[Revascularisation of Asymptomatic Carotid Stenosis - Reasonable or Obsolete?]

INTRODUCTION: Recommendations for surgical versus conservative treatment of asymptomatic carotid stenosis (ACS) are based on prospective randomized trials, some of which were performed several decades ago. However, during this time, "best medical treatment" (BMT) for conservative therapy of arteriosclerotic patients has evolved significantly. Because of the associated risk reduction of ACS, surgical therapy is increasingly being questioned. By identifying clinical and morphological risk parameters, subgroups could be identified that might, however, benefit from invasive therapy. Consequently, multidisciplinary therapy decision-making requires an increasingly patient-individualized approach.

Patients with Acute Limb Ischemia Might Benefit from Endovascular Therapy-A 17-Year Retrospective Single-Center Series of 985 Patients.

Acute lower limb ischemia (ALI) is a common vascular emergency, requiring urgent revascularization by open or endovascular means. The aim of this retrospective study was to evaluate patient demographics, treatment and periprocedural variables affecting the outcome in ALI patients in a consecutive cohort in a tertiary referral center. Primary outcome events (POE) were 30-day (safety) and 180-day (efficacy) combined mortality and major amputation rates, respectively. Secondary outcomes were perioperative medical and surgical leg-related complications and the 5-year combined mortality and major amputation rate. Statistical analysis used descriptive and uni- and multivariable Cox regression analysis. In 985 patients (71 ± 9 years, 56% men) from 2004 to 2020, the 30-day and 180-day combined mortality and major amputation rates were 15% and 27%. Upon multivariable analysis, older age (30 d: aHR 1.17; 180 d: 1.27) and advanced Rutherford ischemia stage significantly worsened the safety and efficacy POE (30 d: TASC IIa aHR 3.29, TASC IIb aHR 3.93, TASC III aHR 7.79; 180 d: TASC IIa aHR 1.97, TASC IIb aHR 2.43, TASC III aHR 4.2), while endovascular treatment was associated with significant improved POE after 30 days (aHR 0.35) and 180 days (aHR 0.39), respectively. Looking at five consecutive patient quintiles, a significant increase in endovascular procedures especially in the last quintile could be observed (17.5% to 39.5%, p < 0.001). Simultaneously, the re-occlusion rate as well as the number of patients with any previous revascularization increased. In conclusion, despite a slightly increasing early re-occlusion rate, endovascular treatment might, if possible, be favorable in ALI treatment.

Preventing Lower Limb Graft Thrombosis after Infrainguinal Arterial Bypass Surgery with Antithrombotic Agents (PATENT Study): An International Expert Based Delphi Consensus.

(1) Background: High-level evidence on antithrombotic therapy after infrainguinal arterial bypass surgery in specific clinical scenarios is lacking. (2) Methods: A modified Delphi procedure was used to develop consensus statements. Experts voted on antithrombotic treatment regimens for three types of infrainguinal arterial bypass procedures: above-the-knee popliteal artery; below-the-knee popliteal artery; and distal, using vein, prosthetic, or biological grafts. The treatment regimens for these nine procedures were then voted on in three clinical scenarios: isolated PAOD, atrial fibrillation, and recent coronary intervention. (3) Results: The survey was conducted with 28 experts from 15 European countries, resulting in consensus statements on 25/27 scenarios. Experts recommended single antiplatelet therapy after above-the-knee popliteal artery bypasses regardless of the graft material used. For below-the-knee popliteal artery bypasses, experts suggested combining single antiplatelet therapy with low-dose rivaroxaban if the graft material used was autologous or biological. They did not recommend switching to triple therapy for patients on oral anticoagulants for atrial fibrillation or dual antiplatelet therapy in any scenario. (4) Conclusions: Great inconsistency in the antithrombotic therapy administered was found in this study. This consensus offers guidance for scenarios that are not covered in the current ESVS guidelines but must be interpreted within its limitations.

ORal anticoagulation risks late aortic intervention in Conservatively managed type B Aortic dissection (ORCA study).

OBJECTIVES: Single-center retrospective cohort study to evaluate the impact of oral anticoagulation (OAC) on long-term outcomes of conservatively managed acute type B aortic dissection. METHODS: Clinical and morphological data of eligible patients from a high-volume vascular centre from 1 January 2003 through 31 December 2020 were evaluated. Patients were excluded for: type A or non-A-non-B dissection, isolated abdominal dissection, intramural haematoma and connective tissue disease. The primary outcome was freedom from late aortic events (intervention, rupture and mortality). Secondary outcomes included spinal cord ischaemia, bleeding, reno-visceral artery occlusion, ilio-femoral intervention, dissection propagation, aortic growth, aortic remodelling, deterioration of false lumen thrombosis as well as 30-day and overall mortality. Time to event was analysed using multivariable Cox proportional hazard models with OAC as time-varying covariate and mortality as a competing risk. The impact of OAC was adjusted for potential confounding factors. RESULTS: A total of 69 patients [50 males, median age 65 (interquartile range: 58-72) years] were enrolled. The median follow-up was 49.3 (28-92) months. A total of 47 patients (68%) received OAC at any time throughout the follow-up for a median length of 26 (11-61) months. Late aortic events occurred in 28 patients (41%) including intervention (n = 27, 39%) and rupture (n = 1, 1%). OAC was associated with more late aortic events (hazard ratio 3.94, 95% confidence interval 1.06-14.6, P = 0.040). Secondary outcomes were not associated with OAC. CONCLUSIONS: Our data suggest a relation of OAC therapy with an increased risk for late aortic interventions. Type B aortic dissection should not be the primary indication for OAC and patients with OAC for other indications require frequent follow-up imaging.

Acute abdominal aortic occlusion: A 16-year single-center experience.

BACKGROUND: Acute abdominal aortic occlusion (AAO) is a rare vascular emergency associated with high morbidity and mortality. In the present study, we analyzed the clinical management and outcomes for a consecutive patient series during a 16-year period. METHODS: We included all patients with an acute AAO and bilateral acute limb ischemia who had been treated between 2004 and 2019. Patients with dissection, aneurysm rupture, or chronic occlusive disease were excluded. The patient characteristics, surgical procedures, and outcomes were extracted retrospectively from a prospective aortic database, electronic patient files, and outpatient examination records. The extent of ischemia was classified according to the TASC II (Inter-Society Consensus for the Management of Peripheral Arterial Disease) section on acute limb ischemia. The primary endpoints were 30-day mortality (safety endpoint) and the combined 6-month amputation and/or death rate (efficacy endpoint). The follow-up outcomes, amputation rates, and 30-day complications were evaluated as secondary endpoints. The patient cohort was divided into four 4-year groups (2004-2007, 2008-2011, 2012-2015, 2016-2019) to assess the outcome changes over time. Statistical analysis included χ2 tests and univariate and linear regression analyses. RESULTS: A total of 74 patients (57% male; median age, 64.5 years) with an acute AAO were identified. Arterial thrombosis was the most common etiology (66%). The extent of ischemia was TASC I, IIa, IIb, and III in 7%, 39%, 40%, and 14%, respectively. The patient numbers had increased significantly over time (P = .016). Of the patients, 42% had undergone open transfemoral recanalization (including hybrid procedures), 35% open aortic surgery, 15% extra-anatomic bypass surgery, and 5% (four patients) endovascular therapy alone. The overall 30-day mortality rate was 23%, and the 6-month amputation and/or death rate was 43%. The 30-day mortality rate had declined significantly from 54% for 2004 to 2007 to 10% for 2011 to 2015 (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.001-0.52) and 20% for 2016 to 2019 (OR, 0.21; 95% CI, 0.05-0.90), a statistically nonsignificant trend showing that the relative decline in the use of open aortic procedures was associated with decreased 30-day mortality (P = .06). Univariate analysis indicated that elevated serum lactate on admission (OR, 3.33; 95% CI, 1.06-10.48) and an advanced stage of limb ischemia (OR, 4.33), were strongly associated with an increased 30-day mortality rate. The incidence of severe postoperative systemic complications also indicated a greater incidence of both primary endpoints. The 6-month amputation and/or mortality rates were also affected by the presence of atrial fibrillation (OR, 3.63; 95% CI, 1.34-9.79) and increased patient age (OR, 3.96; 95% CI, 1.49-10.53). CONCLUSIONS: Acute AAO remains a life-threatening emergency. Immediate transfemoral open or endovascular techniques should be preferred, if technically possible and proper intraoperative imaging is available.

Substitution of perioperative albumin deficiency disorders (SuperAdd) in adults undergoing vascular, abdominal, trauma, or orthopedic surgery: protocol for a randomized controlled trial.

BACKGROUND: Hypalbuminemia is associated with numerous postoperative complications, so a perioperative albumin substitution is often considered. The objective of SuperAdd is to investigate whether substitution of human albumin, aiming to maintain a serum concentration > 30 g/l, can reduce postoperative complications in normovolemic surgical patients in comparison with standard care. METHODS/DESIGN: SuperAdd is a single-center, prospective, randomized, outcome-assessor blinded, patient blinded controlled trial. The primary outcome is the frequency of postoperative complications identified using the Postoperative Morbidity Survey graded ≥ 2 according to the Clavien-Dindo Score. Adult patients at risk to develop hypalbuminemia, i.e., ASA III or IV or high-risk surgery, are recruited after written informed consent was obtained. The albumin concentration is assessed before the induction of anesthesia and every 3 h until admission to the postanesthesia care unit. If albumin concentrations drop below 30 g/l, patients are randomly allocated to the control or the treatment group. The study intervention is a goal-directed human albumin substitution aimed at a concentration > 30 g/l during surgery and postanesthesia care unit stay. The patients in the control group are treated according to standard clinical care. Postoperative visits are to be performed on days 1, 3, 5, 8, and 15, as well as by telephone 6 months after surgery. DISCUSSION: SuperAdd is the first clinical trial in a surgical population investigating the effect of a goal-directed albumin substitution aiming at a serum level > 30 g/l. The nonrestrictive selection of patients guarantees that the patients without albumin screening will most likely not develop hypalbuminemia, thus ensuring generalizability of the study results. TRIAL REGISTRATION: EudraCT 2016-001313-24. Registered on 5 September 2016. Clinical Trials NCT03167645. Registered on 18 October 2016 and has the Universal Trial Number (UTN) U1111-1181-2625.

Biobanking: Objectives, Requirements, and Future Challenges-Experiences from the Munich Vascular Biobank.

Collecting biological tissue samples in a biobank grants a unique opportunity to validate diagnostic and therapeutic strategies for translational and clinical research. In the present work, we provide our long-standing experience in establishing and maintaining a biobank of vascular tissue samples, including the evaluation of tissue quality, especially in formalin-fixed paraffin-embedded specimens (FFPE). Our Munich Vascular Biobank includes, thus far, vascular biomaterial from patients with high-grade carotid artery stenosis (n = 1567), peripheral arterial disease (n = 703), and abdominal aortic aneurysm (n = 481) from our Department of Vascular and Endovascular Surgery (January 2004⁻December 2018). Vascular tissue samples are continuously processed and characterized to assess tissue morphology, histological quality, cellular composition, inflammation, calcification, neovascularization, and the content of elastin and collagen fibers. Atherosclerotic plaques are further classified in accordance with the American Heart Association (AHA), and plaque stability is determined. In order to assess the quality of RNA from FFPE tissue samples over time (2009⁻2018), RNA integrity number (RIN) and the extent of RNA fragmentation were evaluated. Expression analysis was performed with two housekeeping genes-glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and beta-actin (ACTB)-using TaqMan-based quantitative reverse-transcription polymerase chain reaction (qRT)-PCR. FFPE biospecimens demonstrated unaltered RNA stability over time for up to 10 years. Furthermore, we provide a protocol for processing tissue samples in our Munich Vascular Biobank. In this work, we demonstrate that biobanking is an important tool not only for scientific research but also for clinical usage and personalized medicine.

Expression of a metalloproteinase family of ADAMTS in human vulnerable carotid lesions.

AIMS: ADAMTS family of metalloproteases (a disintegrin and metalloprotease with thrombospondin motifs) possesses high proteolytic activity especially regarding proteoglycans. Their expression pattern in carotid plaques is as-yet unknown. The aim of the study was therefore the analysis of expression of ADAMTS1, 4, 5, and 13 and their inhibitors TIMP-1 and TIMP-3 in stable and unstable carotid plaques. METHODS: Atherosclerotic plaques were collected from 40 patients (29 men, 11 women, mean age 70 years) undergoing carotid endarterectomy. The specimens were categorized into two groups (stable/unstable) according to Redgrave und Rothwell (The Oxford Plaque Study, 2008). SYBR Green-based real-time PCR, histology, and immunohistochemistry were performed. RESULTS: All ADAMTS tested in our study were expressed in both stable and unstable plaques, especially in smooth muscle cells (SMCs) and macrophages. Analysis of the expression pattern on mRNA level showed significant higher expression of ADAMTS1 in unstable plaques compared with stable plaques (1.7-fold, P = 0.049). The expression of ADAMTS4 and 5 was also increased in unstable lesions; however, these changes were not statistically significant (1.2-fold, P = 0.667 and 1.6-fold, P = 0.077). Expression of TIMP-1 was significantly reduced in unstable plaques compared with stable ones (1.9-fold, P = 0.014). CONCLUSION: SMCs seem to be an important source of ADAMTS analyzed in our study. Furthermore, expression of ADAMTS1 was found to be increased in unstable carotid lesions and might potentially contribute to plaque vulnerability.

Sodium Bicarbonate Prevents Contrast-Induced Nephropathy in Addition to Theophylline: A Randomized Controlled Trial.

In this study, we investigated whether hydration with sodium bicarbonate is superior to hydration with saline in addition to theophylline (both groups) in the prophylaxis of contrast-induced nephropathy (CIN). It was a prospective, randomized, double-blinded study in a university hospital on 2 general intensive care units (63% of investigations) and normal wards.After approval of the local ethics committee and informed consent 152 patients with screening serum creatinine ≥1.1 mg/dL and/or at least 1 additional risk factor for CIN undergoing intravascular contrast media (CM) exposure were randomized to receive a total of 9 mL/kg bicarbonate 154 mmol/L (group B; n = 74) or saline 0.9% (group S; n = 78) hydration within 7 h in addition to intravenous application of 200 mg theophylline. Serum creatinine was determined immediately before, 24 and 48 h after CM exposure. As primary endpoint we investigated the incidence of CIN (increase of serum creatinine ≥0.5 mg/dL and/or ≥25% within 48 h of CM).Both groups were comparable regarding baseline characteristics. Incidence of CIN was significantly less frequent with bicarbonate compared to sodium hydration (1/74 [1.4%] vs 7/78 [9.0%]; P = 0.035). Time course of serum creatinine was more favorable in group B with decreases in serum creatinine after 24 h (-0.084 mg/dL [95% confidence interval: -0.035 to -0.133 mg/dL]; P = 0.008) and 48 h (-0.093 mg/dL (-0.025 to -0.161 mg/dL); P = 0.007) compared to baseline which were not observed in group S.In patients at increased risk of CIN receiving prophylactic theophylline, hydration with sodium bicarbonate reduces contrast-induced renal impairment compared to hydration with saline.

Single-dose gadobutrol in comparison with single-dose gadobenate dimeglumine for magnetic resonance imaging of chronic myocardial infarction at 3 T.

OBJECTIVES: The aim of this study was to compare the contrast-to-noise ratio (CNR) values of infarct and remote myocardium as well as infarct and blood after application of 0.1 mmol/kg gadobutrol and 0.1 mmol/kg gadobenate dimeglumine on late gadolinium enhancement magnetic resonance (MR) images. MATERIAL AND METHODS: The study was a prospective randomized controlled clinical study. After informed consent was obtained, 20 patients (12 men, 8 women; mean age, 67 ± 11 years) with known chronic myocardial infarction were included for an intraindividual comparison of a single-dose gadobutrol and a single-dose gadobenate dimeglumine. Two MR imaging examinations were performed within a period of 28 days in a crossover design. Late gadolinium enhancement imaging was performed 10 minutes after gadolinium administration using a 2-dimensional phase-sensitive inversion recovery gradient echo sequence at 3 T. Infarct size, signal intensities (SIs), signal-to-noise ratio, and CNR were determined on phase-sensitive MR images. Values for CNR were calculated as CNRinfarct/myocardium = (SIinfarct - SImyocardium)/SDnoise and CNRinfarct/blood = (SIinfarct - SIblood)/SDnoise. In addition, the areas of myocardial infarction were determined on single slices. The entire infarct volumes were calculated by adding the areas with hyperenhancement multiplied by the slice thickness. RESULTS: Late gadolinium enhancement was present in all patients. Median values of the infarct area, infarct volume, and transmurality for gadobutrol and gadobenate dimeglumine showed good to excellent concordance (rc = 0.85, rc = 0.95, and rc = 0.71, respectively). The mean signal-to-noise ratio values for infarct, remote myocardium, and ventricular blood were 18.6 ± 6.5, 4.1 ± 3.7, and 14.6 ± 7.5, respectively, for gadobutrol and 18.8 ± 8.9, 4.9 ± 4.5, and 17.8 ± 10.1, respectively, for gadobenate dimeglumine (P = 0.93, P = 0.48, and P = 0.149, respectively). The mean values of CNRinfarct/myocardium and CNRinfarct/blood were 14.5 ± 5.9 and 4.0 ± 4.6, respectively, for gadobutrol and 13.9 ± 6.1 and 0.9 ± 4.5, respectively, for gadobenate dimeglumine (P = 0.69 and P = 0.02, respectively). CONCLUSION: Both gadobutrol and gadobenate dimeglumine allow for successful late gadolinium enhancement imaging of chronic myocardial infarction after a single-dose application (0.1 mmol/kg) at 3 T. Gadobutrol provides a higher CNR between infarct and blood. The CNRs between infarct and normal myocardium, infarct size, and transmural extent were similar for both contrast agents.

Expression and cellular localization of metalloproteases ADAMs in high graded carotid artery lesions.

Metalloproteases with a disintegrin domain (ADAM) has already been implicated in various cellular processes such as cytokine and growth factor shedding, proliferation, migration, and degradation of extracellular matrix. Their role in the development and progression of atherosclerosis in carotid lesions is however unknown. The aim of the study was to analyze expression of proteolytic ADAMs (8, 9, 10, 12, 15, 17) and their inhibitors TIMP-1, -3 in patients with high-graded carotid artery stenosis. Atherosclerotic plaques were obtained from 44 patients undergoing carotid endarterectomy (CEA) and analyzed by histochemistry, immunohistochemistry, and SYBR green-based real-time PCR. All ADAMs analyzed in our study were expressed in early as well as in advanced atherosclerotic carotid lesions. The highest expression within the plaque was observed for ADAM15 followed by ADAM8. Furthermore, a significant increase was observed in the expression of ADAM10 and ADAM12 in unstable plaques compared to unstable lesions (p = 0.05 and p = 0.036, respectively). In contrast, expression of TIMP-1 was significantly reduced in the same lesions (p = 0.020). Macrophages and smooth muscle cells showed the highest staining intensity and were positive for all ADAMs and TIMPs tested, with the exception of ADAM9. Endothelial cells at the lumen side were positive for ADAM 15 and TIMP-1, neovessels were positive also for ADAM12. In conclusion, the ADAM family of proteases seems to play an important role in the maintenance of proper vessel physiology and some ADAMs such as ADAM10 and ADAM12 might also contribute to the progression of atherosclerosis.

Angiographic assessment of cardiac allograft vasculopathy: results of a Consensus Conference of the Task Force for Thoracic Organ Transplantation of the German Cardiac Society.

Angiograms of cardiac transplant (HTx) recipients were to be evaluated in a ring experiment and a joint consensus on criteria of angiographic evaluation of coronary arteries of HTx patients was to be reached. Twenty-four coronary angiograms from 11 hospitals were circulated. One hundred eighty-eight blinded evaluations were returned. A joint evaluation by six experienced cardiologists was used as reference standard and a consensus evaluation form was developed. Significant lesions (stenosis 75%, 50% in the left main coronary artery) were diagnosed in 10/23 abnormal coronary angiograms (41.7%). Interventional revascularization was recommended in 8/10 (80%). In 21 coronary angiograms distal pruning was found and in 11/21 (52.4%) cases with distal pruning occlusion of at least one peripheral vessel was detected. The best kappa value (0.7) was found for the presence of at least one clinically significant stenosis. Agreement on the site and grade of local stenosis was much less. Some agreement on remodeling was found in assessing diffuse narrowing in the LCA (kappa=0.371, P<0.001). The kappa value for peripheral obliteration was 0.331 (P=0.001). Angiographic evaluation of cardiac allograft vasculopathy, particularly of diffuse and peripheral disease and remodeling, needs standardization. This should be performed in a downward compatible improvement process.

Depression and disease severity as correlates of everyday physical activity in heart transplant candidates.

It is unclear to what extent patients awaiting heart transplantation (HTx) engage in physical activities. We examined the everyday physical activity and its associations with depressive symptoms and disease severity in 318 patients newly registered for HTx in the multi-site study 'Waiting for a New Heart' (aged 53.5 +/- 11.4 years, 18% female patients). Participants completed questionnaires assessing depressive symptomatology and physical activity (number of physical activities, caloric expenditure associated with each activity), and estimated the distance they were able to walk without a break. Medical parameters at the time of listing [e.g. peak oxygen consumption (peakVO(2)); the German Transplant Society Score (GTSS)] were provided by Eurotransplant. Almost 50% of patients engaged in activities of daily living (housework, walking), but <10% engaged in regular exercise. All physical activity measures correlated significantly with peakVO(2) (Ps < 0.01). Elevated depression scores were present in 39% of patients. Controlling for confounding variables (e.g. peakVO(2), diastolic blood pressure, GTSS, age), depressive symptomatology accounted for additional variance in all physical activity measures (Ps < 0.05). The association of depressive symptoms with reduced physical activity suggests two important perspectives: attempts to increase physical activity (especially in the area of daily living) might benefit from targeting depression, and increased physical activity might also help to reduce depressive symptoms.

AP-1 and STAT-1 decoy oligodeoxynucleotides attenuate transplant vasculopathy in rat cardiac allografts.

AIMS: Cardiac allograft vasculopathy (CAV) continues to be an unsolved clinical problem requiring the development of new therapeutic strategies. We have previously demonstrated that ex vivo donor allograft treatment with decoy oligodeoxynucleotides (ODN) targeting the transcription factors, activator protein-1 (AP-1) or signal transducer and activator of transcription-1 (STAT-1), delays acute rejection and prolongs cardiac allograft survival. Here, we investigated whether this treatment regime also prevents the occurrence of CAV in a fully allogeneic rat heart transplantation model. METHODS AND RESULTS: Wistar-Furth rat cardiac allografts were perfused ex vivo with AP-1 decoy ODN, STAT-1 decoy ODN, or buffer solution and transplanted into the abdomen of Lewis rats immunosuppressed with cyclosporine. Treatment with both decoy ODNs but not vehicle significantly attenuated the incidence and severity of CAV. Laser-assisted microdissection/real-time polymerase chain reaction as well as immunohistochemistry analyses revealed a significant increase in CD40 abundance in the coronary endothelial cells and medial smooth muscle cells on day 1 post transplantation which was virtually abolished upon AP-1 or STAT-1 decoy ODN treatment. While the AP-1 decoy ODN primarily attenuated basal CD40 expression, the STAT-1 decoy ODN suppressed tumour necrosis factor-alpha-/interferon-gamma-stimulated expression of CD40 in rat native endothelial cells. CONCLUSION: Treating donor hearts with decoy ODNs neutralizing AP-1 or STAT-1 at the time of transplantation prevents upregulation of CD40 expression in the graft coronary arteries and effectively inhibits CAV.

STAT-1 and AP-1 decoy oligonucleotide therapy delays acute rejection and prolongs cardiac allograft survival.

OBJECTIVE: Acute myocardial rejection is a cell-mediated process characterized by increased leukocyte recruitment into the graft myocardial tissue. Transcription factors like STAT-1 and AP-1 are critically involved in this process by regulating vascular adhesion molecule expression. The aim of our study was to investigate the effect of decoy oligodeoxynucleotide (dODN) treatment targeting transcription factors AP-1 and STAT-1 on acute cardiac allograft rejection in a rat transplant model. METHODS: Wistar-Furth (WF) cardiac allografts were transplanted into Lewis (LEW) rats after perfusion with STAT-1 or AP-1 dODN solution (5 micromol/l), buffer or the corresponding mutant control ODNs. Grafts were harvested and processed for histologic and immunohistochemical evaluation. RESULTS: As demonstrated by fluorescence dye-labelled dODN, exposure of the grafts to the dODNs during 45 min of warm ischemia resulted in a dominant uptake of naked DNA by the graft endothelium. Treatment with AP-1 and STAT-1 dODNs, but not with vehicle or the control dODNs, significantly prolonged cardiac allograft survival by approximately 40% from 5.6+/-0.5 days to 7.8+/-1.3 days and 7.4+/-0.5 days, respectively (mean+/-S.D., p<0.01, n=5 in each group). Immunohistochemical examination on days 1, 3 and 6 revealed a marked reduction of infiltrating leukocytes (AP-1 dODN: 85%, STAT-1 dODN: 50%), namely T-cells, in the dODN-perfused grafts at day 3 post transplantation. In addition, as demonstrated by immunohistochemical analysis, endothelial expression of ICAM-1 and VCAM-1 was found to be markedly reduced in dODN-treated grafts. CONCLUSION: Both AP-1 and STAT-1 dODN treatments suppress graft endothelial adhesion molecule expression, reduce graft infiltration and in turn significantly delay acute rejection. The utilization of dODNs in the cardioplegic solution might be a novel strategy to protect transplanted organs from early damage during transplantation, to preserve organ function and bridge the critical phase after transplantation when standard immunosuppression is not yet completely effective.

3-Deazaadenosine prevents leukocyte invasion by suppression of adhesion molecule expression during acute cardiac allograft rejection: involvement of apoptotic cell death.

BACKGROUND: In the initial phase after cardiac transplantation, mononuclear cells infiltrate the graft, initiating a relevant impulse for rejection. 3-Deazaadenosine (c3Ado), an analog of adenosine, has proven anti-inflammatory properties both in vitro and in vivo. We hypothesized that c3Ado can serve as a therapeutic tool to reduce cellular infiltration in cardiac allograft transplantation. METHODS: Using the Wistar-Furth-to-Lewis rat cardiac allograft model, animals were treated with 5 mg c3Ado subcutaneously twice per day. Allografts of untreated animals served as controls. Grafts were harvested on Days 1, 3 and 6 after transplantation for further examination (n = 4 per group and timepoint). RESULTS: Immunohistochemical examination of c3Ado-treated grafts revealed up to 80% reduction of infiltrating major histocompatability complex (MHC) II-positive cells and T-cell-receptor-positive cells (R73) as well as ED1-positive monocytes and macrophages at Days 3 and 6 after transplantation. Adhesion molecule (ICAM-1 and VCAM-1) expression at Days 1 and 3 was almost completely abolished in c3Ado-treated grafts. However, c3Ado treatment did not prevent apoptotic cell death (TUNEL assay, DNA laddering) at Day 6, nor did it prolong allograft survival. As in controls, grafts were rejected at Day 7. CONCLUSION: c3Ado significantly reduces graft infiltration by preventing leukocyte invasion, most likely through suppression of adhesion molecule expression. Although graft survival was not prolonged, treatment with c3Ado may still serve as a strategy to protect hearts from early damage after transplantation. Further studies will show whether peri-operative use of c3Ado can bridge the critical phase after transplantation when standard immunosuppression is not yet completely efficacious.

Effect of dopamine on inflammatory status in kidneys of brain-dead rats.

BACKGROUND: Brain death has been identified as an independent risk factor for chronic allograft dysfunction. In two independent retrospective clinical studies, we showed that dopamine treatment of brain-dead donors improves long-term kidney graft survival. The mechanisms underlying the protective effects of dopamine treatment in vivo have not been identified. To elucidate the mechanisms underlying the protective effect of dopamine on kidneys of brain-dead donors, we studied a model for brain death in rats. METHODS: In F344 rats, brain death was induced by epidural inflation of a 3F Fogarty catheter. Apneic animals were mechanically ventilated, and clinically relevant dosages of dopamine (2, 6, 10, or 14 microg/kg/min) were given for 6 hr from the onset of brain death. Ventilated, non-brain-dead animals served as controls. RESULTS: Dopamine significantly reduced renal monocyte infiltration and major histocompatibility class II and P-selectin expression in brain-dead animals. It also prevented further up-regulation of the inflammatory markers tumor necrosis factor-alpha and monocyte chemoattractant peptide-1. Concomitantly, the presence of inducible anti-oxidant heme oxygenase-1, known for its cytoprotective effects, was strongly increased by dopamine. CONCLUSION: We identified several mechanisms underlying the protective effects of dopamine treatment on kidney grafts. The identification of these mechanisms may help to design more effective future strategies for treatment of cadaveric kidney donors.