bims-hafaim 2026-04-12 papers

Issue of 2026–04–12
five papers selected by
Kyle McCommis, Saint Louis University

Curr Cardiol Rev. 2026 Mar 27.

SGLT2 Inhibitors as Mitochondrial Therapies in Heart Failure: A Bioenergetic Revolution in Cardiometabolic Medicine.

INTRODUCTION: SGLT2 inhibitors improve outcomes in heart failure (HF), yet mechanisms beyond glycemic control remain debated. We synthesize evidence positioning mitochondrial bioenergetics as the central unifying mechanism through which SGLT2 inhibitors exert cardioprotective effects, reframing them as mitochondrial therapies with systemic metabolic benefits.
METHODS: Narrative critical synthesis of preclinical, translational, and clinical data. Sources were identified through database searches (2010-2025) and screened to include studies linking SGLT2 inhibitors to mitochondrial pathways and HF outcomes.
RESULTS: Preclinical studies show improved oxidative phosphorylation, reduced reactive oxygen species, enhanced mitophagy, and a shift toward ketone oxidation. Translational data suggest AMPK/PGC-1α activation and improved myocardial energetics, while randomized trials consistently reduce HF hospitalizations across phenotypes (HFrEF/HFpEF), with early benefits independent of glycemia.
DISCUSSION: Evidence supports a bioenergetic framework in which SGLT2 inhibitors enhance mitochondrial efficiency and systemic metabolic resilience. Nonetheless, human myocardial data remain limited and heterogeneous, warranting further mechanistic trials with imaging or biopsy endpoints.
CONCLUSION: The cardioprotective actions of SGLT2 inhibitors are plausibly mediated, in part, by mitochondrial modulation. This reframes HF as an energy-deficit syndrome and motivates targeted translational studies to validate mitochondrial endpoints and refine patient selection.

Keywords: SGLT2 inhibitors; heart failure.; mitochondrial

DOI: https://doi.org/10.2174/011573403X435290251201095734

iScience. 2026 Apr 17. 29(4): 115217

The interplay of ketones and succinate: Seeking metabolic balance and novel therapeutic strategies in myocardial hypertrophy and heart failure.

Yaling Li, Sheng Quan Liu, Chun Chu, Jun Yang.

The core pathological mechanisms underlying cardiac hypertrophy and heart failure are closely linked to disturbances in energy metabolism. As pivotal metabolic intermediates in the tricarboxylic acid (TCA) cycle, ketone bodies and succinate engage in a dynamic functional interplay that exerts a critical regulatory influence on the progression of cardiovascular diseases. For the first time, this review systematically proposes the conceptual framework of the "ketone body-succinate metabolic axis," integrating recent advances in understanding their roles within cardiovascular system, and comprehensively elucidating the molecular mechanisms, cellular functions, and clinical relevance of this axis in cardiac hypertrophy and heart failure. Ketone bodies not only function as efficient alternative energy substrates under pathological conditions but also confer cardioprotective effects, including anti-inflammation and antioxidation actions. These benefits are mediated through multiple mechanisms, such as histone β-hydroxybutyrylation, suppression of the NLRP3 inflammasome, and activation of the GPR109A receptor. In contrast, succinate accumulates aberrantly under pathological conditions like ischemia and hypoxia, thereby promoting myocardial inflammation, fibrosis, and hypertrophy. These deleterious effects are driven by activation of the succinate receptor SUCNR1, stabilization of hypoxia-inducible factor-1α (HIF-1α), induction of mitochondrial reactive oxygen species (ROS) bursts, and regulation of protein succinylation. Together, ketone bodies and succinate constitute a tightly interconnected "yin-yang balance" regulatory network, characterized by shared metabolic nodes within the TCA cycle and antagonistic modulation of downstream signaling pathways, including inflammation and oxidative stress. Disruption of this dynamic balance represents a key mechanistic driver of disease progression from cardiac hypertrophy to heart failure. Furthermore, this review examines the regulatory influence of ketogenic diets and epigenetic modifications on the ketone body-succinate metabolic axis, and discusses the therapeutic potential and challenges of targeted interventions, such as ketone ester supplementation, SUCNR1 antagonists, and sodium-glucose cotransporter 2 (SGLT2) inhibitors. Collectively, these insights provide a novel conceptual framework and promising research direction for the development of precise metabolic therapies for cardiovascular diseases.

Keywords: Cardiovascular medicine; Human metabolism; Interdisciplinary application studies; Precision medicine; Signal modeling; Therapeutics

DOI: https://doi.org/10.1016/j.isci.2026.115217

JACC Heart Fail. 2026 Apr 01. pii: S2213-1779(26)00146-0. [Epub ahead of print] 103047

From Fuel to Flow: Translating the Beneficial Hemodynamic Effects of Exogenous Ketones in the ICU.

David M Elliott, Jason N Katz, Senthil Selvaraj.

Keywords: heart failure; hemodynamics; intensive care unit; ketones; low cardiac output; metabolism

DOI: https://doi.org/10.1016/j.jchf.2026.103047

bioRxiv. 2026 Mar 14. pii: 2026.03.11.710889. [Epub ahead of print]

Empagliflozin preserves cardiac function and modulates metabolism in a mouse model of Duchenne muscular dystrophy.

Benjamin J Zeidler, Connor Thomas, John P Salvas, Areli Jannes S Javier, Alyssa M Richards, Linda A Bean, Conner C Earl, Akanksha Agrawal, Niharika Narra, Lifan Zeng, Carol A Witczak, Joshua R Huot, Il-Man Kim, Meena S Madhur, Mark C Kowala, Larry W Markham, Craig J Goergen, Steven S Welc.

Duchenne muscular dystrophy (DMD) is a fatal genetic disorder characterized by skeletal muscle degeneration and cardiomyopathy without a cure. This study examined the therapeutic potential of the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) on cardiac function in the dystrophin-deficient mdx mouse model of DMD. Male mice were fed control chow or EMPA-containing chow (∼25 mg/kg/day), and cardiac function was evaluated longitudinally by four-dimensional ultrasound imaging. EMPA did not alter left ventricular mass or chamber volume but preserved ejection fraction (EF) for 12 weeks, maintained significantly higher EF through 24 weeks, and attenuated global impairment of systolic and diastolic myocardial deformation. These functional improvements were accompanied by reduced cardiomyocyte hypertrophy and decreased expression of cardiac stress genes. EMPA reduced mitochondrial DNA damage, increased mitochondrial DNA copy number, and induced transcriptional signatures consistent with enhanced fatty acid and ketone metabolism, contributing to increased myocardial ATP content. Systemically, EMPA improved body mass trajectory, preserved relative lean mass, enhanced skeletal muscle torque, and did not adversely affect renal function. Together, these findings demonstrate that EMPA improves cardiac performance and mitochondrial integrity while enhancing myocardial energy availability in mdx mice, supporting SGLT2 inhibitors as a promising therapeutic strategy for individuals with DMD.

DOI: https://doi.org/10.64898/2026.03.11.710889

bioRxiv. 2026 Apr 05. pii: 2026.04.01.715996. [Epub ahead of print]

Mitochondrial and Cardiolipin Adaptations to Ventricular Assist Device Support in Pediatric Versus Adult Failing Myocardium.

Caitlyn S Conard, Mariana Casa de Vito, Obed O Nyarko, Raleigh L Jonscher, Elisabeth K Phillips, Kathryn C Chatfield, Amrut V Ambardekar, Jordan Hoffman, Scott R Auerbach, Matthew L Stone, Carmen C Sucharov, Brian L Stauffer, Genevieve C Sparagna, Shelley D Miyamoto.

Background: Ventricular assist devices (VADs) are used as treatment for end-stage heart failure in children and adults. We previously demonstrated decreased mitochondrial function and changes in cardiolipin, a mitochondrial phospholipid, in explanted pediatric and adult failing hearts. In this study, we tested the hypothesis that VAD unloading of failing hearts leads to positive changes in myocardial cardiolipin in both pediatric and adult hearts.
Methods: Ventricular tissue was collected from the same patient at time of VAD implantation and at transplant. Ejection fraction (EF), left ventricular internal diameter at end-diastole (LVIDd) and brain natriuretic peptide (BNP) were assessed pre- and post-VAD. Cardiolipin species from paired VAD core and explants were quantified using liquid chromatography mass spectrometry. Mitochondrial respiration was measured in ventricular tissue pre- and post-VAD in paired pediatric samples using the Oroboros Oxygraph-2k.
Results: VAD support led to increased EF and decreased LVIDd and BNP. The predominant cardiolipin species in cardiac mitochondria, tetralinoleoylcardiolipin, was positively remodeled in pediatric post-VAD myocardium, while adult post-VAD myocardium demonstrated significantly increased total cardiolipin and decreased oxidized cardiolipin but did not demonstrate the tetralinoleoylcardiolipin remodeling seen in pediatric hearts. In pediatric patients, VAD support resulted in significant increases in Complex I+II activity, and a trend toward increases in Complex I activity.
Conclusion: Our data demonstrate age-related differences in VAD-associated cardiolipin remodeling and suggest that improved mitochondrial function in pediatric VAD-supported hearts could be related to increased tetralinoleoylcardiolipin.

DOI: https://doi.org/10.64898/2026.04.01.715996