TY - JOUR
T1 - Differences in Arterial Events in Vascular Ehlers-Danlos, Loeys-Dietz, and Marfan Syndrome
AU - Calderon-Martinez, Ernesto
AU - Velasco, Walter V.
AU - Guo, Dongchuan
AU - Hostetler, Ellen H.
AU - Xun, Zhang
AU - Stephens, Sara
AU - Shalhub, Sherene
AU - De Backer, Julie
AU - Ouzounian, Maral
AU - LeMaire, Scott A.
AU - Milleron, Olivier
AU - Hanna, Nadine
AU - Arnaud, Pauline
AU - Tchitchinadze, Maria
AU - Prakash, Siddharth K.
AU - Lindsay, Mark
AU - Marcadier, Julien
AU - Jeremy, Richmond
AU - Morris, Shaine A.
AU - Yetman, Anji T.
AU - Boileau, Catherine
AU - Braverman, Alan C.
AU - Jondeau, Guillaume
AU - Milewicz, Dianna M.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/6/24
Y1 - 2025/6/24
N2 - Background: Heritable thoracic aortic disease is due to altered genes that confer a highly penetrant risk for thoracic aortic aneurysm and dissection, and a subset of these genes also cause aneurysms and dissections of peripheral arteries beyond the aorta. Arterial aneurysms, dissections, and ruptures are associated with pathogenic variants (PVs) in COL3A1, which is responsible for vascular Ehlers-Danlos syndrome, but arterial events are rare in Marfan syndrome due to PVs in FBN1, and poorly characterized in Loeys-Dietz syndrome due to PVs in the transforming growth factor (TGF)–β pathway genes. Objectives: This study sought to define the relative risk of arterial and aortic events in individuals with PVs in FBN1, COL3A1, and TGF-β pathway genes. Methods: The Montalcino Aortic Consortium provided a retrospective cohort of 1,780 individuals with PVs in COL3A1 (n = 125), FBN1 (n = 1028), and the TGF-β pathway genes (TGFBR1, n = 137; TGFBR2, n = 168; SMAD3, n = 196; TGFB2, n = 126). Arterial events were defined as dissections, ruptures, or aneurysms in arteries beyond the aorta requiring open or endovascular repair, and aortic events were defined by aortic dissections or repair of an aortic aneurysm. Results: Arterial events were identified in 83 individuals, with the highest prevalence in COL3A1 (20.8%), followed by TGFBR2 (7.7%), TGFBR1 (7.3%), TGFB2 (6.4%), SMAD3 (5.6%), and FBN1 (1.5%). Kaplan-Meier curves identified significant gene differences, with COL3A1 having the most and earliest arterial events when compared with TGF-β genes and FBN1. For TGF-β genes and FBN1, aortic events were significantly earlier and more penetrant than arterial events, whereas this difference was not present with COL3A1. Sex impacts arterial events; males with COL3A1 had earlier and more arterial events compared with males with TGF-β genes, and these differences were not observed in females. Arterial events in FBN1 cases occur primarily in men. Conclusions: There are significant gene- and sex-specific differences in the prevalence and age of onset of arterial events associated with these heritable thoracic aortic disease genes, highlighting the importance of tailored counseling and surveillance based on the causative gene. Furthermore, smoking cessation and hypertension control should be emphasized in these patients to reduce the risk of arterial events.
AB - Background: Heritable thoracic aortic disease is due to altered genes that confer a highly penetrant risk for thoracic aortic aneurysm and dissection, and a subset of these genes also cause aneurysms and dissections of peripheral arteries beyond the aorta. Arterial aneurysms, dissections, and ruptures are associated with pathogenic variants (PVs) in COL3A1, which is responsible for vascular Ehlers-Danlos syndrome, but arterial events are rare in Marfan syndrome due to PVs in FBN1, and poorly characterized in Loeys-Dietz syndrome due to PVs in the transforming growth factor (TGF)–β pathway genes. Objectives: This study sought to define the relative risk of arterial and aortic events in individuals with PVs in FBN1, COL3A1, and TGF-β pathway genes. Methods: The Montalcino Aortic Consortium provided a retrospective cohort of 1,780 individuals with PVs in COL3A1 (n = 125), FBN1 (n = 1028), and the TGF-β pathway genes (TGFBR1, n = 137; TGFBR2, n = 168; SMAD3, n = 196; TGFB2, n = 126). Arterial events were defined as dissections, ruptures, or aneurysms in arteries beyond the aorta requiring open or endovascular repair, and aortic events were defined by aortic dissections or repair of an aortic aneurysm. Results: Arterial events were identified in 83 individuals, with the highest prevalence in COL3A1 (20.8%), followed by TGFBR2 (7.7%), TGFBR1 (7.3%), TGFB2 (6.4%), SMAD3 (5.6%), and FBN1 (1.5%). Kaplan-Meier curves identified significant gene differences, with COL3A1 having the most and earliest arterial events when compared with TGF-β genes and FBN1. For TGF-β genes and FBN1, aortic events were significantly earlier and more penetrant than arterial events, whereas this difference was not present with COL3A1. Sex impacts arterial events; males with COL3A1 had earlier and more arterial events compared with males with TGF-β genes, and these differences were not observed in females. Arterial events in FBN1 cases occur primarily in men. Conclusions: There are significant gene- and sex-specific differences in the prevalence and age of onset of arterial events associated with these heritable thoracic aortic disease genes, highlighting the importance of tailored counseling and surveillance based on the causative gene. Furthermore, smoking cessation and hypertension control should be emphasized in these patients to reduce the risk of arterial events.
KW - Loeys-Dietz syndrome
KW - Marfan syndrome
KW - arterial aneurysm
KW - arterial dissection
KW - heritable thoracic aortic disease
KW - vascular Ehlers-Danlos syndrome
UR - https://www.scopus.com/pages/publications/105007446280
U2 - 10.1016/j.jacc.2025.04.023
DO - 10.1016/j.jacc.2025.04.023
M3 - Article
C2 - 40533124
AN - SCOPUS:105007446280
SN - 0735-1097
VL - 85
SP - 2355
EP - 2367
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 24
ER -