Electrocardiographic Characteristics and SCN5A Mutations in Idiopathic Ventricular Fibrillation Associated With Early Repolarization

Abstract

We found reductions in heart rate and cardiac conduction and loss-of-function mutations in SCN5A in patients with idiopathic ventricular fibrillation associated with early repolarization. These findings support the hypothesis that decreased sodium current enhances ventricular fibrillation susceptibility.

Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias

“…Although it is simplest to ascribe the absence of the BrS-type ECG to the lack of calcium-independent transient outward K + current in the pig heart (24-26), we cannot at this time exclude the role of myocardial fibrosis in the development of ST elevations (27,28). The phenotype of SCN5A E558X/+ pigs is comparable to the BrS-negative/ PCCD-positive/SCD-positive sodium channelopathy cohorts reported by both Watanabe and Zumhagen (9,10). Thus, our data suggest that loss of function of sodium channel mutations may be sufficient to sensitize the myocardium to support fibrillatory activity, but multiple factors, whether genetically determined or acquired, must conspire to produce the repolarization heterogeneities or other perturbations responsible for triggering pathologic VPBs and a BrS-pattern ECG (25)(26)(27)(28)(29)(30)(31).…”

“…However, not all loss-of-function SCN5A mutations associated with ventricular tachycardia or VF exhibit BrS-pattern ECG (9,10). These findings highlight the complex relationship between SCN5A mutations and ventricular arrhythmias and underscore the need to better define the arrhythmic substrate in cardiac sodium channelopathies.…”

Brugada Syndrome and Early Repolarisation: Distinct Clinical Entities or Different Phenotypes of the Same Genetic Disease?

“…48 Subsequently, loss of function mutations was found in the SCN5A gene and L-type calcium channel genes (LTCC, CACNA1C, CACNB2, CACNA2D1) in patients with idiopathic VF and ER. 49,50 Moreover, genetic variants have been identified in the ABCC9 gene, encoding the ATP-binding cassette transporters of ATP-sensitive potassium channels. 51 All these gene mutations associated to ER syndrome might enhance the underlying inward-outward current imbalance responsible for accelerated epicardial repolarisation.…”

A Clinical Approach to Early Repolarization

“…The reported implicated gene mutations involve the KCNJ8 gene (responsible for the ATP sensitive potassium channel Kir6.1 -I KATP current), CACNA1C, CACNB2, CACNA2D1 genes (responsible for the cardiac L-type calcium channel -I Ca.L current), and the SCN5A gene (responsible for the sodium channel -I Na current; Figure 2). [13][14][15][16][17] All of these might enhance the underlying inward-outward current imbalance responsible for accelerated epicardial repolarization as illustrated in Figure 2B. The first report of a patient with the KCNJ8 S422L mutation was a case report of a 14-year-old female who experienced numerous episodes of idiopathic VF unresponsive to β-blockers, verapamil, and multiple antiarrhythmic medications.…”