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The mechanisms leading to cardiac remodeling in Marfan syndrome (MFS) are a matter of debate since it could be either due to structural dysfunction of the myocardial extracellular matrix or to increased afterload caused by the dilated aorta. We aim to characterize the presence of abnormal myocardial function in MFS and to investigate its potential association with increased afterload. Aorta, left ventricle (LV) and the postsystolic thickening (PST) were analyzed in echocardiography in Fbn1 C1039G/+ mice and in patients with MFS in comparison with wild type (WT) mice and healthy humans. PST was more frequent in MFS than in WT mice (p < 0.05). MFS mice with PST showed larger aorta than those without PST. Patients with MFS showed larger aorta, poorer LV function and a higher prevalence of PST (56%) than did the healthy controls (23%); p = 0.003. Blood pressure was similar. The higher prevalence of PST in an experimental murine model and in MFS patients, regardless of systemic arterial pressure, suggests an increased afterload on the LV myocardium. This finding supports the use of PST as an indicator of myocardial damage and encourage searching for novel early preventive therapy., (© 2021. The Author(s).)

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene (FBN1), resulting in aortic aneurysm formation and dissections. Interestingly, variable aortopathy is observed even within MFS families with the same mutation. Thus, additional risk factors determine disease severity. Here, we describe a case of a 2-month-old Fbn1 C1039G/+ MFS mouse with extreme aortic dilatation and increased vascular inflammation, when compared to MFS siblings, which coincided with unilateral renal cystic disease. In addition, this mouse presented with increased serum levels of creatinine, angiotensin-converting enzyme, corticosterone, macrophage chemoattractant protein-1, and interleukin-6, which may have contributed to the vascular pathology. Possibly, cystic kidney disease is associated with aneurysm progression in MFS patients. Therefore, we propose that close monitoring of the presence of renal cysts in MFS patients, during regular vascular imaging of the whole aorta trajectory, may provide insight in the frequency of cystic kidney disease and its potential as a novel indicator of aneurysm progression in MFS patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Marfan syndrome (MFS) is a connective tissue disorder in which aortic rupture is the major cause of death. MFS patients with an aortic diameter below the advised limit for prophylactic surgery (<5 cm) may unexpectedly experience an aortic dissection or rupture, despite yearly monitoring. Hence, there is a clear need for improved prognostic markers to predict such aortic events. We hypothesize that elastin fragments play a causal role in aortic calcification in MFS, and that microcalcification serves as a marker for aortic disease severity. To address this hypothesis, we analysed MFS patient and mouse aortas. MFS patient aortic tissue showed enhanced microcalcification in areas with extensive elastic lamina fragmentation in the media. A causal relationship between medial injury and microcalcification was revealed by studies in vascular smooth muscle cells (SMCs); elastin peptides were shown to increase the activity of the calcification marker alkaline phosphatase (ALP) and reduce the expression of the calcification inhibitor matrix GLA protein in human SMCs. In murine Fbn1 C1039G/+ MFS aortic SMCs, Alpl mRNA and activity were upregulated as compared with wild-type SMCs. The elastin peptide-induced ALP activity was prevented by incubation with lactose or a neuraminidase inhibitor, which inhibit the elastin receptor complex, and a mitogen-activated protein kinase kinase-1/2 inhibitor, indicating downstream involvement of extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation. Histological analyses in MFS mice revealed macrocalcification in the aortic root, whereas the ascending aorta contained microcalcification, as identified with the near-infrared fluorescent bisphosphonate probe OsteoSense-800. Significantly, microcalcification correlated strongly with aortic diameter, distensibility, elastin breaks, and phosphorylated ERK1/2. In conclusion, microcalcification co-localizes with aortic elastin degradation in MFS aortas of humans and mice, where elastin-derived peptides induce a calcification process in SMCs via the elastin receptor complex and ERK1/2 activation. We propose microcalcification as a novel imaging marker to monitor local elastin degradation and thus predict aortic events in MFS patients. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

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., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

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. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Objective: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the fibrillin-1 gene. Patients with MFS are at risk of aortic aneurysm formation and dissection. Usually, blood pressure-lowering drugs are used to reduce aortic events; however, this is not sufficient for most patients. In the aorta of smooth muscle cell-specific sirtuin-1-deficient mice, spontaneous aneurysm formation and senescence are observed. Resveratrol is known to enhance sirtuin-1 activity and to reduce senescence, which prompted us to investigate the effectiveness of resveratrol in inhibition of aortic dilatation in the Fbn1(C1039G/+) MFS mouse model., Approach and Results: Aortic senescence strongly correlates with aortic root dilatation rate in MFS mice. However, although resveratrol inhibits aortic dilatation, it only shows a trend toward reduced aortic senescence. Resveratrol enhances nuclear localization of sirtuin-1 in the vessel wall and, in contrast to losartan, does not affect leukocyte infiltration nor activation of SMAD2 and extracellular signal-regulated kinases 1/2 (ERK1/2). Interestingly, specific sirtuin-1 activation (SRT1720) or inhibition (sirtinol) in MFS mice does not affect aortic root dilatation rate, although senescence is changed. Resveratrol reduces aortic elastin breaks and decreases micro-RNA-29b expression coinciding with enhanced antiapoptotic Bcl-2 expression and decreased number of terminal apoptotic cells. In cultured smooth muscle cells, the resveratrol effect on micro-RNA-29b downregulation is endothelial cell and nuclear factor κB-dependent., Conclusions: Resveratrol inhibits aortic root dilatation in MFS mice by promoting elastin integrity and smooth muscle cell survival, involving downregulation of the aneurysm-related micro-RNA-29b in the aorta. On the basis of these data, resveratrol holds promise as a novel intervention strategy for patients with MFS., (© 2016 The Authors.)

Patients with bicuspid aortic valve (BAV) and patients with Marfan syndrome (MFS) are more prone to develop aortic dilation and dissection compared to persons with a tricuspid aortic valve (TAV). To elucidate potential common and distinct pathways of clinical relevance, we compared the histopathological substrates of aortopathy. Ascending aortic wall biopsies were divided in five groups: BAV (n = 36) and TAV (n = 23) without and with dilation and non-dilated MFS (n = 8). General histologic features, apoptosis, the expression of markers for vascular smooth muscle cell (VSMC) maturation, markers predictive for ascending aortic dilation in BAV, and expression of fibrillin-1 were investigated. Both MFS and BAV showed an altered distribution and decreased fibrillin-1 expression in the aorta and a significantly lower level of differentiated VSMC markers. Interestingly, markers predictive for aortic dilation in BAV were not expressed in the MFS aorta. The aorta in MFS was similar to the aorta in dilated TAV with regard to the presence of medial degeneration and apoptosis, while other markers for degeneration and aging like inflammation and progerin expression were low in MFS, comparable to BAV. Both MFS and BAV aortas have immature VSMCs, while MFS and TAV patients have a similar increased rate of medial degeneration. However, the mechanism leading to apoptosis is expected to be different, being fibrillin-1 mutation induced increased angiotensin-receptor-pathway signaling in MFS and cardiovascular aging and increased progerin in TAV. Our findings could explain why angiotensin inhibition is successful in MFS and less effective in TAV and BAV patients.

Background: Patients with Marfan syndrome (MFS) have a highly variable occurrence of aortic complications. Aortic tortuosity is often present in MFS and may help to identify patients at risk for aortic complications., Methods: 3D-visualization of the total aorta by MR imaging was performed in 211 adult MFS patients (28% with prior aortic root replacement) and 20 controls. A method to assess aortic tortuosity (aortic tortuosity index: ATI) was developed and reproducibility was tested. The relation between ATI and age, and body size and aortic dimensions at baseline was investigated. Relations between ATI at baseline and the occurrence of a clinical endpoint (aortic dissection, and/or aortic surgery) and aortic dilatation rate during 3 years of follow-up were investigated., Results: ATI intra- and interobserver agreements were excellent (ICC: 0.968 and 0.955, respectively). Mean ATI was higher in 28 age-matched MFS patients than in the controls (1.92 ± 0.2 vs. 1.82 ± 0.1, p=0.048). In the total MFS cohort, mean ATI was 1.87 ± 0.20, and correlated with age (r=0.281, p<0.001), aortic root diameter (r=0.223, p=0.006), and aortic volume expansion rate (r=0.177, p=0.026). After 49.3 ± 8.8 months follow-up, 33 patients met the combined clinical endpoint (7 dissections) with a significantly higher ATI at baseline than patients without endpoint (1.98 ± 0.2 vs. 1.86 ± 0.2, p=0.002). Patients with an ATI>1.95 had a 12.8 times higher probability of meeting the combined endpoint (log rank-test, p<0.001) and a 12.1 times higher probability of developing an aortic dissection (log rank-test, p=0.003) compared to patients with an ATI<1.95., Conclusions: Increased ATI is associated with a more severe aortic phenotype in MFS patients., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Rationale: A number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of β-blockade. Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial., Design: A prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus β-blockers will be performed. A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes. The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online (http://www.ctsu.ox.ac.uk/research/meta-trials)., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It has been shown that losartan reduces aortic dilatation in patients with Marfan syndrome. However, treatment response is highly variable. This study investigates losartan effectiveness in genetically classified subgroups., Methods and Results: In this predefined substudy of COMPARE, Marfan patients were randomized to daily receive losartan 100 mg or no losartan. Aortic root dimensions were measured by MRI at baseline and after 3 years. FBN1 mutations were classified based on fibrillin-1 protein effect into (1) haploinsufficiency, decreased amount of normal fibrillin-1, or (2) dominant negative, normal fibrillin-1 abundance with mutant fibrillin-1 incorporated in the matrix. A pathogenic FBN1 mutation was found in 117 patients, of whom 79 patients were positive for a dominant negative mutation (67.5%) and 38 for a mutation causing haploinsufficiency (32.5%). Baseline characteristics between treatment groups were similar. Overall, losartan significantly reduced aortic root dilatation rate (no losartan, 1.3±1.5 mm/3 years, n=59 versus losartan, 0.8±1.4 mm/3 years, n=58; P=0.009). However, losartan reduced only aortic root dilatation rate in haploinsufficient patients (no losartan, 1.8±1.5 mm/3 years, n=21 versus losartan 0.5±0.8 mm/3 years, n=17; P=0.001) and not in dominant negative patients (no losartan, 1.2±1.7 mm/3 years, n=38 versus losartan 0.8±1.3 mm/3 years, n=41; P=0.197)., Conclusions: Marfan patients with haploinsufficient FBN1 mutations seem to be more responsive to losartan therapy for inhibition of aortic root dilatation rate compared with dominant negative patients. Additional treatment strategies are needed in Marfan patients with dominant negative FBN1 mutations., Clinical Trial Registration: http://www.trialregister.nl/trialreg/index.asp; Unique Identifier: NTR1423., (© 2015 American Heart Association, Inc.)

Background: Aortic dissections involving the descending aorta are a major clinical problem in patients with Marfan syndrome., Objectives: The purpose of this study was to identify clinical parameters associated with type B aortic dissection and to develop a risk model to predict type B aortic dissection in patients with Marfan syndrome., Methods: Patients with the diagnosis of Marfan syndrome and magnetic resonance imaging or computed tomographic imaging of the aorta were followed for a median of 6 years for the occurrence of type B dissection or the combined end point of type B aortic dissection, distal aortic surgery, and death. A model using various clinical parameters as well as genotyping was developed to predict the risk for type B dissection in patients with Marfan syndrome., Results: Between 1998 and 2013, 54 type B aortic dissections occurred in 600 patients with Marfan syndrome (mean age 36 ± 14 years, 52% male). Independent variables associated with type B aortic dissection were prior prophylactic aortic surgery (hazard ratio: 2.1; 95% confidence interval: 1.2 to 3.8; p = 0.010) and a proximal descending aorta diameter ≥27 mm (hazard ratio: 2.2; 95% confidence interval: 1.1 to 4.3; p = 0.020). In the risk model, the 10-year occurrence of type B aortic dissection in low-, moderate-, and high-risk patients was 6%, 19%, and 34%, respectively. Angiotensin II receptor blocker therapy was associated with fewer type B aortic dissections (hazard ratio: 0.3; 95% confidence interval: 0.1 to 0.9; p = 0.030)., Conclusions: Patients with Marfan syndrome with prior prophylactic aortic surgery are at substantial risk for type B aortic dissection, even when the descending aorta is only slightly dilated. Angiotensin II receptor blocker therapy may be protective in the prevention of type B aortic dissections., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. In the FBN1(C1039G/+) Marfan mouse model, losartan decreases aortic root dilatation. We recently confirmed this beneficial effect of losartan in adult patients with Marfan syndrome. The straightforward translation of this mouse model to man is reassuring to test novel treatment strategies. A number of studies have shown signs of inflammation in aortic tissue of Marfan patients. This study examined the efficacy of anti-inflammatory therapies in attenuating aortic root dilation in Marfan syndrome and compared effects to the main preventative agent, losartan., Methods and Results: To inhibit inflammation in FBN1(C1039G/+) Marfan mice, we treated the mice with losartan (angiotensin II receptor type 1 inhibitor), methylprednisolone (corticosteroid) or abatacept (T-cell-specific inhibitor). Treatment was initiated in adult Marfan mice with already existing aortic root dilatation, and applied for eight weeks. Methylprednisolone- or abatacept-treated mice did not reveal a reduction in aortic root dilatation. In this short time frame, losartan was the only treatment that significantly reduced aorta inflammation, transforming growth factor-beta (TGF-β) signaling and aortic root dilatation rate in these adult Marfan mice. Moreover, the methylprednisolone-treated mice had significantly more aortic alcian blue staining as a marker for aortic damage., Conclusion: Anti-inflammatory agents do not reduce the aortic dilatation rate in Marfan mice, but possibly increase aortic damage. Currently, the most promising therapeutic drug in Marfan syndrome is losartan, by blocking the angiotensin II receptor type 1 and thereby inhibiting pSmad2 signaling.

Cardiovascular manifestations in patients with Marfan syndrome (MFS) are related to aortic and valvular abnormalities. However, dilatation of the left ventricle (LV) can occur, even in the absence of aortic surgery or valvular abnormalities. We evaluated genetic characteristics of patients with MFS with LV dilatation. One hundred eighty-two patients fulfilling the MFS criteria, without valvular abnormalities or previous aortic surgery, with a complete FBN1 analysis, were studied. FBN1 mutations were identified in over 81% of patients. Twenty-nine patients (16%) demonstrated LV dilatation (LV end diastolic diameter corrected for age and body surface area >112%). FBN1-positive patients carrying a non-missense mutation more often had LV dilatation than missense mutation carriers (14/74 versus 5/75; p<0.05). Finally, FBN1-negative MFS patients significantly more often demonstrated LV dilatation than FBN1-positive patients (10/33 versus 19/149; p<0.05). It is concluded that LV dilatation in MFS patients is more often seen in patients with a non-missense mutation and in those patients without an FBN1 mutation. Therefore physicians should be aware of the possibility of LV dilatation in these patients even in the absence of valvular pathology., (© 2013 Elsevier B.V. All rights reserved.)

Aim: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients., Methods and Results: In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 ± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 ± 1.36 vs. 1.35 ± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 ± 1.26 vs. 1.01 ± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated., Conclusion: In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.

Purpose: To assess the reproducibility of aortic volume estimates and to serially test their use in patients with Marfan syndrome., Materials and Methods: The study was approved by the medical ethics committee and all subjects gave written informed consent. In 81 patients with Marfan syndrome and seven healthy control subjects, aortic volumes and diameters at baseline were estimated by means of contrast material-enhanced magnetic resonance (MR) imaging. At 3 years of follow-up, aortic expansion rate were calculated in a subgroup of 22 patients with Marfan syndrome. Total aortic volume was defined as volume measurement from the level of the aortic annulus to the aortic bifurcation. Intra- and interobserver agreement of aortic volume were calculated by using the intraclass correlation coefficient. Differences in variables were analyzed with the Student t test and logistic regression. Effect size was calculated., Results: Intra- and interobserver agreement of aortic volume calculation was 0.996 and 0.980, respectively. Mean aortic volume was significantly greater in patients with Marfan syndrome than in control subjects (104 mL/m(2); 95% confidence interval [CI]: 95, 114 mL/m(2) vs 74 mL/m(2); 95% CI: 62, 87 mL/m(2); P < .001). In 22 patients with Marfan syndrome, mean aortic volume was increased at 3 years of follow-up (17 mL; 95% CI: 8, 26 mL; P = .001; effect size, 0.29), while mean aortic diameter did not increase significantly (0.4 mm; 95% CI: 0.0, 0.9 mm; P = .171; effect size, 0.13)., Conclusion: Assessment of aortic volume is highly reproducible and may be suited for use in the detection of aortic expansion in patients with Marfan syndrome., Supplemental Material: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.13122310/-/DC1., (RSNA, 2013)

Background: Patients with Marfan syndrome (MFS) are at risk for cardiovascular disease. Marfan associated mutations in the FBN1 gene lead to increased transforming growth factor-β (TGF-β) activation. The aim of this study was to investigate the role of plasma TGF-β as a biomarker for progressive aortic root dilatation and dissection., Methods: Plasma TGF-β level and aortic root diameter by means of echocardiography were assessed in 99 MFS patients. After 38 months of follow-up measurement of the aortic root was repeated and individual aortic root growth curves were constructed. Clinical events were evaluated. The primary composite endpoint was defined as aortic dissection and prophylactic aortic root replacement., Results: TGF-β levels were higher in MFS patients as compared to healthy controls (109 pg/ml versus 54 pg/ml, p<0.001). Higher plasma TGF-β levels correlated with larger aortic root dimensions (r=0.26, p=0.027), previous aortic root surgery (161 pg/ml versus 88 pg/ml, p=0.007) and faster aortic root growth rate (r=0.42, p<0.001). During 38 months of follow-up, 17 events were observed (four type B dissections and 13 aortic root replacements). Patients with TGF-β levels above 140 pg/ml had a 6.5 times higher risk of experiencing the composite endpoint compared to patients with TGF-β levels below 140 pg/ml (95% CI: 2.1 to 20.1, p=0.001) with 65% sensitivity and 78% specificity., Conclusion: Elevated TGF-β level in patients with Marfan syndrome is correlated with larger aortic root diameters and faster aortic root growth. Level of plasma TGF-β predicts cardiovascular events and might serve as a prognostic biomarker in MFS., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: In patients with Marfan syndrome (MFS), increased aortic wall stiffening may lead to progressive aortic dilatation. Aortic Pulse Wave Velocity (PWV), a marker of wall stiffness can be assessed regionally, using in-plane multi-directional velocity-encoded MRI. This study examined the diagnostic accuracy of regional PWV for prediction of regional aortic luminal growth during 2-year follow-up in MFS patients., Methods: In twenty-one MFS patients (mean age 36 ± 15 years, 11 male) regional PWV and aortic luminal areas were assessed by 1.5 T MRI. At 2-year follow-up, the incidence of luminal growth, defined as mean luminal diameter increase >2mm was determined for five aortic segments (S1, ascending aorta; S2, aortic arch; S3, thoracic descending aorta, S4, supra-renal and S5, infra-renal abdominal aorta). Regional PWV at baseline was considered increased when exceeding age-related normal PWV (healthy volunteers (n=26; mean age 30 ± 10 years, 15 male)) by two standard-errors. Sensitivity and specificity of regional PWV-testing for prediction of regional luminal growth were determined., Results: Regional PWV at baseline was increased in 17 out of 102 segments (17%). Significant luminal growth at follow-up was reported in 14 segments (14%). The specificity of regional PWV-testing was ≥ 78% for all aortic segments, sensitivity was ≤ 33%., Conclusions: Regional PWV was significantly increased in MFS patients as compared to healthy volunteers within similar age range, in all aortic segments except the ascending aorta. Furthermore, regional PWV-assessment has moderate to high specificity for predicting absence of regional aortic luminal growth for all aortic segments in MFS patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: Prevention of aortic dissection and sudden death in patients with Marfan syndrome (MFS) requires accurate diagnosis. MFS is diagnosed by the Ghent criteria, which are primarily based on clinical features of Caucasian MFS populations. We determined whether the Ghent criteria apply to Asian MFS populations., Methods and Results: In this multicenter study, we included 255 adult MFS patients according to the Ghent criteria of 2010. Patients were excluded if they were neither Caucasian nor Asian. The Asian MFS population (n=49) had a smaller body surface area (BSA: 1.8 m² vs. 2.0 m², P<0.001), a more severely affected aortic root (absolute aortic diameter: 42.9 mm vs. 43.3mm, P=0.802; corrected for BSA: 24.9 mm vs. 21.7 mm, P<0.001; Z-score: 4.5 vs. 3.6, P=0.013), and more often a positive systemic score (75.5% vs. 60.0%, P=0.045), but less frequently ectopia lentis (24.5% vs. 48.1%, P=0.004) compared with the Caucasian population (n=206)., Conclusions: The Ghent criteria do not necessarily apply to Asian MFS populations, resulting in a more severely affected cardiovascular system. This may be related to under diagnosis of MFS by multiple factors, including the use of Z-score, and genetic and racial differences. The Ghent criteria should be adapted for Asian populations in order to accurately diagnose MFS.

Purpose: To evaluate the effect of spatial (ie, number of sampling locations along the aorta) and temporal sampling density on aortic pulse wave velocity (PWV) assessment from velocity-encoded MRI in patients with Marfan syndrome (MFS)., Materials and Methods: Twenty-three MFS patients (12 men, mean age 36 ± 14 years) were included. Three PWV-methods were evaluated: 1) reference PWV(i.p.) from in-plane velocity-encoded MRI with dense temporal and spatial sampling; 2) conventional PWV(t.p.) from through-plane velocity-encoded MRI with dense temporal but sparse spatial sampling at three aortic locations; 3) EPI-accelerated PWV(t.p.) with sparse temporal but improved spatial sampling at five aortic locations with acceleration by echo-planar imaging (EPI)., Results: Despite inferior temporal resolution, EPI-accelerated PWV(t.p.) showed stronger correlation (r = 0.92 vs. r = 0.65, P = 0.03) with reference PWV(i.p.) in the total aorta, with less error (8% vs. 16%) and variation (11% vs. 27%) as compared to conventional PWV(t.p.) . In the aortic arch, correlation was comparable for both EPI-accelerated and conventional PWV(t.p.) with reference PWV(i.p.) (r = 0.66 vs. r = 0.67, P = 0.46), albeit 92% scan-time reduction by EPI-acceleration., Conclusion: Improving spatial sampling density by adding two acquisition planes along the aorta results in more accurate PWV assessment, even when temporal resolution decreases. For regional PWV assessment in the aortic arch, EPI-accelerated and conventional PWV assessment are comparably accurate. Scan-time reduction makes EPI-accelerated PWV assessment the preferred method of choice., (Copyright © 2012 Wiley Periodicals, Inc.)

Aim: To assess the lifetime prevalence of migraine in patients with Marfan syndrome (MFS) and to investigate a history of aortic root replacement (AR) as a possible risk factor., Methods: In a multicentre study 123 MFS patients (n = 52 with AR, n = 71 without AR), 82 age- and sex-matched controls and 51 patients with AR but without MFS, were interviewed using a semi-structured headache questionnaire. A multinomial logistic regression model was used to investigate risk factors for migraine with and without aura, adjusting for age and gender., Results: Lifetime migraine prevalence was increased in female MFS patients (51%) compared to healthy female controls (29%), p = 0.017. In males lifetime migraine prevalence among MFS patients was only numerically increased. Lifetime prevalence of migraine with aura was increased among MFS patients compared to healthy controls both in males (19% vs. 3%, p = 0.048) and females (30% vs. 14%, p = 0.049). A history of AR, independently from MFS, gender and age, increased the lifetime prevalence of migraine with aura (OR 3.1 [1.2-8.0]). In all but one patient migraine started before the AR., Conclusions: The lifetime prevalence of migraine with aura, but not migraine without aura, is increased in patients with MFS. This association is driven by a history of AR. The replacement procedure itself is unlikely to be causally associated with migraine as in nearly all subjects, migraine started before the procedure. However this study adds to the evidence that underlying vessel wall pathology may be involved in migraine with aura.

Introduction: Marfan syndrome is a multisystemic connective tissue disorder caused mainly by mutations in the fibrillin-1 gene. The entire cardiovascular system is affected in patients with Marfan syndrome. Aortic root dilatation, aortic valve regurgitation or - the most feared and life-threatening symptom - aortic root dissection are the most common manifestations. Therapeutic strategies, such as prophylactic aortic root surgery and pharmacological therapy, focus on the prevention of aortic dissection. Currently, the standard medicinal treatments targeting aortic dilatation and dissection consist of agents generally used to lower blood pressure and/or the inotropic state of the heart. By these means, the cyclic repetitive forces exerted on the aortic wall are diminished and thus the onset of aortic dilatation is potentially prevented. Although these pharmacological agents may offer some benefit in reduction of aortic aneurysm expansion rate, they do not target the underlying cause of the progressive aortic degradation., Areas Covered: This review discusses the effectiveness of frequently prescribed medications used to prevent and delay aortic complications in Marfan syndrome. New insights on the biochemical pathways leading to aortic disease are also discussed to highlight new targets for pharmacological therapy., Expert Opinion: Recent insights in the transforming growth factor beta signaling pathway and inflammatory mechanisms in a well-established mouse model of Marfan syndrome, have led to studies exploring new pharmacological treatment strategies with doxycycline, statins and angiotensin II receptor blockers. Pharmacological therapy is focused more on prevention than on delay of aortic wall pathology in Marfan syndrome. Of the new pharmacological treatment strategies targeting aortic pathology in Marfan syndrome, angiotensin receptor type 1 blockers are promising candidates, with several clinical trials currently ongoing.

Background: Marfan syndrome (MFS) is a pleiotropic genetic disorder with major features in cardiovascular, ocular and skeletal systems, associated with large clinical variability. Numerous studies reveal an involvement of TGF-β signaling. However, the contribution of tissue inflammation is not addressed so far., Methodology/principal Findings: Here we showed that both TGF-β and inflammation are up-regulated in patients with MFS. We analyzed transcriptome-wide gene expression in 55 MFS patients using Affymetrix Human Exon 1.0 ST Array and levels of TGF-β and various cytokines in their plasma. Within our MFS population, increased plasma levels of TGF-β were found especially in MFS patients with aortic root dilatation (124 pg/ml), when compared to MFS patients with normal aorta (10 pg/ml; p = 8×10(-6), 95% CI: 70-159 pg/ml). Interestingly, our microarray data show that increased expression of inflammatory genes was associated with major clinical features within the MFS patients group; namely severity of the aortic root dilatation (HLA-DRB1 and HLA-DRB5 genes; r = 0.56 for both; False Discovery Rate(FDR) = 0%), ocular lens dislocation (RAET1L, CCL19 and HLA-DQB2; Fold Change (FC) = 1.8; 1.4; 1.5, FDR = 0%) and specific skeletal features (HLA-DRB1, HLA-DRB5, GZMK; FC = 8.8, 7.1, 1.3; FDR = 0%). Patients with progressive aortic disease had higher levels of Macrophage Colony Stimulating Factor (M-CSF) in blood. When comparing MFS aortic root vessel wall with non-MFS aortic root, increased numbers of CD4+ T-cells were found in the media (p = 0.02) and increased number of CD8+ T-cells (p = 0.003) in the adventitia of the MFS patients., Conclusion/significance: In conclusion, our results imply a modifying role of inflammation in MFS. Inflammation might be a novel therapeutic target in these patients.

Background: Quality of life (QoL) in patients with chronic disease is impaired and cannot be solely explained by disease severity. We explored whether genetic variability and activity contributes to QoL in patients with Marfan syndrome (MFS), a genetic connective tissue disorder., Methodology/principal Findings: In 121 MFS patients, patient characteristics (i.e. demographics and MFS-related symptoms) were assessed. Patients completed the SF-36 to measure QoL. In addition, transcriptome wide gene expression and 484 Single Nucleotide Polymorphysms (SNPs) in cytokine genes were available. QoL was first analyzed and associated with patient characteristics. Patients' physical QoL was impaired and weakly related with age and scoliosis, whereas mental quality of life (MCS) was normal. To explain a largely lacking correlation between disease severity and QoL, we related genome wide gene expression to QoL. Patients with lower MCS scores had high expression levels of CXCL9 and CXCL11 cytokine-related genes (p=0.001; p=0.002); similarly, patients with low vitality scores had high expression levels of CXCL9, CXCL11 and IFNA6 cytokine-related genes (p=0.02; p=0.02; p=0.04), independent of patient characteristics. Subsequently, we associated cytokine related SNPs to mental QoL (MCS and vitality). SNP-cluster in the IL4R gene showed a weak association with MCS and vitality (strongest association p=0.0017). Although overall mental QoL was normal, >10% of patients had low scores for MCS and vitality. Post-hoc analysis of systemic inflammatory mediators showed that patients with lowest MCS and vitality scores had high levels of CCL11 cytokine (p=0.03; p=0.04)., Conclusions/significance: Variation in the cytokine genetic pathway and its activation is related to mental QoL. These findings might allow us to identify and, ultimately, treat patients susceptible to poor QoL.

Background: Marfan syndrome (MFS) is an autosomal, dominantly inherited, connective tissue disorder usually caused by a mutation in the fibrillin-1 gene (FBN1). As fibrillin-1 is a component of the extracellular matrix of the myocardium, mutations in FBN1 may cause impairment of ventricular function. Furthermore, aortic elasticity is decreased in patients with MFS, which might also impair ventricular function. We assessed biventricular function and the influence of aortic elasticity in patients with MFS by means of cardiac MRI., Methods and Results: Cardiac magnetic resonance was performed in 144 patients with MFS without significant valvular dysfunction, previous cardiac surgery or previous aortic surgery. Biventricular diastolic and systolic volumes were measured, and ejection fractions were calculated. Flow wave velocity, a measurable derivative of aortic elasticity, was measured between the ascending aorta and the bifurcation. When compared to healthy controls (n = 19), left ventricular ejection fraction (LVEF) was impaired in patients with MFS (53% ± 7% vs 57% ± 4%, p < 0.005), as was right ventricular ejection fraction (RVEF) (51% ± 7% vs 56% ± 4%, p < 0.005). LVEF and RVEF were strongly correlated. (r = 0.7, p < 0.001). No significant differences were found between patients with β-blocker treatment and those without. There was no correlation between aortic elasticity as measured by flow wave velocity and LVEF., Conclusions: Biventricular ejection fraction was impaired in patients with MFS, and the impairment was independent of aortic elasticity and β-blocker usage. There was also a strong correlation between LVEF and RVEF. Our findings suggest intrinsic myocardial dysfunction in patients with MFS. Clinical trial registration http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 1423. Unique Identifier: NTR1423.

Marfan syndrome (MFS) is a connective tissue disorder with major features in cardiovascular, ocular and skeletal systems. Recently, diagnostic criteria were revised where more weight was given to the aortic root dilatation. We applied the revised Marfan nosology in an established adult Marfan population to define practical repercussions of novel criteria for clinical practice and individual patients. Out of 180 MFS patients, in 91% (n = 164) the diagnosis of MFS remained. Out of 16 patients with rejected diagnosis, four patients were diagnosed as MASS (myopia, mitral valve prolapse, borderline non-progressive aortic root dilatation, skeletal findings and striae) phenotype, three as ectopia lentis syndrome and in nine patients no alternative diagnosis was established. In 13 patients, the diagnosis was rejected because the Z-score of the aortic root was <2, although the aortic diameter was larger than 40 mm in six of them. In three other patients, the diagnosis of MFS was rejected because dural ectasia was given less weight in the revised nosology. Following the revised Marfan nosology, the diagnosis of MFS was rejected in 9% of patients, mostly because of the absence of aortic root dilatation defined as Z-score ≥2. Currently used Z-scores seem to underestimate aortic root dilatation, especially in patients with large body surface area (BSA). We recommend re-evaluation of criteria for aortic root involvement in adult patients with a suspected diagnosis of MFS., (© 2011 John Wiley & Sons A/S.)

Purpose: To study age-related change in aortic stiffness in patients with Marfan syndrome (MFS) versus healthy volunteers using velocity-encoded (VE) MRI., Materials and Methods: Twenty-five MFS patients (age range, 18-63 years; mean age 36 ± 14 years, 13 men) and 25 age-/gender-matched healthy volunteers were examined with VE-MRI. Aortic stiffness was expressed by pulse wave velocity (PWV), assessed in the proximal and distal part of the aorta and in the total aorta. PWV was compared between patients and volunteers and age-relation was determined by linear regression., Results: PWV was significantly higher in all parts of the aorta in patients when compared with healthy volunteers (proximal aorta 5.7 ± 1.5 m/s versus 4.8 ± 0.9 m/s, distal aorta 6.4 ± 2.4 m/s versus 5.0 ± 1.2 m/s and total aorta 5.9 ± 1.7 m/s versus 4.9 ± 1.1 m/s, all P < 0.004). PWV correlated significantly with age (Pearson R between 0.45 and 0.94). Only in the proximal aorta, the increase in PWV with age was significantly higher in patients (7 ± 2 cm/s increase with age) than in volunteers (3 ± 1 cm/s increase, P = 0.03); in the distal or total aorta, the increase in PWV with age was not different between patients and volunteers., Conclusion: Velocity-encoded MRI detects more pronounced age-related aortic stiffening in the proximal aorta in MFS patients versus healthy volunteers, suggesting more severe wall disease in MFS., (Copyright © 2011 Wiley-Liss, Inc.)

Background: Marfan syndrome (MFS) is one of the most common systemic disorders of connective tissue with the incidence of approximately 2-3 per 10 000 individuals. Aortic disease, leading to progressive aneurysmal dilatation and dissection is the main cause of morbidity and mortality of Marfan patients. Current treatment (e.g. beta blockers and elective surgery) does postpone but cannot prevent aortic complications in these patients. Recent studies have found transforming growth factor beta (TGF beta) to be involved in the aortic aneurysm formation. Losartan, an angiotensin II type 1 receptor blocker inhibits TGFbeta in a mouse model of Marfan syndrome leading to inhibition of aortic growth. The main objective of this trial is to assess whether losartan treatment leads to a clinically relevant decrease of aortic dilatation in adult patients with Marfan syndrome., Methods/design: COMPARE study (COzaar in Marfan Patients Reduces aortic Enlargement) is an open-label, randomized, controlled trial with blinded end-points. Treatment with losartan will be compared with no additional treatment after 3 years of follow-up. We will enroll 330 patients with MFS who will be randomly assigned to receive losartan or not. Patients taking beta-blockers will continue taking their standard treatment. The primary end-point is the largest change in aortic diameter at any aortic level measured by means of MRI. Secondary end-points are change in mortality, incidence of dissection, elective aortic surgery, aortic volume, aortic stiffness and ventricular function. We will also investigate gene and protein expression change in the skin under losartan therapy and create prediction models for losartan-treatment response and aortic dilatation., Discussion: The COMPARE study will provide important evidence of effects of losartan treatment in adult Marfan patient population. We expect losartan to significantly reduce the occurrence and progression of aortic dilatation. This trial investigates a wide spectrum of clinical, genetic and biochemical effects of losartan aiming to provide further insight in the pathogenesis and treatment of Marfan syndrome., Trial Registration: Netherlands Trial Register NTR1423.

Objective: A high prevalence of migraine has been described in various forms of congenital heart disease, with and without shunt. In this study we investigated the prevalence of migraine in patients with Marfan syndrome (MFS)., Methods: All 457 adult patients with MFS from the participating centres and 194 controls received a validated questionnaire about headache. Migraine was diagnosed according to the International Headache Society criteria, by three independent neurologists, blinded to patient files., Results: Response rate was 68% and 56% in Marfan patients and controls, respectively. Forty percent of the 309 responding MFS patients (mean age 40+/-14 years; 51% females) and 28% of the 102 controls (mean age 43+/-15 years; 58% females), suffered from migraine (p=0.03). The prevalence of migraine with aura (MA) was 22% in MFS patients and 14% in controls (p=0.06). We found MFS to be an independent risk factor for having overall migraine (OR 1.7; 95%CI 1.1-2.8), also after adjustment for age and gender (OR 1.9; 95%CI 1.1-3.1; p=0.02) and for MA after adjustment for gender (OR 2.0; 95%CI 1.1-3.7; p=0.04). In patient with MFS, previous aortic root surgery appeared to be an independent risk factor for having MA (OR 2.2; 95%CI; 1.2.-4.0, p=0.01) adjusted for gender., Conclusion: MFS is an independent risk factor for having overall migraine and MA. Moreover, we found that a history of aortic root surgery seems to be associated with an increased risk of MA.

We report two families in which the probands have compound-heterozygous Marfan syndrome (MFS). The proband of family 1 has the R2726W FBN1 mutation associated with isolated skeletal features on one allele and a pathogenic FBN1 mutation on the other allele. The phenotype of the compound-heterozygous probands appears to be more severe than that of their heterozygous family members which underlines the possibility that certain trans-located FBN1 mutations might act as modifiers of phenotype explaining some of the intrafamilial variability in Marfan syndrome.

Patients with Marfan syndrome have a tall stature, which could be associated with low orthostatic tolerance. Fatigue, a common complaint of these patients, is also related to orthostatic intolerance. Treatment with beta-blockers, to prevent aortic complications, could be a reinforcing factor of both. This study aimed to investigate (1) the relationship between symptoms of orthostatic tolerance and in patients with Marfan syndrome, and (2) whether termination of beta-blocker therapy improves orthostatic tolerance. Symptoms of fatigue and orthostatic complaints were assessed in 49 subjects using questionnaires (MFI-20 and Autonomic Symptoms Profile). Marfan patients have a high level of fatigue and orthostatic complaints when compared to the general population. Fatigue and orthostatic tolerance are significantly correlated. Orthostatic tolerance was assessed in 9 additional subjects by an active-standing test and head-up tilt for 5 minutes, and 24 hours blood pressure monitoring, once during beta-blocker therapy and once after ceasing beta-blockers for 2 weeks. During hemodynamic testing Marfan patients frequently showed Initial Orthostatic Hypotension and an abnormally high initial heart rate response. Ceasing beta-blockers did not affect the initial blood pressure response. Patients with Marfan syndrome are fatigued and have low orthostatic tolerance, which are significantly correlated. Patients could be educated in physical counterpressure maneuvers to increase orthostatic tolerance.

Objective: To investigate dilatory changes of the aorta distal to the root in patients with Marfan's syndrome., Methods and Results: Data of 268 patients with Marfan's syndrome who were enrolled in the Euro Heart Survey on adult congenital heart disease were analysed. Data used for this study were baseline characteristics, diameters at four levels of the aorta and events during follow up (dissection, aortic repairs and death). At inclusion, 26 patients had a previous dissection and 53 patients without a previous dissection had undergone elective aortic repair, thus leaving 189 patients without previous dissection or repair. During follow up (median 5.4 years), four patients died. A total of 46 aortic events (dissection or elective surgery) occurred in 45 patients, in the distal aorta in 14 patients (31%). Baseline aortic diameter at the levels distal to the root (arch, descending aorta and abdominal aorta) was greater in patients with than in those without a previous elective aortic root intervention (median 26 mm v 24 mm, p = 0.01; 25 mm v 20 mm, p < 0.01; and 20 mm v 17 mm, p < 0.01, respectively). Multivariate analysis showed that a previous elective aortic intervention was associated with a fourfold increased probability of dilatation of the distal aorta, after adjustment for age and sex (p < 0.01). In patients without a previous intervention, the baseline diameter of the descending aorta was an independent predictor of aortic events (hazard ratio 3.0 per quartile, 95% CI 1.5 to 5.9, p = 0.002). Cause for concern is that complete measurements of the aorta (at least one measurement at each level at baseline or during follow up) were available for only 38% of the patients., Conclusions: Almost one in every three aortic events occurring during follow up of these patients involved the distal aorta. After elective aortic root replacement, a dilated distal aorta is more common than before. Moreover, an increased diameter of the descending aorta is associated with a higher risk of aortic events in patients without previous dissection or aortic root replacement, independent of the diameter of the aortic root. Careful monitoring of the entire aorta is essential for the optimal management of patients with Marfan's syndrome, especially after elective surgery, but is insufficiently performed in Europe.

Objective: To investigate the obstetric maternal and neonatal outcome of pregnancy in women with Marfan syndrome., Methods: Retrospective observational multi-center study based on congenital heart disease registry., Results: Sixty-three of the 122 enrolled women with Marfan syndrome had been pregnant 142 times (including 111 pregnancies>20 weeks, 28 (20%) miscarriages and 3 elective abortions). In 40% of all completed pregnancies an obstetric and/ or neonatal complication occurred. The most important complications were an increased percentage of premature deliveries (n=17, 15%) mainly due to preterm premature rupture of membranes and cervical incompetence and a markedly increased combined fetal and neonatal mortality of 7.1%. An obstetric and/or neonatal complication occurred in a similar proportion of pregnancies in women with a diagnosis of Marfan syndrome before pregnancy versus women with a diagnosis of Marfan syndrome after pregnancy (39% vs. 41%, p=0.85, respectively)., Conclusion: In addition to cardiovascular complications, pregnancy in women with Marfan syndrome is associated with a high rate of premature deliveries, preterm premature rupture of membranes and increased mortality in the offspring.

The leading cause of premature death in patients with Marfan's syndrome (MS) is type A aortic dissection or rupture due to progressive aortic root dilation. The aim of this study was to analyze aortic root growth in 113 men and 108 women with MS. All patients were prospectively followed with serial echocardiograms of the native aortic root. At baseline, women had on average a 5-mm smaller aortic root diameter adjusted for age than men. Average aortic root growth was 0.42 mm/year (SE 0.05) in men and 0.38 mm/year (SE 0.04) in women. On the basis of aortic root growth rates, the men and women could be divided into 2 normally distributed subgroups: fast and slow growers. Approximately 1 in 7 men (1.5 mm/year, SE 0.5) and approximately 1 in 9 women (1.8 mm/year, SE 0.3) had fast-growing aortic root diameters. Significantly more type A dissections (25% vs 4%, p <0.001) were observed in fast growers than in slow growers; this was found in men and women. Type A dissections were observed in 4 men and 9 women. By reducing the cut-off value by 5 mm for elective aortic root replacement in women, type A dissections could have been prevented in 3 women. In conclusion, guidelines should take gender differences into account, and therefore, the investigators propose reducing the threshold for elective aortic root replacement in women with MS by 5 mm.

Aims: In women with Marfan syndrome pregnancy presents an increased risk of dilatation, dissection, and rupture of the aorta. The aim of this study was to investigate the influence of pregnancy on growth of the aortic root., Methods and Results: Between 1993 and 2004 127 women with Marfan syndrome were prospectively followed; 61 women had one or more children; in 23 women, 33 pregnancies could be followed prospectively for aortic dimensions. Only one woman had suffered an aortic complication, a type A dissection (limited to the ascending aorta), before pregnancy. Out of 66 childless women a comparison group of 22 women was selected and individually matched. Mean initial aortic root diameter just before pregnancy was 37+/-5 mm (range 25-45). Before, during, and after pregnancy the overall individual aortic root diameter change (in 31 pregnancies) was not significant (P=0.77). Only the woman with a previous type A dissection developed an aortic complication (type B dissection) during her second pregnancy. No cardiac complications occurred in the other 22 women during their pregnancies. During a median follow-up of 6.4 years, no significant difference in growth of the aortic root was observed between the pregnancy group and the matched childless group (0.28 vs. 0.19 mm/year, P=0.08, respectively)., Conclusion: Pregnancy in women with Marfan syndrome seems to be relatively safe up to an aortic root diameter of 45 mm, at least as far as our observed diameter range of 25-45 mm is concerned.

Left ventricular dimensions and systolic function were studied using echocardiography in 234 patients with Marfan's syndrome without significant valvular regurgitation. Left ventricular dimensions and systolic function were found to be normal in most patients with Marfan's syndrome. Some involvement of the left ventricle may have been present in a small group of these patients. No patients, however, fulfilled the criteria for dilated cardiomyopathy.

A 33-year old male patient, with Marfan's syndrome, reported symptoms of orthostatic intolerance and fatigue as a longstanding problem. Orthostatic cardiovascular examination showed poor orthostatic tolerance, with a rise in heart rate and a fall in arterial blood pressure and cerebral blood flow velocity. Self-discovered physical counterpressure manoeuvers improved symptoms, related to a substantial increase in arterial pressure and cerebral perfusion. When orthostatic complaint are reported by patients with Marfan's syndrome, physical counterpressure manoeuvers should be advised to reduce symptoms of postural hypotension.

The Marfan syndrome is an autosomal dominant disorder of connective tissue, caused by mutations in the FBN1 gene on chromosome 15. More than 500 mutations have been identified and almost all are unique to an affected individual or family. Genotype--phenotype correlations in the Marfan syndrome have been complicated by the large number of unique mutations reported, as well as by clinical heterogeneity among individuals with the same mutation. A relatively unknown cardiovascular manifestation of Marfan syndrome is dilatation of the main pulmonary artery. Of 50 patients with Marfan syndrome, MR imaging showed in 74% patients an enlarged pulmonary artery root above the upper limit of normal. Aortic elasticity determined by measurement of local distensibility and flow wave velocity with MR imaging is decreased in non-operated patients with Marfan syndrome. Aortic distensibility of the thoracic descending aorta appeared to be the strongest predictor for descending aortic complications. Over the past 30 years improvement of diagnostic modalities and aggressive medical and surgical therapy, have resulted in considerable improvement of life expectancy of patients with Marfan syndrome. Further studies are needed to investigate the role of modulating genes and genotype--phenotype correlations. Long-term follow-up studies may reveal the prognostic significance of aortic elasticity and may identify patients at risk of aortic complications.

Objective: Beta-blocking therapy is the standard therapy in non-operated Marfan patients, however its efficacy after entire aortic replacement is unknown. The aim of this study was to describe the influence of (nearly) entire aortic replacement and beta-blocking therapy on blood pressure and wave reflections in Marfan patients., Methods: Four Marfan patients (mean age 31+/-3 years) and 8 age matched control subjects were studied. Blood pressure and wave reflections (reflection coefficient and augmentation index) were studied by means of magnetic resonance imaging, continuous non-invasive blood pressure measurements and applanation tonometry. Patients were studied with atenolol, labetalol and without beta-blocking therapy., Results: In Marfan patients, aortic systolic pressure (129+/-13 vs 114+/-10 mmHg), pulse pressure (58+/-13 vs 40+/-5 mmHg), wave speed (11+/-3 vs 4+/-0.4 m s(-1)) and reflection coefficient (65+/-22 vs 41+/-5%) were significantly increased compared to controls. There was no difference in aortic pressure between various medications in Marfan patients (atenolol 129/76 mmHg, labetalol 121/75 mmHg and without beta-blocking therapy 129/71 mmHg). Higher reflection coefficients were seen in patients with atenolol compared to discontinued medication (73+/-18 vs 65+/-22%), and also the augmentation index was higher with atenolol compared to labetalol and discontinued medication (24+/-22 vs 17+/-17 vs 22+/-22%, respectively)., Conclusion: Our results describe increased pulse pressure, systolic pressure, wave speed and wave reflections in four Marfan patients after entire aortic replacement. The use of atenolol or labetalol did not decrease aortic pressure and with atenolol increased wave reflections were observed. Therefore, the beneficial effect of atenolol in these patients is doubtful.

Aim: Patients with Marfan syndrome may develop dissection due to progressive dilatation in the entire aorta, which is not always predictable by mere anatomic assessment of the aortic diameter, especially of the descending aorta. The aim of this study was to identify the predictive value of aortic stiffness on the occurrence of dissection and progressive aortic dilatation., Methods and Results: In 78 non-operated patients with Marfan syndrome (mean age 31+/-8 years, mean aortic root diameter 43+/-6 mm, range 31-55 mm) aortic stiffness and diameters were assessed by magnetic resonance imaging (MRI) at multiple levels. After a median follow-up of 71 months (25-75%: 68-72 months) a second MRI was performed and the incidence of aortic dissection and progressive aortic dilatation, defined as mean aortic diameter increase >1 mm/year was determined. During follow-up, 4 (5%) of 78 patients developed an aortic dissection (1 type A, 2 type B, and 1 infra-renal dissection). Twenty (26%) of the 78 patients had progressive aortic root dilatation. There were 5 (6%) patients with progressive descending thoracic aortic dilatation and 6 (7%) with progressive abdominal aortic dilatation. Multivariate logistic regression analysis revealed that local distensibility was an independent predictor of progressive thoracic descending aortic dilatation (OR=4.14, 95% CI, 1.02-16.7). For progressive aortic root and abdominal aortic dilatation local initial diameter appeared to be the major predictor (OR=1.37, 95% CI, 1.16-1.62; OR=1.36, 95% CI, 1.09-1.69, respectively)., Conclusion: In patients with Marfan syndrome both aortic diameter and aortic distensibility are independent predictors of progressive aortic dilatation. For optimal risk assessment and monitoring of patients with Marfan syndrome, both aortic stiffness and diameter should be assessed at least annually.

Objective: To investigate the heterogeneous response to beta blockade in patients with Marfan syndrome by non-invasive assessment of the aortic pressure-area curve., Design and Patients: 25 patients with the Marfan syndrome who used beta blocking agents (mean (SD) age, 29 (10) years; 20 men, five women), seven without beta blockade (34 (14) years; five men, two women), and 10 controls (29 (5) years; seven men, three women) underwent magnetic resonance imaging and non-invasive continuous blood pressure measurement. Pressure-area curves were constructed at the level of the descending thoracic aorta. A transition point was defined as the pressure at which the pressure-area relation deviated from its elastic (linear) to the collagen (exponential) course., Setting: Tertiary referral centre for adult congenital heart disease., Results: In six patients (five with and one without beta blockade), a transition point in the pressure-area curve was observed, indicating that the load bearing component was not only elastin but also collagen. In the remaining 26 Marfan patients and in the control subjects a linear pressure-area relation was observed., Conclusions: This new non-invasive method to derive aortic pressure-area curves showed that most patients with Marfan syndrome have a similar pressure-area curve to controls with similar blood pressures. Five patients on beta blockade showed a transition point in the pressure-area curve which could play a crucial role in the heterogeneous response to beta blocker treatment in Marfan patients. Patients with a transition at low blood pressures may not benefit from beta blocking agents.

Objective: To investigate if a simple axial spin echo (SE) image can be used for reliable assessment of pulmonary artery dimensions in patients with Marfan syndrome., Methods: Fifty Marfan patients (mean age 33 +/- 10 years; 34 men, 16 women) and 15 normal subjects (mean age 28 +/- 4 years; nine men, six women) underwent cardiac magnetic resonance imaging (MRI). Pulmonary artery dimensions were obtained on axial SE images at two different levels: (1) the level of the pulmonary artery root, and (2) the level of the pulmonary artery bifurcation. To evaluate the accuracy of axial plane measurements 10 Marfan patients also underwent contrast-enhanced MR angiography (CE-MRA)., Results: In the 10 Marfan patients who also underwent CE-MRA, the mean diameter at the pulmonary bifurcation assessed with CE-MRA (31.5 +/- 3.6 mm) was almost equal to mean diameter assessed with axial SE (30.7 +/- 3.6 mm). Agreement of methodology according to Bland and Altman analysis showed a 95% confidence interval ranging from -2.6 to + 4.4 mm for all distances of the pulmonary artery root. In Marfan patients the mean right-left diameter measured on both axial SE images and CE-MRA was approximately 2.5 mm larger than the anterior-right and anterior-left diameters (p < 0.001)., Conclusions: Axial SE MRI is a reliable and easy acquisition to measure pulmonary artery dimensions in patients with Marfan syndrome, and could be used for follow-up, especially in patients with severe involvement of the cardiovascular system. Not only the pulmonary artery trunk but also the asymmetric pulmonary root should be measured, although the clinical relevance of the asymmetric root is not yet known.

Marfan's syndrome is an inherited disorder of connective tissue, caused by mutations in the fibrillin-1 gene located on chromosome 15. Diagnosis is still based on a combination of major and minor clinical features. Prognosis is mainly determined by the cardiovascular complications. Advances in surgical and medical treatment for these complications have dramatically improved the prognosis of the syndrome.