Abstract 2959: TGF-beta Is A Promising Biomarker For Monitoring The Aortic Root Dilatation And Losartan Therapy In Marfan Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Peter Matt ◽  
Jennifer Habashi ◽  
Tammy Holm ◽  
Erin Klein ◽  
Matt Gamradt ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Aortic Root ◽  
Serum Levels ◽  
Serum Concentrations ◽  
Tgf Beta ◽  
Wild Type ◽  
Serum Samples ◽  
Total Acid ◽  
Fibrillin 1 ◽  
Aortic Root Dilatation

Objectives: Aortic root dilatation is the main cause of morbidity and mortality in Marfan syndrome (MFS), a disorder caused by mutations in the gene encoding fibrillin-1 and consequent dysregulation of TGF-beta signaling. The aim of this study was to discover a serological biomarker for the aortic root dilatation in a mouse model of MFS, that was also responsive to losartan therapy. Methods: Serum samples from mice heterozygous for a fibrillin-1 missense mutation (C1039G/+) and wild-type mice treated with losartan or placebo were obtained at 10 weeks, 6 months and 10 months of age. Total (acid activated) TGF-beta 1 serum concentrations were measured by ELISA. Echo measurements of the aortic root were obtained from a parasternal long axis view at 10 months of age. Results: Mean TGF-beta serum concentrations were higher in C1039G/+ mice compared to wild-type mice (p=0.01; 80.0 ng/ml (n=5) vs. 58.3 ng/ml (n=4) at 10 weeks, 117.4 ng/ml (n=11) vs. 87.0 ng/ml (n=6) at 6 months, 137.5 ng/ml (n=3) vs. 103.0 ng/ml (n=2) at 10 months, respectively). Losartan-treated C1039G/+ mice had significantly lower mean TGF-beta serum levels compared to C1039G/+ mice with placebo (p=0.007; 92.9 ng/ml (n=5) vs. 117.4 ng/ml (n=11) at 6 months, 101.2 ng/ml (n=13) vs. 137.5 ng/ml (n=3) at 10 months, respectively). Mean TGF-beta serum concentrations in losartan-treated C1039G/+ mice and wild-type mice with placebo were not significant different (p=0.3; 92.9 ng/ml (n=5) vs. 87.0 ng/ml (n=6) at 6 months, 101.2 ng/ml (n=13) vs. 103.0 ng/ml (n=2) at 10 months, respectively). Echo analyses revealed significantly smaller mean aortic root diameters in 10 months old wild-type and losartan-treated C1039G/+ mice compared to age-matched C1039G/+ mice with placebo (p=0.001; 1.94 mm (n=2) and 2.06 mm (n=13) vs. 2.4 mm (n=3), respectively). Conclusions: TGF-beta serum levels are higher in C1039G/+ mice compared to wild-type mice. Losartan treatment of C1039G/+ mice reduces TGF-beta serum concentrations and aortic root diameters towards wild-type levels. Serum TGF-beta is a promising biomarker for prognostication and monitoring the therapeutic response to losartan therapy in Marfan syndrome.

Abstract 632: Aortic Dilatation in Marfan Syndrome: A Result of Amplification of Molecular Mechanisms of Aging?

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Michael A Hagler ◽  
Grace Casaclang-Verzosa ◽  
Bin Zhang ◽  
Carolyn Roos ◽  
Nassir Thalji ◽  
...  
Keyword(s):  
Gene Expression ◽  
Marfan Syndrome ◽  
Aortic Root ◽  
Expression Patterns ◽  
Mutant Mice ◽  
Aortic Dilatation ◽  
Mrna Levels ◽  
Wild Type ◽  
Fibrillin 1 ◽  
Tgf Β1

Marfan syndrome (MFS) is a genetic disease with a mutation for the microfibrillar constituent protein fibrillin-1 being the most prevalent. MFS is often associated with progressive aortic root dilation, ultimately progressing to aortic aneurysm and dissection. While recent work has shown that increased angiotensin-II receptor type-1 and transforming growth factor beta (TGF-β) signaling contributes to aneurysm formation in aorta, efficacious therapeutic targets remain elusive. Given previous reports of progeriod phenotypes in a subset of Marfan patients, we sought to determine whether there are molecular changes that are consistent with accelerated aging in a mouse model of Marfan syndrome. In mice carrying a loss-of-function mutation in fibrillin-1, we assessed aortic root dimensions by echocardiography and gene expression levels of TGF-β1-3, runt related transcription factor 2 (RUNX2), and the cellular senescent marker CDKN2A by quantitative real time PCR at 3 and 14 months of age. As expected, aortic sinus dimensions did not change significantly with aging in wild type mice, but increased dramatically in fibrillin-1 mutant mice compared to wild-type littermate controls and with age (p < 0.05 for both). TGF-β1 ligand expression paralleled age and disease-dependent changes in aortic dimensions, however TGF-β2 and TGF-β3 mRNA levels did not. Aortic dilatation was associated with increased gene expression of RUNX2 with aging and in marfanoid mice. Interestingly, fibrillin-1 mutant mice demonstrated marked increases in expression of the anti-proliferative cell-cycle checkpoint protein CDKN2A at both time points, and correlated with changes in TGF-β1 (R 2 =0.54) and RUNX2 (R 2 =0.69) mRNA. CDNK2A gene expression patterns, however, demonstrated a poor correlation with expression of TGF-β2 and TGF-β3 (R 2 =0.04 and 0.06. respectively). Collectively, these data lend insight into novel mechanisms that may regulate development of aortic root dilation in patients MFS and are the first to implicate increased senescent cell burden in Marfan syndrome. Furthermore, we propose that clearance of senescent cells could be a viable therapeutic intervention to slow progression aortic root-dilation and aneurysm in patients with Marfan syndrome.

scholarly journals Losartan for Preventing Aortic Root Dilatation in Patients with Marfan Syndrome: A Meta-Analysis of Randomized Trials

2019 ◽  
Vol 8 (2) ◽  
pp. 365-372 ◽  
Author(s):  
Ayman Elbadawi ◽  
Mohamed A. Omer ◽  
Islam Y. Elgendy ◽  
Ahmed Abuzaid ◽  
Ahmed H. Mohamed ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Aortic Root ◽  
Randomized Trials ◽  
Meta Analysis ◽  
Aortic Root Dilatation

scholarly journals Losartan Increases Survival of the Fbn1mgR/mgR Mouse Model of Marfan Syndrome in an Age-Dependent Manner

2021 ◽  
Author(s):  
Jeffrey D. Smith ◽  
Jeff Z. Chen ◽  
Rebecca Phillips ◽  
Alan Daugherty ◽  
Mary B. Sheppard
Keyword(s):  
Marfan Syndrome ◽  
Angiotensin Receptor Blockers ◽  
Primary Objective ◽  
Dependent Manner ◽  
Wild Type ◽  
Age Dependent ◽  
Fibrillin 1 ◽  
Receptor Blockers ◽  
To Receive ◽  
Overall Mortality

AbstractClinical trials investigating angiotensin receptor blockers (ARB) for attenuation of thoracic aortic aneurysm in people with Marfan syndrome have demonstrated variable efficacy. The primary objective of this study was to determine whether the age of mice at the time of losartan initiation affected mortality in fibrillin-1 hypomorphic (Fbn1mgR/mgR) mice. Male (n=40) and female (n=28) Fbn1mgR/mgR mice were randomized to receive losartan in drinking water (0.6 g/L) starting at either 24 or 50 days of age. Controls included Fbn1mgR/mgR mice (20M, 14F) and wild type (15M, 15F) littermates who were not administered the drug. Mortality of Fbn1mgR/mgR males receiving losartan at postnatal day 24 (P24) was not different from wild type controls (p=0.138). Survival of Fbn1mgR/mgR males administered losartan at P50 was not different compared to Fbn1mgR/mgR males receiving no drug (p=0.194) and decreased compared to wild type mice (p=0.002). Survival analysis after P50 demonstrated increased survival of Fbn1mgR/mgR males administered losartan at P50 compared to Fbn1mgR/mgR mice receiving no drug (p=0.017). Age is a critical variable that affects the therapeutic efficacy of losartan in male Fbn1mgR/mgR mice. Since overall mortality in female Fbn1mgR/mgR mice was lower than in male Fbn1mgR/mgR mice, a survival benefit with losartan was not detected in females.

scholarly journals Aortic Root Dilatation in Children and Adolescents At Al-Hawary General Hospital, & National Benghazi Cardiac Center -Libya

2021 ◽  
Vol 36 (4) ◽  
pp. 300-307
Author(s):  
Rasmia H. Feituri ◽  
Hanan El Megasbi ◽  
Mariam M. El maadani ◽  
Amal Khazm
Keyword(s):  
Aortic Valve ◽  
Children And Adolescents ◽  
Marfan Syndrome ◽  
Aortic Root ◽  
Ehlers Danlos Syndrome ◽  
Aortic Root Dilatation ◽  
Adrenergic Blockers ◽  
Danlos Syndrome ◽  
Cardiac Center

Isolated dilatation of the aortic root and/or ascending aorta is a rare but well-known cardiovascular manifestation, can be caused by a variety of congenital or acquired conditions; that lead to the weakening of the aortic wall. The study aimed to detect the cause and the rate of the aortic root dilatation in children and adolescents, and to assess the effect of the Beta-adrenergic blockers in preventing further dilatation in the aortic root. A case series study was perform with five years of follow-up at Al-Hawary General Hospital, National Benghazi Cardiac Center. A total of 91 patients were seen with ascending aortic dilatation and/or root dilatation during the period from 6/2016 - 6/2021 included in the study diagnosed by clinical examination, chest x-ray, and echocardiogram. The diagnosis in 34/91(37%) was Tetralogy of fallout (TOF) and truncus arteriosus, 57/91 (63%) was dilated aortic root, 25/57 (44%) bicuspid aortic valve (BAV), 22/57 (38.5%) Marfan syndrome, 4/57(7%) Noonan syndrome, 2/57(3.5%) Turner syndrome, 3/57(5%) Ehlers-Danlos syndrome, 1/57(2%) idiopathic. Follow-up results of three months – five years: 57/91 patients with aortic root dilatation were followed up, none of the Marfan syndrome and Ehlers-Danlos syndrome patients who received beta-blockers had shown progression in the dilatation of the aortic root, and all patients who had bicuspid aortic valve did not show any progression in the dilatation without using medication. Conclusions: Dilated aortic root is a common finding in Marfan syndrome, bicuspid aortic root, and Ehlers-Danlos syndrome, and its progress could be decreased by using beta-adrenergic blockers in rapidly progressing dilation.

445Effects of losartan and beta-blockers on aortic root dilatation in patients with Marfan Syndrome - results of the extended COMPARE trial

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M M Van Andel ◽  
J Jalalzadeh ◽  
R Indrakusuma ◽  
R Balm ◽  
J Timmermans ◽  
...  
Keyword(s):  
Root Growth ◽  
Marfan Syndrome ◽  
Aortic Root ◽  
Favourable Effect ◽  
Study Cohort ◽  
Aortic Root Dilatation ◽  
Dilatation Rate ◽  
Β Blocker ◽  
Β Blockers

Abstract Introduction Despite several randomized trials, beneficial effects of Losartan and β-blockers in adults with Marfan syndrome (MFS) are not entirely clear. The COMPARE trial previously showed a small but significant beneficial effect of Losartan on top of β-blocker use on aortic root dilatation rate. Yet, this effect was not reproduced by other trials, although in general a favourable effect of Losartan could be demonstrated. All trials in adults with MFS showed lower than expected aortic root dilatation rates, suggesting mildly affected study populations. Therefore we extended the follow-up period of the COMPARE trial up to 10 years and aimed to assess the clinical outcomes of the study cohort, as well as the effect of medication regimes on aortic root dilatation rates in the subgroup of patients with a native aortic root at initial randomization. Methods Patients previously enrolled in the COMPARE trial were retrospectively analyzed. Cardiovascular events (aortic dissections, ruptures and operations) and all-cause mortality were assessed. Individual aortic root dilatation rates were estimated in patients with a native aortic root at time of randomization on the basis of linear regression analysis of multiple transthoracic echocardiogram (TTE) results. Correlations between aortic root dilatation rates and cumulative Losartan or β-blocker treatment days were assessed with Spearman's rho (ρ). Results During a median follow-up of 8.0 years, two dissections and three deaths occurred in the 151 patients with a native aortic root at time of randomization. The 122 patients that were eligible for aortic root dilatation analysis, underwent a median of 6 TTEs. The median aortic root dilatation rate in these patients was 0.28 (interquartile range 0.09 - 0.59) mm/y. These patients were further classified as either patients with a stable aortic root (n=102) or with aortic root growth (n=20), based on the threshold of 0.9 mm per year. Patients with aortic root growth had significantly more aortic root replacements during follow-up (17/20 vs 18/102, P=0.001). Furthermore, aortic root dilatation rate was negatively correlated with the number of Losartan treatment days (ρ=−0.272, P=0.003), β-blocker treatment days (ρ=−0.217, P=0.017) and with the duration of follow-up (ρ=−0.437, P<0.001). Conclusions Our results support previous findings that Losartan and β-blockers appear to be equally effective on aortic root dilatation rate in Marfan Syndrome patients. The low event rate in the long term follow-up of this subgroup of the COMPARE trial represent a relatively mildly affected study population and an aggressive prophylactic surgical regime.

Zespół Marfana u 7-letniej dziewczynki – opis przypadku

2018 ◽  
Vol 22 (2) ◽  
Author(s):  
Małgorzata Ludzia ◽  
Radosław Pietrzak ◽  
Bożena Werner
Keyword(s):  
Marfan Syndrome ◽  
Aortic Root ◽  
Body Height ◽  
Premature Death ◽  
Joint Hypermobility ◽  
Left Ventricular ◽  
Ventricular Enlargement ◽  
Angiotensin Ii Receptor ◽  
Aortic Root Dilatation ◽  
Left Ventricular Enlargement

Marfan syndrome is a systemic, autosomal dominant connective tissue disorder with variable expressivity. An early diagnosis is challenging but important, because Marfan syndrome is associated with premature death in untreated patients. The authors present a case of a 7-year-old girl with Marfan syndrome. The child’s father was diagnosed with Marfan syndrome confirmed by genetic tests. The first symptoms of Marfan syndrome in the presented patient occurred at the age of 2 years, when she presented with mitral and tricuspid valve prolapse, scoliosis, joint hypermobility and body height above 97 percentile. In regular check-ups, aortic root dilatation and the enlargement of the left ventricle were first described one year later. It was decided to introduce beta blocker therapy. Due to the further progression of left ventricular enlargement the girl was given additionally angiotensin II receptor antagonist. In echocardiography follow up no increasing of the aortic root dilatation and the left ventricular enlargement is observed.

444Plasma levels of microfibrillar associated protein type 4 (MFAP4) are predictive for aortic dissection in patients with Marfan Syndrome

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M M Van Andel ◽  
S Wanga ◽  
X Yin ◽  
P Skroblin ◽  
D R Koolbergen ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Marfan Syndrome ◽  
Elastic Fiber ◽  
Aortic Distensibility ◽  
High Plasma ◽  
Type B ◽  
Tgf Beta ◽  
Fibrillin 1 ◽  
Aortic Dissections

Abstract Aim Marfan syndrome is a disorder with mutations in the fibrillin-1 gene, leading to elastic fiber degradation and increased TGF-beta signaling. The life-threatening feature of Marfan is aneurysm formation with a risk of fatal aortic dissections. In a proteomics screen, we identified MFAP4, a protein involved in fibrillin-1 and elastic fiber formation, to be increased in the Marfan aorta. We aim to study the role of MFAP4 in Marfan aortic disease. Methods and results MFAP4 co-localizes in the aorta with elastin and collagen fibers. In vitro experiments show that MFAP4 expression is upregulated by TGF-beta, which could explain the increased MFAP4 protein levels in the Marfan aorta. In a substudy of 96 Marfan patients from the COMPARE trial, MFAP4 levels correlate with aortic root diameter (r=0.30, p=0.01). Patients previously enrolled in the COMPARE trial were retrospectively analyzed. Cardiovascular events, including aortic dissection, were assessed. Plasma samples were prospectively collected at time of inclusion in the study and analyzed retrospectively on MFAP4. In the 7 years of follow up, 5 Type B dissections occurred, all of them in patients in the upper tertile of plasma MFAP4. High plasma MFAP4 associates with poor dissection-free survival (Figure 1). Moreover, the aortic distensibility as measure for aortic stiffness and damage, was calculated throughout the aorta from available MRI images of these patients. Interestingly, in the descending thoracic aorta where type B dissections occur, the aortic distensibility is significantly lower (indicating decreased aortic elasticity) in Marfan patients with high plasma MFAP4, thus associating with aortic damage. Figure 1 Conclusion MFAP4, a protein involved in extracellular matrix assembly, is elevated in the Marfan aorta. High plasma MFAP4 seems to reflect aortic damage and predicted type B aortic dissections in up to 7 years follow up.

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