bims-hafaim 2026-02-01 papers

Issue of 2026–02–01
five papers selected by
Kyle McCommis, Saint Louis University

Front Pharmacol. 2025 ;16 1706936

Levocarnitine improves cardiac energy metabolic remodeling in myocarditis mice.

Shutong Yang, Xiaoou Li, Zhenpeng Lu, Xiang Xu, Zuzhen Guo, Bing He.

Introduction: Energy metabolic remodeling represents a critical pathological mechanism in myocarditis progression. Levocarnitine (LC), an essential cofactor for fatty acid oxidation, demonstrates potential in modulating cardiac metabolism. This study investigated the therapeutic effects of LC on myocardial energy metabolic remodeling and explored the underlying molecular mechanisms.
Methods: The experimental autoimmune myocarditis (EAM) mouse model was constructed using α-myosin. Cardiac function, myocardial inflammatory infiltration, and mitochondrial structure were evaluated using echocardiography, HE staining, and transmission electron microscopy, respectively. Metabolic parameters including free fatty acid (FFA), lactic acid (LAC), mitochondrial complex IV (COX IV) activity, and adenosine triphosphate (ATP) levels were measured using colorimetry. Serum heart-type fatty acid-binding protein (H-FABP) levels were measured by ELISA, and reactive oxygen species (ROS) levels were determined by flow cytometry. The expression of organic carnitine transporter type 2 (OCTN-2) and carnitine palmitoyltransferase-1B (CPT-1B) were determined by Western blot. Furthermore, network pharmacology and molecular docking were employed to predict the therapeutic targets and mechanisms of LC in myocarditis. The activity of the phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) pathway and the expression of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) were verified by Western blot.
Results: LC treatment significantly improved cardiac function and attenuated myocardial inflammatory infiltration in EAM mice. It ameliorated mitochondrial structural damage, enhanced COX IV activity and ATP production, and reduced the accumulation of FFA, LAC and ROS in myocardial tissues. It also lowered serum H-FABP levels while upregulating the expression of OCTN-2 and CPT-1B. Combining network pharmacology and molecular docking, Akt was identified as the key therapeutic target of LC in cardiomyopathy and demonstrated good binding affinity with LC. In vivo validation confirmed that LC decreased Akt phosphorylation in the myocardium of EAM mice, while PGC-1α expression increased.
Conclusion: LC effectively improved myocardial metabolic remodeling and alleviated cardiac insufficiency in myocarditis. The underlying mechanism may involve LC-mediated suppression of the PI3K/Akt signaling pathway, potentially linked to increased expression of the key mitochondrial regulator PGC-1α.

Keywords: PI3K/AKT; experimental autoimmune myocarditis; levocarnitine; metabolic remodeling; mitochondrion

DOI: https://doi.org/10.3389/fphar.2025.1706936

Int J Mol Sci. 2026 Jan 15. pii: 879. [Epub ahead of print]27(2):

Biomarkers of Cardiac Metabolic Flexibility in Health, HFrEF and HFpEF.

Hyeong Rok Yun, Manish Kumar Singh, Sunhee Han, Jyotsna S Ranbhise, Joohun Ha, Sung Soo Kim, Insug Kang.

Cardiac metabolic flexibility is a key determinant of myocardial energetic resilience. In heart failure with reduced ejection fraction (HFrEF), intrinsic mitochondrial dysfunction and lipotoxicity compromise oxidative capacity. In contrast, heart failure with preserved ejection fraction (HFpEF) is orchestrated primarily by systemic comorbidities and coronary microvascular dysfunction, which decouple glycolysis from glucose oxidation. This review integrates these distinct pathophysiologies into a comprehensive biomarker framework. Beyond core hemodynamic markers, we detail indices of metabolic flux (ketones, acylcarnitines, branched-chain amino acids), endothelial injury, and fibrosis. We further prose a shift from static, isolated measurements to dynamic functional profiling using standardized challenges (e.g., mixed-meal or exercise tests) to quantify metabolic suppression and recovery kinetics. This structured hierarchy enables phenotype-tailored risk stratification and guides mechanism-based precision therapies in the era of personalized medicine.

Keywords: dynamic profiling; heart failure; metabolic flexibility; precision medicine

DOI: https://doi.org/10.3390/ijms27020879

Int J Mol Sci. 2026 Jan 21. pii: 1060. [Epub ahead of print]27(2):

Mitochondrial Targeting by Elamipretide Improves Myocardial Bioenergetics Without Translating into Functional Benefits in HFpEF.

Antje Schauer, Daniela Jahn, Beatrice Vahle, Peggy Barthel, Anita Männel, Gunar Fabig, Axel Linke, Volker Adams, Antje Augstein.

Mitochondrial dysfunction contributes to impaired myocardial energetics and performance in heart failure with preserved ejection fraction (HFpEF). Elamipretide (Ela) enhances mitochondrial bioenergetics in preclinical models, yet its relevance in HFpEF remains unclear. This study examined the effects of Ela on cardiac mitochondrial function, structure, and cardiovascular performance in a rodent HFpEF model. Female obese ZSF1 rats received vehicle or Ela for 12 weeks, with age-matched lean rats as controls. Cardiac function and hemodynamics were assessed by echocardiography and pressure-volume analysis. Mitochondrial respiration was measured in permeabilized fibers and ultrastructure evaluated by transmission electron microscopy. Molecular and histological analyses included cardiolipin lipidomics and mRNA/protein profiling of hypertrophic, fibrotic, and inflammatory markers. Ela modestly improved complex I and II respiration, whereas mitochondrial ultrastructure, cardiolipin composition, and tafazzin expression were unchanged. Diastolic dysfunction persisted, reflected by unchanged E/é, ventricular stiffness factor β, and titin phosphorylation. Compared to untreated HFpEF, systolic performance showed a mild decline, with small reductions in LV ejection fraction and end-systolic elastance. Accordingly, cardiac remodeling, including hypertrophy, fibrosis, and inflammatory activation, remained unaltered. Vascular stiffness slightly increased, while carotid reactivity and morphology were preserved. In conclusion, despite enhanced mitochondrial respiration following Ela treatment, no functional or structural benefits were observed in experimental HFpEF, suggesting limited therapeutic efficacy once HFpEF is established.

Keywords: Elamipretide; HFpEF; ZSF1 rat; mitochondria; myocardium; vasculature

DOI: https://doi.org/10.3390/ijms27021060

Front Physiol. 2025 ;16 1764781

Correction: Mechanisms of metabolic transition in hypertrophic cardiomyopathy.

Conghao Tan, Zhexuan Guo, Junjie Zhou, Wei Yuan.

[This corrects the article DOI: 10.3389/fphys.2025.1700313.].

Keywords: glucose metabolism; hypertrophic cardiomyopathy; lipid metabolism; metabolic transition; mitochondrial dysfunction

DOI: https://doi.org/10.3389/fphys.2025.1764781

Front Nutr. 2025 ;12 1678905

Potential causes and significance of elevated blood ketone levels in patients with heart failure with preserved ejection fraction.

Weijie Lu, Ai Liu, Mengyang Liu, Yujie Hu, Kang Yang, Yaoting Deng, Qianrong Li, Bowen Wang, Yanling Li, Bing Jiang, Gang Wang, Xuehan Wang, HuGang Jiang, Ping Xie.

Background: The diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging. Given the critical role of metabolic disturbance and energy expenditure in HFpEF pathophysiology, we investigated the clinical significance and diagnostic value of blood ketone bodies in these patients.
Methods: This case-control study enrolled 160 participants, comprising 80 HFpEF patients and 80 matched healthy controls. Baseline characteristics, levels of blood ketones (acetoacetate, β-hydroxybutyrate, acetone), and NT-proBNP were compared. Multivariate linear regression and correlation analyses were employed to assess the associations between ketone levels, clinical parameters, and NT-proBNP. The diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis.
Results: Compared to controls, HFpEF patients showed significant differences in age, heart rate, BMI, and blood pressure. Multivariate regression revealed a significant linear association between BMI, systolic blood pressure, and acetoacetate levels in the HFpEF group. A weak inverse correlation was found between acetoacetate and NT-proBNP levels. However, no correlation was observed between ketone levels and NYHA functional class. ROC analysis demonstrated that the combination of acetoacetate and NT-proBNP yielded the highest diagnostic efficacy (AUC = 0.9117), superior to NT-proBNP alone (AUC = 0.8328) or any ketone body alone.
Conclusion: Unlike nutritional ketosis, elevated blood ketone levels in patients with HFpEF likely reflect impaired metabolic efficiency rather than a marker of cardiac function. Nevertheless, this phenomenon has diagnostic significance: combining acetoacetate with NT-proBNP can markedly improve diagnostic performance.

Keywords: assessment value; blood ketones; clinical research; diagnostic value; heart failure with preserved ejection fraction

DOI: https://doi.org/10.3389/fnut.2025.1678905