Aortoiliac calcification correlates with 5-year survival after abdominal aortic aneurysm repair.

BACKGROUND: An anatomic severity grade (ASG) score to categorize and to define anatomic factors for abdominal aortic aneurysm (AAA) repair was proposed. Other studies have previously reported that aortic anatomic complexity is a marker of survival and resource utilization after repair, although it remains unclear whether individual components of the ASG score independently contribute to survival. This study analyzed and validated an aortic and iliac artery calcium scoring system that can potentially predict survival after AAA repair. METHODS: Patients who underwent infrarenal AAA repairs from July 2007 to May 2012 were analyzed using complete 5-year records. Those who died ≤30 days of surgery were excluded. Calcium score (CS) was defined using the ASG scoring system for its basis by preoperative imaging <6 months before surgery. A CS for any patient was 0 to 5 points, the sum of the points assigned to aortic neck (2 points total) and iliac artery (3 points total) calcification. A receiver operating characteristic curve was used to determine a CS threshold for mortality. The 5-year survivors and deaths were compared in regard to comorbidities, pharmacology, and CS at or above the defined threshold. Each variable with a P value <.1 between the groups was then placed into a Cox proportional hazards model, with statistical significance of P < .05. RESULTS: There were 356 patients who underwent AAA repair with complete 5-year follow-up data; 26% died within 5 years of surgery. Of these, 13% had CS of 0 with 15% mortality, 28% had CS of 1 with 21% mortality, 24% had CS of 2 with 24% mortality, 23% had CS of 3 with 35% mortality, 10% had CS of 4 with 40% mortality, and 2% had CS of 5 with 17% mortality. The receiver operating characteristic curve demonstrated an appropriate threshold of CS 3. Of these patients, 65% had a CS <3, whereas 35% had a CS ≥3. Patients with a CS ≥3 had a lower 5-year survival probability (P = .003). Comparing 5-year survivors and deaths in a Cox proportional hazards analysis, CS ≥3 was associated with a hazard ratio of 1.579 (95% confidence interval, 1.038-2.402; P = .0328). CONCLUSIONS: A CS ≥3 is linked to a lower 5-year survival after AAA repair in our population. This system potentially can be another measure for risk stratification and serve as a means to predict midterm mortality in AAA repairs. Future study will be needed for further validation to predict midterm mortality and to better guide surgical decision-making.

Acute traumatic aortic injury: practical considerations for the diagnostic radiologist.

The diagnosis of acute traumatic aortic injury (ATAI) relies heavily on accurate and efficient imaging interpretation, thereby making the radiologist integral to the care of patients in whom these life-threatening lesions are suspected. Typically, this evaluation begins with the initial trauma radiograph, in which findings suggestive of mediastinal hematoma or ATAI can be detected. Definitive diagnosis of ATAI is made with the current gold standard, computed tomography, wherein indirect and direct signs of ATAI provide the means for sensitive and specific diagnosis. Although the diagnosis of ATAI on computed tomography can be straightforward, technical and anatomic pitfalls can complicate interpretation and must be understood. Once the diagnosis is made, the radiologist needs to provide a meaningful report that includes an appropriate description of the lesion location and characteristics. The purpose of this article is to review the key aspects of the imaging evaluation of ATAI with a focus on factors that affect the management of these patients.

Early hypercholesterolemia contributes to vasomotor dysfunction and injury associated atherogenesis that can be inhibited by nitric oxide.

OBJECTIVE: Atherosclerosis results in vasomotor dysfunction, in part, through impairment of nitric oxide (NO) dependent vasodilation. It is unclear whether blood vessels are dysfunctional in an early environment of hypercholesterolemia alone and if this contributes to the vascular injury response. We hypothesize that early hypercholesterolemia, prior to gross vascular changes, contributes to vasomotor dysfunction and the vascular injury response. The efficacy of NO therapy to protect against the injury response in this setting was also assessed. METHODS: The effect of oxidized low density lipoprotein (oxLDL) and inducible NO synthase (iNOS) gene transfer on rat aortic smooth muscle cell (SMC) proliferation was measured with (3)H-thymidine incorporation. Common carotid arteries (CCA) from wild-type C57BL6 (WT or C57) and apolipoprotein E deficient (ApoE KO) mice fed normal or Western diets for 6 to 8 weeks were tested for vasomotor function using an arteriograph system. Studies were repeated after CCA injury. The effect of iNOS gene transfer on morphometry by histology and vasomotor responses in injured CCAs in ApoE KO was examined. RESULTS: OxLDL increased SMC proliferation by >50%. In SMC expressing iNOS, NO production was unaffected by oxLDL and reduced oxLDL and still inhibited SMC proliferation. Endothelium dependent vasorelaxation was reduced in uninjured CCAs from ApoE KO and C57 mice on the Western vs normal diet (ApoE 39% ± 2% vs 55% ± 13%; C57 50% ± 13% vs 76% ± 5%, P < .001) and was increased with longer durations of hypercholesterolemia. Endothelium-dependent and independent vasodilator responses were severely disrupted in C57 and ApoE KO mice 2 weeks following CCA injury but both recovered by 4 weeks. CCA injury in ApoE KO mice resulted in the formation of atheromatous lesions while C57 mice showed no change (intima 27,795 ± 1829 vs 237 ± 28 µm(2); media 46,306 ± 2448 vs 11,714 ± 392 µm(2), respectively; P < .001). This structural change in the ApoE KO reduced distensibility and increased stiffness. Finally, iNOS gene transfer to injured CCA in ApoE KO mice dramatically reduced atheromatous neointimal lesion formation. CONCLUSIONS: Early hypercholesterolemia impairs endothelial function, with severity being related to duration and magnitude of hypercholesterolemia. Severe hypercholesterolemia leads to atheromatous lesion formation following injury and stresses the role of vascular injury in atherogenesis and suggests different mechanisms are involved in endothelial dysfunction and the injury response. Despite these changes, iNOS gene transfer still effectively inhibits atheroma formation. These findings support early correction of hypercholesterolemia and emphasize the potential role for NO based therapies in disease states.

Nitric oxide-dependent bone marrow progenitor mobilization by carbon monoxide enhances endothelial repair after vascular injury.

BACKGROUND: Carbon monoxide (CO) has emerged as a vascular homeostatic molecule that prevents balloon angioplasty-induced stenosis via antiproliferative effects on vascular smooth muscle cells. The effects of CO on reendothelialization have not been evaluated. METHODS AND RESULTS: Exposure to CO has diametrically opposite effects on endothelial cell (EC) and vascular smooth muscle cell proliferation in rodent models of carotid injury. In contrast to its effect of blocking vascular smooth muscle cell growth, CO administered as a gas or as a CO-releasing molecule enhances proliferation and motility of ECs in vitro by >50% versus air controls, and in vivo, it accelerates reendothelialization of the denuded artery by day 4 after injury versus day 6 in air-treated animals. CO enhanced EC proliferation via rapid activation of RhoA (Ras homolog gene family, member A), followed by downstream phosphorylation of Akt, endothelial nitric oxide (NO) synthase phosphorylation, and a 60% increase in NO generation by ECs. CO drives cell cycle progression through phosphorylation of retinoblastoma, which is dependent in part on endothelial NO synthase-generated NO. Similarly, endothelial repair in vivo requires NO-dependent mobilization of bone marrow-derived EC progenitors, and CO yielded a 4-fold increase in the number of mobilized green fluorescent protein-Tie2-positive endothelial progenitor cells versus controls, with a corresponding accelerated deposition of differentiated green fluorescent protein-Tie2-positive ECs at the site of injury. CO was ineffective in augmenting EC repair and the ensuing development of intimal hyperplasia in eNOS(-/-) mice. CONCLUSIONS: Collectively, the present data demonstrate that CO accelerates EC proliferation and vessel repair in a manner dependent on NO generation and enhanced recruitment of bone marrow-derived endothelial progenitor cells.

Inhaled carbon monoxide prevents graft-induced intimal hyperplasia in swine.

BACKGROUND: Arteriovenous grafts often fail due to stenosis caused by venous anastomotic intimal hyperplasia (IH) and vascular smooth muscle cell (VSMC) proliferation. We examined the effects of inhaled carbon monoxide (CO), a product of heme-oxygenase-1 degradation of heme, on IH in a porcine arteriovenous graft model. MATERIALS AND METHODS: Eighteen Yorkshire pigs were divided into three groups (N = 6/group): (1) CO 100 ppm preoperatively for 1 h; (2) CO 250 ppm preoperatively for 1 h and intraoperatively; and (3) air-treated controls. Animals underwent end-to-side placement of polytetrafluoroethylene grafts connecting the common femoral artery and vein in both groins. Intimal thickness of the venous anastomosis at 30 days was measured blinded. The effect of CO on pig VSMC proliferation was studied in cell culture using [(3)H]thymidine incorporation. RESULTS: Pigs in the group receiving CO 250 ppm showed significantly less IH compared to animals in the group receiving 100 ppm and the air-treated group (267.5 +/- 21.4, 824 +/- 145.8, and 914.8 +/- 133.7 pixels, respectively, P < 0.0001). This effect was not observed when comparing the 100 ppm group to the air-treated group. COHb levels were significantly elevated in the 100 ppm and 250 ppm compared to air-treated pigs (5.8 +/- 0.47, 13.2 +/- 1.0 versus 2.3 +/- 0.11%, respectively, P < 0.001). Oxygen saturation, respiratory rate, and hemodynamics were not significantly different between the groups. CO induced VSMC growth arrest compared to air in vitro (11.9 +/- 4 versus 20.3 +/- 5 10(3) counts/min/well, P < 0.01). CONCLUSION: A single exposure to a low concentration of inhaled CO (250 ppm) confers protection against intimal proliferation of VSMCs when given perioperatively in a clinically relevant model of arteriovenous grafts. These data are the first to suggest, in a clinically relevant model, the potential role for CO in clinical applications.

Inhaled carbon monoxide inhibits intimal hyperplasia and provides added benefit with nitric oxide.

OBJECTIVE: Carbon monoxide (CO) and nitric oxide (NO) have both been shown to possess vasoprotective properties. NO has successfully inhibited intimal hyperplasia in both small-animal and large-animal experimental models, whereas CO has only been studied in rodents. Evidence suggests that these two molecules may exert their vascular effects through common as well as unique signaling pathways. The purpose of this study was to determine the effect of a low concentration of inhaled CO on intimal hyperplasia in a large-animal model and if CO and NO treatment could exert a synergistic effect to inhibit this process. METHODS: Balloon angioplasty was performed in a porcine model. Animals received inhaled CO (250 ppm) delivered preoperatively for 60 minutes or preoperatively and intraoperatively. Blood was collected for carboxyhemoglobin (COHgb) measurements at the start of the operation and every 30 minutes during the operation. Heart rate, respiratory rate, and oxygen saturation were monitored throughout. To study the effect of combined CO and NO treatment, another group of pigs received inducible NO synthase (iNOS) gene transfer in one iliac artery and control gene transfer (AdlacZ) in the contralateral iliac artery, with or without preoperative and intraoperative inhaled CO. Adenoviral infection was performed immediately after balloon injury. All animals were euthanized at 3 weeks, and iliac arteries were collected for histologic and morphometric analysis. RESULTS: One hour of pretreatment with CO was associated with modest and transient elevations in COHgb levels, resulting in a 25.6% reduction in neointimal area and a 10% reduction in intimal area/medial area ratio (I/M) 3 weeks after injury (NS). In contrast, preoperative followed by intraoperative CO administration increased COHgb in a sustained fashion and inhibited neointima formation by 51.7% and I/M by 31% (P < .001). There was no evidence of toxicity associated with this administration of CO. The treatment of injured iliac arteries with the control adenoviral vector AdlacZ did not further increase the inhibitory effect of CO on intimal hyperplasia. The combination of inhaled CO and iNOS gene transfer resulted in greater protection, however, with a 64% reduction in neointimal area and a 48% reduction in I/M (P < .001). CONCLUSIONS: CO is an effective means of reducing intimal hyperplasia in large animals after vascular injury when delivered during the operative procedure. No toxicity was associated with the increase in COHgb. The combination of CO and NO provided additional protection against the vascular injury response, with a greater reduction in neointima formation. These data suggest that these agents may prove to be clinically beneficial in prolonging vascular patency after interventions.

The role of RAGE in the pathogenesis of intestinal barrier dysfunction after hemorrhagic shock.

The receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of numerous conditions associated with excessive inflammation. To determine whether RAGE-dependent signaling is important in the development of intestinal barrier dysfunction after hemorrhagic shock and resuscitation (HS/R), C57Bl/6, rage(-/-), or congenic rage(+/+) mice were subjected to HS/R (mean arterial pressure of 25 mmHg for 3 h) or a sham procedure. Twenty-four hours later, bacterial translocation to mesenteric lymph nodes and ileal mucosal permeability to FITC-labeled dextran were assessed. Additionally, samples of ileum were obtained for immunofluorescence microscopy, and plasma was collected for measuring IL-6 and IL-10 levels. HS/R in C57Bl/6 mice was associated with increased bacterial translocation, ileal mucosal hyperpermeability, and high circulating levels of IL-6. All of these effects were prevented when C57Bl/6 mice were treated with recombinant human soluble RAGE (sRAGE; the extracellular ligand-binding domain of RAGE). HS/R induced bacterial translocation, ileal mucosal hyperpermeability, and high plasma IL-6 levels in rage(+/+) but not rage(-/-) mice. Circulating IL-10 levels were higher in rage(-/-) compared with rage(+/+) mice. These results suggest that activation of RAGE-dependent signaling is a key factor leading to gut mucosal barrier dysfunction after HS/R.

Nitric oxide modulates vascular inflammation and intimal hyperplasia in insulin resistance and the metabolic syndrome.

Type 2 diabetes mellitus (DM) and the metabolic syndrome, both characterized by insulin resistance, are associated with an accelerated form of atherosclerotic vascular disease and poor outcomes following vascular interventions. These vascular effects are thought to stem from a heightened inflammatory environment and reduced bioavailability of nitric oxide (NO). To better understand this process, we characterized the vascular injury response in the obese Zucker rat by examining the expression of adhesion molecules, the recruitment of inflammatory cells, and the development of intimal hyperplasia. We also evaluated the ability of exogenous NO to inhibit the sequela of vascular injury in the metabolic syndrome. Obese and lean Zucker rats underwent carotid artery balloon injury. ICAM-1 and P-selectin expression were increased following injury in the obese animals compared with the lean rats. The obese rats also responded with increased macrophage infiltration of the vascular wall as well as increased neointima formation compared with their lean counterparts (intima/media = 0.91 vs. 0.52, P = 0.001). After adenovirus-mediated inducible NO synthase (iNOS) gene transfer, ICAM-1, P-selectin, inflammatory cell influx, and oxidized low-density lipoprotein (LDL) receptor expression were all markedly reduced versus injury alone. iNOS gene transfer also significantly inhibited proliferative activity (54% and 73%; P < 0.05) and neointima formation (53% and 67%; P < 0.05) in lean and obese animals, respectively. The vascular injury response in the face of obesity and the metabolic syndrome is associated with increased adhesion molecule expression, inflammatory cell infiltration, oxidized LDL receptor expression, and proliferation. iNOS gene transfer is able to effectively inhibit this heightened injury response and reduce neointima formation in this proinflammatory environment.

Adenovirus-mediated nitric oxide synthase gene transfer.

The varied biological effects of nitric oxide (NO) have led to intense research into its diverse physiologic and pathophysiologic roles in multiple disease processes. It has been implicated in the development of altered vasomotor tone, intimal hyperplasia, atherosclerosis, impotence, host defense, and wound healing. Using the modern technologies of recombinant DNA and gene transfer using adenoviral vectors, the effects of NO derived from various NO synthase (NOS) enzymes can be studied in a variety of tissues and the therapeutic applications of NOS is possible. Such uses of NOS gene transfer have been investigated extensively in the vasculature where NO is critical to regulating vascular homeostasis. NOS gene therapy has the theoretical advantage of allowing NO delivery to be localized, thereby limiting potential adverse effects of NO. The benefits of adenoviral vectors in gene transfer include relatively high transduction efficiencies, both replicating and nonreplicating cells may be infected, and the high titers of adenovirus that can be produced. The methods described in this chapter include the cloning of the iNOS cDNA into a recombinant adenoviral vector, large-scale production of that vector AdiNOS preparation, and the use of the vector to transduce tissue in vitro and in vivo.

Disease progression in contralateral carotid artery is common after endarterectomy.

OBJECTIVE: Although the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Study (ACAS) have helped to define the role of carotid endarterectomy (CEA) for both symptomatic and asymptomatic lesions, the role of surveillance of the contralateral carotid artery remains unclear. The purpose of this study was to determine the progression of contralateral carotid artery disease with serial duplex ultrasound scans after CEA compared with the recurrent stenosis rate for the carotid artery ipsilateral to the CEA. METHODS: From January 1990 to December 2000, 473 CEA procedures were performed at a Veterans Affairs Medical Center. From this group we identified 279 patients who had undergone first-time CEA, as well as preoperative duplex scanning and postoperative duplex scanning at least once, in the vascular laboratory. At each visit stenosis of the internal carotid artery (ICA) was categorized as none (0%-14%), mild (15%-49%), moderate (50%-79%), severe (80%-99%), or occluded. Analysis of probability of freedom from progression was determined. Progression was defined as an increase in ICA stenosis 50% or greater or increase to a higher category of stenosis if baseline was 50% or greater. The Cox proportional hazards model was used for data analysis. RESULTS: Mean patient age was 65.7 years (range, 33-100 years). The 1024 carotid duplex ultrasound scanning examinations performed (mean, 3.7; range, 2-13) included the last study done before the index CEA and all studies done after the CEA. Mean follow-up was 27 months (range, 1-137 months). Forty-six patients were found to have contralateral carotid occlusion at initial duplex scanning, and were therefore excluded from the contralateral progression analysis. Contralateral progression was more frequent than ipsilateral recurrent stenosis at long-term follow-up (P <.01). Annual rates of "any progression" and "progression to severe stenosis or occlusion" were 8.3% and 4.4%, respectively, for contralateral arteries, and 4.3% and 2.4%, respectively for ipsilateral arteries. As a result of surveillance, 43 contralateral CEAs (19% of initial cohort) were performed. Carotid stenosis regressed in 25 arteries (10.7%). Baseline clinical and demographic factors did not predict disease progression. Baseline contralateral stenosis did not predict time to "any progression," but was a strong predictor of "progression to severe stenosis or occlusion" (P <.001). CONCLUSIONS: After CEA, we identified an 8.3% annual rate of progression of contralateral carotid artery stenosis and a 4.4% annual rate of progression to severe stenosis or occlusion. Baseline contralateral stenosis was significantly predictive of progression to severe stenosis or occlusion. Clinical and demographic factors were not helpful in predicting which patients would have disease progression. These data may help in assessing the cost effectiveness of duplex scanning surveillance after CEA.

Color-flow duplex ultrasound scan versus computed tomographic scan in the surveillance of endovascular aneurysm repair.

OBJECTIVE: The purpose of this study is to compare both computed tomographic scan (CT) and color flow duplex ultrasound scanning (CDU) as surveillance modalities for clinically significant endoleaks and to evaluate concordance in abdominal aortic aneurysm (AAA) diameter measurements in patients after endovascular aneurysm repair (EVAR) in a busy hospital vascular laboratory. METHODS: We conducted a retrospective review of all patients who underwent endovascular repair of abdominal aortic aneurysms between February 1996 and November 2002 and had same-day CT and CDU studies. Ninety-seven patients enrolled in phase II clinical studies of Ancure devices had long-term follow-up with both modalities. The other patients underwent simultaneous studies, usually only at the 1-month postoperative visit. Peripheral vascular studies were performed by two certified vascular technicians; all CT scans were reviewed by one vascular surgeon. CT was used as the standard against which the sensitivity, specificity, negative predictive value, and positive predictive value of CDU in endoleak detection was determined. Statistics were performed by using the paired t test; a P value <.05 was considered significant. Kappa statistic was used to assess the correlation between CDU and CT in identifying endoleaks. The correlation between CT and CDU in AAA size measurements as well as in serial size measurements was also determined. RESULTS: Four hundred ninety-five same-day CT and CDU examinations were reviewed in 281 patients. Patients had an average follow-up of 34.6 months (range, 1 to 72 months). Thirty-five leaks were identified among the patients studied (12.4% overall). In comparison with CT, diagnosis of endoleak with ultrasound scanning was associated with a sensitivity of 42.9%, specificity of 96.0%, positive predictive value of 53.9%, and negative predictive value of 93.9%. The correlation between the two modalities was modest (kappa statistic 0.427). The minor axis transverse diameter as measured by ultrasound and CT scans (4.81 +/- 1.1 cm on CT and 4.55 +/- 1.1 cm on ultrasound) correlated closely (r =.93, P <.001.) Seventy percent of paired studies differed by < or =5 mm. Changes in aneurysm size throughout follow-up were -.29 +/-.71 cm on CT scan -.34 +/-.57 cm on duplex ultrasound scan. The correlation coefficient was.65 (P <.001). There was no significant difference in the change as measured by either modality on the paired t test. CONCLUSIONS: Although CDU demonstrates a high degree of correlation with CT scan in determining aneurysm size change over time, it has a low sensitivity and positive predictive value in endoleak detection. In the hospital vascular laboratory at a large tertiary care center, CDU cannot effectively replace CT scan in surveillance after EVAR.