SCN5A H558R polymorphism reduces the risk of flecainide-related toxicity and inefficacy

Background

Previously, low-comorbidity AF patients carrying the heterozygous H558R polymorphism (H558R+/-) showed reduced recurrence and toxicity on flecainide 100 mg/12h (RR 0.42, p=0.023).1,2 However, its effect in populations with higher comorbidities, different flecainide doses, or alternative rhythm control strategies remains unknown. We initiated a prospective cohort study of patients undergoing scheduled electrical cardioversion (ECV).

Purpose

To evaluate if H558R+/- carriers in a real-world cohort with persistent AF experience lower recurrence or toxicity rates following ECV when treated with flecainide versus other strategies.

Methods

Since August 2024, patients referred for scheduled ECV were enrolled. Blood samples were drawn for H558R genotyping. Clinical and genetic data were kept blinded until analysis. Six-month toxicity and recurrence rates were assessed via electronic health records and patient contact. We performed multivariable logistic regression, forcing an interaction term between flecainide use and H558R+/- status into the model to assess effect modification. Other covariates were selected via backward stepwise regression (p<0.10 retention threshold).

We analyzed the first 91 patients completing a 6-month follow-up with available genetic data (Table 1). Regarding antiarrhythmic drug (AAD) therapy, 12 (13.2%) received no AADs, 32 (35.2%) amiodarone, and 47 (51.6%) flecainide. In multivariable analysis, independent predictors were underlying heart disease (OR 0.22, p=0.05), statin use (OR 4.42, p=0.02), and the H558R+/- by flecainide interaction (OR 0.05, 95% CI 0.01-0.66; p=0.02, Figure 1). The "protective" effect of underlying heart disease is likely an artifact: flecainide is contraindicated in these patients, precluding them from meeting QRS widening criteria (>25% increase), a toxicity metric primarily linked to flecainide use.

Conclusions

This study corroborates that H558R+/- carriers have better clinical outcomes on flecainide post-ECV. By validating these findings in a representative, real-world cohort—encompassing diverse comorbidities and flexible flecainide dosing schemes—our study overcomes the limitations of previous research restricted to highly selected populations. Crucially, we demonstrate a specific pharmacogenetic interaction: the H558R+/- genotype offers no advantage with alternative AADs. These findings support a genotype-guided approach to flecainide prescription in everyday practice.Figure 1.