A combination of quinidine/mexiletine reduces arrhythmia in dilated cardiomyopathy in two patients with R814W SCN5A mutation

Abstract

SCN5A gene mutations are described in 2% of patients with dilated cardiomyopathy (DCM) and different rhythm disturbances, including multifocal ectopic Purkinje-related premature contractions. Recent data indicate that sodium channel blockers are particularly effective monotherapy in carriers of the R222Q SCN5A variant. Our purpose is to describe the effectiveness of antiarrhythmic treatment in a family with genetically determined arrhythmogenic DCM associated with the R814W variant in the SCN5A gene. We examined a family with arrhythmogenic DCM (multifocal ectopic Purkinje-related premature contractions phenotype, atrial tachyarrhythmias, automatism, and conduction disorders) and described antiarrhythmic treatment efficacy in heart failure symptoms reduction and myocardial function improvement. We found a heterozygotic mutation R814W in SCN5A by whole exome sequencing in the proband and confirmed its presence in all affected subjects. There were two sudden cardiac deaths and one heart transplantation among first-degree relatives. The 58-year-old father and his 37-year-old daughter had full spectrum of symptoms associated with R814W SCN5A mutation. Both had implanted cardioverter defibrillator. In the father, adding mexiletine to quinidine therapy reduced ventricular arrhythmia (50-60% → 6-8% of whole rhythm) and reverted long-standing atrial fibrillation to sinus rhythm. In the daughter, mexiletine and overdrive pacing were effective in ventricular arrhythmia reduction (25% → 0.01%). Because of a growing number of atrial fibrillation recurrences, a reduced dose of quinidine (subsequently flecainide) was added, resulting in arrhythmia significant reduction. In both cases, antiarrhythmic effectiveness correlated with clinical improvement. In SCN5A R814W-associated DCM, a combination of Class I antiarrhythmics and overdrive pacing is an effective treatment of severe ventricular and atrial arrhythmias.

Titin-Related Dilated Cardiomyopathy: The Clinical Trajectory and the Role of Circulating Biomarkers in the Clinical Assessment

“…Hearts of TTN tv-positive DCM patients have thinner LV walls and lower indexed LV mass compared to TTN tv-negative controls [ 6 ], while in arrhythmogenic DCM related to SCN5A variants, myocardial thickness is normal [ 45 , 46 ]. It results in higher LV wall stress and release of NT-proBNP and is associated with an increased risk of VA [ 6 , 15 , 47 ].…”

Network Pharmacology-based Systematic Analysis of Molecular Mechanisms of Dingji Fumai Decoction for Ventricular Arrhythmia

“…SCN5A plays a vitally important role in the cardiac electrical conduction and arrhythmic risk, a study provided a new effective therapy to reduce arrhythmia through downregulating the expression of SCN5A 53 . Coincidentally, there is a study reported that a combination of quinidine/mexiletine reduces arrhythmia in patients with SCN5A gene mutation 54 . CALM1…”

Effectiveness and safety of mexiletine in patients at risk for (recurrent) ventricular arrhythmias: a systematic review

“…Nine studies ( n = 23 patients) report on mexiletine interacting with other drugs. 95 , 150 , 158 , 182 , 183 , 186 , 216 , 221 , 222 The majority [ n = 5 (56%) studies, 7 (30%) patients] of those studies report an interaction with theophylline. 95 , 158 , 182 , 183 , 216 Clearance of theophylline is reduced as a consequence of CYP1A2 inhibition by mexiletine, which results in increased (possibly toxic) theophylline blood levels.…”