Abstract 103: Circulating sRAGE is Elevated in Patients with Marfan Syndrome and Decreases After Surgical Replacement of Diseased Aortic Segments

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Eric K Lai ◽  
Daniel J Wytowich ◽  
Giovanni Ferrari ◽  
Joseph E Bavaria ◽  
Reed E Pyeritz ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Marfan Syndrome ◽  
Aortic Surgery ◽  
Clinical Information ◽  
Aortic Disease ◽  
Aortic Diameter ◽  
Aortic Tissue ◽  
Post Surgery ◽  
Fibrillin 1 ◽  
One Year

Backgound: The Receptor for Advanced Glycation End products (RAGE) and its ligands are associated with vascular remodeling and trigger the release of a soluble receptor (sRAGE). We previously demonstrated that sRAGE levels are elevated in patients with bicuspid aortic valve and ascending aortic aneurysm. Circulating sRAGE in these patients correlates with the presence of a dysfunctional aortic structure but do not linearly correlate with an increase in the aortic diameter. Severe aortic disease occurs in more than 80% of Marfan Syndrome (MFS) patients. Aortic root and ascending aorta (AA) enlargement in MFS are associated with deficiency/destabilization of fibrillin-1, which leads to a generalized structural impairment of the aortic wall. We hypothesized that sRAGE may be elevated in the plasma of MFS patients and may decrease after surgical replacement of diseased aortic tissue. Methods: Plasma samples and clinical information (MFS=120, Control=37) were obtained from the GenTAC bioregistry and the Tissue Biobank at UPENN. Samples were collected either a few days prior to aortic surgery or at least one year post-surgery. sRAGE was tested using ELISA. Univariate and multivariate analysis were performed. Results: sRAGE levels are significantly higher in MFS patients compared to control (1404±64.35 vs 592±34.86 pg/ml, p<0.001) and are associated with the presence of MFS, independent of age, gender and comorbidities (p<0.001). sRAGE levels are significantly higher in MFS patients undergoing aortic surgery when compared to MFS patients monitored for aortic disease (1485±116.8 vs 1209±82.63 pg/ml, p=0.05). Circulating sRAGE is significantly lower in patients who have received aortic surgery (1185±63.31 pg/ml, p=0.02) and even lower in patients who received more extensive replacement (aortic valve/root and AA) versus those who underwent only aortic valve and root replacement (1313±81.83 vs 963.5±92.54 pg/ml, p=0.008). sRAGE levels do not linearly correlate with root and/or AA diameter. Conclusion: Plasma sRAGE levels are associated with the presence of ascending aortopathies independent of aortic diameter. Longitudinal studies evaluating sRAGE in MFS patients may unveil new markers for the diagnosis and risk stratification of this population.

scholarly journals Cardiomyopathy in Genetic Aortic Diseases

2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Muiño-Mosquera ◽  
Julie De Backer
Keyword(s):  
Marfan Syndrome ◽  
Myocardial Dysfunction ◽  
Genetic Defect ◽  
Positive Family History ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Aortic Diseases ◽  
Pathogenic Variants ◽  
Fibrillin 1

Genetic aortic diseases are a group of illnesses characterized by aortic aneurysms or dissection in the presence of an underlying genetic defect. They are part of the broader spectrum of heritable thoracic aortic disease, which also includes those cases of aortic aneurysm or dissection with a positive family history but in whom no genetic cause is identified. Aortic disease in these conditions is a major cause of mortality, justifying clinical and scientific emphasis on the aorta. Aortic valve disease and atrioventricular valve abnormalities are known as important additional manifestations that require careful follow-up and management. The archetype of genetic aortic disease is Marfan syndrome, caused by pathogenic variants in the Fibrillin-1 gene. Given the presence of fibrillin-1 microfibers in the myocardium, myocardial dysfunction and associated arrhythmia are conceivable and have been shown to contribute to morbidity and mortality in patients with Marfan syndrome. In this review, we will discuss data on myocardial disease from human studies as well as insights obtained from the study of mouse models of Marfan syndrome. We will elaborate on the various phenotypic presentations in childhood and in adults and on the topic of arrhythmia. We will also briefly discuss the limited data available on other genetic forms of aortic disease.

Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽  
2018 ◽  
pp. 713-715
Author(s):  
Dorien Schepers ◽  
Bart Loeys
Keyword(s):  
Extracellular Matrix ◽  
Marfan Syndrome ◽  
Transforming Growth Factor Beta ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Aortic Disease ◽  
Extracellular Matrix Protein ◽  
Genetic Defects ◽  
Fibrillin 1 ◽  
Growth Factor Beta

Marfan syndrome is an autosomal dominant, multisystemic disorder, presenting with skeletal, ocular, and cardiovascular symptoms. This connective tissue disease is caused by mutations in FBN1, encoding fibrillin-1, which is an important extracellular matrix protein. Marfan syndrome shows significant clinical overlap with Loeys–Dietz syndrome, which is caused by genetic defects in components of the transforming growth factor-beta pathway: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, and SMAD3. Overlapping clinical features between Marfan syndrome and Loeys–Dietz syndrome include aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity.

scholarly journals Differences in Aortopathy in Patients with a Bicuspid Aortic Valve with or without Aortic Coarctation

2020 ◽  
Vol 9 (2) ◽  
pp. 290
Author(s):  
Anthonie Duijnhouwer ◽  
Allard van den Hoven ◽  
Remy Merkx ◽  
Michiel Schokking ◽  
Roland van Kimmenade ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Dissection ◽  
Bicuspid Aortic Valve ◽  
Aortic Coarctation ◽  
Care Center ◽  
Aortic Surgery ◽  
Tertiary Care ◽  
Aortic Diameter ◽  
Aortic Dilatation ◽  
Significant Difference

Objective: The combination of aortic coarctation (CoA) and bicuspid aortic valve (BAV) is assumed to be associated with a higher risk of ascending aortic dilatation and type A dissection, and current European Society of Cardiology (ESC) guidelines advise therefore to operate at a lower threshold in the presence of CoA. The aim of our study is to evaluate whether the coexistence of CoA in BAV patients is indeed associated with a higher risk of ascending aortic events (AAE). Methods: In a retrospective study, all adult BAV patients visiting the outpatient clinic of our tertiary care center between February 2003 and February 2019 were included. The primary end point was an ascending aortic event (AAE) defined as ascending aortic dissection/rupture or preventive surgery. The secondary end points were aortic dilatation and aortic growth. Results: In total, 499 BAV patients (43.7% female, age 40.3 ± 15.7 years) were included, of which 121 (24%) had a history of CoA (cBAV). An aortic event occurred in 38 (7.6%) patients at a mean age of 49.0 ± 13.6 years. In the isolated BAV group (iBAV), significantly more AAE occurred, but this was mainly driven by aortic valve dysfunction as indication for aortic surgery. There was no significant difference in the occurrence of dissection or severely dilated ascending aorta (>50 mm) between the iBAV and cBAV patients (p = 0.56). The aortic diameter was significantly smaller in the cBAV group (30.3 ± 6.9 mm versus 35.7 ± 7.6 mm; p < 0.001). The median aortic diameter increase was 0.23 (interquartile range (IQR): 0.0–0.67) mm/year and was not significantly different between both groups (p = 0.74). Conclusion: Coexistence of CoA in BAV patients was not associated with a higher risk of aortic dissection, preventive aortic surgery, aortic dilatation, or more rapid aorta growth. This study suggests that CoA is not a risk factor in BAV patients, and the advice to operate at lower diameter should be reevaluated.

scholarly journals Identification of fibrillin 1 gene mutations in patients with bicuspid aortic valve (BAV) without Marfan syndrome

2014 ◽  
Vol 15 (1) ◽  
Author(s):  
Guglielmina Pepe ◽  
Stefano Nistri ◽  
Betti Giusti ◽  
Elena Sticchi ◽  
Monica Attanasio ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Marfan Syndrome ◽  
Bicuspid Aortic Valve ◽  
Gene Mutations ◽  
Fibrillin 1

scholarly journals Genetic analysis of the contribution of LTBP-3 to thoracic aneurysm in Marfan syndrome

2015 ◽  
Vol 112 (45) ◽  
pp. 14012-14017 ◽  
Author(s):  
Lior Zilberberg ◽  
Colin K. L. Phoon ◽  
Ian Robertson ◽  
Branka Dabovic ◽  
Francesco Ramirez ◽  
...  
Keyword(s):  
Aortic Aneurysm ◽  
Marfan Syndrome ◽  
Autosomal Dominant ◽  
Aortic Disease ◽  
Elastic Fibers ◽  
Thoracic Aneurysm ◽  
Tgfβ Signaling ◽  
Autosomal Dominant Disorder ◽  
Present Evidence ◽  
Fibrillin 1

Marfan syndrome (MFS) is an autosomal dominant disorder of connective tissue, caused by mutations of the microfibrillar protein fibrillin-1, that predisposes affected individuals to aortic aneurysm and rupture and is associated with increased TGFβ signaling. TGFβ is secreted from cells as a latent complex consisting of TGFβ, the TGFβ propeptide, and a molecule of latent TGFβ binding protein (LTBP). Improper extracellular localization of the latent complex can alter active TGFβ levels, and has been hypothesized as an explanation for enhanced TGFβ signaling observed in MFS. We previously reported the absence of LTBP-3 in matrices lacking fibrillin-1, suggesting that perturbed TGFβ signaling in MFS might be due to defective interaction of latent TGFβ complexes containing LTBP-3 with mutant fibrillin-1 microfibrils. To test this hypothesis, we genetically suppressed Ltbp3 expression in a mouse model of progressively severe MFS. Here, we present evidence that MFS mice lacking LTBP-3 have improved survival, essentially no aneurysms, reduced disruption and fragmentation of medial elastic fibers, and decreased Smad2/3 and Erk1/2 activation in their aortas. These data suggest that, in MFS, improper localization of latent TGFβ complexes composed of LTBP-3 and TGFβ contributes to aortic disease progression.

AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of Marfan syndrome

2021 ◽  
Author(s):  
Anca Remes ◽  
Rawa Arif ◽  
Maximilian Franz ◽  
Andreas Jungmann ◽  
Marcin Zaradzki ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Ex Vivo ◽  
Binding Activity ◽  
Aortic Tissue ◽  
Inherited Disorders ◽  
Monocyte Chemoattractant Protein 1 ◽  
Fibrillin 1 ◽  
Decoy Oligonucleotide ◽  
Expression And Activity

Abstract Aims Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome. Methods and results Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography. Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs. Conclusion This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Genetics of vascular disease: Marfan syndrome and aortic disease

ESC CardioMed ◽  
2018 ◽  
pp. 713-715
Author(s):  
Dorien Schepers ◽  
Bart Loeys
Keyword(s):  
Extracellular Matrix ◽  
Marfan Syndrome ◽  
Transforming Growth Factor Beta ◽  
Matrix Protein ◽  
Transforming Growth Factor ◽  
Aortic Disease ◽  
Extracellular Matrix Protein ◽  
Genetic Defects ◽  
Fibrillin 1 ◽  
Growth Factor Beta

Marfan syndrome is an autosomal dominant, multisystemic disorder, presenting with skeletal, ocular, and cardiovascular symptoms. This connective tissue disease is caused by mutations in FBN1, encoding fibrillin-1, which is an important extracellular matrix protein. Marfan syndrome shows significant clinical overlap with Loeys–Dietz syndrome, which is caused by genetic defects in components of the transforming growth factor-beta pathway: TGFBR1, TGFBR2, TGFB2, TGFB3, SMAD2, and SMAD3. Overlapping clinical features between Marfan syndrome and Loeys–Dietz syndrome include aortic root aneurysm, arachnodactyly, scoliosis, and pectus deformity.

Marfan syndrome and the evolving spectrum of heritable thoracic aortic disease: Do we need genetics for clinical decisions?

VASA ◽  
2010 ◽  
Vol 39 (1) ◽  
pp. 17-32 ◽  
Author(s):  
von Kodolitsch ◽  
Rybczynski ◽  
Bernhardt ◽  
Mir ◽  
Treede ◽  
...  
Keyword(s):  
Marfan Syndrome ◽  
Autosomal Dominant ◽  
Aortic Disease ◽  
Aortic Aneurysms ◽  
Clinical Implications ◽  
Thoracic Aortic Disease ◽  
Gene Coding ◽  
Autosomal Dominant Fashion ◽  
Fibrillin 1 ◽  
Work Up

Marfan syndrome (MFS) is a disorder of the connective tissue that is inherited in an autosomal dominant fashion and that is classically caused by mutations in the gene coding for fibrillin-1, FBN1. The high mortality of untreated MFS results almost exclusively from aortic complications such as aortic dissection and rupture. However, more than half of patients with Marfan-like features do not have MFS, but have other diseases including inherited aortic aneurysms and dissections (TAAD). We elucidate the increasing spectrum of syndromes associated with Marfan-like features and discuss the clinical implications of these diseases. We performed a systematic review to tabulate all known inherited diseases and syndromes carrying a risk for thoracic aortic disease. We discuss evidence that different syndromes with different causative genes and mutations have different prognoses and profiles of cardiovascular manifestations. We conclude that future decisions for optimized management of patients with inherited TAAD require a comprehensive clinical and genetic work-up.

6126Peripheral aneurysms in Marfan patients are common and are related to age and advanced aortic disease

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
L Mila ◽  
G Teixido Tura ◽  
C Granato ◽  
J Limeres ◽  
L Servato ◽  
...  
Keyword(s):  
Aortic Dissection ◽  
Ct Angiography ◽  
Marfan Syndrome ◽  
Aortic Surgery ◽  
Aortic Disease ◽  
Arterial System ◽  
Whole Body ◽  
Fbn1 Mutation ◽  
Peripheral Aneurysms

Abstract Background Peripheral aneurysms are not included in the diagnostic criteria for Marfan syndrome (MFS); however, their real prevalence in MFS is unknown. Furthermore, they are commonly seen in other genetic entities such as Loeys-Dietz syndrome. We aimed to investigate the prevalence of peripheral aneurysm in Marfan syndrome. Methods Patients with clinical criteria of Marfan syndrome and identified FBN1 mutation were evaluated. Only patients with either MRI or CT angiography assessing peripheral vessels were included in this study. MRI and CT angiography studies were retrospectively evaluated to detect the presence of peripheral aneurysms. Aortic dissection-related arterial dilations were excluded. Aortic events and those related to aneurysm complications were collected during follow-up. Results Two hundred and nine patients with Marfan and FBN1 mutation were evaluated. Of these 136 (65.1%) had undergone either MRA or CTA with peripheral artery study during follow-up. Mean age at the last follow-up visit was 42.4±14.1yrs; 54.4% were men, and mean follow-up 7.3±3.1 years. Sixty-six aneurysms were identified in 42 (30.9%) patients. The most common locations were the iliac arteries in 23. The rest were: renal (7), vertebral (5), splenic (5), coeliac (3), brachiocephalic (1), subclavian (3), carotid (3), axillary (2), internal mammary (3), femoral (2), hypogastric (3), bronchial (2), coronary (1), hepatic (1), lumbar (1), gastroduodenal (1) and popliteal (1). Twenty-six patients (61.9%) had more than one peripheral aneurysm, and only 4 required surgery. Patients with peripheral aneurysms were older (47.2±14.3yrs vs 40.2±13.6yrs, p=0.06) and more frequently men (69.0% vs 47.9% p=0.026). Although patients with peripheral aneurysms did not more frequently have aortic dissection (16.7% vs 17.0%, p=0.586), they did more frequently have aortic surgery (73.8% vs 47.9% p=0.05). Conclusions Peripheral aneurysms are present in one third of Marfan syndrome patients and are related to age and more advanced aortic disease. Systematic use of whole-body vascular assessment in Marfan patients can provide a comprehensive evaluation of the entire arterial system, identifying other sites of vascular involvement at risk of potential complications, and the subgroup of patients with more aggressive vascular disease expression.

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