Primary Non-Aortic Lesions Are Not Rare in Marfan Syndrome and Are Associated with Aortic Dissection Independently of Age.

PURPOSE: The study sought to estimate the prevalence of primary non-aortic lesions (PNAL) unrelated to extension of aortic dissection (AD) in a cohort of patients with Marfan syndrome (MFS). METHODS: Adult patients presenting with pathogenic FBN1 mutations and an available pan-aortic contrast-enhanced CTA in eight French MFS clinics from April to October 2018 were included. Clinical and radiological data, particularly the presence of aortic lesions and PNAL (including aneurysm and ectasia), were retrospectively analyzed. RESULTS: Out of 138 patients, 28 (20.3%) had PNAL. In total, 27 aneurysms in 13 patients and 41 ectasias in 19 patients were reported mainly in the subclavian, iliac, and vertebral segments. Four patients (31%) with aneurysms and none with ectasia required prophylactic intervention during follow-up (median: 46 months). In multivariate analysis, factors associated with PNAL were history of AD (OR = 3.9, 95%CI: 1.3-12.1, p = 0.018), history of previous descending aortic surgery (OR = 10.3, 95%CI: 2.2-48.3, p = 0.003) and age (per 10 years OR = 1.6, 95%CI: 1.1-2.4, p = 0.008). CONCLUSION: PNAL is not rare in MFS patients with evolutive aortic disease. Natural history may differ between aneurysms and ectasia, emphasizing the need for standardized definitions and systematic screening for PNAL.

Volume Analysis to Predict the Long-Term Evolution of Residual Aortic Dissection after Type A Repair.

Background: The aim of this study was to evaluate the aortic diameter and volume during the first year after a type A repair to predict the long-term prognosis of a residual aortic dissection (RAD). Methods: All patients treated in our center for an acute type A dissection with a RAD and follow-up > 3 years were included. We defined two groups: group 1 with dissection-related events (defined as an aneurysmal evolution, distal reintervention, or aortic-related death) and group 2 without dissection-related events. The aortic diameters and volume analysis were evaluated on three postoperative CT scans: pre-discharge (T1), 3−6 months (T2) and 1 year (T3). Results: Between 2009 and 2016, 54 patients were included. Following a mean follow-up of 75.4 months (SD 31.5), the rate of dissection-related events was 62.9% (34/54). The total aortic diameters of the descending thoracic aorta were greater in group 1 at T1, T2 and T3, with greater diameters in the FL (p < 0.01). The aortic diameter evolution at 3 months was not predictive of long-term dissection-related events. The total thoracic aortic volume was significantly greater in group 1 at T1 (p < 0.01), T2 (p < 0.01), and T3 (p < 0.01). At 3 months, the increase in the FL volume was significantly greater in group 1 (p < 0.01) and was predictive for long-term dissection-related events. Conclusion: This study shows that an initial CT scan volume analysis coupled with another at 3 months is predictive for the long-term evolution in a RAD. Based on this finding, more aggressive treatment could be given at an earlier stage.

A 10-Year Aortic Center Experience with Hybrid Repair of Chronic "Residual" Aortic Dissection After Type A Repair.

PURPOSE: Hybrid aortic arch repair in patients with chronic residual aortic dissection (RAD) is a less invasive alternative to conventional surgical treatment. The aim of this study was to describe the short-term and long-term results of hybrid treatment for RAD after type A repair. METHODS: In this retrospective single-center cohort study, all patients treated for chronic RAD with hybrid aortic arch repair were included. Indications for treatment were rapid aortic growth, aortic diameter > 55 mm, or aortic rupture. RESULTS: Between 2009 and 2020, we performed 29 hybrid treatments for chronic RAD. Twenty-four patients were treated for complete supra-aortic debranching in zones 0 and 5 with left subclavian artery debranching alone in zone 2. There was 1 perioperative death (3.4%): The patient was treated for an aortic rupture. There was no spinal cord ischemia and 1 minor stroke (3.4%). After a median follow-up of 25.4 months (range 3-97 months), the long-term mortality was 10.3% (3/29) with no late aortic-related deaths. Twenty-seven patients (93.1%) developed FL thrombosis of the descending thoracic aorta; the rate of aneurysmal progression on thoraco-abdominal aorta was 41.4% (12/29), and the rate of aortic reintervention was 34.5% (10/29). CONCLUSION: In a high-volume aortic center, hybrid repair of RAD is associated with good anatomical results and a low risk of perioperative morbidity and mortality, including that of patients treated in zone 0. A redo replacement of the ascending aortic segment is sometimes necessary to provide a safer proximal landing zone and reduce the risk of type 1 endoleak after TEVAR.

Results of a prospective follow-up study after type A aortic dissection repair: a high rate of distal aneurysmal evolution and reinterventions.

OBJECTIVES: We investigated the anatomical evolution of residual aortic dissection after type A repair and factors associated with poor prognosis at a high-volume aortic centre. METHODS: Between 2017 and 2019, all type A aortic dissections were included for prospective follow-up. Patients without follow-up computed tomography (CT) scan available for radiological analysis and patients without residual aortic dissection were excluded from this study. The primary end point was a composite end point defined as dissection-related events including aneurysmal evolution (increased diameter > 5 mm/year), aortic reintervention for malperfusion syndrome, aortic diameter >55 mm, rapid aortic growth >10 mm/year or aortic rupture and death. The secondary end points were risk factors for dissection-related events and reintervention analysis. All immediate and last postoperative CT scans were analysed. RESULTS: Among 104 patients, after a mean follow-up of 20.4 months (8-41), the risk of dissection-related events was 46.1% (48/104) and the risk of distal reintervention was 17.3% (18/104). Marfan syndrome (P < 0.01), aortic bicuspid valve (P = 0.038), innominate artery debranching (P = 0.025), short aortic cross-clamp time (P = 0.011), initial aortic diameter >40 mm (P < 0.01) and absence of resection of the primary entry tear (P = 0.015) were associated with an increased risk of dissection-related events or reintervention during follow-up. CONCLUSIONS: Residual aortic dissection is a serious disease requiring close follow-up at an expert centre. This study shows higher reintervention and aneurysmal development rates than currently published. To improve long-term outcomes, the early demographic and anatomic poor prognostic factors identified may be used for more aggressive treatment at an early phase.

Prevalence of Thoracic Aortic Aneurysms in Patients with Degenerative Abdominal Aortic Aneurysms: Results from the Prospective ACTA Study.

OBJECTIVE: There are no recommendations for screening for thoracic aortic aneurysms (TAAs), even in patients with infrarenal abdominal aortic aneurysms (AAAs). The aims of this study were to determine the prevalence of TAAs in patients with AAAs and to analyse the risk factors for this association. METHODS: This was a multicentre prospective study. The Aortic Concomitant Thoracic and Abdominal Aneurysm (ACTA) study included 331 patients with infrarenal AAAs > 40 mm between September 2012 and May 2016. These patients were prospectively enrolled in three French academic hospitals. RESULTS: Patients were classified as having a normal, aneurysmal, or ectatic (non-normal, non-aneurysmal) thoracic aorta according to their maximum aortic diameter indexed by sex, age, and body surface area. Thoracic aortic ectasia (TAE) was defined as above or equal to the 90th percentile of normal aortic diameters according to gender and body surface area. Descending TAA was defined as ≥ 150% of the mean normal value, and ascending TAA as > 47 mm in men and 42 mm in women; 7.6% (n = 25) had either an ascending (seven cases; 2.2%) or descending aortic TAA (18 cases; 5.4%), and 54.6% (n = 181) had a TAE. Among the 25 patients with TAAs, five required surgery; two patients had TAAs related to penetrating aortic ulcers < 60 mm in diameter, and three had a TAA > 60 mm. In the multinomial regression analysis, atrial fibrillation (AF) (odds ratio [OR] 11.36, 95% confidence interval [CI] 2.18 - 59.13; p = .004) and mild aortic valvulopathy (OR 2.89, 1.04-8.05; p = .042) were independent factors associated with TAAs. Age (OR 1.06, CI 1.02 - 1.09; p = .003) and AF (OR 4.36, 1.21 - 15.61; p = .024) were independently associated with ectasia. CONCLUSION: This study confirmed that TAAs coexisting with AAAs are not rare, and one fifth of these TAAs are treated surgically. Systematic screening by imaging the whole aorta in patients with AAAs is clinically relevant and should lead to an effective prevention policy.

Is the Natural Anatomical Evolution of Type B Intramural Hematomas Reliable to Identify the Patients at Risk of Aneurysmal Progression?

BACKGROUND: The natural history of type B intramural hematomas is little-known. Aneurysmal progression or an aortic dissection occurs in 15 to 20% of the cases. The study of the natural anatomical evolution could help identify the patients at risk of unfavorable evolution. METHODS: All the patients monitored for a type B intramural hematoma between 2009 and 2018 were included in this monocentric retrospective study. Computed tomography angiography centerline measurement of diameters was obtained in various points of aortic segmentation on day (D) 0 and at one month (M1). Aortic volumes (lumen, intramural hematoma, and total volume) were calculated. The circulating volume was calculated using the volume rendering method. The volume of the intramural hematoma was measured using a manual section-by-section segmentation tool, and the total volume was obtained by summing up the two preceding volumes. Two groups of patients were compared: group 1 (favorable anatomical evolution) and group 2 (unfavorable anatomical evolution). RESULTS: Between January 2008 and August 2018, 25 patients were managed for a type B intramural hematoma in our center. After an average follow-up of 15.5 months (1-52), 13 patients (52%) presented a favorable evolution and 12 (48%) an unfavorable evolution. At M1, a significant increase of the luminal diameters (37 mm vs. 32 mm; P < 0.01) and a significant reduction in the longitudinal extension (19 mm vs. 26 mm; P < 0.01) were observed. The maximum aortic diameter evolved significantly between D0 and M1 in the unfavorable evolution group (49 mm vs. 44 mm, respectively; P = 0.038). Such a difference was not found in the favorable evolution group (37.4 vs. 37.1, respectively; P = 0.552). An overall significant reduction in the total aortic volume (166 cm3 vs. 219 cm3; P < 0.01), the circulating volume (124 cm3 vs. 145 cm3; P = 0,026), and the volume of the hematoma (42 cm3 vs. 39 cm3; P < 0.01) was observed. The circulating volume decreased significantly between D0 and M1 in the favorable evolution group (110 cm3 vs. 135 cm3; P = 0.05), whereas no difference was noted in the unfavorable group (142 cm3 vs, 157 cm3; P = 0.24). CONCLUSIONS: The progression of the maximum aortic diameter and of the circulating volume after one month of follow-up could be predictive factors of the poor long-term evolution of type B intramural hematomas.

High prevalence of mutations in perilipin 1 in patients with precocious acute coronary syndrome.

BACKGROUND AND AIMS: Genetic partial lipodystrophies are rare heterogeneous disorders characterized by abnormalities of fat distribution and associated metabolic complications including a predisposition for atherosclerotic cardiovascular disease. We hypothesized that the milder forms of these diseases might be underdiagnosed and might result in early acute coronary syndrome (ACS) as the first sign of the pathology. METHODS: We performed targeted sequencing on a panel of 8 genes involved in genetic lipodystrophy for 62 patients with premature ACS, and selected heterozygous missense variations with low frequency. To confirm those results, we analyzed a second independent group of 60 additional patients through Sanger sequencing, and compared to a control group of 120 healthy patients. RESULTS: In the first cohort, only PLIN1 exhibited variants in more than 1 patient. In PLIN1, 3 different variants were found in 6 patients. We then analyzed PLIN1 sequence in the second cohort with premature ACS and found 2 other patients. Altogether, 8 patients were carriers of 4 different mutations in PLIN1. The variant frequencies in the total cohort of 122 patients were compared to frequencies observed in a local control cohort and in 2 different public databases showing a significant difference between patient vs control group frequencies for two mutations out of 4 (c.245C > T p = 10-4; c.839G > A p = 0.014). DISCUSSION: This is the first study that identifies a high frequency of potential pathogenic mutations in PLIN1 related to early onset ACS. These findings could contribute to the prevention and care of precocious ACS in families carrying those mutations.

Impacts of considering sex and gender during intervention studies in occupational health: Researchers' perspectives.

The aim of this article is to examine the impacts of incorporating sex and gender (s/g) analysis in integrated knowledge translation (iKT) initiatives in the field of ergonomics and occupational health. The article presents findings based on a retrospective analysis of twelve intervention-research (IR) studies, including a thematic content analysis of in-depth interviews conducted with 15 researchers involved in these IRs. The findings offer an overview of various categories of impacts, such as changes in partners' views, in workplace settings and conditions, in practices and policies, and in economic outcomes. In these types of IR, health effects measurement is not the main objective, and direct health outcomes are difficult to assess. Explicitly talking about sex/gender led more often to system-level changes but less often to workplace-level changes, compared to interventions where sex/gender was not identified as a specific object of the intervention.

Loss-of-Function Mutations in UNC45A Cause a Syndrome Associating Cholestasis, Diarrhea, Impaired Hearing, and Bone Fragility.

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.

Actionable Genes, Core Databases, and Locus-Specific Databases.

Adoption of next-generation sequencing (NGS) in a diagnostic context raises numerous questions with regard to identification and reports of secondary variants (SVs) in actionable genes. To better understand the whys and wherefores of these questioning, it is necessary to understand how they are selected during the filtering process and how their proportion can be estimated. It is likely that SVs are underestimated and that our capacity to label all true SVs can be improved. In this context, Locus-specific databases (LSDBs) can be key by providing a wealth of information and enabling classifying variants. We illustrate this issue by analyzing 318 SVs in 23 actionable genes involved in cancer susceptibility syndromes identified through sequencing of 572 participants selected for a range of atherosclerosis phenotypes. Among these 318 SVs, only 43.4% are reported in Human Gene Mutation Database (HGMD) Professional versus 71.4% in LSDB. In addition, 23.9% of HGMD Professional variants are reported as pathogenic versus 4.8% for LSDB. These data underline the benefits of LSDBs to annotate SVs and minimize overinterpretation of mutations thanks to their efficient curation process and collection of unpublished data.

UMD-Predictor: A High-Throughput Sequencing Compliant System for Pathogenicity Prediction of any Human cDNA Substitution.

Whole-exome sequencing (WES) is increasingly applied to research and clinical diagnosis of human diseases. It typically results in large amounts of genetic variations. Depending on the mode of inheritance, only one or two correspond to pathogenic mutations responsible for the disease and present in affected individuals. Therefore, it is crucial to filter out nonpathogenic variants and limit downstream analysis to a handful of candidate mutations. We have developed a new computational combinatorial system UMD-Predictor (http://umd-predictor.eu) to efficiently annotate cDNA substitutions of all human transcripts for their potential pathogenicity. It combines biochemical properties, impact on splicing signals, localization in protein domains, variation frequency in the global population, and conservation through the BLOSUM62 global substitution matrix and a protein-specific conservation among 100 species. We compared its accuracy with the seven most used and reliable prediction tools, using the largest reference variation datasets including more than 140,000 annotated variations. This system consistently demonstrated a better accuracy, specificity, Matthews correlation coefficient, diagnostic odds ratio, speed, and provided the shortest list of candidate mutations for WES. Webservices allow its implementation in any bioinformatics pipeline for next-generation sequencing analysis. It could benefit to a wide range of users and applications varying from gene discovery to clinical diagnosis.

DYT6 dystonia: review of the literature and creation of the UMD Locus-Specific Database (LSDB) for mutations in the THAP1 gene.

By family-based screening, first Fuchs and then many other authors showed that mutations in THAP1 (THAP [thanatos-associated protein] domain-containing, apoptosis-associated protein 1) account for a substantial proportion of familial, early-onset, nonfocal, primary dystonia cases (DYT6 dystonia). THAP1 is the first transcriptional factor involved in primary dystonia and the hypothesis of a transcriptional deregulation, which was primarily proposed for the X-linked dystonia-parkinsonism (DYT3 dystonia), provided thus a new way to investigate the possible mechanism underlying the development of dystonic movements. Currently, 56 families present with a THAP1 mutation; however, no genotype/phenotype relationship has been found. Therefore, we carried out a systematic review of the literature on the THAP1 gene to colligate all reported patients with a specific THAP1 mutation and the associated clinical signs in order to describe the broad phenotypic continuum of this disorder. To facilitate the comparison of the identified mutations, we created a Locus-Specific Database (UMD-THAP1 LSDB) available at http://www.umd.be/THAP1/. Currently, the database lists 56 probands and 43 relatives with the associated clinical phenotype when available. The identification of a larger number of THAP1 mutations and collection of high-quality clinical information for each described mutation through international collaborative effort will help investigating the structure-function and genotype-phenotype correlations in DYT6 dystonia.

The p.Asp216His TOR1A allele effect is not found in the French population.

DYT1 dystonia are one of the exceptions in human genetics with its unique and recurrent mutation (c.907delGAG). In this rare movement disorder, the mutation is associated with incomplete penetrance as well as great clinical variability, making this disease a benchmark to search for genetic modifiers. Recently, Risch et al. have demonstrated the implication of the rs1801968 SNP in disease penetrance. We attempted to replicate this result in an exhaustive DYT1 French population with no success. Our results argue that the rs1801968 H allele effect is not part of the modifiers in the French population of DYT1 patients and that others have to be identified in our population.