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

Mohammed Majid Akhtar*, Massimiliano Lorenzini, Menelaos Pavlou, Juan Pablo Ochoa, Constantinos O'Mahony, Maria Alejandra Restrepo-Cordoba, Diego Segura-Rodriguez, Francisco Bermúdez-Jiménez, Pilar Molina, Sofia Cuenca, Flavie Ader, Jose M. Larrañaga-Moreira, Maria Sabater-Molina, Maria I. Garcia-Alvarez, Larraitz Gaztañaga Arantzamendi, Grazyna Truszkowska, Martin Ortiz-Genga, Itziar Solla Ruiz, Søren Kristian Nielson, Torsten Bloch RasmussenAinhoa Robles Mezcua, Jorge Alvarez-Rubio, Hans Eiskjaer, Mathias Gautel, José M. Garcia-Pinilla, Tomas Ripoll-Vera, Jens Mogensen, Javier Limeres Freire, Jose F. Rodríguez-Palomares, Maria Luisa Peña-Peña, Diego Rangel-Sousa, Julian Palomino-Doza, Xabier Arana Achaga, Zofia Bilinska, Estibaliz Zamarreño Golvano, Vincent Climent, Marina Navarro Peñalver, Roberto Barriales-Villa, Philippe Charron, Raquel Yotti, Esther Zorio, Juan Jiménez-Jáimez, Pablo Garcia-Pavia, Perry M. Elliott

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)


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..

Original languageEnglish
Article number1106
Pages (from-to)891-901
Number of pages11
JournalJAMA Cardiology
Issue number8
Publication statusPublished - Aug 2021


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