Distinct Mechanosensory and Metabolic Dysregulation in Left and Right Ventricles in HFpEF: Implications for Comprehensive Treatment Strategies

Introduction: The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, in parallel with the rise in metabolic disorders such as obesity, metabolic syndrome, type 2 diabetes mellitus (T2DM), and salt-sensitive arterial hypertension. These metabolic disorders are all associated with oxidative stress and inflammation. While research has traditionally focused on the left ventricle (LV) in HFpEF, it is important to note that right ventricular (RV) dysfunction is also common and has been linked to higher mortality rates. However, no study has comprehensively characterized the long-term changes in RV structure and function within the same patient cohort.

Methods: In this study, we compared HFpEF patients ( EF>50%) with healthy controls, as well as ZSF1 rats with HFpEF with control rats. Human cardiac biopsies from both the LV and RV of the same heart were analyzed. We measured protein kinase activities, oxidative and inflammation parameters using colorimetric assays and real-time PCR gene expression. Additionally, we measured Ca2+ sensitivity, stiffness, and force generation capacity in single skinned cardiomyocytes. Protein expression and phosphorylation were assessed using Western blot and mass spectrometry.   

Results: Our findings showed that HFpEF biopsies exhibited higher inflammation and oxidative stress in both the LV and RV, with the LV showing higher levels than the RV. Ca2+ sensitivity was elevated in the LV and reduced in the RV compared to controls. Furthermore, we observed distinct mechanical regulation of cardiomyocyte stiffness in both ventricles. Cardiomyocyte stiffness was increased in both the LV and RV in HFpEF patients, with a more pronounced increase in the LV. Additionally, the activity of CaMKII had differential effects on cardiomyocyte passive stiffness in the RV compared to the LV, likely due to distinct regulatory mechanisms. Mass spectrometry analysis revealed significant disruptions in the myocardial NAD pool, suggesting different metabolic remodeling and mitochondrial dysfunction between the RV and LV. In our in vivo study, we found that acute treatment with an SGLT2 inhibitor in ZSF1 rats with diastolic dysfunction reduced LV stiffness to control levels, but had minimal effect on RV stiffness.      

Conclusion: These findings emphasize the importance of considering RV function when developing and recommending treatments for HFpEF, underscoring the necessity for a more comprehensive approach to managing this complex condition.