Comparison of the Reverse-Remodeling Effect of Pharmacological Soluble Guanylate Cyclase Activation With Pressure Unloading in Pathological Myocardial Left Ventricular Hypertrophy.

Mihály Ruppert,Gábor Szabó,Shiliang Li,Sven Pleger,Béla Merkely,Niels Grabe,Attila Oláh,Balázs Tamás Németh,Sevil Korkmaz-Icöz,Gábor Veres,Eszter M Horváth,Paige Brlecic,Tamás Radovits,Matthias Karck

doi:10.3389/fphys.2018.01869

Abstract

Background: Pressure unloading induces the regression of left ventricular myocardial hypertrophy (LVH). Recent findings indicate that pharmacological activation of the soluble guanylate cyclase (sGC) – cyclic guanosine monophosphate (cGMP) pathway may also exert reverse-remodeling properties in the myocardium. Therefore, we aimed to investigate the effects of the sGC activator cinaciguat in a rat model of LVH and compare it to the “gold standard” pressure unloading therapy.Methods: Abdominal aortic banding was performed for 6 or 12 weeks. Sham operated animals served as controls. Pressure unloading was induced by removing the aortic constriction after week 6. The animals were treated from week 7 to 12, with 10 mg/kg/day cinaciguat or with placebo p.o., respectively. Cardiac function and morphology were assessed by left ventricular pressure-volume analysis and echocardiography. Additionally, key markers of myocardial hypertrophy, fibrosis, nitro-oxidative stress, apoptosis and cGMP signaling were analyzed.Results: Pressure unloading effectively reversed LVH, decreased collagen accumulation and provided protection against oxidative stress and apoptosis. Regression of LVH was also associated with a full recovery of cardiac function. In contrast, chronic activation of the sGC enzyme by cinaciguat at sustained pressure overload only slightly influenced pre-established hypertrophy. However, it led to increased PKG activity and had a significant impact on interstitial fibrosis, nitro-oxidative stress and apoptosis. Amelioration of the pathological structural alterations prevented the deterioration of LV systolic function (contractility and ejection fraction) and improved myocardial stiffness.Conclusion: Our results indicate that both cinaciguat treatment and pressure unloading evoked anti-remodeling effects and improved LV function, however in a differing manners.

Highlights

Chronic pressure overload (PO) of the left ventricle induces the manifestation of pathological left ventricular (LV) myocardial hypertrophy (LVH)
Our results indicate that both cinaciguat treatment and pressure unloading evoked anti-remodeling effects and improved LV function, in a differing manners
Pathological left ventricular myocardial hypertrophy (LVH) was present after 6 weeks of aortic banding (AB), as evidenced by an increased heart weight (HW), HW/BW, HW/tibial length (TL), LV mass, LV mass index, LVAWs, LVAWd, LVPWd, cardiomyocyte diameter (CD) and β/α-myosin heavy chain (MHC) ratio compared to the corresponding sham group (Figure 2A, Table 1, and Supplementary Table S2)

Summary

Introduction

Chronic pressure overload (PO) of the left ventricle induces the manifestation of pathological left ventricular (LV) myocardial hypertrophy (LVH). Preclinical, as well as clinical, evidence suggests, that termination of the pathological stimulus of PO by a pressure unloading therapy (antihypertensive therapy, aortic valve replacement) leads to the regression of LVH, a phenomenon called myocardial reverse remodeling (Gao et al, 2005; Ruppert et al, 2016; Treibel et al, 2018). This process involves reduction in LV mass, decreased interstitial collagen accumulation, and improvement in both systolic and diastolic function (Ikonomidis et al, 2001; Biederman et al, 2011). We aimed to investigate the effects of the sGC activator cinaciguat in a rat model of LVH and compare it to the “gold standard” pressure unloading therapy

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