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Background: Aneurysms-osteoarthritis syndrome (AOS), caused by SMAD3 mutations, is a recently described autosomal dominant syndrome characterized by arterial tortuosity and aneurysms throughout the arterial tree in combination with osteoarthritis. This is the first study describing the cardiovascular findings.Methods and results: We describe 44 patients with proven SMAD3 mutations (age 42±17 years) who underwent in extensive cardiovascular evaluation, including TTE and CTA. In 68% of patients, arterial aneurysms were present, predominantly (87%) in the aortic root (Figure). In 11% multiple aneurysms were found and 46% showed arterial tortuosity throughout thorax and abdomen. In addition, in 38% intracranial aneurysms were found and 50% of patients showed intracranial tortuosity.Mortality was high (34%) with a median survival with elective surgery of 62 years. Main cause of death was aortic dissection (60%), which already happened at mildly dilated aortic diameters (mean Sinus of Valsalva diameter 43.2 ± 4.3 mm). Median age at first elective cardiovascular intervention, for example valve-sparing aortic root replacement or splenic artery coiling, was 41 years. Furthermore, intracardiac abnormalities were common, such as congenital heart defects (9%), mitral valve abnormalities (68%), left ventricular hypertrophy (23%) and atrial fibrillation (22%). NT-proBNP was significantly increased in AOS patients compared to matched controls (p<0.001).Conclusion: In conclusion, SMAD3 mutations predispose patients to aggressive and widespread cardiovascular disease. If left untreated, mortality is high. Dissections can occur at relatively small aortic diameters, so aggressive and early elective repair of the ascending aorta should be considered once the diameter reaches 40 mm.