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Insights into the Bioenergetics and Metabolism in Normal and Failing...
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Insights into the Bioenergetics and Metabolism in Normal and Failing Heart

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Animal Metabolism".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 33435

Special Issue Editor

Prof. Dr. Tatsuya Iso

E-Mail Website
Guest Editor
Department of Medical Technology and Clinical Engineering, Faculty of Medical Technology and Clinical Engineering, Gunma University of Health and Welfare, 191-1 Kawamagari-machi, Maebashi, Gunma 371-0823, Japan
Interests: cardiology; molecular biology; metabolism; heart failure; vascular biology

Special Issue Information

Dear Colleagues,

The heart is the most energy-demanding organ and generates a vast amount of ATP (~6 kg/day) from circulating substrates to carry out its function. The heart is a metabolic omnivore that primarily uses fatty acids (FAs) as energy-providing substrates, with the remaining energy obtained from glucose, lactate, ketone bodies, and amino acids. Preference for these substrates is dynamically changed by substrate availability, hormones, oxygen supply, and cardiac workload. In addition to ATP synthesis (catabolism), energy substrates, especially glucose, are linked to the facilitation of anabolic and accessary pathways, depending on the energy status and pathophysiological situations.

Heart metabolism has long been studied primarily in ex vivo perfused hearts. The major benefits of this approach include simultaneously monitoring the oxidation of energy substrates (catabolism) and controlled hemodynamic parameters, which have provided invaluable assets in the metabolic research of the heart. However, this approach has a weakness in addressing questions related to the metabolic disturbance of the heart in the context of systemic metabolism because isolated perfused hearts have   lower oxygen-carrying capacity, regional anoxia due to arteriole constriction, and a lack of neurohumoral feedback. Furthermore, most studies with ex vivo perfused hearts have overlooked the estimation of anabolic and accessary pathways that are invariably accelerated during the progression of heart failure.

Recent advances in metabolic studies have led to the comprehensive profiling of metabolic intermediates through mass spectrometry carried out on in vivo beating hearts. With stable isotopes and calculation of the data, there has been increasing appreciation for the feasibility and importance of tracing the metabolic pathways of major energy substrates in vivo. In combination with other methodologies, such as high-resolution echocardiography, radioisotopes, genome-editing technology, and established heart disease models, we can obtain high-dimensional data of beating hearts to understand the whole picture of both energy catabolism and anabolism. In the Special Issue, we focus on the emerging evidence of metabolic dynamics in normal and diseased hearts, which has recently been analyzed by using in vivo beating hearts. Given that impaired cardiac energy metabolism is a hallmark of heart failure, it is likely that this issue will provide new insight into the mechanism of this disease.

Prof. Dr. Tatsuya Iso
Guest Editor

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Keywords

  • heart
  • metabolism
  • catabolism
  • anabolism
  • mass spectrometry

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Published Papers (9 papers)

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Research

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11 pages, 1289 KiB  
Article
Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice
by Yogi Umbarawan, Ryo Kawakami, Mas Rizky A. A. Syamsunarno, Hideru Obinata, Aiko Yamaguchi, Hirofumi Hanaoka, Takako Hishiki, Noriyo Hayakawa, Norimichi Koitabashi, Hiroaki Sunaga, Hiroki Matsui, Masahiko Kurabayashi and Tatsuya Iso
Metabolites 2021, 11(12), 881; https://doi.org/10.3390/metabo11120881 - 17 Dec 2021
Cited by 2 | Viewed by 3232
Abstract
Cardiac dysfunction is induced by multifactorial mechanisms in diabetes. Deranged fatty acid (FA) utilization, known as lipotoxicity, has long been postulated as one of the upstream events in the development of diabetic cardiomyopathy. CD36, a transmembrane glycoprotein, plays a major role in FA [...] Read more.
Cardiac dysfunction is induced by multifactorial mechanisms in diabetes. Deranged fatty acid (FA) utilization, known as lipotoxicity, has long been postulated as one of the upstream events in the development of diabetic cardiomyopathy. CD36, a transmembrane glycoprotein, plays a major role in FA uptake in the heart. CD36 knockout (CD36KO) hearts exhibit reduced rates of FA transport with marked enhancement of glucose use. In this study, we explore whether reduced FA use by CD36 ablation suppresses the development of streptozotocin (STZ)-induced diabetic cardiomyopathy. We found that cardiac contractile dysfunction had deteriorated 16 weeks after STZ treatment in CD36KO mice. Although accelerated glucose uptake was not reduced in CD36KO-STZ hearts, the total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. The isotopomer analysis with 13C6-glucose revealed that accelerated glycolysis, estimated by enrichment of 13C2-citrate and 13C2-malate, was markedly suppressed in CD36KO-STZ hearts. Levels of ceramides, which are cardiotoxic lipids, were not elevated in CD36KO-STZ hearts compared to wild-type-STZ ones. Furthermore, increased energy demand by transverse aortic constriction resulted in synergistic exacerbation of contractile dysfunction in CD36KO-STZ mice. These findings suggest that CD36KO-STZ hearts are energetically compromised by reduced FA use and suppressed glycolysis; therefore, the limitation of FA utilization is detrimental to cardiac energetics in this model of diabetic cardiomyopathy. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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14 pages, 1002 KiB  
Article
Plasma Lipidomic Patterns in Patients with Symptomatic Coronary Microvascular Dysfunction
by Jonathan R. Lindner, Brian P. Davidson, Zifeng Song, Claudia S. Maier, Jessica Minnier, Jan Frederick Stevens, Maros Ferencik, Sahar Taqui, J. Todd Belcik, Federico Moccetti, Michael Layoun, Paul Spellman, Mitchell S. Turker, Hagai Tavori, Sergio Fazio, Jacob Raber and Gerd Bobe
Metabolites 2021, 11(10), 648; https://doi.org/10.3390/metabo11100648 - 22 Sep 2021
Cited by 7 | Viewed by 2695
Abstract
Coronary microvascular dysfunction (MVD) is a syndrome of abnormal regulation of vascular tone, particularly during increased metabolic demand. While there are several risk factors for MVD, some of which are similar to those for coronary artery disease (CAD), the cause of MVD is [...] Read more.
Coronary microvascular dysfunction (MVD) is a syndrome of abnormal regulation of vascular tone, particularly during increased metabolic demand. While there are several risk factors for MVD, some of which are similar to those for coronary artery disease (CAD), the cause of MVD is not understood. We hypothesized that MVD in symptomatic non-elderly subjects would be characterized by specific lipidomic profiles. Subjects (n = 20) aged 35–60 years and referred for computed tomography coronary angiography (CTA) for chest pain but who lacked obstructive CAD (>50% stenosis), underwent quantitative regadenoson stress-rest myocardial contrast echocardiography (MCE) perfusion imaging for MVD assessment. The presence of MVD defined by kinetic analysis of MCE data was correlated with lipidomic profiles in plasma measured by liquid chromatography and high-resolution mass spectrometry. Nine of twenty subjects had evidence of MVD, defined by reduced hyperemic perfusion versus other subjects (beta-value 1.62 ± 0.44 vs. 2.63 ± 0.99 s−1, p = 0.009). Neither the presence of high-risk but non-obstructive CAD on CTA, nor CAD risk factors were different for those with versus without MVD. Lipidomic analysis revealed that patients with MVD had lower concentrations of long-carbon chain triacylglycerols and diacylglycerols, and higher concentrations of short-chain triacylglycerols. The diacylglycerol containing stearic and linoleic acid classified all participants correctly. We conclude that specific lipidomic plasma profiles occur in MVD involving saturated long-chain fatty acid-containing acylglycerols that are distinctly different from those in non-obstructive CAD. These patterns could be used to better characterize the pathobiology and potential treatments for this condition. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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12 pages, 2347 KiB  
Article
KLF15 Regulates Oxidative Stress Response in Cardiomyocytes through NAD+
by Le Li, Weiyi Xu and Lilei Zhang
Metabolites 2021, 11(9), 620; https://doi.org/10.3390/metabo11090620 - 13 Sep 2021
Cited by 7 | Viewed by 2804
Abstract
KLF15 has recently emerged as a central regulator of metabolism. Although its connection to oxidative stress has been suspected, there has not been any study to date that directly demonstrates the molecular link. In this study, we sought to determine the role of [...] Read more.
KLF15 has recently emerged as a central regulator of metabolism. Although its connection to oxidative stress has been suspected, there has not been any study to date that directly demonstrates the molecular link. In this study, we sought to determine the role of KLF15 in cardiac oxidative stress. We found that KLF15 deficiency in the heart is associated with increased oxidative stress. Acute deficiency of KLF15 in neonatal rat ventricular myocytes (NRVMs) leads to the defective clearance of reactive oxygen species (ROS) and an exaggerated cell death following a variety of oxidative stresses. Mechanistically, we found that KLF15 deficiency leads to reduced amounts of the rate-limiting NAD+ salvage enzyme NAMPT and to NAD+ deficiency. The resultant SIRT3-dependent hyperacetylation and the inactivation of mitochondrial antioxidants can be rescued by MnSOD mimetics or NAD+ precursors. Collectively, these findings suggest that KLF15 regulates cardiac ROS clearance through the regulation of NAD+ levels. Our findings establish KLF15 as a central coordinator of cardiac metabolism and ROS clearance. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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16 pages, 3065 KiB  
Article
High Throughput Procedure for Comparative Analysis of In Vivo Cardiac Glucose or Amino Acids Use in Cardiovascular Pathologies and Pharmacological Treatments
by Marta Tomczyk, Mariola Olkowicz, Ewa M. Slominska and Ryszard T. Smolenski
Metabolites 2021, 11(8), 497; https://doi.org/10.3390/metabo11080497 - 30 Jul 2021
Cited by 3 | Viewed by 3092
Abstract
The heart is characterized by the prominent flexibility of its energy metabolism and is able to use diverse carbon substrates, including carbohydrates and amino acids. Cardiac substrate preference could have a major impact on the progress of cardiac pathologies. However, the majority of [...] Read more.
The heart is characterized by the prominent flexibility of its energy metabolism and is able to use diverse carbon substrates, including carbohydrates and amino acids. Cardiac substrate preference could have a major impact on the progress of cardiac pathologies. However, the majority of methods to investigate changes in substrates’ use in cardiac metabolism in vivo are complex and not suitable for high throughput testing necessary to understand and reverse these pathologies. Thus, this study aimed to develop a simple method that would allow for the analysis of cardiac metabolic substrate use. The developed methods involved the subcutaneous injection of stable 13C isotopomers of glucose, valine, or leucine with mass spectrometric analysis for the investigation of its entry into cardiac metabolic pathways that were deducted from 13C alanine and glutamate enrichments in heart extracts. The procedures were validated by confirming the known effects of treatments that modify glucose, free fatty acids, and amino acid metabolism. Furthermore, we studied changes in the energy metabolism of CD73 knock-out mice to demonstrate the potential of our methods in experimental research. The methods created allowed for fast estimation of cardiac glucose and amino acid use in mice and had the potential for high-throughput analysis of changes in pathology and after pharmacological treatments. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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Review

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15 pages, 1415 KiB  
Review
Qualitative and Quantitative Effects of Fatty Acids Involved in Heart Diseases
by Hidenori Moriyama, Jin Endo, Hidehiko Ikura, Hiroki Kitakata, Mizuki Momoi, Yoshiki Shinya, Seien Ko, Genki Ichihara, Takahiro Hiraide, Kohsuke Shirakawa, Atsushi Anzai, Yoshinori Katsumata and Motoaki Sano
Metabolites 2022, 12(3), 210; https://doi.org/10.3390/metabo12030210 - 25 Feb 2022
Cited by 8 | Viewed by 3492
Abstract
Fatty acids (FAs) have structural and functional diversity. FAs in the heart are closely associated with cardiac function, and their qualitative or quantitative abnormalities lead to the onset and progression of cardiac disease. FAs are important as an energy substrate for the heart, [...] Read more.
Fatty acids (FAs) have structural and functional diversity. FAs in the heart are closely associated with cardiac function, and their qualitative or quantitative abnormalities lead to the onset and progression of cardiac disease. FAs are important as an energy substrate for the heart, but when in excess, they exhibit cardio-lipotoxicity that causes cardiac dysfunction or heart failure with preserved ejection fraction. FAs also play a role as part of phospholipids that compose cell membranes, and the changes in mitochondrial phospholipid cardiolipin and the FA composition of plasma membrane phospholipids affect cardiomyocyte survival. In addition, FA metabolites exert a wide variety of bioactivities in the heart as lipid mediators. Recent advances in measurement using mass spectrometry have identified trace amounts of n-3 polyunsaturated fatty acids (PUFAs)-derived bioactive metabolites associated with heart disease. n-3 PUFAs have a variety of cardioprotective effects and have been shown in clinical trials to be effective in cardiovascular diseases, including heart failure. This review outlines the contributions of FAs to cardiac function and pathogenesis of heart diseases from the perspective of three major roles and proposes therapeutic applications and new medical perspectives of FAs represented by n-3 PUFAs. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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13 pages, 2367 KiB  
Review
In Vivo Magnetic Resonance Spectroscopy Methods for Investigating Cardiac Metabolism
by Morteza Esmaeili and Riyas Vettukattil
Metabolites 2022, 12(2), 189; https://doi.org/10.3390/metabo12020189 - 18 Feb 2022
Cited by 3 | Viewed by 2630
Abstract
Magnetic resonance spectroscopy (MRS) is a non-invasive and non-ionizing technique, enabling in vivo investigation of cardiac metabolism in normal and diseased hearts. In vivo measurement tools are critical for studying mechanisms that regulate cardiac energy metabolism in disease developments and to assist in [...] Read more.
Magnetic resonance spectroscopy (MRS) is a non-invasive and non-ionizing technique, enabling in vivo investigation of cardiac metabolism in normal and diseased hearts. In vivo measurement tools are critical for studying mechanisms that regulate cardiac energy metabolism in disease developments and to assist in early response assessments to novel therapies. For cardiac MRS, proton (1H), phosphorus (31P), and hyperpolarized 13-carbon (13C) provide valuable metabolic information for diagnosis and treatment assessment purposes. Currently, low sensitivity and some technical limitations limit the utility of MRS. An essential step in translating MRS for clinical use involves further technological improvements, particularly in coil design, improving the signal-to-noise ratios, field homogeneity, and optimizing radiofrequency sequences. This review addresses the recent advances in metabolic imaging by MRS from primarily the literature published since 2015. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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15 pages, 1243 KiB  
Review
Cardiac Metabolism and Contractile Function in Mice with Reduced Trans-Endothelial Fatty Acid Transport
by Tatsuya Iso and Masahiko Kurabayashi
Metabolites 2021, 11(12), 889; https://doi.org/10.3390/metabo11120889 - 19 Dec 2021
Cited by 3 | Viewed by 3113
Abstract
The heart is a metabolic omnivore that combusts a considerable amount of energy substrates, mainly long-chain fatty acids (FAs) and others such as glucose, lactate, ketone bodies, and amino acids. There is emerging evidence that muscle-type continuous capillaries comprise the rate-limiting barrier that [...] Read more.
The heart is a metabolic omnivore that combusts a considerable amount of energy substrates, mainly long-chain fatty acids (FAs) and others such as glucose, lactate, ketone bodies, and amino acids. There is emerging evidence that muscle-type continuous capillaries comprise the rate-limiting barrier that regulates FA uptake into cardiomyocytes. The transport of FAs across the capillary endothelium is composed of three major steps—the lipolysis of triglyceride on the luminal side of the endothelium, FA uptake by the plasma membrane, and intracellular FA transport by cytosolic proteins. In the heart, impaired trans-endothelial FA (TEFA) transport causes reduced FA uptake, with a compensatory increase in glucose use. In most cases, mice with reduced FA uptake exhibit preserved cardiac function under unstressed conditions. When the workload is increased, however, the total energy supply relative to its demand (estimated with pool size in the tricarboxylic acid (TCA) cycle) is significantly diminished, resulting in contractile dysfunction. The supplementation of alternative fuels, such as medium-chain FAs and ketone bodies, at least partially restores contractile dysfunction, indicating that energy insufficiency due to reduced FA supply is the predominant cause of cardiac dysfunction. Based on recent in vivo findings, this review provides the following information related to TEFA transport: (1) the mechanisms of FA uptake by the heart, including TEFA transport; (2) the molecular mechanisms underlying the induction of genes associated with TEFA transport; (3) in vivo cardiac metabolism and contractile function in mice with reduced TEFA transport under unstressed conditions; and (4) in vivo contractile dysfunction in mice with reduced TEFA transport under diseased conditions, including an increased afterload and streptozotocin-induced diabetes. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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12 pages, 1056 KiB  
Review
Cardiac Metabolism in Sepsis
by Satoshi Kawaguchi and Motoi Okada
Metabolites 2021, 11(12), 846; https://doi.org/10.3390/metabo11120846 - 6 Dec 2021
Cited by 11 | Viewed by 3864
Abstract
The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of [...] Read more.
The mechanism of sepsis-induced cardiac dysfunction is believed to be different from that of myocardial ischemia. In sepsis, chemical mediators, such as endotoxins, cytokines, and nitric oxide, cause metabolic abnormalities, mitochondrial dysfunction, and downregulation of β-adrenergic receptors. These factors inhibit the production of ATP, essential for myocardial energy metabolism, resulting in cardiac dysfunction. This review focuses on the metabolic changes in sepsis, particularly in the heart. In addition to managing inflammation, interventions focusing on metabolism may be a new therapeutic strategy for cardiac dysfunction due to sepsis. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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26 pages, 1540 KiB  
Review
Lipid Metabolite Biomarkers in Cardiovascular Disease: Discovery and Biomechanism Translation from Human Studies
by Peter McGranaghan, Jennifer A. Kirwan, Mariel A. Garcia-Rivera, Burkert Pieske, Frank Edelmann, Florian Blaschke, Sandeep Appunni, Anshul Saxena, Muni Rubens, Emir Veledar and Tobias Daniel Trippel
Metabolites 2021, 11(9), 621; https://doi.org/10.3390/metabo11090621 - 14 Sep 2021
Cited by 31 | Viewed by 7001
Abstract
Lipids represent a valuable target for metabolomic studies since altered lipid metabolism is known to drive the pathological changes in cardiovascular disease (CVD). Metabolomic technologies give us the ability to measure thousands of metabolites providing us with a metabolic fingerprint of individual patients. [...] Read more.
Lipids represent a valuable target for metabolomic studies since altered lipid metabolism is known to drive the pathological changes in cardiovascular disease (CVD). Metabolomic technologies give us the ability to measure thousands of metabolites providing us with a metabolic fingerprint of individual patients. Metabolomic studies in humans have supported previous findings into the pathomechanisms of CVD, namely atherosclerosis, apoptosis, inflammation, oxidative stress, and insulin resistance. The most widely studied classes of lipid metabolite biomarkers in CVD are phospholipids, sphingolipids/ceramides, glycolipids, cholesterol esters, fatty acids, and acylcarnitines. Technological advancements have enabled novel strategies to discover individual biomarkers or panels that may aid in the diagnosis and prognosis of CVD, with sphingolipids/ceramides as the most promising class of biomarkers thus far. In this review, application of metabolomic profiling for biomarker discovery to aid in the diagnosis and prognosis of CVD as well as metabolic abnormalities in CVD will be discussed with particular emphasis on lipid metabolites. Full article
(This article belongs to the Special Issue Insights into the Bioenergetics and Metabolism in Normal and Failing Heart)
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