Electrocardiographic Features in SCN5A Mutation-Positive Patients with Brugada and Early Repolarization Syndromes: A Systematic Review and Meta-Analysis

Background: Early repolarization syndrome (ERS) and Brugada syndrome (BrS) are both J-wave syndromes. Both can involve mutations in the SCN5A gene but may exhibit distinct electrocardiographic (ECG) differences. The aim of this systematic review and meta-analysis is to investigate possible differences in ECG markers between SCN5A positive patients with ERS and BrS. Methods: PubMed and Embase, were searched from their inception to October 20th, 2021 for human studies containing the search terms “SCN5A” and “variant” and “early reporlarization” or “Brugada”, with no language restrictions. Results: A total of 328 studies were identified. After full text screening, 12 studies met our inclusion criteria and were included in this present study. 104 ERS patients (mean age: 30.86 ±14.45) and 2000 BrS patients (mean age: 36.17 ±11.39) were studied. Our meta-analysis found that ERS patients had a significantly lower heart rate (standardized mean difference [SMD]a= 14.69, 95% confidence interval [CI] = 21.43, 7.94, P = 0.0001), shorter QRS duration (SMD = 13.90, 95% CI = 17.16, 10.65, P = 0.0001) and shorter QTc [corrected QT interval] (SDM = 21.52, 95% CI = 33.77, 9.26, P = 0.0006) than BrS patients. Conclusion: BrS patients with positive SCN5A mutations exhibited prolonged QRS, indicating conduction abnormalities, whereas ERS patients with positive SCN5A mutations showed normal QRS. By contrast, whilst QTc intervals were longer in BrS than in ERS SCN5A positive patients, they were within normal limits. Further studies are needed to examine the implications of these findings for arrhythmic risk stratification.

Local areas of earlier repolarization cause epicardial repolarization heterogeneity in patients with apparently idiopathic ventricular fibrillation

Background Sudden cardiac arrest is often due to ventricular fibrillation (VF). In 5–10% of cases, no cause can be identified despite extensive cardiac examination, hence the designation idiopathic VF. Early repolarization with down sloping ST segments has been previously identified in patients with idiopathic VF. Early repolarization may increase repolarization heterogeneity with steep local repolarization time gradients, and thus form a substrate for idiopathic VF. Purpose To study the presence of local earlier repolarization and increased repolarization dispersion in idiopathic VF patients with noninvasive electrocardiographic imaging (ECGI). Methods A validated, non-commercial, potential-based formulation of ECGI was performed in 17 patients with idiopathic VF and 10 controls with no structural or electrical abnormalities. The ECGI measurement consisted of a body surface potential map with 184–256 electrodes in combination with a CT scan to obtain the torso and heart geometries. ECGI provided local epicardial repolarization times (RT) and RT isochrones. We determined the 1st (RT1%) and 99th percentile (RT99%) of RTs, the total epicardial RT dispersion (ERD: RT99%-RT1%), and the mean RT. Heart-rate corrected QT (QTc), TpTe intervals, and presence of the ER pattern were determined from the 12-lead ECG. All metrics were normalized to the body-surface Q. Results QTc and TpTe did not differ between the two groups (P=0.40 and P=0.83, respectively, Figure 1, panel A). One (10%) control subject and three (17.6%) idiopathic VF patients showed an ER pattern on the 12-lead ECG, with a down sloping ST segment only in 2/4 of the latter. With ECGI, the mean RT was similar between the groups (P=0.31), but the ERD was significantly increased in patients with idiopathic VF (P=0.01, figure 1, panel B). Moreover, RT1% was significantly lower in idiopathic VF patients in comparison to the controls (P=0.002), whereas the RT99% did not differ significantly (P=0.40). Subgroup analysis between ER positive and negative patients did not yield significantly different RT results. Conclusion Noninvasive ECGI, in contrast to the 12-lead ECG, revealed a wider range of epicardial RTs in patients with idiopathic VF, implying increased repolarization heterogeneity. This heterogeneity is caused by areas of earlier repolarization. Our data indicate the value of noninvasively diagnosing these repolarization abnormalities, and suggest promising potential value of the 1st percentile of RT to identify idiopathic VF patients with true early repolarization. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation Figure 1

Electrophysiological characterization of the hERG R56Q LQTS variant and targeted rescue by the activator RPR260243

Human Ether-à-go-go (hERG) channels contribute to cardiac repolarization, and inherited variants or drug block are associated with long QT syndrome type 2 (LQTS2) and arrhythmia. Therefore, hERG activator compounds present a therapeutic opportunity for targeted treatment of LQTS. However, a limiting concern is over-activation of hERG resurgent current during the action potential and abbreviated repolarization. Activators that slow deactivation gating (type I), such as RPR260243, may enhance repolarizing hERG current during the refractory period, thus ameliorating arrhythmogenicity with reduced early repolarization risk. Here, we show that, at physiological temperature, RPR260243 enhances hERG channel repolarizing currents conducted in the refractory period in response to premature depolarizations. This occurs with little effect on the resurgent hERG current during the action potential. The effects of RPR260243 were particularly evident in LQTS2-associated R56Q mutant channels, whereby RPR260243 restored WT-like repolarizing drive in the early refractory period and diastolic interval, combating attenuated protective currents. In silico kinetic modeling of channel gating predicted little effect of the R56Q mutation on hERG current conducted during the action potential and a reduced repolarizing protection against afterdepolarizations in the refractory period and diastolic interval, particularly at higher pacing rates. These simulations predicted partial rescue from the arrhythmic effects of R56Q by RPR260243 without risk of early repolarization. Our findings demonstrate that the pathogenicity of some hERG variants may result from reduced repolarizing protection during the refractory period and diastolic interval with limited effect on action potential duration, and that the hERG channel activator RPR260243 may provide targeted antiarrhythmic potential in these cases.

Androgens, QT, Sex and Ventricular Repolarization: A Double-Edged Sword

The prevalence and incidence of cardiac pro-arrhythmic disorders are often influenced by sex due to specific effects on the QT interval. Androgens shorten QT, which may be protective against acquired long QT syndromes and their related arrhythmias in men such as torsade de pointes (TdP). On the other hand, androgens can potentiate Brugada and early repolarization syndromes, which are most prevalent in men. In this case series, we highlight four male patients with aborted SCD in the setting of abnormal testosterone status; two patients with TdP in a setting of testosterone deprivation (of which one drug-induced) and 2 patients with ventricular fibrillation associated with exogenous androgenic booster (Tribulus terrestris) intake. From this case series, we review the current available literature of the effects of androgen as a double-edged sword on the QTc interval and emphasize the importance of QTc monitoring in this subset of patients.