Arrhythmic risk stratification of filamin C truncating variants carriers

Abstract

Abstract Background Truncating variants in Filamin C (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentation and high incidence of life-threatening ventricular arrhythmias, including sudden cardiac death (SCD). Nevertheless, there is a residual gap in the definition of solid risk markers for the stratification of arrhythmic risk and the significance of conventional predictors (i.e. left ventricular ejection fraction [LVEF]) remains extremely controversial. Purpose The aim of this study was to analyze the risk profile and to identify the factors associated with increased risk of life-threatening arrhythmias in an international multicenter cohort of FLNCtv carriers. Methods Patients were retrospectively collected from 19 international tertiary care centers for genetic cardiomyopathies. Primary endpoint was SCD/major ventricular arrhythmias (MVA, i.e. sustained ventricular tachycardia and appropriate implantable cardioverter defibrillator [ICD] shocks). Multivariate Cox regression analysis was performed to identify the predictors of SCD/MVA, taking into account non-sudden cardiac death/heart transplant/destination left ventricle assist device as competing event and including family clusters in the model as clustering factor. Results Among the 326 included carriers (median age 45 years, IQR 33-57; 51% males), 120 (37%) were probands. 100 (31%) carriers had no clinical signs of overt disease; for the others, phenotypic presentation was heterogeneous (36% dilated cardiomyopathy, 17% arrhythmogenic left dominant cardiomyopathy, 4% arrhythmogenic right or biventricular cardiomyopathy, 11% minor phenotype). Median LVEF was 51% (IQR 35%-59%, 41% had LVEF<50%), 16% had right ventricle dysfunction. During a median follow-up of 32 months (IQR 8-63), 60 carriers (18%) experienced SCD/MVA (65% probands, 97% with overt disease, median age at event 48 years, IQR 38-64, min-max 18-78). Among variables associated with the risk of SCD/MVA at univariable analysis, male sex, previous syncope and non-sustained ventricular tachycardia maintained a significant association with the primary outcome at multivariable analysis (Table), whereas there was no significant association between LVEF and the risk of SCD/MVA neither as a continuous nor categorical (i.e. LVEF<50%) variable. In the subgroup of 175 patients with available cardiac magnetic resonance, 57% had late gadolinium enhancement with no significant association with the outcome. Conclusions In the largest worldwide cohort of FLNCtv carriers the high risk of SCD/MVA was confirmed. Three important factors emerged to be associated with higher arrhythmic risk and should be considered for decisions on ICD implantation. Remarkably, LVEF was not significantly associated with SCD/MVA risk. The higher risk observed in males compared with females advocates for prompt investigations on the influence of sex-related factors on the disease expression in genetic cardiomyopathies.