Effects of ranolazine on the arrhythmic substrate in hypertrophic cardiomyopathy

Area of Science:

• Cardiology
• Computational Biology
• Pharmacology

Background:

• Hypertrophic cardiomyopathy (HCM) is a primary cause of sudden cardiac death in young individuals.
• The antiarrhythmic potential of ranolazine, a late sodium current blocker, in HCM is suggested but not fully elucidated.
• Understanding ranolazine's substrate mechanisms is crucial for optimizing its use in HCM patients.

Purpose of the Study:

• To investigate the substrate mechanisms underlying the safety and antiarrhythmic efficacy of ranolazine in hypertrophic cardiomyopathy.
• To simulate the electrophysiological effects of ranolazine on HCM myocardium with varying degrees of repolarization impairment.
• To identify potential ECG biomarkers associated with ranolazine's antiarrhythmic actions.

Main Methods:

• Utilized computational models of human cardiac tissue and ventricles to simulate HCM electrophysiology.
• Validated models against in vitro and clinical data, employing S1-S2 pacing protocols to assess arrhythmic risk.
• Simulated ranolazine treatment (3µM, 6µM, 10µM) across diverse repolarization heterogeneity and pacing rates, deriving ECGs from biventricular models.

Main Results:

• Ranolazine (10µM) significantly reduced ventricular tachycardia (VT) episodes by 40% in simulations of HCM-remodelled myocardium.
• Optimal antiarrhythmic benefits were observed in models with moderate repolarization impairment (JTc < 370 ms).
• Ranolazine increased VT risk only in models with severe-to-extreme repolarization impairment, highlighting a dose- and condition-dependent effect.

Conclusions:

• Ranolazine's efficacy and safety in HCM are critically linked to the degree of repolarization impairment.
• In moderate impairment, ranolazine may prevent re-entry by reducing refractoriness heterogeneity.
• In severe-extreme impairment, ranolazine's reduction of refractory periods could potentially sustain re-entry, necessitating careful patient selection.