Dissecting the Ketone Metabolic Axis in Heart Failure with Reduced Ejection Fraction

剖析射血分数降低的心力衰竭中的酮代谢轴

• 批准号: 10524277
• 负责人: Senthil Selvaraj
• 金额: $ 18.92万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10524277
• 关键词: Accounting; Activities of Daily Living; Acute; Affect; Aldosterone; Anaerobic Bacteria; Angiotensins; Award; Basic Science; Bioenergetics; Biological Markers; Blood Vessels; Blood flow; Carbohydrates; Cardiac; Cardiac Output; Cardiopulmonary; Cardiovascular system; Cell Respiration; Cessation of life; Chemicals; Clinic; Clinical; Clinical Data; Clinical Research; Coupled; Cross-Over Trials; Data; Dose; Drug Kinetics; EFRAC; Echocardiography; Energy-Generating Resources; Environment; Esters; Exercise; Exercise Test; Exercise Tolerance; Failure; Fatty Acids; Functional disorder; Funding; Future; Gases; Glucose; Glycogen; Goals; Heart; Heart failure; Human; Impairment; Infusion procedures; Intervention; Intramuscular; Ketone Bodies; Ketones; Ketosis; Left Ventricular Remodeling; Literature; Lower Extremity; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Medical; Mentorship; Metabolic; Metabolism; Mitochondria; Molecular; Morbidity - disease rate; Muscle; Myocardial; Myocardial dysfunction; Myocardium; Nutraceutical; Outcome; Output; Oxygen; Oxygen Consumption; Participant; Pathologic; Pathway interactions; Patients; Pennsylvania; Perfusion; Peripheral; Persons; Phenotype; Physiological; Placebos; Plague; Plasma; Population; Positioning Attribute; Production; Protocols documentation; Quality of life; Renin; Research; Research Personnel; Residual state; Risk; Safety; Science; Skeletal Muscle; Sodium; Source; Standardization; Supervision; Sympathetic Nervous System; Symptoms; Syndrome; Techniques; Therapeutic; Time; Training; Translational Research; Universities; Ventricular Dysfunction; Work; Workload; acylcarnitine; animal data; blood pump; carbohydrate metabolism; career; exercise capacity; exercise intolerance; exhaustion; experience; healthy volunteer; hemodynamics; improved; inhibitor; insight; metabolic imaging; metabolomics; mortality; novel; novel therapeutics; optical imaging; oxidation; phenomics; placebo controlled trial; pre-clinical; preservation; randomized trial; respiratory; stable isotope; symptomatic improvement; tonometry; treatment strategy; vasoconstriction

Despite significant advances in the treatment of patients with heart failure with reduced ejection fraction (HFrEF), substantial residual morbidity and mortality continues to plague the contemporary treatment era. The cardinal clinical feature of patients with HF is reduced exercise capacity, which is associated with substantially reduced quality of life. Even with insights into diverse mechanisms of myocardial dysfunction, most current medical treatment focuses on modulating the "neurohormonal axis", and orthogonal approaches are direly needed. Recent preclinical and clinical data from our team and others demonstrate that exogenous delivery of ketone therapy improves HF hemodynamics, suggesting potential ergogenic benefits. Our research has also highlighted the contribution of skeletal muscle abnormalities to impaired exercise tolerance in HF, and limited data suggest beneficial effects of ketones in reducing peripheral anaerobic carbohydrate metabolism in healthy volunteers. We therefore seek to understand the potential benefits of therapeutic ketosis in patients with HFrEF by performing deep phenotyping of myocardial, peripheral musculature, and metabolic contributions. Aim 1 will determine the acute effects of exogenous ketone ester administration on functional capacity and investigate potential myocardial and vascular mechanisms of benefit in a crossover, placebo-controlled trial. Aim 2 will compare whether ketone ester therapy alters systemic carbohydrate metabolism through targeted metabolomics, stable isotope infusions, and exercise measures of gas exchange. Aim 3 will investigate the effects of ketone therapy on peripheral intramuscular lactate production and perfusion using state-of-the-art magnetic resonance imaging protocols. Such studies will leverage the rich translational research environment at the University of Pennsylvania, including the Center for Human Phenomic Sciences, a Clinical and Translational Research Award (CTSA) initiative, and the Center for Magnetic Resonance and Optical Imaging. If beneficial, our results would add to the burgeoning literature, demonstrating the importance of targeting the "ketone metabolic axis" as a treatment strategy to help improve exercise capacity and quality of life, and would inspire larger, randomized trials of ketone therapy. Dr. Selvaraj, an early career investigator and a fellow in advanced heart failure, has a long-term goal of becoming an independently funded cardiovascular researcher with a focus on cardiovascular metabolic interventions in HF and using deep phenotyping techniques to define pathways of benefit. Thsese research aims are part of a comprehensive training plan and will be supervised by a mentorship team spanning the basic science, translational, and clinic spectrum with rich experience in cardiovascular metabolism in HF, metabolomic profiling, deep phenotyping during early stage studies of HF therapeutics, and molecular metabolic imaging. This diverse and collaborative team will guide Dr. Selvaraj's transition to an independently funded research career with extension of findings to low output HF syndromes.

尽管射血分数降低的心力衰竭患者的治疗取得了重大进展 (HFrEF)，大量的残余发病率和死亡率继续困扰着当代的治疗时代。这 心力衰竭患者的主要临床特征是运动能力下降，这与 生活质量下降。即使对心肌功能障碍的不同机制有了深入的了解，目前大多数 医学治疗的重点是调节“神经激素轴”，而正交方法是可怕的 需要。我们团队和其他人的最新临床前和临床数据表明，外源性递送 酮疗法可改善高频血流动力学，表明潜在的强效益处。我们的研究还 强调了骨骼肌异常对心力衰竭运动耐量受损的影响，并有限 数据表明酮在减少健康人的外周无氧碳水化合物代谢方面具有有益作用 志愿者。因此，我们寻求了解治疗性酮症对 HFrEF 患者的潜在益处 通过对心肌、外周肌肉组织和代谢贡献进行深度表型分析。目标1将 确定外源性酮酯给药对功能能力的急性影响并进行研究 在交叉、安慰剂对照试验中潜在的心肌和血管获益机制。目标2将 比较酮酯疗法是否通过靶向改变全身碳水化合物代谢 代谢组学、稳定同位素输注和气体交换的运动测量。目标 3 将调查 使用最先进的技术，酮疗法对外周肌内乳酸产生和灌注的影响 磁共振成像协议。此类研究将利用丰富的转化研究环境 宾夕法尼亚大学，包括人类表型科学中心、临床和 转化研究奖 (CTSA) 倡议以及磁共振和光学成像中心。 如果有益的话，我们的结果将添加到新兴的文献中，证明针对目标的重要性 “酮代谢轴”作为一种治疗策略，有助于提高运动能力和生活质量，并将 激发更大规模的酮疗法随机试验。 Selvaraj 博士是一位早期职业研究员和研究员 晚期心力衰竭，长期目标是成为一名独立资助的心血管研究人员 重点关注心力衰竭的心血管代谢干预，并使用深度表型分析技术来定义 利益途径。这些研究目标是综合培训计划的一部分，并将受到 涵盖基础科学、转化和临床领域的导师团队，在以下方面拥有丰富的经验 心力衰竭的心血管代谢、代谢组学分析、心力衰竭早期研究期间的深度表型分析 疗法和分子代谢成像。这个多元化的协作团队将指导 Selvaraj 博士的 过渡到独立资助的研究生涯，并将研究结果扩展到低输出心力衰竭综合征。