An Electromechanical Model-Based Study on the Dosage Effects of Ranolazine in Treating Failing HCM Cardiomyocyte.

BACKGROUND AND OBJECTIVE

Hypertrophic cardiomyopathy (HCM) is associated with a significant risk of progression to heart failure (HF). Extensive experimental and clinical research has highlighted the therapeutic benefits of ranolazine in alleviating electrophysiological abnormalities and arrhythmias in the context of HCM and HF. Despite these findings, there is a shortage of studies examining the electromechanical responses of failing HCM cardiomyocytes to ranolazine and the impact of ranolazine dosage on outcomes across varying degrees of HF. This study aims to systematically address these issues.

METHODS

A computational modeling approach was utilized to quantify alterations in electromechanical variables within failing HCM cardiomyocytes subsequent to ranolazine treatment. The model parameters were calibrated against extant literature data to delineate the spectrum of HF severities and the changes in ion channels following the administration of various doses of ranolazine.

RESULTS

The inhibition of the augmented late Na current in failing HCM cardiomyocyte with an adequate amount of ranolazine was found to be effective in alleviating electrophysiological abnormalities (e.g., prolongation of action potential (AP), Ca overload in diastole), which contributed to improving the diastolic function of the cardiomyocyte, albeit with a modest negative effect on the systolic function. A threshold drug dose was identified for achieving a significant normalization of the overall electromechanical profile. The threshold drug dose for effective therapy was observed to be contingent upon the severity of HF and the status of certain key ion channels. Furthermore, it was determined that an increase of the drug dose beyond the threshold did not yield substantial additional improvements in the principal electromechanical variables.

CONCLUSIONS

The study demonstrated the presence of a threshold dose of ranolazine for effective treatment of failing HCM cardiomyocyte, and further established that this threshold is influenced by the severity of HF and the functional status of key ion channels. These findings may serve as theoretical evidence for comprehending the mechanisms underlying ranolazine's therapeutic efficacy in treating failing HCM hearts. Moreover, the study underscores the potential clinical value of personalized dosing strategies.

SUPPLEMENTARY INFORMATION

The online version contains supplementary material available at 10.1007/s12195-025-00842-5.