5163Predictors of adverse cardiovascular events in patients with truncating variants in the filamin c (flnc) gene

Abstract

Abstract Background Truncating variants in Filamin C (FLNCtv) are associated with arrhythmogenic (AC) and dilated cardiomyopathies (DCM). Affected patients are reported to demonstrate a high incidence of arrhythmic and heart-failure related cardiovascular events. The aim of this study was to determine factors that predict adverse events in mutation carriers. Methods The study cohort comprised 168 FLNCtv carriers followed at 19 European centres. Baseline and longitudinal follow-up clinical data were collected. The primary endpoint was a composite of sudden cardiac death (SCD), aborted SCD, appropriate implantable cardioverter-defibrillator (ICD) shock, cardiac transplantation (HTx) and mortality from end-stage heart failure (ESHF). Results 47 different pathogenic or likely-pathogenic FLNCtv were identified in 60 unrelated probands. In those with baseline and longitudinal data (160 patients; 57 probands), 114 (71.3%) patients exhibited evidence of cardiac disease at initial evaluation. Gene penetrance was 85% by the age of 40 years. During a median follow-up of 1.5 years (IQR 4.1), 24 individuals (15%) reached the primary endpoint – 16 arrhythmic (SCD/aborted SCD/ICD shock) and 8 heart failure (ESHF/HTx) related-events. Univariable predictors at baseline evaluation of the composite primary endpoint included proband status (HR 4.0, 95% CI: 1.5–10.9, p=0.01), symptoms of dyspnoea (HR 2.8, 95% CI: 1.2–6.4, p=0.02), LV systolic dysfunction (LVSD) (HR 12.4, 95% CI: 2.9–53.2, p=0.001), frequent ventricular ectopy (VE>500) on 24-hour Holter (HR 9.3, 95% CI: 1.2–74.7, p=0.04) and the presence of late gadolinium enhancement on CMR (HR 8.9, 95% CI: 1.2–68.5, p=0.04). Multivariable analysis identified LVSD (LVEF <50%) at baseline as an independent predictor of the primary endpoint with a hazard ratio of 8.6 (95% CI: 1.8–41.5, p=0.007). ROC analysis using LV systolic dysfunction to predict the primary endpoint demonstrated an area under the curve of 0.84 (95% CI: 0.76–0.91, p<0.001) and identified an optimal LVEF “cut-off” of 47% for predicting adverse events with a Youden's index of 0.61 (sensitivity 0.91; specificity 0.70). Kaplan-Meier plot to demonstrate freedom Conclusions LVSD is associated with an over 8-fold increase in the hazard of a primary endpoint event in FLNCtv gene carriers indicating that these patients should be considered for implantable cardioverter-defibrillator (ICD) implantation, optimal heart failure medical therapy and close clinical follow-up. Acknowledgement/Funding NIHR Biomedical Research Centre; Instituto de Salud Carlos III; DETECTIN-HF project; Wellcome Trust;CIBERCV; EU Regional Development Fund; FEDER.