Diabetes mellitus aggravates myocardial inflammation and oxidative stress in aortic stenosis: a mechanistic link to HFpEF features.

Francesco Paneni, Máthé Domokos, Peter Haldenwang, Shan Sasidharan, Ferhat Elci, Andrea Kovács, Benjamin Sasko, Francisca Saraiva, Ibrahim Akin, Nazha Hamdani, Ibrahim El-Battrawy, Jan Wintrich, Adelino F Leite-Moreira, Inês Falcão-Pires, Melissa Herwig, Marcel Sieme, Loek van Heerebeek, Andreas Mügge, Zoltán V Varga, Muchtiar Khan, Wolfgang E Schmidt, Péter Ferdinandy

Journal: Cardiovascular diabetology 2025;24(1):203

PMID: 40361188

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Abstract

BACKGROUND

Patients diagnosed with both aortic stenosis (AS) and diabetes mellitus (DM) encounter a distinctive set of challenges due to the interplay between these two conditions. This study aimed to investigate the effects of DM on the left ventricle in AS patients, specifically focusing on the inflammatory response, oxidative stress, and their implications for cardiomyocyte function, titin phosphorylation, and the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway.

METHODS AND RESULTS

Left ventricular myocardial biopsies (in total: n = 28) were obtained from patients with diabetic AS (n = 11) and compared with those from non-diabetic AS patients (n = 17). Enzyme-linked immunosorbent assay (ELISA) demonstrated significantly elevated levels of pro-inflammatory mediators, including high mobility group box protein 1 (HMGB1) and calprotectin, as well as receptors associated with the inflammatory response, such as Toll-like receptor 2 (TLR2), 4 (TLR4), and receptor for advanced glycation endproducts (RAGE). These were correlated with an enhanced NOD-like receptor protein 3 (NLRP3) inflammasome and the release of interleukins (IL) 1, 6, and 18 in diabetic AS patients compared to their non-diabetic counterparts. Additionally, in the diabetic AS cohort, there was an increase in oxidative stress markers (hydrogen peroxide (HO), 3-nitrotyrosine, lipid peroxidation (LPO), oxidative glutathione (GSSG)/reduced glutathione (GSH) ratio) within the myocardium and mitochondria, accompanied by impaired NO-sGC-cGMP-PKG signaling, decreased titin phosphorylation, and increased passive stiffness (F) of cardiomyocytes relative to non-diabetic AS patients. In vitro anti-inflammatory treatment with an IL-6 inhibitor and antioxidant treatment with GSH effectively normalized the elevated F observed in AS patients with DM to levels comparable to the non-diabetic group. Furthermore, treatment with PKG and the sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin also resulted in a reduction of F in cardiomyocytes from diabetic AS patients, although not to the levels observed in non-diabetic AS patients.

CONCLUSION

DM exacerbates inflammation and oxidative stress in AS patients, leading to impaired NO-sGC-cGMP-PKG signaling and increased cardiomyocyte F. These conditions are reminiscent of the pathophysiology of heart failure with preserved ejection fraction (HFpEF). These alterations can be ameliorated through anti-inflammatory and antioxidant therapies, indicating potential therapeutic strategies for diabetic patients suffering from AS.

Address: Medical Faculty, Department of Cellular and Translational Physiology, Institute of Physiology, Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum, Bochum, Germany.; HCEMM-SU Cardiometabolic Immunology Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; Department of Cardiology, OLVG, Amsterdam, The Netherlands.; Department of Medicine I, St. Josef Hospital, UK RUB, Ruhr University Bochum, Bochum, Germany.; Medical Faculty, Department of Cellular and Translational Physiology, Institute of Physiology, Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum, Bochum, Germany.; HCEMM-SU Cardiovascular Comorbidities Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Department of Cardiothoracic Surgery, University Hospital Bergmannsheil Bochum, Bochum, Germany.; Medical Department II, Marien Hospital Herne, Ruhr University Bochum, Bochum, Germany.; Department of Cardiology, Angiology, Haemostaseology and Medical Intensive Care, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary.; In Vivo Imaging Advanced Core Facility, Hungarian Centre of Excellence for Molecular Medicine, Budapest, Hungary.; Department of Cardiology, Center for Translational and Experimental Cardiology (CTEC), University Hospital Zurich and University of Zurich, Zurich, Switzerland.; University Heart Center, University Hospital Zurich, Zurich, Switzerland.; Medical Faculty, Department of Cellular and Translational Physiology, Institute of Physiology, Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum, Bochum, Germany.; Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, Bochum, Germany.; Department of Surgery and Physiology, Cardiovascular R&D Centre-UnIC@RISE, Faculty of Medicine of the University of Porto, Porto, Portugal.; Center for Pharmacology and Drug Research & Development, Semmelweis University, Budapest, Hungary.; Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary.; Pharmahungary Group, Szeged, Hungary.; Medical Faculty, Department of Cellular and Translational Physiology, Institute of Physiology, Molecular and Experimental Cardiology, Institut für Forschung und Lehre (IFL), Ruhr University Bochum, Bochum, Germany. [email protected].; HCEMM-SU Cardiovascular Comorbidities Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary. [email protected].; Department of Cardiology, St. Josef-Hospital, UK RUB, Ruhr University Bochum, Bochum, Germany. [email protected].; Department of Physiology, Cardiovascular Research Institute, Maastricht, The Netherlands. [email protected].

DOI: 10.1186/s12933-025-02748-y

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MeSH Terms: Humans, Oxidative Stress, Male, Female, Aged, Middle Aged, Stroke Volume, Inflammation Mediators, Aortic Valve Stenosis, Ventricular Function, Left, Signal Transduction, Heart Failure, Diabetic Cardiomyopathies, Phosphorylation, Case-Control Studies, Connectin, Cyclic GMP-Dependent Protein Kinases, Myocytes, Cardiac, Nitric Oxide, Inflammasomes, Myocardium, Soluble Guanylyl Cyclase