bims-hafaim 2026-03-15 papers

Issue of 2026–03–15
four papers selected by
Kyle McCommis, Saint Louis University

Nat Commun. 2026 Mar 14.

Pyruvate metabolism enzyme Dlat induces mitochondria protein hyperacetylation to limit fatty acid oxidation in the HFpEF heart.

Ying Wang, Dong Guo, Jin'ao Zhu, Xue Yang, Chan Wu, Jing Geng, Qi Liang, Nan Sun, Xiaona Niu, Yue Liu, Yanjie Guo, Pan Chang, Yan Li, Lang Hu.

Increased protein acetylation is frequently observed in the failing heart, including in hearts with heart failure with preserved ejection fraction (HFpEF). However, its role in the pathogenesis of HFpEF remains insufficiently investigated. Here, we found that HFpEF hearts displayed significantly protein hyperacetylation, which were predominantly localized to mitochondria and particularly enriched in fatty acid oxidation (FAO) pathway. Notably, Dlat, a pyruvate metabolism enzyme, was identified as the key transacetylase for mitochondrial protein hyperacetylation. Dlat overexpression enhanced FAO-related protein acetylation and exacerbated cardiac lipid metabolism disturbances, whereas Dlat knockdown effectively mitigated FAO inhibition and HFpEF phenotypes. Moreover, we demonstrated that Dlat directly triggers the acetylation of alpha subunit of mitochondrial trifunctional protein (HADHA) at the K728 site, thereby inactivating HADHA enzymatic activity. Our study provides a mechanistic basis linking protein hyperacetylation, FAO inhibition, and HFpEF development. Manipulating mitochondrial protein acetylation may offer potential strategies for therapeutic intervention of HFpEF.

DOI: https://doi.org/10.1038/s41467-026-70703-w

Am J Med. 2026 Mar 08. pii: S0002-9343(26)00177-4. [Epub ahead of print]

Sodium-Glucose Cotransporter 1&2 Inhibitors in Heart Failure and Diabetes Mellitus: From Foundational Therapy to Emerging Frontiers.

Prakash Deedwania, Akshat Banga.

Sodium-glucose cotransporter (SGLT) inhibitors have transformed cardiovascular therapeutics beyond glycemic control. Both selective SGLT2 and dual SGLT1/2 inhibitors demonstrate robust reductions in heart failure hospitalization (∼30%), cardiovascular mortality (13-15%), and all-cause mortality across ejection fraction spectrums, independent of diabetes status. Landmark trials including DAPA-HF, EMPEROR, and DELIVER established SGLT2 inhibitors as foundational therapy alongside RAAS inhibition, β-blockers, and mineralocorticoid receptor antagonists. Dual SGLT1/2 inhibition shows comparable heart failure benefits with potential stroke reduction (∼25%). Mechanisms involve natriuresis, improved myocardial energetics via NHE1 inhibition and ketone utilization, endothelial function improvement, and anti-inflammatory effects, transcending glucose lowering. Common adverse effects include genitourinary infections, mild hypovolemia, and rarely euglycemic ketoacidosis. Current guidelines provide Class I recommendations for SGLT2 inhibitors across heart failure phenotypes. However, despite robust evidence, implementation remains suboptimal and <50% prescription rates remain a challenge. We performed a systematic appraisal of landmark trials, real-world studies, and clinical guidelines to provide a comprehensive review of SGLT inhibitors in heart failure and diabetes.

Keywords: Diabetes mellitus; Heart failure; SGLT-1/2 inhibitors; SGLT-2 inhibitors

DOI: https://doi.org/10.1016/j.amjmed.2026.02.049

Am J Physiol Heart Circ Physiol. 2026 Mar 12.

Diet Modulates Cardiac Metabolic Stress During Anthracycline Treatment.

Kyoungmin Kim, Yaqi Gao, Tanvi Shankar, Anja Karlstaedt.

Diet is a modifiable determinant of cardiovascular risk and may influence tolerance to cancer therapies. The mechanisms by which specific dietary components affect cardiac metabolism during anthracycline treatment remain poorly defined, limiting the incorporation of dietary recommendations into treatment guidelines. Here, we integrated heart proteomics data from patients treated with or without anthracyclines with a genome-scale reconstruction of human cardiac metabolism (CardioNet). Using constraint-based flux analysis, we conducted >30,000 in silico simulations of diet scenarios generated from chemical profiles of ~500 foods curated in the Periodic Table of Food Initiative. These simulations revealed that diets enriched in rapidly absorbable sugars and depleted of essential fatty acids impair cardiac metabolic efficiency, increasing reactive oxygen species production and the demand for purine salvage fluxes. These predicted metabolic patterns were consistent with plasma metabolomics from anthracycline-treated patients, validating our findings. Computational modeling of 39 recipes across six cuisines revealed cardiometabolic effects of omnivorous versus vegan diets in patients. Modeling of a healthy vegan diet increased cardiometabolic efficiency compared to a healthy omnivorous diet in patients treated with anthracyclines, independent of the culinary background. Our approach demonstrates that integrating the molecular composition of food with genome-scale metabolic models enables systematic analysis of diet patterns for translational testing. Ultimately, these in silico studies provide a framework for trials and may inform dietary recommendations for improving cardiometabolic health.

Keywords: cardio-oncology; diet; flux balance analysis; metabolism; multi-omics

DOI: https://doi.org/10.1152/ajpheart.00745.2025

Circ Res. 2026 Mar 11.

Short SCN5A Transcript Yields a NaV1.5 Fragment Influencing Cardiac Metabolism.

Nathan H Witmer, Jasmyn M Hoeger, Jared M McLendon, Colleen S Stein, Jin-Young Yoon, Lili Wang, Elena Berezhnaya, John W Elrod, Björn C Knollmann, Barry L London, Ryan L Boudreau.

BACKGROUND: SCN5A encodes the cardiac NaV1.5 (voltage-gated Na+ channel), classically known for initiating action potentials and recently implicated in cardiomyocyte metabolism via mitochondrial Na+/Ca2+ exchange. SCN5A variants are linked to arrhythmias and heart failure, but mechanisms controlling SCN5A/NaV1.5 expression and its metabolic interface remain understudied.
METHODS: We used bioinformatic approaches to identify novel SCN5A regulatory features and discovered an alternative polyadenylation (APA) signal downstream of exon 2, which is conserved in humans and several other species but not mice. To test its function, we generated knock-in mice harboring the human APA signal. Western blotting, cell fractionation, and fluorescence microscopy were used to characterize the resulting truncated protein isoform that localizes to mitochondria. Mitochondrial functions and metabolites were assessed in neonatal rat cardiomyocytes, human-induced pluripotent stem cell-derived cardiomyocytes, and mouse hearts overexpressing the novel isoform.
RESULTS: We identified a well-conserved APA signal downstream of SCN5A exon 2, yielding a truncated transcript isoform (SCN5A-short). Reanalysis of cardiac APA-seq and mRNA-seq data reveals reduced SCN5A-short expression in failing human hearts. Knock-in of the human APA signal into mice enables expression of SCN5A-short while decreasing full-length SCN5A mRNA. SCN5A-short encodes a novel NaV1.5-NT (N-terminal fragment of NaV1.5) that localizes to the mitochondrial matrix in cardiomyocytes and mouse hearts. Exogenous expression of NaV1.5-NT in cultured cardiomyocytes enhances mitochondrial respiration, ATP production, and mitochondrial ROS while depleting NADH. Native polyacrylamide gel electrophoresis analyses indicate that this coincides with enhanced CI (complex I) activities, as well as context-dependent alterations of CV (complex V) assembly. Moreover, moderate cardiomyocyte-targeted NaV1.5-NT expression in mice was sufficient to rewire the cardiac metabolome, with suggestive evidence of increased fatty acid oxidation.
CONCLUSIONS: APA-mediated regulation of SCN5A produces a short transcript encoding NaV1.5-NT, a novel mitochondrial-targeted peptide that supports cardiomyocyte metabolism. While the precise molecular mechanisms remain unresolved, these findings highlight an unforeseen alternative pathway for expanding SCN5A-mitochondrial crosstalk, with potential implications for metabolic changes in heart failure and arrhythmias.

Keywords: action potentials; cardiomyopathy, dilated; defibrillators, implantable; mitochondria; sodium channels

DOI: https://doi.org/10.1161/CIRCRESAHA.125.326973