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

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.

Low‐intensity pulsed ultrasound attenuates cardiac inflammation of CVB3‐induced viral myocarditis via regulation of caveolin‐1 and MAPK pathways

“…8 In addition, recent studies indicated that p38 MAPK and ERK signallings played pivotal roles in the pathogenesis of viral myocarditis, and suppressing these signallings led to an inhibition of cardiac injury and benefited the recovery from viral myocarditis. [23][24][25] In our study, we also found that p38 MAPK and ERK signallings were activated during viral myocarditis, while LIPUS treatment suppressed these signallings and attenuated the excessive inflammatory response during the disease course. Intriguingly, some studies showed that MAPK signallings could be further activated after receiving mechanical stimulation from LIPUS, which were contrary to our findings.…”

MicroRNA‑381 protects myocardial cell function in children and mice with viral myocarditis via targeting cyclooxygenase‑2 expression

“…Coxsackievirus B3 (CVB3) is one of the most common viruses that cause VM (2). VM can develop into acute heart failure (3,4). According to available clinical studies, the mortality rate of VM in young people is as high as 21%, and sudden deaths caused by VM or fatal ventricular arrhythmias in children account for about 20% (5,6).…”

Safety profile and efficacy of ivabradine in heart failure due to Chagas heart disease: a post hoc analysis of the SHIFT trial

“…19,20 Also, ivabradine in chronic viral myocarditis in mice significantly increased the survival rate; attenuated the myocardial lesions and fibrosis; improved the impairment of the LV function; diminished the heart dimension; decreased the production of collagen I and collagen III; reduced the expression of the proinflammatory cytokines tumour necrosis factor alpha and interleukins 1β and 6; and lowered the production of phospho-p38 MAPK. 21 In HF patients, ivabradine increased LV ejection fraction and led to a significant reduction of tumour necrosis factor alpha serum levels and a reconstitution of circulating dendritic cells. 22 Furthermore, ivabradine reduced microvascular derangements in experimental sepsis and improved endothelial function in patients undergoing percutaneous coronary intervention, 23,24 The mortality observed in our study (60%) in ChD HF is much higher in comparison with that of the SHIFT overall population (~17.5%) and of the recent PARADIGM-HF trial (~15%) at 750 day follow-up.…”

“…Concerning the myocarditis, beneficial pleiotropic effects of ivabradine beyond HR were reported in experimental coxsackievirus B3 myocarditis partially mediated by the inhibition of both the production of proinflammatory cytokines and the synthesis of NO by iNOS 19, 20. Also, ivabradine in chronic viral myocarditis in mice significantly increased the survival rate; attenuated the myocardial lesions and fibrosis; improved the impairment of the LV function; diminished the heart dimension; decreased the production of collagen I and collagen III; reduced the expression of the proinflammatory cytokines tumour necrosis factor alpha and interleukins 1β and 6; and lowered the production of phospho‐p38 MAPK 21. In HF patients, ivabradine increased LV ejection fraction and led to a significant reduction of tumour necrosis factor alpha serum levels and a reconstitution of circulating dendritic cells 22.…”