Novel Model May Predict Arrhythmic Risk in FLNCtv Carriers, Assist Decision of Prophylactic ICD Implantation: JAMA

Filamin C truncating variants are a rare cause of cardiomyopathy that presents a range of phenotypic variations. Despite the high incidence of life-threatening ventricular arrhythmias and sudden cardiac death in individuals with FLNCtv, there is a lack of reliable risk predictors to effectively stratify these carriers. Luisa Mestroni, MD, Molecular Genetics, Cardiovascular Institute and Adult Medical Genetics Program, University of Colorado Denver Anschutz Medical Campus, Aurora, CO, and colleagues aimed to identify factors that could predict the risk of SCD and major ventricular arrhythmias in individuals carrying FLNCtv.

For this purpose, the researchers conducted an international, multicenter, retrospective cohort study between 2023 and 2024. The study, part of the Filamin C Registry Consortium, involved 19 referral centers for genetic cardiomyopathies worldwide. Participants included carriers of pathogenic or likely pathogenic FLNCtv. Phenotype negative was defined as the absence of any pathological findings detected through 12-lead electrocardiogram (ECG), Holter ECG monitoring, echocardiography, or cardiac magnetic resonance imaging. The exposures in the study were a composite of SCD and MVA in FLNCtv carriers.

The primary outcome focused on a composite of SCD and MVA, which included aborted SCD, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) interventions.

Key Findings:

• The study involved 308 individuals with FLNCtv, with a median age of 45 years; 52% were male, 36% were probands, and 23% were phenotype-negative.
• The median left ventricular ejection fraction (LVEF) was 51%, with 34% of participants having an LVEF of less than 45% and 20% showing right ventricular dysfunction.
• During a median follow-up of 34 months, 19% of individuals experienced sudden cardiac death (SCD) or major ventricular arrhythmias (MVA), with an annual incidence rate of 4 cases per 100 person-years.
• Incidence rates were higher among probands compared to nonprobands, and among phenotype-positive individuals compared to phenotype-negative individuals.
• A predictive model for estimating SCD/MVA risk was developed through multivariable analysis, incorporating factors like older age, male sex, previous syncope, nonsustained ventricular tachycardia, and LVEF.
• The model showed a time-dependent area under the curve (AUC) ranging from 0.76 (12 months) to 0.78 (72 months), indicating good accuracy.
• The relationship between LVEF and SCD/MVA risk was non-linear, showing a lower risk for LVEF values greater than 58%, with no increase in risk for values below this threshold.
• Internal validation using bootstrapping confirmed the model's accuracy and calibration.
• Results were consistent in subgroup analysis, including phenotype-positive carriers and those without MVA at the onset.

In the cohort study, the carrier status of pathogenic or likely pathogenic Filamin C truncating variants was linked to a high risk of sudden cardiac death and major ventricular arrhythmias, particularly in probands and phenotype-positive individuals.

The study identified five key variables—nonsustained ventricular tachycardia, syncope, male sex, age, and left ventricular ejection fraction —to create a predictive model for estimating the individualized risk of SCD/MVA. This model requires validation through an independent cohort.

"Additionally, the currently recommended thresholds of LVEF for arrhythmic risk stratification may need to be reconsidered specifically for carriers of FLNCtv," the researchers concluded.

Reference:

Filamin C Registry Consortium. Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants. JAMA Cardiol. Published online February 12, 2025. doi:10.1001/jamacardio.2024.5543