Enhancing NO pathway improves diastolic function in a hamster model of heart failure with preserved ejection fraction associated with nonalcoholic steatohepatitis

Background and aims Heart failure with preserved ejection fraction (HFpEF) is a complex clinical phenotype frequently associated to the presence of multiple non-cardiac comorbidities including nonalcoholic steatohepatitis (NASH) commonly seen in metabolic syndrome and obesity. In this context, the enhanced production of ROS due to systemic inflammatory state participates to the myocardial structural and functional alterations by limiting nitric oxide bioavailability. We thus evaluated the effect of the phosphodiesterase type 5 (PDE5) inhibitor, vardenafil, on cardiac function and remodeling in a NASH hamster model. Method Male Golden Syrian hamsters were fed for 20 weeks with a free choice diet consisting in free access to control chow diet with normal drinking water or a high fat/high cholesterol diet with 10% fructose enriched drinking water. At 15 weeks hamsters were randomized on E/A ratio and ejection fraction to receive either vardenafil (10mg/kg/day orally for 5 weeks) or vehicle before cardiac and metabolic parameters evaluation. Results After 20 weeks of free choice diet, hamsters presented a large increase in hepatic lipid contents and developed NASH. Echocardiography showed that systolic function was preserved with ejection fraction in normal range whatever the diet. In contrast, E/A ratio was significantly increased in free choice fed hamsters (2,1±0,1 vs 1,4±0,04) and E'/A' ratio inverted when compared to control (0,8±0,02 vs 1,3±0,04). This was associated with a decreased isovolumic relaxation time (IVRT) and an increased E/E' ratio signing relaxation impairment and higher filling pressure, respectively. Moreover, pro-BNP was largely increased in free choice fed hamsters when compared to controls. While vardenafil had no impact on NASH, diastolic function was largely improved as evidenced by the significant decrease in E/A and E/E' ratios along with the increase in E'/A' ratio and IVRT. This effect was corroborated by the normalization of the pro-BNP plasma levels induced by the 5 week-treatment with vardenafil. Conclusion The present data demonstrate that free choice fed hamsters developed NASH and showed the ultimate stage of diastolic dysfunction characterized by a restrictive profile combining compliance and relaxation impairments as well as higher filling pressure. While no effect on NASH was observed, enhancing NO pathway with vardenafil treatment significantly improves diastolic function in this hamster model of HFpEF. Funding Acknowledgement Type of funding sources: None.