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Original research article
Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome
  1. Romy Franken1,2,
  2. Gisela Teixido-Tura1,
  3. Maria Brion3,
  4. Alberto Forteza4,
  5. Jose Rodriguez-Palomares1,
  6. Laura Gutierrez1,
  7. David Garcia Dorado1,
  8. Gerard Pals5,
  9. Barbara JM Mulder2,6,
  10. Artur Evangelista7
  1. 1 Servei de Cardiologia, Unitat de Marfan, Hospital Universitari, Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain
  2. 2 Interuniversity Cardiology Institute of the Netherlands, Utrecht, The Netherlands
  3. 3 Xenética de enfermidades cardiovasculares e oftalmolóxicas, Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain
  4. 4 Marfan Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
  5. 5 Department of Clinical Genetics, VU University Medical Centre, Amsterdam, The Netherlands
  6. 6 Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands
  7. 7 Servei de Cardiologia, Unitat de Marfan, Hospital Universitari, Vall d’Hebron,UniversitatAutònoma de Barcelona, CIBERCV, Barcelona, Spain
  1. Correspondence to Dr Artur Evangelista, Artur Evangelista, Servei de Cardiologia, Hospital Universitari, Vall d’Hebron, P° Vall d’Hebron 119. 08035 Barcelona, Spain; aevangel{at}vhebron.net

Abstract

Background The effect of FBN1 mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results.

Objectives This study aims to determine the impact of the FBN1 mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality).

Methods MFS patients with a pathogenic FBN1 mutation followed at two specialised units were included. FBN1 mutations were classified as being dominant negative (DN; incorporation of non-mutated and mutated fibrillin-1 in the extracellular matrix) or having haploinsufficiency (HI; only incorporation of non-mutated fibrillin-1, thus a decreased amount of fibrillin-1 protein). Aortic diameters and the aortic dilation rate at the level of the aortic root, ascending aorta, arch, descending thoracic aorta and abdominal aorta by echocardiography and clinical endpoints comprising dissection and death were compared between HI and DN patients.

Results Two hundred and ninety patients with MFS were included: 113 (39%) with an HI-FBN1 mutation and 177 (61%) with a DN-FBN1. At baseline, patients with HI-FBN1 had a larger aortic root diameter than patients with DN-FBN1 (HI: 39.3±7.2 mm vs DN: 37.3±6.8 mm, p=0.022), with no differences in age or body surface area. After a mean follow-up of 4.9±2.0 years, aortic root and ascending dilation rates were increased in patients with HI-FBN1 (HI: 0.57±0.8 vs DN: 0.28±0.5 mm/year, p=0.004 and HI: 0.59±0.9 vs DN: 0.30±0.7 mm/year, p=0.032, respectively). Furthermore, patients with HI-FBN1 tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-FBN1 (HR: 3.3, 95% CI 1.0 to 11.4, p=0.060).

Conclusions Patients with an HI mutation had a more severely affected aortic phenotype, with larger aortic root diameters and a more rapid dilation rate, and tended to have an increased risk of death and dissections compared with patients with a DN mutation.

  • Marfan syndrome
  • aortic dilation
  • aortic dissection
  • FBN1
  • haploinsufficiency

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Footnotes

  • Funding This study has been funded by Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (CIBERCV), Spain through the project PI14/01062 (Co-funded by European Regional Development Fund). The author RF is funded by a fellowship grant from the Interuniversity Cardiology Institute of the Netherlands. Authors declare no relationships with industry.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval METC Barcelona.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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