See Article by Voros et al

To maintain its intense energy requirements, the heart continuously transforms chemical energy obtained from circulating substrates into mechanical work via an efficient metabolic machinery. Under normal conditions, fatty acids (FA) provide 70% of the fuel requirements to the heart, with the remaining 30% resulting from glucose oxidation. In heart failure (HF), the 3 fundamental steps of cardiac energy metabolism are deranged, that is, substrate uptake, oxidative phosphorylation, and shuttling of energy from mitochondria to the cytosol. Although this metabolic remodeling is a heterogeneous process, which varies largely depending on the stage and the cause of cardiac dysfunction, it is generally accepted that in HF, mitochondrial oxidative metabolism is impaired, which is accompanied by decreased reliance on FA oxidation for ATP production and a mismatch between enhanced glycolytic rates and decreased glucose oxidation in mitochondria.¹ Based on proteomic and metabolomic evidence, 2 groups independently proposed that ketone bodies may become a predominant source of energy in the failing heart.^2,3

In the current issue of Circulation: Heart Failure, Voros et al⁴ measured concentration gradients of ketone bodies and FA between arterial and coronary sinus blood samples obtained from patients with HF with reduced ejection fraction or aortic stenosis (AS)–induced cardiac hypertrophy.⁴ The control group consisted of individuals without structural cardiac disease undergoing catheter ablation for atrial arrhythmias. Both HF with reduced ejection fraction and AS patients displayed a marked increase in ketone bodies concentration gradients, suggesting increased uptake, whereas the FA gradient across (and therefore, uptake into) the heart was increased exclusively in the AS group. Although this confirms previous evidence that myocardial ketone body utilization is increased in patients with HF, the study represents an important addition to the field in that it investigates substrate uptake also in individuals with cardiac hypertrophy but without failure, a subgroup of patients which has not been characterized in this respect to date.

Ketone bodies are produced from acetyl-CoA in the liver and released into the bloodstream to provide extra-hepatic tissues with a substrate for ATP production during prolonged fasting or starvation. In fact, starvation is associated with a predominance of glucagon over insulin signaling, which stimulates gluconeogenesis and thereby depletes Krebs cycle intermediates in the liver, diverting acetyl-CoA toward synthesis of ketone bodies. In end-stage HF, neurohormonal activation enhances mobilization of FA from adipose tissue,⁵ and peripheral tissues become resistant to insulin activity.⁶ Together, these processes promote ketogenesis and increase circulating levels of ketone bodies in HF patients.^3,7 Because ketone bodies availability is a key determinant of their uptake and utilization in the myocardium, it has been proposed that perturbed metabolism in extracardiac tissues contributes to metabolic remodeling in the failing heart. In agreement with previous studies,⁷ Voros et al⁴ observed a mild increase in arterial levels of ketone bodies and an increase in their myocardial extraction in both HF with reduced ejection fraction and AS patients. Intriguingly, the increased cardiac uptake of ketone bodies in patients with compensated hypertrophy is corroborated by the observation that enzymes involved in ketone bodies oxidation are upregulated in mice with pressure overload–induced cardiac hypertrophy before the development of overt HF.² Although it remains unclear whether a metabolic shift towards ketone bodies oxidation in the failing human heart is an adaptive or maladaptive response, experimental evidence argues in favor of the former. Because the energy yield from β-hydroxybutyrate oxidation is higher than of FA (but not of glucose), ketone bodies may represent a more oxygen-efficient substrate for the energetically starved heart.⁸ Furthermore, cardiac-specific deletion of one of the key enzymes of ketone bodies oxidation does not result in a pathological phenotype at baseline, but exacerbates HF in mice subjected to aortic banding,⁹ suggesting that this metabolic pathway plays a compensatory role in the pressure-overloaded heart. Finally, ketone bodies may have beneficial effects not directly related to energy metabolism, such as anti-inflammatory properties related to inhibition of inflammasome activation.¹⁰

FA utilization for ATP production is achieved predominantly via the β-oxidative pathway, which is accomplished inside mitochondria by the cleavage of 2 carbons at a time from the fatty acyl chain (Figure). FA import into mitochondria is mediated by the carnitine shuttle, which entails the conjugation of a fatty acyl chain with a carnitine moiety, which is again replaced by CoA once the acyl-carnitine intermediate reaches the mitochondrial matrix (Figure). Of note, although increases in plasma fatty acyl-carnitines are commonly observed in HF patients, they represent a poor or even misleading indirect indicator of inefficient β-oxidation. In fact, lipid metabolism depends on the tight balance between FA synthesis (de novo lipogenesis from dietary carbohydrate metabolism), uptake, and oxidation of lipid intermediates (dietary lipids). A low-fat carbohydrate-enriched diet contributes up to 27-fold more to de novo lipogenesis than a low carbohydrate diet during prolonged fasting.^11,12 Considering that over the past decades, the western world has adopted a high-carbohydrate diet consumption (eg, sugar-sweetened beverages),¹³ the large increases in plasma fatty acyl-carnitines can also be factored in by greater liver FA synthesis. The latter, which is not generally taken into account, can potentially explain the confounding reports of diminished,¹⁴ unchanged,¹⁵ or even increased myocardial FA oxidation in HF with reduced ejection fraction populations.¹⁶

Figure. Ketone and fatty acid metabolism. Ketone bodies produced from acetyl-CoA in the liver are released into circulation and transported into cardiomyocyte`s cytosol via the MCTs (monocarboxylate transporters). Mitochondrial passive diffusion allows ketone bodies to access the mitochondrial matrix, to be metabolized to acetyl-CoA and oxidized in the Krebs cycle. Fatty acids are carried in the blood bound to either albumin or lipoproteins. In addition to passive diffusion, sarcolemmal fatty acid translocase (FAT/CD36), FABP_pm (fatty acid-binding protein), and FATP (fatty acid transport protein) traffic fatty acids across the plasma membrane to the cytosol. In the cytosol, fatty acids are activated to fatty acyl-CoA. They enter the mitochondrial outer membrane via CPT1 (carnitine O-palmitoyltransferase 1, which resides within the membrane) and are subsequently linked to carnitine (carnitine exchanges with CoA). Fatty acyl-carnitine enters the inner mitochondrial membrane via a translocase (T). Inside the inner mitochondrial membrane (mitochondrial matrix), fatty acyl-carnitine is again exchanged back to fatty acyl-CoA via CPT2 (which resides attached to the interior of the inner mitochondrial membrane). In the mitochondrial matrix, fatty acyl-CoA is degraded via the β-oxidation pathway that cleaves 2 carbons at a time from the acyl chain, forming an acetyl-CoA molecule. Furthermore, β-oxidation produces reduced nicotinamide and flavin adenine dinucleotide (NADH and FADH₂), electron donors for the respiratory chain. Finally, acetyl-CoA enters the Krebs cycle to provide more NADH and FADH₂. In the liver, acetyl-CoA can additionally be used to produce ketone bodies. Ketone bodies uptake increases in both patients with end-stage HF with reduced ejection fraction (HFrEF) and aortic stenosis, whereas fatty acid uptake increases solely in patients with aortic stenosis (left), but not with HFrEF (right).

Interestingly, the study by Voros et al⁴ observes net increases of FA concentration gradients (and thereby, myocardial uptake) solely in the AS population (Figure). An increase in cardiac afterload, such as observed in patients with AS or hypertension, increases the energetic demand of the heart. It can be assumed that the increased FA and ketone body utilization is an adaptive process to match the elevated energetics requirements of the heart. Furthermore, it may be speculated that despite the maintained elevated ketone body utilization, a decrease in FA utilization may contribute to the transition of compensated hypertrophy towards failure.

In conclusion, Voros et al⁴ need to be commended for providing novel and important insights into metabolic remodeling in the hypertrophied and failing human heart. The emerging concept that ketone bodies represent a thrifty substrate⁸ compensating for compromised glucose and FA oxidation is intriguing and might eventually translate into novel therapeutic approaches for HF patients. For instance, nutritional ketosis shifts metabolism away from glucose utilization and increases FA oxidation during exercise in skeletal muscle, thereby improving endurance performance.¹⁷ Furthermore, increased metabolic efficiency of myocardial ketone body oxidation might partly account for the beneficial effects associated with SGLT2 (sodium/glucose cotransporter 2) inhibitors, a new class of antidiabetic agents which substantially reduced the risk for HF hospitalization and mortality in diabetic patients at high cardiovascular risk.^18,19 In fact, SGLT2 inhibition induces glycosuria, removing a substantial amount of glucose from the body and consequently reducing the insulin/glucagon ratio.²⁰ This metabolic milieu stimulates ketogenesis in the liver, and thereby, the energetically starved heart is provided with a more oxygen-efficient fuel. Overall, this novel avenue of research might spark new enthusiasm towards targeting metabolic remodeling in the failing heart.

Dr Maack is supported by the Deutsche Forschungsgemeinschaft (Ma 2528/7-1, SFB-894 and TRR-219), Corona Foundation, and the Federal Ministry of Education and Science (Bundesministerium für Bildung und Forschung).

Dr Maack received speaker honoraria from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb, Berlin Chemie, Daiichi Sankyo, Pfizer, Servier, and Novartis and is an advisor to Servier. The other authors report no conflicts.

The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.

参见Voros等人的文章

为了维持其强烈的能量需求，心脏通过有效的新陈代谢机制将循环的底物获得的化学能不断转化为机械功。在正常情况下，脂肪酸（FA）可为心脏提供70％的燃料需求，其余30％来自葡萄糖氧化。在心力衰竭（HF）中，心脏能量代谢的3个基本步骤处于混乱状态，即底物吸收，氧化磷酸化以及从线粒体到细胞质的能量穿梭。尽管这种代谢重塑是一个异质过程，取决于心脏功能障碍的阶段和病因，其变化很大，但通常认为，在HF中，线粒体的氧化代谢会受到损害，¹根据蛋白质组学和代谢组学证据，有2个研究组独立地提出，酮体可能成为衰竭心脏的主要能量来源。^2,3

在当前发行的《循环：心力衰竭》一书中，Voros等人[ ^4]测量了从射血分数降低或主动脉瓣狭窄（AS）引起的心脏肥大的HF患者获得的动脉和冠状窦血样中酮体和FA的浓度梯度。⁴对照组由无结构性心脏病的患者进行导管消融治疗房性心律失常。射血分数降低的心衰患者和AS患者均显示出酮体浓度梯度显着增加，表明摄取增加，而AS组中整个心脏的FA梯度（因此吸收到心脏中）的FA梯度却增加了。尽管这证实了先前的证据表明心力衰竭患者心肌酮体利用率增加，但这项研究是该领域的重要补充，因为该研究还调查了具有心肌肥厚但没有衰竭的患者的底物摄取，该亚组患者并未在这方面迄今具有特色。

酮体是由肝脏中的乙酰辅酶A产生并释放到血流中，从而为肝外组织提供长时间禁食或饥饿期间产生ATP的底物。实际上，饥饿与胰高血糖素在胰岛素信号传导方面的优势有关，后者刺激糖异生，从而消耗肝脏中的Krebs循环中间体，从而使乙酰辅酶A转向合成酮体。在终末期HF中，神经激素激活增强了FA从脂肪组织中的动员[ ^5]，并且外周组织变得对胰岛素活性具有抗性。⁶这些过程共同促进了HF患者的生酮作用并增加了酮体的循环水平。^3,7由于酮体的可利用性是决定其在心肌中摄取和利用的关键因素，因此，有人提出，心外组织中代谢紊乱有助于衰竭心脏的代谢重塑。与先前的研究一致，⁷ VÖRÖS等⁴观察到酮体水平动脉轻度增加和在两个HF具有降低的射血分数和AS患者的增加他们的心肌萃取。有趣的是，通过观察到在明显的HF出现之前，压力超负荷引起的心脏肥大的小鼠中，参与酮体氧化的酶被上调，从而证实了代偿性肥大患者对酮体的心脏摄取增加。^2个尽管尚不清楚在衰竭的人心脏中向酮体氧化的代谢转变是适应性反应还是适应不良的反应，但实验证据表明，后者是有利的。由于β-羟基丁酸酯氧化产生的能量高于FA（而非葡萄糖）产生的能量，因此酮体可能代表能量不足的心脏的氧气效率更高的底物。⁸此外，心脏特异的酮体氧化关键酶之一的缺失在基线时不会导致病理表型，但会加剧主动脉束缚小鼠的HF，⁹这表明该代谢途径在压力超负荷的心脏中起补偿作用。最后，酮体可能具有与能量代谢不直接相关的有益作用，例如与抑制炎症小体活化有关的抗炎特性。¹⁰

FA用于生产ATP的方法主要是通过β-氧化途径实现的，该途径是通过从脂肪酰基链上一次裂解2个碳原子而在线粒体内完成的（图）。FA进入线粒体的途径是通过肉碱的穿梭介导的，这需要脂肪酰基链与肉碱的部分结合，一旦酰基肉碱的中间体到达线粒体基质，脂肪酰基链就会再次被CoA取代（图）。值得注意的是，尽管在HF患者中血浆脂肪酰基肉碱的增加很常见，但它们代表了β-氧化效率低下的不良指标甚至是误导性的间接指标。实际上，脂质代谢取决于FA合成（饮食中碳水化合物代谢的从新脂代谢），脂质中间物（饮食脂质）的摄取和氧化之间的紧密平衡。^11,12考虑到在过去的几十年中，西方世界已采用了高碳水化合物饮食（例如加糖的饮料），¹³血浆脂肪酰基肉碱的大量增加也可以归因于肝脏FA合成的增加。后者，通常不予考虑，可以潜在地解释混杂的报告，即射血分数减少的心衰患者中心肌FA氧化减少，¹⁴不变，¹⁵甚至增加。¹⁶

数字。 酮和脂肪酸代谢。肝脏中由乙酰辅酶A产生的酮体释放到循环中，并通过MCT（单羧酸盐转运蛋白）转运到心肌细胞的胞质溶胶中。线粒体的被动扩散允许酮体进入线粒体基质，并在克雷布斯循环中被代谢为乙酰辅酶A并被氧化。脂肪酸携带在血液中，与白蛋白或脂蛋白结合。除被动扩散外，肌膜脂肪酸转位酶（FAT / CD36），FABP _pm（脂肪酸结合蛋白）和FATP（脂肪酸转运蛋白）将脂肪酸穿过质膜运输到细胞质中。在胞质溶胶中，脂肪酸被激活为脂肪酰基辅酶A。它们通过CPT1（位于膜内的肉碱O-棕榈酰转移酶1）进入线粒体外膜，随后与肉碱连接（与CoA进行肉碱交换）。脂肪酰基肉碱通过转位酶（T）进入线粒体内膜。在内部线粒体膜（线粒体基质）内部，脂肪酰基肉碱再次通过CPT2（驻留在内部线粒体膜内部）被交换回脂肪酰基辅酶A。在线粒体基质中，脂肪酰基辅酶A通过β-氧化途径降解，该途径一次从酰基链上裂解出2个碳原子，从而形成乙酰辅酶A分子。₂），电子供体为呼吸链。最后，乙酰辅酶A进入克雷布斯循环以提供更多的NADH和FADH ₂。在肝脏中，乙酰辅酶A还可用于生产酮体。射血分数降低（HFrEF）和主动脉瓣狭窄的终末期HF患者的酮体摄取均增加，而主动脉瓣狭窄的患者仅酮体摄取的脂肪酸升高（左），而HFrEF则不升高（右）。

有趣的是，Voros等人[ ^4]的研究仅在AS人群中观察到了FA浓度梯度的净增加（从而增加了心肌吸收）（图）。心脏后负荷的增加（例如在AS或高血压患者中观察到）会增加心脏的能量需求。可以假设增加的FA和酮体利用率是一种适应性过程，可以匹配心脏对能量的更高要求。此外，可以推测，尽管维持了较高的酮体利用率，但FA利用率的下降可能有助于代偿性肥大向衰竭的过渡。

总之，需要对Voros等人⁴提出的有关在肥厚和衰竭的人类心脏中进行代谢重塑的新颖且重要的见解进行表扬。酮体代表节俭的底物^8来补偿受损的葡萄糖和FA氧化这一新兴概念引起了人们的兴趣，并且最终可能转化为HF患者的新型治疗方法。例如，营养性酮症会使新陈代谢远离葡萄糖的利用，并在骨骼肌运动期间增加FA氧化，从而提高耐力表现。¹⁷此外，心肌酮体氧化代谢效率的提高可能部分解释了与SGLT2（钠/葡萄糖共转运蛋白2）抑制剂相关的有益作用，SGLT2抑制剂是一类新型的抗糖尿病药物，可显着降低高糖尿病患者发生HF住院的风险和死亡率心血管风险。^18,19实际上，SGLT2抑制可诱导糖尿，从体内清除大量葡萄糖，从而降低胰岛素/胰高血糖素的比例。²⁰这种新陈代谢的环境刺激了肝脏中的生酮作用，因此，精力充沛的心脏被提供了更多的氧气效率更高的燃料。总体而言，这种新颖的研究途径可能会激发出新的热情，以针对衰竭心脏中的代谢重塑为目标。

Maack博士得到Deutsche Forschungsgemeinschaft（Ma 2528 / 7-1，SFB-894和TRR-219），Corona基金会和联邦教育与科学部（联邦教育与科学基金会）的支持。

Maack博士获得了勃林格殷格翰，拜耳，百时美施贵宝，柏林化学，第一三共制药，辉瑞，施维雅和诺华公司的演讲嘉宾，并且是施维雅的顾问。其他作者报告没有冲突。

本文表达的观点不一定是编辑者或美国心脏协会的观点。