Thoracic Aortic Disease Research Articles

Abstract 4138455: Employing Bioinformatic Tools to Identify High-Risk Variants of Unknown Significance in Aortopathy Genes Associated with Aortic Dissection

Introduction: Pathogenic (P) or likely pathogenic (LP) aortopathy gene variants cause hereditary thoracic aortic aneurysm and dissection, but P/LP variants only explain approximately 20% of cases of thoracic aortic disease. Variants of unknown significance (VUS) are frequently identified among individuals undergoing genetic testing for thoracic aortic disease, however managing patients with VUSs remains clinically challenging. Hypothesis: Bioinformatic tools can be used to determine thresholds above which VUSs may be considered “high-risk.” Methods: Primary analyses were performed in the Penn Medicine Biobank (PMBB) which is composed of 43,731 participants who volunteered to have clinical information linked to biospecimen data including DNA which has undergone whole exome sequencing. PMBB participants were screened for VUSs in one of 11 aortopathy genes. VUS REVEL, AlphaMissense and minor allele frequency (MAF) high-risk thresholds were derived using cutpointR, a statistical package to optimize continuous variable thresholds based on binary outcomes. These thresholds were applied to VUS carriers in the PMBB and two independent validation cohorts. Logistic regression analysis was performed to test the association of high-risk VUSs with prevalent thoracic aortic disease. Results: There were 11,925 individuals in PMBB who carried at least one missense VUS. Carrying a VUS was associated with a modest increased risk of thoracic aortic aneurysm (TAA: OR=1.14, 95% confidence interval [CI] 1.01 to 1.29, P =0.034) but no increased risk of thoracic aortic dissection (OR=1.04, 95%CI 0.55 to 2.00, P =0.896). As VUS REVEL or AlphaMissense increased, or MAF decreased, the association between VUSs and thoracic aortic disease became statistically significant. Using cutpointR, we derived REVEL (>0.649), AlphaMissense (>0.2543), and MAF (<8.16x10 -6 ) thresholds that together identified 435 high-risk VUSs robustly associated with prevalent dissection (OR=7.85, 95%CI 4.73 to 13.03, P <0.001), though the association with TAA was attenuated (OR=2.35, 95%CI 1.62 to 3.42, P <0.001). Similar results were observed in the UK Biobank (UKB) and Early Onset Sporadic Thoracic Aortic Dissection (ESTAD) cohorts. Conclusions: VUSs that met high-risk bioinformatic thresholds were strongly associated with prevalent aortic dissection in the PMBB, UKB and ESTAD. Future investigation is warranted to determine if these thresholds can instruct clinical care of individuals carrying aortopathy gene VUSs.

Abstract 4124655: Multi-trait analysis identifies 307 genomic loci for thoracic aortic diameter and disease

Introduction: Thoracic aortic aneurysm and dissection (TAAD) is a morbid cardiovascular disease with 21 known common-variant genomic risk loci. Aneurysm represents an extreme of diameter, so we sought to jointly analyze TAAD and aortic diameter to enhance discovery power. Methods: Genome-wide association studies (GWAS) were performed for UK Biobank MRI-derived aortic diameter measured at the aortic root (N=62,919), ascending aorta (N=61,156), and descending aorta (N=62,412). Separately, TAAD GWAS summary statistics from UKB (1,076 cases, 416,263 controls), FinnGen (3,880 cases, 381,977 controls), and the Million Veteran Program (8,626 cases, 453,043 controls) were meta-analyzed. Genetic correlation was assessed with ldsc . Multi-trait analysis was then performed for the aortic measurements and TAAD with MTAG . A 1.1-million-variant polygenic risk score (PRS) was produced and tested in the All of Us biobank. Results: The genetic correlation between ascending aortic diameter and TAAD was 0.83 (P=6.6E-129). The TAAD meta-analysis had an effective sample size of 53,516, augmented to 147,377 after multi-trait analysis. We identified 59 risk loci for TAAD (189 in the multi-trait analysis). These loci included one on the X-chromosome near MIR222HG , previously reported to be regulated by angiopoietin-2; others were near TGF-β-superfamily members ( FBN1 , FBN2 , GDF6 , GDF7 , LTBP4 , TGFB2 , SMAD3 ); genes involved in vasoconstriction ( ADRA1D , ADRB1 , ANGPT1 , EDN1 , EDN2 , EDNRA , PDE3A ); and cell cycle regulators ( CCND2 , CCNE1 , CDC27 , CDK6 , CDKN1A , CDKN1B , CENPW , DSCC1 , MAD2L1 , TP53 ). 307 distinct loci were significantly associated with at least one of the four traits; all but 7 TAAD loci were genome-wide significant for one of the three aortic measurements, and all loci had at least sub-significant signal in those traits. Gene-set analyses highlighted contributions from fibroblasts, pericytes, and vascular smooth muscle cells. In All of Us , a one standard deviation (SD) greater PRS was associated with a hazard ratio (HR) of 1.88 for TAAD (P=1.2E-78) and 1.62 for thoracic aortic dissection (P=5.7E-05). Individuals in the top 5% for the PRS had HR 3.77 for TAAD (P=2.7E-48) and HR 2.87 for thoracic aortic dissection (P=3.3E-03). Discussion: The multi-trait analysis yielded an eight-fold expansion of loci for TAAD risk. The findings underscore that sporadic TAAD is a complex, common disease—intricately linked with the processes associated with normal variation in aortic diameter.

Abstract 4117345: Predicting Downstream Aneurysmal Degeneration Following Type A Dissection Repair With Computational Fluid Dynamics

Introduction: Acute type A aortic dissection (ATAAD) is typically treated by replacement of the ascending aorta (+/- root) and proximal arch. However, 70-85% of patients have residual distal dissection post-repair, and 20-40% require late reoperation for aneurysmal degeneration of the distal aorta (ADDA). Since an individual patient’s risk of ADDA cannot be accurately predicted, current guidelines recommend lifelong aortic surveillance imaging for all patients. Hypothesis: Computational fluid dynamics (CFD) simulations of aortic hemodynamics post-repair can accurately identify patients at late risk of ADDA. Methods: We performed CFD simulations of 50 patients following hemi-arch replacement for ATAAD. Patient-specific 3D models were generated from the aortic root to iliac bifurcation (including arch branches) from postoperative 0.6mm contrast-enhanced CT angiograms taken <1 year after index repair (Figure). Exclusion criteria were known heritable thoracic aortic disease and absence of residual dissection. The primary outcome was ADDA, defined as late growth of the distal arch/descending thoracic aorta (DTA) to a diameter ≥5.5cm. Hemodynamic simulations were run for 6 cardiac cycles on a high-performance computing cluster using HARVEY, a CFD solver implementing the lattice Boltzmann method. The primary hemodynamic metric was time-averaged wall shear stress (TAWSS) ratio between the false and true lumens. Results: ADDA developed in 22 patients (44%) at a mean of 3.2 years postoperatively. There were no significant clinical differences between those with and without ADDA (Table). The development of late aneurysm growth was significantly associated with a higher TAWSS ratio in the proximal DTA ( p <0.05, Figure). Conclusion: ADDA following hemi-arch repair for ATAAD is associated with significantly higher false lumen TAWSS as early as the first surveillance scan. CFD simulations may help clinicians risk-stratify patients years before they meet reoperation criteria.

Genetic insights from a Brazilian cohort of aortopathies through targeted next-generation sequencing and FBN1 direct sequencing

Thoracic aortic diseases (or aortopathies) result from complex interactions between genetic and hemodynamic factors. Often clinically silent, these diseases can lead to lethal complications such as aortic dissection or rupture. This study focused on a Brazilian cohort of 79 individuals with thoracic aortic diseases and explored genetic factors through targeted next-generation sequencing (tNGS) of 15 priority genes and FBN1 direct sequencing. The majority of individuals had nonsyndromic aortopathy, with eight diagnosed with Marfan syndrome (MFS). Pathogenic or likely pathogenic variants (PV/LPV) were found in five genes, namely, FBN1, ACTA2, TGFBR2, MYLK, and SMAD3. Notably, novel variants in FBN1 were identified that contributed to Marfan-like phenotypes. The diagnostic yield for isolated aortopathies was 7.1%, which increased to 55.5% for syndromic cases. Variants of uncertain significance (VUS) were identified, emphasizing the need for further research and familial investigations to refine variant classifications. This study provides valuable insights into the genetic landscape of aortopathies in Brazil, aiding early diagnosis and personalized management.

Deep learning to predict cardiovascular mortality from aortic disease in heavy smokers

Aortic angiopathy is a common manifestation of cardiovascular disease (CVD) and may serve as a surrogate marker of CVD burden. While the maximum aortic diameter is the primary prognostic measure, the potential of other features to improve risk prediction remains uncertain. This study developed a deep learning framework to automatically quantify thoracic aortic disease features and assessed their prognostic value in predicting CVD mortality among heavy smokers. Using non-contrast chest CTs from the National Lung Screening Trial (NLST), aortic features quantified included maximum diameter, volume, and calcification burden. Among 24,770 participants, 440 CVD deaths occurred over a mean 6.3-year follow-up. Aortic calcifications and volume were independently associated with CVD mortality, even after adjusting for traditional risk factors and coronary artery calcifications. These findings suggest that deep learning-derived aortic features could improve CVD risk prediction in high-risk populations, enabling more personalized prevention strategies.

The Complexity of Familial Inheritance in Pectus Excavatum: A Ten-Family Exome Sequencing Analysis

Background/Objectives: Pectus excavatum (PEx) is considered, at least partially, a familial disorder. A variety of inheritance patterns, associations with genetic syndromes, and pathogenic variants have been reported. However, the etiology of this condition is still not completely understood, and no known genes have been identified as definitive contributors. Methods: Family members with a confirmed PEx diagnosis (one proband and two first-degree relatives) and non-affected members were recruited into this study. Exome sequencing was performed on all affected familial PEx cases to systematically screen for candidate genes that are likely to be causative for PEx, and on non-affected family members for variant segregation analysis. Results: Ten families, with three affected members each, participated, providing thirty familial PEx cases. Different inheritance patterns were represented across the ten pedigrees, with possible incomplete penetrance. Genetic variants in REST (essential for neuronal development and associated with pectus deformities in prior studies), SMAD4 (variants can predispose individuals to thoracic aortic diseases), and COL5A (associated with Ehlers–Danlos syndrome and Fibromuscular dysplasia) were initially identified as potentially linked to the development of pectus deformities and segregated with the phenotype. No variants were shared across families in the studied population. Conclusions: Germline exome sequencing of families with multiple individuals affected by PEx in our study identified potential gene candidates linked to PEx. These candidates are private to individual families and no strong candidates shared across multiple families were identified. These findings suggest that the inheritance of PEx may not be strongly related to a shared single genetic variant in known genes. Given the accumulating evidence for the genetic basis of familial PEx, further studies, including polygenic analyses, as well as assessment of the non-coding genome and possible epigenetic markers are warranted.

Mitral valve phenotypes in SMAD3-related thoracic aortic disease: insights from the Montalcino Aortic Consortium

Abstract Background SMAD3 pathogenic variants (PV) predispose to heritable thoracic aortic aneurysms and dissections (HTAD). Mitral annular disjunction (MAD) associated with mitral valve prolapse (MVP) and mitral regurgitation (MR) was identified as a potential new marker of disease severity in Marfan syndrome. The prevalence and prognostic impact of these mitral phenotypes in other forms of HTAD are less known. Purpose We hypothesize that mitral abnormalities are increased in SMAD3-related HTAD and are associated with increased risk for valve and aortic complications. Methods The Montalcino Aortic Consortium (MAC) registry has enrolled participants with PV in 15 HTAD genes. Subjects >16 years old with complete imaging and clinical data were included in this study. MVP was defined according to current guidelines. MR was classified as mild, moderate, or severe. MAD was defined by a >3-millimeter gap between the posterior mitral valve leaflet hinge point and the inferolateral myocardium as confirmed by direct measurement of echocardiogram images. Frequencies of MVP, MR, and MAD were compared between MAC participants with SMAD3 PV and other HTAD PV. Associations between clinical and echo characteristics and the composite outcome of arrhythmia, aortic surgery, aortic dissection, or congestive heart failure was evaluated with multivariable logistic regression. Results In 671 MAC participants (129 with SMAD3 PV, 36 [IQR 19-51] years, 49% female), the prevalence of MVP was 15% and the prevalence of MR was 22%. Both MVP (31/129, 24%, vs. 67/542, 12%, OR 2.2 [1.4-3.6], P<0.001) and MR (40/129, 31%, vs. 108/542, 20%, OR 1.8 [1.2-2.8], P<0.006) were more common in participants with SMAD3 PV compared to other PV and were further enriched in cases with SMAD3 missense PV compared to loss of function PV (MR or MVP: 26/48, 54% vs. 7/30, 23%, OR 3.9 [1.4-10.8], P<0.007). Images were available from 238 MAC participants (67 with SMAD3 PV) to assess for MAD. MAD (29/67, 43%, vs. 28/171, 16%, OR 3.9 [2.1-7.3], P<0.0001), or the composite of MR, MVP, or MAD (42/67, 63%, vs. 69/171, 35%, OR 3.2 [1.8-5.7], P<0.0001) was more common with SMAD3 PV compared to other PV (Figure 1). Twelve participants with SMAD3 PV (18%) had prominent mitral phenotypes (>mild MR, >10 mm MAD, or MAD with MVP) but no significant aortic dilation (Z<3). When controlling for age and sex, MR or MVP, but not MAD, was independently associated with the composite outcome (OR 16 [2.4-110], Figure 2). Conclusion Mitral valve pathology, including MVP, MR, and MAD, is increased in individuals with SMAD3 PV compared to other HTAD PV. Prominent mitral phenotypes related to SMAD3 missense PV may identify a high-risk subgroup with adverse cardiovascular outcomes. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for HTAD should be considered for such patients, especially if they also have a family history of thoracic aortic disease.

Short-term mechanical circulatory support in adults with congenital heart disease: indications and outcomes

Abstract Background An increasing number of adults with congenital heart disease (ACHD) present with heart failure (HF), which may require short- or long-term mechanical circulatory support (MCS), often around cardiac surgery or other interventions. Even though MCS has entered ACHD practice over the last few years, little is known on its indications and outcomes in this population. Purpose To assess the use and outcomes of short-term MCS in ACHD patients in a specialist centre, and assess the predictive power of the Survival After Veno-Arterial Extracorporeal Membrane Oxygenation (SAVE) score in this population. Methods Data on all ACHD patients who received MCS since 2008 in a single tertiary centre were collected. Immediate, short and longer-term outcomes were also collected, including death, complications, and weaning success. Logistic regression and ROC analysis were performed to identify predictors of in-hospital mortality. Result There were 65 episodes of MCS in 63 patients during the study period: age 36.9+-13.6 years, 61.5% male. Most patients had CHD of moderate or severe complexity (49.2% moderate and 10.8% severe according to ESC guidelines). The most common anatomical diagnoses were left outflow tract obstruction in 35.4%, Marfan syndrome in 20.0% and tetralogy of Fallot or pulmonary atresia in 10.8%. The most common indications for ECMO were perioperative support (not endocarditis) in 55.6%, HF in 14.3%, pneumonia in 12.7% and endocarditis-related surgery in 7.9%. A critical preoperative status was present in 26.8%; median PEACH score (a validated ACHD peri-operative risk score) was 1.0[1.0-3.0] and ACHS score was 0.6[0.6-1.0]. Median SAVE score was -4.0[-9.0–2.0], with 21(43.8%) in SAVE class 4 or 5. VA-ECMO was used in 69.2%, VV-ECMO in 21.5%, BiVAD-ECMO in 4.6% and RVAD support in 4.6% of patients. The median duration of ECMO support was 198.6[133.0-354.2] hours. Complications included ischemic stroke (15.4%), intracerebral bleeding (9.2%), and other thromboembolism (23.8%). Successful weaning was achieved in 56.2%, whereas 4.6% were switched to more definitive MCS. In-hospital mortality was 47.7%, and this was higher in patients receiving VA support (OR 4.92, 95%CI:1.32-23.93, p=0.03). For patients on VA-ECMO or BiVAD support, the presence of Marfan syndrome (OR 4.92, 95%CI:1.32-23.93, p=0.03) and a lower (worse) SAVE score (OR 1.3 per point reduction, 95%CI:1.11-1.59, p=0.004) were associated with in-hospital mortality. An adjusted SAVE score that accounted for the presence of heritable thoracic aortic diseases (HTAD, -3 points) performed well at predicting in-hospital mortality (AUC increasing from 0.73 to 0.8, Figure). Conclusions Short-term MCS is a useful temporary rescue intervention in patients with ACHD, as a bridge to recovery or durable support, with 1 in 2 patients surviving to hospital discharge. The SAVE score adjusted for HTAD can reliably predict outcomes in patients with VA-ECMO and requires external validation.Figure

Mitral Annular Disjunction in Heritable Thoracic Aortic Disease: Insights From the Montalcino Aortic Consortium.

Mitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium registry. MAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using χ2 or Fisher exact tests. MR and MVP were enriched in Montalcino Aortic Consortium participants (672) with pathogenic variants (PV) in transforming growth factor-β pathway genes. The combination of MR and MVP was associated with mitral surgery and arrhythmias. In the subgroup with available images, MAD was enriched in SMAD3 PV compared with other transforming growth factor-β PV (prevalence ratio 1.8 [1.1-2.8], P <0.02). Severe disjunction (>10 mm) was only observed in the transforming growth factor-β subgroup and was further enriched in participants with SMAD3 PV (prevalence ratio 3.1 [1.1-8.6]). MVP (prevalence ratio 5.2 [3.0-9.0]) and MR (PR 2.7 [1.8-3.9]) were increased in participants with MAD, but MAD was not independently associated with adverse cardiac or aortic events. Pathological mitral valve phenotypes are more prevalent in individuals with PV in transforming growth factor-β pathway genes, particularly SMAD3. MR and MVP but not MAD are associated with adverse aortic and cardiac events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for heritable thoracic aortic disease should be considered for such individuals, especially if they also have a family history of heritable thoracic aortic disease.

Identification of Genetic Variants Associated with Hereditary Thoracic Aortic Diseases (HTADs) Using Next Generation Sequencing (NGS) Technology and Genotype-Phenotype Correlations.

Hereditary thoracic aorta diseases (HTADs) are a heterogeneous group of rare disorders whose major manifestation is represented by aneurysm and/or dissection frequently located at the level of the ascending thoracic aorta. The diseases have an insidious evolution and can be encountered as an isolated manifestation or can also be associated with systemic, extra-aortic manifestations (syndromic HTADs). Along with the development of molecular testing technologies, important progress has been made in deciphering the heterogeneous etiology of HTADs. The aim of this study is to identify the genetic variants associated with a group of patients who presented clinical signs suggestive of a syndromic form of HTAD. Genetic testing based on next-generation sequencing (NGS) technology was performed using a gene panel (Illumina TruSight Cardio Sequencing Panel) or whole exome sequencing (WES). In the majority of cases (8/10), de novo mutations in the FBN1 gene were detected and correlated with the Marfan syndrome phenotype. In another case, a known mutation in the TGFBR2 gene associated with Loeys-Dietz syndrome was detected. Two other pathogenic heterozygous variants (one de novo and the other a known mutation) in the SLC2A10 gene (compound heterozygous genotype) were identified in a patient diagnosed with arterial tortuosity syndrome (ATORS). We presented the genotype-phenotype correlations, especially related to the clinical evolution, highlighting the particularities of each patient in a family context. We also emphasized the importance of genetic testing and patient monitoring to avoid acute aortic events.

Baseline Diameter Does Not Predict Growth Rate in a Presurgical Ascending Thoracic Aortic Aneurysm Population.

Patients with ascending thoracic aortic aneurysm are recommended to undergo routine imaging surveillance. Although maximal diameter is the primary metric of disease severity, recent American College of Cardiology/American Heart Association guidelines emphasize the importance of aortic growth in determining surgical candidacy and risk. As diameter increases, it is assumed that aortic growth rate accelerates because of increased wall tension; however, this relationship is poorly studied. We aim to investigate the relationship between ascending thoracic aortic aneurysm diameter and growth rate using vascular deformation mapping, a validated technique for 3-dimensional growth mapping with submillimeter accuracy. We retrospectively identified adult patients with ascending aortic dilation (≥4.0 cm) and serial gated computed tomography angiograms separated by ≥2 years, excluding confirmed heritable thoracic aortic disease. Ascending growth rate was defined as 90th percentile radial wall deformation by vascular deformation mapping. Maximal diameter measurements were derived from the baseline computed tomography angiogram, and aortic length and body size-adjusted indexes were calculated. Among 258 included patients (63.2% men; age of 63 years [interquartile range, 55-69 years]), mean±SD baseline diameter was 46.3±3.6 mm and median growth rate was 0.21 mm/year (interquartile range, 0.13-0.38 mm/year). No correlation was noted between growth rate and baseline diameter (r=0.02, P=0.74) or other aortic size metrics. On multivariate analysis, age was independently predictive of growth rate (β=-0.007, P=0.021), alongside weight (β=0.003, P=0.016) and the presence of moderate or severe aortic valve insufficiency (β=0.146, P=0.049). Maximal aortic diameter is not predictive of aortic growth rate, in this contemporary cohort of patients with sizes under current surgical thresholds (<55 mm).

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Peer Review of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Authors’ Response to Peer Reviews of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Authors’ Response to Peer Reviews of “Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease”

Development and Assessment of a Point-of-Care Application (Genomic Medicine Guidance) for Heritable Thoracic Aortic Disease.

Genetic testing can determine familial and personal risks for heritable thoracic aortic aneurysms and dissections (TAD). The 2022 American College of Cardiology/American Heart Association guidelines for TAD recommend management decisions based on the specific gene mutation. However, many clinicians lack sufficient comfort or insight to integrate genetic information into clinical practice. We therefore developed the Genomic Medicine Guidance (GMG) application, an interactive point-of-care tool to inform clinicians and patients about TAD diagnosis, treatment, and surveillance. GMG is a REDCap-based application that combines publicly available genetic data and clinical recommendations based on the TAD guidelines into one translational education tool. TAD genetic information in GMG was sourced from the Montalcino Aortic Consortium, a worldwide collaboration of TAD centers of excellence, and the National Institutes of Health genetic repositories ClinVar and ClinGen. The application streamlines data on the 13 most frequently mutated TAD genes with 2286 unique pathogenic mutations that cause TAD so that users receive comprehensive recommendations for diagnostic testing, imaging, surveillance, medical therapy, and preventative surgical repair, as well as guidance for exercise safety and management during pregnancy. The application output can be displayed in a clinician view or exported as an informative pamphlet in a patient-friendly format. The overall goal of the GMG application is to make genomic medicine more accessible to clinicians and patients while serving as a unifying platform for research. We anticipate that these features will be catalysts for collaborative projects aiming to understand the spectrum of genetic variants contributing to TAD.

Beyond the root: Geometric characterization for the diagnosis of syndromic heritable thoracic aortic diseases

Syndromic heritable thoracic aortic diseases (sHTAD), such as Marfan (MFS) or Loeys–Dietz (LDS) syndromes, involve high risk of life threatening aortic events. Diagnosis of syndromic features alone is difficult, and negative genetic tests do not necessarily exclude a genetic or hereditary condition. Periodic 3D imaging of the aorta is recommended in patients with aortic disease. Thus, an imaging-based approach aimed at identifying unique features of aortic geometry can be highly effective for diagnosing sHTAD and assessing risk. In this study, we present a method that can help identify the manifestations of sHTAD by focusing on the entire geometry of the thoracic aorta, rather than only using measurements of dilation of the aortic root. We analyze the geometric phenotype of 97 patients with genetically confirmed sHTAD (79 MF and 18 LDS) and of 45 healthy volunteers, using 3D aorta meshes obtained from phase contrast-enhanced magnetic resonance angiograms computed from 4D flow cardiac magnetic resonance. We build a geometric encoding of the aorta, based on a vessel coordinate system, and use several mathematical models to discriminate between controls and patients with sHTAD: a baseline scenario, based on aortic root dimensions only, a descriptor typically used in sHTAD patients; a low dimensional scenario, with a reduce encoding using principal component analysis; and a high-dimensional scenario, which included the full coefficient representation for geometry encoding, aiming to capture finer geometric details. The results indicate that considering the anatomy of the whole thoracic aorta can improve predictive ability. We achieve precision and sensitivity values over 0.8, with a specificity of over 70% in all the models used, while a single value classifiers (based only on aortic root diameter) demonstrated a trade-off between sensitivity and specificity. Using the mathematical properties of the vessel coordinate system representation, feature importance is mapped onto a set of anatomical traits that are used by the models to do the classification, thus providing interpretability of the results. This analysis indicates that in addition to the diameter of the aortic root, aortic elongation and a narrowing of the descending thoracic aorta may be markers of positive sHTAD.

Clinical impact of proximal fixation augmentation using the Najuta thoracic fenestrated stent graft during endovascular treatment for distal aortic arch aneurysm

ObjectivePrevention of late type 1a endoleaks is the main concern in thoracic endovascular aortic aneurysm repair (TEVAR) for thoracic aortic aneurysm (TAA). Since 2017, we have performed zone 0 TEVAR with proximal fixation augmentation using a Najuta thoracic fenestrated stent graft in addition to zone 2 TEVAR for distal arch aneurysms. We report the early-midterm outcomes of TEVAR performed using this strategy. MethodsThis single-center retrospective study enrolled 386 cases of TEVAR for thoracic aortic disease between January 2013 and December 2020. Patients with TAA treated by TEVAR landing at zone 2 was referred to as the Standard group (S group), whereas those treated by TEVAR landing at zone 0 using a Najuta fenestrated stent graft in addition to zone 2 TEVAR was referred to as the Augmentation group (A group). We retrospectively compared the clinical outcomes between the two groups. The primary endpoint was secondary intervention for postoperative type1a endoleaks. Secondary endpoints were technical success, aneurysm-related death (ARD), and major adverse events (MAEs) including stroke, paraplegia, endoleaks, and secondary interventions. ResultsWe performed TEVAR in 41 and 30 cases in the S and A groups, respectively. The mean aneurysm sizes in the S and A group were 54.5 and 57.3 mm (p=0.23), and the proximal neck lengths were 16.8 and 17.4 mm (p = 0.65), respectively. The anatomical characteristics appeared to be similar in both groups. The technical success rate in both groups was 100%. Three cases in the S group had MAEs, including two stroke and one brachial artery pseudoaneurysm; whereas, 2 cases had MAEs in the A group, including one stroke and one paraplegia. There was no 30-day mortality or retrograde type A dissection in both groups. The mean observation periods in the S and A groups were 46 (1–123) and 35 (1–73) months, respectively. At 36 and 60 months post-procedure, the freedom from ARD was 97.6% and 97.6% in the S group, 100.0% and 100.0% in the A group (p=0.39); and the freedom from re-intervention for type1a endoleaks was 79.2% and 65.2% in the S group, 100.0% and 100.0% in the A group (p = 0.0087 < 0.05). A statistically significant reduction in re-intervention for type1a endoleaks was observed in the A group. ConclusionsProximal fixation augmentation using the Najuta fenestrated stent graft during TEVAR for distal arch aneurysm is effective in preventing the postoperative late type 1a endoleaks.

Exercise, Sports Participation, and Quality of Life in Young Patients with Heritable Thoracic Aortic Disease.

Patients with heritable thoracic aortic disease (HTAD)are often restricted from sports and certain types of exercise. This study was designed to investigate the effect of lifetime exercise exposure and competitive sports participation on quality of life (QOL) in patients aged 15-35 with syndromic [Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), vascular Ehlers-Danlos syndrome (vEDS)] and non-syndromic heritable thoracic aortic disease (nsHTAD). This cross-sectional study employed questionnaires to assess lifetime exercise exposure and utilized the PedsQL QOL Inventory. We developed an Exercise Exposure Score (EES) to quantify lifetime exercise exposure. Questionnaires were completed via telephone with complimentary medical record review. Forty patients were enrolled. Mean age was 26 years. The diagnosis was MFS in 83%. Despite 88% of patients being restricted by their provider, 65% reported competitive sports participation and 93% reported recreational exercise. Participants with an EES greater than the median had significantly better total QOL scores compared to those below the median (78 vs 65, p = 0.03). There were significant positive correlations between current frequency of exercise and psychosocial QOL (slope = 3.9, 95% CI: (1.2, 6.6), p = 0.005), physical QOL (slope = 8.1, 95% CI: (4.1, 12), p < 0.001), and total QOL score (slope = 6.0, 95% CI: (3.1, 9.0), p < 0.001). We found no difference in aortic size or need for surgical intervention between those above and below the median EES, or between those who did and did not participate in competitive sports. Despite exercise restrictions, young HTAD patients are physically active. Increased lifetime exercise and current physical activity levels were associated with improved QOL in HTAD patients.