Thoracic Aortic Aneurysm Patients Research Articles

Patient-specific ascending aortic intervention criteria.

Ascending aortic aneurysms pose a different risk to each patient. We aim to provide personalized risk stratification for such patients based on sex, age, body surface area, and aneurysm location (root vs ascending). Root and ascending diameters, and adverse aortic events (dissection, rupture, death) of ascending thoracic aortic aneurysm patients were analyzed. Aortic diameter was placed in context vis-a-vis the normal distribution in the general population with similar sex, age, and BSA, by conversion to z scores. These were correlated of major adverse aortic events, producing risk curves with 'hinge points' of steep risk, constructed separately for the aortic root and mid ascending aorta. 1162 patients were included. Risk curves unveiled generalized thresholds of z = 4 for the aortic root, and z = 5 for the mid ascending aorta. These correspond to individualized thresholds of less than the standard criterion of 5.5 cm in the vast majority of patients. Indicative results include a 75 year-old typical male with 2.1 m2 body surface area, who was found to be at increased risk of adverse events if root diameter exceeds 5.15 cm, or mid ascending exceeds 5.27 cm. An automated calculator is presented which identifies patients at high risk of adverse events based on sex, age, height, weight, and root and ascending size. This analysis exploits a large sample of aneurysmal patients, demographic features of the general population, pre-dissection diameter, discrimination of root and supracoronary segments, and statistical tools to extract thresholds of increased risk tailor-made for each patient.

Analysis of Vascular Smooth Muscle Cells from Thoracic Aortic Aneurysms Reveals DNA Damage and Cell Cycle Arrest as Hallmarks in Bicuspid Aortic Valve Patients.

Thoracic aortic aneurysm (TAA) is mainly sporadic and with higher incidence in the presence of a bicuspid aortic valve (BAV) for unknown reasons. The lack of drug therapy to delay TAA progression lies in the limited knowledge of pathophysiology. We aimed to identify the molecular hallmarks that differentiate the aortic dilatation associated with BAV and tricuspid aortic valve (TAV). Aortic vascular smooth muscle cells (VSMCs) isolated from sporadic TAA patients with BAV or TAV were analyzed by mass spectrometry. DNA oxidative damage assay and cell cycle profiling were performed in three independent cohorts supporting proteomics data. The alteration of secreted proteins was confirmed in plasma. Stress phenotype, oxidative stress, and enhanced DNA damage response (increased S-phase arrest and apoptosis) were found in BAV-TAA patients. The increased levels of plasma C1QTNF5, LAMA2, THSB3, and FAP confirm the enhanced stress in BAV-TAA. Plasma FAP and BGN point to an increased inflammatory condition in TAV. The arterial wall of BAV patients shows a limited capacity to counteract drivers of sporadic TAA. The molecular pathways identified support the need of differential molecular diagnosis and therapeutic approaches for BAV and TAV patients, showing specific markers in plasma which may serve to monitor therapy efficacy.

Flow patterns in ascending aortic aneurysms: Determining the role of hypertension using phase contrast magnetic resonance and computational fluid dynamics

Thoracic aortic aneurysm (TAA) is a local dilation of the thoracic aorta. Although universally used, aneurysm diameter alone is a poor predictor of major complications such as rupture. There is a need for better biomarkers for risk assessment that also reflect the aberrant flow patterns found in TAAs. Furthermore, hypertension is often present in TAA patients and may play a role in progression of aneurysm. The exact relation between TAAs and hypertension is poorly understood. This study aims to create a numerical model of hypertension in the aorta by using computational fluid dynamics. First, a normotensive state was simulated in which flow and resistance were kept unaltered. Second, a hypertensive state was modeled in which blood inflow was increased by 30%. Third, a hypertensive state was modeled in which the proximal and peripheral resistances and capacitance parameters from the three-element Windkessel boundary condition were adjusted to mimic an increase in resistance of the rest of the cardiovascular system. One patient with degenerative TAA and one healthy control were successfully simulated at hypertensive states and were extensively analyzed. Furthermore, three additional TAA patients and controls were simulated to validate our method. Hemodynamic variables such as wall shear stress, oscillatory shear index, endothelial cell activation potential (ECAP), vorticity and helicity were studied to gain more insight on the effects of hypertension on flow patterns in TAAs. By comparing a TAA patient and a control at normotensive state at peak-systole, helicity and vorticity were found to be lower in the TAA patient throughout the entire domain. No major changes in flow and flow derived quantities were observed for the TAA patient and control when resistance was increased. When flow rate was increased, regions with high ECAP values were found to reduce in TAA patients in the aneurysm region which could reduce the risk of thrombogenesis. Thus, it may be important to assess cardiac output in patients with TAA.

Immune Response Associated Gene Signatures in Aortic Dissection Compared to Aortic Aneurysm.

Thoracic aortic dissections (TAD) are life-threatening events mostly requiring immediate surgical treatment. Although dissections mainly occur independently of thoracic aortic aneurysms (TAA), both share a high comorbidity. There are several indications for an involvement of the immune system in the development of TAD, just as in TAA. Nevertheless, specific disease-relevant genes, biomolecular processes, and immune-specific phenotypes remain unknown. RNA from isolated aortic smooth muscle cells from TAD (n = 4), TAA (n = 3), and control patients were analyzed using microarray-based technologies. Additionally, three publicly available bulk RNA-seq studies of TAD (n = 23) and controls (n = 17) and one single-cell RNA-seq study of TAA (n = 8) and controls (n = 3) were analyzed. Differentially expressed genes were identified and used to identify affected pathways in TAD. Five selected genes were validated by quantitative real-time polymerase chain reaction (PCR). We identified 37 genes that were significantly dysregulated in at least three TAD studies-24 of them were not shown to be associated with TAD, yet. Gene ontology analysis showed that immune response was significantly affected. Five of the genes (CCL2, RNASE2, HAVCR2, CXCL8, and IL6R) were revealed as core genes that affect immune response in TAD. We compared the gene expression of those genes to TAA and found that CXCL8, IL6R, and potentially also CCL2 were upregulated in TAD. The identified immune-related genes showed TAD-specificity, independent of possible pre-existing comorbidities like TAA. So, these genes represent potential biomarkers and therapeutic targets linked to the immune response in acute TAD. Additionally, we identified a set of differentially expressed genes that represents a resource for further studies.

Integrative multi-omics analyses reveal vesicle transport as a potential target for thoracic aortic aneurysm

BackgroundThoracic aortic aneurysm (TAA) refers to dilation and enlargement of the thoracic aorta caused by various reasons. Most patients have no apparent symptoms in the early stage and are subject to a poor prognosis once the aneurysm ruptures. It is crucial to identify individuals who are predisposed to TAA and to discover effective therapeutic targets for early intervention. MethodsWe conducted a label-free quantitative proteomic analysis among aorta tissue samples from TAA patients to screen differentially expressed proteins (DEPs) and key co-expression modules. Two datasets from Gene Expression Omnibus (GEO) database were included for integrative analysis, and the identified genes were subjected to immunohistochemistry (IHC) validation. Detailed vesicle transport related enrichment analysis was conducted and two FDA-approved drugs, chlorpromazine (CPZ) and chloroquine (CQ), were selected for in vivo inhibition of vesicle transport in mice TAA model. The diameter of thoracic aorta, mortality and histological differences after interventions were evaluated. ResultsWe found significant enrichments in functions involved with vesicle transport, extracellular matrix organizing, and infection diseases in TAA. Endocytosis was the most essential vesicle transport process in TAA formation. Interventions with CPZ and CQ significantly reduced the aneurysm diameter and elastin degradation in vivo and enhanced the survival rates of TAA mice. ConclusionsWe systematically screened the aberrantly regulated bioprocesses in TAA based on integrative multi-omics analyses, identified and demonstrated the importance of vesicle transport in the TAA formation. Our study provided pilot evidence that vesicular transport was a potential and promising target for the treatment of TAA.

Exploring a Transcriptome-forward Approach for Genetic Evaluation in Thoracic Aortopathy

Background/Objective: Thoracic aortic aneurysm (TAA) is an aortopathy that predisposes to aortic dissection and rupture. Transcriptomic analysis has diagnostic utility in other diseases, but this has not been developed for TAA. We therefore sought to implement the Genome Analysis Toolkit (GATK) as a tool for high-throughput detection of novel variants in RNA sequencing (RNA-seq) data from patients with TAA.
 Methods: Human proximal aortic tissue samples from 63 TAA patients and 15 controls were used to establish primary smooth muscle cell (SMC) lines in culture. Total RNA was extracted at early passage; RNA-seq was performed using 150 base pair paired-end reads. Variants were called from RNA-seq reads using the GATK’s HaplotypeCaller tool. The MarkDuplicates tool tagged duplicate reads, but these were retained for variant analysis. Singletons were defined as heterozygous variants unique to one sample in the overall group.
 Results: The RNA-seq pipeline was validated by confirming known mutations in 2 patients, inspecting reads directly in the Integrative Genomics Viewer (IGV), and genotyping for a common single nucleotide polymorphism. Across all 78 samples, the GATK pipeline identified 4,823,462 variant sites, 236,495 of which were in coding regions. Variant sites were filtered for those located within the coding regions of 31 genes curated for known evidence of aortic disease causality. Among the 511 coding variant sites in these genes, 330 single nucleotide variants and 33 insertions/deletions were identified as singletons. Singleton variant calls were evaluated for quality and annotated in order to predict their likelihood of pathogenicity, thus far identifying strong candidate causal variants in FBN1, TGFBR1, TGFB3, GATA4, and HEY2.
 Conclusion: Application of the GATK RNA-seq pipeline expands our prior IGV analysis, further demonstrating the potential diagnostic utility of transcriptomic analysis of aortic SMCs in TAA.
 Scientific Impact: Identifying novel aortopathy-associated variants could improve future disease detection and prediction of severity.

Whole-exome sequencing uncovers a novel EFEMP2 gene variant (c.C247T) associated with dominant nonsyndromic thoracic aortic aneurysm.

Thoracic aortic aneurysm (TAA) is a multifactorial disorder. Familial TAA, which is more clinically aggressive, is associated with a high risk of lethal dissection or rupture. Genetic evaluation can provide TAA patients with personalized treatment and help in predicting risk to family members. The purpose of this investigation was to report a likely pathogenic variant in the EFEMP2 gene that may contribute to TAA in a family with a documented history of the condition. In the index patient, the causative genetic predisposition was identified using whole-exome sequencing. The potential likely pathogenic effect of the candidate variant was further analyzed through bioinformatics analysis, homology modeling, and molecular docking. The results revealed a likely pathogenic heterozygous variant, c.247C>T p.Arg83Cys, in exon 4 of the EFEMP2 gene (NM_016938), which was predicted to have disease-causing effects by MutationTaster, PROVEAN, SIFT, and CADD (phred score = 27.6). In this study, a likely pathogenic variant in the EFEMP2 gene was identified in an Iranian family with a dominant pattern of autosomal inheritance of TAA. This finding underscores the importance of conducting molecular genetic evaluations in families with nonsyndromic TAA and the significance of early detection of at-risk family members.

Identification of immune-related signatures and pathogenesis differences between thoracic aortic aneurysm patients with bicuspid versus tricuspid valves via weighted gene co-expression network analysis.

Thoracic aortic aneurysm (TAA) occurs due to pathological aortal dilation, and both individuals with normal tricuspid aortic valves (TAV) or abnormal bicuspid aortic valves (BAV), the latter being a congenital condition, are at risk. However, some differences are present between TAA/BAV and TAA/TAV with respect to their pathophysiological processes and molecular mechanisms, but their exact nature is still mostly unknown. Therefore, it is necessary to elucidate TAA developmental differences among BAV vs. TAV patients. Publically-available gene expression datasets, aortic tissue derived from TAA/BAV and TAA/TAV individuals, were analyzed by weighted gene co-expression network analysis (WGCNA) to identify gene modules associated with those conditions. Gene Ontology (GO) enrichment analysis was performed on those modules to identify the enriched genes within those modules, which were verified by Gene Set Variation Analysis (GSVA) on a dataset derived from aortic smooth muscle cell gene expression between TAA/TAV and TAV/BAV patients. Immune cell infiltration patterns were then analyzed by CIBERSORT, and a protein-protein interaction (PPI) network was constructed based on WGCNA and enrichment analysis results to identify hub genes, followed by validation via stepwise regression analysis. Three signatures most strongly associated with TAA/TAV were confirmed by receiver operating characteristic (ROC) and decision curve analyses (DCA) between prior-established training and testing gene sets. WGCNA delineated 2 gene modules being associated with TAA/TAV vs. TAA/BAV; both were enriched for immune-associated genes, such as those relating to immune responses, etc., under enrichment analysis. TAA/TAV and TAA/BAV tissues also had differing infiltrating immune cell proportions, particularly with respect to dendritic, mast and CD4 memory T cells. Identified three signatures, CD86, integrin beta 2 (ITGB2) and alpha M (ITGAM), as yielding the strongest associations with TAA/TAV onset, which was verified by areas under the curve (AUC) at levels approximating 0.8 or above under ROC analysis, indicating their predictive value for TAA/TAV onset. However, we did not examine possible confounding variables, so there are many alternative explanations for this association. TAA/TAV pathogenesis was found to be more associated with immune-related gene expression compared to TAA/BAV, and the identification of three strongly-associated genes could facilitate their usage as future biomarkers for diagnosing the likelihood of TAA/TAV onset vs. TAA/BAV, as well as for developing future treatments.

In-depth analysis of human vascular smooth muscle cells from idiopathic thoracic aortic aneurysm patients evidences the mechanisms predisposing to aortic dilatation in bicuspid aortic valve

In-depth analysis of human vascular smooth muscle cells from idiopathic thoracic aortic aneurysm patients evidences the mechanisms predisposing to aortic dilatation in bicuspid aortic valve

Circ_0008285 silencing suppresses angiotensin II-induced vascular smooth muscle cell apoptosis in thoracic aortic aneurysm via miR-150-5p/BASP1 axis.

Vascular smooth muscle cells (VSMCs) are the predominant cell type of the aortic middle layer, the abnormal number or function of which has been demonstrated to have a role in thoracic aortic aneurysm (TAA). Here, this study aimed to identify the function of circ_0008285 in VSMC apoptosis. Human VSMCs were treated with angiotensin II (Ang II) for functional experiments. Cell counting kit-8, 5-ethynyl-2'-deoxyuridine (EdU), and flow cytometry were applied for function analysis. The interaction between miR-150-5p and circ_0008285 or brain acid-soluble protein 1 (BASP1) was also evaluated by dual-luciferase reporter assay and RNA immunoprecipitation assay. Exosomes were isolated by the commercial kit. A highly expressed circ_0008285 was observed in the aortic tissues of TAA patients and Ang-II-induced VSMCs. Circ_0008285 deficiency dramatically reversed Ang-II-induced proliferation arrest and apoptosis promotion in VSMCs. Circ_0008285 functionally targeted miR-150-5p. MiR-150-5p inhibition attenuated the inhibitory effects of circ_0008285 silencing on Ang-II-evoked apoptosis in VSMCs. BASP1 was verified to be a target of miR-150-5p, and was proved to attenuate miR-150-5p-triggered apoptosis arrest in Ang-II-stimulated VSMCs. Additionally, extracellular circ_0008285 was packaged into exosomes, which could be transferred into the recipient cells. Circ_0008285 silencing could suppress Ang-II-induced VSMCs apoptosis via miR-150-5p/BASP1 axis, adding further understanding of the pathogenesis of TAA.

Association of simple renal cysts to aneurysm sac shrinkage in true thoracic aortic aneurysms after thoracic endovascular aortic repair

BackgroundAn increased prevalence of thoracic aortic aneurysms (TAA) has been demonstrated in patients with simple renal cysts (SRC); patients with SRC have a less elastic aortic wall than those without SRC. The purpose of this study was to evaluate aneurysm sac shrinkage after thoracic endovascular aortic repair (TEVAR) for true TAA in patients with and without SRC. MethodsOne hundred three patients with true aneurysms of the thoracic aorta who underwent TEVAR at our university hospital from November 2013 to December 2021 were included in this study. Aneurysm sac size was compared between that on baseline preoperative computed tomography and that on postoperative computed tomography scans at 1 year. A change in aneurysm sac size ≥5 mm was considered to be significant, whether due to expansion or shrinkage. ResultsThe patients were divided into two groups: those with SRC (46 patients [45%]) and those without SRC (57 patients [55%]). At 1 year, there was a significant difference in the proportion of aneurysm sac shrinkage between patients with SRC and those without SRC (23.9% vs 59.6%; P < .001). Patients with SRC showed significantly less aneurysm sac shrinkage than those without SRC (−1.8 ± 5.6 mm vs −5.1 ± 6.6 mm; P = .009). Univariable and multivariable analyses showed that the initial sac diameter (odds ratio, 1.08; 95% confidence interval, 1.03-1.14; P = .002) and the presence of SRC (odds ratio, 0.15; 95% confidence interval, 0.06-0.40; P < .001) were positively and negatively associated with aneurysm sac shrinkage after TEVAR, respectively. ConclusionsThe presence of a SRC was independently associated with failure of aneurysm sac shrinkage after TEVAR for true TAA. This suggests that the presence of a SRC may be a predictor for the failure of aneurysm sac shrinkage after TEVAR.

AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signaling

Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1+/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1+/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1.

340 The Effects of PTSD-Dependent Neurogenic Hypertension and Inflammation on Thoracic Aortic Aneurysm Progression

OBJECTIVES/GOALS: Nearly all thoracic aortic aneurysm patients suffer from hypertension leading to elevated wall tension and abnormal extracellular matrix remodeling. PTSD patients have higher blood pressure both at rest and in response to stimuli. Although stress is associated with cardiovascular disease, the exact mechanism linking the two is still unknown. METHODS/STUDY POPULATION: Adult C57BL/6 mice underwent a PTSD induction protocol consisting of inescapable foot shock followed by single prolonged stress. The mice were assessed incrementally for their PTSD-like phenotype using specific behavioral tests chosen to assess for each of the human criteria of PTSD according to the DSM-V. Tail cuff blood pressure measurements were taken serially throughout the 16-week protocol. At terminal study, thoracic aortic diameter measurements were obtained through digital microscopy and plasma was harvested for cytokine analysis. Thoracic aortic aneurysms (TAA) were induced through periadventitial application of a calcium chloride solution on the descending thoracic aorta in BPH/2J and BPN/3J adult mice. The thoracic aortic diameter was measured at terminal study through digital microscopy. RESULTS/ANTICIPATED RESULTS: Using our PTSD-like mouse model we have demonstrated that PTSD-like mice have significantly higher systolic blood pressure following a reminder of the traumatic event than control mice recapitulating the human phenotype. They also had increased plasma proinflammatory cytokines and larger thoracic aortic diameters than control mice. Although the increased thoracic aortic diameter is not an aneurysm, it suggests ECM remodeling is occurring predisposing the aorta to aneurysm formation. Finally, we have shown that in neurogenic hypertensive mice, TAA formation was accelerated by 12 weeks with roughly 70% dilation at 4 weeks post-TAA induction surgery as compared to roughly a 20% dilation in control mice. DISCUSSION/SIGNIFICANCE: Altogether, these studies reinforce the link between stress and TAA development, and our mouse model will allow for the underlying mechanism to be elucidated. Better understanding of the mechanism linking PTSD and TAA will allow for the creation of novel therapeutics to treat PTSD symptoms while also delaying TAA progression.

Detection of unexpected aortic aneurysms by using computed tomography in emergency department: A retrospective analysis of more than 10.000 patients

Aim: This study aims to determine the prevalence of aortic aneurysms (AA) on computed tomography (CT) in the emergency department. Material and Methods: A total of 10219 CT images were retrospectively analyzed (7610 thoracic, 6148 abdominal CT). A thoracic aortic diameter greater than 50 mm, an abdominal aortic diameter greater than 30 mm, or an aortic diameter greater than 50% of normal were considered AA. The baseline demographic and clinical characteristics of patients with thoracic AA (TAA) and abdominal AA (AAA) were compared to those without AA. Results: TAA was found in 990 (13%) of 7610 patients who had thoracic CT, while AAA was found in 66 (1.07%) of 6148 patients who had abdominal CT. In aneurysm groups, advanced age (p&lt;0.001), male gender (p&lt;0.001), aortic calcification (p&lt;0.001), hyperlipidemia (p&lt;0.001), coronary artery disease (p&lt;0.001), hypertension (p&lt;0.001), and diabetes mellitus (p&lt;0.001) were more common and significantly different. Smoking was observed more frequently in the group with aneurysms (p&lt;0.001). Among the groups, hospital mortality was higher in the aneurysm group (p&lt;0.001). Surgery was recommended in 30 (3%) of TAA patients whose aortic diameter was greater than 55 mm; however, surgery could be performed in 20 (2%) of these patients. Surgery was recommended for 16 (24%) of AAA patients, but surgery could be performed only in 12 of them (18%). Conclusion: Attention to aortic pathologies, particularly AA, in patients undergoing radiological imaging in the emergency department for various reasons allows for the early detection of asymptomatic but potentially fatal aneurysms.

Are Thoracic Aortic Aneurysm Patients at Increased Risk for Cardiovascular Diseases?

Objectives: Abdominal aortic aneurysms are associated with a sharply increased cardiovascular risk. Cardiovascular risk management is therefore recommended in prevailing guidelines for abdominal aneurysm patients. It has been hypothesized that associated risk relates to loss of aortic compliance. If this hypothesis is correct, observations for abdominal aneurysms would also apply to thoracic aortic aneurysms. The objective of this study is to test whether thoracic aneurysms are also associated with an increased cardiovascular risk burden. Methods: Patients who underwent aortic valve or root surgery were included in the study (n = 239). Cardiovascular risk factors were studied and atherosclerosis was scored based on the preoperative coronary angiographies. Multivariate analyses were performed, controlling for cardiovascular risk factors and aortic valve morphology. Comparisons were made with the age- and gender-matched general population and non-aneurysm patients as control groups. A thoracic aortic aneurysm was defined as an aortic aneurysm of ≥45 mm. Results: Thoracic aortic aneurysm was not associated with an increased coronary atherosclerotic burden (p = 0.548). Comparison with the general population revealed a significantly higher prevalence of hypertension (61.4% vs. 32.2%, p < 0.001) and a lower prevalence of diabetes (1.4% vs. 13.1%, p = 0.001) in the thoracic aneurysm group. Conclusions: The extreme cardiovascular risk associated with abdominal aortic aneurysms is location-specific and not explained by loss of aortic compliance. Thoracic aortic aneurysm, in contrast to abdominal, is not part of the atherosclerotic disease spectrum and, therefore, cardiovascular risk management does not need to be implemented in treatment guidelines of isolated thoracic aneurysms. Hypertension should be treated.

Abstract 15193: Coronary Ectasia in Patients With Thoracic Aortic Aneurysm

Introduction: Coronary ectasia is identified on coronary angiography in 1-5% of cases; however, its etiology, associations, and prognostic significance are poorly characterized Methods: In a large retrospective cohort of thoracic aortic aneurysm (TAA) patients, we identified rates of coronary ectasia and the presence of aortic aneurysm and bicuspid aortic valve. Two reviewers independently assessed coronary angiograms for the presence of coronary ectasia, defined as a diameter 1.5 times larger than the adjacent healthy reference segment or an absolute diameter &gt; 4.5 mm. Results: Of the 474 TAA patients assessed, coronary ectasia was identified in 87 (18.4%). Amongst patients with coronary ectasia, 59 (67.8%) had isolated thoracic aortic aneurysms [11 (18.6%) had aortic root involvement, 46 (78.0%) had ascending aortic involvement, and 2 (3.4%) had descending aortic involvement]. Further, 28 patients had aneurysms across vascular beds [5 (17.9%) had root and ascending aortic involvement; 11 (39.3%) had combined ascending and descending aortic involvement; 9 (32.1%) had both thoracic and abdominal aortic aneurysms and 3 (10.8%) had diffuse aneurysmal disease involving other beds including intracranial, iliac and distal aortic aneurysms]. Additionally, 16 (18.39%) patients with coronary ectasia were found to have a bicuspid aortic valve where fused right and left coronary cusps were the most common anatomic variant [7 (43.75%) patients]. Of the 87 ectasia patients, there were no major adverse cardiac events including rupture of the ectatic coronary segments or related thrombosis or myocardial infarction during the mean follow-up period of 5 years. Conclusion: This study identifies that coronary ectasia occurs in TAA patients at a rate higher than expected for the general population, demonstrating a potential association between these conditions. At 5-year follow up, the presence of coronary ectasia is not associated with any major adverse cardiac events.

Abstract 15742: Thoracic Aortic Aneurysmal Disease Prevalence and Outcomes in Women With Connective Tissue Diseases

Introduction: Connective tissue disease patients are at risk for thoracic aortic aneurysm (TAA) and its complications. We sought to clarify risk factors for TAA specific to women. Methods: Using Yale Aortic Institute database, we identified 266 female patients with diagnosis of Marfan’s, Ehlers-Danlos, or Loeys-Dietz Syndromes. We included imaging, clinical and surgical information collected using retrospective chart review. Results: Amongst women with CTD, the prevalence of TAA in our population was 25%. MFS patients constituted 23% of the study population but accounted for 70% of aneurysm patients. EDS patients comprised 74% of the study population and 24% aneurysm patients. LDS comprised a small percentage of both populations. Non-Caucasian ethnicities seemed to have much higher likelihood of developing an aneurysm. CTD patients with aortic aneurysms were more likely to have valvular heart disease (VHD: MVP, AI), HTN, DLP, and DM. Aneurysm rates were slightly higher in ever-pregnant patients, with highest rates in MFS. TAA patients had higher rates of all-cause mortality (15% vs 2%). CV/aortic-related complications and death occurred only in TAA patients. Aortic dissection occurred in 24%; 30/67 required aortic surgery, with 13/67 requiring multiple surgeries. MFS manifested higher rates of aortic dissection (40%), surgery (40%), and mortality (both all cause and CV/Ao). Conclusions: TAA is common amongst women with CTD, with Marfan’s patients being at highest risk for TAA and its complications (aortic dissection, need for surgery, and death). Risk factors for TAA were VHD, HTN, DLP, and DM. Pregnancy appears to be a risk factor for TAA in select CTD subgroups.

Construction of a high-throughput aorta smooth muscle-on-a-chip for thoracic aortic aneurysm drug screening

Thoracic aortic aneurysm (TAA), in which arteries enlarge asymptomatically over time until dissection or rupture occurs, is a serious health risk. The mainstay of TAA treatment remains surgical repair due to the lack of effective drugs. The complex etiology and pathogenesis of TAA, including hemodynamic alterations and genetic factors, lead to inaccuracies in preclinical models for drug screening. Previously, our group designed an aorta smooth muscle-on-a-chip to emulate human aorta physiology and pathophysiology and screened three promising therapeutic drugs targeting mitochondrial dynamics in TAA. On this foundation, we updated the one-channel chip to an eighteen-well chip platform with four polydimethylsiloxane layers. Benefiting from this high-throughput chip, we rapidly screened multiple drugs simultaneously using distinct cell lines in vitro. In addition, we observed the abnormal activation of hypoxia-inducible factor 1-alpha (HIF-1alpha) in aortas from TAA patients by Western blot and bioinformatics analyses. Intriguingly, this phenomenon was replicated only when smooth muscle cells (SMCs) were strained on the chip. We then screened seven specific HIF-1alpha inhibitors and selected the two most effective drugs (2-methoxyestradiol and digoxin) by quantitative PCR and colorimetric methods. The results demonstrated that these two drugs can improve respiratory chain function and rescue the SMC contractile phenotype, showing applicability for the clinical treatment of TAA. This high-throughput aorta smooth muscle-on-a-chip will become a potential preclinical model for TAA drug screening.

Prevalence of thoracic aortic aneurysm in patients referred for no/low-charge coronary artery calcium scoring: Insights from the CLARIFY registry

ObjectiveLow-dose cardiac-gated chest CTs allow for simultaneous evaluation of coronary artery calcification and aortic size. We sought to evaluate the prevalence of thoracic aortic dilation (TAD) and thoracic aortic aneurysm (TAA) in a large cohort of patients undergoing coronary artery calcium (CAC) screening. MethodsWe reviewed all patients from a large, prospective no-charge CAC screening program (CLARIFY, Clinicaltrials.gov NCT04075162) for whom measurements of the ascending aorta were available. TAD was defined as an ascending aortic diameter ≥4.0cm, while TAA was defined as ascending aortic diameter ≥ 4.5cm. We explored associations between patient characteristics, CAC, and the prevalence of TAD/TAA. ResultsA total of 36,356 patients enrolled in the CLARIFY program underwent analysis for TAD/TAA. 3,130 patients (8.6%) had TAD and 237 (0.7%) had TAA. Patients with TAA were older (63±8 vs 59±10 years, p < 0.001), more likely to be male (87% vs 49%, p < 0.001), have higher BMI (32 vs 30 kg/m2, p < 0.001), and 10-year atherosclerotic cardiovascular disease estimated risk (18% vs 12%, p < 0.001). Similar differences were observed for individuals with TAD compared to individuals without TAD with respect to age (63 vs 59 years, p < 0.001), percent male (76% vs 46%, p < 0.001), BMI (32 vs 30 kg/m2, p < 0.001), and 10-year predicted risk (17% vs 11%, p < 0.001). CAC score was associated with prevalence of TAD (4.9% in those with CAC 0 to 16.5% in those with CAC≥400) and TAA (0.3% in those with CAC of 0 to 1.5% in those with CAC ≥400). ConclusionIn this large, prospective study of patients undergoing no-charge CAC screening, 8.6% had TAD (≥4.0cm) and 0.7% had TAA (≥4.5cm). Our results highlight a high yield of TAD/TAA diagnosis in this targeted cohort with cardiovascular risk factors and supports the role of no-charge CAC as a population-level strategy.

Diagnostic and predictive values of circulating tetrahydrobiopterin levels as a novel biomarker in patients with thoracic and abdominal aortic aneurysms

We have previously shown that circulating levels of tetrahydrobiopterin (H4B) function as a robust biomarker for aortic aneurysms in several independent animal models. In the present study, we examined diagnostic and predictive values of circulating H4B levels in human patients of thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA) for the first time, while clinically applicable biomarkers for aortic aneurysms have never been previously available. Ninety-five patients scheduled for TAA repair surgeries and 53 control subjects were recruited at University of California Los Angeles (UCLA) Ronald Regan Medical Center, while 44 control subjects and 29 AAA patients were recruited through National Institute of Health (NIH) National Disease Research Interchange (NDRI) program. We had intriguing observations that circulating H4B levels were substantially lower in TAA and AAA patients, linearly correlated with aortic H4B levels (blood: R = 0.8071, p < 0.0001, n = 75; plasma: R = 0.7983, p < 0.0001, n = 75), and associated with incidence of TAA (blood: adjusted OR 0.495; 95% CI 0.379–0.647; p < 0.001; plasma: adjusted OR 0.501; 95% CI 0.385–0.652; p < 0.001) or AAA (blood: adjusted OR 0.329; 95% CI 0.125–0.868; p = 0.025) after adjustment for other factors. Blood or plasma H4B levels below 0.2 pmol/μg serve as an important threshold for prediction of aortic aneurysms independent of age and gender (for TAA risk - blood: adjusted OR 419.67; 95% CI 59.191–2975.540; p < 0.001; plasma: adjusted OR 206.11; 95% CI 40.956–1037.279; p < 0.001). This threshold was also significantly associated with incidence of AAA (p < 0.001 by Chi-square analysis). In addition, we observed previously unrecognized inverse association of Statin use with TAA, and an association of AAA with arrhythmia. Taken together, our data strongly demonstrate for the first time that circulating H4B levels can serve as a first-in-class, sensitive, robust and independent biomarker for clinical diagnosis and prediction of TAA and AAA in human patients, which can be rapidly translated to bedside to fundamentally improve clinical management of the devastating human disease of aortic aneurysms.