bims-hafaim 2026-03-22 papers

Issue of 2026–03–22
four papers selected by
Kyle McCommis, Saint Louis University

Am J Physiol Heart Circ Physiol. 2026 Mar 18.

Combined high-fat, high sucrose diet and streptozotocin treatment induces cardiometabolic heart failure with preserved ejection fraction in mice.

Andre Heinen, Andre Spychala, Lucas Ballmann, Stefanie Gödecke, Zewa Faradj, Florian Bresch, Martina Krüger, Katharina Bottermann, Heba Zabri, Jens Fischer, Patrick Petzsch, Axel Gödecke.

Diabetes is associated with an increased incidence of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms are poorly understood. A shortage of mouse models reflecting the diverse HFpEF pathophysiology contributes to this inadequate understanding of disease mechanisms. We conducted a comprehensive analysis of a non-genetic, inducible T2DM mouse model with regard to its suitability as preclinical model of cardiometabolic, diabetes-induced HFpEF. T2DM was induced in C57Bl/6-mice by high-fat/high-sucrose diet and low-dose streptozotocin (DIO-STZ). Cardiac function was assessed in vivo by echocardiography and left ventricular catheterization, and in vitro using the isolated perfused heart. Structural, molecular and bioenergetic disturbances were analyzed by immunohistochemistry, RNA-seq, qPCR, westernblot, and extracellular flux analysis of myocardial tissue. Blood glucose, fatty acids and ketone body levels were elevated, and insulin level was reduced in DIO-STZ compared to chow. DIO-STZ mice showed a HFpEF-phenotype with reduced cardiac output, end-diastolic volume, and increased filling pressure. No differences in myocardial fibrosis nor in in vitro stiffness were detected between DIO-STZ and chow. RNA-Seq pointed towards disturbances in lipid and ketone metabolism. Extracellular flux analysis revealed increased fatty acid oxidation capacity without differences in glucose metabolism. No general mitochondrial dysfunction was observed, but a reduced capacity for β-hydroxybutyrate oxidation. The diabetic DIO-STZ mouse model showed a pronounced functional HFpEF phenotype with underlying mechanisms that remarkably differ from other HFpEF models making the DIO-STZ model a relevant extension of the range of HFpEF mouse models, especially for investigating molecular mechanisms or therapeutical interventions in diabetes associated HFpEF.

Keywords: cardiac substrate metabolism; diabetes mellitus; diastolic dysfunction; heart failure with preserved ejection fraction; mouse model

DOI: https://doi.org/10.1152/ajpheart.00843.2025

Dis Mon. 2026 Mar 19. pii: S0011-5029(26)00037-4. [Epub ahead of print] 102099

Efficacy and safety of Tirzepatide in patients with heart failure with preserved ejection fraction: A systematic review and meta-analysis.

Sneha Annie Sebastian, Tanesh Ayyalu, Tia Bimal, Bhavin Patel, Michelle M Kittleson, Salvatore Carbone, Amin Yehya.

BACKGROUND: Obesity-related heart failure with preserved ejection fraction (HFpEF) is associated with high morbidity and limited therapeutic options. Tirzepatide, a dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has demonstrated reductions in cardiovascular mortality and worsening heart failure events in a recent randomized controlled trial. However, pooled evidence for tirzepatide's cardiovascular and clinical effects in HFpEF remains limited. Moreover, head-to-head comparisons of tirzepatide with semaglutide, another incretin-mimetic therapy shown to be beneficial in HFpEF, are sparse. This meta-analysis aims to systematically analyze the efficacy and safety of tirzepatide in patients with HFpEF.
METHODS: We conducted a systematic review by searching multiple databases up to December 5, 2025 evaluating tirzepatide versus standard therapy and semaglutide for cardiovascular outcomes in patients with obesity-related HFpEF. Statistical analysis was performed using RevMan 5.4, with an inverse variance random effects model to calculate hazard ratios (HR) and odds ratios (OR). Heterogeneity was assessed using the Higgins I² test. The study protocol is registered in PROSPERO (CRD420251170117).
RESULTS: Our final analysis included five studies, including RCTs and observational studies with a total of 47,710 patients with HFpEF and BMI ≥ 30 kg/m2, a mean age of 64.7 years, and follow-up ranging from 52 to 146 weeks. Tirzepatide was associated with a significant reduction in the composite outcome of cardiovascular mortality and worsening heart failure events compared with standard therapy (HR 0.50; 95% CI: 0.42-0.60; p < 0.001). A significant reduction in heart failure exacerbation events alone was also observed with tirzepatide versus standard therapy (HR 0.75; p = 0.04), whereas no significant difference was seen when compared with semaglutide (HR 0.95; p = 0.31). Heart failure hospitalization and all-cause mortality did not differ significantly between tirzepatide and either standard therapy or semaglutide. No statistically significant difference in adverse drug reactions was observed.
CONCLUSION: In this meta-analysis, tirzepatide was associated with a significant reduction in the composite outcome of cardiovascular mortality and worsening heart failure events in patients with HFpEF and obesity. When compared to semaglutide, there were no significant differences in heart failure hospitalization or all-cause mortality.

Keywords: HFpEF; Heart failure with preserved ejection fraction; Obesity; Semaglutide; Tirzepatide

DOI: https://doi.org/10.1016/j.disamonth.2026.102099

Life Sci. 2026 Mar 12. pii: S0024-3205(26)00132-3. [Epub ahead of print] 124323

ACSL6 alleviates myocardial hypertrophy by ameliorating cardiac lipid synthesis and mitochondrial function.

Qiying Xie, Ziting Xie, Qiong Liu, Yixia Zhao, Nabeel M Abdo, Hong Qi.

AIMS: Myocardial hypertrophy is a key pathological basis for heart failure, closely related to disturbances in cardiac lipid metabolism and impaired mitochondrial function. Long-chain acyl-CoA synthetase 6 (ACSL6) is a pivotal enzyme in fatty acid metabolism, but its role in myocardial hypertrophy remains unclear. This study aims to investigate the role of ACSL6 in myocardial hypertrophy and its potential mechanisms.
MATERIALS AND METHODS: Mouse models of myocardial hypertrophy induced by isoproterenol (ISO) and neonatal mouse cardiomyocyte (NMCM) hypertrophy models intervened by angiotensin II (Ang II) were established. Using lentivirus-mediated ACSL6 overexpression, co-immunoprecipitation, mass spectrometry, lipidomics, transmission electron microscopy, and molecular biology techniques, the functions and mechanisms of ACSL6 were explored.
KEY FINDINGS: ACSL6 was downregulated in ISO-induced myocardial hypertrophic mouse tissues and Ang II-treated NMCMs, with expression decreasing as Ang II intervention duration increased. ACSL6 overexpression significantly alleviated myocardial hypertrophy, improved cardiac function, and mitigated cell damage and hypertrophic marker upregulation. Additionally, ACSL6 overexpression inhibited myocardial lipid synthesis and accumulation, ameliorated lipid metabolic disorder, and enhanced mitochondrial function in ISO-induced mice. Mechanistically, KRT17 bound to ACSL6, competing with E3 ubiquitin ligase MIB1, protecting ACSL6 from ubiquitination and degradation. KRT17 knockdown reversed the protective effects of ACSL6 overexpression, exacerbating lipid accumulation and mitochondrial dysfunction.
SIGNIFICANCE: ACSL6 alleviated myocardial hypertrophy by ameliorating cardiac lipid synthesis and mitochondrial function. KRT17 stabilized ACSL6 expression by inhibiting its ubiquitination and degradation, mediating ACSL6's protective effects. Targeting the KRT17-ACSL6 axis emerged as a promising strategy for treating myocardial hypertrophy.

Keywords: ACSL6; KRT17; Lipid metabolism; Mitochondrion; Myocardial

DOI: https://doi.org/10.1016/j.lfs.2026.124323

Mol Metab. 2026 Mar 16. pii: S2212-8778(26)00036-0. [Epub ahead of print] 102352

Pregnancy precipitates metabolic imbalance and accelerates death in an animal model of mitochondrial cardiomyopathy.

Nicole M Sayles, Gabriella Casalena, Dazhi Zhao, Ryan W Dellinger, Holly E Holmes, Onorina Manzo, Alexander Galkin, Annarita Di Lorenzo, Giovanni Manfredi.

During pregnancy, the heart undergoes major physiological and metabolic changes to increase cardiac workload and the demand for energy production is especially elevated during the trial of labor. Normally, cardiac structure and metabolism revert to the pre-pregnancy state shortly after delivery. However, in some cases peripartum/postpartum cardiomyopathy (PPCM) occurs, which increases a person's risk of major cardiac events following pregnancy. The molecular mechanisms underlying PPCM remain poorly understood. In this study, we investigate the transcriptional, metabolic, and bioenergetic profiles of postpartum (PP) hearts in a mouse model of cardiomyopathy caused by the pathogenic p.S55L mutation in the mitochondrial protein coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10). Heterozygote p.S55L mutant CHCHD10 mice develop acute heart failure during the immediate PP period. We observe cardiac remodeling, mitochondrial stress, and profound metabolic rewiring in PP mutant CHCHD10 hearts. Metabolic rewiring results decreased levels of heme and the depletion of key cofactors of energy metabolism, including NAD(H) and ADP. These findings suggest that mutant CHCHD10 hearts fail to meet the increased energy demands associated with the trial of labor due to the insufficient turnover rate of NAD+/NADH and ADP/ATP. We propose that this metabolic insufficiency drives PP mortality in mutant CHCHD10 mice. In support of this hypothesis, dietary supplementation with nicotinamide riboside and pterostilbene, a naturally derived polyphenol, increased PP survival and cardiac energy metabolites in mutant CHCHD10 mice. Our work provides novel insights into the molecular mechanisms of PP cardiomyopathy associated with mitochondrial stress and suggests potential beneficiary effects of dietary NAD(H) supplementation.

Keywords: CHCHD10; NAD(H); cardiomyopathy; metabolism; mitochondria; postpartum

DOI: https://doi.org/10.1016/j.molmet.2026.102352