https://doi.org/10.1007/s00392-025-02625-4
1Institut für Physiologie, Institut für Forschung und Lehre (IFL), Ruhr-Universität Bochum, Bochum Abteilung für Zelluläre und Translationale Physiologie, Molekulare und Experimentelle Kardiologie, Bochum, Deutschland; 2Department of Cardiology Onze Lieve Vrouw Gasthuis Amsterdam AC Amsterdam, NL, Niederlande
Background: Increased diastolic stiffness of the left ventricle (LV) is a significant contributor to heart failure in patients with diabetes mellitus. Diabetes exacerbates LV stiffness through enhanced collagen deposition in the myocardium and elevated passive stiffness of cardiomyocytes, particularly in cases of heart failure with preserved ejection fraction (HFpEF). This study investigates the impact of diabetes mellitus on cardiomyocyte function and beta-adrenergic (Beta-AR) signaling pathways in HFpEF patients with diabetes compared to those without
Methods and Results: Endomyocardial biopsy samples were collected from 30 patients with LVEF >50% and no coronary artery disease, 16 of whom had diabetes mellitus. The biopsies were analyzed for cardiomyocyte function and beta-adrenergic pathway components. Diabetic heart failure patients showed increased diastolic LV stiffness regardless of LVEF. Diabetes was associated with increased cardiomyocyte passive stiffness, increased calcium sensitivity, and reduced maximal force generation. These alterations were reversible with protein kinase A (PKA) treatment, as PKA activity was significantly lower in diabetic HFpEF compared to non-diabetic HFpEF. Furthermore, diabetic HFpEF patients exhibited lower levels of Beta1-AR, Beta2-AR, G protein-coupled receptor kinase 2 (GRK2), and GRK5 compared to non-diabetic HFpEF. Expression of the G-stimulatory (Gs) protein was diminished, while the G-inhibitory (Gi) protein was elevated in diabetic HFpEF relative to non-diabetic HFpEF. These differences are associated with decreased phosphorylation of myofilament proteins (such as myosin light chain, troponin I, myosin-binding protein C, and titin) and calcium-handling proteins (including phospholamban and SERCA2a), along with disruptions in the kinase activities necessary for their phosphorylation. The reduced PKA activity is also influenced by elevated oxidative stress and inflammation in diabetic HFpEF patients, where increased PKA oxidation is associated with impaired cardiomyocyte function and lower PKA expression. Consequently, alterations in kinase oxidation and activity also impacted the oxidation of myofilament proteins, with diabetic HFpEF patients showing reduced levels of myosin-binding protein C and troponin I oxidation compared to non-diabetic HFpEF patients.
Conclusion: Diabetic HFpEF exhibit significant increases in diastolic LV stiffness, driven by enhanced passive stiffness of cardiomyocytes and disturbances in beta-adrenergic signaling. These changes result from diminished PKA activity and the dysregulation of phosphorylation and oxidation in myofilament and calcium-handling proteins. Targeting these pathways may offer therapeutic opportunities to enhance diastolic function in patients with diabetic HFpEF.