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

尽管射血分数降低的心力衰竭患者的治疗取得了显著进展， （HFrEF），大量的残留发病率和死亡率继续困扰着当代治疗时代。的 HF患者的主要临床特征是运动能力降低，这与 生活质量下降。即使了解了心肌功能障碍的各种机制， 医学治疗的重点是调节“神经激素轴”，而正交方法则非常困难。 needed.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 酮体治疗可改善HF血流动力学，提示潜在的增能获益。我们的研究也 强调了骨骼肌异常对HF运动耐量受损的作用， 数据表明，在健康人中，酮在减少外周无氧碳水化合物代谢方面具有有益作用。 志愿者因此，我们试图了解酮症治疗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，并研究 在一项交叉、安慰剂对照试验中发现潜在的心肌和血管获益机制。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运动测量。目标3将调查 使用最新技术水平研究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。这些研究将利用丰富的翻译研究环境 在宾夕法尼亚大学，包括人类表型科学中心，一个临床和 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，我们的结果将增加新兴的文献，证明靶向治疗的重要性。 “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 激发了更大规模的酮治疗随机试验。Selvaraj博士是一名早期职业调查员，也是一名研究员， 他的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HF的心血管代谢干预，并使用深度表型分析技术来定义 利益之路。这些研究目标是一个全面的培训计划的一部分，将由 导师团队涵盖基础科学、转化和临床领域，具有丰富的 HF的心血管代谢、代谢组学分析、HF早期研究中的深层表型分析 治疗和分子代谢成像。这个多元化和协作的团队将指导塞尔瓦拉杰博士的 过渡到一个独立资助的研究生涯，将研究结果扩展到低输出HF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.