TY - JOUR
T1 - Relationship between fibrillin-1 genotype and severity of cardiovascular involvement in Marfan syndrome
AU - Franken, Romy
AU - Teixido-Tura, Gisela
AU - Brion, Maria
AU - Forteza, Alberto
AU - Rodriguez-Palomares, Jose
AU - Gutierrez, Laura
AU - Garcia Dorado, David
AU - Pals, Gerard
AU - Mulder, Barbara Jm
AU - Evangelista, Artur
PY - 2017/11/1
Y1 - 2017/11/1
N2 - 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
AB - 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
KW - FBN1
KW - Marfan syndrome
KW - aortic dilation
KW - aortic dissection
KW - haploinsufficiency
UR - http://www.scopus.com/inward/record.url?scp=85030118972&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/heartjnl-2016-310631
DO - https://doi.org/10.1136/heartjnl-2016-310631
M3 - Article
C2 - 28468757
SN - 1355-6037
VL - 103
SP - 1795
EP - 1799
JO - Heart (British Cardiac Society)
JF - Heart (British Cardiac Society)
IS - 22
ER -