Effect of Riociguat and Sildenafil on Right Heart Remodeling and Function in Pressure Overload Induced Model of Pulmonary Arterial Banding.

Nabham Rai,Werner Seeger,Hossein Ardeschir Ghofrani,Johannes-Peter Stasch,Norbert Weissmann,Wiebke Janssen,Ralph Theo Schermuly,Baktybek Kojonazarov,Tatyana Novoyatleva,Astrid Wietelmann,Swathi Veeroju,Yves Schymura

doi:10.1155/2018/3293584

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and a rise in right ventricular (RV) afterload. The increased RV afterload leads to right ventricular failure (RVF) which is the reason for the high morbidity and mortality in PAH patients. The objective was to evaluate the therapeutic efficacy and antiremodeling potential of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil and the soluble guanylate cyclase stimulator riociguat in a model of pressure overload RV hypertrophy induced by pulmonary artery banding (PAB). Mice subjected to PAB, one week after surgery, were treated with either sildenafil (100 mg/kg/d, n = 5), riociguat (30 mg/kg/d, n = 5), or vehicle (n = 5) for 14 days. RV function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometry. Both sildenafil and riociguat prevented the deterioration of RV function, as determined by a decrease in RV dilation and restoration of the RV ejection fraction (EF). Although both compounds did not decrease right heart mass and cellular hypertrophy, riociguat prevented RV fibrosis induced by PAB. Both compounds diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Treatment with either riociguat or sildenafil prevented the progression of pressure overload-induced RVF, representing a novel therapeutic approach.

Highlights

Pulmonary arterial hypertension (PAH) involves complex and multifactorial changes in pulmonary vasculature resulting in an increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) [1, 2]
pulmonary artery banding (PAB) resulted in an increase of right ventricular (RV) systolic pressure in Placebo, sildenafil, and riociguattreated mice to the same extent, depicting the accuracy of the surgery to reproduce the extent of constriction of the pulmonary artery (PA) to a predefined magnitude (RVPsys: 24.7 ± 3.081 mmHg for sham versus 58.7 ± 6.534 mmHg for Placebo, 58.23 ± 9.42 mmHg and 60.03 ± 7.42 mmHg for riociguat and sildenafil, resp., P < 0.001) (Figure 1(a))
RV end diastolic volume (RV EDV) was increased in the Placebo group, as compared to sham (RV EDV: 46.3 ± 10.0 μl versus 79.6 ± 13.6 μl, P < 0.001), and this effect was significantly diminished by the treatment with either sildenafil or riociguat (59.9 ± 7.2 μl for sildenafil, P < 0.5 and 44.0 ± 8.3 μl for riociguat, P < 0.001) (Figure 1(c))

Summary

Introduction

Pulmonary arterial hypertension (PAH) involves complex and multifactorial changes in pulmonary vasculature resulting in an increase in pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) [1, 2]. The changes in PVR and PAP lead to an increased right ventricular afterload followed by right ventricular hypertrophy (RVH). RVH can initially compensate for the increased afterload and maintain cardiac output, while sustained pressure overload leads to RV ischemia and decompensation of the RV, culminating in right heart failure [3]. The mortality rate due to right heart failure in patients with PAH remains high and the capability of the right heart to cope with these changes is a critical factor in the survival of PAH patients [4]. The long-term prognosis in PAH remains poor despite recent improvements in diagnosis and treatment [5, 6]

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