Ranolazine antagonizes catecholamine-induced dysfunction in isolated cardiomyocytes, but lacks long-term therapeutic effectsin vivoin a mouse model of hypertrophic cardiomyopathy

Abstract

Ranolazine improved tolerance to high workload in mouse HCM cardiomyocytes, not by blocking late Na(+) current, but by antagonizing β-adrenergic stimulation and slightly desensitizing myofilaments to Ca(2+). This effect did not translate in therapeutic efficacy in vivo.

Ranolazine Prevents Phenotype Development in a Mouse Model of Hypertrophic Cardiomyopathy

“…Ranolazine has a significant β-blocking effect when the plasma concentration is >13 μmol/L, 47 much higher than the clinically relevant concentration range (from 2 to 5 μmol/L). Indeed, Flenner et al 46 reached very high plasma ranolazine concentrations in their treated mice (>20 μmol/L), so a β-blocking effect observed with their protocol is expected, but scarcely clinically relevant. In our ranolazine-treated male mice, plasma ranolazine concentration ranged from 2.5 to 5.5 μmol/L (average 4 μmol/L).…”

“…In human cardiomyocytes from adult patients with HCM, however, we previously showed that similar electric abnormalities (including increased I NaL ) are also present in cardiomyocytes from patients carrying MyBPC mutations, 10 and the benefits of acute ranolazine administration seemed independent from the presence of a specific mutation. The cardiac pathological phenotype of the MyBPC mouse model in the work by Flenner et al 46 was rather mild, with slight diastolic dysfunction, minimal LV hypertrophy, and little cellular abnormalities, 33 and provided a lesser approximation of advanced human disease as observed in patient samples, 10 as compared with the R92Q model. Moreover, Flenner et al started treatment in young adult mice of 2 months of age when disease phenotype was already fully expressed, 33 while we initiated treatment right after birth, before HCM phenotypic expression.…”

“…A recent study by Flenner et al 46 showed that a 6-month treatment with ranolazine did not reduce cardiac hypertrophy or diastolic dysfunction in an MyBPC -mutant HCM mouse model. The lack of effects of ranolazine in that work stems from the absence of a significant increase of I NaL in cardiomyocytes from MyBPC -mutant mice as compared with WT littermates, 46 at variance with the R92Q-TnT model.…”

“…A recent study by Flenner et al 46 showed that a 6-month treatment with ranolazine did not reduce cardiac hypertrophy or diastolic dysfunction in an MyBPC -mutant HCM mouse model. The lack of effects of ranolazine in that work stems from the absence of a significant increase of I NaL in cardiomyocytes from MyBPC -mutant mice as compared with WT littermates, 46 at variance with the R92Q-TnT model. In human cardiomyocytes from adult patients with HCM, however, we previously showed that similar electric abnormalities (including increased I NaL ) are also present in cardiomyocytes from patients carrying MyBPC mutations, 10 and the benefits of acute ranolazine administration seemed independent from the presence of a specific mutation.…”

“…In a recent work by Flenner et al, 46 mice carrying an MyBPC mutation related to HCM were treated with ranolazine, and most of the observed effects of the drug in that model were found to be related with a significant inhibition of β-adrenergic receptors. Ranolazine has a significant β-blocking effect when the plasma concentration is >13 μmol/L, 47 much higher than the clinically relevant concentration range (from 2 to 5 μmol/L).…”