bims-hafaim 2026-04-26 papers

Issue of 2026–04–26
five papers selected by
Kyle McCommis, Saint Louis University

Life Sci. 2026 Apr 21. pii: S0024-3205(26)00222-5. [Epub ahead of print] 124413

Toward metabolic precision medicine in heart failure: Timing, tissue specificity, and network reconstruction.

Li Chen, Xin-Rui Yang, Yan Jiang, Shi-Qi Cheng, Zhen-Xun Wan, Jin-Wen Wu, Ming-Tai Chen, Yuan-Yuan Li, Gang Luo, Meng-Nan Liu.

Heart failure (HF) remains a major global health burden, with high morbidity and mortality closely linked to disturbances in cardiac energy metabolism. Targeting metabolic reprogramming has emerged as a key strategy to overcome the limitations of conventional hemodynamic-based therapies. This review systematically elucidates critical alterations in the cardiac energy metabolism network associated with HF, including mitochondrial dysfunction, aberrant substrate utilization, and dysregulation at both the transcriptional and post-translational levels. It also explores multidimensional therapeutic strategies focused on restoring mitochondrial function, enhancing metabolic flexibility, and modulating the neurometabolic axis. Compounds such as metformin, Omecamtiv Mecarbil (OM), and SGLT2 inhibitors have demonstrated significant clinical benefits by optimizing energy substrate utilization, improving mitochondrial function, and enhancing autophagy. Future research should prioritize optimizing intervention timing, achieving tissue-specific targeting, and integrating systemic metabolic control to advance the evolution of HF management strategies.

Keywords: Energy metabolism; Heart failure; Metabolic reprogramming; Metabolic therapy; Mitochondrial dysfunction

DOI: https://doi.org/10.1016/j.lfs.2026.124413

Am J Physiol Heart Circ Physiol. 2026 Apr 21.

Cardiac Metabolic Remodeling Drives Dicarbonyl Stress-Induced Mitochondrial Dysfunction in Experimental Heart Failure with Preserved Ejection Fraction.

Ankit Aryal, Parnia Mobasheran, Luther Bishop, Sabyasachi Chatterjee, Scott Jennings, Huijing Xia, Eric Lazartigues, Qinglin Yang.

Heart failure (HF) affects over 60 million people worldwide, with increasing prevalence as HF with preserved ejection fraction (HFpEF) among adults. Although metabolic remodeling and mitochondrial dysfunction are central features of HFpEF, the direct mechanistic link between altered cardiac metabolism and mitochondrial impairment remains elusive. Here, we investigated how cardiac metabolic remodeling drives mitochondrial impairment, leading to diastolic dysfunction in HFpEF, independent of extracardiac metabolic syndrome. Infusion of angiotensin-II (1.5 μg/g/day) and phenylephrine (50 μg/g/day) in 8-10-week-old male and female mice reproduced hallmark HFpEF features, including preserved EF, elevated E/E' ratio, reduced physical endurance, and impaired lung function. Cardiac mitochondria showed markedly reduced respiration, diminished complex II abundance, and impaired mitochondrial supercomplexes, accompanied by a ~20% reduction in mitochondrial calcium retention capacity and increased susceptibility to opening of the mitochondrial permeability transition pore (mPTP). Metabolomic analysis suggests a shift in mitochondrial metabolism from fatty acid (FA) to the utilization of alternative glucose substrates, characterized by reduced mitochondrial FA trafficking despite increased FA translocase. Dicarbonyl and glycative stress were substantially elevated, with mitochondrial protein glycation increased by 7-fold. Mass spectrometry identified 18 mitochondrial proteins present in a significantly glycated form, with potential implications for impairing metabolic flexibility, reducing electron transport efficiency, and promoting susceptibility to mPTP opening. Our findings demonstrate that metabolic remodeling contributes to dicarbonyl and glycative stress, which in turn compromises the integrity of mitochondrial electron transport complexes, respiratory function, and calcium retention capacity in the HFpEF heart, highlighting mitochondrial dicarbonyl detoxification and anti-glycation strategies as promising therapeutic avenues.

Keywords: Heart failure with preserved ejection fraction; metabolic remodeling; mitochondrial health; mitochondrial respiration

DOI: https://doi.org/10.1152/ajpheart.00029.2026

Cardiovasc Res. 2026 Apr 22. pii: cvag084. [Epub ahead of print]

Integrated left ventricular multi-omics landscape of human cardiometabolic HFpEF.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF), the leading form of heart failure, is burdened by high morbidity and mortality, owing to gaps in our understanding of its molecular and pathophysiological mechanisms. The obese/cardiometabolic HFpEF phenotype is particularly prevalent and morbid, and obesity is increasingly recognized as a driver of the syndrome, though the underlying mechanisms distinguishing cardiometabolic HFpEF from obesity remain unclear. Comprehensive multi-omics characterization of left ventricular samples from patients with HFpEF and obesity, compared with obese non-failing counterparts, will help to solve this issue.
METHODS AND RESULTS: We applied an integrated multi-omics approach to compare left ventricular (LV) endomyocardial biopsies (EMB) from overweight/obese HFpEF patients (n=19) and non-failing overweight/obese (NFO) individuals (n=4). Proteomic, metabolomic, and lipidomic data were integrated with clinical parameters, imaging and invasive hemodynamics to investigate the molecular mechanisms and clinical relevance of metabolic dysregulation in HFpEF.HFpEF patients exhibited distinct proteomic signatures marked by extracellular matrix (ECM) remodeling and impaired energy metabolism compared with NFO individuals. Specifically, HFpEF hearts showed diminished glycolysis, altered glucose metabolism, preserved fatty acid oxidation (FAO) and accumulation of succinate, consistent with myocardial energy deprivation. Changes in purine and pyrimidine metabolism further indicated altered nucleotide homeostasis. Integrative analyses revealed strong correlations between metabolic derangements, ECM proteins expression, and clinical indices of cardiac function and disease severity.
CONCLUSIONS: Our findings indicate that metabolic remodeling - particularly dysregulated glycolysis and TCA cycle intermediates changes - contributes to myocardial dysfunction in cardiometabolic HFpEF. Importantly, comprehensive multi-omics analysis of LV EMBs identified HFpEF-specific alterations in cardiac metabolism and remodeling occurring independently from obesity. These insights highlight the interplay between metabolic dysregulation, ECM remodeling, and clinical phenotype in cardiometabolic HFpEF, offering a foundation for targeted metabolic interventions in this syndrome.

Keywords: HFpEF; metabolism; metabolomics; multi-omics network; obesity; proteomics

DOI: https://doi.org/10.1093/cvr/cvag084

Arch Biochem Biophys. 2026 Apr 22. pii: S0003-9861(26)00102-5. [Epub ahead of print] 110831

Mitochondria-Targeted Cardioprotection of Gentianella acuta Xanthones in Doxorubicin-Induced Heart Failure Through AMPK/PGC-1α Activation.

Yuxin Wei, Huiyue Yuan, Lihong Wu, Deqiang Yang, Meng Wang, Yanping Sun, Zhenyue Wang, Haixue Kuang, Zhibin Wang.

BACKGROUND: Heart failure (HF) is closely associated with mitochondrial dysfunction and impaired energy metabolism. Doxorubicin (DOX)-induced cardiomyopathy is a well-established model for investigating mitochondrial-driven HF. Gentianella acuta (GA), a traditional medicinal herb, has shown cardioprotective potential, yet the mechanisms of its major bioactive constituents, xanthones, in HF remain incompletely understood.
METHODS: A combined strategy integrating network pharmacology, in vitro cardiomyocyte injury models, and an in vivo DOX-induced HF rat model was employed to elucidate the cardioprotective mechanisms of GA-derived xanthones (XAN). Network pharmacology analysis was used to predict key targets and signaling pathways. Mitochondrial function, cardiomyocyte apoptosis, cardiac function, ultrastructural changes, energy metabolism indices, and AMPK/PGC-1α pathway-related proteins were systematically evaluated using H9c2 cells and HF rats.
RESULTS: Network pharmacology identified the AMPK signaling pathway as a key target of XAN in HF. In H9c2 cardiomyocytes, XAN attenuated DOX-induced mitochondrial membrane potential loss and apoptosis, accompanied by increased AMPK phosphorylation and upregulation of PGC-1α and SIRT1. In DOX-induced HF rats, XAN improved cardiac diastolic function, alleviated electrocardiographic abnormalities, reduced myocardial apoptosis, and preserved mitochondrial ultrastructure. XAN also restored myocardial energy metabolism by increasing ATP production and mitochondrial enzyme activities while reducing HF-related biomarkers. These effects were dose-dependent and closely associated with activation of the AMPK/PGC-1α pathway.
CONCLUSION: XAN confer mitochondria-targeted cardioprotection against DOX-induced HF by reprogramming myocardial energy metabolism via activation of the AMPK/PGC-1α pathway. These findings provide mechanistic evidence supporting XAN as promising natural candidates for metabolic intervention in HF.

Keywords: AMPK/PGC-1α; Doxorubicin; Gentianella acuta; Heart failure; Network pharmacology; Xanthones

DOI: https://doi.org/10.1016/j.abb.2026.110831

Science. 2026 Apr 23. eadz7118

Severe obesity in human HFpEF alters contractile protein function and organization.

Heart failure with preserved ejection fraction (HFpEF) causes substantial morbidity and mortality and has few effective therapies. Its phenotype has changed over time, with morbid obesity and metabolic defects supplanting hypertension and cardiac hypertrophy. We reveal that cardiomyocytes from patients with severe obesity and HFpEF have very depressed contractile reserve, including reduced calcium- and length-stimulated tension, power, and myosin activation compared to less-obese HFpEF and non-failing (NF) controls ±obesity, but similar to advanced HF with reduced EF. Myocyte defects correlate with body mass index and exercise hemodynamics in patients with HFpEF but not NF and appear reversible upon weight loss. Increased troponin-I phosphorylation at Thr181 occurs only in HF+obesity contributing to sarcomere dysfunction. Weight reduction and sarcomere enhancers may offer benefits in HFpEF with obesity.

DOI: https://doi.org/10.1126/science.adz7118