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

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 (HTAD) gene in in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium (MAC) registry. Methods MAD 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. Results MR 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 in SMAD3 PV compared to other TGF-β PV (OR 2.4 [1.2-4.7], P< 0.02). Severe disjunction (>10 mm) was only observed in the TGFβ subgroup and was further enriched in participants with SMAD3 PV (OR 3.5 [1.2-10.7]). MVP (OR 8.7 [4.2-18.2]) and MR (OR 4.5 [2.5-8.6]) were increased in participants with MAD, but MAD was not independently associated with adverse cardiac or aortic events. Conclusions Mitral phenotypes are more prevalent in patients with PV in TGF-β pathway genes, particularly in SMAD3, 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 patients, especially if they also have a family history of HTAD. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement DM Milewicz and SK Prakash are funded by the Genetic Aortic Disorders Association (GADA) and the John Ritter Foundation for Aortic Health. DM Milewicz is also funded by the Temerty Family Foundation. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was reviewed and approved by the Committee for the Protection of Human Subjects at the University of Texas Health Science Center at Houston (IRB HSC-MS-16-0191). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The authors declare that all supporting data are available within the article and its online supplementary files