Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent Ventricular Arrhythmia and End-stage Heart Failure

Abstract

IMPORTANCETruncating variants in the gene encoding filamin C (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies with a reportedly high risk of ventricular arrhythmia.OBJECTIVE To determine the frequency of and risk factors associated with adverse events among FLNCtv carriers compared with individuals carrying TTN truncating variants (TTNtv). DESIGN, SETTING, AND PARTICIPANTSThis cohort study recruited 167 consecutive FLNCtv carriers and a control cohort of 244 patients with TTNtv matched for left ventricular ejection fraction (LVEF) from 19 European cardiomyopathy referral units between 1990 and 2018. Data analyses were conducted between June and October, 2020. MAIN OUTCOMES AND MEASURESThe primary end point was a composite of malignant ventricular arrhythmia (MVA) (sudden cardiac death, aborted sudden cardiac death, appropriate implantable cardioverter-defibrillator shock, and sustained ventricular tachycardia) and end-stage heart failure (heart transplant or mortality associated with end-stage heart failure). The secondary end point comprised MVA events only. RESULTSIn total, 167 patients with FLNCtv were studied (55 probands [33%]; 89 men [53%]; mean [SD] age at baseline evaluation, 43 [18] years). For a median follow-up of 20 months (interquartile range, 7-60 months), 29 patients (17.4%) reached the primary end point (19 patients with MVA and 10 patients with end-stage heart failure). Eight (44%) arrhythmic events occurred among individuals with baseline mild to moderate left ventricular systolic dysfunction (LVSD) (LVEF = 36%-49%). Univariable risk factors associated with the primary end point included proband status, LVEF decrement per 10%, ventricular ectopy (Ն500 in 24 hours) and myocardial fibrosis detected on cardiac magnetic resonance imaging. The LVEF decrement (hazard ratio [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 independent risk factors on multivariable analysis (excluding myocardial fibrosis and ventricular ectopy owing to case censoring). There was no difference in freedom from MVA between FLNCtv carriers with mild to moderate or severe (LVEF Յ35%) LVSD (HR, 1.29 [95% CI,]; P = .64). Carriers of FLNCtv with impaired LVEF at baseline evaluation (n = 69) had reduced freedom from MVA compared with 244 TTNtv carriers with similar baseline LVEF (for mild to moderate LVSD: HR, 16.41 [95% CI,]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03). CONCLUSIONS AND RELEVANCEThe high frequency of MVA among patients with FLNCtv with mild to moderate LVSD suggests that higher LVEF values than those currently recommended should be considered for prophylactic implantable cardioverter-defibrillator therapy in FLNCtv carriers.

Loss-of-Function FLNC Variants are Associated with Arrhythmogenic Cardiomyopathy Phenotypes when Identified through Exome Sequencing of a General Clinical Population

“…These studies have broadly found that cardiomyopathy in individuals with FLNCLOF is characterized by LV dysfunction/dilation, a high burden of malignant arrhythmia/sudden cardiac arrest, frequent findings of myocardial fibrosis, and reported high rates of penetrance. 2,3,6,10,26,27 Despite the stark differences in clinical context, the characteristics of this genome-first cohort generally recapitulate these findings. For example, FLNCLOF variants were associated with LV dilatation (increased LVIDd) and decreased LVEF, with 25% of carriers being classified as having ventricular dysfunction from EHR-based phenotypes (18% via chart review).…”

“…A total of 171,948 MyCode participants had available sequencing data linked to their EHR. Of these, 60 individuals (0.03%) were identified harboring 27 unique FLNCLOF variants, comprising frameshift (n=14), splice site (10), and stop gained (3). Variant details are presented in Table 1.…”

“…Characterizing the risk of severe arrhythmia for individuals with FLNCLOF is particularly important given that FLNC is included in the Heart Rhythm Society's list of genes that warrant consideration for ICD placement for primary prevention of ACMassociated sudden cardiac death. 22 Furthermore, emerging data suggest that, as for LMNA and DSP, 28 significant arrhythmia risk may be present with FLNCLOF even in the setting of only mild reductions in LVEF, 10,27 potentially requiring alternate criteria for use.…”

“…[2][3][4][5] Commonly cited characteristics from clinical evaluation of individuals with FLNC variants have included frequent ventricular arrhythmias or sudden cardiac death, reduced left ventricular (LV) systolic function, and regional structural abnormalities such as non-ischemic late gadolinium enhancement (LGE) patterns on cardiac MRI (CMR). [6][7][8][9][10] To date, these studies have primarily investigated gene-phenotype associations in individuals or families with known cardiomyopathy. However, little is known of the disease burden and phenotype characteristics associated with FLNC variants when identified through broad exome sequencing within an unselected clinical population.…”

Whole-Exome Sequencing Identifies a Novel Variant (c.1538T > C) of TNNI3K in Arrhythmogenic Right Ventricular Cardiomyopathy

“…Patients with DSP mutations can be presented with typical ARVC, biventricular cardiomyopathy, or isolated LV, as well as DCM ( 19 ). Recent research have found that truncating variants in the gene-encoding filamin C ( FLNCtv ) are associated with arrhythmogenesis and DCM, with a reportedly high risk of ventricular arrhythmia ( 20 ). In addition, many genes have been identified in ARVC and are listed as pathogenic genes in DCM, such as PKP2, JUP, LMNA, DES, PLN , and SCN5A ( 1 , 21 ).…”