bims-hafaim 2025-09-07 papers

Issue of 2025–09–07
seven papers selected by
Kyle McCommis, Saint Louis University

Int J Mol Med. 2025 Nov;pii: 183. [Epub ahead of print]56(5):

Alteration of cardiac energetics and mitochondrial function in doxorubicin‑induced cardiotoxicity: Molecular mechanism and prospective implications (Review).

Gong Qing, Chao Huang, Jixiang Pei, Bo Peng.

Doxorubicin (DOX)‑induced cardiotoxicity (DIC) remains a critical challenge in cancer therapy, significantly limiting its use in clinical practice. The underlying mechanisms involve disruptions in cardiac metabolism and mitochondrial dysfunction. The heart relies on mitochondrial oxidative phosphorylation to produce ATP, which is essential for maintaining both contraction and relaxation. DOX disrupts glucose metabolism and fatty acid oxidation, resulting in energy shortages and excessive production of reactive oxygen species (ROS). These ROS contribute to mitochondrial damage, organelle malfunction and eventually cardiomyocyte death. This review describes the pathophysiological aspects of DIC, emphasising the molecular mechanisms underlying mitochondrial dysfunction and metabolic dysregulation in the heart during DIC progression. Additionally, the potential diagnostics, therapeutic interventions and drugs targeting metabolic pathways are summarised, focusing on metabolic modulation, combining non‑pharmacological therapies, such as exercise, fasting and mitochondrial transplantation, and approaches to enhance mitochondrial quality control, offering promising theoretical insights and practical strategies for DIC prevention and management.

Keywords: cardiotoxicity; doxorubicin; metabolism; mitochondrial dysfunction

DOI: https://doi.org/10.3892/ijmm.2025.5624

Circ Res. 2025 Sep 05.

DWORF Gene Therapy Improves Cardiac Calcium Handling and Mitochondrial Function.

Omar Brito-Estrada, Yasuhide Kuwabara, Aaron M Gibson, Keira R Hassel, Michael L Kamradt, Joseph P Verry, N Scott Blair, Michael J Bround, Jiuzhou Huo, Jeffery D Molkentin, Catherine A Makarewich.

BACKGROUND: Calcium (Ca2+) dysregulation is a hallmark of heart failure, impairing excitation-contraction coupling and contributing to pathological remodeling. The SERCA2a (sarco/endoplasmic reticulum Ca2+ ATPase isoform 2a) mediates Ca2+ reuptake into the sarcoplasmic reticulum (SR) during diastole, but its activity declines in failing hearts. DWORF (dwarf open reading frame), a newly identified cardiac microprotein, enhances SERCA2a activity and improves cardiomyocyte Ca2+ cycling and contractility. SR Ca2+ release also influences mitochondrial metabolism and ATP production. Here, we investigated whether DWORF overexpression improves SR Ca2+ handling, augments mitochondrial Ca2+ signaling, and protects against heart failure progression.
METHODS: Transgenic and adeno-associated virus approaches were used to overexpress DWORF in the heart. Mice underwent transverse aortic constriction to model pressure overload-induced heart failure. Cardiac function, mitochondrial metabolism, SR Ca2+ uptake, and remodeling were assessed.
RESULTS: Mitochondria from DWORF transgenic hearts displayed increased basal respiration, maximal respiration, and spare respiratory capacity, correlating with enhanced mitochondrial Ca2+ uptake kinetics. Western blot analysis showed elevated levels of active PDH (pyruvate dehydrogenase) and mitochondrial Ca2+ uniporter expression in DWORF transgenic hearts, supporting a role for DWORF in Ca2+-driven metabolic regulation. Similarly, MyoAAV-mediated DWORF overexpression enhanced mitochondrial respiration and increased levels of active PDH in adult mice. Following TAC, MyoAAV-DWORF-treated mice maintained higher left ventricular function and were protected from further deterioration compared with controls. This benefit was observed when DWORF gene therapy was delivered preventively at the time of pressure overload or after heart failure was already established. DWORF gene therapy also attenuated remodeling, with lower heart weight and lung weight-to-tibia length ratios. Seahorse analysis confirmed sustained mitochondrial improvements in both treatment paradigms.
CONCLUSIONS: DWORF overexpression enhances SR Ca2+ dynamics, improves mitochondrial energetics, and attenuates pathological remodeling and heart failure progression in response to pressure overload. These findings support DWORF as a promising therapeutic target for heart failure.

Keywords: calcium; cardiomyopathy, dilated; genetic therapy; mitochondria; myocytes, cardiac

DOI: https://doi.org/10.1161/CIRCRESAHA.125.326550

J Am Coll Cardiol. 2025 Sep 09. pii: S0735-1097(25)07096-2. [Epub ahead of print]86(10): 696-707

Influence of Type 2 Diabetes on the Effects of Tirzepatide in Patients With Heart Failure and a Preserved Ejection Fraction With Obesity: A Prespecified Stratification-Based Analysis.

SUMMIT Trial Study Group

BACKGROUND: Incretin-based therapies are used to treat type 2 diabetes and obesity, but the presence of diabetes diminishes the magnitude of weight loss produced by these drugs in people with obesity. It is not known whether this attenuated weight change is relevant to the clinical benefits of these drugs in heart failure.
OBJECTIVES: The goal of this study was to assess the influence of diabetes on the efficacy and safety of tirzepatide in the SUMMIT trial.
METHODS: In a double-blind trial, 731 patients with heart failure and a preserved ejection fraction (HFpEF) with a body mass index ≥30 kg/m2 were randomly assigned in a 1:1 ratio to receive tirzepatide (up to 15 mg subcutaneously weekly) or placebo for a median of 104 weeks. History of diabetes was a stratification variable for randomization. The 2 primary outcomes were: 1) time to first cardiovascular death or worsening heart failure event; and 2) change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 52 weeks. Paired cardiac magnetic resonance imaging was used to assess changes in left ventricular mass and paracardiac fat at 52 weeks.
RESULTS: Overall, cardiovascular death or worsening heart failure events occurred less frequently in the tirzepatide group (HR: 0.62; 95% CI: 0.41-0.95; P = 0.026), primarily related to fewer worsening heart failure events. The effect in patients with or without diabetes was similar: HR of 0.64 (95% CI: 0.35-1.15) in patients with diabetes and 0.61 (95% CI: 0.33-1.10) in patients without diabetes (Pinteraction = 0.95). The magnitude of the improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, 6-minute walk distance, quality-of-life scores, and NYHA functional class with tirzepatide was statistically significant and did not differ in patients with and without type 2 diabetes. At 52 weeks, weight loss was less pronounced in patients with type 2 diabetes; patients with diabetes lost 10.4% (95% CI: 8.7%-12.2%) of body weight, compared with 12.9% (95% CI: 11.2%-14.6%) in patients without diabetes (Pinteraction = 0.04). However, patients with or without diabetes showed similar decreases in visceral adiposity (as reflected by the decline in paracardiac fat) and in left ventricular mass.
CONCLUSIONS: Despite less pronounced weight loss, patients with HFpEF, obesity, and type 2 diabetes responded favorably to tirzepatide. This favorable response was reflected by a reduced risk of adverse heart failure outcomes and improved health status, quality of life, and functional capacity, as well as a decrease in left ventricular mass and paracardiac fat, to a degree that was similar to that in patients without diabetes. These observations raise the possibility that the heart failure benefits of incretin-based drugs may not be faithfully estimated by measuring the magnitude of the change in body weight. (SUMMIT [A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity]; NCT04847557).

Keywords: heart failure with preserved ejection fraction; obesity; tirzepatide

DOI: https://doi.org/10.1016/j.jacc.2025.06.058

FEBS Lett. 2025 Jul 22.

Detyrosinated α-tubulin mediates mitochondrial dysfunction and diastolic impairment in heart failure with preserved ejection fraction.

Shunsuke Miura, Tomofumi Misaka, Toranosuke Sekine, Ryo Ogawara, Shohei Ichimura, Yusuke Tomita, Tetsuro Yokokawa, Masayoshi Oikawa, Takafumi Ishida, Yasuchika Takeishi.

Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction, yet its molecular basis remains unclear. Here, we identified detyrosinated α-tubulin as a key cause of mitochondrial dysfunction and impaired mitophagy in HFpEF. In a SAUNA-induced HFpEF mouse model, elevated vasohibin-1 (VASH1) expression was associated with increased detyrosinated α-tubulin. In H9c2 cardiomyocytes, VASH1 overexpression or tubulin tyrosine ligase knockout raised detyrosinated α-tubulin levels, leading to reduced mitochondrial respiration. Detyrosinated α-tubulin on mitochondria impaired Parkin recruitment and polyubiquitination of voltage-dependent anion channel 1, suppressing mitophagy. Cardiac-specific VASH1 expression recapitulated HFpEF-like phenotypes, including diastolic dysfunction, reduced exercise capacity, and decreased mitochondrial complex activity. These findings suggest that α-tubulin detyrosination contributes to HFpEF pathogenesis and may serve as a therapeutic target. Impact statement This study reveals a novel cytoskeletal mechanism linking α-tubulin detyrosination to mitochondrial dysfunction in heart failure with preserved ejection fraction (HFpEF). Our findings may advance understanding of the pathogenesis of HFpEF and provide new molecular targets for therapeutic strategies aimed at preserving mitochondrial quality control in heart failure.

Keywords: heart failure with preserved ejection fraction; mitochondria; mitophagy; vasohibin 1; α‐tubulin detyrosination

DOI: https://doi.org/10.1002/1873-3468.70119

Curr Atheroscler Rep. 2025 Aug 28. 27(1): 85

Salutary Effects of Nutritional Ketosis for the Diseased Human Heart.

Christopher D Crabtree, Alex Buga, Yuchi Han, Orlando P Simonetti, Jeff S Volek.

PURPOSE OF REVIEW: We provide an overview of cardiac metabolism, ketone physiology and terminology, methods of elevating ketones and their effect on cardiac function and disease. We discuss future research directions and speculate what ketogenic strategies may yield optimal effects on the heart and cardiovascular disease.
RECENT FINDINGS: Nutritional ketosis acutely elevates cardiac function (cardiac output, myocardial perfusion, etc.) in healthy people and those with cardiovascular disease in a dose-dependent manner between circulating ketones and cardiac function. Despite therapeutic potential, long-term studies have not been performed. This acute effect is rapid, dose-dependent, and has been seen to be durable for up to 14 days following intervention onset. There are numerous methods to elicit ketogenesis and promote nutritional ketosis. There is growing evidence to suggest that higher ketone levels may offer greater cardiac benefits. It is pertinent to consider what ketone levels to target, and the best methods to safely and feasibly reach those targets over sustained periods of time.

Keywords: Cardiac Function; Cardiovascular disease; Cardiovascular performance; Ketogenic; Ketone ester; Ketones

DOI: https://doi.org/10.1007/s11883-025-01333-8

JAMA. 2025 Aug 31.

Semaglutide and Tirzepatide in Patients With Heart Failure With Preserved Ejection Fraction.

Nils Krüger, Sebastian Schneeweiss, Kenshiro Fuse, Sofiya Matseyko, Sushama Kattinakere Sreedhara, Georg Hahn, Heribert Schunkert, Shirley V Wang.

Importance: Heart failure with preserved ejection fraction (HFpEF) is a major cause of hospitalization, often occurring in patients with cardiometabolic comorbidities such as obesity and type 2 diabetes. Although early trials of semaglutide and tirzepatide have shown promising results in improving symptoms, those findings were based on few clinical events, leaving treatment recommendations uncertain.
Objective: To evaluate the effectiveness and safety of semaglutide and tirzepatide in patients with cardiometabolic HFpEF in clinical practice.
Design, Setting, and Participants: Five cohort studies using national US health care claims data from 2018 to 2024. Two cohort studies emulated the STEP-HFpEF DM (semaglutide) and SUMMIT (tirzepatide) trials to benchmark results. Eligibility criteria were then expanded to evaluate treatment effects in patients typically treated in clinical practice. Finally, a head-to-head comparison of tirzepatide and semaglutide was implemented. Follow-up was up to 52 weeks.
Exposures: New use of semaglutide, tirzepatide, or sitagliptin as a placebo proxy.
Main Outcomes and Measures: The primary end point was a composite of hospitalization for heart failure or all-cause mortality. Negative control outcomes, secondary end points, subgroups, and sensitivity analyses were prespecified. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by fitting proportional hazards models with propensity score weighting to adjust for a comprehensive set of pretreatment patient characteristics.
Results: Benchmarking of the 2 trial emulations demonstrated high agreement on all prespecified metrics. In analyses using expanded eligibility criteria, 58 333 patients were included in the semaglutide vs sitagliptin cohort, 11 257 for tirzepatide vs sitagliptin, and 28 100 for tirzepatide vs semaglutide. Initiators of semaglutide (HR, 0.58 [95% CI, 0.51-0.65]) and tirzepatide (HR, 0.42 [95% CI, 0.31-0.57]) had substantially lower risk of the primary end point compared with sitagliptin. Tirzepatide had no meaningfully lowered risk compared with semaglutide (HR, 0.86 [95% CI, 0.70-1.06]). Negative controls, secondary end points, subgroups, and sensitivity analyses showed consistent results. No substantially increased risk was observed for select safety end points.
Conclusions and Relevance: In patients with cardiometabolic HFpEF, semaglutide and tirzepatide showed more than 40% risk reduction for the composite of hospitalization for heart failure or all-cause mortality compared with a placebo proxy. Tirzepatide showed no meaningful benefit over semaglutide.
Trial Registration: ClinicalTrials.gov Identifiers: NCT06914102, NCT06914154, NCT06914141.

DOI: https://doi.org/10.1001/jama.2025.14092