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

尽管心力衰竭患者的治疗取得了重大进展，但射血分数降低 (HFrEF)，相当大的残余发病率和死亡率继续困扰着当代治疗时代。这个 心力衰竭患者的主要临床特征是运动能力降低，这与显著 生活质量下降。即使对心肌功能障碍的不同机制有深入的了解，最新的 医学治疗的重点是调节“神经荷尔蒙轴”，而正交法是非常重要的。 需要的。我们团队和其他人最近的临床前和临床数据表明，外源性递送 酮治疗可改善心力衰竭的血流动力学，提示有潜在的促进性益处。我们的研究也 强调骨骼肌异常对心力衰竭患者运动耐量受损的贡献，并有限 数据提示酮在降低健康人外周无氧碳水化合物代谢中的有益作用 志愿者。因此，我们试图了解治疗性酮症对HFrEF患者的潜在益处。 通过对心肌、外周肌肉和代谢的贡献进行深入的表型分析。目标1将 确定外源性酮酯给药对功能能力的急性影响并调查 一项交叉的安慰剂对照试验中潜在的心肌和血管机制的益处。目标2将 比较酮酯治疗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锻炼措施。目标3将调查 应用最新技术研究酮类药物对外周肌内乳酸生成和灌流的影响 磁共振成像协议。这样的研究将利用丰富的翻译研究环境 在宾夕法尼亚大学，包括人类物候学中心，临床和 翻译研究奖(CTSA)倡议，以及磁共振和光学成像中心。 如果有益，我们的结果将增加蓬勃发展的文献，证明以 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博士是职业生涯早期的调查员，也是 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，并使用深层表型技术来确定 受益的途径。这些研究目标是全面培训计划的一部分，将由 一支涵盖基础科学、翻译和临床领域的导师团队，具有丰富的 心力衰竭患者的心血管代谢、代谢组谱、心力衰竭早期研究中的深层表型 治疗学和分子代谢成像。这个多样化和协作的团队将指导Selvaraj博士的 过渡到独立资助的研究生涯，将研究结果扩展到低产出的心衰综合征。

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.