The Protective Effects of Ivabradine in Preventing Progression from Viral Myocarditis to Dilated Cardiomyopathy.

Li Yue-Chun,Ge Li-Sha,Lin Cong,Tian Xinqiao,Dai Xiao-Ya,Chen Guang-Yi,Xing Chao,Yang Xiangjun

doi:10.3389/fphar.2016.00408

Abstract

To study the beneficial effects of ivabradine in dilated cardiomyopathy (DCM) mice, which evolved from coxsackievirus B3-induced chronic viral myocarditis. Four-to-five-week-old male balb/c mice were inoculated intraperitoneally with coxsackievirus B3 (Strain Nancy) on days 1, 14, and 28. The day of the first virus inoculation was defined as day 1. Thirty-five days later, the surviving chronic viral myocarditis mice were divided randomly into two groups, a treatment group and an untreated group. Ivabradine was administered by gavage for 30 consecutive days in the treatment group, and the untreated group was administered normal saline. Masson’s trichrome stain was used to evaluate the fibrosis degree in myocardial tissue. The expression levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), collagen I, collagen III and p38-MAPK signaling pathway proteins were detected by Western blot. Electrocardiogram was used to investigate the heart rate and rhythm. The thickness of the ventricular septum and left ventricular posterior wall, left ventricular end diastolic dimension, left ventricular end systolic dimension, left ventricular ejection fractions and fractional shortening were studied by echocardiography. Compared with the untreated chronic viral myocarditis mice, ivabradine significantly increased the survival rate, attenuated the myocardial lesions and fibrosis, improved the impairment of the left ventricular function, diminished the heart dimension, decreased the production of collagen I and collagen III, reduced the expression of the proinflammatory cytokines TNF-α, IL-1β, and IL-6, and lowered the production of phospho-p38 MAPK. The findings indicate the therapeutic effect of ivabradine in preventing the progression from viral myocarditis to DCM in mice with chronic viral myocarditis induced by coxsackievirus B3, is associated with inhibition of the p38 MAPK pathway, downregulated inflammatory responses and decreased collagen expression. Ivabradine appears a promising approach for the treatment of patients with viral myocarditis.

Highlights

Coxsackievirus B3 (CVB3), considered one of the most widespread causative factors of viral myocarditis, induced more than half of the cases of acute myocarditis and one-fourth of the cases of dilated cardiomyopathy (DCM) (Henke et al, 2003)
In the present study, we investigated if ivabradine attenuated inflammation and prevented the progression from viral myocarditis to DCM in mice with chronic viral myocarditis induced by coxsackievirus B3
We propose that the main mechanism by which ivabradine exerts these effects is the reduction in heart rate (HR) because previous animal studies have shown that a reduction in HR by other means, eg, by ablation of the sinoatrial node in cynomolgus monkeys, beneficially affects the heart (Beere et al, 1984; Beere et al, 1992) and most effects of ivabradine can be reversed by atrial pacing (Heusch, 2008)

Summary

Introduction

Coxsackievirus B3 (CVB3), considered one of the most widespread causative factors of viral myocarditis, induced more than half of the cases of acute myocarditis and one-fourth of the cases of dilated cardiomyopathy (DCM) (Henke et al, 2003). Acute viral myocarditis would evolve to the chronic stage if there is no effective treatment, and the worst outcome is DCM and chronic heart failure (HF), even cardiac sudden death. The heart rate (HR) has been shown to be directly related to the risk of cardiovascular disease, HF, and mortality (Opasich et al, 2001). An increased HR is known to be associated with systemic inflammation and cytokines (Sajadieh et al, 2004). With an increased HR, inflammation would be aggravated, and the cardiovascular death rate and hospital admissions because of HF are significantly increased (Sajadieh et al, 2004; Fox et al, 2008; DominguezRodriguez et al, 2012; O Hartaigh et al, 2013)

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