Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Initial Outcomes of the Gore TAG Thoracic Branch Endoprosthesis for Endovascular Repair of Blunt Thoracic Aortic Injury.

BACKGROUND: Endovascular repair of blunt thoracic aortic injury (BTAI) has dramatically reduced the morbidity and mortality of intervention. Injuries requiring zone 2 coverage of the aorta traditionally require left subclavian artery (LSA) sacrifice or open revascularization. Furthermore, these injuries are associated with an increased risk of in-hospital mortality and long-term morbidity. Here we report 1-year outcomes of total endovascular repair of BTAI with the GORE® TAG® Thoracic Branch Endoprosthesis for LSA preservation. METHODS: Across 34 investigative sites, 9 patients with BTAI requiring LSA coverage were enrolled in a nonrandomized, prospective study of a single-branched aortic endograft. The thoracic branch endoprosthesis device allows for graft placement proximal to the LSA and incorporates a single side branch for LSA perfusion. RESULTS: This initial cohort included 8 male and 1 female patient with a median age of 43 (22, 76) and 12 months of follow-up. Five total years of follow-up are planned. All participants had grade 3 BTAI. All procedures took place between 2018 and 2019. The median injury severity score was 2 (0, 66). The median procedure time was 109 min (78, 162). All aortic injuries were repaired under general anesthesia and with heparinization. A spinal drain was used in one patient. Post-deployment balloon angioplasty was conducted in one case at the distal landing zone. There was one asymptomatic LSA branch occlusion 6 months after repair. It was attributed to the purposeful proximal deployment of the branch stent to accommodate an early vertebral takeoff. The occlusion did not require revascularization. There were no strokes, mortalities, or aortic adverse events (migration, endoleak, native aortic expansion, dissection, or thrombosis) through 12 months of follow-up. CONCLUSIONS: Initial cohort outcomes suggest that endovascular repair of zone 2 BTAI is feasible and has favorable outcomes using the thoracic branch device with LSA preservation. Additional cases and longer-term follow-up are required for a definitive assessment of the device's safety and durability in traumatic aortic injuries.

Using Machine Learning to Predict Outcomes of Patients with Blunt Traumatic Aortic Injuries.

INTRODUCTION: The optimal management of blunt thoracic aortic injury (BTAI) remains controversial, with experienced centers offering therapy ranging from medical management to TEVAR. We investigated the utility of a machine learning (ML) algorithm to develop a prognostic model of risk factors on mortality in patients with BTAI. METHODS: The Aortic Trauma Foundation registry was utilized to examine demographics, injury characteristics, management and outcomes of patients with BTAI. A STREAMLINE (A Simple, Transparent, End-To-End Automated Machine Learning Pipeline Facilitating Data Analysis and Algorithm Comparison) model as well as logistic regression (LR) analysis with imputation using chained equations was developed and compared. RESULTS: From a total of 1018 patients in the registry, 702 patients were included in the final analysis. Of the 258 (37%) patients who were medically managed, 44 (17%) died during admission, 14 (5.4%) of which were aortic related deaths. 444 (63%) patients underwent TEVAR and 343 of which underwent TEVAR within 24 hours of admission. Amongst TEVAR patients, 39 (8.8%) patients died and 7 (1.6%) had aortic related deaths. (Table 1) Comparison of the STREAMLINE and LR model showed no significant difference in ROC curves and high AUCs of 0.869 (95% CI, 0.813 - 0.925) and 0.840 (95% CI, 0.779 - 0.900) respectively in predicting in-hospital mortality. Unexpectedly, however, the variables prioritized in each model differed between models (Figure 1A-B). The top three variables identified from the LR model were similar to that from existing literature. The STREAMLINE model, however, prioritized location of the injury along the lesser curve, age and aortic injury grade (Figure 1A). CONCLUSIONS: Machine learning provides insight on prioritization of variables not typically identified in standard multivariable logistic regression. Further investigation and validation in other aortic injury cohorts are needed to delineate the utility of ML models. LEVEL OF EVIDENCE: Level IIIStudy TypeOriginal research (prognostic/epidemiological).

Treatment of calcific arterial disease via enhancement of autophagy using GSK343.

Vascular calcification is a hallmark of atherosclerotic disease and serves as a strong predictor and risk factor for cardiovascular events. Growing evidence suggests that autophagy may play a protective role in early atherosclerosis. The precise effects of autophagy on VSMC-mediated calcification remain unknown. In this study, we utilized multi-omic profiling to investigate impaired autophagy at the transcriptional level as a key driver of VSMC calcification. Our findings revealed that impaired autophagy is an essential determinant of VSMC calcification. We observed that an osteogenic environment affects the open chromatin status of VSMCs, compromising the transcriptional activation of autophagy initiation genes. In vivo experiments involve pharmacological and genetic activation of autophagy using mouse models of spontaneous large (Mgp-/-) and small (Abcc6-/-) artery calcification. Taken together, these data advance our mechanistic understanding of vascular calcification and provide important insights for a broad range of cardiovascular diseases involving VSMC phenotype switch.

The Genetic Determinants of Aortic Distention.

BACKGROUND: As the largest conduit vessel, the aorta is responsible for the conversion of phasic systolic inflow from ventricular ejection into more continuous peripheral blood delivery. Systolic distention and diastolic recoil conserve energy and are enabled by the specialized composition of the aortic extracellular matrix. Aortic distensibility decreases with age and vascular disease. OBJECTIVES: In this study, we sought to discover epidemiologic correlates and genetic determinants of aortic distensibility and strain. METHODS: We trained a deep learning model to quantify thoracic aortic area throughout the cardiac cycle from cardiac magnetic resonance images and calculated aortic distensibility and strain in 42,342 UK Biobank participants. RESULTS: Descending aortic distensibility was inversely associated with future incidence of cardiovascular diseases, such as stroke (HR: 0.59 per SD; P = 0.00031). The heritabilities of aortic distensibility and strain were 22% to 25% and 30% to 33%, respectively. Common variant analyses identified 12 and 26 loci for ascending and 11 and 21 loci for descending aortic distensibility and strain, respectively. Of the newly identified loci, 22 were not significantly associated with thoracic aortic diameter. Nearby genes were involved in elastogenesis and atherosclerosis. Aortic strain and distensibility polygenic scores had modest effect sizes for predicting cardiovascular outcomes (delaying or accelerating disease onset by 2%-18% per SD change in scores) and remained statistically significant predictors after accounting for aortic diameter polygenic scores. CONCLUSIONS: Genetic determinants of aortic function influence risk for stroke and coronary artery disease and may lead to novel targets for medical intervention.

A Mendelian randomization-based exploration of red blood cell distribution width and mean corpuscular volume with risk of hemorrhagic strokes.

Red blood cell distribution width (RCDW) and mean corpuscular volume (MCV) are associated with different risk factors for hemorrhagic stroke. However, whether RCDW and MCV are causally related to hemorrhagic stroke remains poorly understood. Therefore, we explored the causality between RCDW/MCV and nontraumatic hemorrhagic strokes using Mendelian randomization (MR) methods. We extracted exposure and outcome summary statistics from the UK Biobank and FinnGen. We evaluated the causality of RCDW/MCV on four outcomes (subarachnoid hemorrhage [SAH], intracerebral hemorrhage [ICH], nontraumatic intracranial hemorrhage [nITH], and a combination of SAH, cerebral aneurysm, and aneurysm operations) using univariable MR (UMR) and multivariable MR (MVMR). We further performed colocalization and mediation analyses. UMR and MVMR revealed that higher genetically predicted MCV is protective of ICH (UMR: odds ratio [OR] = 0.89 [0.8-0.99], p = 0.036; MVMR: OR = 0.87 [0.78-0.98], p = 0.021) and nITH (UMR: OR = 0.89 [0.82-0.97], p = 0.005; MVMR: OR = 0.88 [0.8-0.96], p = 0.004). There were no strong causal associations between RCDW/MCV and any other outcome. Colocalization analysis revealed a shared causal variant between MCV and ICH; it was not reported to be associated with ICH. Proportion mediated via diastolic blood pressure was 3.1% (0.1%,14.3%) in ICH and 3.4% (0.2%,15.8%) in nITH. The study constitutes the first MR analysis on whether genetically elevated RCDW and MCV affect the risk of hemorrhagic strokes. UMR, MVMR, and mediation analysis revealed that MCV is a protective factor for ICH and nITH, which may inform new insights into the treatments for hemorrhagic strokes.

Aortic Cellular Diversity and Quantitative Genome-Wide Association Study Trait Prioritization Through Single-Nuclear RNA Sequencing of the Aneurysmal Human Aorta.

BACKGROUND: Mural cells in ascending aortic aneurysms undergo phenotypic changes that promote extracellular matrix destruction and structural weakening. To explore this biology, we analyzed the transcriptional features of thoracic aortic tissue. METHODS: Single-nuclear RNA sequencing was performed on 13 samples from human donors, 6 with thoracic aortic aneurysm, and 7 without aneurysm. Individual transcriptomes were then clustered based on transcriptional profiles. Clusters were used for between-disease differential gene expression analyses, subcluster analysis, and analyzed for intersection with genetic aortic trait data. RESULTS: We sequenced 71 689 nuclei from human thoracic aortas and identified 14 clusters, aligning with 11 cell types, predominantly vascular smooth muscle cells (VSMCs) consistent with aortic histology. With unbiased methodology, we found 7 vascular smooth muscle cell and 6 fibroblast subclusters. Differentially expressed genes analysis revealed a vascular smooth muscle cell group accounting for the majority of differential gene expression. Fibroblast populations in aneurysm exhibit distinct behavior with almost complete disappearance of quiescent fibroblasts. Differentially expressed genes were used to prioritize genes at aortic diameter and distensibility genome-wide association study loci highlighting the genes JUN, LTBP4 (latent transforming growth factor beta-binding protein 1), and IL34 (interleukin 34) in fibroblasts, ENTPD1, PDLIM5 (PDZ and LIM domain 5), ACTN4 (alpha-actinin-4), and GLRX in vascular smooth muscle cells, as well as LRP1 in macrophage populations. CONCLUSIONS: Using nuclear RNA sequencing, we describe the cellular diversity of healthy and aneurysmal human ascending aorta. Sporadic aortic aneurysm is characterized by differential gene expression within known cellular classes rather than by the appearance of novel cellular forms. Single-nuclear RNA sequencing of aortic tissue can be used to prioritize genes at aortic trait loci.

Machine learning algorithms identify demographics, dietary features, and blood biomarkers associated with stroke records.

OBJECTIVE: We conducted a comprehensive evaluation of features associated with stroke records. METHODS: We screened the dietary nutrients, blood biomarkers, and clinical information from the National Health and Nutrition Examination Survey (NHANES) 2015-16 database to assess a self-reported history of all strokes (136 strokes, n = 4381). We computed feature importance, built machine learning (ML) models, developed a nomogram, and validated the nomogram on NHANES 2007-08, 2017-18, and the baseline UK Biobank. We calculated the odds ratios with/without adjusting sampling weights (OR/ORw). RESULTS: The clinical features have the best predictive power compared to dietary nutrients and blood biomarkers, with 22.8% increased average area under the receiver operating characteristic curves (AUROC) in ML models. We further modeled with ten most important clinical features without compromising the predictive performance. The key features positively associated with stroke include age, cigarette smoking, tobacco smoking, Caucasian or African American race, hypertension, diabetes mellitus, asthma history; the negatively associated feature is the family income. The nomogram based on these key features achieved good performances (AUROC between 0.753 and 0.822) on the test set, the NHANES 2007-08, 2017-18, and the UK Biobank. Key features from the nomogram model include age (OR = 1.05, ORw = 1.06), Caucasian/African American (OR = 2.68, ORw = 2.67), diabetes mellitus (OR = 2.30, ORw = 1.99), asthma (OR = 2.10, ORw = 2.41), hypertension (OR = 1.86, ORw = 2.10), and income (OR = 0.83, ORw = 0.81). CONCLUSIONS: We identified clinical key features and built predictive models for assessing stroke records with high performance. A nomogram consisting of questionnaire-based variables would help identify stroke survivors and evaluate the potential risk of stroke.

Vascular trainee perceptions of diversity, equity, and inclusion within United States vascular surgery training programs.

OBJECTIVES: Vascular surgery training programs face multiple pressures, including attracting and retaining trainees. Current knowledge of trainees' views with respect to diversity and equity in vascular training programs is limited. We sought to understand United States vascular surgery trainees' perceptions and expectations regarding diversity, equity, and inclusion (DEI). METHODS: The Association of Program Directors in Vascular Surgery designed and administered the Annual Training Survey to specifically address DEI and administered it to all trainees (Integrated Residents/Fellows; n = 637) at 122 institutions in August 2020. RESULTS: Of the 637 vascular trainees, 227 (35%) responded. The respondents included 115 male and 62 female trainees, with 50 not disclosing or not answering the question. The majority of respondents (96.9%) believed their programs incorporated a diverse background of trainees. Of the trainees, 89.8% felt that the faculty were similarly comprised of a diverse background. The majority of respondents (63.6%) felt that their training program was both more diverse and focused on inclusion compared with other training programs at their institution. However, 20% of respondents had experienced discrimination. Seventy-three percent (n = 143) of trainees felt empowered to disagree or engage in a discussion should they observe a faculty member make a disparaging remark about a patient's background/race/gender, although 27% (n = 35) trainees expressed fear of retaliation as a reason to not engage. Trainees view their program director (82.6%), faculty mentor (60.9%), and Graduate Medical Education office (52.7%) as potential resources for support. Overall, 83.7% (n = 160) of trainees believe that their program has been open to discussion of race relations within the medical community. CONCLUSIONS: Trainees are committed to multifaceted diversity and inclusion. The perception of trainees regarding DEI issues within vascular surgery training programs appears to be positive; however, trainees did describe discrimination and gender biases in their institutions. This data has the potential to improve institutional education of faculty and trainees about the multidimensional levels of diversity and increased awareness and incorporation of this philosophy can assist in the recruitment of diverse vascular surgeons.

Risk factors and consequences of graft infection after femoropopliteal bypass: A 25-year experience.

OBJECTIVE: In this multi-institutional series, we aimed to determine the incidence, risk factors, and long-term outcomes of graft infection in patients post-femoropopliteal bypass. METHODS: A multi-institutional database was retrospectively queried for all femoropopliteal bypass procedures from 1995 through 2020. Cumulative incidence function estimated the long-term rate of bypass graft infection (BGI), and the Fine-Gray model was used to determine independent risk factors for BGI to account for death as a competing risk. RESULTS: Over the 25-year period, 1315 femoral popliteal bypasses were identified with a median follow-up of 2.89 years (interquartile range, 0.75-6.55 years). BGI was diagnosed in 34 patients (2.6%). BGI occurred between 9 days and 11.2 years postoperatively, with a median of 109 days. Estimated 1- and 5-year incidence of BGI was 2.1% (95% confidence interval [CI], 1.4%-3.1%) and 2.8% (95% CI, 1.9%-3.9%), respectively. Medical comorbidities, indications for bypass, and popliteal bypass targets (above- vs below-knee) were similar between patients with BGI and all patients (P = not significant for each). Patients with BGI were more frequently complicated by postoperative hematoma (14.7% vs 3.7%), superficial wound infection (38.2% vs 19.2%), lymphocele/lymphorrhea (8.8% vs 2.1%), and 30-day readmission rates (47.1% vs 21.3%) (P < .05 for each). Most commonly isolated pathogens were Staphylococcus aureus (n = 19; 55.9%) and polymicrobial cultures (n = 5; 14.7%). Reoperation for BGI involved incision and drainage (n = 7; 20.6%), graft excision without reconstruction (n = 12; 35.3%), graft excision with in-line reconstruction (n = 11; 32.4%), and graft excision with extra-anatomic reconstruction (n = 2; 5.9%). Nine patients with BGI (26.5%) ultimately required major amputation. Prosthetic bypass (subdistribution hazard ratio [SHR], 3.73; 95% CI, 1.64-8.51; P = .002), postoperative hematoma (SHR, 3.44; 95% CI, 1.23-9.61; P = .018), and 30-day readmission (SHR, 2.75; 95% CI, 1.27-5.44; P = .010) were independently associated with BGI. One-year amputation-free survival was 50% (95% CI, 31.9%-65.7%) after BGI. CONCLUSIONS: BGI is a rare complication of femoral-popliteal bypass with significant morbidity. Graft infection is associated with the use of prosthetic grafts, postoperative hematoma, and unplanned hospital readmission. Mitigation of these risk factors may decrease the risk of this dreaded complication.

Fibrillar Collagen Variants in Spontaneous Coronary Artery Dissection.

IMPORTANCE: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized nonatherosclerotic cause of acute myocardial infarction enriched among individuals with early-onset myocardial infarction but is of unclear etiology. OBJECTIVE: To assess which genes contribute to the development of SCAD. DESIGN, SETTING, AND PARTICIPANTS: To prioritize genes influencing risk for SCAD, whole-exome sequencing was performed among individuals with SCAD in the discovery and replication cohorts from a tertiary care hospital outpatient specialty clinic, and gene set enrichment analyses were also performed for disruptive coding variants. All patients were sequentially enrolled beginning July 2013. Aggregate prevalence of rare disruptive variants for prioritized gene sets was compared between individuals with SCAD with population-based controls comprising 46 468 UK Biobank participants with whole-exome sequencing. Complementary mice models were used for in vivo validation. Analysis took place between June 2020 and January 2021. MAIN OUTCOMES AND MEASURES: The frequency and identity of rare genetic variants in individuals with SCAD. RESULTS: Of 130 patients, 109 (83.8%) were female (26 of 32 [81.2%] in the discovery cohort and 83 of 98 [84.7%] in the replication cohort) with mean (SD) age at first SCAD event of 48.41 (8.76) years in the discovery cohort and 47.74 (10.09) years in the replication cohort. Across all patients with SCAD, rare disruptive variants were found within 10 collagen genes (COL3A1, COL5A1, COL4A1, COL6A1, COL5A2, COL12A1, COL4A5, COL1A1, COL1A2, and COL27A1) were 17-fold (P = 1.5 × 10-9) enriched among individuals with SCAD compared with a background of 2506 constrained genes expressed in coronary artery. Furthermore, compared with individuals from the UK Biobank, individuals with SCAD were 1.75-fold (P = .04) more likely to carry disruptive rare variants within fibrillar collagen genes. Complementary mice models haploinsufficient for Col3a1 or Col5a1, the 2 most common collagen gene variants identified in SCAD cases, demonstrated increased risk of arterial dissection and increased size of arterial diameters especially in female mice, with resulting changes in collagen fibril organization and diameter. CONCLUSIONS AND RELEVANCE: Unbiased gene discovery in patients with SCAD with independent human and murine validation highlights the role of the extracellular matrix dysfunction in SCAD.

Vascular smooth muscle cell phenotype switching in carotid atherosclerosis.

Carotid plaque instability contributes to large vessel ischemic stroke. Although vascular smooth muscle cells (VSMCs) affect atherosclerotic growth and instability, no treatments aimed at improving VSMC function are available. Large genetic studies investigating atherosclerosis and carotid disease in relation to the risk of stroke have implicated polymorphisms at the HDAC9 locus. The HDAC9 protein has been shown to affect the VSMC phenotype; however, how this might affect carotid disease is unknown. We conducted a pilot investigation using single nuclei RNA sequencing of human carotid tissue to identify cells expressing HDAC9 and specifically investigate the role of the HDAC9 in carotid atherosclerosis. We found that carotid VSMCs express HDAC9 and genes typically associated with immune characteristics. Using cellular assays, we have demonstrated that recruitment of macrophages can be modulated by HDAC9 expression. HDAC9 expression might affect carotid plaque stability and progression through its effects on the VSMC phenotype and recruitment of immune cells.

Surgical resection and graft replacement for primary inferior vena cava leiomyosarcoma: A multicenter experience.

OBJECTIVE: Primary leiomyosarcoma of the inferior vena cava (IVC) is best managed with surgical resection when technically feasible. However, consensus is lacking regarding the best choice of conduit and reconstruction technique. The aim of the present multicenter study was to perform a comprehensive assessment through the VLFDC (Vascular Low Frequency Disease Consortium) to determine the most effective method for caval reconstruction after resection of primary leiomyosarcoma of the IVC. METHODS: A multicenter, standardized database review of patients who had undergone surgical resection and reconstruction of the IVC for primary leiomyosarcoma from 2007 to 2017 was performed. The demographics, periprocedural details, and postoperative outcomes were analyzed. RESULTS: A total of 92 patients (60 women and 32 men), with a mean age of 60.1 years (range, 30-88 years) were treated. Metastatic disease was present in 22%. The tumor location was below the renal veins in 49 (53%), between the renal and hepatic veins in 52 (57%), and above the hepatic veins in 13 patients (14%). The conduits used for reconstruction included ringed polytetrafluoroethylene (PTFE; n = 80), nonringed PTFE (n = 1), Dacron (n = 1), autogenous vein (n = 1), bovine pericardium (n = 4), and cryopreserved tissue (n = 5). Complete R0 resection was accomplished in 73 patients (79%). In-hospital mortality was 2%, with a median length of stay of 8 days. The primary patency of PTFE reconstructed IVCs was 97% and 92% at 1 and 5 years, respectively, compared with 73% at 1 and 5 years for the non-PTFE reconstructed IVCs. The overall 1-, 3-, and 5-year survival for the entire cohort were 94%, 86%, and 65%, respectively CONCLUSIONS: The findings from our multi-institutional study have demonstrated that complete en bloc resection of IVC leiomyosarcoma with vascular surgical reconstruction in selected patients results in low perioperative mortality and is associated with excellent long-term patency. A ringed PTFE graft was the most commonly used conduit for caval reconstruction, yielding excellent long-term primary patency.

Association of Premature Menopause With Risk of Abdominal Aortic Aneurysm in the Women's Health Initiative.

OBJECTIVE: To determine if premature menopause and early menarche are associated with increased risk of AAA, and to explore potential effect modification by smoking history. SUMMARY OF BACKGROUND DATA: Despite worse outcomes for women with AAA, no studies have prospectively examined sex-specific risk factors, such as premature menopause and early menarche, with risk of AAA in a large, ethnically diverse cohort of women. METHODS: This was a post-hoc analysis of Women's Health Initiative participants who were beneficiaries of Medicare Parts A&B fee-for-service. AAA cases and interventions were identified from claims data. Follow-up period included Medicare coverage until death, end of follow-up or end of coverage inclusive of 2017. RESULTS: Of 101,119 participants included in the analysis, the mean age was 63 years and median follow-up was 11.3 years. Just under 10,000 (9.4%) women experienced premature menopause and 22,240 (22%) experienced early men-arche. Women with premature menopause were more likely to be overweight, Black, have >20 pack years of smoking, history of cardiovascular disease, hypertension, and early menarche. During 1,091,840 person-years of follow-up, 1125 women were diagnosed with AAA, 134 had premature menopause (11.9%), 93 underwent surgical intervention and 45 (48%) required intervention for ruptured AAA. Premature menopause was associated with increased risk of AAA [hazard ratio 1.37 (1.14, 1.66)], but the association was no longer significant after multivariable adjustment for demographics and cardiovascular disease risk factors. Amongst women with ≥20 pack year smoking history (n = 19,286), 2148 (11.1%) had premature menopause, which was associated with greater risk of AAA in all models [hazard ratio 1.63 (1.24, 2.23)]. Early menarche was not associated with increased risk of AAA. CONCLUSIONS: This study finds that premature menopause may be an important risk factor for AAA in women with significant smoking history. There was no significant association between premature menopause and risk of AAA amongst women who have never smoked. These results suggest an opportunity to develop strategies for better screening, risk reduction and stratification, and outcome improvement in the comprehensive vascular care of women.

Deep learning enables genetic analysis of the human thoracic aorta.

Enlargement or aneurysm of the aorta predisposes to dissection, an important cause of sudden death. We trained a deep learning model to evaluate the dimensions of the ascending and descending thoracic aorta in 4.6 million cardiac magnetic resonance images from the UK Biobank. We then conducted genome-wide association studies in 39,688 individuals, identifying 82 loci associated with ascending and 47 with descending thoracic aortic diameter, of which 14 loci overlapped. Transcriptome-wide analyses, rare-variant burden tests and human aortic single nucleus RNA sequencing prioritized genes including SVIL, which was strongly associated with descending aortic diameter. A polygenic score for ascending aortic diameter was associated with thoracic aortic aneurysm in 385,621 UK Biobank participants (hazard ratio = 1.43 per s.d., confidence interval 1.32-1.54, P = 3.3 × 10-20). Our results illustrate the potential for rapidly defining quantitative traits with deep learning, an approach that can be broadly applied to biomedical images.

The current status of the diversity pipeline in surgical training.

OBJECTIVE: Recent initiatives have emphasized the importance of diversity, equity, and inclusion in academic surgery. Racial/ethnic disparities remain prevalent throughout surgical training, and the "diversity pipeline" in resident recruitment and retention remains poorly defined. METHODS: Data was retrospectively collected using two separate datasets. The Association of American Medical Colleges database was used to obtain demographic data on US medical school graduates. The US Graduate Medical Education annual report was used to obtain demographic data on surgical residents. Wilcoxon signed-rank test was used to compare racial/ethnic distribution within surgical residency programs with graduating medical students. Linear regression analysis was performed to analyze population trends over time. RESULTS: The study population included 184,690 surgical residents from 2011 to 2020. Nine resident cohorts were created according to surgical specialty - general surgery, neurosurgery, ophthalmology, orthopedic surgery, otolaryngology, plastic surgery, cardiothoracic surgery, urology, and vascular surgery. Among surgical programs, White residents were overrepresented in 8 of 9 specialties compared to the concurrent graduating medical student class for all years (p < 0.01 each, no difference in ophthalmology). Black residents were underrepresented in 8 of 9 specialties (p < 0.01 each, no difference in general surgery). Asian representation was mixed among specialties (4 overrepresented, 1 equal, 4 underrepresented), as was Hispanic representation (5 overrepresented, 4 equal) (p < 0.01 each). CONCLUSIONS: These data suggest that racial/ethnic disparities are inherent to the process of recruitment and retention of surgical residents. Efforts to improve the "diversity pipeline" should focus on mentorship and development of minority medical students and creating an equitable learning environment.

Evolution in the Presentation, Treatment, and Outcomes of Patients with Acute Mesenteric Ischemia.

OBJECTIVES: Acute mesenteric ischemia (AMI) is a life-threatening condition associated with dismal outcomes. This study sought to evaluate the evolution of presentation, treatment, and outcomes of AMI over the past two decades. METHODS: AMI patients presenting at a single institution were reviewed (1993-2016). Venous thrombosis patients were excluded. Primary outcome was 30-day mortality. Patients were stratified by etiology and diagnosis date (before 2004 versus 2004 and later). Ordered logistic regression was performed for longitudinal temporal analysis. RESULTS: 303 patients were identified. AMI mechanisms included: embolic (49%), thrombotic (29%), and non-occlusive (NOMI) (22%). The majority were women (55%), 50% had atrial fibrillation, and 23% were on anticoagulation (AC) therapy. Mean age was 72±13 years. 345 procedures were performed in 242 patients: 321 open and 24 hybrid/endovascular. Among the 189 embolic/thrombotic patients who were managed operatively, 45% (n=85) underwent mesenteric revascularization while 39 (21%) had findings of non-survivable bowel necrosis (NSBN). Among the 104 patients who did not undergo revascularization, 64 (62%) died within 30-days compared to 36 out of 85 (42%) patients who were revascularized (P=0.01). 30-day mortality was 61% and stable over time (P=0.91); when stratified by AMI etiology, the thrombotic cohort had worse survival than embolic and NOMI patients (P=0.04). Since 2000, there was a significant decrease in the percentage of embolic AMI events (P=0.04). The percentage of patients who underwent operative management decreased also over time (P=0.01, 81% → 61%), which was correlated with an increasing number of patients being made comfort measures only (CMO) prior to surgical intervention (50% → 70%, P=0.02). The majority of patients (55%) were ultimately made CMO during their hospitalization. Predictors of 30-day mortality included a preoperative white blood cell count (WBC) ≥ 25 K/ µL. (OR 3.0, P=0.002) and lactate ≥ 2.3 mmol/L (OR 2.8, P=0.045). NSBN predictors included WBC ≥ 24 K/ µL. (OR 3.4 P=0.03) and lactate ≥ 3.8 mmol/L (OR 3.6, P=0.04). CONCLUSIONS: Despite advances in critical care over the past 25 years, AMI continues to be associated with poor prognosis. The survival benefit observed in patients who undergo revascularization supports an aggressive approach towards early vascular intervention, although this requires further study. The importance of early diagnosis, prognostication and advanced directives is highlighted given the high morbidity, mortality and use of comfort measures associated with AMI.

Venous mesenteric ischemia carries high procedural burden and elevated mortality in patients with severe presentation.

OBJECTIVE: Venous mesenteric ischemia (VMI) presents with variable severity resulting in a spectrum of outcomes. This study sought to characterize the natural history of VMI and identify drivers of intervention and adverse outcomes. METHODS: All patients who presented to our institution with acute and subacute VMI between 1993 and 2016 were identified. Images were reviewed to determine thrombosis location and charts were reviewed to identify clinical factors and outcomes. Univariate analysis was performed for demographics, comorbidities, and presenting characteristics, with primary outcomes of intervention, readmission, and 30-day mortality. A survival analysis was performed with log-rank difference testing for demographics, comorbidities, and presenting characteristics. RESULTS: We identified 103 patients with acute and subacute VMI. The locations of the thrombosis included the superior mesenteric vein (SMV) (31.1%); SMV and portal vein (35.9%); SMV, portal, and splenic veins (15.5%); and other combinations of portomesenteric veins (17.4%), without correlation between the location and outcomes. Most patients were male (60.6%), 22.3% were actively smoking, and the median Charlson comorbidity score was 4 (interquartile range, 2-7). The mean patient age was 61.3 years. More than one-half had a known hypercoagulability (52.4%), 22.3% had prior bowel resection, and 8.7% had prior mesenteric venous intervention, including transjugular intrahepatic portosystemic shunt procedures. Thirty-five patients underwent 83 procedures during their hospitalization, and 23 patients underwent surgical intervention specifically. Prior mesenteric venous procedure, abdominal tenderness, and lactatemia of more than 1.5 mmol/L were associated with an increased need for surgical intervention (P < .05). Patients with leukocytosis of greater than 10K/µL had increased surgical intervention (P = .10), although without statistical significance. However, symptoms for less than 2 weeks (P < .05) were associated with decreased surgical intervention. The 30-day mortality was low in this cohort (6.8%), but was increased in patients requiring intervention (11.4%). For those undergoing procedures, a shorter time to intervention was associated with an improved 30-day mortality (8.7% for procedures on hospital days 0-1 vs 16.7% for hospital day 2 or later; P = .01). Abdominal tenderness and lactatemia were associated with increased 30-day mortality (6.8% vs 3.6% [P < .01] and 16.0% vs 3.8% [P = .03], respectively). A Kaplan-Meier survival analysis revealed a median survival of 7.1 years, with a 1-year survival rate of 74.9%, a 3-year survival rate of 67.1%, and a 5-year survival rate of 57.9%. Negative predictors of survival included a higher Charlson comorbidity index (hazard ratio, 3.7; P < .01) and malignancy (hazard ratio, 3.1; P < .01). CONCLUSIONS: The 30-day mortality of VMT is low, but more than one-third of patients required an intervention beyond anticoagulation. Comorbidity, a prior mesenteric vessel or intestinal operation, and presentation with tenderness or relevant laboratory abnormalities portend worse outcomes. Early intervention is associated with improved outcomes.

Comparative Analysis of Outcomes in Patients Undergoing Femoral Endarterectomy plus Endovascular (Hybrid) or Bypass for Femoropopliteal Occlusive Disease.

INTRODUCTION: The gold-standard for management of combined common femoral artery (CFA) and superficial femoral artery (SFA) atherosclerotic occlusive disease has traditionally been open femoral endarterectomy and femoral-popliteal bypass. Hybrid approaches involving an open and endovascular component are increasingly common. The aim of this study was to compare perioperative outcomes in patients who underwent an open versus hybrid revascularization. METHODS: NSQIP data, years 2012-2017, were queried for patients who underwent nonemergent CFA endarterectomy with either SFA transluminal intervention or bypass. The primary outcome of interest was a composite of cardiovascular, pulmonary, and renal complications (systemic) and mortality. Two propensity-weight adjusted analyses were performed: 1) comparing hybrid and prosthetic bypass 2) comparing hybrid and vein bypass. RESULTS: There were 4,478 patients included (1,537 hybrid, 1,408 prosthetic, 1,533 vein); 64.8% were men, and the mean age was 67.8 ± 9.7 years; 29.9% had claudication, 38.8% had tissue loss, and 31.3 were unspecified. In the propensity-weighted analysis comparing hybrid to prosthetic bypass, there was no difference in systemic complications (OR = 1.29 for prosthetic vs. hybrid; 95% CI: 0.95-1.76; P = 0.107) or mortality (OR = 1.54; 95% CI: 0.71-3.33; P = 0.275). Prosthetic bypass was associated with more deep surgical-site infections (OR = 2.02; 95% CI: 1.19-3.45; P = 0.010), postoperative sepsis (OR = 2.07; 95% CI: 1.13-3.76; P = 0.018), unplanned 30-day readmission (OR = 1.28; 95% CI: 1.04-1.58; P = 0.021), and the composite of any complication (OR = 1.38; 95% CI: 1.18-1.61; P < 0.001). In the propensity-weighted analysis comparing hybrid to vein bypass, there was no difference in systemic complications (OR = 1.10 for vein vs. hybrid; 95% CI: 0.81-1.49; P = 0.552) or mortality (OR = 0.91; 95% CI: 0.42-2.00; P = 0.819). Vein bypass was associated with more superficial surgical-site infections (OR = 1.45; 95% CI: 1.04-2.02; P = 0.028), and the composite of any complication (OR = 1.32; 95% CI: 1.13-1.54; P = 0.001). Overall mortality was significantly higher patients with systemic complications (13.9% vs 0.1%; P < 0.001). Systemic complications were less common in patients with claudication undergoing hybrid revascularization than vein or prosthetic bypass. CONCLUSIONS: Claudicants undergoing bypass experienced more systemic complications than those undergoing hybrid procedures, but there appears to be no increased risk of systemic complications or mortality with open reconstruction when compared to hybrid procedures for other indications. Other complications, such as infection, postoperative transfusion, and readmission, were more common in the bypass groups.

Lipoprotein(a) levels and risk of abdominal aortic aneurysm in the Women's Health Initiative.

OBJECTIVE: Few studies have prospectively examined the associations of lipoprotein(a) [Lp(a)] levels with the risk of abdominal aortic aneurysm (AAA), especially in women. Accounting for commonly recognized risk factors, we investigated the baseline Lp(a) levels and the risk of AAA among postmenopausal women participating in the ongoing national Women's Health Initiative. METHODS: Women's Health Initiative participants with baseline Lp(a) levels available who were beneficiaries of Medicare parts A and B fee-for-service at study enrollment or who had aged into Medicare at any point were included. Participants with missing covariate data or known AAA at baseline were excluded. Thoracic aneurysms were excluded owing to the different pathophysiology. The AAA cases and interventions were identified using the International Classification of Diseases, 9th and 10th revision, codes and Current Procedural Terminology codes from claims data. Hazard ratios were computed using Cox proportional hazard models according to the quintiles of Lp(a). RESULTS: The mean age of the 6615 participants included in the analysis was 65.3 years. Of the 6615 participants, 66.6% were non-Hispanic white, 18.9% were black, 7% were Hispanic and 4.7% were Asian/Pacific Islander. Compared with the participants in the lowest Lp(a) quintile, those in higher quintiles were more likely to be overweight, black, and former or current smokers, to have hypertension, hyperlipidemia, and a history of cardiovascular disease, and to use menopausal hormone therapy and statins. During 65,476 person-years of follow-up, with a median of 10.4 years, 415 women had been diagnosed with an AAA and 36 had required intervention. More than one half had required intervention for a ruptured AAA. We failed to find a statistically significant association between Lp(a) levels and incident AAA. Additional sensitivity analyses stratified by race, with exclusion of statin users and alternative categorizations of Lp(a) using log-transformed levels, tertiles, and a cutoff of >50 mg/dL, were conducted, which did not reveal any significant associations. CONCLUSIONS: We found no statistically significant association between Lp(a) levels and the risk of AAA in a large and well-phenotyped sample of postmenopausal women. Women with high Lp(a) levels were more likely to be overweight, black, and former or current smokers, and to have hypertension, hyperlipidemia, and a history of cardiovascular disease, or to use hormone therapy and statins compared with those with lower Lp(a) levels. These findings differ from previous prospective, case-control, and meta-analysis studies that had supported a significant relationship between higher Lp(a) levels and an increased risk of AAA. Differences in the association could have resulted from study limitations or sex differences.