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

Tourneau, Thierry Le; Scouarnec, Solena Le; Cueff, Caroline; Bernstein, Daniel; Aalberts, Jan J.J.; Lecointe, Simon; Mérot, Jean; Bernstein, Jonathan A.; Oomen, Toon; Dina, Christian; Karakachoff, Matilde; Desal, Hubert; Habash, Ousama Al; Delling, Francesca N.; Capoulade, Romain; Suurmeijer, Albert; Milan, David J.; Norris, Russell A.; Markwald, Roger R.; Aikawa, Elena; Slaugenhaupt, Susan A.; Jeunemaı̂tre, Xavier; Hagège, Albert; Roussel, J; Trochu, Jean Noël; Levine, Robert A.; Kyndt, Florence; Probst, Vincent; Marec, Hervé Le; Schott, Jean Jacques

doi:10.1093/eurheartj/ehx505

Cited by 56 publications

(62 citation statements)

References 30 publications

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“…Both MVP and prodromal forms in parents predict the development of MVP in offsprings 11 12. Other atypical manifestations have been highlighted in Filamin-A ( FLNA) -MVP such as a restrictive motion in diastole 13. Finally, mitral regurgitation (MR) degree varies from trivial to severe according to the failure of coaptation driven essentially by chordal elongation, chordal rupture or annular enlargement.…”

Section: Mvp Phenotypementioning

confidence: 99%

“…The penetrance of the disease was complete in men and incomplete in women. Additional FLNA mutations have recently been identified in families with an X linked form of MVP/dystrophy 13 . FLNA -MVP phenotype is now clearly characterised and comprises both congenital and degenerative alterations of the MV apparatus and frequent polyvalvular involvement in men.…”

Section: Genetics Of Non-syndromic Mvpmentioning

confidence: 99%

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Genetics of syndromic and non-syndromic mitral valve prolapse

Tourneau¹,

Mérot

Rimbert

et al. 2018

Heart

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Mitral valve prolapse (MVP) is a common condition that affects 2%–3% of the general population. MVP is thought to include syndromic forms such as Marfan syndrome and non-syndromic MVP, which is the most frequent form. Myxomatous degeneration and fibroelastic deficiency (FED) are regarded as two different forms of non-syndromic MVP. While FED is still considered a degenerative disease associated with ageing, frequent familial clustering has been demonstrated for myxomatous MVP. Familial and genetic studies led to the recognition of reduced penetrance and large phenotypic variability, and to the identification of prodromal or atypical forms as a part of the complex spectrum of the disease. Whereas autosomal dominant mode is the common inheritance pattern, an X linked form of non-syndromic MVP was recognised initially, related to Filamin-A gene, encoding for a cytoskeleton protein involved in mechanotransduction. This identification allowed a comprehensive description of a new subtype of MVP with a unique association of leaflet prolapse and paradoxical restricted motion in diastole. In autosomal dominant forms, three loci have been mapped to chromosomes 16p11-p12, 11p15.4 and 13q31–32. Although deciphering the underlying genetic defects is still a work in progress, DCHS1 mutations have been identified (11p15.4) in typical myxomatous disease, highlighting new molecular pathways and pathophysiological mechanisms leading to the development of MVP. Finally, a large international genome-wide association study demonstrated the implication of frequent variants in MVP development and opened new directions for future research. Hence, this review focuses on phenotypic, genetic and pathophysiological aspects of MVP.

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Section: Mvp Phenotypementioning

confidence: 99%

Section: Genetics Of Non-syndromic Mvpmentioning

confidence: 99%

Genetics of syndromic and non-syndromic mitral valve prolapse

Tourneau¹,

Mérot

Rimbert

et al. 2018

Heart

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“…In addition, Filamin-A, an important cytoskeletal protein involved with organization of ECM, could also be affected by the mechanisms of interest in the present studies. Filamin A mutations cause an X-linked myxomatous mitral valve disease 31 , and mice with an endocardial specific conditional Filamin-A deletion demonstrate thickening of mitral leaflets 40 . Diminished 5HT internalization due to reduced SLC6A4 activity results in diminished serotonylation of Filamin A in the mouse model 40 , thereby impairing Filamin-A structural interactions with actin, enhancing ECM pathologic remodeling in mitral leaflets.…”

Section: Discussionmentioning

confidence: 99%

“…Exclusion criteria for this study included Marfan's syndrome, congenital mitral valve abnormalities, endocarditis, rheumatic heart disease, ischemic mitral regurgitation, a history of cancer, autoimmune diseases, previous mitral surgery, and any history of cardiac trauma. To the best of our knowledge no patients with the X-linked Filamin-A mutation associated with mitral regurgitation 31 were included. Normal leaflet retrievals also excluded valve leaflets from patients with mitral valve disease.…”

Section: Methodsmentioning

confidence: 99%

“…Fluoxetine, a representative SSRI, enhances plat activation, and increases platelet secretion of 5HT thus enhancing HTR signaling ( Figure 3A-C). Asp administration inhibits platelet activation ( Figure 3) and thus, could mitigate MR progression by reducing plat activation associated 5HT release from platelets ( Figure 3D-F Age range (years) (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)…”

Section: Fundingmentioning

confidence: 99%

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Inhibition and down regulation of the serotonin transporter contribute to the progression of degenerative mitral regurgitation

Levy

Fitzpatrick

Castillero

et al. 2020

Preprint

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Aims: Heart valve disease attributed to serotonin (5HT) has been observed with 5HT-secreting carcinoid tumors and in association with medications, such as the diet drug, Dexfenfluoramine, a serotonin transporter (SLC6A4) inhibitor and 5HT receptor (HTR) 2B agonist. HTR2B signaling upregulates TGFβ-1 resulting in increased production of extracellular matrix proteins. SLC6A4 internalizes 5HT, limiting HTR signaling. Selective 5HT reuptake inhibitors (SSRI), widely used antidepressants, target SLC6A4, thus enhancing HTR signaling. However, 5HT and SLC6A4 mechanisms have not been previously associated with degenerative mitral regurgitation (MR). The present studies investigated the hypothesis that both dysregulation of SLC6A4 and inhibition of SLC6A4 contribute to the pathophysiology of MR. Methods and Results:Here we report SLC6A4 related studies of 225 patients with MR requiring surgery. A multivariate analysis showed that SSRI use in MR patients was associated with surgery at a younger age, indicating more rapidly progressive MR (p=0.0183); this was confirmed in a national dataset (p<0.001). Aspirin use by MR patients was associated with surgery at an older age (p=0.0055). Quantitative reverse transcriptase PCR of MR leaflet RNA from 44 patients, and 20 normal mitral leaflets from heart transplant recipients, demonstrated down regulation in MR of both SLC6A4 and vesicular monoamine transporter-2 (SLC18A2), that packages 5HT (p<0.001). Human mitral valve interstitial cells cultivated with Fluoxetine, a SSRI, demonstrated down regulation of SLC6A4 and upregulation of HTR2B, compared to untreated, in cells from both normal and MR leaflets. Platelet 5HT studies in healthy subjects without heart disease used ADP-induced activation to model MR-associated activation. Fluoxetine significantly increased platelet activation and plasma 5HT levels, while Aspirin inhibited ADP platelet activation.Conclusions: Down regulation and inhibition of SLC6A4 influences MR through enhanced HTR signaling. SSRI may further influence MR through inhibition and down regulation of SLC6A4, upregulation of HTR2B, and increased platelet release of 5HT. Translational PerspectiveDegenerative mitral valve regurgitation (MR) affects millions, and there is no medical therapy for this disease. MR becomes progressively worse, and for severe MR, the only option is cardiac surgery. Serotonin (5HT) is best known as a neurotransmitter. However, 5HT secreting carcinoid tumors cause a cardiac valve disorder in many cases, and 5HT related medications, such as the diet drug Fenfluoramine, have been associated with the development of cardiac valve disease. The present paper presents evidence that diminished serotonin transporter (SLC6A4) expression and inhibition, lead to increased 5HT receptor signaling, contributing to the progression of MR.

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