Ranolazine Reduces Remodeling of the Right Ventricle and Provoked Arrhythmias in Rats with Pulmonary Hypertension

Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease that often results in right ventricular (RV) failure and death. During disease progression, structural and electrical remodeling of the right ventricle impairs pump function, creates proarrhythmic substrates, and triggers for arrhythmias. Notably, RV failure and lethal arrhythmias are major contributors to cardiac death in patients with PAH that are not directly addressed by currently available therapies. Ranolazine (RAN) is an antianginal, antiischemic drug that has cardioprotective effects in experimental and clinical settings of left-sided heart dysfunction. RAN also has antiarrhythmic effects due to inhibition of the late sodium current in cardiomyocytes. We therefore hypothesized that RAN could reduce the maladaptive structural and electrical remodeling of the right ventricle and could prevent triggered ventricular arrhythmias in the monocrotaline rat model of PAH. Indeed, in both in vivo and ex vivo experimental settings, chronic RAN treatment reduced electrical heterogeneity (right ventricular-left ventricular action potential duration dispersion), shortened heart-rate corrected QT intervals in the right ventricle, and normalized RV dysfunction. Chronic RAN treatment also dose-dependently reduced ventricular hypertrophy, reduced circulating levels of B-type natriuretic peptide, and decreased the expression of fibrotic markers. In addition, the acute administration of RAN prevented isoproterenol-induced ventricular tachycardia/ventricular fibrillation and subsequent cardiovascular death in rats with established PAH. These results support the notion that RAN can improve the electrical and functional properties of the right ventricle, highlighting its potential benefits in the setting of RV impairment.

Therapeutic effect of prostaglandin E1 in monocrotaline-induced pulmonary arterial hypertension rats

“…Pulmonary artery hypertension (PAH) is a progressive chronic disease with a high mortality rate [1]. PAH has a complex disease mechanism.…”

“…They also cause damage to the pulmonary microvasculature and impact blood flow from heart to lungs [67]. Although current treatments may prolong and improve quality of life of patients, the long-term prognosis for PAH remains poor with survival of 2 to 3 years since the time of diagnosis [1]. …”

Reduced immunoreactivities of B-type natriuretic peptide in pulmonary arterial hypertension rats after ranolazine treatment

“…Level of BNP, a clinically validated biomarker of RV failure, were also significantly decreased in rats treated with RAN, indicating improved RV function [ 24 ]. In in vivo studies using rats with already established PAH and heart remodeling, demonstrated that the acute administration of RAN significantly reduced isoproterenol-induced ventricular tachycardia/ventricular fibrillation and associated cardiovascular death [ 1 ]. The results from these in vivo experiments support that RAN reduces the arrhythmogenic substrate formation in the heart presumably by decreasing cardiac fibrosis.…”

“…Pulmonary arterial hypertension (PAH) is a disease characterized by vascular remodeling and vasoconstriction of the pulmonary arterial circulation that results in right ventricular (RV) failure. The progressive vasculopathy leads to intraluminal narrowing and obstruction of the resistance vasculature leading to sustained increases in pulmonary vascular resistance [ 1 ]. Nevertheless, most common and aggressive form results from wall thickening in small pulmonary arteries, of uncertain aetiology, but often observed in association with systemic diseases.…”

Ranolazine prevents pressure overload‐induced cardiac hypertrophy and heart failure by restoring aberrant Na+ and Ca2+ handling

“…According to the current animal experiments (De Angelis et al, 2016;Liles et al, 2015;Rocchetti et al, 2014;Toischer et al, 2013), ranolazine was effective on cardiac hypertrophy on those acquired models, which were treated shortly after hypertrophic modeling.…”