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Multicenter Study
. 2024 Nov 5;13(21):e036274.
doi: 10.1161/JAHA.124.036274. Epub 2024 Oct 18.

Mitral Annular Disjunction in Heritable Thoracic Aortic Disease: Insights From the Montalcino Aortic Consortium

Kishan L Asokan  1 , Jennifer R Landes  1 , Wannes Renders  2 , Laura Muiño Mosquera  2 , Julie De Backer  2 , David W Jantzen  3 , Anji T Yetman  3 , Gisela Teixido-Tura  4 , Arturo Evangelista  4 , Richmond Jeremy  5 , Edward G Jones  6 , Shaine Morris  6 , Tam Doan  6 , Maral Ouzonian  7 , Alan Braverman  8 , Guillaume Jondeau  9 , Olivier Milleron  9 , Dianna M Milewicz  1 , Siddharth K Prakash  1 ; Montalcino Aortic Consortium *
Collaborators, Affiliations
Multicenter Study

Mitral Annular Disjunction in Heritable Thoracic Aortic Disease: Insights From the Montalcino Aortic Consortium

Kishan L Asokan et al. J Am Heart Assoc. .

Abstract

Background: Mitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium registry.

Methods and results: MAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using χ2 or Fisher exact tests. MR and MVP were enriched in Montalcino Aortic Consortium participants (672) with pathogenic variants (PV) in transforming growth factor-β pathway genes. The combination of MR and MVP was associated with mitral surgery and arrhythmias. In the subgroup with available images, MAD was enriched in SMAD3 PV compared with other transforming growth factor-β PV (prevalence ratio 1.8 [1.1-2.8], P <0.02). Severe disjunction (>10 mm) was only observed in the transforming growth factor-β subgroup and was further enriched in participants with SMAD3 PV (prevalence ratio 3.1 [1.1-8.6]). MVP (prevalence ratio 5.2 [3.0-9.0]) and MR (PR 2.7 [1.8-3.9]) were increased in participants with MAD, but MAD was not independently associated with adverse cardiac or aortic events.

Conclusions: Pathological mitral valve phenotypes are more prevalent in individuals with PV in transforming growth factor-β pathway genes, particularly SMAD3. MR and MVP but not MAD are associated with adverse aortic and cardiac events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for heritable thoracic aortic disease should be considered for such individuals, especially if they also have a family history of heritable thoracic aortic disease.

Keywords: Loeys–Dietz syndrome; cardiovascular genetics; congenital heart disease; mitral valve; thoracic aortic aneurysms and dissections.

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Figures

Figure 1
Figure 1. Flow chart depicting patient selection for study.
MAC indicates Montalcino Aortic Consortium registry; MAD, mitral annular disjunction; MR, mitral regurgitation; MVP, mitral valve prolapse; PV, pathogenic variant in a heritable thoracic aortic disease gene; and VUS, variants of uncertain significance.
Figure 2
Figure 2. Prevalence of MAD in MAC participants with PV in TGF‐β pathway genes compared with other HTAD genes.
HTAD indicates heritable thoracic aortic disease; MAC, Montalcino Aortic Consortium registry; MAD, mitral annular disjunction; PV, pathogenic variant; and TGF‐β, transforming growth factor‐β. TGF‐β pathway genes are SKI, SMAD3, SMAD6, TGFBR1, TGFBR2, TGFB2, and TGFB3.
See this image and copyright information in PMC

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