Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants

Area of Science:

• Cardiology
• Genetics
• Clinical Research

Background:

• Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy.
• FLNCtv carriers face a high risk of life-threatening ventricular arrhythmias and sudden cardiac death (SCD).
• Reliable risk predictors for stratifying FLNCtv carriers are currently lacking.

Purpose of the Study:

• To identify factors that predict SCD and major ventricular arrhythmias (MVA) in individuals with FLNCtv.
• To develop a risk prediction model for SCD/MVA in FLNCtv carriers.

Main Methods:

• International, multicenter, retrospective cohort study (February 2023 - June 2024) involving 308 FLNCtv carriers from 19 centers.
• Primary outcome: composite of SCD and MVA (including aborted SCD, sustained ventricular tachycardia, appropriate ICD interventions).
• Multivariable analysis used to derive a 5-variable predictive model.

Main Results:

• During a median follow-up of 34 months, 19% of individuals experienced SCD/MVA.
• A predictive model incorporating age, male sex, syncope, nonsustained ventricular tachycardia, and LVEF demonstrated good accuracy (AUC 0.76-0.78).
• Left ventricular ejection fraction (LVEF) showed a non-linear association with risk, with lower risk above 58%.

Conclusions:

• The risk of SCD/MVA is high in phenotype-positive FLNCtv carriers.
• A 5-variable predictive model can aid clinicians in risk stratification and decisions regarding prophylactic ICD implantation.
• External validation of the predictive model is recommended.