*Niklas Hegemann and Uwe Primessnig contributed equally

Heart failure with preserved ejection fraction (HFpEF), projected to account for approximately 50% of HF patients, frequently coincides with right ventricular dysfunction (RVD), which in turn contributes relevantly to HF related mortality. Since underlying mechanisms of RV remodeling and cellular adaptations in this patient cohort are not well understood, we assessed RV cardiomyocyte function in a rat model of metabolically-induced HFpEF.

HFpEF-prone animals (ZSF-1 obese) and control rats (Wistar Kyoto) were fed a high-caloric diet for 13 weeks. In vivo characterization was performed by echocardiography and left-heart catheterization at 22 and 23 weeks, respectively. After sacrifice, organ morphometry, right ventricular (RV) cardiomyocytes were isolated and cardiomyocyte contraction and transients in intracellular Ca²⁺ concentration [Ca²⁺]_i in response to field stimulation were assessed. ZSF-1 obese rats presented with a characteristic HFpEF phenotype featuring left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end-diastolic pressures and E/e´ ratio) and preserved LV ejection fraction (EF). HFpEF rats developed RV dilatation (50% increased end-diastolic area) and mildly impaired RV systolic function (RV EF 42%) with evidence of RV hypertrophy. Isolated RV cardiomyocytes from HFpEF animals revealed preserved cell shortening, albeit peak systolic [Ca²⁺]_i and consequently, [Ca²⁺]_i amplitude were markedly reduced. Consequentially, myofilament sensitivity was increased, whereas contractile kinetics remained largely unchanged. Western blot analysis revealed an increased phosphorylation of cardiac myosin-binding protein C (Ser282 cMyBP-C) but no change in the phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium of HFpEF rats.

RVD in ZSF-1 obese rats with HFpEF is associated with reduced [Ca²⁺]_i amplitudes, and a compensatory increase in myofilament Ca²⁺ sensitivity in isolated RV cardiomyocytes. As such, cardiomyocyte [Ca²⁺]_i homeostasis may present a putative target for prevention or reversal of RVD in HFpEF.