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Published on: November 21, 2019
Aortic Disease Presentation and Outcome Associated With ACTA2 Mutations
Ellen S Regalado1, Dong-chuan Guo1, Siddharth Prakash1
1Departments of Internal Medicine (E.S.R., D.G., S.P., T.A.B., K.F., D.M.M.), Cardiothoracic and Vascular Surgery (A.E., H.S.), University of Texas Health Science Center at Houston; Department of Medicine, Stanford University Medical Center, CA (D.L.); Connective Tissue Gene Tests, Allentown, PA (J.H.); Department of Cardiac and Vascular Sciences, St. George's, University of London, London, United Kingdom (A.C., G.A.); AP-HP, Hôpital Bichat, Centre National de Référence pour le syndrome de Marfan et apparentés, Paris, France (C.B., G.J.), Université Paris 7, Paris, France (C.B., G.J.), AP-HP, Hôpital Bichat, Laboratoire de Génétique moléculaire, Boulogne, France (C.B.), and INSERM, U1148, Paris, France (C.B., G.J.); AP-HP, Hôpital Bichat, Service de Cardiologie, Paris, France (G.J.); Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO (A.B.); Genomic Medicine Institute, Cleveland Clinic, OH (R.M.); Department of Bioscience and Genetics, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan (T.M., H.M.); Perelman School of Medicine, University of Pennsylvania, Philadelphia (R.P.); Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX (J.C., S.L.); and Texas Heart Institute and Baylor St. Luke's Medical Center, Houston (J.C., S.L.).
Insights
ACTA2 gene mutations frequently cause thoracic aortic aneurysms and dissections. While 48% of individuals experienced aortic events, lifetime risk is 76%, indicating other factors influence disease.
Area of Science:
- Genetics
- Cardiovascular Medicine
- Aortic Diseases
Background:
- Actin alpha 2 (ACTA2) mutations are the primary genetic cause of familial thoracic aortic aneurysms and dissections (FTAAD).
- Understanding the clinical spectrum and outcomes associated with ACTA2 mutations is crucial for patient management.
Purpose of the Study:
- To characterize the aortic diseases, management strategies, and outcomes in a large cohort of individuals with ACTA2 mutations.
Main Methods:
- Retrospective review of medical records for 277 individuals with 41 distinct ACTA2 mutations.
- Data abstracted included aortic events, management, and outcomes.
Main Results:
- Aortic events occurred in 48% of individuals, predominantly thoracic aortic dissections (88%) with 25% mortality.
- Type A dissections were more common (54%) but Type B dissections had a younger onset (median 27 years).
- Cumulative risk of an aortic event by age 85 was 0.76; specific mutations (p.R179, p.R258) increased risk, while others (p.R185Q, p.R118Q) showed lower risk.
Conclusions:
- ACTA2 mutations confer a high risk of acute aortic dissection.
- The lifetime risk of 76% suggests that environmental or other genetic factors contribute to the expression of aortic disease.
Background:
ACTA2 mutations are the major cause of familial thoracic aortic aneurysms and dissections. We sought to characterize these aortic diseases in a large case series of individuals with ACTA2 mutations.
Methods And Results:
Aortic disease, management, and outcome associated with the first aortic event (aortic dissection or aneurysm repair) were abstracted from the medical records of 277 individuals with 41 various ACTA2 mutations. Aortic events occurred in 48% of these individuals, with the vast majority presenting with thoracic aortic dissections (88%) associated with 25% mortality. Type A dissections were more common than type B dissections (54% versus 21%), but the median age of onset of type B dissections was significantly younger than type A dissections (27 years versus 36 years). Only 12% of aortic events were repair of ascending aortic aneurysms, which variably involved the aortic root, ascending aorta, and aortic arch. Overall, cumulative risk of an aortic event at age 85 years was 0.76 (95% confidence interval, 0.64-0.86). After adjustment for intrafamilial correlation, sex and race, mutations disrupting p.R179 and p.R258 were associated with significantly increased risk for aortic events, whereas p.R185Q and p.R118Q mutations showed significantly lower risk of aortic events compared with other mutations.
Conclusions:
ACTA2 mutations are associated with high risk of presentation with an acute aortic dissection. The lifetime risk for an aortic event is only 76%, suggesting that additional environmental or genetic factors play a role in expression of aortic disease in individuals with ACTA2 mutations.
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