In HFpEF, cardiomyocyte Ca²⁺ sensitivity was increased in the left ventricle but reduced in the right ventricle, highlighting distinct mechanosensory remodeling between the two.
HFpEF involves divergent mechanosensory, metabolic, and inflammatory remodeling in the left versus right ventricles, suggesting a need for ventricle-specific therapeutic strategies.
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Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) is a rising global health concern closely linked to metabolic comorbidities such as obesity, metabolic syndrome, type 2 diabetes mellitus (T2D), and hypertension. While the majority of research has focused on left ventricular (LV) dysfunction, right ventricular (RV) dysfunction is prevalent and strongly predicts adverse outcomes. Yet, the pathophysiological mechanisms in the RV, especially in comparison to the LV within the same heart remain poorly understood. Due to anatomical and hemodynamic differences, we hypothesized that stress sensing and intracellular signaling diverge between LV and RV in HFpEF. Methods Paired LV and RV myocardial samples were collected from HFpEF patients and age-matched controls, as well as from obese ZSF1 rats, a well-established preclinical HFpEF model. Cardiomyocyte passive stiffness and Ca²⁺ sensitivity were assessed using skinned fiber techniques. Phosphorylation profiles of key sarcomeric proteins (MyBPC, TnI, MLC2, and titin) and kinase activity (CaMKII, PKG, PKC, and PKA) were evaluated through phospho-specific immunoblotting and kinase assays. Inflammatory cytokines and oxidative stress markers were also quantified. Additional groups were acutely treated with an SGLT2 inhibitor to test therapeutic responsiveness. Results In both HFpEF patients and ZSF1 rats, cardiomyocyte Ca²⁺ sensitivity was increased in the LV but reduced in the RV. Passive stiffness was elevated in both ventricles, with kinase-dependent modulation. CaMKII phosphorylation reduced stiffness selectively in the RV, while PKG exerted beneficial effects in both ventricles. PKC activity was upregulated in the RV, and PKA activation was reduced in the LV. These changes were accompanied by distinct phosphorylation patterns of sarcomeric proteins across ventricles. Notably, PDEs were significantly upregulated in the LV and downregulated in the RV. Inflammatory cytokine levels and oxidative stress markers were significantly higher in the LV compared to the RV in both human and ZSF1 HFpEF samples. Acute SGLT2 inhibitor treatment had only minimal effects on RV stiffness and signaling pathways. Conclusion This study provides compelling evidence for ventricle-specific mechanosensory, metabolic, and inflammatory remodeling in HFpEF, consistently observed in both human and ZSF1 animal models. The findings underscore the need for tailored therapeutic strategies targeting RV and LV separately, moving toward a more comprehensive and individualized management of HFpEF.Study designFor image description, please refer to the figure legend and surrounding text. Partial resultsFor image description, please refer to the figure legend and surrounding text.
Shi et al. (Sun,) reported a other. In HFpEF, cardiomyocyte Ca²⁺ sensitivity was increased in the left ventricle but reduced in the right ventricle, highlighting distinct mechanosensory remodeling between the two.