Comparative Risks of Initial Aortic Events Associated With Genetic Thoracic Aortic Disease

Ellen S. Regalado, Shaine A. Morris, Alan C. Braverman, Ellen M. Hostetler, Julie De Backer, Ruosha Li, Reed E. Pyeritz, Anji T. Yetman, Elena Cervi, Sherene Shalhub, Richmond Jeremy, Scott LeMaire, Maral Ouzounian, Arturo Evangelista, Catherine Boileau, Guillaume Jondeau, Dianna M. Milewicz

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


Background: Pathogenic variants in 11 genes predispose individuals to heritable thoracic aortic disease (HTAD), but limited data are available to stratify the risk for aortic events associated with these genes. Objectives: This study sought to compare the risk of first aortic event, specifically thoracic aortic aneurysm surgery or an aortic dissection, among 7 HTAD genes and variant types within each gene. Methods: A retrospective cohort of probands and relatives with rare variants in 7 genes for HTAD (n = 1,028) was assessed for the risk of first aortic events based on the gene altered, pathogenic variant type, sex, proband status, and location of recruitment. Results: Significant differences in aortic event risk were identified among the smooth muscle contraction genes (ACTA2, MYLK, and PRKG1; P = 0.002) and among the genes for Loeys-Dietz syndrome, which encode proteins in the transforming growth factor (TGF)-β pathway (SMAD3, TGFB2, TGFBR1, and TGFBR2; P < 0.0001). Cumulative incidence of type A aortic dissection was higher than elective aneurysm surgery in patients with variants in ACTA2, MYLK, PRKG1, and SMAD3; in contrast, patients with TGFBR2 variants had lower cumulative incidence of type A aortic dissection than elective aneurysm surgery. Cumulative incidence of type B aortic dissection was higher for ACTA2, PRKG1, and TGFBR2 than other genes. After adjusting for proband status, sex, and recruitment location, specific variants in ACTA2 and TGFBR2 were associated with substantially higher risk of aortic event with childhood onset. Conclusions: Gene- and variant-specific data on aortic events in individuals with HTAD support personalized aortic surveillance and clinical management.

Original languageEnglish (US)
Pages (from-to)857-869
Number of pages13
JournalJournal of the American College of Cardiology
Issue number9
StatePublished - Aug 30 2022


  • Loeys-Dietz syndrome
  • aortic dissection
  • pathogenic variant
  • precision medicine
  • thoracic aortic aneurysm

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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