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Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants
, Marta Gigli1,2, Davide Stolfo1,3
1Cardiothoracovascular Department, Azienda Sanitaria-Universitaria Giuliano Isontina, Trieste, Italy.
Insights
Filamin C truncating variants (FLNCtv) increase risk for sudden cardiac death (SCD) and major ventricular arrhythmias (MVA). A new 5-variable model helps predict risk in FLNCtv carriers, aiding decisions on prophylactic ICD implantation.
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.
Importance:
Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking.
Objective:
To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv.
Design, Setting, And Participants:
This was an international, multicenter, retrospective cohort study conducted from February 2023 to June 2024. The Filamin C Registry Consortium included 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 by 12-lead electrocardiogram (ECG), Holter ECG monitoring, echocardiography, or cardiac magnetic resonance.
Exposures:
Composite of SCD and MVA in carriers of FLNCtv.
Main Outcomes And Measures:
The primary outcome was a composite of SCD and MVA, the last including aborted SCD, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) interventions.
Results:
Among 308 individuals (median [IQR] age, 45 [33-56] years; 160 male [52%]) with FLNCtv, 112 (36%) were probands, and 72 (23%) were phenotype negative. Median (IQR) left ventricular ejection fraction (LVEF) was 51% (38%-59%); 89 participants (34%) had LVEF less than 45%, and 50 (20%) had right ventricular dysfunction. During a median (IQR) follow-up of 34 (8-63) months, 57 individuals (19%) experienced SCD/MVA, with an annual incidence rate of 4 cases per 100 person-years (95% CI, 3-6). Incidence rates were higher in probands vs nonprobands and in phenotype-positive vs phenotype-negative individuals. A predictive model estimating SCD/MVA risk was derived from multivariable analysis, which included older age, male sex, previous syncope, nonsustained ventricular tachycardia, and LVEF with a time-dependent area under the curve (AUC) ranging between 0.76 (95% CI, 0.67-0.86) at 12 months and 0.78 (95% CI, 0.70-0.86) at 72 months. Notably, the association of LVEF with the SCD/MVA risk was not linear, showing significant lower risk for values of LVEF greater than 58%, and no increase for values less than 58%. Internal validation with bootstrapping confirmed good accuracy and calibration of the model. Results were consistent in subgroups analysis (ie, phenotype-positive carriers and phenotype-positive carriers without MVA at onset).
Conclusions And Relevance:
Results suggest that the risk of SCD/MVA in phenotype-positive carriers of FLNCtv was high. A 5-variable predictive model derived from this cohort allows risk estimation and could support clinicians in the shared decision for prophylactic ICD implantation. External cohort validation is warranted.
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