bims-hafaim 2025-07-13 papers

Issue of 2025–07–13
four papers selected by
Kyle McCommis, Saint Louis University

J Transl Med. 2025 Jul 10. 23(1): 770

Role of circadian rhythms in heart failure: insights from myocardial energy metabolism.

Pengwei Wang, Binhe Yu, Longjun Liu, Chenglin Zhang, Sizhi Ai.

Heart failure, which is often the final stage of various cardiovascular diseases, remains a major cause of mortality, challenging the efficacy of current therapeutic advancements. Contemporary pharmacological treatments for heart failure aim to mitigate neurohormonal activation, alleviate volume overload, and provide inotropic support, particularly under conditions of hemodynamic instability. Despite these efforts and advancements in medications and medical technology, the mortality rates associated with heart failure continue to be alarmingly high. Recent research has increasingly focused on disruptions in cardiac energy metabolism and their contributions to the development of heart failure. These metabolic disturbances are closely associated with the circadian clock, which is a critical regulator of cardiac energy balance and essential for maintaining heart function. In this review, we summarize how the circadian clock influences cardiac energy homeostasis and how its disruption can lead to detrimental changes in various metabolic pathways in the heart, potentially precipitating heart failure. Furthermore, we propose preventive and therapeutic strategies that focus on correcting the imbalances in myocardial energy metabolism regulated by circadian rhythms. These strategies may present promising avenues for improving the treatment and management of heart failure.

Keywords: Circadian clock; Heart failure; Myocardial energy metabolism; Treatment

DOI: https://doi.org/10.1186/s12967-025-06828-1

Int J Cardiol. 2025 Jul 05. pii: S0167-5273(25)00647-3. [Epub ahead of print]438 133604

GLP-1RA versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: An updated meta-analysis of randomized controlled trials.

Sanchit Duhan, Krishna Prasad Kurpad, Bijeta Keisham, Jurgen Shtembari, Alina Brener, Uday B Kanakadandi, Anuj Garg, Naveed A Adoni, Sanjay S Mehta.

INTRODUCTION: Currently, limited guideline-directed medical therapies are available for heart failure (HF) with preserved and mildly reduced ejection fraction (EF). Both are associated with an increased risk of hospitalization and death, especially in overweight, obese, or diabetic individuals.
METHODS: We searched Cochrane, Embase, and MEDLINE from inception to November 2024. Trials with HF patients randomized for GLP-1RA (glucagon-like peptide-1 receptor agonists) and reported adverse cardiovascular and mortality outcomes were included. Statistical analysis was performed using Cochrane Review Manager 5.4.1.
RESULTS: 4474 patients with HF (preserved and mildly reduced EF) were included in the study. 2278 (50.91 %) received a GLP-1RA [either semaglutide (1914, 84 %) or Tirzepatide (364, 16 %)], and 2196 (49.01 %) received a placebo. GLP-1RA reduced the composite event of cardiovascular mortality and worsening HF exacerbation [139 vs. 194, RR: 0.64 (95 % CI: 0.45-0.92)]. However, on subgroup analysis, there was no significant difference in cardiovascular (CV) deaths [67 vs. 71, RR 0.89 (95 % CI: 0.65-1.24)]. The HF exacerbations were significantly reduced in the GLP-1RA group [83 vs. 138, RR 0.59 (95 % CI: 0.45-0.76)]. Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) was favorable for GLP-1RA [Std Mean Difference (SMD): 7.38 (95 % CI: 5.51-9.26)], reflected by an increase in 6-min walk distance in GLP-1RA groups [SMD: 17.69 (95 % CI: 11.87-23.34)] and contributed by a decrease in body weight in GLP-1RA groups [SMD -9.56 (95 % CI -12.74 to -6.39)].
CONCLUSION: GLP-1RA reduce HF exacerbations and can play a role in reducing hospitalizations, improving patient's functional status, and significantly impacting the global healthcare burden of HF. However, the current data does not indicate any overall mortality benefit.

Keywords: GLP-1 receptor agonist; Heart failure; Meta-analysis; Randomized controlled trials

DOI: https://doi.org/10.1016/j.ijcard.2025.133604

bioRxiv. 2025 Jul 04. pii: 2025.07.01.662580. [Epub ahead of print]

PGM1 deficiency disrupts sarcomere and mitochondrial function in a stem-cell cardiomyocyte model.

Silvia Radenkovic, Graeme Preston, Rohit Budhraja, Irena Muffels, Anna Ligezka, Nathan P Staff, Ron Hrstka, Biijina Balakrishnan, Rameen Shah, Sanne Verberkmoes, Ibrahim Shammas, Inez Bosnyak, Kyle M Stiers, Kent Lai, Lesa J Beamer, Akhilesh Pandey, Eva Morava, Tamas Kozicz.

Background: Phosphoglucomutase-1 (PGM1) plays a pivotal role in glycolysis, glycogen metabolism, and glycosylation. Pathogenic variants in PGM1 cause PGM1-congenital disorder of glycosylation (PGM1-CDG), a multisystem disorder with cardiac involvement. While glycosylation abnormalities in PGM1-CDG are treatable with galactose, cardiomyopathy does not improve suggesting a glycosylation-independent pathomechanism. Recently, mitochondrial abnormalities have been shown in a heart of a PGM1-deficicient patient and PGM1-mouse model. In addition, PGM1 has been associated with LDB3 (ZASP/Cypher), a sarcomeric Z-disk protein also associated with cardiomyopathy. However, the cardiac-specific role of PGM1 remains poorly understood, and targeted therapies for PGM1-related cardiomyopathy are currently lacking.
Methods: Induced pluripotent stem cell-derived cardiomyocytes (iCMs) were generated from PGM1-deficient patient fibroblasts. Multielectrode array (MEA) recordings, untargeted (glyco)proteomics, and pathway analysis were performed to assess functional and molecular changes. Key findings were validated using tracer metabolomics and mitochondrial respiration assays.
Results: PGM1-deficient iCMs exhibited reduced beating frequency, impaired contractility, and prolonged contraction kinetics. Proteomic analyses revealed depletion of Z-disk components, including LDB3. AlphaFold3 structural modeling predicted a direct interaction between PGM1 and LDB3, implicating PGM1 in Z-disk integrity, which was confirmed in vitro . In addition, mitochondrial proteins were severely depleted, prompting us to investigate mitochondrial function. Functional validation confirmed extensive metabolic rewiring, energy depletion, and severely impaired mitochondrial respiration. Finally, the in silico drug repurposing identified possible therapeutic options that could target PGM1-deficient cardiomyopathy.
Conclusion: PGM1 is a key regulator of cardiomyocyte function, linking sarcomeric Z-disk integrity with mitochondrial metabolism. These mechanistic insights offer a foundation for developing targeted therapies for PGM1-CDG and potentially other cardiomyopathies involving Z-disk dysfunction.
Graphical abstract:

DOI: https://doi.org/10.1101/2025.07.01.662580

Eur J Med Res. 2025 Jul 08. 30(1): 592

Impact of SGLT2 inhibitors on myocardial fibrosis in diabetic HFpEF: a longitudinal study.

Arif Albulushi, Kimia M Askari, Ammar M Al-Abedi, Malak A Al-Kulaibi, Murtadha S Hasan, Zahra Hosseini, Mezon T Al-Rahman, Desmond B Tanoh, Amjad S Hasan, Yaseen Al-Helli, Ahmed Basouni.

BACKGROUND: Sodium-glucose co-transporter 2 (SGLT2) inhibitors offer cardiovascular benefits in patients with heart failure, yet their direct effects on myocardial fibrosis-particularly in heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D)-remain underexplored. This study investigates the antifibrotic impact of dapagliflozin in diabetic HFpEF patients, with a focus on its potential as a disease-modifying therapy.
METHODS: In a multicenter, double-blind, placebo-controlled trial, 100 patients with HFpEF and T2D were randomized (1:1) to receive dapagliflozin 10 mg daily or placebo for 12 months. Stratification was performed by baseline extracellular volume fraction (ECV). Myocardial fibrosis was assessed using cardiac MRI-derived ECV at baseline, 6 months, and 12 months. Secondary endpoints included changes in left ventricular mass index (LVMI), HbA1c, and 6-min walk test (6MWT) distance.
RESULTS: Dapagliflozin significantly reduced myocardial fibrosis (mean ΔECV: - 3.5% [95% CI - 4.2 to - 2.8]) compared to placebo (- 0.8% [95% CI - 1.3 to - 0.4]; p < 0.001). Additional benefits included greater reductions in LVMI (- 8.2 g/m2 vs. - 2.1 g/m2; p = 0.002), improved glycemic control (HbA1c: - 1.2% vs. - 0.4%; p = 0.01), and enhanced functional capacity (+ 45 m vs. + 10 m in 6MWT; p = 0.01).
CONCLUSIONS: Dapagliflozin demonstrated a significant reduction in myocardial fibrosis and improvements in cardiac structure, metabolic control, and exercise tolerance in HFpEF patients with T2D. These findings support the evolving role of SGLT2 inhibitors as validated components of guideline-directed therapy, with potential disease-modifying effects through targeted myocardial fibrosis regression.

Keywords: Cardiac MRI; Dapagliflozin; HFpEF; Myocardial fibrosis; SGLT2 inhibitors; Type 2 diabetes

DOI: https://doi.org/10.1186/s40001-025-02834-7