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An Electromechanical Model-Based Study on the Dosage Effects of Ranolazine in Treating Failing HCM Cardiomyocyte
Taiwei Liu1, Mi Zhou2, Fuyou Liang1,3,4
1Department of Engineering Mechanics, School of Ocean and Civil Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240 China.
Insights
Ranolazine effectively treats hypertrophic cardiomyopathy (HCM) heart failure by normalizing cardiomyocyte electromechanical function. A specific threshold dose is crucial, influenced by heart failure severity and ion channel status, for optimal therapeutic outcomes.
Area of Science:
- Cardiology
- Computational Biology
- Pharmacology
Background:
- Hypertrophic cardiomyopathy (HCM) carries a high risk of heart failure (HF) progression.
- Ranolazine shows therapeutic benefits in HCM and HF, but its effects on electromechanical responses and optimal dosage in failing HCM cardiomyocytes require further investigation.
Purpose of the Study:
- To computationally quantify the electromechanical responses of failing HCM cardiomyocytes to ranolazine.
- To determine the impact of ranolazine dosage on outcomes across varying degrees of HF severity.
Main Methods:
- Utilized a computational modeling approach to simulate ranolazine treatment in failing HCM cardiomyocytes.
- Calibrated model parameters against literature data to represent HF severity and ion channel changes.
Main Results:
- Ranolazine effectively inhibited the late Na+ current, alleviating electrophysiological abnormalities and improving diastolic function, with a modest impact on systolic function.
- A threshold dose of ranolazine was identified for significant normalization of the electromechanical profile.
- The effective therapeutic dose was dependent on HF severity and key ion channel status; higher doses offered no additional benefit.
Conclusions:
- Established a threshold dose for ranolazine efficacy in failing HCM cardiomyocytes, influenced by HF severity and ion channel function.
- Findings provide theoretical evidence for ranolazine's mechanism in HCM and highlight the potential for personalized dosing strategies.
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), Ca2+ 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.
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