Kathleen G. Raman

SUPPRESSION OF ACCELERATED DIABETIC ATHEROSCLEROSIS BY THE SOLUBLE RECEPTOR FOR ADVANCED GLYCATION ENDPRODUCTS

Accelerated atherosclerosis in patients with diabetes is a major cause of their morbidity and mortality, and it is unresponsive to therapy aimed at restoring relative euglycemia. In hyperglycemia, nonenzymatic glycation and oxidation of proteins and lipids results in the accumulation of irreversibly formed advanced glycation endproducts. These advanced glycation endproducts engage their receptor in cells of the blood vessel wall, thereby activating mechanisms linked to the development of vascular lesions. We report here a model of accelerated and advanced atherosclerosis in diabetic mice deficient for apolipoprotein E. Treatment of these mice with the soluble extracellular domain of the receptor for advanced glycation endproducts completely suppressed diabetic atherosclerosis in a glycemia- and lipid-independent manner. These findings indicate interaction between the advanced glycation endproducts and their receptor is involved in the development of accelerated atherosclerosis in diabetes, and identify this receptor as a new therapeutic target in diabetic macrovascular disease.

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.

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.

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.

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.

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.

Aortoiliac Calcification Correlates With 5-Year Survival After Abdominal Aorta Aneurysm Repair

Background: In 2002, the Committee for Standardized Reporting Practices in Vascular Surgery of the Society for Vascular Surgery/American Association for Vascular Surgery proposed an anatomic severity grade score to categorize and to define anatomic factors as they relate to infrarenal abdominal aorta aneurysms (AAAs). The original purpose of this score was to quantitatively assess anatomic complexity of the aorta before undertaking a repair. Our group previously reported that aortic anatomic complexity is a marker of atherosclerotic risk and resource utilization at the time of repair. However, it remains unclear whether individual components to this scoredspecifically the aortic and iliac calcium burdend independently contribute to midterm survival after AAA repair. The purpose of this study was to analyze and to validate an aortic and iliac artery calcium scoring system that can predict midterm mortality after AAA repair. These data have direct implications for the population management-based treatment of aortic aneurysmal disease. Methods: Patients with complete 5-year records who underwent open and endovascular infrarenal AAA repairs between July 2007 and May 2012 at the University of Rochester Medical Center were retrospectively identified using Current Procedural Terminology (American Medical Association, Chicago, Ill) codes 34800, 34802, 34803, 34804, and 34805. To avoid potential interference from perioperative mortality, those who died within 30 days of surgery were not included. Degree of vessel calcification was obtained from preoperative computed tomography scans no more than 6 months before surgery, calculated manually using three-dimensional reconstruction software (Philips Intellispace Portal; Koninklijke Philips Electronic NV, Andover, Mass) by two blinded reviewers. Calcium score (CS) was defined using the anatomic severity grade scoring system for its basis. The scoring is as follows: For aortic neck calcium:

IP159. Inpatient Hemodialysis Access Surgery Results in Higher 30-Day and 2-Year Mortality Compared with Outpatient Surgery

Adjusted HR (95% CI) P value Medicaid 1.31 (1.29-1.33) <.001 Medicare/Veterans Affairs 1.46 (1.44-1.48) <.001 Primary reason of ESRD Diabetes 1 (Reference) Hypertension 0.96 (0.95-0.97) <.001 Glomerulonephritis 0.81 (0.80-0.82) <.001 Cystic kidney disease 0.65 (0.64-0.68) <.001 Other 1.04 (1.03-1.05) <.001 Comorbidities Obesity 0.88 (0.87-0.89) <.001 Alcohol dependence 1.19 (1.17-1.22) <.001 Current smoker 1.15 (1.14-1.17) <.001 Congestive heart failure 1.30 (1.29-1.31) <.001 Cerebrovascular disease 1.08 (1.07-1.09) <.001 Peripheral arterial disease 1.10 (1.10-1.11) <.001 Hypertension 0.85 (0.84-0.86) <.001 Diabetes 1.07 (1.06-1.08) <.001 Chronic obstructive pulmonary disease 1.25 (1.23-1.26) <.001 Atherosclerotic heart disease 1.04 (1.03-1.05) <.001 Cancer 1.30 (1.29-1.31) <.001 Amputation 1.16 (1.14-1.18) <.001 Drug dependence 1.21 (1.18-1.24) <.001 Inability to ambulate 1.56 (1.55-1.58) <.001 Nephrocare None 1 (Reference) <6 months 0.99 (0.98-1.00) .04 6-12 months 0.98 (0.97-0.99) <.001 >12 months 0.91 (0.91-0.92) <.001