Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants
Authors:   Filamin C Registry Consortium, Gigli Marta , Stolfo Davide , Barbati Giulia , Graw Sharon , Chen Suet Nee , Merlo Marco , Medo Kristen , Gregorio Caterina , Dal Ferro Matteo , Paldino Alessia , Perotto Maria , Peter van Tintelen J. , Te Riele Anneline S. J. M. , Baas Annette F. , Wilde Arthur M. , Amin Ahmad S. , Houweling Arjan C. , Elliott Perry , Cannie Douglas , Michels Michelle , Schoonvelde Stephan A. C. , Prasad Sanjay , Tayal Paz Upasana , Yazdani Momina , Morris-Rosendahl Deborah , Garcia-Pavia Pablo , Cabrera-Romero Eva , Bauce Barbara , Pilichou Kalliopi , Fatkin Diane , Johnson Renee , Judge Daniel P. , Foil Kimberly L. , Heymans Stephane , Verdonschot Job A. J. , Stroeks Sophie L.V. M. , Lakdawala Neal K. , Anisha Purohit , O’Neill Matthew , Shoemaker M. Benjamin , Roden Dan M. , Calkins Hugh , James Cynthia A. , Murray Brittney , Parikh Victoria N. , Ashley Euan A. , Reuter Chloe , Imazio Massimo , Canepa Marco , Ameri Pietro , Song Jiangping , Sinagra Gianfranco , Taylor Matthew R. G. , Mestroni Luisa 
Published: February 2025

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.