Background
Clinical presentation
Echocardiographic findings
Histological findings
History of myxomatous mitral valve disease
Methods
Literature search and study selection
Proband selection
Chromosome 16 (MMVP1)
Chromosome 13 (MMVP3)
Chromosome 11 (MMVP2)
X-linked-MVD (XMVD)
The role of TGF-β-signalling and increased oxidative stress in MMVD
Results
Literature search and study characteristics
Disse et al. [13] | Freed et al. [15] | Nesta et al. [14] | Monteleone et al. [18] | Hagler et al. [19] | Thalji et al. [20] | |
---|---|---|---|---|---|---|
No° of pedigrees included | 4 | 1 | 1 | 1 | – | – |
No° of individuals included | 64 | 41 | 46 | n/a (> 300) | 48 | 22 |
Underlying disease | MMVD (in probands during surgery, in relatives by echo) | Mitral valve prolapse | Mitral valve prolapse | Co-existent myxomatous valvular dystrophy and hemophilia A | MMVD (during surgery) | MMVD (during surgery) |
Exclusion criteria | n/a | (1) Marfan’s syndrome; (2) Genetical linkage to MMVP1 | (1) Marfan’s syndrome /other CTD (2) genetical linkage to MMVP 1 or 2 | (1) Marfan‘s and Ehlers-Danlos syndromes | (1) Marfan’s- syndome, Loeys-Dietz, osteogenesis imperfecta | n/a |
Echochardiography | Transthoracic, blinded by two physicians | Transthoracic, blinded by two physicians | Transthoracic | Transthoracic, blinded by two physicians | n/a | – |
Echocardiographic inclusion criteria | 1)Thickness > 5 mm + leaflet displacement > 8 mm + annular displacement 2) Thickness 4-5 mm + leaflet displacement 3-8 mm + MVR | MVP > 2 mm | 1)Classic: MVP > 2 mm + Leaflet thickening ≥ 5 mm 2) non-classic: MVP > 2 mm + leaflet thickness < 5 mm | Leaflet thickness > 4 mm | Severe mitral valve regurgitation | – |
Genetic analysis + Gene expression | Genescan and Genotyper | Linkage and Genehunter, linkage to MMVP1 excluded | SLINK, linkage to MMVP1 + 2 excluded | Linkage analysis | TaqMan gene expression assay | qRT-PCR + Immunhistochemistry |
Genetics of myxomatous mitral valve disease
Genetic findings in chromosome 16 (MMVP1)
Genetic findings in chromosome 13 (MMVP3)
Genetic findings in chromosome 11 (MMVP2)
X-linked MVD (XMVD)
Disse et al. [13] | Freed et al. [15] | Nesta et al. [14] | Monteleone et al. [18]; | |
---|---|---|---|---|
Underlying disease | MMVD | MVP | MVP | Myxomatous valvular dystrophy + hemophilia type A |
No° of included individuals (echocardiography + genetics) | 64 | 28 (11 m, 17f) | 43 | 92 |
Mean age (years) | 49 | 34 | 55 | 32 |
Affected individuals (positive in genetic testing) (%) | 25 (39%) | 12 (43%) | 9 (21%) | 21 (23%) |
MR present | 23 | 10 (3 m,7f) | 9 (5 m,4f) | 38 (14 m, 24f) |
- Trace to mild | 15 (11 m, 4f) | 8 (3 m, 5f) | 7 (4 m, 3f) | 20 (0 m, 20f) |
- Moderate | 3 (2 m, 1f) | 0 | 1 (f) | 16 (12 m, 4f) |
- Severe | 5 (3 m, 2f) | 2 (0 m, 2f) | 1 (m) | 2 (2 m,0f) |
Individuals with MVP | 25 (39%) (16 m,9f) | 12 (43%) | 9 (21%) | 21 (23%) |
Prolapse localisation | ||||
- AML | 10 | 0 | 0 | 16 (12 m, 4f) |
- PML | 5 | 7 (3 m, 4f) | 1(f) | 9 (8 m, 1f) |
- Bileaflet | 10 | 5 (1 m, 4f) | 8 (5 m, 3f) | n/a |
Mean LVEF in MVP patients | n/a | 65.5% | 63.7% | 69 + 8% m / 72 + 6% f |
Chromosome | 16 | 11 | 13 | X |
Locus | 16p12.1.-p11.2 | 11p15.4 | 13.q31.3-q32.1 | Xq28 |
Name of Gene | MMVP 1 | MMVP 2 | MMVP 3 | XMVD |
Mode of inheritance | Autosomal dominant | Autosomal dominant (incomplete penetrance) | Autosomal dominant | X-linked |
Pathophysiological biomolecular pathways in MMVD
Hagler et al. [19] | Thalji et al. [20] | Geirsson et al. [21] | |
---|---|---|---|
Underlying disease | Surgery due to myxomatous mitral valve disease, histological confirmation of myxomatous changes | Surgery due to myxomatous mitral valve disease | Surgery due to myxomatous mitral valve disease |
No° of mitral valves | 48 | 22 | 49 |
Individuals with myxomatous valves | 24 (50%) | 11 (50%) | 26 (53%) |
Echocardiographical findings | Severe mitral regurgitation: - 100% with MMVD vs. 58% with non-myxomatous valves | n/a | Severe mitral regurgitation in 26 diseased patients, not more than mild MVR in 23 non-diseased patients |
Control group | Visually normal mitral valves from cardiac transplant recipients | Visually normal mitral valves from transplant patients | organ/tissue donors and explanted hearts of transplant recipients without abnormalities of mitral valve |
Affected signalling protein | TGF-ß2-; BMP-; WNT/ß-catenin activation | TGF-ß, increased phosphorylation of SMAD2/3, increased oxidative stress | TGF-ß |