Targeting Ketone Metabolism as a Novel Heart Failure Therapy

总结 心力衰竭（HF）是一种全球性的健康威胁，其发病率正在增长。目前的HF治疗主要针对 在适应不良的心脏外神经激素回路在一个“一刀切”的方法。有证据表明， 心肌燃料和能量代谢紊乱促成HF的早期阶段，导致恶性循环 能量缺乏和收缩功能障碍。我们进行了心肌代谢组学和蛋白质组学研究 在明确定义的早期HF小鼠模型和终末期衰竭的人类心脏中进行分析。结果 这些分析研究已经确定了HF中指示瓶颈的蛋白质和代谢物特征 心肌脂肪酸氧化（FAO）是TCA循环乙酰辅酶A的主要来源，沿着有证据表明 在肥大和衰竭的心脏中增加酮体氧化。最近，我们发现， 增加酮体3-羟基丁酸酯（3OHB）向心脏的输送，可延缓HF的发展， 小鼠和犬快速起搏模型。然而，生物学机制解释了 3OHB的心脏保护作用尚不清楚。例如，这些有益的影响是心脏自主的吗？是 3OHB是提供燃料还是通过其他机制起作用？本MPI提案旨在测试 假设增加心肌酮通过提供一种 更容易氧化的燃料线粒体ATP生产。为了解决这个假设：1）我们将探索 3OHB在HF发展过程中的心脏特异性有益作用。一组口服 将在野生型和非野生型中评估施用的酮酯对心脏功能和病理性重塑的影响。 心脏特异性Bdh 1缺陷小鼠（不能在心脏中氧化3OHB）在HF发展过程中。此外，本发明还提供了一种方法， 将在心肌细胞中评估3OHB对收缩性和钙瞬变的细胞自主影响 2）我们将研究3OHB作为心肌燃料在其有益作用中的作用 通过评估R-3OHB（氧化）与S-3OHB（未氧化）的疗效，对病理性心脏重塑的影响 酮酯对小鼠HF发展的影响; 3）我们将开发和验证增加 心肌3OHB递送作为大型动物模型中HF的治疗策略，通过评估 R-3OHB和S-3OHB对犬快速起搏模型心脏血流动力学和底物代谢的影响 进行性HF。最后，将通过比较3OHB作为治疗剂的影响来探索其潜力。 以及测试口服3OHB酯。计划中的研究将 为3OHB改善HF的机制提供了重要的新见解，并将提供深入的预 增加酮体向心脏的递送作为一种新的治疗方法的临床评估。

SUMMARY The incidence of heart failure (HF), a global health threat, is growing. Current therapies for HF are largely directed at maladaptive extra-cardiac neurohormonal circuits in a “one size fits all” approach. Evidence has emerged that myocardial fuel and energy metabolic disturbances contribute to the early stages of HF leading to a vicious cycle of energy starvation and contractile dysfunction. We have conducted myocardial metabolomic and proteomic profiling in well-defined mouse models of early stage HF and in the end-stage failing human heart. The results of these profiling studies have identified protein and metabolite signatures in HF that are indicative of bottlenecks in cardiac fatty acid oxidation (FAO), the chief source of acetyl-CoA for the TCA cycle along with evidence for increased ketone body oxidation in the hypertrophied and failing heart. More recently, we have found that increasing delivery of the ketone body, 3-hydroxybutyrate (3OHB) to heart, retards the development of HF in mice and in a canine tachypacing model. However, the biological mechanisms accounting for the cardioprotective effect of 3OHB are unknown. For example, are these beneficial effects cardiac autonomous? Is 3OHB providing a fuel or does it act via other mechanisms? This MPI proposal is designed to test the hypothesis that increasing myocardial ketones reduces pathological cardiac remodeling by providing a more readily oxidizable fuel for mitochondrial ATP production. To address this hypothesis: 1) we will probe the cardiac-specific beneficial actions of 3OHB during the development of HF. The efficacy of a panel of orally administered ketone esters on cardiac function and pathological remodeling will be assessed in wild-type and cardiac-specific Bdh1-deficient mice (unable to oxidize 3OHB in heart) during development of HF. In addition, the cell-autonomous impact of 3OHB on contractility and calcium transients will be assessed in cardiac myocytes isolated from humans with HF; 2) we will investigate the role of 3OHB as a myocardial fuel in its beneficial actions on pathologic cardiac remodeling by assessing the efficacy of R-3OHB (oxidized) vs S-3OHB (unoxidized) ketone esters on the development of HF in mice; and 3) we will develop and validate strategies to increase myocardial 3OHB delivery as a therapeutic strategy for HF in a large animal model by assessing the effects of R-3OHB and S-3OHB on cardiac hemodynamics and substrate metabolism in a canine tachypacing model of progressive HF. Lastly, the potential of 3OHB as a therapeutic agent will be explored by comparing the impact of administration before and after the onset of HF as well as testing oral 3OHB esters. The planned studies will provide important new insight into the mechanisms whereby 3OHB ameliorates HF and will provide in-depth pre- clinical assessment of increasing delivery of ketone bodies to heart as a novel therapeutic.