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Cardiac Metabolism in Heart Failure

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 12443

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Dr. Chrishan J. Ramachandra

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National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore 169609, Singapore
Interests: cardiac hypertrophy; cardiac metabolism; myeloperoxidase; oxidative stress; induced pluripotent stem cells; drug discovery
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Special Issue Information

Dear Colleagues,

The heart has a substantial demand for ATP in order to maintain its continuous mechanical work. While most ATP is generated by the oxidation of fatty acids, metabolic flexibility allows for the use of other fuels, such as glucose, lactate, ketones, and amino acids, which depend on substrate availability and cardiac workload. In the failing heart, energy production is compromised due to metabolic inflexibility, impaired oxidative metabolism, and an overall decrease in cardiac efficiency. Crucially, cardiometabolic derangement is not exclusive to patients with metabolic syndromes or to those with end-stage heart failure (HF), as disruptions in metabolic and/or energy-producing pathways have been observed in various cardiomyopathies, and even at early stages of disease. Moreover, depending on the type and severity of HF, substrate preference may vary, and this is mainly attributed to transcriptional changes and post-translational modifications of mitochondrial proteins and key metabolic enzymes. Importantly, strategies for modulating substrate utilization to improve oxidative metabolism are rapidly becoming popular as therapeutic modalities. This Special Issue welcomes original articles and reviews that provide new mechanistic insights into the metabolic changes that occur in HF, and whereby the targeting of metabolic pathways could potentially improve contractile function and health outcomes in HF patients.

Dr. Martijn Hoes (martijn.hoes@maastrichtuniversity.nl) will assist Dr. Chrishan Ramachandra in managing this Special Issue.

Dr. Chrishan J. Ramachandra
Guest Editor

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Keywords

heart failure
cardiomyopathies
metabolic syndrome
diabetes
obesity
cardiac metabolism
mitochondria
insulin resistance
glucose oxidation
fatty acid oxidation
ketones
branched-chain amino acids
oxidative stress
mitophagy
SGLT2 inhibitors

Published Papers (5 papers)

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Research

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16 pages, 4663 KiB

Open AccessArticle

Impact of Prenatal Exposure to Maternal Diabetes and High-Fat Diet on Postnatal Myocardial Ketone Body Metabolism in Rats

by Prathapan Ayyappan, Tricia D. Larsen, Tyler C. T. Gandy, Eli J. Louwagie and Michelle L. Baack

Int. J. Mol. Sci. 2023, 24(4), 3684; https://doi.org/10.3390/ijms24043684 - 12 Feb 2023

Viewed by 2860

Abstract

Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. Using a rat model, we showed how fetal exposure to maternal diabetes causes cardiac disease through fuel-mediated mitochondrial dysfunction, and that a maternal high-fat diet (HFD) exaggerates the risk. Diabetic pregnancy increases circulating maternal ketones which can have a cardioprotective effect, but whether diabetes-mediated complex I dysfunction impairs myocardial metabolism of ketones postnatally remains unknown. The objective of this study was to determine whether neonatal rat cardiomyocytes (NRCM) from diabetes- and HFD-exposed offspring oxidize ketones as an alternative fuel source. To test our hypothesis, we developed a novel ketone stress test (KST) using extracellular flux analyses to compare real-time ß-hydroxybutyrate (βHOB) metabolism in NRCM. We also compared myocardial expression of genes responsible for ketone and lipid metabolism. NRCM had a dose-dependent increase in respiration with increasing concentrations of βHOB, demonstrating that both control and combination exposed NRCM can metabolize ketones postnatally. Ketone treatment also enhanced the glycolytic capacity of combination exposed NRCM with a dose-dependent increase in the glucose-mediated proton efflux rate (PER) from CO2 (aerobic glycolysis) alongside a decreased reliance on PER from lactate (anaerobic glycolysis). Expression of genes responsible for ketone body metabolism was higher in combination exposed males. Findings demonstrate that myocardial ketone body metabolism is preserved and improves fuel flexibility in NRCM from diabetes- and HFD-exposed offspring, which suggests that ketones might serve a protective role in neonatal cardiomyopathy due to maternal diabetes. Full article

(This article belongs to the Special Issue Cardiac Metabolism in Heart Failure)

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20 pages, 10917 KiB

Open AccessArticle

Regular Exercise in Drosophila Prevents Age-Related Cardiac Dysfunction Caused by High Fat and Heart-Specific Knockdown of skd

by Yurou Cao, Shiyi He, Meng Ding, Wenzhi Gu, Tongquan Wang, Shihu Zhang, Jiadong Feng, Qiufang Li and Lan Zheng

Int. J. Mol. Sci. 2023, 24(2), 1216; https://doi.org/10.3390/ijms24021216 - 7 Jan 2023

Cited by 4 | Viewed by 1948

Abstract

Skuld (skd) is a subunit of the Mediator complex subunit complex. In the heart, skd controls systemic obesity, is involved in systemic energy metabolism, and is closely linked to cardiac function and aging. However, it is unclear whether the effect of cardiac skd on cardiac energy metabolism affects cardiac function. We found that cardiac-specific knockdown of skd showed impaired cardiac function, metabolic impairment, and premature aging. Drosophila was subjected to an exercise and high-fat diet (HFD) intervention to explore the effects of exercise on cardiac skd expression and cardiac function in HFD Drosophila. We found that Hand-Gal₄>skd RNAi (KC) Drosophila had impaired cardiac function, metabolic impairment, and premature aging. Regular exercise significantly improved cardiac function and metabolism and delayed aging in HFD KC Drosophila. Thus, our study found that the effect of skd on cardiac energy metabolism in the heart affected cardiac function. Exercise may counteract age-related cardiac dysfunction and metabolic disturbances caused by HFD and heart-specific knockdown of skd. Skd may be a potential therapeutic target for heart disease. Full article

(This article belongs to the Special Issue Cardiac Metabolism in Heart Failure)

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20 pages, 2624 KiB

Open AccessArticle

Ketone Body Exposure of Cardiomyocytes Impairs Insulin Sensitivity and Contractile Function through Vacuolar-Type H⁺-ATPase Disassembly—Rescue by Specific Amino Acid Supplementation

by Shujin Wang, Dietbert Neumann, B. Daan Westenbrink, Francesco Schianchi, Li-Yen Wong, Aomin Sun, Agnieszka Strzelecka, Jan F. C. Glatz, Joost J. F. P. Luiken and Miranda Nabben

Int. J. Mol. Sci. 2022, 23(21), 12909; https://doi.org/10.3390/ijms232112909 - 26 Oct 2022

Cited by 2 | Viewed by 1947

Abstract

The heart is metabolically flexible. Under physiological conditions, it mainly uses lipids and glucose as energy substrates. In uncontrolled diabetes, the heart switches towards predominant lipid utilization, which over time is detrimental to cardiac function. Additionally, diabetes is accompanied by high plasma ketone levels and increased utilization of energy provision. The administration of exogenous ketones is currently being investigated for the treatment of cardiovascular disease. Yet, it remains unclear whether increased cardiac ketone utilization is beneficial or detrimental to cardiac functioning. The mechanism of lipid-induced cardiac dysfunction includes disassembly of the endosomal proton pump (named vacuolar-type H+-ATPase; v-ATPase) as the main early onset event, followed by endosomal de-acidification/dysfunction. The de-acidified endosomes can no longer serve as a storage compartment for lipid transporter CD36, which then translocates to the sarcolemma to induce lipid accumulation, insulin resistance, and contractile dysfunction. Lipid-induced v-ATPase disassembly is counteracted by the supply of specific amino acids. Here, we tested the effect of ketone bodies on v-ATPase assembly status and regulation of lipid uptake in rodent/human cardiomyocytes. 3-β-hydroxybutyrate (3HB) exposure induced v-ATPase disassembly and the entire cascade of events leading to contractile dysfunction and insulin resistance, similar to conditions of lipid oversupply. Acetoacetate addition did not induce v-ATPase dysfunction. The negative effects of 3HB could be prevented by addition of specific amino acids. Hence, in sedentary/prediabetic subjects ketone bodies should be used with caution because of possible aggravation of cardiac insulin resistance and further loss of cardiac function. When these latter maladaptive conditions would occur, specific amino acids could potentially be a treatment option. Full article

(This article belongs to the Special Issue Cardiac Metabolism in Heart Failure)

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18 pages, 5544 KiB

Open AccessArticle

Bioenergetic and Metabolic Impairments in Induced Pluripotent Stem Cell-Derived Cardiomyocytes Generated from Duchenne Muscular Dystrophy Patients

by Lubna Willi, Ifat Abramovich, Jonatan Fernandez-Garcia, Bella Agranovich, Margarita Shulman, Helena Milman, Polina Baskin, Binyamin Eisen, Daniel E. Michele, Michael Arad, Ofer Binah and Eyal Gottlieb

Int. J. Mol. Sci. 2022, 23(17), 9808; https://doi.org/10.3390/ijms23179808 - 29 Aug 2022

Cited by 8 | Viewed by 2276

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in the dystrophin gene and dilated cardiomyopathy (DCM) is a major cause of morbidity and mortality in DMD patients. We tested the hypothesis that DCM is caused by metabolic impairments by employing induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) generated from four DMD patients; an adult male, an adult female, a 7-year-old (7y) male and a 13-year-old (13y) male, all compared to two healthy volunteers. To test the hypothesis, we measured the bioenergetics, metabolomics, electrophysiology, mitochondrial morphology and mitochondrial activity of CMs, using respirometry, LC–MS, patch clamp, electron microscopy (EM) and confocal microscopy methods. We found that: (1) adult DMD CMs exhibited impaired energy metabolism and abnormal mitochondrial structure and function. (2) The 7y CMs demonstrated arrhythmia-free spontaneous firing along with “healthy-like” metabolic status, normal mitochondrial morphology and activity. In contrast, the 13y CMs were mildly arrhythmogenic and showed adult DMD-like bioenergetics deficiencies. (3) In DMD adult CMs, mitochondrial activities were attenuated by 45–48%, whereas the 7y CM activity was similar to that of healthy CMs. (4) In DMD CMs, but not in 7y CMs, there was a 75% decrease in the mitochondrial ATP production rate compared to healthy iPSC-CMs. In summary, DMD iPSC-CMs exhibit bioenergetic and metabolic impairments that are associated with rhythm disturbances corresponding to the patient’s phenotype, thereby constituting novel targets for alleviating cardiomyopathy in DMD patients. Full article

(This article belongs to the Special Issue Cardiac Metabolism in Heart Failure)

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Review

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21 pages, 1221 KiB

Open AccessReview

Unravelling the Interplay between Cardiac Metabolism and Heart Regeneration

by Fan Yu, Shuo Cong, En Ping Yap, Derek J. Hausenloy and Chrishan J. Ramachandra

Int. J. Mol. Sci. 2023, 24(12), 10300; https://doi.org/10.3390/ijms241210300 - 18 Jun 2023

Viewed by 2358

Abstract

Ischemic heart disease (IHD) is the leading cause of heart failure (HF) and is a significant cause of morbidity and mortality globally. An ischemic event induces cardiomyocyte death, and the ability for the adult heart to repair itself is challenged by the limited proliferative capacity of resident cardiomyocytes. Intriguingly, changes in metabolic substrate utilisation at birth coincide with the terminal differentiation and reduced proliferation of cardiomyocytes, which argues for a role of cardiac metabolism in heart regeneration. As such, strategies aimed at modulating this metabolism-proliferation axis could, in theory, promote heart regeneration in the setting of IHD. However, the lack of mechanistic understanding of these cellular processes has made it challenging to develop therapeutic modalities that can effectively promote regeneration. Here, we review the role of metabolic substrates and mitochondria in heart regeneration, and discuss potential targets aimed at promoting cardiomyocyte cell cycle re-entry. While advances in cardiovascular therapies have reduced IHD-related deaths, this has resulted in a substantial increase in HF cases. A comprehensive understanding of the interplay between cardiac metabolism and heart regeneration could facilitate the discovery of novel therapeutic targets to repair the damaged heart and reduce risk of HF in patients with IHD. Full article

(This article belongs to the Special Issue Cardiac Metabolism in Heart Failure)

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