Filamin A heart valve disease as a genetic cause of inherited bicuspid and tricuspid aortic valve disease.

Abstract

Variants in the <i>FLNA</i> gene have been associated with mitral valve dystrophy (MVD), and even polyvalvular disease has been reported. This study aimed to analyse the aortic valve and root involvement in <i>FLNA</i>-MVD families and its impact on outcomes. 262 subjects (37 (18-53) years, 140 male, 79 carriers: <i>FLNA</i>+) from 4 <i>FLNA</i>-MVD families were included. Echocardiography was performed in 185 patients and histological analysis in 3 explanted aortic valves. The outcomes were defined as aortic valve surgery or all-cause mortality. Aortic valve alterations were found in 58% of <i>FLNA</i>+ compared with 6% of <i>FLNA</i>- (p<0.001). 9 (13.4%) <i>FLNA</i>+ had bicuspid aortic valve compared with 4 (3.4%) <i>FLNA</i>- (p=0.03). Overall, the transvalvular mean gradient was slightly increased in <i>FLNA</i>+ (4.8 (4.1-6.1) vs 4.0 (2.9-4.9) mm Hg, p=0.02). The sinuses of Valsalva and sinotubular junction diameters were enlarged in <i>FLNA</i>+ subjects (all p<0.05). 8 <i>FLNA</i>+ patients underwent aortic valve surgery (0 in relatives; p<0.001). Myxomatous remodelling with an infiltration of immune cells was observed. Overall survival was similar between <i>FLNA+</i> versus <i>FLNA</i>- subjects (86±5% vs 85±6%, p=0.36). There was no statistical evidence for an interaction between genetic status and sex (p=0.15), but the survival tended to be impaired in <i>FLNA</i>+ men (p=0.06) whereas not in women (p=0.71). The patients with <i>FLNA</i> variants present frequent aortic valve disease and worse outcomes. Bicuspid aortic valve is more frequent in patients carrying the <i>FLNA</i>-MVD variants. These unique features should be factored into the management of patients with dystrophic and/or bicuspid aortic valve.