Key result
LV dilatation in SCN5A variant carriers is linked to ~4-fold higher odds of major arrhythmic events.
Why the study?
Although pathogenic SCN5A variants are definitely associated with dilated cardiomyopathy, the prevalence and clinical significance of ventricular dysfunction and dilatation in carriers of pathogenic or likely pathogenic SCN5A variants had not been systematically characterized.
Cohort (n=196)
Yes
Approximately 20% of SCN5A variant carriers exhibit left ventricular dilatation/dysfunction—which is significantly associated with major arrhythmic events—and 16% have isolated right ventricular abnormalities, supporting routine structural imaging in this population.
Answers are grounded in this paper and cite their sources.
LV dilatation associated with arrhythmic events in SCN5A carriers supports imaging evaluation; hypothesis-generating and requires prospective validation.
Background/introduction Pathogenic variants in the SCN5A gene, encoding the cardiac sodium channel, have definite evidence for an association with dilated cardiomyopathy (DCM). However, the prevalence and clinical significance of ventricular dysfunction and dilatation in carriers of a pathogenic/likely pathogenic variant in SCN5A (SCN5A-P/LP-carriers) have not been systematically characterized. In routine clinical practice, DCM is not commonly recognized in this population. Purpose We aim to determine the prevalence of DCM, and its association with major arrhythmic events (MAEs), in a large multicenter cohort of SCN5A-P/LP-carriers. Methods In this retrospective multicenter study, we reviewed medical records of adult (≥18 years) SCN5A-P/LP-carriers. Clinical characteristics, conventional DCM risk factors (hypertension, alcohol use, coronary artery disease), genetic data, and echocardiographic parameters obtained during routine clinical care, were collected. Patients with severe valvular disease, ischemic cardiomyopathy, or missing echocardiographic data were excluded. DCM and ventricular dilatation/dysfunction were defined using guideline-based reference values. MAEs were defined as sustained ventricular tachycardia, ventricular fibrillation, appropriate ICD therapy, or sudden cardiac death. Results In total, 196 SCN5A-P/LP-carriers were included (73% loss-of-function, 13% gain-of-function, 14% overlap variants). Median age at echocardiogram was 47 years (IQR 31-61); 29% were probands and 55% were male. Left ventricular (LV) dysfunction and/or dilatation was found in 20% of the patients, and isolated right ventricular (RV) dysfunction and/or dilatation was found in 16%. Post-systolic contraction was frequently observed (92%). LV dilatation (OR 3.99, 95% CI 1.44–11.06; p=0.008) was significantly associated with MAEs. Conclusion(s) Approximately one in five SCN5A-P/LP-carriers exhibits LV dilatation and/or dysfunction, whereas 16% of the carriers exhibit isolated RV dilatation and/or dysfunction. LV dilatation was associated with MAEs, although causal directionality remains uncertain. Taken together, these findings support systematic structural assessment in SCN5A variant carriers.Structural abnormalities
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Tuijnenburg et al. (2026) conducted a cohort in Pathogenic or likely pathogenic SCN5A variant carriers (n=196). Left ventricular dilatation in SCN5A pathogenic/likely pathogenic variant carriers vs. Absence of left ventricular dilatation was evaluated on Major arrhythmic events (sustained ventricular tachycardia, ventricular fibrillation, appropriate ICD therapy, or sudden cardiac death) (OR 3.99, 95% CI 1.44-11.06, p=0.008). In SCN5A variant carriers, LV dysfunction/dilatation occurred in 20% and LV dilatation was associated with major arrhythmic events (OR 3.99; 95% CI 1.44-11.06; p=0.008).
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