Abstract
Vascular smooth muscle cells (vSMCs) play a crucial role in both the pathogenesis of Aneurysms and Dissections of the ascending thoracic aorta (TAAD) in humans and in the associated adaptive ...compensatory responses, since thrombosis and inflammatory processes are absent in the majority of cases. Aneurysms and dissections share numerous characteristics, including aetiologies and histopathological alterations: vSMC disappearance, medial areas of mucoid degeneration, and extracellular matrix (ECM) breakdown. Three aetiologies predominate in TAAD in humans: (i) genetic causes in heritable familial forms, (ii) an association with bicuspid aortic valves, and (iii) a sporadic degenerative form linked to the aortic aging process. Genetic forms include mutations in vSMC genes encoding for molecules of the ECM or the TGF-β pathways, or participating in vSMC tone. On the other hand, aneurysms and dissections, whatever their aetiologies, are characterized by an increase in wall permeability leading to transmural advection of plasma proteins which could interact with vSMCs and ECM components. In this context, blood-borne plasminogen appears to play an important role, because its outward convection through the wall is increased in TAAD, and it could be converted to active plasmin at the vSMC membrane. Active plasmin can induce vSMC disappearance, proteolysis of adhesive proteins, activation of MMPs and release of TGF-β from its ECM storage sites. Conversely, vSMCs could respond to aneurysmal biomechanical and proteolytic injury by an epigenetic phenotypic switch, including constitutional overexpression and nuclear translocation of Smad2 and an increase in antiprotease and ECM protein synthesis. In contrast, such an epigenetic phenomenon is not observed in dissections. In this context, dysfunction of proteins involved in vSMC tone are interesting to study, particularly in interaction with plasma protein transport through the wall and TGF-β activation, to establish the relationship between these dysfunctions and ECM proteolysis.
AbstractObjectiveFailure of thoracic endovascular aortic repair (TEVAR) in chronic aortic dissections can be partially explained by retrograde false lumen (FL) flow through distal re-entry tears. ...After implantation of a thoracic stent graft, FL thrombosis occurs in less than 50% of the cases. The objectives of this study were to describe the feasibility and outcomes of FL embolization in patients with chronic aortic dissections. MethodsBetween June 2015 and January 2018, 27 patients (mean age, 61 ± 14 years) with chronic aortic dissection underwent FL embolization as an adjunct during or after TEVAR placement procedure. Indications for embolization were (1) symptomatic chronic aortic dissections with pain or rapid growth of aortic diameter (≥5 mm/y) requiring rapid exclusion of the aneurysm, (2) aneurysmal dilatation with persistent FL retrograde flow after TEVAR, and (3) large FL aneurysms (≥55 mm) that might lead to persistent retrograde flow. Twenty patients presented with type B chronic aortic dissections (74.1%) and seven presented a residual type A chronic aortic dissections (25.9%). Eight patients had a previous aortic arch replacement (29.6%). Six patients had previous repair with TEVAR (22.2%). The delay between the onset of dissection and the first endovascular repair was 47 months (range, 3-144). Spinal fluid drainage was used in 74.1% of cases (20/27 patients). Embolization devices included coils and vascular plugs. ResultsThe technical success rate was 100% (27/27). Complete spinal cord ischemia was observed in one patient (3.7%). There was one hospital death from pneumonia after zone 1 supra-aortic trunk debranching with TEVAR and embolization. After the index procedure, FL thrombosis was observed in 81.5% of patients (22/27) on late phase computed tomography angiography. Five patients required two or more embolization procedures, leading to a high rate of complete FL thrombosis (92.6%). One patient presented a type IB endoleak and one patient presented a type II endoleak. Radiologic follow-up was 20 ± 10 months. The maximum thoracic aortic diameter significantly decreased from 63 mm to 54 ± 10 mm ( P < .001). ConclusionsEmbolization of the FL of chronic aortic dissections is technically feasible with a low morbidity rate. The FL thrombosis is observed in the majority of case and promotes favorable thoracic aortic remodeling. Longer follow-up is needed to confirm these good results on the thoracic aorta and this technique may, therefore, improve the results of TEVAR in chronic aortic dissections.
Marfan syndrome (MFS) is a connective tissue disorder in which several systems are affected with great phenotypic variability. Although known to be associated with pathogenic variants in the FBN1 ...gene, few genotype–phenotype correlations have been found in proband studies only.
In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype–phenotype correlations.
A risk chart could be established with clinical and genetic data. Premature termination codon variants were not only associated with a shorter life expectancy and a high lifelong risk of aortic event, but also with the highest risk of severe scoliosis and a lower risk for ectopia lentis (EL) surgery. In-frame variants could be subdivided according to their impact on the cysteine content of fibrillin-1 with a global higher severity for cysteine loss variants and the highest frequency of EL surgery for cysteine addition variants.
This study shows that FBN1 genotype–phenotype correlations exist for both aortic and extra-aortic features. It can be used for optimal risk stratification of patients with a great importance for genetic counseling and personalized medicine. This also provides additional data for the overall understanding of the role of fibrillin-1 in various organs.
Marfan syndrome Milewicz, Dianna M; Braverman, Alan C; De Backer, Julie ...
Nature reviews. Disease primers,
09/2021, Volume:
7, Issue:
1
Journal Article
Peer reviewed
Marfan syndrome (MFS) is an autosomal dominant, age-related but highly penetrant condition with substantial intrafamilial and interfamilial variability. MFS is caused by pathogenetic variants in ...FBN1, which encodes fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues, particularly in arteries, the pericondrium and structures in the eye. Up to 25% of individuals with MFS have de novo variants. The most prominent manifestations of MFS are asymptomatic aortic root aneurysms, aortic dissections, dislocation of the ocular lens (ectopia lentis) and skeletal abnormalities that are characterized by overgrowth of the long bones. MFS is diagnosed based on the Ghent II nosology; genetic testing confirming the presence of a FBN1 pathogenetic variant is not always required for diagnosis but can help distinguish MFS from other heritable thoracic aortic disease syndromes that can present with skeletal features similar to those in MFS. Untreated aortic root aneurysms can progress to life-threatening acute aortic dissections. Management of MFS requires medical therapy to slow the rate of growth of aneurysms and decrease the risk of dissection. Routine surveillance with imaging techniques such as transthoracic echocardiography, CT or MRI is necessary to monitor aneurysm growth and determine when to perform prophylactic repair surgery to prevent an acute aortic dissection.
To evaluate the benefit of adding Losartan to baseline therapy in patients with Marfan syndrome (MFS).
A double-blind, randomized, multi-centre, placebo-controlled, add on trial comparing Losartan ...(50 mg when <50 kg, 100 mg otherwise) vs. placebo in patients with MFS according to Ghent criteria, age >10 years old, and receiving standard therapy. 303 patients, mean age 29.9 years old, were randomized. The two groups were similar at baseline, 86% receiving β-blocker therapy. The median follow-up was 3.5 years. The evolution of aortic diameter at the level of the sinuses of Valsalva was not modified by the adjunction of Losartan, with a mean increase in aortic diameter at the level of the sinuses of Valsalva of 0.44 mm/year (s.e. = 0.07) (-0.043 z/year, s.e. = 0.04) in patients receiving Losartan and 0.51 mm/year (s.e. = 0.06) (-0.01 z/year, s.e. = 0.03) in those receiving placebo (P = 0.36 for the comparison on slopes in millimeter per year and P = 0.69 for the comparison on slopes on z-scores). Patients receiving Losartan had a slight but significant decrease in systolic and diastolic blood pressure throughout the study (5 mmHg). During the study period, aortic surgery was performed in 28 patients (15 Losartan, 13 placebo), death occurred in 3 patients 0 Losartan, 3 placebo, sudden death (1) suicide (1) oesophagus cancer (1).
Losartan was able to decrease blood pressure in patients with MFS but not to limit aortic dilatation during a 3-year period in patients >10 years old. β-Blocker therapy alone should therefore remain the standard first line therapy in these patients.
Summary Background Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with ...positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo. Methods RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov , NCT00520806. Findings 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120–775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients 26%; serelaxin, 156 27%; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events 60-day Kaplan-Meier estimate, 13·0%; serelaxin, 76 events 13·2%; hazard ratio HR 1·02 0·74–1·41, p=0·89 or days alive out of the hospital up to day 60 (placebo, 47·7 SD 12·1 days; serelaxin, 48·3 11·6; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42–0·93; p=0·019). Interpretation Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. Funding Corthera, a Novartis affiliate company.
Abstract
This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist ...cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant of unknown or uncertain significance is a limitation of genetic testing, but current guidelines for the interpretation of genetic variants include essential contributions from clinical family screening that can establish a de novo assignment of the variant or its segregation with the phenotype in the family. A partnership between clinicians and patients helps to solve major uncertainties and provides reliable and clinically actionable information.
Graphical Abstract
Impact of the cardiologic phenotyping of probands and relatives on ACMG criteria. The ideal ‘drawing’ of the family pedigree is complete and correct when all available family members have been clinically evaluated and, eventually, longitudinally monitored. *Cardiologists and geneticists may add their own experience, data, and local population information. oEndomyocardial biopsy - anti-GB3 immuno-stain (positive brown; §Typical ultrastructural pattern. DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; RCM = restrictive cardiomyopathy; ACM = arrhythmogenic cardiomyopathy; ASD = atrial septal defect; VSD = ventricular septal defect; GB3 = globotriaosylceramide.
The international recommendations tend to avoid physical activity (PA) for patients with Marfan syndrome (MFS). However, exceptions have recently been made in the most recent recommendations for ...these patients, suggesting benefits from doing PA at low intensity only. Furthermore, there is no evidence that moderate aerobic or weight training can worsen the disease symptoms and increase mortality of MFS patients. The present review sums up the work carried out in the field of PA and MFS. The review aims to (1) identify the different types of exercise testing and training protocols and (2) discuss the feasibility and potentially beneficial nature of PA as an innovative way to manage MFS patients.
The scientific literature was reviewed using the following words: Marfan syndrome, training, physical activity, evaluation, weight training, arterial disease, aneurysms, lung damage, aortic dissection, rupture. A total of 345 studies were prospected and 43 studies were included.
A limited number of studies were done in humans, however one demonstrated the feasibility of the management of MFS patients with PA. There were potential beneficial effects of PA on arterial structures, but this review also showed deleterious effects when PA was conducted at high intensities, corresponding to 75-85% of the maximal oxygen uptake. However, these effects have only been reported in animal studies.
Individuals with mosaic pathogenic variants in the FBN1 gene are mainly described in the course of familial screening. In the literature, almost all these mosaic individuals are asymptomatic. In this ...study, we report the experience of our team on more than 5,000 Marfan syndrome (MFS) probands.
Next-generation sequencing (NGS) capture technology allowed us to identify five cases of MFS probands who harbored a mosaic pathogenic variant in the FBN1 gene.
These five sporadic mosaic probands displayed classical features usually seen in Marfan syndrome. Combined with the results of the literature, these rare findings concerned both single-nucleotide variants and copy-number variations.
This underestimated finding should not be overlooked in the molecular diagnosis of MFS patients and warrants an adaptation of the parameters used in bioinformatics analyses. The five present cases of symptomatic MFS probands harboring a mosaic FBN1 pathogenic variant reinforce the fact that apparently asymptomatic mosaic parents should have a complete clinical examination and a regular cardiovascular follow-up. We advise that individuals with a typical MFS for whom no single-nucleotide pathogenic variant or exon deletion/duplication was identified should be tested by NGS capture panel with an adapted variant calling analysis.
Marfan syndrome (MFS) is a rare autosomal dominant connective tissue disorder related to variants in the FBN1 gene. Prognosis is related to aortic risk of dissection following aneurysm. MFS clinical ...variability is notable, for age of onset as well as severity and number of clinical manifestations. To identify genetic modifiers, we combined genome-wide approaches in 1070 clinically well-characterized FBN1 disease-causing variant carriers: (1) an FBN1 eQTL analysis in 80 fibroblasts of FBN1 stop variant carriers, (2) a linkage analysis, (3) a kinship matrix association study in 14 clinically concordant and discordant sib-pairs, (4) a genome-wide association study and (5) a whole exome sequencing in 98 extreme phenotype samples.Three genetic mechanisms of variability were found. A new genotype/phenotype correlation with an excess of loss-of-cysteine variants (P = 0.004) in severely affected subjects. A second pathogenic event in another thoracic aortic aneurysm gene or the COL4A1 gene (known to be involved in cerebral aneurysm) was found in nine individuals. A polygenic model involving at least nine modifier loci (named gMod-M1-9) was observed through cross-mapping of results. Notably, gMod-M2 which co-localizes with PRKG1, in which activating variants have already been described in thoracic aortic aneurysm, and gMod-M3 co-localized with a metalloprotease (proteins of extra-cellular matrix regulation) cluster. Our results represent a major advance in understanding the complex genetic architecture of MFS and provide the first steps toward prediction of clinical evolution.
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