Riociguat for treatment of experimental right heart hypertrophy

Abstract

Rationale Right heart failure is a prevalent mechanism of cardiovascular collapse and distinctly different from left heart failure. Afterload reduction has been the main focus to treat right ventricular (RV) dysfunction, but it cannot be achieved in many cases. A new strategy is to directly target increased RV hypertrophy. In this study we assessed the effects of the sGC stimulator riociguat and the PDE5 inhibitor sildenafil on RV function and RV hypertrophy. Methods Chronic pressure-overload RV hypertrophy was induced by pulmonary artery banding (PAB) in male C57/Bl6 wild-type mice. Drug treatment was started seven days after surgery for the duration of 2 weeks, after which RV morphology and function were assessed using Magnetic Resonance Imaging (MRI) and RV catheterization. Results Three weeks after PAB, placebo-treated mice showed several signs of RV dysfunction as compared to sham-operated mice. PAB led to RV systolic dysfunction, and treatment with sildenafil did neither lead to significant changes in RV end-systolic volume, RV stroke volume nor RV ejection fraction, while treatment with riociguat led to significant improvement in RV end-systolic volume, RV stroke volume and RV ejection fraction. Drug treatment had no effects on either RV hypertrophy or RV/(LV + S) ratio. However, histological assessment of fibrosis showed that sildenafil had no effects on the collagen content while riociguat significantly decreased the amount of collagen. Conclusion Riociguat led to significant improvements in RV function, accompanied by decreased fibrosis and may thus offer for right heart specific treatment in pulmonary vascular diseases.