bims-hafaim 2025-03-30 papers

J Cardiovasc Transl Res. 2025 Mar 26.

The Role of Mitophagy in Cardiac Metabolic Remodeling of Heart Failure: Insights of Molecular Mechanisms and Therapeutic Prospects.

Fangying Yan, Liwen Bao.

Heart failure (HF) treatment remains one of the major challenges in cardiovascular disease management, and its pathogenesis requires further exploration. Cardiac metabolic remodeling is of great significance as a key pathological process in the progression of HF. The complex alterations of metabolic substrates and associated enzymes in mitochondria create a vicious cycle in HF. These changes lead to increased reactive oxygen species, altered mitochondrial Ca2+ handling, and the accumulation of fatty acids, contributing to impaired mitochondrial function. In this context, mitophagy plays a significant role in clearing damaged mitochondria, thereby maintaining mitochondrial function and preserving cardiac function by modulating metabolic remodeling in HF. This article aims to explore the role of mitophagy in cardiac metabolic remodeling in HF, especially in obesity cardiomyopathy, diabetic cardiomyopathy, and excessive afterload-induced heart failure, thoroughly analyze its molecular mechanisms, and review the therapeutic strategies and prospects based on the regulation of mitophagy.

Keywords: Cardiac metabolic remodeling; Heart failure; Mitophagy; Molecular mechanisms; Therapeutic prospects

DOI: https://doi.org/10.1007/s12265-025-10606-1

JACC Basic Transl Sci. 2025 Mar;pii: S2452-302X(24)00393-0. [Epub ahead of print]10(3): 290-303

Metabolic and Pharmacokinetic Profiling of a Ketone Ester by Background SGLT2 Inhibitor Therapy in HFrEF.

Growing evidence supports therapeutic ketosis in heart failure with reduced ejection fraction, though uncertainty exists regarding use with SGLT2i and dose-dependent effects. In a phase I trial of 2 ketone ester (KE) doses in 20 heart failure with reduced ejection fraction participants, stratified by background SGLT2i, the authors detailed pharmacokinetic parameters, noting rapid ketosis and short half-life. KE was associated with lower non-esterified fatty acid, branched-chain amino acids, and most acylcarnitines (except C2 and C4-OH, which increased); differences were observed by SGLT2i and KE dose. Increases in heart rate and decreases in systolic blood pressure, pH, and bicarbonate were generally transient. KE ingestion induces rapid changes in key metabolic pathways, differentially affected by SGLT2i (fatty acid metabolism) and KE dose (ketone metabolism). Hemodynamic effects were transient and irrespective of dose or SGLT2i. (Ketone Pharmacokinetic Study in HFrEF; NCT05757193).

Keywords: SGLT2 inhibitor; acylcarnitine; heart failure with reduced ejection fraction; insulin; ketone bodies; metabolomics

DOI: https://doi.org/10.1016/j.jacbts.2024.10.014

JACC Basic Transl Sci. 2025 Mar;pii: S2452-302X(24)00488-1. [Epub ahead of print]10(3): 304-306

Have Your Sodium-Glucose Cotransporter 2 Inhibitor-Derived Ketones and Eat Them Too.

Virginia S Hahn, Navid Koleini.

Keywords: heart failure; ketones; metabolomics; sodium glucose cotransporter 2 inhibitors

DOI: https://doi.org/10.1016/j.jacbts.2024.12.013

Commun Med (Lond). 2025 Mar 27. 5(1): 93

AAV9-cBIN1 gene therapy rescues chronic heart failure due to ischemic cardiomyopathy in a canine model.

Muhammad S Khan, Douglas Smego, Jing Li, Yuki Ishidoya, Emmanuel Offei, Martha Sofia Ruiz Castillo, Annie M Hirahara, Pia Balmaceda, Jennifer Hunter, Anand Athavale, Monica P Revelo, Joseph A Palatinus, Craig H Selzman, Ravi Ranjan, TingTing Hong, Derek J Dosdall, Robin M Shaw.

BACKGROUND: Ischemic cardiomyopathy and resultant heart failure (HF) is a significant cause of morbidity and mortality worldwide. Downregulation of cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein responsible for organizing t-tubules and organizing the calcium handing apparatus, occurs in progressive HF. Therefore, gene therapy upregulating cBIN1 production may rescue failing muscle and clinical HF.
METHODS: Adult mongrel dogs underwent ligation of the left anterior descending artery and developed progressive dilated cardiomyopathy and chronic HF. When left ventricular ejection fraction (LVEF) dropped below 40%, the animals received a one-time series of endocardial injections of either of low dose gene therapy composed of either adeno-associated virus serotype 9 packaged cBIN1 (AAV9-cBIN1, n = 6) or AAV9-GFP (green fluorescent protein, n = 4). Animals were followed up to 7 weeks after therapy delivery with laboratory, echocardiography, and endocardial mapping assessment.
RESULTS: Post injection of the negative control, animals develop progressive symptomatic HF requiring early termination of all but one animal prior to the end of the study. In contrast, the AAV9-cBIN1-treated group reveals a significant improvement in LV function, with a noticeable improvement in LVEF (29 ± 3% vs. 42 ± 2%, p = 0.0095) and global longitudinal strain (-7.1 ± 0.9% vs. -12.5 ± 1.6%, p = 0.0095). Compared to the control animals, the AAV9-cBIN1-treated group displays improved T-tubule morphology, left ventricular chamber size, plasma biomarkers, and endocardial voltage, and survives the study period.
CONCLUSIONS: Chronic HF from ischemic cardiomyopathy can be successfully treated with low dose AAV9-cBIN1 gene therapy. This study indicates that myocardial specific therapy can dramatically reverse HF progression.

DOI: https://doi.org/10.1038/s43856-025-00787-w

Circulation. 2025 Mar 25.

XBP1s-EDEM2 Prevents the Onset and Development of HFpEF by Ameliorating Cardiac Lipotoxicity.

BACKGROUND: Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing and treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying endoplasmic reticulum degradation enhancing EDEM2 (endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2) regulation of cardiac lipid homeostasis and assess strategies that inhibit the incidence and progression of HFpEF.
METHODS: Metabolic stress was induced in C57BL/6 male mice using a high-fat diet and Nω-nitro-l-arginine methyl ester. The recombinant adeno-associated virus 9 delivery system was used for loss- and gain-of-function studies. Palmitic acid and oleic acid stimulation of rat cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes imitated a condition of high lipids in vitro. Molecular mechanisms were investigated via RNA sequencing, mass spectrometry proteomics, lipidomic analyses, transmission electron microscopy, histology, and luciferase reporter assays.
RESULTS: In the human heart, we first detected lipid overload accompanied by a reduction of XBP1 (X-box binding protein 1) under metabolic stress. Thereafter, a decrease in EDEM2 was confirmed in human and mouse HFpEF hearts. Given that the spliced form of XBP1 (XBP1s) is a transcription factor, EDEM2 was identified as its new target in cardiomyocytes. EDEM2 knockdown mice manifested lipid droplet accumulation and higher levels of triglycerides and diglycerides in the myocardium, aggravating oxidative stress, hypertrophy, and the onset and progression of HFpEF under metabolic stress. XBP1s ablation mice displayed a similar myocardial lipid disturbance and cardiac phenotypes, which were reversed by EDEM2 overexpression. Mechanistically, the findings obtained from rat cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes demonstrated that, in the presence of EDEM2, SEC23A mediated intracellular translocation of ATGL (adipose triglyceride lipase) under fatty acid stimulation, inhibiting ATGL degradation and excessive intracellular lipid droplets. Furthermore, the functional studies supported that EDEM2 prevention of lipid overload occurred in an ATGL-dependent manner. Therapeutically, cardiac XBP1s or EDEM2 restoration mitigated lipid deposition and preserved lipid profiles in the myocardium, thus preventing the development of HFpEF.
CONCLUSIONS: We demonstrate a cardioprotective mechanism regulating myocardial lipid homeostasis. The findings provide a promising therapeutic target to prevent and treat HfpEF, a condition with limited treatment options.

Keywords: EDEM2; HFpEF; XBP1s; cardiac lipotoxicity; heart failure; metabolic stress

DOI: https://doi.org/10.1161/CIRCULATIONAHA.124.072194