Non-invasive electrocardiographic imaging in arrhythmia-susceptible patients with the SCN5A founder mutation c.4850_4852delTCT reveals concealed regional activation and repolarization abnormalities

Background

Mutations in the SCN5A gene encoding the cardiac sodium-channel subunit NaV1.5 are associated with heterogeneous and overlapping electrical phenotypes that predispose to ventricular arrhythmia. Standard 12-lead ECGs only provide limited insights into the underying electrophysiological substrate.

Purpose

To characterize regional epicardial ventricular activation and repolarization using ECG-imaging (ECGI) in patients harboring the founder mutation SCN5A c.4850_4852delTCT, encoding for p.(Phe1617del), with heterogeneous proarrhythmic phenotypes.

Methods

ECGI reconstruction of epicardial unipolar electrograms from body-surface potential maps combined with cardiac CT or MRI was performed in 10 familial mutation carriers and 25 controls (3 genotype-negative family members, 22 unrelated individuals). Beta-blockers were interrupted ≥5 half-lives before ECGI.

Results

Mutation-positive patients and controls were comparable by age (44±12 vs. 48±13 years, p=0.38), sex (9/10 vs. 18/25 female, p=0.39), and left-ventricular (LV) ejection fraction (62±5 vs. 61±5 %, p=0.83). Figure 1 shows representative findings from a mutation-positive patient with a history of torsades de pointes. Eligible patients (8/10) underwent late gadolinium enhancement (LGE) MRI 6.5±5.2 years before ECGI. Despite normal QRS durations and absence of LGE, ECGI in mutation-positive patients exhibited prolonged mean (p=0.04) and maximum (p=0.03) epicardial activation times (AT), along with increased maximum AT gradients (p=0.003), particularly in the right ventricle (RV; p<0.0001) (Fig. 2A). Activation patterns were comparable between patients with positive and negative ajmaline tests.

Mutation-positive patients had longer QTc relative to controls (446±19 vs. 423±20 ms; p=0.003), paralleled by longer ECGI-derived epicardial recovery times (RTs; p=0.01). The physiological base-to-apex RT gradient was abolished (Fig. 2B), and both RT duration and dispersion were greater in the RV. While RT gradients (RTG) did not differ between mutation carriers and controls, symptomatic patients (N=5; syncope or documented ventricular tachyarrhythmia) exhibited substantially elevated mean (p=0.02) and maximum (p=0.007) RTGs (Fig. 2C). A maximum RTG of >106 ms/cm distinguished symptomatic from asymptomatic patients.

Premature ventricular complexes (PVCs) in symptomatic patients (N=2/5) originated predominantly from basal segments with shorter repolarization, and PVC propagation was slower than in asymptomatic patients (N=2/5) or controls (N=2/25).

Conclusion

Carriers of the SCN5A founder mutation c.4850_4852delTCT demonstrate concealed abnormalities in ventricular activation and repolarization (RV>LV) that are not captured by standard ECG. Increased RTGs and abnormal PVC propagation may identify individuals at increased arrhythmia risk. These data underscore the translational potential of ECGI for substrate-based risk stratification in SCN5A-related channelopathies.Figure 1Figure 2