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

Abstract

AbstractBackgroundMitral 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 (HTAD) gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium (MAC) registry.MethodsMAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using chi-squared or Fisher exact tests.ResultsMR and MVP were enriched in MAC participants (672) with pathogenic variants (PV) in TGF-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 inSMAD3PV compared to other TGF-β PV (PR 1.8 [1.1-2.8],P< 0.02). Severe disjunction (>10 mm) was only observed in the TGF-β subgroup and was further enriched in participants withSMAD3PV (PR 3.1 [1.1-8.6]). MVP (PR 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.ConclusionsMitral phenotypes are more prevalent in individuals with PV in TGF-β pathway genes, particularlySMAD3, and are associated with adverse aortic and cardiac events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for HTAD should be considered for such individuals, especially if they also have a family history of HTAD.Clinical/Research PerspectiveWhat Is New?1)Mitral regurgitation, mitral valve prolapse, and mitral annular disjunction (MAD) are common in heritable thoracic aortic disease (HTAD) caused by pathogenic variants (PV) in TGF-β pathway genes (SMAD3,TGFBR1,TGFBR2,TGFB2, orTGFB3) and are associated with adverse cardiac events.2)Pathological mitral phenotypes are particularly prominent in people withSMAD3PV and may be the presenting feature of HTAD in some cases.What Are the Clinical Implications?3)Pathological mitral valve phenotypes may identify a high-risk subgroup of HTAD cases with more frequent adverse cardiovascular events. Because congenital mitral disease may be the primary presenting feature ofSMAD3PV, genetic testing for HTAD should be considered for such individuals, especially if they also have a family history of HTAD.