Malondialdehyde-Acetaldehyde Modified (MAA) Proteins Differentially Effect the Inflammatory Response in Macrophage, Endothelial Cells and Animal Models of Cardiovascular Disease.

Chronic inflammation plays a critical role in the pathogenesis of atherosclerosis. Currently, the mechanism(s) by which inflammation contributes to this disease are not entirely understood. Inflammation is known to induce oxidative stress, which can lead to lipid peroxidation. Lipid peroxidation can result in the production of reactive by-products that can oxidatively modify macromolecules including DNA, proteins, and lipoproteins. A major reactive by-product of lipid peroxidation is malondialdehyde (MDA). MDA can subsequently break down to form acetaldehyde (AA). These two aldehydes can covalently interact with the epsilon (ε)-amino group of lysines within proteins and lipoproteins leading to the formation of extremely stable, highly immunogenic malondialdehyde/acetaldehyde adducts (MAA-adducts). The aim of this study was to investigate the inflammatory response to MAA-modified human serum albumin (HSA-MAA) and low-density lipoprotein (LDL-MAA). We found that animals injected with LDL-MAA generate antibodies specific to MAA-adducts. The level of anti-MAA antibodies were further increased in an animal model of atherosclerosis fed a Western diet. An animal model that combined both high fat diet and immunization of MAA-modified protein resulted in a dramatic increase in antibodies to MAA-adducts and vascular fat accumulation compared with controls. In vitro exposure of endothelial cells and macrophages to MAA-modified proteins resulted in increased fat accumulation as well as increased expression of adhesion molecules and pro-inflammatory cytokines. The expression of cytokines varied between the different cell lines and was unique to the individual modified proteins. The results of these studies demonstrate that different MAA-modified proteins elicit unique responses in different cell types. Additionally, the presence of MAA-modified proteins appears to modulate cellular metabolism leading to increased accumulation of triglycerides and further progression of the inflammatory response.

Outcome of rectus femoris muscle flaps performed by vascular surgeons for the management of complex groin wounds after femoral artery reconstructions.

OBJECTIVE: Groin wound complications after femoral artery reconstructions are highly morbid and notoriously difficult to treat. Successful techniques include long-term antibiotic therapy, operative débridement, and muscle flap coverage. Historically, more complex muscle flap coverage, such as a rectus femoris muscle flap (RFF), has been performed by plastic and reconstructive surgeons. In this study, the experience of vascular surgeons performing RFF in the management of wound complications after femoral artery reconstructions is reported. METHODS: Clinical data between 2012 and 2018 were retrospectively analyzed. Data were summarized, and standard statistical analysis was performed. RESULTS: There were 23 patients who underwent 24 RFFs for coverage of complex groin wounds after femoral artery reconstructions. One of the 23 patients underwent bilateral RFFs. In this study cohort, patients had a median age of 67.5 years, and 79% (n = 19) were male. Median body mass index was 28.0 kg/m2, and 38% of patients were classified as obese on the basis of body mass index criteria. A history of tobacco use was present in 88%; however, only 29% were current smokers. Diabetes was present in 38% of patients and chronic kidney disease in 29%. Of the 24 RFFs, 14 (58%) were constructed in patients with reoperative groin surgery resulting in the need for muscle flap coverage. Femoral endarterectomy was the most common index procedure (46%), followed by infrainguinal leg bypass surgery (17%) and aortobifemoral bypass (17%). Grafts used during the original reconstruction included 12 bovine pericardial patches (50%), 6 Dacron grafts (25%), 4 PTFE grafts (17%), and 2 autogenous reconstructions (8%). Microbiology data identified 33% of patients (n = 8) to have gram-positive bacterial infections alone, 21% (n = 5) to have gram-negative infections alone, and 29% (n = 7) to have polymicrobial infections; 4 patients (13%) had negative intraoperative culture data. Median hospital stay after RFF was 8 days, and median follow-up time was 29.3 months. Major amputation was avoided in 20 of 24 limbs (83%) undergoing RFF. Eight patients underwent intentional graft or patch explantation (33%) before RFF, whereas 14 of the remaining 15 patients (93%) had successful salvage of the graft or patch after RFF. Two of the patients (13%) who underwent RFF with the intention of salvaging a prosthetic graft or patch required later graft excision. After RFF, 30-day and 1-year survival was 96% and 87%, respectively. CONCLUSIONS: RFF coverage of complex groin wounds after femoral artery reconstructions may safely be performed by vascular surgeons with excellent outcomes.

Outcomes of familial abdominal aortic aneurysm repair in the Vascular Quality Initiative.

OBJECTIVE: Recent investigations have reported increased rates of aneurysm-related complications after endovascular aneurysm repair (EVAR) in familial abdominal aortic aneurysm (fAAA) patients. The purpose of this study was to evaluate the outcomes of open aortic repair (OAR) and EVAR in sporadic AAA (spAAA) and fAAA patients in the Society for Vascular Surgery Vascular Quality Initiative. METHODS: This was a retrospective review of all AAA repairs in the Vascular Quality Initiative from 2003 to 2017. Patients' data were summarized, and standard statistical analysis was performed. Patients with known genetic syndromes and centers with long-term follow-up of <50% of patients were excluded. RESULTS: From 2003 to 2017, there were 1997 fAAA patients compared with 18,185 spAAA patients undergoing OAR and EVAR during the same study period. Compared with their spAAA counterparts, fAAA patients were younger (P < .001), were more likely to be living at home before surgery (P = .008), and demonstrated a lower incidence of coronary artery disease (P = .001) and hypertension (P = .039). Rates of smoking and end-stage renal disease did not differ between groups. However, fAAA patients were more likely to have aneurysmal degeneration of their iliac arteries (P < .001) and to undergo OAR (P < .001). When analyzing patients undergoing OAR, we found that fAAA patients were more likely to require concomitant renal bypass surgery (P = .012) but were extubated sooner (P = .005), received fewer blood transfusions (P < .001), and had a shorter length of stay (P = .018). Although individual complication rates did not differ between fAAA and spAAA groups after OAR, a composite end point of all early postoperative complications was decreased in fAAA patients (P = .020). When comparing fAAA and spAAA patients who underwent EVAR, we found a greater incidence of early lumbar branch endoleaks (type II) in fAAA patients; however, the rate of proximal type IA endoleaks (P = .279) and the rate of late reintervention for sac growth (P = .786), any endoleak (P = .439), or rupture (P = .649) did not differ between the groups. Whereas spAAA patients undergoing EVAR required longer postoperative intensive care unit stays (P < .001) and had a greater incidence of blood transfusions (P < .001), fAAA and spAAA patients had similar rates of postoperative complications (P = .510), 30-day mortality (P = .177), and long-term mortality (P = .259). CONCLUSIONS: This study shows that patients with a familial form of AAA do not have increased morbidity or mortality after AAA repair. Our findings suggest that EVAR and OAR are both safe and effective for fAAA patients. Further studies with longer follow-up are needed to best care for this unique cohort of patients.

Outcomes of endovascular treatments for in-stent restenosis in patients with mesenteric atherosclerotic disease.

OBJECTIVE: Mesenteric angioplasty and stenting (MAS) has surpassed open revascularization as the treatment of choice for mesenteric ischemia. Despite the lower perioperative mortality associated with MAS, the need for reintervention is not infrequent. The purpose of this study was to review the outcomes of patients treated for mesenteric artery in-stent restenosis (MAISR). METHODS: Clinical data from a single center between 2004 and 2017 were retrospectively analyzed. Standard statistical analysis including Kaplan-Meier estimate for time-dependent outcomes, χ2 test for categorical variables, and two-sample t-test for continuous variables was performed. Primary end points included stent patency and reintervention rate. Secondary end points included mortality and morbidity. RESULTS: During the study period, 91 patients underwent primary MAS. In total, 113 mesenteric vessels were treated with 20 covered stents and 93 bare-metal stents. Overall primary patency was 69% at 2 years. At 2 years, primary patency was 83% for covered stents compared with 65% for bare-metal stents (P = .17). Of these 91 primary MAS patients, 27 (30%) were treated for MAISR (32 vessels). Two covered stent patients developed significant restenosis (11%) compared with 25 (34%) bare-metal stent patients (P = .02). The mean age of patients requiring reintervention was 69 years (36% male), with the majority having a history of tobacco use (85%), hypertension (75%), and hyperlipidemia (78%). Fourteen reintervention patients (52%) presented with recurrent symptoms, 10 (37%) had asymptomatic restenosis, and 3 (11%) developed intestinal ischemia. Twelve patients (44%) underwent reintervention with balloon angioplasty alone and 15 (56%) underwent repeated stent placement. Of the 15 patients who had repeated stent placement, 7 patients had covered stents placed. The 30-day mortality rate after reintervention for mesenteric stent restenosis was 0%. Postoperative complications occurred in 15% of patients (myocardial infarction, 4%; reversible kidney injury, 4%; and bowel ischemia requiring surgical exploration, 7%). There was no difference in the perioperative morbidity in comparing symptomatic and asymptomatic patients undergoing reintervention. Mean follow-up after mesenteric reintervention was 31 months, with one-third of patients (n = 9) requiring another reintervention because of either recurrence of symptoms or asymptomatic high-grade restenosis. Assisted primary patency at 2 years was 92% after reintervention with balloon angioplasty and 87% for repeated stent placement, with no statistically significant difference between the groups (P = .66). CONCLUSIONS: Treatment of MAISR is associated with low mortality and acceptable morbidity. The initial use of covered stents may reduce the need for reintervention.

Long-term comparative effectiveness of carotid stenting versus carotid endarterectomy in a large tertiary care vascular surgery practice.

OBJECTIVE: Carotid interventional trials have strict inclusion and exclusion criteria that make translation of their results to the real-world population challenging. Furthermore, the specialty of the operating surgeon and the role of clinical decision-making are not well studied. This study compares the effectiveness of carotid endarterectomy (CEA) vs carotid artery stenting (CAS) in a real-world setting when the procedure is performed by fellowship-trained vascular surgeons. METHODS: A retrospective study was conducted of all consecutive patients undergoing CEA and CAS performed by vascular surgeons in a large rural tertiary health care system from 2004 to 2014. Postoperative outcomes of stroke, acute myocardial infarction (AMI), and death were analyzed at 30 days and during the long term (median follow-up of 5.5 years for CEA and 4.8 years for CAS). Standard statistical analysis was performed. Differences in long-term outcomes were expressed as cumulative incidence functions for nondeath outcomes (stroke and AMI), which account for the high death rate in this population of vascular patients, and as Kaplan-Meier curves for death itself. RESULTS: From January 1, 2004, through December 31, 2014, there were 2331 carotid interventions performed (CEA, 1853; CAS, 478), all by fellowship-trained vascular surgeons. The average age of the patients was 71 years, and 63% were male, with more men in the CAS group (61.5% vs 67.8%; P = .011). Preoperatively, 30% of patients were symptomatic, and 77% of patients had high-grade stenosis in the 70% to 99% range. CEA patients were more likely to have preoperative hypertension (89.7% vs 86.2%; P = .029) and were less likely to have a history of cardiovascular disease (53.4% vs 59.4%; P = .018). There were no significant differences in 30-day outcomes between CEA and CAS (stroke, 1.1% vs 1.3% [P = .743]; AMI, 2.2% vs 1.7% [P = .474]; death, 0.7% vs 0.6% [P = .859]) or long-term outcomes (stroke, 6.8% vs 7.7% [P = .321]; AMI, 22.7% vs 21.0% [P = .886]; death, 28.4% vs 28.2% [P = .122]). CONCLUSIONS: The short- and long-term outcomes after CEA vs CAS are similar when the procedure is performed in a real-world setting by fellowship-trained vascular surgeons.

Patency and limb salvage after femoral endarterectomy and iliac stenting are not affected by severity of iliac disease.

OBJECTIVE: The hybrid procedure of femoral endarterectomy and iliac artery stenting (FEIS) has been used as an alternative to traditional open surgical repair of iliofemoral arterial occlusive disease, but whether the severity of the iliac disease component affects long-term results is not well understood. METHODS: This was a retrospective cohort study of patients undergoing FEIS at Geisinger Health System from January 1, 2004, through December 31, 2013, for the treatment of symptomatic iliofemoral atherosclerotic occlusive disease. The cohort was stratified according to the severity of the iliac occlusive disease component into patients with mild iliac disease (group 1) and patients with severe iliac disease (group 2). RESULTS: Between January 1, 2004, and December 31, 2013, 99 patients underwent 111 total FEIS procedures. The mean age of the cohort was 67.4 years. Men composed 61% of patients. Indications for surgery were claudication (41%), ischemic rest pain (36%), and tissue loss (23%). At 5 years of follow-up, there was no difference in primary patency (73% in group 1 vs 68% in group 2 [P = .67]) and limb salvage (90% in group 1 vs 92% in group 2 [P = .51]). There was a trend toward higher overall mortality in group 2 patients vs group 1 patients (53% vs 81%; P = .08), but this did not reach statistical significance. Univariate analysis did not identify any device-related or anatomic factors predictive of patency. CONCLUSIONS: When combined iliofemoral arterial occlusive disease is treated with FEIS, the severity of the iliac disease component does not affect long-term patency or limb salvage.

Value of delayed duplex ultrasound assessment after endothermal ablation of the great saphenous vein.

OBJECTIVE: Endothermal ablation (ETA) of the great saphenous vein (GSV) is associated with a small but definite risk of endothermal heat-induced thrombosis (EHIT) extending into the common femoral vein. Follow-up duplex ultrasound imaging to detect EHIT after ETA is considered standard of care, although the exact timing of duplex ultrasound imaging to detect EHIT after ETA remains unclear. We hypothesized that an additional duplex ultrasound assessment 1 week after ETA would not identify a significant number of patients with EHIT and would significantly increase health care costs. METHODS: This was a retrospective review of consecutive ETA GSV procedures from 2007 to 2014. All patients were evaluated with duplex ultrasound imaging on postprocedure day 1, and 79% of patients underwent a second ultrasound assessment 1 week postprocedure. EHIT was considered present when proximal GSV closure progressed to level ≥4, based on a six-tier classification system. RESULTS: From January 1, 2007, until December 31, 2014, 842 patients underwent GSV ETA. Patients with EHIT were more likely to have had a prior deep venous thrombosis (DVT; P = .002) and a larger GSV (P = .006). Forty-three procedures (5.1%) were classified as having EHIT requiring anticoagulation, based on a level ≥4 proximal closure level. Of the 43 patients with EHIT, 20 (47%) were found on the initial ultrasound assessment performed 24 hours postprocedure, but 19 patients (44%) with EHIT would not have been identified with a single postoperative ultrasound scan performed 24 hours after intervention. These 19 patients had a level ≤3 closure level at the duplex ultrasound scan performed 24 hours postprocedure and progressed to EHIT on the delayed duplex ultrasound scan. Lastly, thrombotic complications in four patients (9%), representing three late DVT and one DVT/pulmonary embolism presenting to another hospital, would not have been identified regardless of the postoperative surveillance strategy. Maximum GSV diameter was the only significant predictor of progression to EHIT on multivariate analysis (P = .007). Based on 2014 United States dollars, the two-ultrasound surveillance paradigm is associated with health care charges of $31,109 per identified delayed venous thromboembolism event. CONCLUSIONS: Delayed duplex ultrasound assessment after ETA of the GSV comes with associated health care costs but does yield a significant number of patients with progression to EHIT. Better understanding of the timing, risk factors, and significance of EHIT is needed to cost-effectively care for patients after ETA for varicose veins.

Patients with familial abdominal aortic aneurysms are at increased risk for endoleak and secondary intervention following elective endovascular aneurysm repair.

OBJECTIVE: A recent investigation has documented an increased risk of aneurysm-related complications after endovascular aneurysm repair (EVAR) of familial abdominal aortic aneurysms (fAAAs). We hypothesized that fAAA patients are not at increased risk for complications following open AAA repair or EVAR when compared with sporadic abdominal aortic aneurysm (spAAA) patients. To this end, we performed a single institution retrospective review. METHODS: Epidemiologic data were collected through the electronic medical record. Family history data were obtained from a questionnaire administered at the initial vascular surgery consultation. Major adverse events were defined as myocardial infarction, respiratory failure, renal failure, bowel ischemia, limb ischemia, multisystem organ failure, intracranial hemorrhage, paraplegia, hemorrhage, or death. Endoleaks were classified in accordance with the standardized reporting practices of the Society for Vascular Surgery. AAA-related complications were defined as the need for a secondary intervention due to endoleak, limb ischemia, or postimplantation rupture. RESULTS: A total of 392 patients with complete clinical data underwent elective AAA repair from 2004 to 2014. Of these 392 patients, 89 (23%) were classified as fAAA patients and 303 (77%) were classified as spAAA patients. With the exception of increased rates of chronic obstructive pulmonary disease (P = .0009) and pack-years smoked (P = .03) in spAAA patients, demographics did not differ. Sixty-two percent (n = 55) of fAAA patients and 68% (n = 205) of spAAA patients underwent EVAR (P = .30). fAAA patients did not incur any significant difference in major adverse events following open AAA repair (fAAA, 9% vs spAAA, 11%; P = .75). Additionally, fAAA patients did not incur any significant difference in major adverse events following EVAR (fAAA, 4% vs spAAA, 5%; P = .70). Patients with fAAA did have a significantly increased rate of endoleak (fAAA, 24% vs spAAA, 12%; P = .03) and secondary intervention following EVAR (fAAA, 21% vs spAAA, 12%; P = .04). CONCLUSIONS: The current study shows that patients with fAAA do not have increased perioperative morbidity following open or endovascular AAA repair. However, patients with fAAA do have an increased risk of endoleak and secondary intervention following EVAR. These findings suggest that EVAR and open AAA repair are both safe and effective for fAAA patients. The increased rate of endoleak and secondary intervention in patients with fAAA suggests that this subpopulation may benefit from closer post-EVAR surveillance or open surgical repair in good risk patients.

Proinflammatory role of stem cells in abdominal aortic aneurysms.

OBJECTIVE: The pathogenesis of abdominal aortic aneurysm (AAA) formation includes inflammation, vascular smooth muscle cell apoptosis, extracellular matrix degradation, and oxidative stress. That multipotent stem cells have an important role in cardiovascular health and disease has been well established, but the role of stem cells in aortic structural deterioration is poorly defined. We sought to describe the presence of stem cells in human AAA tissue and also investigated the differentiation of stem cells within the aneurysmal aorta. METHODS: Infrarenal aortic wall specimens were collected from patients (n = 7) undergoing open AAA surgical repair. Nonaneurysmal infrarenal aortic control samples (n = 4) were collected at autopsies. Using immunohistochemistry, we compared the abundance of Stro1-positive ((+)), c-kit(+), and CD34(+) cells in aortic tissue. Using double-immunofluorescence staining, we evaluated stem cell differentiation into smooth muscle cells (SM22), fibroblasts (FSP1), and macrophages (CD68). We then investigated the colocalization of CD68(+) cells with the cellular marker of proliferation Ki67. RESULTS: The media and adventitia of infrarenal AAA samples both demonstrated a significantly greater number of c-kit(+) and CD34(+) cells compared with matched control nonaneurysmal aortic tissues; however, the abundance of Stro1(+) cells was not significantly different between the groups. Using double-immunofluorescence staining, we identified that AAA stem cells express the macrophage marker CD68 but not the smooth muscle cell marker SM22 or the fibroblast marker FSP1. CD68(+) cells within the aortic wall colocalized with the cellular marker of proliferation Ki67. CONCLUSIONS: Stem cells are significantly elevated in infrarenal AAA tissue compared with matched control aortic tissue. Our data also demonstrate that AAA stem cells express macrophage surface antigens but not smooth muscle cell or fibroblast markers. Furthermore, CD68(+) cells within the aortic wall colocalized with the cellular marker of proliferation Ki67. These finding suggest an inflammatory/immune role of stem cells during AAA pathogenesis and raise the possibility of localized replenishment therapy within the aneurysm wall.

The potential role of DNA methylation in abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) is a complex disorder that has a significant impact on the aging population. While both genetic and environmental risk factors have been implicated in AAA formation, the precise genetic markers involved and the factors influencing their expression remain an area of ongoing investigation. DNA methylation has been previously used to study gene silencing in other inflammatory disorders and since AAA has an extensive inflammatory component, we sought to examine the genome-wide DNA methylation profiles in mononuclear blood cells of AAA cases and matched non-AAA controls. To this end, we collected blood samples and isolated mononuclear cells for DNA and RNA extraction from four all male groups: AAA smokers (n = 11), AAA non-smokers (n = 9), control smokers (n = 10) and control non-smokers (n = 11). Methylation data were obtained using the Illumina 450k Human Methylation Bead Chip and analyzed using the R language and multiple Bioconductor packages. Principal component analysis and linear analysis of CpG island subsets identified four regions with significant differences in methylation with respect to AAA: kelch-like family member 35 (KLHL35), calponin 2 (CNN2), serpin peptidase inhibitor clade B (ovalbumin) member 9 (SERPINB9), and adenylate cyclase 10 pseudogene 1 (ADCY10P1). Follow-up studies included RT-PCR and immunostaining for CNN2 and SERPINB9. These findings are novel and suggest DNA methylation may play a role in AAA pathobiology.

Ultrasound-guided percutaneous thrombin injection of iatrogenic upper extremity pseudoaneurysms.

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of ultrasound-guided thrombin injection (TI) for the treatment of upper extremity iatrogenic pseudoaneurysms (PAs) after percutaneous upper extremity arterial access. METHODS: This is a retrospective single-institution study from January 2009 to December 2012. All patients with clinical suspicion of an upper extremity PA after arterial puncture underwent duplex examination. Patients with and without PAs were compared to identify risk factors for development of PAs. Outcomes were analyzed in those patients with PAs that were treated with TI. RESULTS: Between January 1, 2009, and December 31, 2012, there were 61 upper extremity arterial duplex examinations performed for a clinical suspicion of an upper extremity PA. Eighteen ultrasound examinations (29.5%) demonstrated an iatrogenic upper extremity PA (13 brachial and five radial). Those patients with an upper extremity PA were more likely to have a history of hypertension, atrial fibrillation, and chronic kidney disease. Sheath size, preprocedural antiplatelet therapy, periprocedural anticoagulation regimen, service specialty performing the procedure, and procedure type did not influence the development of PA. Of 18 patients with PA, 14 were treated with TI with an overall success rate of 86%. There was one PA that failed to thrombose with TI, and there was one native brachial artery thrombosis requiring emergent surgical intervention. Outpatient clinical follow-up in the successfully treated patients demonstrated no recurrences at an average follow-up of 8 months. CONCLUSIONS: Ultrasound-guided percutaneous TI appears safe and effective for the treatment of iatrogenic brachial and radial artery PAs.

Endoleak visualized with carbon dioxide angiography during endovascular aneurysm repair using the Endurant stent-graft.

PURPOSE: To make interventionists aware of the potential for type IV endoleak on completion carbon dioxide (CO2) angiography during endovascular aneurysm repair (EVAR) using the Endurant stent-graft. CASE REPORT: A 74-year-old man with chronic kidney disease underwent EVAR with an Endurant stent-graft using CO2 angiography to guide graft placement. Completion CO2 angiography demonstrated immediate accumulation of CO2 in the aneurysm sac suggestive of an endoleak, but confirmatory angiography with conventional iodinated contrast showed no evidence of an endoleak. We speculate that this is a type IV endoleak, and graft porosity may be responsible. CONCLUSION: Interventionists should be alerted to the possibility of visualizing these endoleaks through Endurant stent-grafts under CO2 angiography. Further work should be done to elucidate the exact mechanism of the endoleak.

Coronary stent migration to aorta with successful recovery during aortobifemoral bypass.

We present with full and proper consent of the patient, the case of a 64-year-old man with severe peripheral arterial disease and a known chronic infrarenal aortic occlusion causing severe short-distance claudication. Preoperative computed tomography angiography was significant for a new "cylindrical" calcified lesion. During the elective surgery, the lesion was confirmed to be a coronary stent. The coronary stent was confirmed to be from the patient's prior percutaneous coronary intervention to the left anterior descending artery 1 year prior. The stent was removed without complications by the surgical team. To the best of our knowledge, this is the first such case to be described in current literature. This patient is currently alive, and a revision of his left anterior descending artery intervention was found to be unwarranted on repeat coronary angiography.

IL-6 and its receptors in coronary artery disease and acute myocardial infarction.

Biomarkers such as interleukin-6 (IL-6), soluble interleukin-6 receptor (sIL-6R), and high sensitive C-reactive protein (hsCRP) have been reported to be elevated in acute myocardial infarction (AMI). The aim of this study is to determine the relationship between these markers during AMI, as well as their relationship to clinical parameters in an effort to discern their predictive potential in cardiac events. Serum was collected from 73 patients with; AMI, stable coronary artery disease (CAD), and controls during cardiac catheterization. Biomarker levels were determined and correlated with clinical data. IL-6 (11.75pg/ml, P<0.05) and sIL-6R (41,340pg/ml, P=0.05) were elevated in AMI compared with CAD and controls. At presentation, hsCRP was elevated in AMI patients (4.69mg/L) compared to controls (2.69mg/L, P<0.05); however, there was a significant decrease in hsCRP between AMI (4.69mg/L) and CAD patients (7.4mg/L, P<0.05). After 24h post-AMI hsCRP levels were increased compared to stable CAD (60.46mg/L, P<0.05) and were preceded by increased IL-6 at presentation. Soluble Gp130 (sGp130) showed no significant change between AMI, CAD, and control patients. However, sGp130 positively correlated with peak troponin in AMI (R=0.587, P<0.01), and negatively correlated with previous AMI (R=-0.382, P<0.05). Circulating monocyte mRNA expression isolated from selected AMI patients showed an increase in IL-6 mRNA (5.28-fold, P<0.01) and a decrease in both IL-6R (0.374-fold, P<0.01) and sGp130 mRNA (0.38-fold, P<0.01) as compared to CAD and controls. Results demonstrate that IL-6 and sIL-6R are associated with AMI and cardiac injury. These data support the hypothesis that trans-IL-6 receptor binding may alter intracellular signaling, and blocking of IL-6 receptor binding may be pathogenic in AMI. These data may be predictive of mechanism(s) by which plaques become unstable and rupture.

Novel pathways in the pathobiology of human abdominal aortic aneurysms.

OBJECTIVES: Abdominal aortic aneurysm (AAA), a dilatation of the infrarenal aorta, typically affects males >65 years. The pathobiological mechanisms of human AAA are poorly understood. The goal of this study was to identify novel pathways involved in the development of AAAs. METHODS: A custom-designed 'AAA-chip' was used to assay 43 of the differentially expressed genes identified in a previously published microarray study between AAA (n = 15) and control (n = 15) infrarenal abdominal aorta. Protein analyses were performed on selected genes. RESULTS: Altogether 38 of the 43 genes on the 'AAA-chip' showed significantly different expression. Novel validated genes in AAA pathobiology included ADCY7, ARL4C, BLNK, FOSB, GATM, LYZ, MFGE8, PRUNE2, PTPRC, SMTN, TMODI and TPM2. These genes represent a wide range of biological functions, such as calcium signaling, development and differentiation, as well as cell adhesion not previously implicated in AAA pathobiology. Protein analyses for GATM, CD4, CXCR4, BLNK, PLEK, LYZ, FOSB, DUSP6, ITGA5 and PTPRC confirmed the mRNA findings. CONCLUSION: The results provide new directions for future research into AAA pathogenesis to study the role of novel genes confirmed here. New treatments and diagnostic tools for AAA could potentially be identified by studying these novel pathways.

Hemodynamic Monitoring Devices in the Management of Outpatient Heart Failure.

The prevalence of heart failure continues to increase throughout the world. This rise in diagnoses corresponds with high rates of hospitalization, patient and caregiver fatigue, and ever-increasing economic costs. While numerous investigations have been undertaken in the past looking into remote monitoring or telemedicine strategies, they were unable to show an improvement in clinical outcomes with use. Invasive hemodynamic monitoring in the ambulatory setting has been an area of focus for the last several decades as a possible proactive strategy aiding in the evaluation and management of the heart failure population. Several large, randomized trials have not only shown the safety of a pulmonary artery pressure sensor in the heart failure population but have also confirmed the efficacy of pulmonary artery pressure-guided heart failure management in reducing rates of heart failure hospitalizations. Additional novel implantable devices are in various stages of development and clinical investigation and aim to further help aid in the management of this complex patient population. Future strategies are emerging and include the increased development of wearable devices as well as novel technologies to assess hemodynamics and volume status.

Comparison of outcomes with coils versus vascular plug embolization of the internal iliac artery for endovascular aortoiliac aneurysm repair.

OBJECTIVE: To compare the safety and efficacy of coil embolization (COIL) to Amplatzer vascular plug embolization (PLUG) to achieve internal iliac artery (IIA) occlusion prior to endovascular aortiliac aneurysm repair (EVAR). METHODS: Data from consecutive patients who underwent IIA embolization prior to EVAR over a 6-year period (2004-2010) were retrospectively reviewed. Patient demographics, treatment modalities, and outcomes were compared. RESULTS: From January 1, 2004 to December 31, 2010, a total of 53 patients underwent percutaneous embolization of 57 IIAs prior to EVAR. Twenty-nine IIAs underwent COIL and 28 IIAs underwent PLUG embolization. Patient demographics and risk factors were similar between the two groups. Patients underwent repair for aneurysmal dilation of the infrarenal aorta in conjunction with the common or internal iliac arteries (n = 35, 62%) or isolated iliac artery aneurysms (n = 19, 38%). A significantly greater number of embolization devices were used in the COIL group (5.8 ± 3.8 vs 1.1 ± 0.4; P < .0001). Patients undergoing PLUG embolization demonstrated significantly shorter procedure times (118.4 ± 64.7 minutes vs 72.6 ± 22.4 minutes; P = .008) and fluoroscopy times (32.6 ± 14.6 vs 14.4 ± 8.6 minutes; P = .002). However, radiation dose between the groups did not differ (COIL: 470,192.7 ± 190,606.6 vs PLUG: 300,972.2 ± 191,815.7 mGycm(2); P = .10). Overall periprocedural morbidity did not differ between the groups (COIL: 11% vs PLUG: 6%; P = 1.0), and there were no perioperative mortalities or severe complications. Nontarget embolization occurred in two COIL and no PLUG cases (COIL: 6.9% vs PLUG: 0%; P = .49). Patient-reported buttock claudication at 1 month was 17.2% for COIL and 39.3% for PLUG patients (P = .08). At last follow-up, persistent buttock claudication was reported in 13.8% of COIL and in 14.3% of PLUG embolizations (P = 1.0). There was no significant difference in charges for the embolization material, operating room, or overall hospital charges (COIL: 44,720 ± 19,153 vs 37,367 ± 10,915; P = .22). Lastly, zero endoleaks in the COIL group and three in the PLUG group (P = .40) were detected on the most recent follow-up computed tomography imaging. No endoleak was related to the site of IIA embolization. CONCLUSIONS: COIL and PLUG embolization both provide effective IIA embolization with low complication rates when used for EVAR. Buttock claudication did occur in approximately one-third of patients but resolved in half of those affected. PLUG embolization took significantly less time to perform and required decreased fluoroscopy times. Based on outcomes and cost-analysis, COIL and PLUG embolization are equivalent methods to achieve IIA occlusion during EVAR.

Role of complement cascade in abdominal aortic aneurysms.

OBJECTIVE: The goal of this study was to investigate the role of complement cascade genes in the pathobiology of human abdominal aortic aneurysms (AAAs). METHODS AND RESULTS: Results of a genome-wide microarray expression profiling revealed 3274 differentially expressed genes between aneurysmal and control aortic tissue. Interestingly, 13 genes in the complement cascade were significantly differentially expressed between AAA and the controls. In silico analysis of the promoters of the 13 complement cascade genes showed enrichment for transcription factor binding sites for signal transducer and activator of transcription (STAT)5A. Chromatin-immunoprecipitation experiments demonstrated binding of transcription factor STAT5A to the promoters of the majority of the complement cascade genes. Immunohistochemical analysis showed strong staining for C2 in AAA tissues. CONCLUSIONS: These results provide strong evidence that the complement cascade plays a role in human AAA. Based on our microarray studies, the pathway is activated in AAA, particularly via the lectin and classical pathways. The overrepresented binding sites of transcription factor STAT5A in the complement cascade gene promoters suggest a role for STAT5A in the coordinated regulation of complement cascade gene expression.

Albumin-based microbubbles bind up-regulated scavenger receptors following vascular injury.

We have shown previously that perfluorocarbon-exposed sonicated dextrose albumin (PESDA) microbubbles bind to injured vascular tissue and can be detected with ultrasound imaging techniques. Prior studies have shown that scavenger receptors (SRs) are regulators of innate and adaptive immune responses and are involved in the progression of vascular disease such as atherosclerosis. In this study, we sought to determine the molecular mechanism of PESDA binding to balloon-injured vasculature. RT-PCR analysis of angioplastied aortas demonstrated a significantly (p ≤ 0.01) increased expression of SRs. Binding to SRs was confirmed using SR-expressing CHO cells, and this binding was blocked by competitive inhibition with the SR-binding ligands oxidized LDL and malondialdehyde-acetaldehyde-modified LDL. Confocal imaging confirmed the co-localization of PESDA microbubbles to CD36, SRB-1, and Toll-like receptor 4, but not to monocytes/macrophages. This study demonstrates that PESDA binds to SRs and that this binding is in major part dependent upon the oxidized nature of PESDA microbubble shell proteins. The extent of SR mRNA expression was increased with injury and associated with microbubble retention as defined by scanning electron microscopy and immunohistochemistry. These findings clarify the mechanisms of how albumin-based microbubbles bind to injured and inflamed vasculature and further support the potential of this imaging technique to detect early vascular innate inflammatory pathophysiologic processes.

Regional expression of HOXA4 along the aorta and its potential role in human abdominal aortic aneurysms.

BACKGROUND: The infrarenal abdominal aorta exhibits increased disease susceptibility relative to other aortic regions. Allograft studies exchanging thoracic and abdominal segments showed that regional susceptibility is maintained regardless of location, suggesting substantial roles for embryological origin, tissue composition and site-specific gene expression. RESULTS: We analyzed gene expression with microarrays in baboon aortas, and found that members of the HOX gene family exhibited spatial expression differences. HOXA4 was chosen for further study, since it had decreased expression in the abdominal compared to the thoracic aorta. Western blot analysis from 24 human aortas demonstrated significantly higher HOXA4 protein levels in thoracic compared to abdominal tissues (P < 0.001). Immunohistochemical staining for HOXA4 showed nuclear and perinuclear staining in endothelial and smooth muscle cells in aorta. The HOXA4 transcript levels were significantly decreased in human abdominal aortic aneurysms (AAAs) compared to age-matched non-aneurysmal controls (P < 0.00004). Cultured human aortic endothelial and smooth muscle cells stimulated with INF-γ (an important inflammatory cytokine in AAA pathogenesis) showed decreased levels of HOXA4 protein (P < 0.0007). CONCLUSIONS: Our results demonstrated spatial variation in expression of HOXA4 in human aortas that persisted into adulthood and that downregulation of HOXA4 expression was associated with AAAs, an important aortic disease of the ageing population.