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Comparative Study
. 2018 Apr 14;39(15):1269-1277.
doi: 10.1093/eurheartj/ehx505.

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study

Thierry Le Tourneau  1   2 , Solena Le Scouarnec  1 , Caroline Cueff  1   2 , Daniel Bernstein  3 , Jan J J Aalberts  4 , Simon Lecointe  1 , Jean Mérot  1 , Jonathan A Bernstein  5 , Toon Oomen  6 , Christian Dina  1   2 , Matilde Karakachoff  1   2 , Hubert Desal  1 , Ousama Al Habash  2 , Francesca N Delling  7 , Romain Capoulade  1   2   8 , Albert J H Suurmeijer  9 , David Milan  10 , Russell A Norris  11 , Roger Markwald  11 , Elena Aikawa  12 , Susan A Slaugenhaupt  13 , Xavier Jeunemaitre  14   15   16 , Albert Hagège  14   15   16 , Jean-Christian Roussel  1   2 , Jean-Noël Trochu  1   2 , Robert A Levine  8 , Florence Kyndt  1 , Vincent Probst  1   2 , Hervé Le Marec  1   2 , Jean-Jacques Schott  1   2
Affiliations
Comparative Study

New insights into mitral valve dystrophy: a Filamin-A genotype-phenotype and outcome study

Thierry Le Tourneau et al. Eur Heart J. .

Abstract

Aims: Filamin-A (FLNA) was identified as the first gene of non-syndromic mitral valve dystrophy (FLNA-MVD). We aimed to assess the phenotype of FLNA-MVD and its impact on prognosis.

Methods and results: We investigated the disease in 246 subjects (72 mutated) from four FLNA-MVD families harbouring three different FLNA mutations. Phenotype was characterized by a comprehensive echocardiography focusing on mitral valve apparatus in comparison with control relatives. In this X-linked disease valves lesions were severe in men and moderate in women. Most men had classical features of mitral valve prolapse (MVP), but without chordal rupture. By contrast to regular MVP, mitral leaflet motion was clearly restricted in diastole and papillary muscles position was closer to mitral annulus. Valvular abnormalities were similar in the four families, in adults and young patients from early childhood suggestive of a developmental disease. In addition, mitral valve lesions worsened over time as encountered in degenerative conditions. Polyvalvular involvement was frequent in males and non-diagnostic forms frequent in females. Overall survival was moderately impaired in men (P = 0.011). Cardiac surgery rate (mainly valvular) was increased (33.3 ± 9.8 vs. 5.0 ± 4.9%, P < 0.0001; hazard ratio 10.5 [95% confidence interval: 2.9-37.9]) owing mainly to a lifetime increased risk in men (76.8 ± 14.1 vs. 9.1 ± 8.7%, P < 0.0001).

Conclusion: FLNA-MVD is a developmental and degenerative disease with complex phenotypic expression which can influence patient management. FLNA-MVD has unique features with both MVP and paradoxical restricted motion in diastole, sub-valvular mitral apparatus impairment and polyvalvular lesions in males. FLNA-MVD conveys a substantial lifetime risk of valve surgery in men.

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Figures

Figure 1
Figure 1
(A) Filamin-A protein with the C-terminal and N-terminal parts, and the three missense mutations localization, (B) microphotograph of a mitral leaflet piece (FLNA-G288R, Family 4, resection during mitral valve repair) showing a nodular thickened valve with myxomatous degeneration (colloidal iron, original magnification × 20), (C) typical aspect in echocardiography of the paradoxical association of mitral valve prolapse (systole) and restrictive motion in diastole (doming, arrows) in a P637Q patient in the parasternal long-axis view, (D) with moderate MR in the apical view.
Figure 2
Figure 2
Schematic of MV apparatus morphology averaged in systole (top) and diastole (bottom) (A) in adult controls, (B) in FLNA-MVD (FLNA+) men and (C) in FLNA-MVD women. In men (B) mitral annulus is 25% larger, mitral leaflets are thickened, redundant, elongated, and prolapsed in systole (top). In addition the distance between papillary muscles tip and mitral annulus line (symbolized by the double black arrow) is reduced by 20%. In diastole (bottom), mitral leaflets motion is limited with a doming aspect. In women (C) MV apparatus changes are moderate. PM, papillary muscle; FLNA, Filamin-A; MVD, mitral valve dystrophy.
Figure 3
Figure 3
Relation of age to (A) anterior and posterior leaflets length, (B) mitral annulus diameter, and (C and D) leaflets thickness in patients of both genders, with (black squares or circles) or without (white squares or circles) FLNA mutations. Values of all MV parameters increase with age up to 16–20 years old and were eventually quite stable in controls. All parameters have greater values in FLNA-MVD patients at any adult age, with a divergence between the regression slope in FLNA-MVD patients and controls. AL, anterior leaflet; PL, posterior leaflet.
Figure 4
Figure 4
Life-time influence of FLNA-MVD (FLNA+) up to 70 years old on (A) overall survival, (B) survival in male patients, (C) overall cardiac surgery rate, and (D) cardiac surgery rate in male patients. The life-time risk of cardiac surgery depends essentially on the substantial increase in valve surgery in FLNA-MVD males.
Take home figure
Take home figure
(A) Aspect of mitral valve apparatus with the paradoxical association of mitral valve prolapse (systole) and restrictive motion in diastole (doming, arrows) in FLNA-MVD, (B) myxomatous change of a mitral leaflet (colloidal iron), (C) degenerative aspect of FLNA-MVD with progressive lengthening of leaflets (AL, anterior leaflet; PL, posterior leaflet), and (D) substantial life-time risk of cardiac surgery in FLNA-MVD males.
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