Romy Franken1,2, Maarten Groenink1,2,3, Vivian de Waard4, Helena M A Feenstra1, Arthur J Scholte5, Maarten P van den Berg6, Gerard Pals7, Aeilko H Zwinderman8, Janneke Timmermans9, Barbara J M Mulder10,2. 1. Department of Cardiology, Academic Medical Center Amsterdam, B2-240, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands. 2. Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands. 3. Department of Radiology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands. 4. Department of Medical Biochemistry, Academic Medical Center Amsterdam, Amsterdam, The Netherlands. 5. Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. 6. Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands. 7. Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands. 8. Department of Clinical Epidemiology and Biostatistics, Academic Medical Center, Amsterdam, The Netherlands. 9. Department of Cardiology, st. Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. 10. Department of Cardiology, Academic Medical Center Amsterdam, B2-240, Meibergdreef 9, Amsterdam 1105 AZ, The Netherlands b.j.mulder@amc.uva.nl.
Abstract
AIMS: The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFS patients. METHODS AND RESULTS: We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 ± 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 ± 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P < 0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to a DN effect (abnormal fibrillin-1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P < 0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014). CONCLUSION: Marfan syndrome patients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The aorta in Marfan syndrome (MFS) patients is variably affected. We investigated the assumed genotype-effect on protein production as a risk factor for a severe aortic phenotype in adult MFSpatients. METHODS AND RESULTS: We collected clinical and genetic data from all 570 adults with MFS who had been included in the Dutch CONgenital CORvitia registry since the start in 2001. Mean age was 36.5 ± 13.5 years (51.2% male, 28.9% prior aortic surgery, 8.2% prior aortic dissection). Patients were prospectively followed for a mean duration of 8.2 ± 3.1 years. Men had more frequently aortic surgery at baseline (38.0 vs. 19.4%, P < 0.001) and during follow-up (24.0 vs. 15.1%, P = 0.008) compared with women. After 10-year follow-up cumulative survival was 93.8% and dissection-free survival was 84.2%. We found a pathogenic FBN1 mutation in 357 patients, of whom 146 patients (40.9%) were positive for a mutation causing haploinsufficiency (reduced fibrillin-1 protein) and 211 (59.1%) for a mutation leading to a DN effect (abnormal fibrillin-1 protein). Corrected for age, sex, and previous aortic complications, patients with a haploinsufficient (HI) mutation had a 2.5-fold increased risk for cardiovascular death (hazard ratio, HR: 2.5, 95% CI: 1.0-6.1, P = 0.049), a 2.4-fold increased risk for the combined endpoint comprising death and dissection (HR: 2.4, 95% CI: 1.4-4.2, P < 0.001) and a 1.6-fold increased risk for any aortic complication compared with patients with a DN mutation (HR: 1.6, 95% CI 1.1-2.3, P = 0.014). CONCLUSION:Marfan syndromepatients with an HI mutation are at increased risk for cardiovascular death and aortic dissection compared with patients with a DN mutation. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Mitzi M van Andel; Pim van Ooij; Vivian de Waard; Lukas M Gottwald; Roland R J van Kimmenade; Arthur J Scholte; Michael G Dickinson; Aeilko H Zwinderman; Barbara J M Mulder; Aart J Nederveen; Maarten Groenink Journal: Int J Cardiol Heart Vasc Date: 2022-10-17
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: Zoltán Szabolcs; Kálmán Benke; Roland Stengl; Bence Ágg; Miklós Pólos; Gábor Mátyás; Gábor Szabó; Béla Merkely; Tamás Radovits Journal: Orphanet J Rare Dis Date: 2021-05-31 Impact factor: 4.123