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Association of Left Ventricular Systolic Dysfunction Among Carriers of Truncating Variants in Filamin C With Frequent
Mohammed Majid Akhtar1,2, Massimiliano Lorenzini1, Menelaos Pavlou3
1Department of Inherited Cardiovascular Diseases, Bart's Heart Centre St Bartholomew's Hospital, London, United Kingdom.
Insights
Truncating variants in filamin C (FLNCtv) are linked to cardiomyopathies and high ventricular arrhythmia risk. FLNCtv carriers with impaired ejection fraction face significantly reduced freedom from malignant ventricular arrhythmia compared to TTNtv carriers.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Truncating variants in the filamin C gene (FLNCtv) are associated with arrhythmogenic and dilated cardiomyopathies.
- These variants reportedly carry a high risk of ventricular arrhythmia.
Purpose of the Study:
- To determine the frequency of adverse events in FLNCtv carriers.
- To identify risk factors for adverse events in FLNCtv carriers.
- To compare adverse events between FLNCtv carriers and TTN truncating variant (TTNtv) carriers.
Main Methods:
- A cohort study involving 167 FLNCtv carriers and 244 TTNtv controls matched for left ventricular ejection fraction (LVEF).
- Data collected from 19 European cardiomyopathy referral units between 1990 and 2018.
- Primary endpoint: composite of malignant ventricular arrhythmia (MVA) and end-stage heart failure. Secondary endpoint: MVA events.
Main Results:
- 17.4% of FLNCtv carriers reached the primary endpoint during a median 20-month follow-up.
- Independent risk factors for the primary endpoint included LVEF decrement and proband status.
- FLNCtv carriers with impaired LVEF had reduced freedom from MVA compared to TTNtv carriers, particularly those with mild to moderate LVSD.
Conclusions:
- FLNCtv carriers with mild to moderate left ventricular systolic dysfunction (LVSD) exhibit a high frequency of MVA.
- Current recommendations for prophylactic implantable cardioverter-defibrillator therapy may need adjustment for FLNCtv carriers.
- Higher LVEF thresholds should be considered for prophylactic ICD therapy in FLNCtv carriers.
Importance:
Truncating 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 Participants:
This 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 Measures:
The 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.
Results:
In 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 (≥500 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 ≤35%) LVSD (HR, 1.29 [95% CI, 0.45-3.72]; 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, 3.45-78.11]; P < .001; for severe LVSD: HR, 2.47 [95% CI, 1.04-5.87]; P = .03).
Conclusions And Relevance:
The 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.
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