Dilated cardiomyopathy in SCN5A variant carriers
F Tuijnenburg, H A C M Bon, R Walsh, C A Remme, C R Bezzina, A S AminAbstract
Background
Dilated cardiomyopathy (DCM) has been associated with pathogenic variants in SCN5A, which encodes the cardiac sodium channel. The National Human Genome Research Institute (ClinGen) classifies this association as definitive, yet the prevalence of DCM in carriers of a (likely-)pathogenic variant in SCN5A (SCN5A-LP/P) remains unknown and the underlying mechanism is unclear.
Purpose
To determine the prevalence of DCM in a large cohort of SCN5A-LP/P carriers.
Methods
In this retrospective study, clinical characteristics, echocardiographic parameters, and conventional DCM risk factors (e.g., hypertension, alcohol use, coronary artery disease) were collected in all SCN5A-LP/P carriers. Patients with severe valvular disease, severe ischemic heart disease, or missing echocardiographic data were excluded. Occurrence of arrhythmic events during follow-up was also recorded.
Results
A total of 182 carriers were included; 38 (19%) showed signs of DCM, with 17 (11%) having reduced LVEF, 18 (12%) LV dilatation, and 3 (2%) both. Carriers with DCM features had larger LV dimensions: LVIDd (5.28 vs. 4.87 cm, p<0.001) and LVIDs (3.59 vs. 3.09 cm, p=0.002). They also had higher LV mass index (96 vs. 76 g/m², p=0.011), larger LAESVI (34 vs. 30 ml/m², p=0.029), and impaired systolic function: lower LVEF (49% vs. 56%, p<0.001), higher LVESV (61 vs. 50 ml, p=0.002), and reduced global longitudinal strain (−16% vs. −18%, p<0.001). Diastolic indices differed only for septal E′ (9.94 vs. 10.6 cm/s, p=0.045). Sex distribution, proband status, presentation type, and mutation subtype did not differ. Conventional risk factors were infrequent and not associated with DCM. Device implantation was more frequent in affected patients (ICD 55% vs. 38%, p=0.055). DCM was present in carriers of both loss- and gain- of function variants.
Conclusion
In this large single-center cohort, ~20% of both loss- and gain-of-function SCN5A-LP/P carriers demonstrated DCM. Affected carriers were older and displayed larger LV dimensions, reduced systolic function, and greater LV mass, while traditional risk factors were uncommon. These findings suggest that SCN5A variants may contribute to a distinct DCM phenotype, although age-related effects likely influence disease expression. Further studies are needed to clarify mechanisms and prognostic impact.