Beneficial effects of treatment with a soluble guanylate cyclase stimulator on cardiac function and mitochondrial activity in an animal model of early-stage HFpEF

Abstract Background Targeting cardiac mitochondrial dysfunction represents still an unmet need which could result in improved treatment of chronic heart failure in heart failure with reduce ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). The soluble guanylate cyclase (sGC) stimulator represents a novel mode of action in HFrEF treatment but its impact in HFpEF, especially on myocardial bioenergetics, has not been defined yet. Purpose We aimed to clarify the effects of sGC stimulator on cardiac function in a preclinical murine model of early-stage heart failure which also mimics parts of HFpEF phenotypes. Methods Male obese and lean Zucker fatty and spontaneously hypertensive (ZSF1) rats at 13 weeks of age were treated at 14 weeks of age for 4 weeks with the sGC stimulator given at a dose of 3 mg/kg orally (once daily) in an aqueous suspension with a syringe. Randomized groups: obese group (vehicle, mineral drinking water, n=10), lean group (vehicle, mineral drinking water, n=10) and obese sGC-treated group (n=10). At 17 weeks of age the echocardiographic evaluation was performed. The oxygen consumption rate of mitochondria from left ventricle permeabilized fibres (pfi) was performed using a high-resolution respirometer. Left ventricle tissue samples were examined under a transmission electron microscope. Results Treatment with sGC stimulator for three weeks improved diastolic function (IVRT) of the ZSF1 obese sGC-treated group compared with the obese control group but did not modify others echocardiographic parameters like EF (ejection fraction), fractional shortening or E/e' (E: early diastolic transmitral flow velocity / e': peak early-diastolic annular velocity) (Fig. 1a, 1b, 1c, 1d). The increase in mitochondrial respiration in the obese sGC-treated group was not statistically significant compared to the obese control group, although the levels achieved were similar to those observed in the lean group suggesting a normalization of mitochondrial respiration after treatment (Fig. 2a, 2b). The analysis of mitochondrial ultrastructure by electron microscopy showed a huge heterogeneity in mitochondrial cristae disintegration. We observed significant differences in the percentage of mitochondrial cristae destruction between the three experimental groups. Remarkably, the treatment with sGC stimulator partially restored the mitochondrial cristae destruction of the obese animals towards the lean condition (Fig. 3a, 3b). Conclusions We demonstrate that the treatment with the sGC stimulator elicits beneficial functional and metabolic responses at cardiac level in an animal model of HFpEF when administered at an early-stage of the disease, inducing a significant improvement of diastolic dysfunction and indicating an improvement in mitochondrial respiration ameliorating mitochondrial function by partially restoring the mitochondrial cristae destruction.Figure 1