bims-hafaim 2026-08-02 papers

Issue of 2026–08–02
six papers selected by
Kyle McCommis, Saint Louis University

Res Sq. 2026 Jul 17. pii: rs.3.rs-10157404. [Epub ahead of print]

Integrated Myocardial and Plasma Lipidome Across the Human Obesity-Heart Failure Spectrum.

David J Polhemus, Annie Butt, Craig Resch, Kathryn Tsai, Vatsa A Batra, Shuyi Yan, Atharva Mulay, Cinthia Drachenberg, Flora Sam, Traci T Goodchild, David J Lefer, Mariam Meddeb, Kenneth B Margulies, Kenneth C Bedi, Kavita Sharma, Navid Koleini, Amir Ravandi, David A Kass.

Heart failure with preserved ejection fraction (HFpEF) has become the dominant heart failure phenotype, with many patients impacted by marked obesity. Lipid dyshomeostasis is thought to contribute, but human myocardial lipidomic data remain lacking. We performed untargeted lipidomics (>1,000 species) of ventricular samples for non-failing (NF) controls (n=40), HFpEF (n=29), and HFrEF (n=13) patients, integrating results with myocardial transcriptomics, ultrastructure, and plasma lipidomics, across a broad obesity spectrum. Multiple lipid classes increased in HFpEF myocardium including phospholipids, sphingolipids, neutral lipids, and free fatty acids, but acylcarnitines declined. HFrEF had far fewer lipid changes, and cardiolipin and phosphatidylethanolamine depletion. Lipids were minimally altered in NF hearts from obese individuals. Plasma lipidomics identified few inter-group disparities. Heart lipidomics from major animal HFpEF models (high fat diet+L-NAME, ZSF-1 rat, obese-DOCA-salt pig) all differed from human HFpEF. Thus, human HFpEF myocardium has distinctive cardiac lipid accumulation not found with obesity alone or HFrEF, nor mirrored by common preclinical HFpEF models.

Keywords: HFpEF; HFrEF; acylcarnitines; cardiolipin; ceramides; lipotoxicity; metabolic remodeling; myocardial lipidomics

DOI: https://doi.org/10.21203/rs.3.rs-10157404/v1

J Biochem Mol Toxicol. 2026 Aug;40(8): e71033

Myocardial Lipid Metabolism Imbalance: The Pathological Core and Novel Diagnostic-Therapeutic Directions of Cardiovascular Diseases.

Peiyun Xie, Qun Zeng, Hongrui Wang, Meihua She.

Cardiac lipid metabolism is fundamental to myocardial energy homeostasis, with fatty acid oxidation (FAO) supplying the majority of ATP in the healthy adult heart. This review synthesizes the core regulatory network governing cardiac lipid metabolism, encompassing lipid droplet dynamics mediated by perilipins (e.g., Plin5, Plin2), fatty acid uptake via CD36, systemic lipid modulation by apolipoproteins (e.g., APOC3), and the central energy-sensing AMPK/PGC-1α/PPARα axis. Dysregulation of this network initiates a self-perpetuating lipotoxic cycle, characterized by the accumulation of toxic lipid intermediates (e.g., diacylglycerols, ceramides), oxidative stress, and inflammatory activation, which serves as a common pathological mechanism across diverse cardiovascular diseases (CVDs), including atherosclerosis, heart failure, diabetic cardiomyopathy, and ischemic injury. Emerging from this mechanistic understanding is a promising landscape of biomarkers-such as specific ceramide species, the ApoB/ApoA-1 ratio, and circulating perilipins-and targeted therapeutic strategies, including APOC3 inhibitors, SGLT2 inhibitors, and Plin5-directed therapies. Future advances will depend on integrating multi-omics technologies and precision medicine approaches to tailor interventions to specific metabolic phenotypes, thereby opening new avenues for the prevention and treatment of CVDs.

Keywords: cardiac lipid metabolism; cardiovascular diseases; fatty acid oxidation; lipotoxicity; targeted therapy

DOI: https://doi.org/10.1002/jbt.71033

J Cardiovasc Dev Dis. 2026 Jun 29. pii: 297. [Epub ahead of print]13(7):

Global Profiling of Protein Lysine Lactylation in Mouse Cardiac Hypertrophy: A Lactylome Analysis.

Wengen Zhu, Siyu Guo, Yunyao Yang, Yugang Dong, Chen Liu, Cong Chen.

BACKGROUND: Cardiac hypertrophy, a major feature of heart failure, is closely linked to metabolic remodeling and energy deficiency. Lysine lactylation (Kla), a recently discovered post-translational modification (PTM), has been implicated in various cellular processes. However, its specific role in cardiac hypertrophy remains poorly understood.
METHODS: We conducted quantitative proteomics and Kla PTM analysis on left ventricular tissues from both sham-operated and aortic banding-induced hypertrophic mouse hearts. Protein samples were extracted, enriched for lactylation, and subjected to mass spectrometry. Bioinformatic analyses were performed to uncover pathways and protein-protein interactions (PPI) related to Kla-modified proteins.
RESULTS: Our lactylome analysis identified 159 Kla-modified sites across 80 proteins, with 72 proteins exhibiting elevated Kla levels, particularly in mitochondrial and sarcomeric proteins. Pathway enrichment analysis highlighted significant involvement of fatty acid metabolism, the tricarboxylic acid (TCA) cycle, and cardiomyopathy-related pathways, underscoring the role of Kla in energy metabolism and cardiac remodeling. PPI analysis further revealed the central role of metabolic and structural proteins in the hypertrophic response.
CONCLUSIONS: Our study provides the comprehensive analysis of Kla in cardiac hypertrophy, revealing its significant role in modulating proteins involved in mitochondrial energy metabolism and sarcomeric structure. Our findings provide a comprehensive overview of the lactylation landscape in cardiac hypertrophy and reveal extensive lactylation changes in proteins associated with mitochondrial metabolism and sarcomeric organization. These observations suggest a potential link between Kla and cardiac hypertrophy, which warrants further functional investigation.

Keywords: cardiac hypertrophy; heart failure; lysine lactylation; mitochondria; sarcomere

DOI: https://doi.org/10.3390/jcdd13070297

Rev Cardiovasc Med. 2026 Jul;27(7): 47433

Mechanistic Studies of Lactate in Heart Failure: From Metabolic Biomarker to Therapeutic Target.

Zhongjian Zhang, Ting Zeng, Xiaoyu Li, Zhiling He, Shuang Li.

Heart failure (HF) is a significant cardiovascular syndrome with a high prevalence of morbidity and mortality across the globe. Meanwhile, lactate, a byproduct of glycolysis, has been implicated in myocardial hypoxia and disarranged energy metabolism and has drawn attention in the context of HF. In addition to serving as a highly sensitive biomarker, lactate might also contribute to myocardial remodeling and inflammation via multiple signaling pathways, thereby affecting disease course and prognosis; however, the mechanisms through which lactate impacts HF remain incompletely elucidated, and published results are contradictory. Therefore, this review encompassed lactate metabolism and the associated physiological and pathological functions in HF, underlining the clinical significance of lactate as a metabolic biomarker. Moreover, this review discussed recent progress targeting lactate metabolism or lactylation as potential treatments to promote a clearer understanding of the mechanistic aspects of metabolic regulation in HF and to guide clinical diagnosis and treatment.

Keywords: heart failure; inflammatory response; lactate; metabolic biomarker; myocardial remodeling; therapeutic target

DOI: https://doi.org/10.31083/RCM47433

Nat Rev Cardiol. 2026 Jul 27.

Cardioprotective properties of empagliflozin and other SGLT2 inhibitors.

Thomas A Zelniker, Eugene Braunwald.

Since the publication of the landmark EMPA-REG OUTCOME trial, sodium-glucose cotransporter 2 (SGLT2) inhibitors have redefined the therapeutic landscape of cardiovascular-kidney-metabolic disease. Initially developed as glucose-lowering drugs, empagliflozin and subsequent SGLT2 inhibitors have demonstrated robust benefits in reducing hospitalization for heart failure, slowing the progression of chronic kidney disease and lowering cardiovascular mortality across diverse populations. Although the precise mechanisms underlying these effects are not completely understood, the cardioprotective effects of empagliflozin seem to be mediated by an interconnected network of pleiotropic mechanisms. Empagliflozin modulates haemodynamics, restores endothelial and vascular function, improves mitochondrial bioenergetics through increased mitochondrial activity and substrate flexibility, and attenuates maladaptive cardiac remodelling. In this Review, we synthesize the current mechanistic understanding of SGLT2 inhibitors and highlight key directions for the future of cardiovascular-kidney-metabolic disease management. The next decade of research on SGLT2 inhibitors will be shaped by efforts to close evidence gaps, including in kidney failure and cardio-oncology, as well as the integration of SGLT2 inhibitors with other guideline-directed therapies, optimization of therapeutic sequencing and broad implementation in clinical care.

DOI: https://doi.org/10.1038/s41569-026-01325-4

medRxiv. 2026 Jul 22. pii: 2026.07.20.26358530. [Epub ahead of print]

Plasma Metabolite Associations with Incident Heart Failure with Reduced and Preserved Ejection Fraction.

Bhavya Chebrolu, Priyam Choksi, Salvatore Carbone, Brittany N Weber, Jessica Lasky-Su, Elizabeth W Karlson, Sheila Hegde, Leo F Buckley.

Background: Prior studies on metabolite associations with incident heart failure (HF) used billing code-based definitions and lacked the data on left ventricular ejection fraction needed to determine associations with HF with reduced (HFrEF) and preserved (HFpEF) ejection fraction.
Objectives: Identify potentially causal plasma metabolite associations with HFrEF and HFpEF, ascertained using a validated machine learning- and natural language processing-based algorithm, in up to 38,000 individuals.
Methods: We included MGB Biobank participants who had available metabolomics data and no history of HF at baseline. The primary exposures were plasma levels of 42 metabolites measured using a H 1 nuclear magnetic resonance platform. The primary outcome was incident HF, ascertained by a validated machine learning- and natural language processing-based algorithm. Multivariable Cox proportional hazards regression to quantify the associations between a 1-SD difference in metabolite level and the time to incident HF. Mendelian randomization analysis was used test the potential causality of each metabolite-HF association.
Results: The final analytical cohort included 38,628 individuals with a mean age of 63 years (56% women). Higher plasma levels of glutamine associated with a higher risk of incident HF (HR [95% CI]: 1.21 [1.07-1.35]) while higher levels of docosahexaenoic acid (an omega-3 fatty acid) (0.85 [0.75-0.95]), phosphatidylcholines (0.85 [0.75-0.97]), phosphoglycerides (0.86 [0.76- 0.97]) and total cholines (0.85 [0.75-0.97]) associated with a lower HF risk. Docosahexaenoic acid and total omega-3 fatty acids associated with HFpEF. Associations with HFpEF tended to be stronger than with HFrEF for several fatty acids, including omega-3 fatty acids, in individuals with obesity, but not coronary artery disease or diabetes. Mendelian randomization analysis supported causal associations between higher levels of docosahexaenoic acid and omega-3 fatty acids with a higher risk of HF and greater left ventricular mass index.
Conclusions: Dysregulated omega-3 fatty acid metabolism may be causally associated with a higher risk of incident HFpEF.
Condensed Abstract: We investigated metabolic contributors to incident heart failure (HF) in the MGB Biobank, leveraging metabolomics and a validated machine learning/NLP algorithm for HF ascertainment. Among 38,628 participants without HF at baseline, plasma levels of 42 metabolites were evaluated using multivariable Cox models and Mendelian randomization. Higher glutamine levels were associated with increased HF risk, while docosahexaenoic acid (DHA), phosphatidylcholines, phosphoglycerides, and total cholines were inversely associated. DHA and total omega-3 fatty acids were linked to HFpEF. Mendelian randomization suggested causal associations between higher DHA and omega-3 fatty acid levels and elevated HF risk, implicating dysregulated omega-3 metabolism in HF development.

DOI: https://doi.org/10.64898/2026.07.20.26358530