Norifumi Takeda1, Ryo Inuzuka2, Sonoko Maemura3, Hiroyuki Morita3, Kan Nawata4, Daishi Fujita3, Yuki Taniguchi5, Haruo Yamauchi4, Hiroki Yagi3, Masayoshi Kato3, Hiroshi Nishimura3, Yoichiro Hirata2, Yuichi Ikeda3, Hidetoshi Kumagai3,6, Eisuke Amiya3, Hironori Hara3, Takayuki Fujiwara3, Hiroshi Akazawa3, Jun-Ichi Suzuki3,6, Yasushi Imai7,8, Ryozo Nagai9, Shinichi Takamoto10, Yasunobu Hirata11, Minoru Ono4, Issei Komuro3. 1. Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.), notakeda-tky@umin.ac.jp. 2. Department of Pediatrics (R.I., Y.H.). 3. Department of Cardiovascular Medicine (N.T., S.M., H.M., D.F., H. Yagi, M.K., H.N., Y. Ikeda, H.K., E.A., H.H., T.F., H.A., J.-i.S., I.K.). 4. Department of Cardiac Surgery (K.N., H. Yamauchi, M.O.). 5. Department of Orthopedic Surgery (Y.T.). 6. Department of Advanced Clinical Science and Therapeutics (H.K., J.-i.S.). 7. The University of Tokyo Hospital, Tokyo, Japan. Division of Clinical Pharmacology, Department of Pharmacology (Y. Imai). 8. Division of Cardiovascular Medicine, Department of Internal Medicine (Y. Imai). 9. Jichi Medical University, Shimotsuke, Tochigi, Japan. Jichi Medical University, Shimotsuke, Tochigi, Japan (R.N.). 10. Mitsui Memorial Hospital, Tokyo, Japan (S.T.). 11. Tokyo Teishin Hospital, Tokyo, Japan (Y.H.).
Abstract
BACKGROUND: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death). METHODS: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death). RESULTS: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P<0.001). CONCLUSIONS: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms.
BACKGROUND: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death). METHODS: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death). RESULTS: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P<0.001). CONCLUSIONS:DN-CD+HIpatients should be monitored more carefully than DN-nonCDpatients for rapid development of aortic root aneurysms.
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