scholarly journals Letter by Groth et al Regarding Article, “Impact of Pathogenic FBN1 (Fibrillin-1) Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome”

2018 ◽  
Vol 11 (9) ◽  
Author(s):  
Kristian A. Groth ◽  
Claus H. Gravholt ◽  
Niels H. Andersen
2021 ◽  
Vol 9 ◽  
Author(s):  
Laura Muiño-Mosquera ◽  
Julie De Backer

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.


ESC CardioMed ◽  
2018 ◽  
pp. 713-715
Author(s):  
Dorien Schepers ◽  
Bart Loeys

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.


2015 ◽  
Vol 112 (45) ◽  
pp. 14012-14017 ◽  
Author(s):  
Lior Zilberberg ◽  
Colin K. L. Phoon ◽  
Ian Robertson ◽  
Branka Dabovic ◽  
Francesco Ramirez ◽  
...  

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.


2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Eric K Lai ◽  
Daniel J Wytowich ◽  
Giovanni Ferrari ◽  
Joseph E Bavaria ◽  
Reed E Pyeritz ◽  
...  

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.


ESC CardioMed ◽  
2018 ◽  
pp. 713-715
Author(s):  
Dorien Schepers ◽  
Bart Loeys

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.


VASA ◽  
2010 ◽  
Vol 39 (1) ◽  
pp. 17-32 ◽  
Author(s):  
von Kodolitsch ◽  
Rybczynski ◽  
Bernhardt ◽  
Mir ◽  
Treede ◽  
...  

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.


Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 128
Author(s):  
Keiichi Asano ◽  
Anna Cantalupo ◽  
Lauriane Sedes ◽  
Francesco Ramirez

About 20% of individuals afflicted with thoracic aortic disease have single-gene mutations that predispose the vessel to aneurysm formation and/or acute aortic dissection often without associated syndromic features. One widely studied exception is Marfan syndrome (MFS) in which mutations in the extracellular protein fibrillin-1 cause additional abnormalities in the heart, eyes, and skeleton. Mouse models of MFS have been instrumental in delineating major cellular and molecular determinants of thoracic aortic disease. In spite of research efforts, translating experimental findings from MFS mice into effective drug therapies for MFS patients remains an unfulfilled promise. Here, we describe a series of studies that have implicated endothelial dysfunction and improper angiotensin II and TGFβ signaling in driving thoracic aortic disease in MFS mice. We also discuss how these investigations have influenced the way we conceptualized possible new therapies to slow down or even halt aneurysm progression in this relatively common connective tissue disorder.


2015 ◽  
Vol 113 (03) ◽  
pp. 668-670 ◽  
Author(s):  
Philipp von Hundelshausen ◽  
Konrad Oexle ◽  
Kiril Bidzhekov ◽  
Martin Schmitt ◽  
Michael Hristov ◽  
...  
Keyword(s):  
De Novo ◽  

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