https://doi.org/10.1007/s00392-025-02737-x
1Ruhr University Bochum Department of Cellular and Translational Physiology Bochum, Deutschland; 2Universitätsklinikum Mannheim GmbH I. Medizinische Klinik Mannheim, Deutschland; 3University Hospital Bergmannsheil Department for Cardiothoracic Surgery Bochum, Deutschland; 4Klinikum der Ruhr-Universität Bochum Medizinische Klinik II, Kardiologie Bochum, Deutschland; 5OLVG Department of Cardiology Amsterdam, Niederlande
Introduction:
Heart failure with preserved ejection fraction (HFpEF) is rising in prevalence, driven in large part by the global increase in metabolic disorders. These conditions contribute to oxidative stress, chronic inflammation, and cardiac remodeling. While most HFpEF research has focused on the left ventricle (LV), right ventricular (RV) dysfunction is also common and associated with increased morbidity and mortality. Despite this, no study has systematically compared long-term structural and functional alterations in both ventricles within the same patient cohort.
Methods:
We examined cardiac biopsies from both the LV and RV of the same hearts from HFpEF patients (LVEF >50%) and healthy controls, alongside parallel analyses in ZSF1 rats a well-established preclinical HFpEF model. We assessed oxidative stress, inflammation, and protein kinase activity using colorimetric assays and real-time PCR. Cardiomyocyte mechanical properties, including passive stiffness, Ca²⁺ sensitivity, and maximal force were evaluated in demembranated single cells. Protein expression and phosphorylation status were analyzed using Western blotting and mass spectrometry.
Results:
HFpEF was associated with elevated oxidative stress and inflammation in both ventricles, with more pronounced changes in the LV. Ca²⁺ sensitivity was significantly increased in LV cardiomyocytes but reduced in the RV. Passive stiffness was elevated in both ventricles, with a greater increase in the LV. Notably, CaMKII activity differentially influenced cardiomyocyte stiffness in the RV versus the LV, suggesting distinct regulatory mechanisms between the chambers. Proteomic analysis revealed compartment-specific disruptions in the myocardial NAD⁺ pool and mitochondrial remodeling. Strikingly, phosphodiesterases (PDEs), including PDE1, 2, 3, 4, and 9 were consistently upregulated in the LV but downregulated in the RV, indicating divergent cGMP/cAMP pathway remodeling.
In vivo, acute treatment with an SGLT2 inhibitor in ZSF1 rats normalized LV stiffness but had minimal impact on RV mechanics. Similarly, in isolated human cardiomyocytes, SGLT2 inhibition significantly reduced cardiomyocyte stiffness in the LV, but showed a limited effect on RV stiffness.
Conclusion:
Our study reveals chamber-specific differences in mechanosensory regulation, inflammatory signaling, and metabolic remodeling between the LV and RV in HFpEF. These findings underscore the necessity of incorporating RV-targeted strategies into HFpEF treatment paradigms. A comprehensive, bi-ventricular approach is critical to improving outcomes in this heterogeneous and increasingly prevalent disease.