Life-Long Treatment with Late Sodium Current Blocker Reduces Myocardial Dysfunction and Remodeling in a Mouse Model of Hypertrophic Cardiomyopathy

Abstract

No drugs are capable to prevent phenotype development and adverse cardiac remodeling in hypertrophic cardiomyopathy (HCM). Ranolazine, a late Na+ current blocker, reduced arrhythmogenicity and improved relaxation in cardiomyocytes and trabeculae from HCM patients (Coppini et al., Circulation 2013). Employing a transgenic mouse model carrying the HCM-associated R92Q mutation in the TNNT2 gene, we previously showed that acute in vitro treatment with ranolazine is capable to reverse some electromechanical alterations, including the prolonged kinetics of Ca2+ transients, the higher diastolic [Ca2+] and the increased frequency of arrhythmogenic spontaneous activity (Pioner et al., Biophys J 2014, 106, 644a). Here we employed the same mouse model to assess whether long-term oral treatment with ranolazine since birth is capable to prevent the HCM phenotype and the associated myocardial remodeling. We compared the behavior of WT, R92Q-untreated and R92Q-treated 1 year old mice. Echocardiographic measurements showed that the R92Q-treated in vivo hearts lacked the left ventricular hypertrophy, hypercontractility and diastolic dysfunction found in the R92Q-untreated mice. Gadolinium-contrast magnetic resonance showed that the intramyocardial fibrosis of the R92Q-untreated hearts was largely reduced in the treated mice.Both amelioration of cardiomyocyte function and reduction of extracellular fibrosis may contribute to the positive effect of the long-term treatment with ranolazine that could represent a candidate for preventive treatment of phenotype-negative mutation carriers. Mechanical experiments in intact left and right ventricular trabeculae confirmed the alterations we had previously reported in R92Q-untreated mice compared to WT and showed that those alterations were mostly reversed in the R92Q-treated mice. In the R92Q-treated preparations the inotropic response to isoproterenol was preserved and the occurrence of spontaneous activity was markedly reduced compared to the untreated trabeculae and was comparable to that of WT trabeculae.