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

doi:10.1016/j.jacc.2022.05.054

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

J Am Coll Cardiol. 2022 Aug 30;80(9):857-869. doi: 10.1016/j.jacc.2022.05.054.

Authors

Ellen S Regalado¹, Shaine A Morris², Alan C Braverman³, Ellen M Hostetler¹, Julie De Backer⁴, Ruosha Li⁵, Reed E Pyeritz⁶, Anji T Yetman⁷, Elena Cervi⁸, Sherene Shalhub⁹, Richmond Jeremy¹⁰, Scott LeMaire¹¹, Maral Ouzounian¹², Arturo Evangelista¹³, Catherine Boileau¹⁴, Guillaume Jondeau¹⁴, Dianna M Milewicz¹⁵

Affiliations

¹ Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA.
² Division of Pediatric Cardiology, Baylor College of Medicine, Houston, Texas, USA.
³ Cardiovascular Division, Department of Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
⁴ Department of Cardiology and Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium; European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), Heritable Thoracic Aortic Disease Working Group.
⁵ Department of Biostatistics and Data Science, School of Public Health, UTHealth, Houston, Texas, USA.
⁶ Departments of Medicine and Genetics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Division of Pediatric Cardiology, Children's Hospital & Medical Center, University of Nebraska Medical Center, Omaha, Nebraska, USA.
⁸ Centre for Inherited Cardiovascular Diseases, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.
⁹ Department of Vascular Surgery, University of Washington, Seattle, Washington, USA.
¹⁰ Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
¹¹ Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas, USA.
¹² Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, University of Toronto, Toronto, Ontario, Canada.
¹³ European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), Heritable Thoracic Aortic Disease Working Group; Department of Cardiology, Hospital Vall d'Hebron, Vall d'Hebron Research Institute, CIBER-CV, Barcelona, Spain.
¹⁴ European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), Heritable Thoracic Aortic Disease Working Group; CRMR Syndrome de Marfan et apparentés, Department of Cardiology, AP-HP, INSERM U1148, Hopital Bichat, Université de Paris, Paris, France.
¹⁵ Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston (UTHealth), Houston, Texas, USA. Electronic address: Dianna.M.Milewicz@uth.tmc.edu.

PMID: 36007983
DOI: 10.1016/j.jacc.2022.05.054

Abstract

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.

Keywords: Loeys-Dietz syndrome; aortic dissection; pathogenic variant; precision medicine; thoracic aortic aneurysm.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aortic Aneurysm, Thoracic* / genetics
Aortic Dissection* / genetics
Child
Humans
Mutation
Receptor, Transforming Growth Factor-beta Type II / genetics
Retrospective Studies

Substances

Receptor, Transforming Growth Factor-beta Type II

Abstract

Publication types

MeSH terms

Substances

Grants and funding