEF），最终得出非常需要的精度 - 指导疗法。 HFPEF目前代表全球全部心力衰竭的一半以上，其流行率 正在上升，发病率和死亡率很大，但是我们仍然有很少的有效疗法。是一个 NIH的主要未满足医疗需求和疾病优先级。使很难的因素之一 在过去的二十年中，治疗是一次重大转变，使大多数患者现在肥胖，许多患者 严重的是，糖尿病和代谢综合征也很常见。这种肥胖代谢综合征 （OMS-HFPEF）表型改变了疾病的表现和进展，预后恶化。 然而，我们对肥胖的潜在心肌病理生物学作用的了解有限。约翰 霍普金斯建立了一个专用的临床HFPEF中心，该中心获得了HFPEF的详细表型 患者，大多数是OMS-HFPEF，非裔美国人和女性。表型包括 获得已经为细胞和分子提供了新见解的心肌活检 特征。我们最近的研究表明纤维化少于预期，脂肪代谢和葡萄糖 OMS-HFPEF似乎都抑郁了代谢，在HF中发现的异常与EF降低了 和肥胖/糖尿病分别分别是两全其最差的世界，这限制了灵活性。但不像 HFREF，氧化磷酸化似乎增强了，特别是在肥胖患者中。我们也发现一个强壮 肥胖与钙刺激的肌丝功能之间的反相关性 - 非常沮丧 OMS-HFPEF±糖尿病，高血压或LV肥大。因此，肥胖是基本的主要驱动力 HFPEF的变化。该R35程序在OMS-HFPEF中剖析了代谢和肌膜失调， 从分析人类心肌组织，并在具有的动物模型中测试异常 标记的OMS和心脏血流动力学应激。模型是基准的，与人类配对 分子/细胞病理生物学，而不仅仅是像历史上这样做的器官水平生理学。我们的代谢 研究将确定OMS-HFPEF心脏使用的燃料基板，其中瓶装代谢中的瓶颈 发生，如何绕过这些影响以及影响是什么，形成哪些代谢物可以 影响表观遗传学（组蛋白修饰）以改变控制新陈代谢和其他关键的基因程序 细胞功能。对克雷布斯循环中间体（例如柠檬酸盐，琥珀酸酯和富马酸）的主要兴趣是 和多胺可以影响组蛋白甲基化和乙酰化。我们的心肌研究将决定 肥胖如何抑制肌节功能，找到所涉及的蛋白质和结构变化，它们 原因，证明是偶然的。最后，我们将测试疗法以提高新陈代谢的灵活性和肌膜 在OMS-HFPEF中的性能可以为这种常见表型提供精确指导的药物。