1. Higher frequencies of malignant ventricular arrhythmia and end-stage heart failure were found among individuals carrying truncating variants of the gene encoding filamin C versus the gene encoding TTN.
2. These results suggest that higher left ventricular ejection fraction values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in patient carriers of truncating variants in filamin C.
Evidence Rating Level: 2 (Good)
Study Rundown: Pathogenic truncating variants in the gene encoding filamin C account for up to 4% of dilated cardiomyopathy (DCM) cases, which are characterized by an arrhythmogenic phenotype with extensive left ventricular myocardial fibrosis. This cohort study sought to determine the frequency of adverse events and their association with the severity of left ventricular systolic dysfunction (LVSD) in a large cohort of carriers of the heterozygous FLNC truncating variant (FLNCtv) compared with a control cohort of patients with DCM having truncating variants in the TTN gene (TTNtv), the most common genetic subtype of DCM. The primary end point for the study was a combination of 1) malignant ventricular arrhythmia (MVA) including sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator (ICD) shock, and sustained ventricular tachycardia as well as 2) end-stage heart failure requiring heart transplant or mortality associated with end-stage heart failure. The secondary end point consisted of MVA events only. Among 167 consecutive FLNCtv carriers recruited to the study, 29 (17.4%) of them reached the primary end point with 19 patients developing MVA and 10 patients in end-stage heart failure. There was no significant difference in freedom from MVA among FLNCtv carriers with mild to moderate vs severely impaired left ventricular ejection fraction (LVEF). However, carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with the control cohort of 244 patients with TTNtv matched for baseline LVEF. A limitation of this study was that all 19 participating European centers were cardiomyopathy referral units, where a majority of the patients recruited were of White race/ethnicity (92%). Thus, the results of the study may not be generalizable in all clinical scenarios and across all races/ethnicities.
In-Depth [prospective cohort]: This multicenter, longitudinal cohort study consisted of patients with FLNCtv recruited from 19 European cardiomyopathy units between 1990 and 2018. In total, 167 patients with FLNCtv were recruited (89 men [53%]; mean [SD] age, 43  years) along with a control cohort of 244 patients with TTNtv matched for LVEF at baseline. After a median follow-up of 20 months (IQR, 7-60 months), 29 of 167 patients (17.4%) reached the primary end point of MVA (19 patients) or end-stage failure (10 patients). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy and myocardial fibrosis assessed via cardiac magnetic resonance (CMR) imaging where LVEF decrement (HR per 10%, 1.83 [95%CI, 1.30-2.57]; P < .001) and proband status (HR, 3.18 [95%CI, 1.12-9.04]; P = .03) remained as independent risk factors on multivariable analysis. There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF ≤35%) LVSD (HR, 1.29 [95%CI, 0.45-3.72]; P = .64). However, carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared to the TTNtv control cohort with similar baseline characteristics and LVEF (for mild to moderate LVSD: HR, 16.41 [95%CI, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95%CI, 1.04-5.87]; P = .03).
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