Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and fatality rate in men than women. However, the mechanism by which androgen mediates aortic aneurysms is largely unknown. Herein, we found that male mice, not female mice, developed aortic aneurysms when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (AR) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and aortic aneurysms. We demonstrated that administration of anti-PD-1 Ab and adoptive PD-1 deficient T cell transfer reinstated Aldo-salt-induced aortic aneurysms in orchiectomized mice, and genetic deletion of PD-1 exacerbated aortic aneurysms induced by high-fat diet and angiotensin II (Ang II) in non-orchiectomized mice. Mechanistically, we discovered that AR bound to the PD-1 promoter to suppress its expression in the spleen. Thus, our study unveils a mechanism by which androgen aggravates aortic aneurysms by suppressing PD-1 expression in T cells. Moreover, our study suggests that some cancer patients might benefit from screenings for aortic aneurysms during immune checkpoint therapy.

Androgen aggravates aortic aneurysms via suppressing PD-1 in mice.

Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms, a devastating vascular disease with a higher prevalence and mortality rate in men than women. However, the molecular mechanism by which androgen mediates aortic aneurysms is largely unknown. Here, we report that male but not female mice develop aortic aneurysms in response to aldosterone and high salt (Aldo-salt). We demonstrate that both androgen and androgen receptors (AR) are crucial for the sexually dimorphic response to Aldo-salt. We identify T cells expressing programmed cell death protein 1 (PD-1), an immune checkpoint molecule important in immunity and cancer immunotherapy, as a key link between androgen and aortic aneurysms. We show that intraperitoneal injection of anti-PD-1 antibody reinstates Aldo-salt-induced aortic aneurysms in orchiectomized mice. Mechanistically, we demonstrate that AR binds to the PD-1 promoter to suppress its expression in the spleen. Hence, our study reveals an important but unexplored mechanism by which androgen contributes to aortic aneurysms by suppressing PD-1 expression in T cells. Our study also suggests that cancer patients predisposed to the risk factors of aortic aneurysms may be advised to screen for aortic aneurysms during immune checkpoint therapy.

Effect of a Decision Aid on Agreement Between Patient Preferences and Repair Type for Abdominal Aortic Aneurysm: A Randomized Clinical Trial.

Importance: Patients with abdominal aortic aneurysm (AAA) can choose open repair or endovascular repair (EVAR). While EVAR is less invasive, it requires lifelong surveillance and more frequent aneurysm-related reinterventions than open repair. A decision aid may help patients receive their preferred type of AAA repair. Objective: To determine the effect of a decision aid on agreement between patient preference for AAA repair type and the repair type they receive. Design, Setting, and Participants: In this cluster randomized trial, 235 patients were randomized at 22 VA vascular surgery clinics. All patients had AAAs greater than 5.0 cm in diameter and were candidates for both open repair and EVAR. Data were collected from August 2017 to December 2020, and data were analyzed from December 2020 to June 2021. Interventions: Presurgical consultation using a decision aid vs usual care. Main Outcomes and Measures: The primary outcome was the proportion of patients who had agreement between their preference and their repair type, measured using χ2 analyses, κ statistics, and adjusted odds ratios. Results: Of 235 included patients, 234 (99.6%) were male, and the mean (SD) age was 73 (5.9) years. A total of 126 patients were enrolled in the decision aid group, and 109 were enrolled in the control group. Within 2 years after enrollment, 192 (81.7%) underwent repair. Patients were similar between the decision aid and control groups by age, sex, aneurysm size, iliac artery involvement, and Charlson Comorbidity Index score. Patients preferred EVAR over open repair in both groups (96 of 122 [79%] in the decision aid group; 81 of 106 [76%] in the control group; P = .60). Patients in the decision aid group were more likely to receive their preferred repair type than patients in the control group (95% agreement [93 of 98] vs 86% agreement [81 of 94]; P = .03), and κ statistics were higher in the decision aid group (κ = 0.78; 95% CI, 0.60-0.95) compared with the control group (κ = 0.53; 95% CI, 0.32-0.74). Adjusted models confirmed this association (odds ratio of agreement in the decision aid group relative to control group, 2.93; 95% CI, 1.10-7.70). Conclusions and Relevance: Patients exposed to a decision aid were more likely to receive their preferred AAA repair type, suggesting that decision aids can help better align patient preferences and treatments in major cardiovascular procedures. Trial Registration: ClinicalTrials.gov Identifier: NCT03115346.

Accuracy of Point-of-Care Ultrasound in Follow Up Abdominal Aortic Aneurysm Imaging.

BACKGROUND: Point-of-care ultrasound (POCUS) has been reported as a valuable tool for bedside diagnoses of abdominal Aortic Aneurysms (AAA). However, no data exist regarding POCUS in measuring follow-up AAA diameter studies in patients with existing AAAs. The purpose of this study was to determine the variability of aortic measurements performed by a non-physician using POCUS vs standard of care (SOC) measurements by a registered vascular technologist or an abdominal/pelvic CT scan. METHODS: A prospective observational ultrasound study was performed from 1/1/2019 to 3/31/2021 on patients with a diagnosis of an AAA (≥3.0 cm). A research coordinator (non-physician) underwent a 3-hour training session in ultrasound operation and basic human anatomy to measure AAA diameter. The maximum aortic diameter was documented and compared to measurements obtained by SOC ultrasonography or CT scan. The POCUS and SOC ultrasounds were separated by no more than 90 days. Clinical risk factors including age, race, body mass index, coronary artery disease, hypertension, peripheral vascular disease, cerebrovascular disease, diabetes, and current smoking were also collected. RESULTS: Eighty-one patients (mean age: 73.6 ± 5.8 years, body mass index: 29.5 ± 6.2 kg/m2) were being followed in a vascular clinic and underwent both a POCUS and SOC ultrasounds. One indeterminant study was reported in identifying an AAA diagnosis, due to an overlying colostomy. The average follow-up time from initial screening aortic diameter to POCUS was 4.4 ± 3.7 years. Overall average aortic diameter measurements obtained were 4.1 ± .9 cm for POCUS and 4.0 ± .9 cm for SOC (P = NS). Average difference in aortic measurement for POCUS and SOC was -.1 ± .3 cm. CONCLUSIONS: POCUS is an accurate method to follow AAA diameter in patients. POCUS could improve patient follow up with AAA diameter measurements, streamline care and reduce overall burden for both patients and Radiology Departments in assessing follow up AAA diameters.

Costs of abdominal aortic aneurysm care at a regional Veterans Affairs medical center with the implementation of an abdominal aortic aneurysm screening program.

BACKGROUND: Abdominal aortic aneurysm (AAA) screening has demonstrated to be cost-effective in reducing AAA-related morbidity and all-cause mortality. However, the downstream care costs of an implemented AAA screening in clinical practice have not been reported. The purpose of this study is to determine direct regional Department of Veterans Affairs (VA) costs in implementing and sustaining an AAA screening program over a 10-year period. METHODS: A cost data analysis (adjusted to 2021 U.S. dollars) of an AAA screening program was conducted from 2007 to 2016, where 19,649 veteran patients aged 65-75 with a smoking history were screened at a regional VA medical center. A decision support system tracked direct and indirect encounter costs from Medicare billing codes associated with AAA care. Costs from a patient's initial screening, follow-up imaging, to AAA repair or at the end of the analysis period, March 31, 2021, were recorded. Costs for AAA repairs outside the VA system were also tracked. RESULTS: A total of 1,183 patients screened were identified with an AAA ≥3.0 cm without history of repair. Estimated screening costs were $2.8 million or $280,000 annually ($143/screening) in the care of 19,649 screened patients. There were 221 patients who required repair (143 repairs in VA, 78 repairs outside VA). The average cost of elective endovascular repair was $43,021 and that of open repair was $49,871. The total costs for all elective repairs were $9,692,591. Screening, implementation, maintenance, and surgical repair cost involved in the management of patients with AAA disease was $13.7 million, with $10,686 per life-year lived after repair (5.8 ± 3.5 mean life-years) and $490 per life-year lived after screening (6.9 ± 3.5 mean life-years) for all patients screened. There were 13 deaths of unknown causes and one patient with a ruptured AAA that required emergency repair at a cost of $124,392. CONCLUSIONS: Despite known limitations, the implementation of an AAA ultrasound screening program is feasible, cost-effective, and a worthwhile endeavor.

Patient information sources when facing repair of abdominal aortic aneurysm.

OBJECTIVE: Shared medical decision making is most important when there are competing options for repair such as in treatment of abdominal aortic aneurysm (AAA). We sought to understand the sources of patients' pre-existing knowledge about AAA to better inform treating physicians about patients' needs for preoperative counseling. METHODS: We performed a multicenter survey of patients facing AAA repair at 20 Veterans Affairs hospitals across the United States as part of the Preferences for Open Versus Endovascular Repair of AAA study. A validated survey instrument was administered to examine the sources of information available and commonly used by patients to learn about their repair options. The survey was administered by study personnel before the patient had any interaction with the vascular surgeon because survey data were collected before the vascular clinic visit. RESULTS: Preliminary analysis of data from 99 patients showed that our cohort was primarily male (99%) and elderly (mean age 73 years). Patients commonly had a history of hypertension (86%), prior myocardial infarction (32%), diabetes (32%), and were overweight (58%). Patients arrived at their surgeon's office appointment with limited information. A majority of patients (52%) reported that they had not talked to their primary care physician at all about their options for AAA repair, and one-half (50%) reported that their view of the different surgical options had not been influenced by anyone. Slightly less than one-half of patients reported that they did not receive any information about open surgical aneurysm repair and endovascular aortic aneurysm repair (41% and 37%, respectively). Few patients indicated using the internet as their main source of information about open surgical aneurysm repair and endovascular aortic aneurysm repair (10% and 11%, respectively). CONCLUSIONS: Patients are commonly referred for AAA repair having little to no information regarding AAA pathology or repair options. Fewer than one in five patients searched the internet or had accessed other sources of information on their own. Most vascular surgeons should assume that patients will present to their first vascular surgery appointment with minimal understanding of the treatment options available to them.

Design of the PReferences for Open Versus Endovascular Repair of Abdominal Aortic Aneurysm (PROVE-AAA) Trial.

For patients with abdominal aortic aneurysm (AAA), randomized trials have found endovascular AAA repair (EVAR) is associated with lower perioperative morbidity and mortality than open surgical repair (OSR). However, OSR has fewer long-term aneurysm-related complications, such as endoleak or late rupture. Patients treated with EVAR and OSR have similar survival rates within two years after surgery, and OSR does not require intensive surveillance. Few have examined if patient preferences are aligned with the type of treatment they receive for their AAA. Although many assume that patients may universally prefer the less-invasive nature of EVAR, our preliminary work suggests that patients who value the lower risk of late complications may prefer OSR. In this study, called The PReferences for Open Versus Endovascular Repair of Abdominal Aortic Aneurysm (PROVE-AAA) trial, we describe a cluster-randomized trial to test if a decision aid can better align patients' preferences and their treatment type for AAA. Patients enrolled in the study are candidates for either endovascular or open repair and are followed up at VA hospitals by vascular surgery teams who regularly perform both types of repair. In Aim 1, we will determine patients' preferences for endovascular or open repair and identify domains associated with each repair type. In Aim 2, we will assess alignment between patients' preferences and the repair type elected and then compare the impact of a decision aid on this alignment between the intervention and control groups. This study will help us to accomplish two goals. First, we will better understand the factors that affect patient preference when choosing between EVAR and OSR. Second, we will better understand if a decision aid can help patients be more likely to receive the treatment strategy they prefer for their AAA. Study enrollment began on June 1, 2017. Between June 1, 2017 and November 1, 2018, we have enrolled 178 of a total goal of 240 veterans from 20 VA medical centers and their vascular surgery teams across the country. We anticipate completing enrollment in PROVE-AAA in June 2019, and study analyses will be performed thereafter.

Risk of developing an abdominal aortic aneurysm after ectatic aorta detection from initial screening.

OBJECTIVE: Current abdominal aortic aneurysm (AAA) surveillance guidelines lack any follow-up recommendations after initial abdominal aortic screening diameter of less than 3.0 cm. Some reports have demonstrated patients with late AAA formation and late ruptures after initial ultrasound screening detection of patients with an aortic diameter of 2.5 to 2.9 cm (ectatic aorta). The purpose of this study was to determine ectatic aorta prevalence, AAA development, rupture risk, and risk factor profile in patients with detected ectatic aortas in a AAA screening program. METHODS: A retrospective chart review of all patients screened for AAA from January 1, 2007, to December 31, 2016, within a regional health care system was conducted. Screening criteria were men 65 to 75 years of age that smoked a minimum of 100 cigarettes in their lifetime. An ectatic aorta was defined as a maximum aortic diameter from 2.5 to 2.9 cm. An AAA was defined as an aortic diameter of 3 cm or greater. Patients screened with ectatic aortas who had subsequent follow-up imaging of the aorta with a minimum of 1-year follow-up were analyzed for associated clinical and cardiovascular risk factors. All data were collected through December 3,/2018. A logistic regression of statistically significant variables from univariate and χ2 analyses were performed to identify risks associated with the development of AAA from an initially diagnosed ectatic aorta. A Cox proportional hazard model was used to assess survival data. A P value of less than .05 was considered statistically significant. RESULTS: From a screening pool of 19,649 patients, 3205 (16.3%) with a mean age of 72.1 ± 5.3 years were identified to have an ectatic aorta from January 1, 2007, to December 31, 2016. The average screening ectatic aortic diameter was 2.6 ± 0.1 cm. There were 672 patients (21.0%) with a mean age of 73.0 ± 5.7 years who received subsequent imaging for other clinical indications and 193 of these patients (28.7%) with ectatic aortas developed an AAA from the last follow-up scan (4.2 ± 2.5 years). The average observation length of all patients was 6.4 ± 2.9 years. No ruptures were reported, but 27.8% of deaths were of unknown cause. One patient had aortic growth to 5.5 cm or greater (0.15%). Larger initial screening diameter (P < .01), presence of chronic obstructive pulmonary disease (P < .01), and active smoking (P = .01) were associated with AAA development. CONCLUSIONS: Patients with diagnosed ectatic aortas from screening who are active smokers or have chronic obstructive pulmonary disease are likely to develop an AAA.

The 10-year outcomes of a regional abdominal aortic aneurysm screening program.

OBJECTIVE: In 2007, Medicare established ultrasound screening guidelines to identify patients at risk for abdominal aortic aneurysm (AAA). The purpose of this study was to evaluate AAA diagnosis rates and compliance with screening during 10 years (2007-2016) of the Screen for Abdominal Aortic Aneurysms Very Efficiently Act implementation within a regional health care system. METHODS: A retrospective chart review of all patients screened for AAA from 2007 to 2016 within a regional Veterans Affairs health care system was conducted. Screening criteria were men 65 to 75 years of age who smoked a minimum of 100 cigarettes in their lifetime. An AAA was defined as a maximum aortic diameter ≥3 cm. A comparison was made of the AAA diagnosis rate and clinical adherence rate of screening criteria between the first 5 years and total years evaluated. AAA-related mortality was identified by using terminal diagnosis notes or autopsy reports. All data were recorded by August 31, 2017. RESULTS: A total of 19,649 patients (70.7 ± 4.8 years of age, mean ± standard deviation) were screened from January 1, 2007, to December 31, 2016. There were 9916 new patients screened from 2012 to 2016. A total of 1232 aneurysms (6.3% total patients) were identified during the 10-year period. The overall AAA diagnosis rate has declined from 7.2% in the first 5 years to 6.3% in 10 years (13.5% decrease; P < .01). There were 66 patients found with AAA ≥5.5 cm (5.3% of AAAs), and 54 of these patients received successful elective repair. A total of 2321 patients died (11.8%) and 6 deaths were suspected AAA ruptures (0.03%) within the analysis period. A total of 3680 patients screened (18.7%) did not meet screening criteria: 593 patients were <65 years of age, 3087 patients were >75 years of age, and 59 patients were women. This rate has declined from 28.2% within the first 5 years to 18.7% overall in 10 years (33.7% decrease; P < .01). The compliance of screened patients using screening criteria improved significantly from 61.7% in 2007 to 92.4% in 2016 (P < .01). The overall compliance rate since implementation of the screening program during the past 10 years is 81.3%. CONCLUSIONS: The overall 10-year rate of AAA diagnosis is 6.3%. There are more smaller aneurysms (3.0-4.4 cm) detected and fewer large AAAs ≥5.5 cm in the last 5 years compared with the first 5 years of the screening program. The overall AAA-related mortality rate of all screened patients is 0.03%. There were 54 patients with AAA ≥5.5 cm who underwent successful elective repair resulting from the AAA screening program. The overall compliance of screened patients using screening criteria improved significantly from 61.7% in 2007 to 81.3% since implementation of the screening program during the past 10 years.

Effects of aging and environmental tobacco smoke exposure on ocular and plasma circulatory microRNAs in the Rhesus macaque.

Purpose: To identify changes induced by environmental tobacco smoke (ETS) in circulatory microRNA (miRNA) in plasma and ocular fluids of the Rhesus macaque and compare these changes to normal age-related changes. Tobacco smoke has been identified as the leading environmental risk factor for age-related macular degeneration (AMD). Methods: All Rhesus macaques were housed at the California National Primate Research Center (CNPRC), University of California, Davis. Four groups of animals were used: Group 1 (1-3 years old), Group 2 (19-28 years old), Group 3 (10-16 years old), and Group 4 (middle aged, 9-14 years old). Group 4 was exposed to smoke for 1 month. Ocular fluids and plasma samples were collected, miRNAs isolated, and expression data obtained using Affymetrix miRNA GeneTitan Array Plates 4.0. Bioinformatics analysis was done on the Affymetrix Expression Console (EC), Transcriptome Analysis Software (TAS) using ANOVA for candidate miRNA selection, followed by Ingenuity Pathway Analysis (IPA). Results: The expression of circulatory miRNAs showed statistically significant changes with age and ETS. In the plasma samples, 45 miRNAs were strongly upregulated (fold change >±1.5, p<0.05) upon ETS exposure. In the vitreous, three miRNAs were statistically significantly downregulated with ETS, and two of them (miR-6794 and miR-6790) were also statistically significantly downregulated with age. Some retinal layers exhibited a thinning trend measured with optical coherence tomography (OCT) imaging. The pathways activated were IL-17A, VEGF, and recruitment of eosinophils, Th2 lymphocytes, and macrophages. Conclusions: ETS exposure of Rhesus macaques resulted in statistically significant changes in the expression of the circulatory miRNAs, distinct from those affected by aging. The pathways activated appear to be common for ETS and AMD pathogenesis. These data will be used to develop an animal model of early dry AMD.

Surveillance outcomes of small abdominal aortic aneurysms identified from a large screening program.

OBJECTIVE: Surveillance of patients identified with small abdominal aortic aneurysm (AAA) from an AAA screening program poses a challenge for health systems because of numerous patient follow-ups. This study evaluates the surveillance outcomes of patients identified with small AAA from a large screening program. METHODS: A retrospective chart review of all patients screened for small AAA (3.0-5.4 cm) from 2007 to 2011 was conducted. Patients with small AAA and no previous history of repair were tracked for follow-up using the 2013 RESCAN follow-up guidelines according to aortic diameter (3.0-3.9 cm, 3 years; 4.0-4.4 cm, 2 years; 4.5-5.4 cm, 1 year). Socioeconomic factors that may influence the follow-up rate and all-cause mortality after screening, including marital status, distance to hospital from residence, estimated household income, and employment disability status, were also evaluated. RESULTS: A total of 568 patients (mean ± standard deviation, 73.4 ± 7.2 years old) with small AAA (3.6 ± 0.6 cm) were analyzed. Patient follow-up rate was 65.1% (n = 370 of 568). Reasons for follow-up failure were lack of the physician's ordering a scan (n = 139; 70.2%), delayed ordering of scans (n = 36; 18.2%), patient no-show (n = 18; 9.1%), or patient death before follow-up (n = 5; 2.5%). Of all patient-specific factors, patients with smaller diameters were unlikely to achieve follow-up scans (P < .001). A significantly higher risk of all-cause mortality was found for patients with no ultrasound follow-up scan (hazard ratio [HR], 0.369; P < .001), assisted living (HR, 0.381; P < .001), older age (HR, 1.04; P = .001), and lower household incomes (HR, 0.989; P = .01). CONCLUSIONS: The follow-up rate of patients with small AAA was poor at 65.1%. The data indicate that socioeconomic factors do not significantly affect follow-up success. Therefore, physician ordering of scans may exert the greatest influence on follow-up rates in patients with small AAA. Automatic ordering of follow-up scans for patients with small AAAs is proposed to improve follow-up rates.

Aneurysms: abdominal aortic aneurysms.

Ruptured abdominal aortic aneurysms (AAAs) cause approximately 16,000 deaths per year in the United States. Smoking, male sex, advanced age, hypertension, and family history are risk factors. AAAs suspected on physical examination should be evaluated with ultrasonography. In addition, ultrasonography screening for AAA is recommend for men ages 65 to 75 years with smoking histories. For men ages 65 to 75 years who have never smoked, screening should be performed selectively, such as for those with family histories of AAA. Screening women currently is not recommended, regardless of smoking status. Surgical repair is indicated for men with AAA diameters of 5.5 cm or greater. The common practice for women is to repair AAAs with diameters of 5.0 cm or greater. For patients with smaller AAAs, cardiac risk factor management is recommended along with interval ultrasonography monitoring. Surgery is indicated if monitoring shows that an AAA is enlarging (by 1 cm or more per year) or reaches the noted limits. Repair of AAA (ruptured or unruptured) is accomplished with open surgery or endovascular procedures (eg, transcatheter placement of a stent graft). Endovascular procedures are now used more frequently than open surgery and have similar outcomes.

Aneurysms: thoracic aortic aneurysms.

Thoracic aortic aneurysms (TAAs) have many possible etiologies, including congenital heart defects (eg, bicuspid aortic valves, coarctation of the aorta), inherited connective tissue disorders (eg, Marfan, Ehlers-Danlos, Loeys-Dietz syndromes), and degenerative conditions (eg, medial necrosis, atherosclerosis of the aortic wall). Symptoms of rupture include a severe tearing pain in the chest, back, or neck, sometimes associated with cardiovascular collapse. Before rupture, TAAs may exert pressure on other thoracic structures, leading to a variety of symptoms. However, most TAAs are asymptomatic and are found incidentally during imaging for other conditions. Diagnosis is confirmed with computed tomography scan or echocardiography. Asymptomatic TAAs should be monitored with imaging at specified intervals and patients referred for repair if the TAAs are enlarging rapidly (greater than 0.5 cm in diameter over 6 months for heritable etiologies; greater than 0.5 cm over 1 year for degenerative etiologies) or reach a critical aortic diameter threshold for elective surgery (5.5 cm for TAAs due to degenerative etiologies, 5.0 cm when associated with inherited syndromes). Open surgery is used most often to treat asymptomatic TAAs in the ascending aorta and aortic arch. Asymptomatic TAAs in the descending aorta often are treated medically with aggressive blood pressure control, though recent data suggest that endovascular procedures may result in better long-term survival rates.

Aneurysms: popliteal and visceral artery aneurysms.

Popliteal artery aneurysms (PAAs) occur in approximately 1 of every 100 men ages 65 to 80 years. They can occur bilaterally, and abdominal aortic aneurysm is simultaneously present in 50% of cases. Therefore, patients with PAAs should undergo ultrasonography to exclude abdominal aortic aneurysms and contralateral PAAs. The main risk of PAAs is thrombus/embolus formation causing lower limb ischemia. Any symptomatic PAA or PAA containing a thrombus should be repaired regardless of size. Asymptomatic PAAs should be considered for repair if the diameter is 2 cm or greater. Visceral artery aneurysms are rare and typically are diagnosed incidentally during imaging for other conditions. The most common is splenic artery (SA) aneurysm, but aneurysms also occur in hepatic, mesenteric, celiac, and other arteries. Although uncommon and typically asymptomatic, SA aneurysms are significant because of rupture risk. Current recommendations are that SA aneurysms 2 cm or larger should be repaired. SA aneurysms of any size should be repaired in pregnant women and women of childbearing age because of the high maternal (75%) and fetal (95%) mortality rates associated with rupture. Superior mesenteric artery aneurysms should be repaired, regardless of size because of rupture risk. Other visceral artery aneurysms typically can be monitored and repaired if they reach 2 cm in diameter.

Monocyte activity is linked with abdominal aortic aneurysm diameter.

BACKGROUND: Systemic inflammation and increased matrix metalloproteinase (MMP) cause elastin degradation leading to abdominal aortic aneurysm (AAA) expansion. Several prospective studies report that statin therapy can reduce AAA expansion through anti-inflammation. We hypothesize that monocyte activity plays a pivotal role in this AAA development and this study examines patient peripheral blood monocyte cell adhesion, transendothelial migration, and MMP concentrations between AAA and non-AAA patients. MATERIALS AND METHODS: Peripheral blood was collected and monocytes isolated from control (n=15) and AAA (n=13) patients. Monocyte adhesion, transmigration, and permeability assays were assessed. Luminex assays determined MMP-9 and tissue inhibitor of metalloproteinase-4 (TIMP-4) concentrations from cell culture supernatant and patient serum. RESULTS: AAA patient monocytes showed increased adhesion to the endothelium relative fluorescence units (RFU, 0.33±0.17) versus controls (RFU, 0.13±0.04; P=0.005). Monocyte transmigration was also increased in AAA patients (RFU, 0.33±0.11) compared with controls (RFU, 0.25±0.04, P=0.01). Greater numbers of adhesive (R2=0.66) and transmigratory (R2=0.86) monocytes were directly proportional to the AAA diameter. Significantly higher serum levels of MMP-9 (2149.14±947 pg/mL) were found in AAA patients compared with controls (1189.2±293; P=0.01). TIMP-4 concentrations were significantly lower in AAA patients (826.7±100 pg/mL) compared with controls (1233±222 pg/mL; P=0.02). Cell culture supernatant concentrations of MMP and TIMP from cocultures were higher than monocyte-only cultures. CONCLUSIONS: Monocytes from AAA patients have greater adhesion and transmigration through the endothelium in vitro, leading to elevated MMP-9 levels and the appropriate decrease in TIMP-4 levels. The ability to modulate monocyte activity may lead to novel medical therapies to decrease AAA expansion.

Risk factors associated with the diagnosis of abdominal aortic aneurysm in patients screened at a regional Veterans Affairs health care system.

BACKGROUND: An active abdominal aortic aneurysm (AAA) screening program at a regional Veterans Affairs (VA) health system identifies patients at risk for AAA. The purpose of this study is to evaluate unique risk factors associated with the AAA diagnosis upon AAA screening examination to identify the most at risk patients for AAA. METHODS: Data were extracted from a regional VA health care system to identify patients who underwent AAA screening within a 3-year period. An aortic diameter ≥3.0 cm was defined as an AAA. Patient risk factors included age, body mass index, total cholesterol, estimated glomerular filtration rate (eGFR), statin use, and active smoking status; the presence of hypertension, diabetes, coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), or peripheral vascular disease (PVD) was also evaluated. Risk factors were compared in a multivariate analysis between patients with AAA and patients with a normal aorta. RESULTS: A total of 6,142 patients (mean ± SD age: 72.7 ± 5.3 years) were screened for AAA between January 2007 and December 2009. A total of 469 patients (7.6%) with AAA were identified. The following risk factors were significantly associated with a diagnosis of AAA: age >75 years (39.6% vs. 28.9%; P < 0.001), prevalence of CAD (43.1% vs. 28.5%; P < 0.001), COPD (26% vs. 11.4%; P < 0.001), PVD (37.3% vs. 7.7%; P < 0.001), eGFR <60 mL/min (36.7% vs. 24.3%; P < 0.001), and current smoking (23.2% vs. 15.3%; P < 0.001). The risk factors significantly associated with normal aortic size were the presence of diabetes (18.6% vs. 27.4%; P < 0.001) and total cholesterol ≥200 mg/dL (10.4% vs. 15%; P = 0.04). CONCLUSIONS: The diagnosis of AAA in a large screening study is typically identified in patients who are at high risk for cardiovascular disease. The presence of diabetes is a major cardiovascular risk factor that is more associated with normal aorta when compared to patients with the AAA diagnosis. Total cholesterol ≥200 mg/dL was associated with decreased AAA risk, and renal insufficiency was associated with increased AAA risk.

Increased levels of CD34+ cells are associated in patients with abdominal aortic aneurysms compared with patients with peripheral vascular disease.

BACKGROUND: Circulating progenitor cells are integral to vascular health and effectively predict vascular reactivity. CD34 is a known marker of circulating progenitor cells. Few studies have examined the role of CD34+ cells in abdominal aortic aneurysm (AAA) disease and peripheral vascular disease (PVD). The aim of this study was to compare the percentage of CD34+ cells between patients with AAA versus PVD. MATERIALS AND METHODS: We collected peripheral whole blood from AAA or PVD patients. The blood was stained with fluorescently labeled antibodies against CD34 or isotype controls. We collected data using a flow cytometer and analyzed them. We also recorded risk factors such as hypertension, diabetes, total cholesterol, serum white blood cells, serum creatinine, body mass index, blood pressure, statin use, current smoking status, coronary artery disease, cerebral vascular accident, and chronic obstructive pulmonary disease. RESULTS: We enrolled 24 patients in this study (AAA, n = 12; PVD, n = 12). The AAA patients had a greater percentage of CD34+ cells compared with PVD patients. (r = 0.84; P = 0.016). There were no significant risk factors differences between AAA and PVD patients. CONCLUSIONS: Based on CD34+ cell counts, AAA is a less severe vascular disease than PVD. Whether CD34+ cells can serve as a biomarker for risk stratification or a potential therapy warrants further study.

Outcomes of an abdominal aortic aneurysm screening program.

OBJECTIVE: In 2007, Medicare guidelines were established to identify persons at risk for the presence of an abdominal aortic aneurysm (AAA). The purpose of this study is to evaluate the 5-year outcomes of an AAA screening program in a regional Veterans Affairs (VA) health care system. METHODS: Data were extracted from a regional VA health care network identifying all veteran males 65 to 75 years of age who smoked at least 100 cigarettes during their lifetime. In 2007, an AAA screening mandate was implemented allowing patients meeting screening criteria to be evaluated for AAA as part of the patient's health maintenance. AAA is identified as an aortic diameter size of 3.0 cm or greater. Clinician adherence to screening protocols and referral to a vascular surgeon for aneurysms >5.5 cm were also evaluated. RESULTS: A total of 9751 patients (71.5 ± 5.6 standard deviation years of age) were screened for an AAA over a 5-year period from January 1, 2007 to December 31, 2011. A total of 698 aneurysms (7.1%) were found. Referrals to a vascular surgeon were made on 45 patients with aneurysms >5.5 cm. Over a 5-year period, a total of 2754 patients (28.2%) were inappropriately screened: 416 patients were under 65 years old, 2243 patients were over 75 years old, 36 patients were women, and 123 patients without aneurysms had multiple screenings. In 2007, during the first year of implementation, 39.2% of patients were inappropriately screened. Over the next 4 years, inappropriate screenings decreased with 33.7% in 2008, 28.6% in 2009, 17.7% in 2010, and 14.3% in 2011. CONCLUSIONS: A large AAA screening program at the VA detects more aneurysms, but at smaller diameters than that published in clinical trials. Over time, the number of inappropriate AAA screenings has continued to decrease, demonstrating greater awareness and application of the AAA screening guidelines by primary care providers. Developing surveillance guidelines for small and medium aneurysms is a potential area for future research.

A disintegrin and metalloproteinase 15 contributes to atherosclerosis by mediating endothelial barrier dysfunction via Src family kinase activity.

OBJECTIVE: Endothelium dysfunction is an initiating factor in atherosclerosis. A disintegrin and metalloproteinase 15 (ADAM 15) is a multidomain metalloprotease recently identified as a regulator of endothelial permeability. However, whether and how ADAM15 contributes to atherosclerosis remains unknown. METHODS AND RESULTS: Genetic ablation of ADAM15 in apolipoprotein E-deficient mice led to a significant reduction in aortic atherosclerotic lesion size (by 52%), plaque macrophage infiltration (by 69%), and smooth muscle cell deposition (by 82%). In vitro studies implicated endothelial-derived ADAM15 in barrier dysfunction and monocyte transmigration across mouse aortic and human umbilical vein endothelial cell monolayers. This role of ADAM15 depended on intact functioning of the cytoplasmic domain, as evidenced in experiments with site-directed mutagenesis targeting the metalloprotease active site (E349A), the disintegrin domain (Arginine-Glycine-Aspartic acid→Threonine-Aspartic acid-Aspartic acid), or the cytoplasmic tail. Further investigations revealed that ADAM15-induced barrier dysfunction was concomitant with dissociation of endothelial adherens junctions (vascular endothelial [VE]-cadherin/γ-catenin), an effect that was sensitive to Src family kinase inhibition. Through small interfering RNA-mediated knockdown of distinct Src family kinase members, c-Src and c-Yes were identified as important mediators of these junctional effects of ADAM15. CONCLUSIONS: These results suggest that endothelial cell-derived ADAM15, signaling through c-Src and c-Yes, contributes to atherosclerotic lesion development by disrupting adherens junction integrity and promoting monocyte transmigration.

Monocytic adhesion molecule expression and monocyte-endothelial cell dysfunction are increased in patients with peripheral vascular disease versus patients with abdominal aortic aneurysms.

BACKGROUND: Statin therapy is used in the medical management of patients with peripheral vascular disease (PVD) and abdominal aortic aneurysm (AAA) for the pleiotropic and anti-inflammatory benefits. We hypothesize that the inflammatory mechanisms of monocyte-endothelial cell interactions in endothelial barrier dysfunction are more significant in patients with PVD compared with those with AAA. The purpose of this study was to assess patient peripheral blood monocyte adhesion molecules by flow cytometry and monocyte-induced endothelial barrier dysfunction by using an in vitro endothelial cell layer and electric cell-substrate impedance sensing (ECIS) system. METHODS: Peripheral blood was collected from patients with either PVD (ankle-brachial index <0.9, toe-arm index <0.8, or required lower extremity vascular intervention) or AAA (aortic diameter >3.0 cm). Monocytes were isolated from fresh whole blood using an accuspin-histopaque technique. The separated monocytes underwent flow cytometry analysis to evaluate the expression levels of the cell membrane adhesion molecules: CD18, CD11a/b/c, and very late antigen-4. Endothelial cell function was assessed by adding monocytes to an endothelial monolayer on ECIS arrays and coculturing overnight. Peak changes in transendothelial electrical resistance were measured and compared between patient groups. RESULTS: Twenty-eight monocyte samples were analyzed for adhesion molecules (PVD, 19 and AAA, 9) via flow cytometry, and 11 patients were evaluated for endothelial dysfunction (PVD, 7 and AAA, 4) via ECIS. There was no significant difference between risk factors among PVD and AAA patients except for age, where AAA patients were significantly older than PVD patients in both flow cytometry and ECIS groups (P=0.02 and 0.01, respectively). There were significantly higher levels of adhesion molecules CD11a, CD18, and CD11c (averaged mean fluorescent intensity P values: 0.047, 0.038, and 0.014, respectively) in PVD patients compared with AAA patients. No significant difference was found for CD11b and very late antigen-4 expression (P=0.21 and 0.15, respectively). There was significantly more monocyte-endothelial cell dysfunction in patients with PVD versus patients with AAA, with a maximal effect seen at 15h after monocyte addition (P=0.032). CONCLUSIONS: Patients with PVD have increased expression levels of certain monocyte adhesion molecules and greater monocyte-induced endothelial layer dysfunction compared with those with AAA. This may lead to other methods of targeted therapy to improve outcomes of these vascular patients.