Hungry Hearts
2018; Lippincott Williams & Wilkins; Volume: 11; Issue: 12 Linguagem: Inglês
10.1161/circheartfailure.118.005642
ISSN1941-3297
AutoresEdoardo Bertero, Vasco Sequeira, Christoph Maack,
Tópico(s)Diet and metabolism studies
ResumoHomeCirculation: Heart FailureVol. 11, No. 12Hungry Hearts Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHungry HeartsEnergetic Substrate Metabolism in Human Cardiac Hypertrophy and Failure Edoardo Bertero, MD, Vasco Sequeira, PhD and Christoph Maack, MD Edoardo BerteroEdoardo Bertero Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Germany. , Vasco SequeiraVasco Sequeira Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Germany. and Christoph MaackChristoph Maack Christoph Maack, MD, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Am Schwarzenberg 15, Haus A15, 97078 Würzburg, #8232, Germany. Email E-mail Address: [email protected] Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Germany. Originally published12 Dec 2018https://doi.org/10.1161/CIRCHEARTFAILURE.118.005642Circulation: Heart Failure. 2018;11:e005642This article is a commentary on the followingIncreased Cardiac Uptake of Ketone Bodies and Free Fatty Acids in Human Heart Failure and Hypertrophic Left Ventricular RemodelingSee Article by Voros et alTo 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.2,3In 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.10FA 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.16Download figureDownload PowerPointFigure. 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), FABPpm (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.AcknowledgmentsDr 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).DisclosuresDr 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.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Christoph Maack, MD, Comprehensive Heart Failure Center (CHFC), University Clinic Würzburg, Am Schwarzenberg 15, Haus A15, 97078 Würzburg, #8232, Germany. Email [email protected]deReferences1. Bertero E, Maack C. 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Lopez R, Marzban B, Gao X, Lauinger E, Van den Bergh F, Whitesall S, Converso-Baran K, Burant C, Michele D and Beard D (2020) Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts, Function, 10.1093/function/zqaa018, 1:2, Online publication date: 14-Sep-2020. Related articlesIncreased Cardiac Uptake of Ketone Bodies and Free Fatty Acids in Human Heart Failure and Hypertrophic Left Ventricular RemodelingGabor Voros, et al. Circulation: Heart Failure. 2018;11 December 2018Vol 11, Issue 12 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.118.005642PMID: 30537855 Originally publishedDecember 12, 2018 KeywordshumanEditorialsfatty acidshypertrophyheart failurePDF download Advertisement SubjectsHeart FailureMetabolismPathophysiologyTranslational Studies
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