A Frailty-Based Risk Score Predicts Morbidity and Mortality After Elective Endovascular Repair of Descending Thoracic Aortic Aneurysms.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) has expanded access to descending thoracic aortic aneurysm (DTAA) repair particularly for elderly and frail patients. This high-risk population has limited long-term overall survival, such that appropriate patient selection is required to optimize patient benefit and resource utilization. Our objective is to develop and validate a frailty-based, procedure-specific risk score for patients undergoing elective TEVAR for DTAA. METHODS: Patients undergoing nonemergent TEVAR for DTAA during 2005-2016 were identified in the National Surgical Quality Improvement Program database. Those with concurrent cardiac or open aortic surgery, abdominal visceral intervention, or Zone 0 deployment were excluded. Patients were randomly divided between derivation and validation samples. The primary outcome was 30-day major adverse events (MAE), including mortality and major systemic complications. Using the derivation cohort, variables associated with MAE were identified by univariable analyses. Those with P < 0.05 were included in multivariable logistic regression analysis. Independent procedure-specific and frailty-related risk factors for MAE were used to develop a pragmatic score to assess risk for TEVAR. RESULTS: Overall, 1,784 patients were included. 14% of the derivation patients had MAE (14% major complications, 4% mortality). Independent risk factors for MAE were primarily associated with markers of frailty and TEVAR extent and complexity and included functional dependence (OR 2.9, 95% CI 1.6-5.4), pulmonary disease (1.6, 1.1-2.4), thoracoabdominal extent (2.2 (1.4-3.4), need for iliac access (2.1, 1.1-3.8), and Zone I or II deployment (OR 1.7, 1.1-2.5). According to their respective beta coefficients, each variable was assigned a single point. Based on total points, patients were stratified as low- (0 points), intermediate- (1 point), or high-risk (≥2 points), with stepwise increases in mortality (0%, 4%, and 9%) and major complications (7%, 11%, and 23%) between strata. Validation patients had similar characteristics, risk strata distribution, and outcomes as the derivation patients, and the risk model had similar performance in both groups. CONCLUSIONS: Markers of frailty and procedure complexity strongly predict MAE after TEVAR for DTAA and can improve patient selection by enabling patient and procedure-specific risk stratification. While TEVAR is safe in low-risk patients, intermediate-risk patients warrant careful discussion of the risks and benefits of aortic intervention; under certain circumstances, high-risk patients may not benefit. Further study is required to define the association between frailty and long-term outcomes.

Attrition rates in integrated vascular and cardiothoracic surgery residency and fellowship programs.

BACKGROUND: Attrition in surgical programs remains a significant problem resulting in trainee dissatisfaction and wasted time and educational dollars. Attrition rates in general surgery training programs approximate 5% per year (30% cumulative). Attrition rates in cardiovascular surgery training for the traditional vascular surgery fellowship (VSF), the vascular surgery residency (VSR), and the corresponding programs in cardiothoracic surgery have yet to be described, although they are assumed to be similar to those associated with general surgery training. METHODS: A retrospective review of the Association of American Medical Colleges Annual Physician Specialty Data Book was performed. Data from consecutive academic years 2007-2008 to 2013-2014 were analyzed. The number of total residents, the number who did not complete their training, and those who successfully completed the program were recorded. Attrition rates were then calculated for VSF, VSR, general surgery residency (GSR), cardiothoracic surgery fellowship (CTF), and cardiothoracic surgery integrated residency (CTR). RESULTS: Annually, between 2007-2008 and 2013-2014, there were zero to two vascular surgery residents who failed to complete the program (0%-5.9%). In the last 4 years of the study, whereas the absolute number of residents who failed to complete the program remained constant at 1 or 2 per year, the attrition rate decreased to 1 of 171 trainees (0.6%) in 2013-2014 as the total number of programs (and numbers of vascular surgery residents) significantly increased. During the same 7-year period, the number of vascular surgery fellows who did not complete their training ranged from one to six annually (0.4%-2.5%). Compared with the VSF, the VSR data show a relatively low and constant rate of attrition. In contrast, the number of general surgery residents who did not complete their program during the study period varied from 255 to 388 residents annually (3.3%-5.2%). During its first 3 years of inception, the CTR program had an attrition rate of 0%, and it was not until 2012-2013 that trainees failed to complete the program, resulting in an annual attrition rate of 1.2% to 3.2% from that point on. The annual attrition rate of CTF training programs ranged from 7 to 15 fellows (2.9%-6.8%) during the study period. CONCLUSIONS: The inception of VSR and CTR programs dramatically changed the paradigms for training in these highly specialized surgical fields. Comparisons of attrition rates between these two programs and the traditional VSF and CTR as well as GSR suggests lesser rates of attrition in the integrated programs. These data may prove reassuring to VSR and CTR program directors, whose significantly smaller programs are more vulnerable to the loss of even a single trainee than general surgery training programs are. In addition, the VSF program has stable and lower attrition rates compared with the CTF and GSR programs.

Natural history of the proximal aorta in patients with descending thoracic aortic disease.

OBJECTIVE: This study investigated the growth and behavior of the ascending aorta in patients with descending thoracic aortic disease. METHODS: We examined 200 patients with descending thoracic aortic disease including acute type B dissection (n = 95), chronic type B dissection (n = 38), intramural hematoma (n = 23), and thoracoabdominal aortic aneurysms (n = 44). Images from computed tomography and magnetic resonance imaging were evaluated after three-dimensional reconstruction to examine the growth rate in those with >1 year of imaging follow-up (n = 108). Survival data were derived from all 200 patients in this study. RESULTS: Average proximal aortic dimensions at the index image were relatively small, measuring 3.65 ± 0.51 cm in the root, 3.67 ± 0.48 cm in the ascending aorta, and 3.50 ± 0.44 cm in the proximal arch. Average growth rate was low for the aortic root, ascending aorta, and proximal arch at 0.36 ± 0.64 mm/y, 0.26 ± 0.44 mm/y, and 0.25 ± 0.44 mm/y, respectively. There was no difference in baseline proximal aortic dimensions and growth rate between the four subgroups. An index aortic diameter ≥4.1 cm grew faster than those <4.1 cm at the ascending aorta (P = .028) and proximal arch (P = .019). There was no difference in aortic growth rates at the aortic root (P = .887). After the index scan, five patients underwent six ascending aortic replacement procedures, leading to a 3% ascending aortic intervention rate. Overall median life expectancy was 86.15 years. CONCLUSIONS: Native ascending aortic growth in patients with descending thoracic aortic disease is slow. We suggest regular follow-up for index ascending aorta ≥4.1 cm because of its larger initial size and more rapid growth.

Acute retrograde type A aortic dissection: morphologic analysis and clinical implications.

BACKGROUND: This study compares the morphology and outcomes of acute retrograde type A dissections (RTADs) with acute antegrade type A dissections (ATADs), and acute type B dissections. MATERIALS AND METHODS: From 2000 to 2016, there were 12 acute RTADs, 96 ATADs, and 92 type B dissections with available imaging. Dissections were characterized using computerized tomography angiography images. We examined clinical features, tear characteristics, and various morphologic measurements. RESULTS: Compared with acute type B dissections, RTAD primary tears were more common in the distal arch (75% versus 43%, P = 0.04), and the false-to-true lumen contrast intensity ratio at the mid-descending thoracic aorta was lower (0.46 versus 0.71, P = 0.020). RTAD had less false lumen decompression because there were fewer aortic branch vessels distal to the subclavian that were perfused through the false lumen (0.40 versus 2.19, P < 0.001). Compared with ATAD, RTAD had less root involvement where root true-to-total lumen area ratio was higher (0.88 versus 0.76, P = 0.081). Furthermore, RTAD had a lower false-to-true lumen contrast intensity ratio at the root (0.25 versus 0.57, P < 0.05), ascending aorta (0.25 versus 0.72, P < 0.001), and proximal arch (0.39 versus 0.67, P < 0.05). RTAD were more likely to undergo aortic valve resuspension (100% versus 74%, P = 0.044). CONCLUSIONS: RTAD tends to occur when primary tears occur in close proximity to the aortic arch and when false lumen decompression through the distal aortic branches are less effective. Compared with ATAD, RTAD has less root involvement, and successful aortic valve resuspension is more likely.

Phosphorylation of AKT and abdominal aortic aneurysm formation.

It is hypothesized that differential AKT phosphorylation between sexes is important in abdominal aortic aneurysm (AAA) formation. Male C57BL/6 mice undergoing elastase treatment showed a typical AAA phenotype (80% over baseline, P < 0.001) and significantly increased phosphorylated AKT-308 (p308) and total-AKT (T-AKT) at day 14 compared with female mice. Elastase-treated Raw cells produced increased p308 and significant amounts of matrix metalloproteinase 9 (MMP-9), and these effects were suppressed by LY294002 treatment, a known AKT inhibitor. Male and female rat aortic smooth muscle cells treated with elastase for 1, 6, or 24 hours demonstrated that the p308/T-AKT and AKT-Ser-473/T-AKT ratios peaked at 6 hours and were significantly higher in the elastase-treated cells compared with controls. Similarly, male cells had higher phosphorylated AKT/T-AKT levels than female cells. LY294002 also inhibited elastase-induced p308 formation more in female smooth muscle cells than in males, and the corresponding cell media had less pro-MMP-9. AKT siRNA significantly decreased secretion of pro-MMP-9, as well as pro-MMP-2 and active MMP-2 from elastase-treated male rat aortic smooth muscle cells. IHC of male mice AAA aortas showed increased p308, AKT-Ser-473, and T-AKT compared with female mice. Aortas from male AAA patients had a significantly higher p308/T-AKT ratio than female AAA tissues. These data suggest that AKT phosphorylation is important in the upstream regulation of MMP activity, and that differential phosphorylation may be important in sex differences in AAA.

Isolated celiac artery dissection.

OBJECTIVE: Spontaneous celiac artery dissection is rare, and its natural history is not well studied. The objective of this study was to review our experience with the evaluation and management of this condition. METHODS: During the last 8 years, 19 patients (14 men, five women) presented with the diagnosis of spontaneous celiac artery dissection. Each patient's clinical course was retrospectively reviewed, and patients were contacted for assessment of current symptoms. RESULTS: All patients had computed tomography scans documenting a celiac artery dissection without concomitant aortic dissection. Ages ranged from 39 to 76 years. Seven patients presented with abdominal pain, and 12 were diagnosed incidentally. All patients were initially treated with observation because none had threatened end organs. Patients presenting with aspirin or clopidogrel therapy were continued on these medications, but no patients were prescribed any medications due to their dissection. Three patients continued to have abdominal pain and eventually underwent celiac artery stenting. Pain improved after the intervention in all three. One patient with aneurysmal degeneration of the celiac artery underwent surgical repair. No other patients required intervention. Eighteen patients had follow-up within a year of data collection in the clinic or over the phone. The average time from the initial diagnosis to follow-up for the entire cohort was 46 months. None had abdominal or back pain related to the celiac dissection, had lost weight, or had to change their eating habits. CONCLUSIONS: Celiac artery dissection can be safely managed initially with observation. If abdominal pain is persistent, endovascular stenting may stabilize or improve the pain, and surgical reconstruction can be done for aneurysmal degeneration or occlusion, both unusual events. Long-term anticoagulation does not appear necessary in these patients.

Increased PAI-1 in females compared with males is protective for abdominal aortic aneurysm formation in a rodent model.

The serine proteases, along with their inhibitor plasmin activator inhibitor-1 (PAI-1), have been shown to play a role in abdominal aortic aneurysm (AAA) formation. The aim of this study is to determine if PAI-1 may be a protective factor for AAA formation and partially responsible for the gender difference observed in AAAs. Male and female wild-type (WT) C57BL/6 and PAI-1(-/-) mice 8-12 wk of age underwent aortic perfusion with porcine pancreatic elastase. Animals were harvested 14 days following perfusion and analyzed for phenotype, PAI-1 protein levels, and matrix metalloproteinase (MMP)-9 and -2 activity. WT males had an average increase in aortic diameter of 80%, whereas females only increased 32% (P < 0.001). PAI-1(-/-) males increased 204% and females 161%, significantly more than their WT counterparts (P < 0.001). Western blot revealed 61% higher PAI-1 protein levels in the WT females compared with the WT males (P = 0.01). Zymography revealed higher levels of pro-MMP-2 and active MMP-2 in the PAI-1(-/-) males and females compared with their WT counterparts. PAI-1(-/-) females had significantly higher serum plasmin levels compared with WT females (P = 0.003). In conclusion, WT female mice are protected from aneurysm formation and have higher levels of PAI-1 compared with males during experimental aneurysm formation. Additionally, both male and female PAI-1(-/-) animals develop significantly larger aneurysms than WT animals, correlating with higher pro- and active MMP-2 levels. These findings suggest that PAI-1 is protective for aneurysm formation in the elastase model of AAA and plays a role in the gender differences seen in AAA formation.

Increased JNK in males compared with females in a rodent model of abdominal aortic aneurysm.

BACKGROUND: In humans, there is a 4:1 male:female ratio in the incidence of abdominal aortic aneurysms (AAAs). c-Jun-N-terminal kinase (JNK) is an important upstream regulator of several enzymes involved in AAA formation, including the matrix metalloproteinases (MMPs). The purpose of this study was to determine if there is a gender difference between males and females in JNK during AAA formation. MATERIALS AND METHODS: Male and female C57/B6 mice underwent aortic perfusion with elastase or heat inactivated elastase with aortas harvested at d 3 and 14 for phenotype determination, RT-PCR, Western blot, and zymography. Additionally, in vitro experiments using siRNA were conducted to define JNK regulation of matrix metalloproteinases (MMPs). A t-test was used to compare between groups. RESULTS: Males formed larger AAAs at d 14 compared with females (P < 0.001), with significantly higher levels of JNK1 protein, proMMP9, proMMP2, and active MMP2. At d 3, males had more JNK1 mRNA, protein, and MMP activity. Knockdown of JNK 1 or 2 in vitro decreased MMP activity, while knockdown of JNK 1 and 2 together blocked all MMP activity. CONCLUSION: Alterations in JNK between genders is partially responsible for the differential rates of experimental AAA formation, likely through differential regulation of MMPs.

Association Between Body Mass Index and Perioperative Mortality After Repair of Ruptured Abdominal Aortic Aneurysms.

OBJECTIVE: The attempt to repair a ruptured abdominal aortic aneurysm carries a significant risk of perioperative mortality. The relationship between body mass index (BMI) and outcomes after repair of ruptured abdominal aortic aneurysms (AAAs) has not been well defined. We report the association of BMI with outcomes after ruptured AAA repair. METHODS: Patients undergoing ruptured AAA repairs between 2008 and 2017 at 2 tertiary academic centers were included in this retrospective study. Demographics (including BMI), type of repair, length of stay, and admission mortality risk scores were gathered and analyzed using bivariate and multivariate logistic regressions. Adjusted odds ratio (AOR) was reported with 95% CIs and P values from the multivariate analysis. The primary outcome was 30-day mortality. Akaike information criterion (AIC) and c-statistics were used to assess the predictive power of models including physiologic score with or without BMI. RESULTS: A total of 202 patients underwent repair of ruptured AAA. In bivariate relationship, increased BMI was significantly associated with 30-day mortality. With multivariate analysis, adjusting for demographics, type of procedure, and physiologic score, for each kg/m2 increase in BMI, an 8% increase in the likelihood of perioperative mortality (AOR = 1.08, 95% CI: 1.01-1.17; P = .04) was observed. CONCLUSION: When adjusted for admission risk score, type of procedure, and demographics, obesity was associated with increased 30-day mortality. With BMI as an additional data point, the c-statistics and AIC comparisons indicated that we would have a greater ability to preoperatively estimate mortality after ruptured AAA repair. Consideration could be made to include BMI in future mortality risk scoring systems for ruptured AAA.

Cluster analysis of acute ascending aortic dissection provides novel insight into mechanisms of distal progression.

BACKGROUND: Whether primary tear size impacts extent of type A dissection is unclear. Using statistical groupings based on dissection morphology, we examined its relationship to primary tear area. METHODS: We retrospectively reviewed 108 patients who underwent acute ascending dissection repair from 2000-2016. Dissection morphology was characterized using 3-dimensional (3D) reconstructions of computed tomography (CT) scan images. Two-step cluster analysis was performed to group the dissections by examining the true lumen area as a fraction of the total aortic area at various levels. RESULTS: Cluster analysis defined two distinct categories. This first grouping corresponds to DeBakey type I (n=71, 65.7%) with a dissection extending from the ascending aorta to the aortic bifurcation. The second grouping conforms more closely to DeBakey type II dissection (n=37, 34.3%). It differs however from the classic type II definition as the dissection may extend up to the distal arch from the ascending aorta. Compared to type I, this "extended" DeBakey type II had no malperfusion (P<0.05), a larger primary tear area (6.6 vs. 3.7 cm2, P=0.009), and a greater burden of atherosclerotic coronary artery disease (P<0.05). A smaller aortic valve annulus (P=0.025) and a smaller root false lumen area (P=0.017) may explain less aortic valve insufficiency (P<0.05) in extended type II dissections. No differences in complications or survival were seen. CONCLUSIONS: In this series, limited distal extension of DeBakey type II dissections appears to be related to a larger primary tear area and greater atherosclerotic disease burden. It is also associated with less malperfusion and aortic valve insufficiency.

Development of a novel murine model of aortic aneurysms using peri-adventitial elastase.

BACKGROUND: Our aim was to establish a novel model of abdominal aortic aneurysms (AAA) in mice using application of peri-adventitial elastase. METHODS: C57BL/6J male mice underwent infrarenal peri-adventitial application of either (1) sodium chloride (control; n = 7), (2) porcine pancreatic elastase (PPE; n = 14), or (3) PPE and doxycycline (PPE + doxycycline 200 mg/kg; n = 11) for 14 days. Aortas were analyzed by video micrometry, immunohistochemistry, qualitative polymerase chain reaction, and zymography. Groups underwent Mann-Whitney U comparisons. RESULTS: At day 14 compared with baseline, control animals had minimal aortic dilation, whereas fusiform aneurysms were seen in PPE (control, 20 ± 3%; PPE, 82 ± 15%; P ≤ .003). Doxycycline abrogated aneurysm formation (PPE, 82 ± 15%; PPE + doxycycline, 37 ± 10%; P ≤ .03). Compared with control and PPE + doxycycline, immunohistochemistry demonstrated greater elastin fiber degradation, macrophage infiltration, and matrix metalloproteinase-9 expression in PPE. Ki-67 and cleaved caspase-3 were lower in control versus PPE. The loss of smooth muscle marker expression seen with PPE was preserved in PPE + doxycycline. Zymography confirmed that both MMP-2 and -9 were more active in PPE than PPE + doxycycline. CONCLUSION: Peri-adventitial application of elastase is a simple, reproducible in vivo model of aneurysm formation leading to consistent infrarenal aortic aneurysm development by day 14, with inflammatory cell infiltration and MMP upregulation. Doxycycline inhibits AAA progression in this model via limiting matrix degradation and preserving differentiated smooth muscle cells.

The role of extracellular signal-related kinase during abdominal aortic aneurysm formation.

BACKGROUND: It is hypothesized that activation of extracellular signal-related kinase (ERK) is critical in activating matrix metalloproteinases (MMPs) during abdominal aortic aneurysm (AAA) formation. STUDY DESIGN: C57BL/6 male mice underwent either elastase or heat-inactivated elastase aortic perfusion (n = 9 per group). Mouse aortic smooth muscle cells were transfected with ERK-1 and 2 siRNA along with or without elastase treatment. Mouse and human aortic tissue were analyzed by Western blots, zymograms, and immunohistochemistry, and statistical analysis was done using Graphpad and Image J softwares. RESULTS: Western blot and immunohistochemistry documented increased phospho-mitogen-activated protein kinase kinase-1/2 (pMEK-1/2; 153%, p = 0.270 by Western) and pERK (171%, p = 0.004 by Western blot) in the elastase perfused aortas. Male ERK-1(-/-) mice underwent elastase perfusion, and aortic diameter was determined at day 14. ERK-1(-/-) mice failed to develop AAA, and histologic analysis depicted intact collagen and elastin fibers in the aortas. Zymography of aortas of elastase-treated ERK-1(-/-) mice showed lower levels of proMMP2 (p < 0.005) and active MMP2 (p < 0.0001), as well as proMMP9 (p = 0.037) compared with C57BL/6 mice. siRNA transfection of ERK-1 and -2 significantly reduced formation of pro- and active MMP2 (p < 0.01 for both isoforms) in aortic smooth muscle cells treated with elastase in vitro. Human AAA tissue had significantly elevated levels of pMEK-1/2 (150%, p = 0.014) and pERK (159%, p = 0.013) compared with control tissues. CONCLUSIONS: The MAPK (mitogen-activated protein kinase)/ERK pathway is an important modulator of MMPs during AAA formation. Targeting the ERK pathway by reagents that inhibit either the expression or phosphorylation of ERK isoforms could be a potential therapy to prevent AAA formation.

Transhiatal esophagectomy for distal and cardia cancers: implications of a positive gastric margin.

BACKGROUND: A common operation for cancer of the esophagus and cardia consists of transhiatal esophagectomy, proximal gastrectomy, and a cervical esophagogastric anastomosis. The oncologic adequacy of dividing the stomach 4 to 6 cm distal to palpable tumor is not well documented, and when a positive gastric margin is present on the final pathologic analysis, the appropriate management is not established. This study was undertaken to determine the incidence of a positive gastric margin in these patients and the impact of adjuvant treatment. METHODS: A retrospective review was performed of 1044 patients undergoing transhiatal esophagectomy for adenocarcinoma of the distal esophagus or cardia. Twenty (1.9%) had a positive gastric margin on final the pathologic evaluation and met inclusion criteria for this study. RESULTS: Nine patients (45%) received adjuvant therapy consisting of radiation in 3, chemotherapy in 4, or both in 2. Their average postoperative survival was 477 days, compared with 455 days in those not receiving adjuvant therapy (p = 0.898). Local tumor recurrence developed in 1 patient (11%) in the treatment group and in 3 (27%) in the no treatment group (p = 0.386). CONCLUSIONS: A transhiatal esophagectomy and proximal gastrectomy for carcinoma of the distal esophagus and cardia, dividing the stomach 4 to 6 cm from palpable tumor, provides a negative gastric margin in 98% of patients. In the few patients who have a positive gastric margin, 80% die with distant metastases, which would not be influenced by more extensive gastric resection, and in about 20%, local tumor recurrence develops in the intrathoracic stomach, seldom causing dysphagia. Adjuvant therapy for a positive gastric margin neither improves survival nor reduces local tumor recurrence.