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

Abstract

Background: Filamin C truncating variants (FLNCtv) cause a form of arrhythmogenic cardiomyopathy: the mode of presentation, natural history, and risk stratification of FLNCtv remain incompletely explored. We aimed 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 10 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), nonarrhythmic death/HT/LVAD, and sudden cardiac death/major ventricular arrhythmias. Previously established cohorts of 46 patients with LMNA and 60 with DSP-related arrhythmogenic cardiomyopathies were used for prognostic comparison.

Results: Eighty-five patients carrying FLNCtv were included (42±15 years, 53% men, 45% probands). Phenotypes were heterogeneous at presentation: 49% dilated cardiomyopathy, 25% arrhythmogenic left dominant cardiomyopathy, 3% arrhythmogenic right ventricular cardiomyopathy. Left ventricular ejection fraction 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%) experienced nonarrhythmic death/HT/LVAD, and 23 (27%) experienced sudden cardiac death/major ventricular arrhythmias. The sudden cardiac death/major ventricular arrhythmias incidence of FLNCtv carriers did not significantly differ from LMNA carriers and DSP carriers. In FLNCtv carriers, left ventricular ejection fraction was associated with the risk of D/HT/LVAD and nonarrhythmic death/HT/LVAD.

Conclusions: Among patients referred to tertiary referral centers, FLNCtv arrhythmogenic cardiomyopathy is phenotypically heterogeneous and characterized by a high risk of life-threatening arrhythmias, which does not seem to be associated with the severity of left ventricular dysfunction.

Keywords: FLNC protein, human; arrhythmogenic right ventricular dysplasia; death, sudden, cardiac; heart failure; outcome studies; prognosis.

Figure 1.. Mapping of FLNCtv variants.

Diagrams representing the structure of FLNC and the distribution of FLNCtv variants. FLNCtv were distributed across all gene domains. However, clusters were noted in the Actin Binding Domain (ABD domains 1 and 2) and in the Z-disk region (Ig-like 19–21) of the Rod Domain 2. Nonsense mutations, and insertion/deletion (indel) variants are indicated in the upper scheme, splice site mutations in the lower (gray) scheme. 1 to 24, Ig-like domains; H1 and H2, hinge domains.

Figure 2.. Distribution of right and left ventricular function in FLNCtv carriers.

The FLNCtv population showed a wide distribution of RV and LV dysfunction. Dashed lines mark the cut-offs defining LV dysfunction (LVEF<50%) and RV dysfunction (RVFAC<35%). LVEF=left ventricular ejection fraction, RVFAC=right ventricle fractional area change, RV= right ventricular.

Figure 3.. Characteristics of LGE in carriers of FLNCtv.

Left panel shows the typical subepicardial “ring-like” distribution of LGE in a carrier of FLNCtv (male, 48 years old, LVEF 54%), involving the inferior, posterior and lateral wall. Right panel summarizes the distribution of LGE in the 43 FLNCtv carriers with available cardiac magnetic resonance (CMR). Percentages are reported within bars.

Figure 4.. Association between LVEF and the study outcomes in the FLNCtv cohort.

In this high-risk population the burden of D/HT/LVAD and SCD/MVA was 22% and 27%, respectively, over a median ~5 years follow-up. The association of LVEF with the study outcomes varies according to the type of outcome. As LVEF decreases, the HR for the outcomes D/HT/LVAD (green line) and non-arrhythmic death/HT/LVAD (orange line) get progressively higher, whereas no variation in risk was observed for the outcome SCD/MVA (blue line). Light painted areas indicate 95 % confidence intervals. D/HT/LVAD=all-cause mortality/heart transplantation/left ventricular assist device; HR=hazard ratio, LVEF=left ventricular ejection fraction; SCD/MVA=sudden cardiac death/major ventricular arrhythmias.

Figure 5.. Comparison of outcome between the study population of FLNCtv carriers (n=85), LMNA mutation carriers (n=46) and DSP mutation carriers (n=60).

Left panel: all-cause mortality/heart transplantation/left ventricular assist device (D/HT/LVAD) in FLNCtv (green lines) vs LMNA (blue lines) vs DSP carriers (red line). Central panel: Cumulative Incidence Function (CIF) of non-arrhythmic death/HT/LVAD in FLNCtv vs LMNA vs DSP carriers. Right panel: CIF of sudden cardiac death/major ventricular arrhythmias (SCD/MVA) in FLNCtv vs LMNA vs DSP carriers. LMNA patients showed a higher risk of D/HT/LVAD (p=0.017) and non-SCD/HT/LVAD (p=0.006), whereas the risk of SCD/MVA was comparable across the three groups.