Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome

• Published in: Heart (British Cardiac Society) Vol. 103; no. 22; p. 1795
• Main Authors: Franken, Romy, Teixido-Tura, Gisela, Brion, Maria, Forteza, Alberto, Rodriguez-Palomares, Jose, Gutierrez, Laura, Garcia Dorado, David, Pals, Gerard, Mulder, Barbara Jm, Evangelista, Artur
• Format: Journal Article
• Language: English
• Published: England 01-11-2017
• Subjects: Adolescent; Adult; Aneurysm, Dissecting - diagnostic imaging; Aneurysm, Dissecting - genetics; Aneurysm, Dissecting - metabolism; Aorta - diagnostic imaging; Aorta - pathology; Aortic Aneurysm - diagnostic imaging; Aortic Aneurysm - genetics; Aortic Aneurysm - mortality; Dilatation, Pathologic; Disease Progression; DNA Mutational Analysis; Echocardiography; Female; Fibrillin-1 - genetics; Genetic Predisposition to Disease; Haploinsufficiency; Humans; Male; Marfan Syndrome - complications; Marfan Syndrome - diagnosis; Marfan Syndrome - genetics; Marfan Syndrome - mortality; Middle Aged; Mutation; Phenotype; Predictive Value of Tests; Prognosis; Retrospective Studies; Risk Factors; Severity of Illness Index; Spain; Time Factors; Young Adult; haploinsufficiency; aortic dissection; Marfan syndrome; aortic dilation; FBN1
• ISSN: 1468-201X
• DOI: 10.1136/heartjnl-2016-310631

The effect of
mutation type on the severity of cardiovascular manifestations in patients with Marfan syndrome (MFS) has been reported with disparity results.
This study aims to determine the impact of the
mutation type on aortic diameters, aortic dilation rates and on cardiovascular events (ie, aortic dissection and cardiovascular mortality).
MFS patients with a pathogenic
mutation followed at two specialised units were included.
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.
Two hundred and ninety patients with MFS were included: 113 (39%) with an HI-
mutation and 177 (61%) with a DN-
. At baseline, patients with HI-
had a larger aortic root diameter than patients with DN-
(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-
(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-
tended to be at increased risk for the combined endpoint of dissection and death compared with patients with DN-
(HR: 3.3, 95% CI 1.0 to 11.4, p=0.060).
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.