bims-hafaim 2024-10-27 papers

Issue of 2024‒10‒27
seven papers selected by
Kyle McCommis, Saint Louis University

Cardiovasc Res. 2024 Oct 25. pii: cvae231. [Epub ahead of print]

Advances in myocardial energy metabolism: metabolic remodeling in heart failure and beyond.

Qiuyu Sun, Qutuba G Karwi, Nathan Wong, Gary D Lopaschuk.

The very high energy demand of the heart is primarily met by ATP production from mitochondrial oxidative phosphorylation, with glycolysis providing a smaller amount of ATP production. This ATP production is markedly altered in heart failure, primarily due to a decrease in mitochondrial oxidative metabolism. Although an increase in glycolytic ATP production partly compensates for the decrease in mitochondrial ATP production, the failing heart faces an energy deficit, that contributes to the severity of contractile dysfunction. The relative contribution of the different fuels for mitochondrial ATP production dramatically changes in the failing heart, which depends to a large extent on the type of heart failure. A common metabolic defect in all forms of heart failure (including HFrEF, HFpEF, and diabetic cardiomyopathies) is a decrease in mitochondrial oxidation of pyruvate originating from glucose (i.e. glucose oxidation). This decrease in glucose oxidation occurs regardless of whether glycolysis is increased, resulting in an uncoupling of glycolysis from glucose oxidation that can decrease cardiac efficiency. The mitochondrial oxidation of fatty acids by the heart increases or decreases, depending on the type of heart failure. For instance, in HFpEF and diabetic cardiomyopathies myocardial fatty acid oxidation increases, while in HFrEF myocardial fatty acid oxidation either decreases or remains unchanged. The oxidation of ketones (which provides the failing heart with an important energy source) also differs depending on the type of heart failure, being increased in HFrEF, and decreased in HFpEF and diabetic cardiomyopathies. The alterations in mitochondrial oxidative metabolism and glycolysis in the failing heart are due to transcriptional changes in key enzymes involved in the metabolic pathways, as well as alterations in redox state, metabolic signaling, and posttranslational epigenetic changes in energy metabolic enzymes. Of importance, targeting the mitochondrial energy metabolic pathways has emerged as a novel therapeutic approach to improving cardiac function and cardiac efficiency in the failing heart.

Keywords: HFpEF; HFrEF; fatty acid oxidation; glucose oxidation; ketone oxidation

DOI: https://doi.org/10.1093/cvr/cvae231

Am J Physiol Heart Circ Physiol. 2024 Oct 25.

Recent Advances Associated with Cardiometabolic Remodeling in Diabetes-induced Heart Failure.

Gaurav Sharma, Shyam S Chaurasia, Mark A Carlson, Paras K Mishra.

Diabetes mellitus (DM) is characterized by chronic hyperglycemia, and despite intensive glycemic control, the risk of heart failure in diabetic patients remains high. Diabetes-induced heart failure (DHF) presents a unique metabolic challenge, driven by significant alterations in cardiac substrate metabolism, including increased reliance on fatty acid oxidation, reduced glucose utilization, and impaired mitochondrial function. These metabolic alterations lead to oxidative stress, lipotoxicity, and energy deficits, contributing to the progression of heart failure. Emerging research has identified novel mechanisms involved in the metabolic remodeling of diabetic hearts, such as autophagy dysregulation, epigenetic modifications, polyamine regulation, and branched-chain amino acid (BCAA) metabolism. These processes exacerbate mitochondrial dysfunction and metabolic inflexibility, further impairing cardiac function. Therapeutic interventions targeting these pathways-such as enhancing glucose oxidation, modulating fatty acid metabolism, and optimizing ketone body utilization-show promise in restoring metabolic homeostasis and improving cardiac outcomes. This review explores the key molecular mechanisms driving metabolic remodeling in diabetic hearts and advanced methodology, highlighting the latest therapeutic strategies to mitigate the progression of DHF. Understanding these emerging pathways offers new opportunities to develop targeted therapies that address the root metabolic causes of heart failure in diabetes.

Keywords: Cardiac metabolism; Diabetes mellitus; Metabolic therapies; Mitochondrial dysfunction; Oxidative stress

DOI: https://doi.org/10.1152/ajpheart.00539.2024

J Mol Cell Cardiol Plus. 2024 Jun;pii: 100073. [Epub ahead of print]8

Allele-specific dysregulation of lipid and energy metabolism in early-stage hypertrophic cardiomyopathy.

Arpana Vaniya, Anja Karlstaedt, Damla Gulkok, Tilo Thottakara, Yamin Liu, Sili Fan, Hannah Eades, Styliani Vakrou, Ryuya Fukunaga, Hilary J Vernon, Oliver Fiehn, M Roselle Abraham.

Introduction: Hypertrophic cardiomyopathy (HCM) results from pathogenic variants in sarcomeric protein genes that increase myocyte energy demand and lead to cardiac hypertrophy. However, it is unknown whether a common metabolic trait underlies cardiac phenotype at the early disease stage. To address this question and define cardiac biochemical pathology in early-stage HCM, we studied two HCM mouse models that express pathogenic variants in cardiac troponin T (Tnt2) or myosin heavy chain (Myh6) genes, and have marked differences in cardiac imaging phenotype, mitochondrial function at early disease stage.Methods: We used a combination of echocardiography, transcriptomics, mass spectrometry-based untargeted metabolomics (GC-TOF, HILIC, CSH-QTOF), and computational modeling (CardioNet) to examine cardiac structural and metabolic remodeling at early disease stage (5 weeks of age) in R92W-TnT+/- and R403Q-MyHC+/- mutant mice. Data from mutants was compared with respective littermate controls (WT).
Results: Allele-specific differences in cardiac phenotype, gene expression and metabolites were observed at early disease stage. LV diastolic dysfunction was prominent in TnT mutants. Differentially-expressed genes in TnT mutant hearts were predominantly enriched in the Krebs cycle, respiratory electron transport, and branched-chain amino acid metabolism, whereas MyHC mutants were enriched in mitochondrial biogenesis, calcium homeostasis, and liver-X-receptor signaling. Both mutant hearts demonstrated significant alterations in levels of purine nucleosides, trisaccharides, dicarboxylic acids, acylcarnitines, phosphatidylethanolamines, phosphatidylinositols, ceramides and triglycerides; 40.4 % of lipids and 24.7 % of metabolites were significantly different in TnT mutants, whereas 10.4 % of lipids and 5.8 % of metabolites were significantly different in MyHC mutants. Both mutant hearts had a lower abundance of unsaturated long-chain acyl-carnitines (18:1, 18:2, 20:1), but only TnT mutants showed enrichment of FA18:0 in ceramide and cardiolipin species. CardioNet predicted impaired energy substrate metabolism and greater phospholipid remodeling in TnT mutants than in MyHC mutants.
Conclusions: Our systems biology approach revealed marked differences in metabolic remodeling in R92W-TnT and R403Q-MyHC mutant hearts, with TnT mutants showing greater derangements than MyHC mutants, at early disease stage. Changes in cardiolipin composition in TnT mutants could contribute to impairment of energy metabolism and diastolic dysfunction observed in this study, and predispose to energetic stress, ventricular arrhythmias under high workloads such as exercise.

Keywords: HCM mouse models; Hypertrophic cardiomyopathy; Lipidomics; RNAseq; Untargeted metabolomics

DOI: https://doi.org/10.1016/j.jmccpl.2024.100073

Circ Res. 2024 Oct 25. 135(10): 1018-1020

HFpEF's Fuel Flaw: Impaired Fatty Acid Oxidation Stalls Mitophagy.

Xi Fang, Åsa B Gustafsson.

Keywords: Editorials; diet, high-fat; heart failure; metabolism; mitochondria, heart; myocytes, cardiac

DOI: https://doi.org/10.1161/CIRCRESAHA.124.325501

JACC Basic Transl Sci. 2024 Sep;9(9): 1144-1158

Towards Metabolomic-Based Precision Approaches for Classifying and Treating Heart Failure.

Virginia S Hahn, Senthil Selvaraj, Kavita Sharma, Svati H Shah.

Both heart failure and cardiometabolic disease are on the rise, and abnormal cardiac and peripheral metabolism are central to the syndrome of heart failure. Advances in metabolomic profiling have improved our understanding of the heart's metabolic flexibility in patients with and without heart failure. Prior studies have noted patients with heart failure display metabolomic profiles associated with marked abnormalities in the metabolism of fatty acids, branched-chain amino acids, ketones, and glucose compared with control subjects. Metabolomics can highlight specific pathways that are dysregulated; however, other metabolites beyond those related to fuel metabolism may also play a role in precision-medicine approaches. Novel approaches include metabolic flux studies, spatial and single-cell analysis, serial monitoring of treatment response, and integration with other -omics data. The goal of these innovative approaches should be to harness metabolomic technologies to affect precision care for patients with heart failure.

Keywords: heart failure; metabolism; metabolomics; obesity; precision medicine

DOI: https://doi.org/10.1016/j.jacbts.2024.04.008

J Surg Res. 2024 Oct 21. pii: S0022-4804(24)00629-2. [Epub ahead of print]303 600-612

Sodium-Glucose Cotransporter-2 Inhibition Normalizes Metabolic Derangements in the Ischemic Myocardium.

Christopher Stone, Dwight D Harris, Mark Broadwin, Sharif A Sabe, Krishna Bellam, Meghamsh Kanuparthy, M Ruhul Abid, Frank W Sellke.

INTRODUCTION: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in the context of heart failure but have not been well-studied in ischemic heart disease. We employed a large animal model of chronic coronary artery disease and metabolic syndrome (MS) to investigate the hemodynamic and metabolic consequences of SGLT2i administration.METHODS: Thirty-eight Yorkshire swine were divided into two groups, with half (n = 21) receiving a high fat diet to induce MS, and the other half fed a standard diet (n = 17). All animals underwent thoracotomy for ameroid constrictor placement over the left circumflex coronary artery. Treatment with SGLT2i was then initiated, generating four groups: regular diet placebo (CON, n = 9), regular diet canagliflozin (n = 8), high-fat control (n = 11), and high-fat canagliflozin (n = 10). After 5 wks, all animals underwent terminal myocardial harvest with pressure-volume loop acquisition, perfusion studies, and tissue resection for molecular analysis.
RESULTS: SGLT2i improved multiple measures of myocardial performance, including a nearly 1.5-fold increase in both cardiac output and ejection fraction; these changes were associated with augmented capillary density and a twofold increase perfusion to the ischemic myocardium. These augmentations were blunted; however, in the presence of MS, and associated with modulated myocardial expression of multiple major metabolic enzymes.
CONCLUSIONS: SGLT2i significantly improved cardiac function in our large animal model of coronary artery disease, with metabolic modulation of the myocardial tissue serving as a candidate account of these changes. The blunting seen with MS underscores the dependence of clinical translatability on faithful representation of the biochemical environment of human disease.

Keywords: Coronary artery disease; Large animal model; Metabolic syndrome; Sodium-glucose cotransporter-2 inhibitor

DOI: https://doi.org/10.1016/j.jss.2024.09.065

J Diabetes. 2024 Oct;16(10): e70018

Potential mechanisms of metabolic reprogramming induced by ischemia-reperfusion injury in diabetic myocardium.

Haping Ma, Jiyao Zhao, Yan Zheng, Junjie Wang, Yultuz Anwar, Yuxuan He, Jiang Wang.

OBJECTIVE: This study aimed to explore metabolic reprogramming in diabetic myocardium subjected to ischemia-reperfusion injury (I/RI) and potential mechanisms.BACKGROUND: Increased vulnerability after I/RI in diabetic myocardium is a major cause of the high prevalence of perioperative adverse cardiac events, and the specific alterations in energy metabolism after I/RI in diabetic myocardium and the impact on increased vulnerability are not fully understood.
METHODS: Metabolomic methods were used to explore the differences and characteristics of metabolites in the heart tissues of four groups, and then, single-cell RNA sequencing (ScRNA-seq) was used to explore the potential mechanism of metabolic reprogramming.
RESULTS: It was found that the fatty acid metabolism of db/db mouse I/RI (DMI) showed a significant upward trend, especially the metabolites of ultra-long and medium-long-chain fatty acids; the metabolic flow analysis found that the U-13C glucose M + 6 was significantly higher in the C57BL mouse sham operation (NM) group than in the db/db mouse sham operation (DM) group, and in the C57BL mouse I/RI (NMI) than in the DMI group. Compared with the NMI group, the intermediate metabolites of glycolysis and tricarboxylic acid (TCA) cycle were significantly reduced in the DMI group; all comparisons were statistically significant (p < 0.05), indicating that the glucose uptake of diabetic myocardetis, the ability of glucose glycolysis after I/RI, and the contribution of glucose to TCA were significantly reduced. The results of ScRNA-seq revealed that the number of Cluster 0 myocardial isoforms was significantly increased in diabetic myocardium, and the differential genes were mainly enriched in fatty acid metabolism, and the PPARA signaling pathway was found to be over-activated and involved in the regulation of metabolic reprogramming of diabetic myocardial I/RI.
CONCLUSION: Metabolic reprogramming of diabetic myocardial I/RI may be the main cause of increased myocardial vulnerability. The number of myocardial subtype Cluster 0 increased significantly, and PPARA PPARA is a ligand-activated receptor of the nuclear hormone receptor family that plays a central regulatory role in lipid metabolism. signaling pathway activation may be a potential mechanism for reprogramming metabolism in diabetic myocardium.

Keywords: diabetic myocardium; energy metabolism; ischemia–reperfusion injury; metabolic reprogramming; vulnerability

DOI: https://doi.org/10.1111/1753-0407.70018