bims-hafaim 2026-01-11 papers

Issue of 2026–01–11
five papers selected by
Kyle McCommis, Saint Louis University

Int J Mol Sci. 2025 Dec 26. pii: 284. [Epub ahead of print]27(1):

Pathophysiology of HFpEF: Insights from a Metabolic-Mitochondrial Perspective.

Cristina Gatto, Maria Rosaria Rusciano, Valeria Visco, Carmine Vecchione, Michele Ciccarelli.

Heart failure with preserved ejection fraction (HFpEF) represents a growing clinical challenge, accounting for more than half of all cases of heart failure, for which there are currently no effective treatments. Emerging evidence identifies mitochondrial dysfunction as a central mechanism linking metabolic comorbidities, systemic inflammation, and energy failure in HFpEF. This review provides a comprehensive overview of the metabolic-mitochondrial mechanisms underlying the pathophysiology of HFpEF. Loss of metabolic flexibility, characterized by reduced fatty acid and glucose oxidation, leads to energy inefficiency, lipid accumulation, and oxidative stress. Structural and functional mitochondrial abnormalities, including damaged cristae, altered fission-fusion dynamics, and impaired oxidative phosphorylation, contribute to diastolic dysfunction and ventricular remodeling. In parallel, chronic inflammation and redox imbalance amplify mitochondrial damage through cytokine- and ROS-mediated pathways, creating a cycle of bioenergetic failure. From a therapeutic perspective, strategies aimed at restoring mitochondrial homeostasis, such as physical training, metabolic modulation, SGLT2 inhibition, ketone supplementation, and mitochondria-targeted antioxidants, show promising preclinical results. However, clinical translation remains limited. Deepening the understanding of mitochondrial metabolism could enable the development of personalized treatments capable of improving outcomes for HFpEF patients.

Keywords: HFpEF; inflammation; metabolic flexibility; mitochondria; oxidative stress

DOI: https://doi.org/10.3390/ijms27010284

Circulation. 2026 Jan 05.

GRSF1 Protects Against Heart Failure by Maintaining BCAA Homeostasis.

Hu Wang, Jiaxing Wang, Min Zhu, Ling Jin, Hao Cui, Cihang Liu, Chenyu Fan, Hui Li, Jichun Yang, Ming Cui, Jiangping Song, Wengong Wang, Ming Xu.

BACKGROUND: Imbalances in cardiac branched-chain amino acid (BCAA) metabolism and mitochondrial homeostasis are implicated in the onset and development of heart failure. However, the mechanisms triggering the downregulation of cardiac BCAA metabolism in heart failure remain unclear. Here, we identify a novel role of the RNA-binding protein GRSF1 (guanine-rich RNA sequence binding factor 1) in post-transcriptionally regulating cell-intrinsic BCAA metabolic pathways, ultimately contributing to the pathogenesis of heart failure.
METHODS: We examined GRSF1 expression in the heart tissues of patients with dilated cardiomyopathy and generated mice with cardiomyocyte-specific deletion or overexpression of GRSF1 in vivo to investigate its role in heart failure. The effect of GRSF1 on BCAA homeostasis was assessed through untargeted and targeted metabolomics and mitochondrial function analysis. To elucidate the mechanisms underlying GRSF1-mediated metabolic regulation, we employed mice with cardiomyocyte-specific deletion of BCKDHB (branched-chain keto acid dehydrogenase E1 subunit β) and mice with cardiomyocyte-specific expression of GRSF1 lacking a quasi-RNA recognition motif.
RESULTS: GRSF1 expression was significantly decreased in the hearts of patients with heart failure and failing murine hearts. Cardiomyocyte-specific GRSF1 deletion resulted in cardiac dysfunction, spontaneous progression to dilated cardiomyopathy, and heart failure, accompanied by increased cardiac hypertrophy and fibrosis. Conversely, GRSF1 overexpression attenuated cardiac remodeling and heart failure induced by transverse aortic constriction. Mechanistically, GRSF1 maintained BCAA homeostasis and mitochondrial function by directly interacting with the G-tracts in the coding region of BCKDHB mRNA through a quasi-RNA recognition motif to promote the stability of BCKDHB mRNA at the post-transcriptional level, thereby increasing its protein expression. Functional recovery mediated by GRSF1 overexpression in cardiomyocytes was partially blocked upon cardiac-specific deletion of BCKDHB.
CONCLUSIONS: Our study identified GRSF1 as a cell-intrinsic metabolic checkpoint that maintains cardiac BCAA homeostasis by regulating BCKDHB mRNA turnover. Targeting GRSF1 may offer therapeutic benefits for heart failure and other cardiometabolic diseases requiring BCAA manipulation.

Keywords: BCAA metabolism; GRSF1; RNA-binding protein; heart failure

DOI: https://doi.org/10.1161/CIRCULATIONAHA.125.074700

JACC Heart Fail. 2026 Jan 07. pii: S2213-1779(25)00816-9. [Epub ahead of print] 102886

Hemodynamic Effects of Oral Ketone Ester in Acutely Decompensated Heart Failure With Low Cardiac Output Syndrome.

Marek Sramko, Peter Wohlfahrt, Filip Kissimon, Veronika Svirlochova, Janka Franekova, Josef Kautzner, Vojtech Melenovsky.

Keywords: congestive heart failure; hemodynamics; inotropic agents; ketone bodies; metabolism

DOI: https://doi.org/10.1016/j.jchf.2025.102886

JACC Heart Fail. 2026 Jan;pii: S2213-1779(25)00329-4. [Epub ahead of print]14(1): 102460

"Arising" Above Heart Failure: Sex Differences in Diabetic Cardiomyopathy.

Ersilia M DeFilippis, Eileen O'Meara.

Keywords: diabetic cardiomyopathy; heart failure; obesity; sex differences

DOI: https://doi.org/10.1016/j.jchf.2025.03.021

J Clin Med. 2026 Jan 04. pii: 378. [Epub ahead of print]15(1):

Effects of SGLT2 Inhibitors on Clinical Outcomes, Symptoms, Functional Capacity, and Cardiac Remodeling in Heart Failure: A Comprehensive Systematic Review and Multidomain Meta-Analysis of Randomized Trials.

Olivia-Maria Bodea, Stefania Serban, Maria-Laura Craciun, Diana-Maria Mateescu, Eduard Florescu, Camelia-Oana Muresan, Ioana-Georgiana Cotet, Marius Badalica-Petrescu, Andreea Munteanu, Dana Velimirovici, Nilima Rajpal Kundnani, Simona Ruxanda Dragan.

Background: SGLT2 inhibitors are key therapies in heart failure (HF), but their combined multidomain effects have not been analyzed together. Methods: We conducted a PROSPERO-registered (CRD420251235850) systematic review and meta-analysis of all randomized controlled trials (RCTs) comparing SGLT2i (dapagliflozin, empagliflozin, canagliflozin, sotagliflozin) with placebo in adults with HF, regardless of ejection fraction or diabetes status. We searched PubMed/MEDLINE, Embase, Cochrane CENTRAL, and Web of Science through 1 February 2025. Outcomes were grouped into four domains: (1) clinical events, (2) symptoms/health status (Kansas City Cardiomyopathy Questionnaire, KCCQ), (3) functional capacity (6 min walk distance, peak VO2), and (4) cardiac remodeling/energetics (cardiac MRI, 31P-MRS). We used random-effects models with Hartung-Knapp adjustment and assessed heterogeneity by I2 and prediction intervals. Results: Eleven RCTs with 23,812 patients (HFrEF, HFmrEF, HFpEF, and acute or recently decompensated HF) were included. SGLT2i lowered the risk of cardiovascular death or first HF hospitalization by 23% (HR 0.77, 95% CI 0.72-0.82; p < 0.0001; I2 = 28%; prediction interval 0.68-0.87), with similar effects across ejection fraction, diabetes status, and presentation type. All-cause and cardiovascular mortality dropped by 12% (HR 0.88, 95% CI 0.81-0.96) and 14% (HR 0.86, 95% CI 0.78-0.95), respectively. SGLT2i improved KCCQ-Clinical Summary Score by 4.6 points (95% CI 3.4-5.8; p < 0.0001) and increased the odds of a ≥5-point improvement (OR 1.49, 95% CI 1.32-1.68; NNT = 12). Six-minute walk distance increased by 21.8 m (95% CI 9.4-34.2; p = 0.001), and mechanistic trials showed significant reverse remodeling (ΔLVEDV -19.8 mL, ΔLVEF +6.1%; both p < 0.001). No improvement was observed in myocardial PCr/ATP ratio. Safety was favorable, with no excess ketoacidosis or severe hypoglycemia. Conclusions: This multidomain synthesis demonstrates that SGLT2 inhibitors provide consistent, robust reductions in mortality and hospitalizations, while also delivering early, clinically meaningful improvements across multiple patient-centered domains. These results establish SGLT2i as a foundational component of contemporary HF management.

Keywords: Kansas City Cardiomyopathy Questionnaire; SGLT2 inhibitors; functional capacity; health-related quality of life; heart failure; meta-analysis; multidomain analysis; reverse remodeling; six-minute walk test; systematic review

DOI: https://doi.org/10.3390/jcm15010378