Publications by authors named "Guillaume Jondeau"

167 Publications

Preliminary Experience With Custom Made Hourglass Shaped Thoracic Stent Grafts for Endovascular Thoracic Aortic Coarctation Repair in Adults.

Eur J Vasc Endovasc Surg 2021 Oct 6. Epub 2021 Oct 6.

Vascular and Thoracic Surgery Department, Bichat Hospital, Assistance Publique-Hopitaux de Paris, Paris, France; Centre de Référence pour le Syndrome de Marfan et apparentés, Bichat Hospital, Assistance Publique-Hopitaux de Paris, Paris, France; INSERM (Institu National de la Santé et de la Recherche Médicale) U 1148, LVTS (Laboratory for Vascular Translational Science), Bichat Hospital, Paris, France; University of Paris, Paris, France.

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http://dx.doi.org/10.1016/j.ejvs.2021.08.016DOI Listing
October 2021

Marfan syndrome.

Nat Rev Dis Primers 2021 09 2;7(1):64. Epub 2021 Sep 2.

Montalcino Aortic Consortium (MAC), Houston, TX, USA.

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.
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http://dx.doi.org/10.1038/s41572-021-00298-7DOI Listing
September 2021

Hyperventilation as one of the mechanisms of persistent dyspnoea in SARS-CoV-2 survivors.

Eur Respir J 2021 08 26;58(2). Epub 2021 Aug 26.

Service de Physiologie Clinique-Explorations Fonctionnelles, Assistance Publique Hôpitaux de Paris, Hôpital Bichat-Claude Bernard, Paris, France.

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http://dx.doi.org/10.1183/13993003.01578-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361302PMC
August 2021

Inhibition of HIPK2 Alleviates Thoracic Aortic Disease in Mice With Progressively Severe Marfan Syndrome.

Arterioscler Thromb Vasc Biol 2021 09 29;41(9):2483-2493. Epub 2021 Jul 29.

Department of Pharmacological Sciences, Institute for Systems Biomedicine (C.I.C., J.H., B.C., T.H., R.I., F.R.), Icahn School of Medicine at Mount Sinai, New York.

Objective: Despite considerable research, the goal of finding nonsurgical remedies against thoracic aortic aneurysm and acute aortic dissection remains elusive. We sought to identify a novel aortic PK (protein kinase) that can be pharmacologically targeted to mitigate aneurysmal disease in a well-established mouse model of early-onset progressively severe Marfan syndrome (MFS).

Approach And Results: Computational analyses of transcriptomic data derived from the ascending aorta of MFS mice predicted a probable association between thoracic aortic aneurysm and acute aortic dissection development and the multifunctional, stress-activated HIPK2 (homeodomain-interacting protein kinase 2). Consistent with this prediction, Hipk2 gene inactivation significantly extended the survival of MFS mice by slowing aneurysm growth and delaying transmural rupture. HIPK2 also ranked among the top predicted PKs in computational analyses of DEGs (differentially expressed genes) in the dilated aorta of 3 MFS patients, which strengthened the clinical relevance of the experimental finding. Additional in silico analyses of the human and mouse data sets identified the TGF (transforming growth factor)-β/Smad3 signaling pathway as a potential target of HIPK2 in the MFS aorta. Chronic treatment of MFS mice with an allosteric inhibitor of HIPK2-mediated stimulation of Smad3 signaling validated this prediction by mitigating thoracic aortic aneurysm and acute aortic dissection pathology and partially improving aortic material stiffness.

Conclusions: HIPK2 is a previously unrecognized determinant of aneurysmal disease and an attractive new target for antithoracic aortic aneurysm and acute aortic dissection multidrug therapy.
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http://dx.doi.org/10.1161/ATVBAHA.121.316464DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8530207PMC
September 2021

Coronavirus disease vaccination in heart failure: No time to waste.

Arch Cardiovasc Dis 2021 05 24;114(5):434-438. Epub 2021 May 24.

Fédération des services de cardiologie, faculté de médecine, Institute CARDIOMET, Université Paul Sabatier-Toulouse III, CHU de Toulouse-Rangueil, 31059 Toulouse, France; UMR UT3 CNRS 5288 Evolutionary Medicine, Obesity and Heart Failure: Molecular and Clinical Investigations, INI-CRCT F-CRIN, GREAT Networks, 31432 Toulouse, France.

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http://dx.doi.org/10.1016/j.acvd.2021.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141713PMC
May 2021

Phenotype/Genotype Relationship in Left Ventricular Noncompaction: Ion Channel Gene Mutations Are Associated With Preserved Left Ventricular Systolic Function and Biventricular Noncompaction: Phenotype/Genotype of Noncompaction.

J Card Fail 2021 06;27(6):677-681

Cardiology Department, APHM, La Timone Hospital, Marseille, France; Aix Marseille Univ, IRD, APHM, MEPHI, IHU-Méditerranée Infection, Marseille, France. Electronic address:

Background: Few data exist concerning genotype-phenotype relationships in left ventricular noncompaction (LVNC).

Methods And Results: From a multicenter French Registry, we report the genetic and clinical spectrum of 95 patients with LVNC, and their genotype-phenotype relationship. Among the 95 LVNC, 45 had at least 1 mutation, including 14 cases of mutation in ion channel genes. In a complementary analysis including 16 additional patients with ion channel gene mutations, for a total of 30 patients with ion channel gene mutation, we found that those patients had higher median LV ejection fraction (60% vs 40%; P < .001) and more biventricular noncompaction (53.1% vs 18.5%; P < .001) than the 81 other patients with LVNC. Among them, both the 19 patients with an HCN4 mutation and the 11 patients with an RYR2 mutation presented with a higher LV ejection fraction and more frequent biventricular noncompaction than the 81 patients with LVNC but with no mutation in the ion channel gene, but only patients with HCN4 mutation presented with a lower heart rate.

Conclusions: Ion channel gene mutations should be searched systematically in patients with LVNC associated with either bradycardia or biventricular noncompaction, particularly when LV systolic function is preserved. Identifying causative mutations is of utmost importance for genetic counselling of at-risk relatives of patients affected by LVNC.
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http://dx.doi.org/10.1016/j.cardfail.2021.01.007DOI Listing
June 2021

eHealth for patients with rare diseases: the eHealth Working Group of the European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN).

Orphanet J Rare Dis 2021 04 8;16(1):164. Epub 2021 Apr 8.

Cardiovascular-Genetic Center, IRCCS Policlinico San Donato, Via Morandi 30, 20097, San Donato Milanese, MI, Italy.

Background: The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) was launched in 2017 and involves, to date, 35 highly specialised multidisciplinary expert centres (from the 30 full Healthcare Provider members) coming from 11 countries and more than 70 patient organizations from 16 countries. The eHealth Working Group (WG) of VASCERN was set up to develop practical, patient-centred solutions and strategies for effective use of eHealth tools to answer the needs of patients with multisystemic vascular rare diseases.

The Ehealth Wg: Following the identified patients' needs and following the guiding principles of collaboration and patient-centredness, the eHealth WG was created with the following aims: to develop a mobile app to help patients find expert centres and patient organizations, and to develop resources (Pills of Knowledge, PoK) for training and education via digital platforms (eLearning). The mobile app includes, to date, functionalities that allow users to find expert centres and patient organizations across Europe in the area of rare multisystemic vascular diseases. Discussed app developments include personalized digital patient passports, educational material, emergency management guidelines and remote consultations. Regarding training and education, a variety of PoK have been developed. The PoK cover several topics, target several user groups, and are delivered in various formats so that they are easy-to-use, easy-to-understand, informative, and viable for delivery and sharing through digital platforms (eLearning) including, e.g., the VASCERN YouTube™ channel.

Conclusion: Overall, the work carried out by the eHealth WG of VASCERN can be seen as a pilot experience that may serve as a basis to for collaborative development of patient-centred eHealth tools that answer the needs of patients with various rare diseases, not limited to rare multisystemic vascular diseases. By expanding the multidisciplinary approach here described, clinical and research networks can take advantage of eHealth services and use them as strategic assets in achieving the ultimate goal of ensuring equity of access to prevention programs, timely and accurate diagnosis and specialized care for patients with rare diseases throughout Europe.
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http://dx.doi.org/10.1186/s13023-020-01604-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034087PMC
April 2021

[Marfan syndrome and related disorders].

Rev Prat 2020 Nov;70(9):1005-1009

CRMR syndrome de Marfan et apparentés, AP-HP, hôpital Bichat, Paris France ; Université de Paris.

Marfan syndrome and related disorders. Marfan syndrome is an autosomal dominant disease, affecting about 1/5000 persons. It includes aortic wall fragility responsible for aortic root dilatation and risk of dissection, mitral valve prolapse, ophthalmological features (ectopia lentis, flat cornea, myopia), skeletal features (excessive height, arachnodactyly, thoracic deformity with pectus, scoliosis, and flat feet), cutaneous striae, particularly in the front of the shoulders, and dural ectasia. The gene affected is mainly FBN1 coding for fibrillin 1. Care includes beta-blockers, sport restriction, and prophylactic aortic surgery when the maximal aortic diameter (usually aortic root diameter) exceeds 50 mm. Many new related disorders have been discovered these last years.
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November 2020

Clinical relevance of genotype-phenotype correlations beyond vascular events in a cohort study of 1500 Marfan syndrome patients with FBN1 pathogenic variants.

Genet Med 2021 07 17;23(7):1296-1304. Epub 2021 Mar 17.

Université de Paris, LVTS, INSERM U1148, Hôpital Bichat-Claude-Bernard, Paris, France.

Purpose: 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.

Methods: In 1,575 consecutive MFS probands and relatives from the most comprehensive database worldwide, we established survival curves and sought genotype-phenotype correlations.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1038/s41436-021-01132-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257477PMC
July 2021

Unsuspected somatic mosaicism for FBN1 gene contributes to Marfan syndrome.

Genet Med 2021 05 25;23(5):865-871. Epub 2021 Jan 25.

Université de Paris, Laboratory for Vascular Translational Science, INSERM U1148, Hôpital Bichat-Claude-Bernard, Paris, France.

Purpose: 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.

Methods: 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.

Results: 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.

Conclusion: 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.
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http://dx.doi.org/10.1038/s41436-020-01078-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105163PMC
May 2021

Pregnancy outcome in thoracic aortic disease data from the Registry Of Pregnancy And Cardiac disease.

Heart 2021 Nov 19;107(21):1704-1709. Epub 2021 Jan 19.

Cardiology Department, Erasmus Medical Center, Rotterdam, Netherlands

Background: Cardiovascular disease is the leading cause of death during pregnancy with thoracic aortic dissection being one of the main causes. Thoracic aortic disease is commonly related to hereditary disorders and congenital heart malformations such as bicuspid aortic valve (BAV). Pregnancy is considered a high risk period in women with underlying aortopathy.

Methods: The ESC EORP Registry Of Pregnancy And Cardiac disease (ROPAC) is a prospective global registry that enrolled 5739 women with pre-existing cardiac disease. With this analysis, we aim to study the maternal and fetal outcome of pregnancy in women with thoracic aortic disease.

Results: Thoracic aortic disease was reported in 189 women (3.3%). Half of them were patients with Marfan syndrome (MFS), 26% had a BAV, 8% Turner syndrome, 2% vascular Ehlers-Danlos syndrome and 11% had no underlying genetic defect or associated congenital heart defect. Aortic dilatation was reported in 58% of patients and 6% had a history of aortic dissection. Four patients, of whom three were patients with MFS, had an acute aortic dissection (three type A and one type B aortic dissection) without maternal or fetal mortality. No complications occurred in women with a history of aortic dissection. There was no significant difference in median fetal birth weight if treated with a beta-blocker or not (2960 g (2358-3390 g) vs 3270 g (2750-3570 g), p value 0.25).

Conclusion: This ancillary analysis provides the largest prospective data review on pregnancy risk for patients with thoracic aortic disease. Overall pregnancy outcomes in women with thoracic aortic disease followed according to current guidelines are good.
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http://dx.doi.org/10.1136/heartjnl-2020-318183DOI Listing
November 2021

Staged hybrid repair of type II thoracoabdominal aneurysms.

J Vasc Surg 2021 07 16;74(1):20-27. Epub 2020 Dec 16.

Vascular and Thoracic Surgery Department, Bichat Hospital, Assistance Publique-Hopitaux de Paris, Paris, France; Centre de Référence pour le Syndrome de Marfan et apparentés, Bichat Hospital, Assistance Publique-Hopitaux de Paris, Paris, France; Université de Paris, Paris, France; Laboratory for Vascular Translational Science, Inserm U1148, Université de Paris, Paris, France.

Background: Open repair of type II thoracoabdominal aortic aneurysms (TAAAs) remains a challenging procedure. Staged procedures could decrease the incidence and severity of complications after complex aortic repair. In the present report, we have described a strategy using thoracic endovascular aortic repair (TEVAR) for proximal repair, followed by distal open repair.

Methods: From 2014 to 2018, 14 patients had undergone TEVAR, followed by distal open repair, for type II TAAAs. All patients should have a suitable proximal landing zone according to the current guidelines. In cases of chronic dissection, false lumen embolization was performed to achieve total exclusion.

Results: The mean patient age was 48 ± 15 years. Of the 14 patients, 5 had had Marfan syndrome (36%) and 6 had undergone previous aortic arch repair (43%). Ten patients had had a chronic dissection. The maximal aortic diameter was 73 ± 12 mm. The TEVAR technical success rate was 100%. The aortic length coverage was 211 ± 63 mm. The number of covered segmental arteries was 6 (range, 4-13). Two endoleaks were observed, one type Ib and one type II. The delay between TEVAR and open repair was 12 ± 8 weeks. Cerebrospinal fluid drainage was used in 13 patients. Six patients had undergone segmental artery reattachment during surgery. No spinal cord ischemic event was observed. One patient had died 5 weeks after open repair of multiple organ failure. During the 32 months of follow-up, no aortic-related deaths had occurred. No new aortic procedure was needed. The type Ib endoleak had resolved during open repair, and the type II TAAA had resolved spontaneously. The mean maximal thoracic aortic diameter had significantly decreased to 49 ± 8 mm (P < .0001). Aneurysmal shrinkage of ≥5 mm was observed in 13 patients (93%).

Conclusions: Staged hybrid repair of type II TAAAs appears to be efficient, with low morbidity and mortality rates. This technique could improve postoperative outcomes after open repair, and TEVAR might have a role in ischemic preconditioning to protect against spinal cord ischemia.
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http://dx.doi.org/10.1016/j.jvs.2020.12.049DOI Listing
July 2021

Cardiovascular Magnetic Resonance May Avoid Unnecessary Coronary Angiography in Patients With Unexplained Left Ventricular Systolic Dysfunction: A Retrospective Diagnostic Pilot Study.

J Card Fail 2020 Dec 15;26(12):1067-1074. Epub 2020 Sep 15.

Department of Cardiology, Hôpital Bichat, Paris, France; Faculté Denis Diderot, INSERM U1148 LVTS, France.

Background: Coronary angiography (CA) is usually performed in patients with reduced left ventricular ejection fraction (LVEF) to search ischemic cardiomyopathy. Our aim was to examine the agreement between CA and cardiovascular magnetic resonance (CMR) imaging among a cohort of patients with unexplained reduced LVEF, and estimate what would have been the consequences of using CMR imaging as the first-line examination.

Methods: Three hundred five patients with unexplained reduced LVEF of ≤45% who underwent both CA and CMR imaging were retrospectively registered. Patients were classified as CMR or CMR according to presence or absence of myocardial ischemic scar, and classified CA or CA according to presence or absence of significant coronary artery disease.

Results: CMR (n = 89) included all 54 CA patients, except 2 with distal coronary artery disease in whom no revascularization was proposed. Among the 247 CA patients, 15% were CMR. CMR imaging had 96% sensitivity, 85% specificity, 99% negative predictive value, and 58% positive predictive value for detecting CA patients. Revascularization was performed in 6.5% of the patients (all CMR). Performing CA only for CMR patients would have decreased the number of CAs by 71%.

Conclusions: In reduced LVEF, performing CA only in CMR patients may significantly decrease the number of unnecessary CAs performed, without missing any patients requiring revascularization.
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http://dx.doi.org/10.1016/j.cardfail.2020.09.005DOI Listing
December 2020

Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm.

Genet Med 2021 01 28;23(1):111-122. Epub 2020 Aug 28.

Laboratory for Vascular Translational Science, INSERM U1148, Université de Paris, Centre Hospitalo-Universitaire Xavier Bichat, APHP, Paris, France.

Purpose: Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease with often unrecognized inherited forms. We sought to identify novel pathogenic variants associated with autosomal dominant inheritance of TAAD.

Methods: We analyzed exome sequencing data from 35 French TAAD families and performed next-generation sequencing capture panel of genes in 1114 unrelated TAAD patients. Functional effects of pathogenic variants identified were validated in cell, tissue, and mouse models.

Results: We identified five functional variants in THSD4 of which two heterozygous variants lead to a premature termination codon. THSD4 encodes ADAMTSL6 (member of the ADAMTS/L superfamily), a microfibril-associated protein that promotes fibrillin-1 matrix assembly. The THSD4 variants studied lead to haploinsufficiency or impaired assembly of fibrillin-1 microfibrils. Thsd4 mice showed progressive dilation of the thoracic aorta. Histologic examination of aortic samples from a patient carrying a THSD4 variant and from Thsd4 mice, revealed typical medial degeneration and diffuse disruption of extracellular matrix.

Conclusion: These findings highlight the role of ADAMTSL6 in aortic physiology and TAAD pathogenesis. They will improve TAAD management and help develop new targeted therapies.
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http://dx.doi.org/10.1038/s41436-020-00947-4DOI Listing
January 2021

Marfan sartan saga, episode X.

Eur Heart J 2020 11;41(43):4188-4190

Centre national de référence pour le syndrome de Marfan et apparentés, VASCERN HTAD European Reference Center, AP-HP, Hôpital Bichat, Paris, France.

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http://dx.doi.org/10.1093/eurheartj/ehaa418DOI Listing
November 2020

Quantifying the Genetic Basis of Marfan Syndrome Clinical Variability.

Genes (Basel) 2020 05 20;11(5). Epub 2020 May 20.

INSERM U1148, 75018 Paris, France.

Marfan syndrome (MFS) is an autosomal dominant connective tissue disorder with considerable inter- and intra-familial clinical variability. The contribution of inherited modifiers to variability has not been quantified. We analyzed the distribution of 23 clinical features in 1306 well-phenotyped MFS patients carrying mutations. We found strong correlations between features within the same system (i.e., ophthalmology vs. skeletal vs. cardiovascular) suggesting common underlying determinants, while features belonging to different systems were largely uncorrelated. We adapted a classical quantitative genetics model to estimate the heritability of each clinical feature from phenotypic correlations between relatives. Most clinical features showed strong familial aggregation and high heritability. We found a significant contribution by the major locus on the phenotypic variance only for ectopia lentis using a new strategy. Finally, we found evidence for the "Carter effect" in the MFS cardiovascular phenotype, which supports a polygenic model for MFS cardiovascular variability and indicates additional risk for children of MFS mothers with an aortic event. Our results demonstrate that an important part of the phenotypic variability in MFS is under the control of inherited modifiers, widely shared between features within the same system, but not among different systems. Further research must be performed to identify genetic modifiers of MFS severity.
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http://dx.doi.org/10.3390/genes11050574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288268PMC
May 2020

Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability.

J Med Genet 2020 07 10;57(7):466-474. Epub 2020 Apr 10.

Centre de Compétence Anomalies du Développement et Syndromes Malformatifs Sud-Est, CHI de Toulon - La Seyne-sur-Mer, France.

Purpose: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects.

Methods: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.

Results: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals ( and ). Using simulation models, we showed that five genes ( and ) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including and , which are known to be mutated in overgrowth syndromes.

Conclusion: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10) and genes regulated by the fragile X mental retardation protein (p=3×10), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.
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http://dx.doi.org/10.1136/jmedgenet-2019-106425DOI Listing
July 2020

Clinical and genetic data of 22 new patients with SMAD3 pathogenic variants and review of the literature.

Mol Genet Genomic Med 2020 05 10;8(5):e1132. Epub 2020 Mar 10.

Service de génétique médicale, Hôpital Purpan, CHU de Toulouse, Toulouse, France.

Background: Pathogenic SMAD3 variants are responsible for a cardiovascular phenotype, mainly thoracic aortic aneurysms and dissections. Precocious identification of the vascular risk such as aortic dilatation in mutated patients has a major impact in terms of management, particularly to avoid dissection and sudden death. These vascular damages are classically associated with premature osteoarthritis and skeletal abnormalities. However, variable expressivity and incomplete penetrance are common with SMAD3 variants.

Methods: To investigate the clinical variability observed within SMAD3 patients, we reviewed the phenotypic and genetic data of 22 new patients from our Centre and of 133 patients reported in the literature. From this cohort of 155 mutated individuals, we first aimed to delineate an estimated frequency of the main clinical signs associated with SMAD3 pathogenic variants and, then, to look for genotype-phenotype correlations, mainly to see if the aortic phenotype (AP) could be predicted by the SMAD3 variant type.

Results: We showed, herein, the absence of correlation between the SMAD3 variant type and the occurrence of an AP in patients.

Conclusion: Therefore, this report brings additional data for the genotype-phenotype correlations of SMAD3 variants and the need to explore in more detail the effects of genetic modifiers that could influence the phenotype.
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http://dx.doi.org/10.1002/mgg3.1132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216810PMC
May 2020

Pathogenic FBN1 Genetic Variation and Aortic Dissection in Patients With Marfan Syndrome.

J Am Coll Cardiol 2020 03;75(8):843-853

Centre de référence pour le syndrome de Marfan et apparentés, VASCERN HTAD European Reference Center, AP-HP, Hôpital Bichat, Paris, France; INSERM U1148, LVTS, Hôpital Bichat, Paris, France; Université de Paris, Paris, France. Electronic address:

Background: Aortic risk has not been evaluated in patients with Marfan syndrome and documented pathogenic variants in the FBN1 gene.

Objectives: This study sought to describe aortic risk in a population with Marfan syndrome with pathogenic variants in the FBN1 gene as a function of aortic root diameter.

Methods: Patients carrying an FBN1 pathogenic variant who visited our reference center at least twice were included, provided they had not undergone aortic surgery or had an aortic dissection before their first visit. Aortic events (aortic surgery or aortic dissection) and deaths were evaluated during the 2 years following each patient visit. The risk was calculated as the number of events divided by the number of years of follow-up.

Results: A total of 954 patients were included (54% women; mean age 23 years). During follow-up (9.1 years), 142 patients underwent prophylactic aortic root surgery, 5 experienced type A aortic dissection, and 12 died (noncardiovascular causes in 3, unknown etiology in 3, post-operative in 6). When aortic root diameter was <50 mm, risk for proven type A dissection (0.4 events/1,000 patient-years) and risk for possible aortic dissection (proven aortic dissection plus death of unknown cause, 0.7 events/1,000 patients-years) remained low in this population that was treated according to guidelines. Three type A aortic dissections occurred in this population during the 8,594 years of follow-up, including 1 in a patient with a tubular aortic diameter of 50 mm, but none in patients with a family history of aortic dissection. The risk for type B aortic dissection in the same population was 0.5 events/1,000 patient-years.

Conclusions: In patients with FBN1 pathogenic variants who receive beta-blocker therapy and who limit strenuous exercise, aortic risk remains low when maximal aortic diameter is <50 mm. The risk of type B aortic dissection is close to the remaining risk of type A aortic dissection in this population, which underlines the global aortic risk.
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http://dx.doi.org/10.1016/j.jacc.2019.12.043DOI Listing
March 2020

Strain predicts left ventricular functional recovery after acute myocardial infarction with systolic dysfunction.

Int J Cardiol 2020 05 15;307:1-7. Epub 2020 Feb 15.

Hôpital Bichat, Paris, France.

Objective: Regional and global longitudinal strain (RLS-GLS) are considered reliable indexes of myocardial viability in chronic ischemic patients and prediction of left ventricular (LV) functional recovery after acute myocardial infarction (MI) with preserved left ventricular ejection fraction (LVEF). We tested in the present study whether RLS and GLS could also identify transmural extent of myocardial scar and predict LV functional recovery and remodeling in patients with reduced LVEF after acute MI.

Methods: Echocardiography and late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) were performed in 71 patients with reduced LVEF (≤45%) after acute MI treated with acute percutaneous coronary intervention. At 8-month follow-up, echocardiography was repeated to determine global LV functional recovery and remodeling.

Results: RLS was worse in transmural than in non-transmural infarcted segments (-6.6 ± 6.1% vs -10.3 ± 5.9%, p < 0.0001) and in non-transmural than in normal segments (-10.3 ± 5.9% vs -14.5 ± 6.4%, p < 0.0001). RLS > -12% had sensitivity of 78% and specificity of 69% to identify transmural infarcted segments (AUC = 0.79; 95% CI, 0.77-0.81, p < 0.0001). GLS > -11.3% had sensitivity of 53% and specificity of 100% to predict the absence of LV global functional improvement (AUC = 0.73, CI, 0.55-0.87, p = 0.01) at 8-month follow-up. GLS < -12.5% predicted the absence of adverse LV remodeling with sensitivity of 100% and specificity of 54% (AUC = 0.83; CI, 0.66-0.94, p < 0.0001). GLS > -11.5% was associated with a poor prognosis.

Conclusions: In patients with reduced LVEF after acute MI, RLS and GLS allow: (1) identification of transmural extent of myocardial scar and (2) predict LV global functional recovery and remodeling at 8-month follow-up.
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http://dx.doi.org/10.1016/j.ijcard.2020.02.039DOI Listing
May 2020

A new mutational hotspot in the SKI gene in the context of MFS/TAA molecular diagnosis.

Hum Genet 2020 Apr 24;139(4):461-472. Epub 2020 Jan 24.

Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Hôpital d'Enfants, Centre Hospitalier Universitaire Dijon, 14, Rue Gaffarel, 21079, Dijon Cedex, France.

SKI pathogenic variations are associated with Shprintzen-Goldberg Syndrome (SGS), a rare systemic connective tissue disorder characterized by craniofacial, skeletal and cardiovascular features. So far, the clinical description, including intellectual disability, has been relatively homogeneous, and the known pathogenic variations were located in two different hotspots of the SKI gene. In the course of diagnosing Marfan syndrome and related disorders, we identified nine sporadic probands (aged 2-47 years) carrying three different likely pathogenic or pathogenic variants in the SKI gene affecting the same amino acid (Thr180). Seven of these molecular events were confirmed de novo. All probands displayed a milder morphological phenotype with a marfanoid habitus that did not initially lead to a clinical diagnosis of SGS. Only three of them had learning disorders, and none had intellectual disability. Six out of nine presented thoracic aortic aneurysm, which led to preventive surgery in the oldest case. This report extends the phenotypic spectrum of variants identified in the SKI gene. We describe a new mutational hotspot associated with a marfanoid syndrome with no intellectual disability. Cardiovascular involvement was confirmed in a significant number of cases, highlighting the importance of accurately diagnosing SGS and ensuring appropriate medical treatment and follow-up.
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http://dx.doi.org/10.1007/s00439-019-02102-9DOI Listing
April 2020

Optimising Aortic Endovascular Repair in Patients with Marfan Syndrome.

Eur J Vasc Endovasc Surg 2020 04 18;59(4):577-585. Epub 2019 Dec 18.

Vascular and Thoracic Surgery Department, Bichat Hospital, Assistance Publique-Hopitaux de Paris (AP-HP), Paris, France; Paris-Diderot University, Paris, France.

Objective: In Marfan syndrome (MFS) patients, endovascular repair carries a risk of aortic wall injury, which may result in retrograde aortic dissection, dilatation, or false aneurysm at the landing zones. It was hypothesised that potentially these complications may be avoided using modified practices. This study aimed to describe experience of a specific protocol for endovascular aortic repair in patients with MFS.

Methods: All MFS patients treated by aortic endovascular repair between February 2015 and August 2018 were included prospectively. The following rules were applied: (i) excluding stent grafts with bare stents and barbs, (ii) proximal landing in a pre-existing graft, or (iii) minimising proximal oversizing when landing in the proximal native aorta (<10%), and (iv) distal undersizing for chronic dissection cases.

Results: In eighteen patients (55% men, mean age: 47 ± 17 years), the index procedures were initial endovascular aortic repair (n = 10), elephant trunk completion (n = 6), and anastomotic pseudo-aneurysm after thoracic open repair (n = 2). The technical success rate was 100%. Proximal landing was in the native aorta in 11 patients (61%), with a mean proximal oversizing of 2.4 mm (8% oversized). Distal landing in the native aorta was performed in 16 cases (89%), with a mean distal undersizing of 8.9 mm (- 23%). No mortality, spinal cord ischaemia, stroke, or retrograde aortic dissection occurred post-operatively. One type 1b endoleak was observed. The mean follow up was 21.4 months. Aortic aneurysm related mortality was 5% (n = 1) and occurred after distal thoraco-abdominal surgery planned from the outset (prior to endovascular repair). Another patient presented a proximal landing zone complication with aortic enlargement. The mean maximum aortic diameter decreased significantly from 59 mm to 45 mm (p = .0005) after treatment.

Conclusion: The specific protocol described in this study seems to optimise the results of endovascular aortic repair in MFS patients with significant aortic remodelling.
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http://dx.doi.org/10.1016/j.ejvs.2019.09.501DOI Listing
April 2020

European reference network for rare vascular diseases (VASCERN) consensus statement for the screening and management of patients with pathogenic ACTA2 variants.

Orphanet J Rare Dis 2019 11 21;14(1):264. Epub 2019 Nov 21.

VASCERN HTAD European Reference Centre, Ghent, Belgium.

The ACTA2 gene encodes for smooth muscle specific α-actin, a critical component of the contractile apparatus of the vascular smooth muscle cell. Pathogenic variants in the ACTA2 gene are the most frequently encountered genetic cause of non-syndromic hereditary thoracic aortic disease (HTAD). Although thoracic aortic aneurysm and/or dissection is the main clinical manifestation, a variety of occlusive vascular disease and extravascular manifestations occur in ACTA2-related vasculopathy. Current data suggest possible mutation-specific manifestations of vascular and extra-aortic traits.Despite its relatively high prevalence, comprehensive recommendations on the care of patients and families with pathogenic variants in ACTA2 have not yet been established. We aimed to develop a consensus document to provide medical guidance for health care professionals involved in the diagnosis and treatment of patients and relatives with pathogenic variants in ACTA2.The HTAD Working Group of the European Reference Network for Rare Vascular Diseases (VASCERN) convened to review current literature and discuss expert opinions on clinical management of ACTA2 related vasculopathy. This consensus statement summarizes our recommendations on diagnosis, monitoring, treatment, pregnancy, genetic counselling and testing in patients with ACTA2-related vasculopathy. However, there is a clear need for additional prospective multicenter studies to further define proper guidelines.
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http://dx.doi.org/10.1186/s13023-019-1186-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868850PMC
November 2019

Incidence of cardiovascular events and risk markers in a prospective study of children diagnosed with Marfan syndrome.

Arch Cardiovasc Dis 2020 Jan 14;113(1):40-49. Epub 2019 Nov 14.

Department of Paediatric Cardiology and Paediatric Endocrinology, Centre de Référence pour le Syndrome de Marfan et Apparentés, Hôpital des Enfants, CHU Toulouse, 31300 Toulouse, France.

Background: Little is known about the incidence of cardiovascular events (CVEs) and their associated risk markers in children with Marfan syndrome (MFS).

Aims: To assess the incidence of CVEs and determine risk markers in a cohort diagnosed with Marfan syndrome during childhood and followed for several years.

Methods: From a French multicentre nationwide database, 462 patients with MFS diagnosed during childhood were included prospectively. Patients' files were screened for a period of 20 years (1993-2013). CVEs (e.g. death, aortic dissection, cardiac valve or aortic root surgery) were assessed during the prospective follow-up.

Results: Median (interquartile range) age at the end of follow-up was 17.2 (11.1-21.3) years. CVEs were reported for 35 participants (7.6%; 95% confidence interval [CI] 5.3-10.4%). First CVEs were prophylactic aortic root surgery (n=29), aortic dissection (n=4; two aged <18 years) and death (n=2). Kaplan-Meier cumulative incidence of CVEs was 5.3% (95% CI 3.3-8.7%) during childhood (aged≤18 years) and 19.4% (95% CI 13.3-27.9%) at 25years of age. The cumulative rate of CVEs was higher in case of Valsalva sinus Z-score increase of≥0.1 per year (P=0.0003), maximal Valsalva sinus diameter growth speed ≥5mm per year (P=0.03), aortic regurgitation≥2 (P=0.0005) and maximal Valsalva sinus Z-score≥3 before 16 years of age (P<0.0001). In a multivariable Cox proportional analysis, the Valsalva sinus Z-score remained significantly related to outcome. Considering aortic root evolution, aortic regurgitation, age at diagnosis and beta-blocker therapy were related to Valsalva sinus Z-score evolution during follow-up.

Conclusions: CVEs in children with MFS are mainly related to prophylactic aortic root surgery. Aortic dissections are rarely observed in children. The Valsalva sinus Z-score is a strong indicator of subsequent CVEs in children with MFS. Attention to follow-up and beta-blocker observance may be warranted in high-risk children.
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http://dx.doi.org/10.1016/j.acvd.2019.09.010DOI Listing
January 2020

Genetic testing for aortopathies: primer for the nongeneticist.

Curr Opin Cardiol 2019 11;34(6):585-593

VASCERN HTAD European Reference Centre, Centre National Maladies Rares pour le Syndrome de Marfan et apparente[Combining Acute Accent]s.

Purpose Of Review: Although the majority of thoracic aortic aneurysms and dissections (TAD) in the overall population are mainly related to arterial hypertension and atherosclerosis, Heritable Thoracic Aortic Disease (HTAD) are increasingly recognized, especially in younger individuals. As fatal events in the setting of HTAD are preventable with timely detection and appropriate management, this review aims to provide an overview of the genetic basis of HTAD and practical recommendations for genetic evaluation in this setting.

Recent Findings: Thanks in part to a number of important efforts to set up (inter)national networks and consortia for collecting clinical and genetic data from patients with these rare disorders, significant progress has been made in understanding the natural evolution of these disorders. These insights are now starting to enable the development of recommendations for the management of these patients.In addition, pathogenic variants in a number of new genes have been identified in HTAD patients. On the basis of more extensive genetic screening in cohorts of patients with TAD, it is becoming clear that there is no strict boundary between syndromal and nonsyndromal HTAD entities. It is, therefore, important to at least consider genetic evaluation, not only for patients presenting with syndromic forms but also for more isolated TAD.Finally, there are indications that we will -- up to a certain point -- soon be able to draw up a more precise policy for individual patients, based on the underlying genetic defects SUMMARY: Genetic evaluation in (young) patients with both syndromic and nonsyndromic forms of HTAD should be considered and is helpful for the development of more precise medicine.
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http://dx.doi.org/10.1097/HCO.0000000000000669DOI Listing
November 2019

Genetic counselling and testing in adults with congenital heart disease: A consensus document of the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics.

Eur J Prev Cardiol 2020 09 11;27(13):1423-1435. Epub 2019 Jun 11.

European Reference Network for Rare Multisystemic Vascular Disease (VASCERN), HTAD Rare Disease Working Group.

Thanks to a better knowledge of the genetic causes of many diseases and an improvement in genetic testing techniques, genetics has gained an important role in the multidisciplinary approach to diagnosis and management of congenital heart disease and aortic pathology. With the introduction of strategies for precision medicine, it is expected that this will only increase further in the future. Because basic knowledge of the indications, the opportunities as well as the limitations of genetic testing is essential for correct application in clinical practice, this consensus document aims to give guidance to care-providers involved in the follow-up of adults with congenital heart defects and/or with hereditary aortic disease. This paper is the result of a collaboration between the ESC Working Group of Grown-Up Congenital Heart Disease, the ESC Working Group on Aorta and Peripheral Vascular Disease and the European Society of Human Genetics. Throughout the document, the importance of correct counseling in the process of genetic testing is emphasized, indications and timing for genetic studies are discussed as well as the technical modalities of genetic testing. Finally, the most important genetic diseases in adult congenital heart disease and aortic pathology are also discussed.
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http://dx.doi.org/10.1177/2047487319854552DOI Listing
September 2020

Systems pharmacology-based integration of human and mouse data for drug repurposing to treat thoracic aneurysms.

JCI Insight 2019 06 6;4(11). Epub 2019 Jun 6.

Department of Pharmacological Sciences and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Marfan syndrome (MFS) is associated with mutations in fibrillin-1 that predispose afflicted individuals to progressive thoracic aortic aneurysm (TAA) leading to dissection and rupture of the vessel wall. Here we combined computational and experimental approaches to identify and test FDA-approved drugs that may slow or even halt aneurysm progression. Computational analyses of transcriptomic data derived from the aortas of MFS patients and MFS mice (Fbn1mgR/mgR mice) predicted that subcellular pathways associated with reduced muscle contractility are key TAA determinants that could be targeted with the GABAB receptor agonist baclofen. Systemic administration of baclofen to Fbn1mgR/mgR mice validated our computational prediction by mitigating arterial disease progression at the cellular and physiological levels. Interestingly, baclofen improved muscle contraction-related subcellular pathways by upregulating a different set of genes than those downregulated in the aorta of vehicle-treated Fbn1mgR/mgR mice. Distinct transcriptomic profiles were also associated with drug-treated MFS and wild-type mice. Thus, systems pharmacology approaches that compare patient- and mouse-derived transcriptomic data for subcellular pathway-based drug repurposing represent an effective strategy to identify potential new treatments of human diseases.
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http://dx.doi.org/10.1172/jci.insight.127652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629138PMC
June 2019

Pulmonary haemodynamic effects of interatrial shunt in heart failure with preserved ejection fraction: a preclinical study.

EuroIntervention 2020 Aug;16(5):434-440

Denis Diderot University, Xavier Bichat Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France.

Aims: The aim of this study was to evaluate the effect of the creation of a left-to-right interatrial shunt on pulmonary haemodynamics in rats with heart failure with preserved ejection fraction (HFPEF).

Methods And Results: An interatrial communication (IAC) was created in 11 healthy rats (Lewis rats) and 11 rats which developed HFPEF (36-week-old spontaneously hypertensive rats [SHR]). Effects of the interatrial shunt were compared to 11 sham-operated Lewis and 11 sham-operated SHR. At 45 days post shunt, strain effect was observed in diastolic function (E/A ratio, p<0.001; isovolumetric relaxation time, p<0.001), left atrial volume (p=0.005) and pulmonary wall shear rate (WSR) (p=0.02) measured by Doppler echo. At sacrifice of the animals (60 days), a strain effect was also noted in elastin density (p=0.003) and eNOS protein expression (p=0.001). Interatrial shunt creation resulted in (i) an increase in pulmonary WSR (p=0.04) and a decrease in left atrial volume (p<0.001), (ii) an increase in elastin density (p<0.005), and (iii) an increase in eNOS protein expression (p=0.03).

Conclusions: Creation of a left-to-right atrial shunt in rats with HFPEF was effective in improving pulmonary haemodynamics. In addition, this study provides preliminary evidence of the potential risk of right volume overload and pulmonary hypertension due to atrial shunting.
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http://dx.doi.org/10.4244/EIJ-D-18-01100DOI Listing
August 2020

Pregnancy outcomes in women with cardiovascular disease: evolving trends over 10 years in the ESC Registry Of Pregnancy And Cardiac disease (ROPAC).

Eur Heart J 2019 12;40(47):3848-3855

Department of Cardiology, University of East Anglia, Faculty of Medicine, Norwich Research Park, Norwich, UK.

Aims: Reducing maternal mortality is a World Health Organization (WHO) global health goal. Although maternal deaths due to haemorrhage and infection are declining, those related to heart disease are increasing and are now the most important cause in western countries. The aim is to define contemporary diagnosis-specific outcomes in pregnant women with heart disease.

Methods And Results: From 2007 to 2018, pregnant women with heart disease were prospectively enrolled in the Registry Of Pregnancy And Cardiac disease (ROPAC). Primary outcome was maternal mortality or heart failure, secondary outcomes were other cardiac, obstetric, and foetal complications. We enrolled 5739 pregnancies; the mean age was 29.5. Prevalent diagnoses were congenital (57%) and valvular heart disease (29%). Mortality (overall 0.6%) was highest in the pulmonary arterial hypertension (PAH) group (9%). Heart failure occurred in 11%, arrhythmias in 2%. Delivery was by Caesarean section in 44%. Obstetric and foetal complications occurred in 17% and 21%, respectively. The number of high-risk pregnancies (mWHO Class IV) increased from 0.7% in 2007-2010 to 10.9% in 2015-2018. Determinants for maternal complications were pre-pregnancy heart failure or New York Heart Association >II, systemic ejection fraction <40%, mWHO Class 4, and anticoagulants use. After an increase from 2007 to 2009, complication rates fell from 13.2% in 2010 to 9.3% in 2017.

Conclusion: Rates of maternal mortality or heart failure were high in women with heart disease. However, from 2010, these rates declined despite the inclusion of more high-risk pregnancies. Highest complication rates occurred in women with PAH.
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http://dx.doi.org/10.1093/eurheartj/ehz136DOI Listing
December 2019

False lumen embolization in chronic aortic dissection promotes thoracic aortic remodeling at midterm follow-up.

J Vasc Surg 2019 Sep 6;70(3):710-717. Epub 2019 Mar 6.

Vascular Surgery Department, Bichat Hospital, Assistance Publique-Hopitaux de Paris, Paris, France; Paris-Diderot University, Paris, France.

Objective: Failure 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.

Methods: Between 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.

Results: The 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).

Conclusions: Embolization 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.
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http://dx.doi.org/10.1016/j.jvs.2018.11.038DOI Listing
September 2019
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