Phenotypic Expression, Natural History and Risk Stratification of Cardiomyopathy Caused by Filamin C Truncating Variants

Background: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy (ACM): the mode of presentation, natural history and risk stratification of FLNCtv remain incompletely explored. We sought to develop a risk profile for refractory heart failure and life-threatening arrhythmias in a multicenter cohort of FLNCtv carriers. Methods: FLNCtv carriers were identified from ten tertiary care centers for genetic cardiomyopathies. Clinical and outcome data were compiled. Composite outcomes were all-cause mortality/heart transplantation/left ventricle assist device (D/HT/LVAD), non-arrhythmic death/HT/LVAD and SCD/major ventricular arrhythmias (SCD/MVA). Previously established cohorts of 46 patients with LMNA and 60 with DSP-related ACM were used for prognostic comparison. Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% males, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction (LVEF) was <50% in 64% of carriers and 34% had right ventricular fractional area changes (RVFAC=(right ventricular end-diastolic area - right ventricular end-systolic area)/ right ventricular end-diastolic area) <35%. During follow-up (median time 61 months), 19 (22%) carriers experienced D/HT/LVAD, 13 (15%) non-arrhythmic death/HT/LVAD and 23 (27%) SCD/MVA. The SCD/MVA incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, LVEF was associated with the risk of D/HT/LVAD and non-arrhythmic death/HT/LVAD. CConclusions: Among patients referred to tertiary referral centers, FLNCtv ACM is phenotypically heterogeneous and characterized by high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of LV dysfunction.