Aggressive Cardiovascular Phenotype of Aneurysms-Osteoarthritis Syndrome Caused by Pathogenic SMAD3 Variants.

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Title:	Aggressive Cardiovascular Phenotype of Aneurysms-Osteoarthritis Syndrome Caused by Pathogenic SMAD3 Variants.
Author(s):	Linde, D. van der; Laar, I.M. van de; Bertoli-Avella, A.M.; Oldenburg, R.A.; Bekkers, J.A.; Mattace-Raso, F.U.; Meiracker, A.H. van den; Moelker, A.; Kooten, F. van; Frohn-Mulder, I.M.; Timmermans, J. ; Moltzer, E.; Cobben, J.M.; Laer, L. van; Loeys, B.L.; Backer, J. de; Coucke, P.J.; Paepe, A. de; Hilhorst-Hofstee, Y.; Wessels, M.W.; Roos-Hesselink, J.W.
Publication year:	2012
Source:	Journal of the American College of Cardiology, vol. 60, iss. 5, (2012), pp. 397-403
ISSN:	0735-1097
DOI:	https://doi.org/10.1016/j.jacc.2011.12.052
Publication type:	Article / Letter to editor
Please use this identifier to cite or link to this item : http://hdl.handle.net/2066/108881
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Subject:	IGMD 3: Genomic disorders and inherited multi-system disorders NCEBP 14: Cardiovascular diseases
Organization:	Cardiology Human Genetics
Journal title:	Journal of the American College of Cardiology
Volume:	vol. 60
Issue:	iss. 5
Page start:	p. 397
Page end:	p. 403
Abstract:	OBJECTIVES: The purpose of this study was describe the cardiovascular phenotype of the aneurysms-osteoarthritis syndrome (AOS) and to provide clinical recommendations. BACKGROUND: AOS, caused by pathogenic SMAD3 variants, is a recently described autosomal dominant syndrome characterized by aneurysms and arterial tortuosity in combination with osteoarthritis. METHODS: AOS patients in participating centers underwent extensive cardiovascular evaluation, including imaging, arterial stiffness measurements, and biochemical studies. RESULTS: We included 44 AOS patients from 7 families with pathogenic SMAD3 variants (mean age: 42 +/- 17 years). In 71%, an aortic root aneurysm was found. In 33%, aneurysms in other arteries in the thorax and abdomen were diagnosed, and in 48%, arterial tortuosity was diagnosed. In 16 patients, cerebrovascular imaging was performed, and cerebrovascular abnormalities were detected in 56% of them. Fifteen deaths occurred at a mean age of 54 +/- 15 years. The main cause of death was aortic dissection (9 of 15; 60%), which occurred at mildly increased aortic diameters (range: 40 to 63 mm). Furthermore, cardiac abnormalities were diagnosed, such as congenital heart defects (6%), mitral valve abnormalities (51%), left ventricular hypertrophy (19%), and atrial fibrillation (22%). N-terminal brain natriuretic peptide (NT-proBNP) was significantly higher in AOS patients compared with matched controls (p < 0.001). Aortic pulse wave velocity was high-normal (9.2 +/- 2.2 m/s), indicating increased aortic stiffness, which strongly correlated with NT-proBNP (r = 0.731, p = 0.005). CONCLUSIONS: AOS predisposes patients to aggressive and widespread cardiovascular disease and is associated with high mortality. Dissections can occur at relatively mildly increased aortic diameters; therefore, early elective repair of the ascending aorta should be considered. Moreover, cerebrovascular abnormalities were encountered in most patients.