Tomislav Stojanovic

New brain lesions after carotid revascularization are not associated with cognitive performance

PURPOSE Carotid angioplasty and stenting (CAS) is increasingly being used as a treatment alternative to endarterectomy (CEA) for patients with significant carotid stenosis. However, diffusion-weighted imaging (DWI) has indicated that CAS is associated with a significantly higher burden of microemboli. This study evaluated the potential effect on intellectual functions of new DWI lesions after CEA or CAS. METHODS This prospective study analyzed the neuropsychologic outcomes after revascularization in 24 CAS and 31 CEA patients with severe carotid stenosis compared with a control group of 27 healthy individuals. All patients underwent clinical examinations, magnetic resonance imaging scans, and a neuropsychologic test battery that assessed six major cognitive domains performed immediately before CEA or CAS, ≤ 72 hours after, and at 3 months. RESULTS New DWI lesions were detected among 15 of 21 (71%) of the CAS patients immediately after treatment but in only 1 of the 28 CEA patients (4%; P < .01). As a group, patients with new DWI lesions showed a decline in their performance in the cognitive domains, attention, and visuoconstructive functions within 72 hours of carotid revascularization. Individually, however, in none of the cognitive domains did the decreases reach a clinically relevant threshold of z < -1.5. Moreover, the cognitive performance was not significantly different between patients with and without new DWI lesions 3 months after treatment. The cognitive performance was similar between CEA and CAS patients at all points. CONCLUSIONS The findings support the assumption that new brain lesions, as detected with DWI after CAS or CEA, do not affect cognitive performance in a manner that is long-lasting or clinically relevant. Despite the higher embolic load detected by DWI, CAS is not associated with a greater cognitive decline than CEA.

Expression of A20 in the vessel wall of rat-kidney allografts correlates with protection from transplant arteriosclerosis.

Background. Chronic rejection with development of transplant arteriosclerosis is the major culprit involved in loss of kidney allografts. The allografts’ fate was thought to depend on the intensity of the host immune responses and the potency of immunosuppressive regimens. Recent data suggests that grafts contribute to their own survival by way of up-regulation of “cytoprotective” genes. Methods. We analyzed the expression of four cytoprotective genes, A20, Bcl-2, Bcl-xL and heme oxygenase (HO)-1, in three rat renal allograft models of chronic rejection: Fisher 344–Lewis (F344/Lew), Dark Agouti–Brown Norway (DA/BN), and DA–Wistar-Furth (WF). We chose these genes for their known anti-inflammatory and anti-apoptotic function in endothelial cells (EC) and the atheroprotective function of A20 in smooth muscle cells (SMC). Results. Twenty-eight and 9 weeks following transplantation, F344/Lew and DA/BN transplants had stable graft function. Histopathologic analysis showed moderate tissue damage, minimal cellular infiltrates, and preserved vascular integrity correlating with high expression of A20 in SMC. Conversely, impaired allograft function in the DA/WF combination with substantial transplant arteriosclerosis was noted in 60% of the grafts correlating with absent or decreased A20 expression in EC and SMC. In all combinations, expression of HO-1, Bcl-2, and Bcl-xL colocalized with infiltrating cells and was not informative on the graft status. Conclusions. We demonstrate for the first time a strict correlation between A20 expression in the vessel and the absence of transplant arteriosclerosis in rat kidney-allograft models. This data is similar to data obtained in human kidney allografts and suggests that A20 may represent a novel therapeutic target for the prevention of chronic allograft rejection.

Thalidomide impairment of trinitrobenzene sulphonic acid‐induced colitis in the rat–role of endothelial cell‐leukocyte interaction

Immune response‐modulating drugs such as thalidomide may be of therapeutic value in the treatment of chronic inflammatory bowel diseases including Crohns disease (CD). In the present study, we have investigated whether thalidomide exerts this effect by impairing endothelial cell‐leukocyte interaction through down‐regulation of the expression of pro‐inflammatory gene products in these cells. Transient CD‐like colitis was induced in male Wistar rats by single enema with trinitrobenzene sulphonic acid (TNBS) in ethanol followed by macroscopic scoring, histology, intravital microscopy, RT–PCR and immunohistochemistry (IHC) analyses. Thalidomide or its analogue supidimide were administered in olive oil by intragastric instillation 6 h prior to the induction of colitis and then daily for one week. Both thalidomide and supidimide (200 mg kg−1 d−1) significantly attenuated TNBS‐induced colitis as compared to vehicle‐treated control animals (44 and 37% inhibition, respectively), and this effect persisted for 7 days post cessation of thalidomide treatment (46% inhibition). Moreover, thalidomide significantly reduced leukocyte sticking to postcapillary venular endothelial cells in the submucosa (by 45%), improved functional capillary density and perfusion, and attenuated endothelial interleukin‐8 expression, as judged by IHC analysis. According to RT–PCR analysis, both thalidomide and supidimide also significantly reduced vascular cell adhesion molecule‐1 mRNA expression in the affected part of the descending colon. These findings suggest that thalidomide and one of its derivatives impairs CD‐like TNBS‐induced colitis in the rat by down‐regulating endothelial adhesion molecule and chemokine expression and, as a consequence, the interaction of these cells with circulating leukocytes.

Role of xanthine oxidoreductase in experimental acute renal-allograft rejection.

Background. Increased oxygen radical production may not only contribute to posttransplant ischemia-reperfusion injury but also to acute rejection of renal allografts. Xanthine oxidoreductase (XOR) may constitute a relevant reactive oxygen species (ROS) source. The study was conducted (1) to determine ROS production as well as oxidant and antioxidant enzyme activities in renal grafts and (2) to modulate acute rejection by tungsten administration, a specific inhibitor of XOR. Methods. Syngraft (Lewis to Lewis, Fisher344 to Fisher344) and allograft (Fisher344 to Lewis) kidney transplantations were performed with or without tungsten administration. Analysis was performed at day 1, 3, or 9 posttransplantation. Results. Generation of ROS was enhanced, being 10-fold higher in renal allografts versus control kidneys at day 9 (P <0.01); this was associated with histologic signs of acute rejection. Oxygen radicals were generated to a significant degree by enhanced XOR activity, which increased more than 10-fold in renal allografts at day 9 posttransplantation; XOR protein in glomeruli and tubulointerstitium was also elevated in allo-grafts. In addition, NADPH oxidase activity increased significantly in allografts. The activity of antioxidant enzymes tended to decrease. Tungsten treatment resulted in a pronounced reduction of XOR activity and ROS production, without any effect on NADPH-oxidase activity; mononuclear cell infiltration and rejection signs were significantly ameliorated at day 9 post-transplantation by selective inhibition of XOR. Conclusions. A major part of ROS generation in acute rejection was contributed by XOR. ROS are not only associated with but also contribute to acute allograft rejection because inhibition of XOR alleviated rejection phenomena.

Met-RANTES inhibition of mucosal perfusion failure in acute intestinal transplant rejection - Role of endothelial cell-leukocyte interaction

Acute rejection-induced microvascular injury results in graft dysfunction, ultimately leading to graft loss. Infiltration of T cells and monocytes as a consequence of an enhanced endothelial cell-leukocyte interaction appears to play an important role in this deleterious process. Recruitment of these pro-inflammatory cells to the vessel wall is mediated by chemokines such as RANTES. Heterotopic small bowel transplantation was performed in rats with the fully allogeneic Brown Norway-Lewis strain combination and, as a control, the syngeneic Lewis-Lewis strain combination. Intravital microscopy was performed from postoperative day 1–7 in both groups. The percentages of perfused villi and villus stasis, mucosal and muscular functional capillary densities, red blood cell velocities, and finally, firm adherence of leukocytes in postcapillary submucosal venules were assessed. Syngeneic small bowel transplantation revealed homogeneous perfusion of villi and muscle layers over the whole study period. Allogeneic small bowel transplantation showed a decline in perfusion from postoperative day 1 until complete failure on postoperative day 7. This was accompanied by a continuous increase in endothelial cell-leukocyte interaction which reached a plateau on postoperative day 5. Met-RANTES treatment at 200 µg/day for 5 days markedly attenuated both the decrease in functional capillary density and the increased endothelial cell-leukocyte interaction in rats following allogeneic small bowel transplantation. We conclude that blocking chemokine receptors, thereby limiting endothelial cell-leukocyte interaction, may constitute a useful therapeutic approach to the prevention of microcirculatory perfusion failure in acute transplant rejection.

Vasoactive intestinal polypeptide and gastrin-releasing peptide attenuate hepatic microvasculatory disturbances following intestinal ischemia and reperfusion

Background/Aims: In addition to the primarily affected small bowel, intestinal ischemia and reperfusion (IIR) also leads to a marked decrease in hepatic microcirculation. The aim was to determine the potentially protective effect of the vasoactive hormones vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP) on hepatic microcirculation following IIR. Methods: Using a rat model, three animal groups were subjected to 40 min of intestinal ischemia, two of which were infused with either VIP or GRP (n = 12 each). Following reperfusion, hepatic intravital microscopy was performed. Portal venous perfusion, activities of serum glutamate pyruvate transaminase and alkaline phosphatase, mucosal injury in the small intestine and the expression of antioxidant enzymes glutathione peroxidase, copper-zinc-superoxide dismutase (Cu-Zn-SOD), glutathione reductase and catalase (CAT) in the liver were investigated. Results: Infusion of either VIP or GRP improved hepatic microcirculation and bile flow when compared with the untreated IIR group. VIP and GRP increased portal venous blood flow during reperfusion. VIP reduced the extent of mucosal damage resulting from IIR. GRP caused a decrease in expression of CAT and Cu-Zn-SOD, whereas VIP simply reduced CAT expression. Conclusion: This study indicates that vasoactive hormones may attenuate intestinal and hepatic injuries and circulatory disturbances following IIR.

A Three-Group Model to Predict Mortality in Emergent Coronary Artery Bypass Graft Surgery

BACKGROUND Emergent coronary artery bypass graft surgery (CABG) for acute myocardial infarction is associated with an increased operative risk. For estimation of mortality risk, the European System for Cardiac Operative Risk Evaluation (EuroSCORE) is appropriate up to a medium risk score (<6 points). To predict mortality risk more accurately in cases of higher EuroSCORE, additional cardiac data can be helpful. METHODS Over a 3-year period, patient data including acute myocardial infarction and emergent CABG were retrospectively reviewed. Univariate and multivariate analysis for in-hospital mortality was performed. The EuroSCORE analysis and follow-up was investigated. RESULTS Overall in-hospital mortality was 18.3%. Preoperative cardiac related predictors for in-hospital mortality were cardiogenic shock (p < 0.001), very poor left ventricular function (p = 0.001), and ST-segment elevation (p = 0.012). In multivariate regression analysis, age, cardiogenic shock, and pulmonary hypertension were independent preoperative risk factors. According to the EuroSCORE, we could define three statistically different groups: intermediate-risk, high-risk, and very high risk, with an observed mortality of 3.3%, 20.0%, and 63.2%, respectively. The EuroSCORE correlates with but overestimates the mortality risk. In subgroup analysis, the creatine kinase-myocardial band/hour ratio for the intermediate-risk group and ST-segment elevation for the high-risk group were additional cardiac risk factors. CONCLUSIONS Patients with an acute myocardial infarction and emergency aortocoronary CABG have an elevated operative risk. Logistic EuroSCORE overestimates the mortality rate. Three different risk groups can be defined, in which creatine kinase-MB/h-ratio and ST-segment elevation can more accurately predict operative risk.

Accelerated intimal hyperplasia in aortocoronary internal mammary vein grafts in minipigs

BackgroundMore than 50% of aortocoronary saphenous vein grafts are occluded 10 years after surgery. Intimal hyperplasia is the initial critical step in the progression toward occlusion. Internal mammary veins, which are physiologically prone to less hydrostatic pressure, may undergo an accelerated progression to intimal hyperplasia and thus be suitable for investigation of the mechanisms of aortocoronary vein graft disease.MethodsSix minipigs underwent aortocoronary bypass grafting using standard cardiopulmonary bypass and cardioplegic arrest. Mammary vein were grafted in a reversed manner from ascending aorta to left anterior descending coronary artery (LAD). The proximal LAD was ligated, rendering the anterior left ventricle vein graft-dependent. Minipigs were killed after 4 weeks, and vein grafts were harvested. Histological and immunohistological investigation were performed with respect to morphometric analysis, endothelial damage/dysfunction (v-Willebrand-factor (vWF)), smooth muscle cells (α-smooth actin) and proliferation rate (proliferation marker Ki 67).ResultsMean intimal area of vein grafts was increased compared to ungrafted mammary veins. Intimal hyperplasia in vein grafts was characterized by massive accumulation of smooth muscle cells with a high proliferation rate and endothelial perturbation. Significant (p = 0.001) intimal hyperplasia of the grafted mammary vein compared to the ungrafted mammary vein was found. These changes were absent in ungrafted mammary veins.ConclusionThe present study demonstrates a pig model of aortocoronary vein graft intimal hyperplasia which is characterized by an accelerated progression within internal mammary veins. The model is suitable to investigate the pathophysiology of aortocoronary vein graft intimal hyperplasia as well as therapeutic approaches.

A peritoneal cavity chamber for intravital microscopy of the liver under conditions of pneumoperitoneum.

BACKGROUND Intravital microscopy allows direct visualization of the hepatic microvasculature. We report on a novel application of this technique using a chamber model that simulates the conditions of pneumoperitoneum. METHODS For this purpose, we designed a peritoneal cavity chamber for rats. In the present study, we evaluated the technical procedure without any induction of increased intraabdominal pressure to assess undisturbed hepatic microcirculation. Intravital microscopy of the liver was performed in 12 rats. Animals that underwent the same operative procedure without the chamber served as controls (n = 12). RESULTS Hepatic sinusoidal perfusion rate, leukocyte-endothelial cell interaction, and bile flow showed no significant differences between the groups. Operating time was longer in the chamber group. CONCLUSION The peritoneal cavity chamber is an attractive approach for the study of hepatic microvascular, cellular, and molecular mechanisms that are important to our understanding of the potential harmful effects of laparoscopy on hepatic circulation and liver function.

Is There an Alternative to the Surgical Above-Knee Bypass in Treatment of Superficial Femoral Artery Disease? Experiences With Viabahn Stent Graft

Objective: We conducted a retrospective study to compare short- and mid-term patencies of Viabahn with surgical above-knee prosthetic bypass (pAKB). Methods: The records of 52 patients with either pAKB (n = 25) or Viabahn (n = 27) were reviewed. The majority had Rutherford clinical grade 3. Patients were followed after 3, 6, and 12 months and yearly thereafter. Results: For Viabahn, the short-term (1-16 months) primary patency rate was 60% with a secondary patency rate of 90%, and mid-term (1-68 months) patencies of 47% and 83.3%, respectively. In pAKB, the short-term results revealed a primary patency rate of 78% with a secondary patency of 91% and mid-term results of 65% and 90%, respectively. No statistical difference was found concerning short-term patencies. Mid-term primary patency was lower for Viabahn (P < .05) and secondary patency proved no significant difference. Conclusion: Viabahn revealed similar short-term primary and secondary patencies but lower mid-term primary patency. It provides a good alternative therapy to pAKB.