Ellen S Regalado1, Dong-chuan Guo1, Siddharth Prakash1, Tracy A Bensend1, Kelly Flynn1, Anthony Estrera1, Hazim Safi1, David Liang1, James Hyland1, Anne Child1, Gavin Arno1, Catherine Boileau1, Guillaume Jondeau1, Alan Braverman1, Rocio Moran1, Takayuki Morisaki1, Hiroko Morisaki1, Reed Pyeritz1, Joseph Coselli1, Scott LeMaire1, Dianna M Milewicz2. 1. Departments 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.). 2. Departments 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.). Dianna.M.Milewicz@uth.tmc.edu.
Abstract
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.
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.
Authors: Ingrid M B H van de Laar; Denise van der Linde; Edwin H G Oei; Pieter K Bos; Johannes H Bessems; Sita M Bierma-Zeinstra; Belle L van Meer; Gerard Pals; Rogier A Oldenburg; Jos A Bekkers; Adriaan Moelker; Bianca M de Graaf; Gabor Matyas; Ingrid M E Frohn-Mulder; Janneke Timmermans; Yvonne Hilhorst-Hofstee; Jan M Cobben; Hennie T Bruggenwirth; Lut van Laer; Bart Loeys; Julie De Backer; Paul J Coucke; Harry C Dietz; Patrick J Willems; Ben A Oostra; Anne De Paepe; Jolien W Roos-Hesselink; Aida M Bertoli-Avella; Marja W Wessels Journal: J Med Genet Date: 2012-01 Impact factor: 6.318
Authors: P G Hagan; C A Nienaber; E M Isselbacher; D Bruckman; D J Karavite; P L Russman; A Evangelista; R Fattori; T Suzuki; J K Oh; A G Moore; J F Malouf; L A Pape; C Gaca; U Sechtem; S Lenferink; H J Deutsch; H Diedrichs; J Marcos y Robles; A Llovet; D Gilon; S K Das; W F Armstrong; G M Deeb; K A Eagle Journal: JAMA Date: 2000-02-16 Impact factor: 56.272
Authors: Ellen S Regalado; Dong-Chuan Guo; Carlos Villamizar; Nili Avidan; Dawna Gilchrist; Barbara McGillivray; Lorne Clarke; Francois Bernier; Regie L Santos-Cortez; Suzanne M Leal; Aida M Bertoli-Avella; Jay Shendure; Mark J Rieder; Deborah A Nickerson; Dianna M Milewicz Journal: Circ Res Date: 2011-07-21 Impact factor: 17.367
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Authors: Hans Ulrik Moller; Hans C Fledelius; Dianna M Milewicz; Ellen S Regalado; John R Ostergaard Journal: Br J Ophthalmol Date: 2012-07-11 Impact factor: 4.638
Authors: Ellen S Regalado; Dong-chuan Guo; Anthony L Estrera; L Maximilian Buja; Dianna M Milewicz Journal: Am J Med Genet A Date: 2013-11-15 Impact factor: 2.802
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Authors: Peggy Robinet; Dianna M Milewicz; Lisa A Cassis; Nicholas J Leeper; Hong S Lu; Jonathan D Smith Journal: Arterioscler Thromb Vasc Biol Date: 2018-01-04 Impact factor: 8.311
Authors: Hailong Lu; Patricia M Fagnant; Carol S Bookwalter; Peteranne Joel; Kathleen M Trybus Journal: Proc Natl Acad Sci U S A Date: 2015-07-07 Impact factor: 11.205
Authors: Dianna M Milewicz; Kathleen M Trybus; Dong-Chuan Guo; H Lee Sweeney; Ellen Regalado; Kristine Kamm; James T Stull Journal: Arterioscler Thromb Vasc Biol Date: 2016-11-22 Impact factor: 8.311
Authors: Adam J Brownstein; Bulat A Ziganshin; Helena Kuivaniemi; Simon C Body; Allen E Bale; John A Elefteriades Journal: Aorta (Stamford) Date: 2017-02-01
Authors: Marjolijn Renard; Catherine Francis; Rajarshi Ghosh; Alan F Scott; P Dane Witmer; Lesley C Adès; Gregor U Andelfinger; Pauline Arnaud; Catherine Boileau; Bert L Callewaert; Dongchuan Guo; Nadine Hanna; Mark E Lindsay; Hiroko Morisaki; Takayuki Morisaki; Nicholas Pachter; Leema Robert; Lut Van Laer; Harry C Dietz; Bart L Loeys; Dianna M Milewicz; Julie De Backer Journal: J Am Coll Cardiol Date: 2018-08-07 Impact factor: 24.094