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Background: Marfan syndrome can cause life-threatening aortic complications. We investigated the relationship between FBN1 genotype and severe aortopathy (aortic root replacement, type A dissections, and related death)., Methods: We evaluated 248 patients with pathogenic or likely pathogenic FBN1 variants. The variants were classified as haploinsufficient type (HI, n=93) or dominant-negative type (DN, n=155) based on their location and predicted amino acid alterations, and we examined the effects of the FBN1 genotype on severe aortic events (aortic root replacement, type A dissections, and related death)., Results: The cumulative event-free probability was significantly lower in the HI group than in the DN group (adjusted hazard ratio, 2.1; 95% confidence interval, 1.4 -3.2; P <0.001)., Conclusions: DN-CD+HI patients should be monitored more carefully than DN-nonCD patients for rapid development of aortic root aneurysms., (© 2018 American Heart Association, Inc.)

Objective: To investigate pregnancy outcomes, especially the risk of pregnancy-related aortic dissection (AD), in patients with Marfan syndrome (MFS) after prophylactic aortic root replacement (ARR)., Design: Retrospective case series study., Setting: Tertiary perinatal care centre at a university hospital., Population: Pregnant women fulfilling the revised Ghent nosology (2010) criteria for MFS who were managed at our institute., Methods: The pregnancy outcomes of all patients with MFS managed at our institute between 1982 and September 2016 were reviewed retrospectively based on medical records., Main Outcome Measures: Obstetrical management and complication including the incidence of AD throughout the peripartum period., Results: Among 22 patients (28 pregnancies) who had been managed as potential MFS or related disorders, 14 (17 pregnancies) fulfilled the revised Ghent nosology (2010) criteria for MFS and were enrolled in this study. Five patients (five pregnancies) had received ARR before conception: three (60%) developed type B aortic dissection [AD(B)] during the peripartum period, compared with only one of 10 patients (12 pregnancies) without ARR (P < 0.05, Chi-square test)., Conclusions: Our study results suggest that MFS patients after prophylactic ARR are still at high risk of AD(B) during the peripartum period. Careful pre-pregnancy counselling and multidisciplinary care throughout the peripartum period are essential for the management of MFS, even after surgical repair of an ascending aortic aneurysm., Tweetable Abstract: MFS patients after prophylactic ARR are still at high risk of type B aortic dissection during the peripartum period., (© 2017 Royal College of Obstetricians and Gynaecologists.)

Marfan syndrome (MFS) is an autosomal dominant heritable disorder of connective tissue that affects the cardiovascular, skeletal, ocular, pulmonary, and nervous systems and is usually caused by mutations in the FBN1 gene, which encodes fibrillin-1. MFS is traditionally considered to result from the structural weakness of connective tissue. However, recent investigations on molecular mechanisms indicate that increased transforming growth factor-β (TGF-β) activity plays a crucial role in the pathogenesis of MFS and related disorders, such as Loeys-Dietz syndrome (LDS), which is caused by mutation in TGF-β signaling-related genes. In addition, recent studies show that angiotensin II type 1 receptor (AT1R) signaling enhances cardiovascular pathologies in MFS, and the angiotensin II receptor blocker losartan has the potential to inhibit aortic aneurysm formation. However, the relationship between TGF-β and AT1R signaling pathways remains poorly characterized. In this review, we discuss the recent studies on the molecular mechanisms underlying cardiovascular manifestations of MFS and LDS and the ensuing strategies for management.

Background: In valve-sparing aortic root replacement (VSARR), how to reproduce Valsalva sinus has been an issue. In the original David V procedure, they put plication stitches at sinotubular junction level, although the reefing effect is limited and distal graft remains larger than native. Other modified techniques are two-grafts technique and ready-made Valsalva graft. However, the former needs graft-graft anastomosis and may not be cost-effective, while in the latter, the shape of sinus is fixed and minor adjustment is difficult. David V University of Tokyo modification (David V-UT) is our original solution to that, creating pseudosinus with one straight graft by longitudinal size-reduction running sutures above each pseudosinus. The purpose of the present study is to investigate long-term outcome of David V-UT., Methods: We analyzed 59 David V-UT patients from February 2004 to February 2013 and long-term outcomes were investigated by Kaplan-Meier methods. Risk factors for adverse events "death or recurrent aortic insufficiency (AI) with or without aortic valve reoperation" were analyzed by using Cox proportional hazard models., Results: Mean age was 33.1±14.5 years, and 38 patients (64%) were male. Marfan syndrome (MFS) accounts for 47 patients (80%). Only one patient was with bicuspid aortic valve. No in-hospital mortality was observed. Mean follow-up was 4.9±2.4 years. Estimated survival was 94.0±3.4% at 5 years. Freedoms from aortic valve reoperation and recurrent AI greater than mild were 95.7±3.0% and 88.9±4.7% at 5 years, respectively. In Cox proportional hazard analysis, preoperative AI greater than mild and Z score of annular diameter were significant risks for adverse events (p=0.027 and 0.045, hazard ratio 6.084 and 1.432, 95% C.I. 1.225-30.21 and 1.008-2.035, respectively)., Conclusions: Even in Marfan-characterized population, David V-UT provided satisfactory long-term outcome, comparable to other VSARR modifications. It is simple but can freely reproduce trilobed sinus with one straight graft., (Copyright © 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Marfan syndrome is an inherited disorder characterized by genetic abnormality of microfibrillar connective tissue proteins. Endothelial dysfunction is thought to cause aortic dilation in subjects with a bicuspid aortic valve; however, the role of endothelial dysfunction and endothelial damaging factors has not been elucidated in Marfan syndrome. Flow-mediated dilation, a noninvasive measurement of endothelial function, was evaluated in 39 patients with Marfan syndrome. Aortic diameter was measured at the aortic annulus, aortic root at the sinus of Valsalva, sinotubular junction and ascending aorta by echocardiography, and adjusted for body surface area (BSA). The mean value of flow-mediated dilation was 6.5 ± 2.4 %. Flow-mediated dilation had a negative correlation with the diameter of the ascending thoracic aorta (AscAd)/BSA (R = -0.39, p = 0.020) and multivariate analysis revealed that flow-mediated dilation was an independent factor predicting AscAd/BSA, whereas other segments of the aorta had no association. Furthermore, Brinkman index had a somewhat greater influence on flow-mediated dilation (R = -0.42, p = 0.008). Although subjects who smoked tended to have a larger AscAd compared with non-smokers (AscA/BSA: 17.3 ± 1.8 versus 15.2 ± 3.0 mm/m(2), p = 0.013), there was no significant change in flow-mediated dilation, suggesting that smoking might affect aortic dilation via an independent pathway. Common atherogenic risks, such as impairment of flow-mediated dilation and smoking status, affected aortic dilation in subjects with Marfan syndrome.

Marfan syndrome (MFS) is an inherited connective tissue disorder mainly caused by the fibrillin-1 mutation. Deficient fibrillin-1 is thought to result in the failed sequestration of transforming growth factor β (TGFβ) and subsequent activation of the TGFβ signaling pathway, suggesting that the circulating TGFβ level may be elevated in MFS, although its accurate measurement is complex due to ex vivo release from platelet stores upon platelet activation. We measured the plasma TGFβ1 levels of 32 Japanese MFS patients (22 medically untreated, 10 treated, 20 males, 30.1 ± 9.6 years old) and 30 healthy volunteers (19 males, 29.5 ± 5.8 years old) by ruthenium-based electrochemiluminescence platform (ECL). PF4 was also measured by enzyme immunoassay (EIA) as a platelet degranulation marker. There was no significant difference in the mean plasma TGFβ1 level between the MFS group (1.31 ± 0.40 ng/mL) and controls (1.17 ± 0.33 ng/mL) (P = 0.16, NS). Also, there was no significant difference between the untreated (1.24 ± 0.37 ng/mL) and treated (1.46 ± 0.45 ng/mL) MFS patients (P = 0.15, NS). We also measured PF4, which showed wide deviations but no significant difference between the two groups (P = 0.50). A difference in circulating TGFβ1 levels between MFS patients and controls was not detected in this Japanese population. Circulating TGFβ1 is not a diagnostic and therapeutic marker for Japanese MFS patients, although our findings do not eliminate the possible association of TGFβ with the pathogenesis of MFS.

Marfan syndrome (MS) is an inherited connective tissue disorder, and detailed evaluations of multiple organ systems are required for its diagnosis. Genetic testing of the disease-causing fibrillin-1 gene (FBN1) is also important in this diagnostic scheme. The aim of this study was to define the clinical characteristics of Japanese patients with MS and enable the efficient and accurate diagnosis of MS with mutational analysis using a high-throughput microarray-based resequencing system. Fifty-three Japanese probands were recruited, and their clinical characteristics were evaluated using the Ghent criteria. For mutational analysis, an oligonucleotide microarray was designed to interrogate FBN1, and the entire exon and exon-intron boundaries of FBN1 were sequenced. Clinical evaluation revealed more pulmonary phenotypes and fewer skeletal phenotypes in Japanese patients with MS compared to Caucasians. The microarray-based resequencing system detected 35 kinds of mutations, including 23 new mutations. The mutation detection rate for patients who fulfilled the Ghent criteria reached 71%. Of note, splicing mutations accounted for 19% of all mutations, which is more than previously reported. In conclusion, this comprehensive approach successfully detected clinical phenotypes of Japanese patients with MS and demonstrated the usefulness and feasibility of this microarray-based high-throughput resequencing system for mutational analysis of MS., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Annuloaortic ectasia is frequently related with Marfan syndrome, and Bentall procedure or aortic root replacement with valved conduit has been the conventional standard operation for this disease. Recently, some institutes have adopted valve-sparing aortic root replacement (VSARR) instead of Bentall procedure. Young female patients with Marfan syndrome who wishes for childbearing seem to be a group of good candidates of this type of operation, because it let them free from morbidities after artificial valve implantation. Valve-sparing operation should be taken into consideration when the size of Valsalva sinus reaches 45 mm for patients with Marfan syndrome and when it reaches 40 mm for patients with past histories or family histories of aortic dissection or aortic rupture. Since pregnancy is one of the most serious risk factors for aortic events, Valsalva sinus of 40 mm or larger could be the new standard for surgical indication if VSARR is applicable.

Objective: To investigate pregnancy outcomes, especially the risk of pregnancy-related aortic dissection (AD), in patients with Marfan syndrome (MFS) after prophylactic aortic root replacement (ARR).Design: Retrospective case series study.Setting: Tertiary perinatal care centre at a university hospital.Population: Pregnant women fulfilling the revised Ghent nosology (2010) criteria for MFS who were managed at our institute.Methods: The pregnancy outcomes of all patients with MFS managed at our institute between 1982 and September 2016 were reviewed retrospectively based on medical records.Main Outcome Measures: Obstetrical management and complication including the incidence of AD throughout the peripartum period.Results: Among 22 patients (28 pregnancies) who had been managed as potential MFS or related disorders, 14 (17 pregnancies) fulfilled the revised Ghent nosology (2010) criteria for MFS and were enrolled in this study. Five patients (five pregnancies) had received ARR before conception: three (60%) developed type B aortic dissection [AD(B)] during the peripartum period, compared with only one of 10 patients (12 pregnancies) without ARR (P < 0.05, Chi-square test).Conclusions: Our study results suggest that MFS patients after prophylactic ARR are still at high risk of AD(B) during the peripartum period. Careful pre-pregnancy counselling and multidisciplinary care throughout the peripartum period are essential for the management of MFS, even after surgical repair of an ascending aortic aneurysm.Tweetable Abstract: MFS patients after prophylactic ARR are still at high risk of type B aortic dissection during the peripartum period. [ABSTRACT FROM AUTHOR]