15-deoxyspergualin 对移植心冠状动脉硬化及血小板衍化生长因子A mRNA表达的影响

目的　探讨免疫抑制剂 15 deoxyspergualin(15 DSG)对移植心冠状动脉硬化 (GCA)的影响及可能机理。方法　以大鼠异位心脏移植为模型 ,受鼠按组分别给予环孢素A (CsA) 10mg·kg-1·d-1(对照组 )或 15 DSG 5mg·kg-1·d-1(DSG组 )腹腔内注射 ,于移植后第 6 0d摘取移植心 ,切片观察管径大于 5 0 μm的所有冠状动脉、排斥反应程度及移植心血小板衍化生长因子A(PDGF A)mRNA的表达。结果　DSG组的冠状动脉硬化发生率及其程度、移植心PDGF AmRNA的表达程度均显著低于对照组 (P <0 .0 5及P <0 .0 1) ,而排斥反应程度两组间的差异无显著性 (P >0 .0 5 )。结论　 15 DSG能减缓移植心冠状动脉硬化 ,该作用可能与 15 DSG抑制移植心PDGF AmRNA的表达有关。     

The angiotensin II type 1 receptor blocker candesartan attenuates graft vasculopathy

OBJECTIVE: Transplant arteriosclerosis remains the major cause of graft failure after cardiac transplantation, although recent progress in immunosuppressive therapy has dramatically improved short-term survival of recipient. We investigated the effects of the angiotensin II type 1 receptor (AT(1)R) blocker candesartan on the development of transplant arteriosclerosis in a murine model of cardiac transplantation. MATERIALS AND METHODS: Hearts from DBA/2 (H-2(d)) mice were heterotopically transplanted into B10.D2 (H-2(d)) mice. Recipients were treated with oral administration of candesartan (1 mg/kg per day) or vehicle. Allografts were analyzed at 14 or 30 days after transplantation. RESULTS: Candesartan significantly reduced the development of coronary arteriosclerosis (intima/media ratio: 0.86 +/- 0.09 versus 0.57 +/- 0.10, P < 0.05), without affecting the degree of parenchymal rejection at 30 days. There was no significant difference in the expression of adhesion molecules and cytokines at 14 days. Candesartan significantly reduced the number of peripheral mononuclear cells that differentiated into smooth muscle-like cells in the presence of basic fibroblast growth factor and platelet-derived growth factor BB (27.1 +/- 3.1 versus 17.3 +/- 1.8 cells/HPF, P < 0.05). CONCLUSIONS: Angiotensin II may play a role in the pathogenesis of transplant arteriosclerosis. Blockade of AT(1)R might be effective as a prophylactic therapy for transplant arteriosclerosis along with conventional immunosuppressive drugs.     

Effect of angiotensin-converting enzyme inhibition on growth factor mRNA in chronic renal allograft rejection in the rat

BACKGROUND: Despite considerable progress in immunosuppression, the incidence of chronic renal allograft rejection has not decreased. Recent studies have revealed that angiotensin-converting enzyme (ACE) inhibition ameliorates graft arteriosclerosis, glomerulosclerosis, and tubular atrophy. Moreover, it decreases systemic and glomerular capillary hydrostatic pressure in a rat kidney allograft model. We evaluated the effects of the ACE inhibitor enalapril on cytokine and growth factor expression in chronically rejecting rat kidney allografts. METHODS: Kidneys of Fisher (F344) rats were orthotopically transplanted into Lewis (Lew) rats. To prevent acute rejection, cyclosporine A (1.5 mg/kg/day) was given to all recipients during the first 10 days after transplantation. Enalapril (60 mg/L) or vehicle was added to the drinking water 10 days after transplantation. Animals were harvested 20 weeks after transplantation for histologic and immunohistologic studies, as well as for evaluation of cytokine and growth factor mRNA by semiquantitative polymerase chain reaction. RESULTS: Controls developed severe signs of chronic rejection, such as glomerular and vascular lesions, associated with a large number of infiltrating leukocytes. Enalapril-treated animals developed less proteinuria and other signs of chronic rejection. The mRNA levels of transforming growth factor-beta 1 (TGF-beta 1), platelet-derived growth factor A and B chain (PDGF A and B), insulin-like growth factor-I (IGF-I), interleukin-1 (IL-1), and monocyte chemoattractant protein-1 (MCP-1) were significantly reduced in the enalapril group and were most pronounced for IL-1 and PDGF A. In addition, we found an increased level of renal angiotensinogen mRNA after treatment with enalapril. CONCLUSIONS: Treatment with enalapril attenuated the development of proteinuria, ameliorated morphological damage, decreased leukocyte infiltration, and prevented a rise in renal mRNA levels of growth factors and cytokines in kidney grafts in a rat model of chronic renal allograft rejection.     

Inhibition of accelerated cardiac allograft arteriosclerosis by fish oil

Accelerated coronary arteriosclerosis remains the most important factor limiting long-term survival of heart transplant recipients, and dietary fish oil supplementation with omega-3 polyunsaturated fatty acids has been suggested to have a protective effect against coronary disease in epidemiologic studies and to inhibit arteriosclerosis in animal experiments. Therefore we tested the hypothesis that fish oil administration inhibits the development of allograft coronary arteriosclerosis by using a heterotopic heart transplant model. Three groups of Lewis rats (n = 10 each) received heterotopic heart transplants from Brown-Norway donors and were treated with cyclosporine intraperitoneally on a tapering schedule. Group 1 received fish oil daily by gavage (2 ml/kg/day; Emulsified Super MaxEpa, Twin Labs, Ronkonkona, N.Y.). Group 2 received an equal amount of safflower oil, as well as aspirin (1 mg/kg/day) and dipyridamole (3 mg/kg/day). Group 3 received safflower oil only. All rats were put to death 110 days later, at which time there was no statistically significant difference in graft function as assessed by palpation (scale 0 to 4, mean = 3.7 +/- 0.5 [+/- standard deviation]; analysis of variance: p = 0.72) or in microscopic grade of rejection (scale, 0 = none to 3 = severe, mean 2.1 +/- 0.6; analysis of variance: p = 0.68) between any of the groups. The coronary arteries were histologically scored for the degree of arteriosclerosis (scale, 0 = normal to 3 = occluded), and a mean grade of coronary disease was calculated for each heart. The fish oil-treated group had significantly less severe allograft coronary arteriosclerosis (analysis of variance: p = 0.005) than did groups 2 and 3 (mean grade 0.23 +/- 0.22 versus 1.04 +/- 0.75 and 0.96 +/- 0.55 (p less than 0.05, Scheffe F test), whereas groups 2 and 3 had similar degrees of coronary disease (p = no significant difference). These data demonstrate that fish oil supplementation inhibited accelerated coronary arteriosclerosis in this cyclosporine-treated heart allograft rat model, whereas antiplatelet agents in these doses were ineffective. Although the mechanism of this protective effect remains incompletely understood, it does not appear to involve enhanced immunosuppression. Fish oil and specific omega-3 polyunsaturated fatty acids should be further investigated as potentially useful agents to ameliorate accelerated allograft coronary arteriosclerosis in other animal species and perhaps eventually in man.     

A 10-year experience with intravenous thymoglobuline in induction of immunosuppression following heart transplantation

BACKGROUND: Intravenous thymoglobuline (125 mg a day for 3 days, Institut Mérieux, France) has been used to induce immunosuppression following heart transplantation. Cyclosporine and prednisone, with and without azathioprine or mycophenolate mofetil were used as maintenance immunosuppression. OBJECTIVE: The objective of the study was to determine the clinical effect of antibody induction of immunosuppression following heart transplantation. METHODS: A retrospective analysis of the clinical experience at the Montreal Heart Institute. From 1988 to 1998, 163 patients were administered a 3-day course of intravenous thymoglobuline immediately following heart transplantation (Group 1). From 1983 to 1987 and during an isolated period in 1994, intravenous and oral cyclosporine was used immediately following heart transplantation in 48 patients (Group 2). Routine endomyocardial biopsies were performed in all patients and only moderate and severe rejection was treated. RESULTS: One, 5- and 10-year actuarial survival rate averaged 85%+/-3, 77%+/-4 and 67%+/-5 in Group 1 compared with 88%+/-5, 81%+/-6 and 76%+/-6 in Group 2 (p = 0.5). At 1 year, the freedom rate from an episode of acute rejection averaged 43%+/-4 in Group 1 and 30%+/-7 in Group 2 (p = 0.03) and the freedom rate from an episode of infection averaged 44%+/-4 in Group 1 and 31%+/-7 in Group 2 (p = 0.2). At 1, 5 and 10 years, the freedom rate from graft coronary artery disease averaged 93%+/-2, 68%+/-5 and 50%+/-7 in Group 1 compared with 93%+/-4, 58%+/-8 and 30%+/-8 in Group 2 (p = 0.1) and the freedom rate from cancer averaged 98%+/-1, 91%+/-3 and 67%+/-8 in Group 1 compared with 100%, 95%+/-3 and 77%+/-8 in Group 2 (p = 0.2). There was no side-effect related to the systemic injection of thymoglobuline. CONCLUSION: In a cyclosporine based protocol of immunosuppression, induction with an initial 3-day course of intravenous thymoglobuline is associated with a lower rate of acute rejection. Moreover, the risk of infection and of developing cancer is not increased whereas there was a trend towards a lower incidence of coronary atherosclerosis 5 and 10 years after transplantation.     

Use of basiliximab and cyclosporine in heart transplant patients with pre-operative renal dysfunction.

BACKGROUND: The combined use of basiliximab and cyclosporine in heart transplantation is under investigation. In this study we sought to evaluate the safety and efficacy of basiliximab and delayed initiation of cyclosporine in patients with renal dysfunction undergoing heart transplantation. METHODS: Seven patients (Group A) with renal dysfunction (creatinine > or =200 micromol/liter) received induction therapy with basiliximab. Seven patients (Group B) with renal dysfunction comprised the control group and received induction therapy with rabbit anti-thymocyte serum. Cyclosporine was initiated 5 days post-transplant in Group A and within 5 days post-transplant in Group B. RESULTS: All patients were alive at the end of the 6-month follow-up. In Group A, mean pre-transplant creatinine was 243 +/- 48 micromol/liter, at 1 week post-transplant was 180 +/- 39 micromol/liter (p = 0.02), at 1 month was 166 +/- 57 micromol/liter (p = 0.019), at 3 months was 182 +/- 25 micromol/liter (p = 0.01) and at 6 months was 179 +/- 45 micromol/liter (p = 0.024). In Group B, mean pre-transplant creatinine was 242 +/- 41 micromol/liter, at 1 week was 140 +/- 35 micromol/liter (p = 0.0003), at 1 month was 143 +/- 38 mumol/liter (p = 0.0005), at 3 months was 138 +/- 37 micromol/liter (p = 0.0003) and at 6 months was 154 +/- 30 micromol/liter (p = 0.0006). There were no differences in renal dysfunction between both groups at 1 week (p = 0.069), 1 month (p = 0.39) or 6 months (p = 0.24) post-HT. Fewer episodes of cellular rejection were identified in Group B within the 6-month follow-up period. CONCLUSIONS: The use of induction therapy either with basiliximab or rabbit anti-thymocyte serum in patients with pre-operative renal dysfunction confers renal protection early and up to 6 months post-transplant. Delayed initiation of cyclosporine might be considered to provide additional renal protection.     

Sirolimus attenuates chronic allograft nephropathy in an experimental rat kidney transplantation model

Chronic allograft nephropathy (CAN) is the primary reason for late allograft loss in kidney transplantation. The use of calcineurin inhibitors is suggested to be a risk factor for the development of CAN. Thus, calcineurin-inhibitor-free immunosuppressive protocols are needed to improve long-term graft outcome. Sirolimus affects the immune response by interfering with postreceptor interleukin-2 signaling. Safety profile of sirolimus is different from that of calcineurin inhibitors. We investigated the long-term effects of sirolimus on kidney allografts and fibrogenic growth factor expression and compared it to cyclosporine A. Kidney transplantations were performed from DA to WF rats and syngenic controls were done between DA rats. Allograft recipients were immunosuppressed daily with sirolimus 2 p.o. or CsA 1.5 mg/kg s.c. In addition, sirolimus-treated animals were treated with cyclosporine 1.5 mg/kg s.c. for the first 7 days after transplantation. Serum creatinine levels were measured once a week. Grafts were harvested 90 days after transplantation for histology and immunohistochemistry. Histological changes were scored according to the chronic allograft damage index (CADI). No signs of CAN were seen in syngenic grafts, CADI 0.8 +/- 0.2 (mean +/- SEM). In cyclosporine-treated allografts moderate to intense chronic changes were seen; CADI 10.3 +/- 0.6. Sirolimus significantly ameliorated the development of CAN compared to cyclosporine, CADI 3.0 +/- 0.5 (P < .05). Creatinine values of sirolimus-treated allografts were lower compared to the cyclosporine-treated allografts and were nearly similar to the syngenic grafts. Our results demonstrate that sirolimus attenuates the development of CAN and restores kidney function. Based on our findings, sirolimus improves the long-term kidney graft outcome.     

Immunomodulatory functions of hyaluronate in the LEW-to-F344 model of chronic cardiac allograft rejection

BACKGROUND: CD44 is an important leukocyte cell surface glycoprotein with diverse functions including cell adhesion, homing, migration, and activation. METHODS: Because administration of the principal ligand of CD44, hyaluronate (HA), in soluble form, can inhibit CD44-HA interaction, we tested the effects of HA in vivo in an established model of chronic allograft rejection. Control F344 recipients of LEW hearts received either no treatment or low-dose cyclosporine (CsA) for 30 days from the day of transplantation. Experimental animals received 30 days of CsA in combination with 30 or 90 days of low molecular weight HA (LMW-HA). RESULTS: CsA therapy alone resulted in approximately 40% long-term (>100 days) graft survival, whereas CsA + LMW-HA (30-day and 90-day protocols) significantly increased long-term graft survival to 60% and 92%, respectively. Light microscopy and immunohistology of CsA-treated and CsA + LMW-HA-treated grafts harvested at day 30 after transplantation demonstrated that LMW-HA + CsA therapy decreased mononuclear cell infiltration and afforded better preservation of myocardial architecture. In addition, LMW-HA + CsA-treated grafts exhibited decreased expression of interferon-gamma and the growth factors transforming growth factor-beta, platelet-derived growth factor, and fibrogenic growth factor-beta. Long-term surviving grafts were assessed for arteriosclerosis, the sine qua non of chronic rejection in this model. Using a standardized scoring system, significantly less arteriosclerosis was seen in grafts from LMW-HA + CsA-treated animals at 120 days after transplantation compared with CsA alone-treated grafts. This difference was not significant, however, in grafts harvested at >150 days. CONCLUSION: This is the first report indicating that CD44-HA interactions play an important role in chronic allograft rejection.     

Increased expression of transforming growth factor-beta and eosinophil infiltration is associated with the development of transplant arteriosclerosis in long-term surviving cardiac allografts

BACKGROUND: Transplant arteriosclerosis is a major limiting factor for long-term function of allografts in clinical transplantation. This study investigated the impact of three different protocols capable of inducing long-term allograft survival on the development of transplant arteriosclerosis and immune response in cardiac allografts. METHODS: CBA.Ca (H2k) recipients of fully allogeneic C57/BL10 (H2b) heart grafts received a short-term course of anti-CD154 antibody or were pretreated with anti-CD4 antibody in combination with donor alloantigen in the form of CBK (H2k+Kb) bone marrow or C57BL/10 donor-specific transfusion (DST). Grafts were analyzed on day 40 or 100 after transplantation for transplant arteriosclerosis and expression of interferon-gamma, interleukin (IL)-2, IL-4, IL-10, IL-12p40, inducible nitric oxide synthase, and transforming growth factor (TGF)-beta1 mRNA. Serum was analyzed for the presence of alloantibodies. RESULTS: Intimal proliferation was 62%+/-11% on day 40 in the anti-CD154 group, progressed from 31%+/-10% on day 40 to 68%+/-8% on day 100 in the CBK-bone marrow group, but remained stable at 39%+/-4% in the DST group. Increased transplant arteriosclerosis on day 100 was associated with high intragraft TGF-beta1 mRNA production and eosinophil infiltration, but not alloantibody production. Progressing transplant arteriosclerosis was associated with increased IL-4 expression. CONCLUSION: Treatment protocols for the induction of long-term allograft survival can differ substantially in the extent and kinetics of transplant arteriosclerosis. IL-4 and TGF-beta1 may be two potential therapeutic targets to attenuate the development of transplant arteriosclerosis in the long term.     

Effects of enalapril and L-158809 on myocardial beta-adrenergic receptor density in transplanted rat hearts.

BACKGROUND: We compare the effects of angiotensin-converting enzyme (ACE) inhibitor or angiotensin II type 1 (AT(1)) receptor blocker on density of myocardial beta-adrenergic receptors (beta-ARs) in a heterotopic heart transplantation model. METHODS: Hearts of F344 rats were heterotopically transplanted into Lewis rat recipients immunosuppressed with cyclosporine (10 mg/kg/day). Recipients were treated orally with the AT(1) receptor blocker L-158809 (3 mg/kg/day, n = 6), enalapril (3 mg/kg/day, n = 6), or vehicle only (n = 6) for 90 days. Density of myocordial beta-ARs was determined with an autoradiographic technique using [(3)H]CGP-12177. RESULTS: Graft status, the sum of the functional score and the score for color, was preserved better in the L-158809-treated group (5.8 +/- 0.9) and in the enalapril-treated group (5.6 +/- 0.8) than in the vehicle-treated group (3.8 +/- 0.9, p < 0.05). The grades of graft coronary artery disease in the L-158809-treated group and in the enalapril-treated group were significantly less than that seen in the vehicle-treated group. The density of myocardial beta-AR (fmol/mg of protein) was 3.5 +/- 0.5 in the L-158809-treated group (p < 0.05 vs. vehicle-treated group) and 3.2 +/- 0.5 (p < 0.05) in the enalapril-treated group but was 2.2 +/- 0.4 in the vehicle-treated group. CONCLUSION: L-158809 is as effective as enalapril in restoring myocardial beta-AR density in immunosuppressed rat transplant model, and this efficacy, as well as the prevention of graft coronary arteriosclerosis, is probably associated with the preservation of graft status.     

Dose response of fish oil versus safflower oil on graft arteriosclerosis in rabbit heterotopic cardiac allografts.

With the advent of cyclosporin A, accelerated coronary arteriosclerosis has become the major impediment to the long-term survival of heart transplant recipients. Due to epidemiologic reports suggesting a salutary effect of fish oil, the dose response of fish oil on graft coronary arteriosclerosis in a rabbit heterotopic cardiac allograft model was assessed using safflower oil as a caloric control. Seven groups of New Zealand White rabbits (n = 10/group) received heterotropic heart transplants from Dutch-Belted donors and were immunosuppressed with low-dose cyclosporin A (7.5 mg/kg/day). Group 1 animals were fed a normal diet and served as control. Group 2, 3, and 4 animals received a daily supplement of low- (0.25 mL/kg/day), medium- (0.75 mL/kg/day), and high- (1.5 mL/kg/day) dose fish oil (116 mg n-3 polyunsaturated fatty acid/mL), respectively. Group 5, 6, and 7 animals were supplemented with equivalent dose of safflower oil (i.e., 0.25, 0.75, and 1.5 mL/kg/day). Oil-supplemented rabbits were pretreated for 3 weeks before transplantation and maintained on the same diet for 6 weeks after operation. The extent of graft coronary arteriosclerosis was quantified using computer-assisted, morphometric planimetry. When the animals were killed, cyclosporin A was associated with elevated plasma total cholesterol and triglyceride levels in the control group. While safflower oil prevented the increase in plasma lipids at all dosages, fish oil ameliorated the cyclosporin-induced increase in total cholesterol only with high doses. Compared to control animals, there was a trend for more graft vessel disease with increasing fish oil dose, as assessed by mean luminal occlusion and intimal thickness. A steeper trend was observed for increasing doses of safflower oil; compared to the high-dose safflower oil group, animals supplemented with low-dose safflower oil had less mean luminal occlusion (16.3% +/- 5.9% versus 41.4% +/- 7.6%, p less than 0.017) and intimal thickness (7.9 +/- 1.9 microns versus 34.0 +/- 13.0 microns, analysis of variance: p = 0.054). Low-dose safflower oil also had a slight, but nonsignificant, beneficial effect on graft vessel disease when compared to control rabbits. The same trends were observed in the degree of histologic rejection (0 = none to 3 = severe) in fish oil- and safflower oil-treated animals. Rejection score correlated weakly but significantly (p = 0.0001) with mean luminal occlusion (r = 0.52) and intimal thickness (r = 0.46). Therefore allograft coronary disease in this model appeared to exhibit an unfavorable, direct-dose response to fish oil and safflower oil, independent of effects on plasma lipids.(ABSTRACT TRUNCATED AT 400 WORDS)     

Platelet-derived growth factor receptor inhibition reduces allograft arteriosclerosis of heart and aorta in cholesterol-fed rabbits

BACKGROUND: Crosstalk between pro-inflammatory cytokines and platelet-derived growth factor (PDGF) regulates smooth-muscle-cell proliferation in cardiac-allograft arteriosclerosis. In this study, we tested the effect of STI 571, a novel orally active protein tyrosine kinase (PTK) inhibitor selective for PDGF receptor (PDGF-R) on transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. METHODS: Cardiac allografts were transplanted heterotopically from Dutch Belted to New Zealand White rabbits. A 0.5% cholesterol diet was begun 4 days before transplantation. Recipients received STI 571 5 mg/kg per day or vehicle intraperitoneally throughout the study period of 6 weeks. Cyclosporine A was given as background immunosuppression. RESULTS: In cardiac allografts of vehicle-treated rabbits, 76.2+/-2.1% of medium-sized arteries were affected by intimal thickening, and the percentage of arterial occlusion was 45.0+/-5.0%. Treatment with STI 571 reduced the incidence of affected medium-sized arteries to 41.2+/-8.1% (P <0.05) and the arterial occlusion to 27.6+/-5.0% ( P<0.05). In addition, we observed that STI 571 treatment reduced intimal lesion formation in proximal ascending aorta of transplanted hearts from 72.3+/-19.9 to 12.7+/-1.9 microm ( P<0.05). Our results also show that STI 571 significantly inhibited accelerated arteriosclerosis in medium-sized arteries of recipients' own hearts. CONCLUSIONS: The results of the present study suggest that PDGF-R activation may regulate the development of transplant and accelerated arteriosclerosis in hypercholesterolemic rabbits. Thus, PTK inhibitors may provide new strategies for prevention of these fibroproliferative vascular disorders.     

Reversed-J inferior versus full median sternotomy: which is better for awake coronary bypass surgery

BACKGROUND: The aim of this study was to ascertain whether the approach with a less invasive reversed-J inferior sternotomy could improve intraoperative patient compliance and postoperative recovery than the standard median sternotomy. METHODS: Seventeen patients underwent elective single coronary artery bypass graft operation under high thoracic epidural anesthesia without endotracheal intubation. The reversed-J sternotomy was performed in 10 patients (Group A) and full sternotomy in 7 patients (Group B). The technical and surgical difficulties, pulmonary functions (by spirometric tests) and hospital stay were assessed. RESULTS: Through the reversed-J sternotomy coronary revascularization was accomplished without any additional technical difficulties and with a good exposure of both the left anterior descending artery and the left internal thoracic artery. No conversion to standard sternotomy and no intubation were observed. Additional doses of local anesthetic at jugular notch was not required in Group A. Pleura was opened more in Group B (57% vs. 20%; p = 0.14). Oxygen saturation was better in Group A during the surgical procedure (98.8 +/- 0.7% vs. 97.1 +/- 2.1%; p = 0.033), however, intraoperative PaCO2 was similar in both the groups. The patients in Group A were discharged from the hospital earlier (3.2 +/- 1.5 vs. 7.3 +/- 3.5 days; p = 0.004). CONCLUSIONS: Less invasive approach to coronary artery bypass graft operations is possible through combination of the high thoracic epidural anesthesia and a reversed-J sternotomy. This technique is less traumatic for patient and provides practical better oxygenation and shorter hospital stay.     

Effect of the TNF-alpha-promoter polymorphism on cardiac allograft rejection.

BACKGROUND: A polymorphism exists in the tumor necrosis factor alpha (TNF-alpha) promoter (position -308, G/A = TNFA1/TNFA2). The TNFA2 allele is associated with increased TNF-alpha production in vitro and has been reported to increase the risk of allograft rejection in pediatric recipients of cardiac transplantation. We examined the effect of the TNFA2 allele on the risk of allograft rejection in adult cardiac transplant recipients. METHODS: We prospectively analyzed 57 subjects (aged 54 +/- 11 years, 84% men, 49% ischemic) who underwent cardiac transplantation between October 1996 and July 2001. Patients were observed after transplantation (mean, 910 +/- 605 days) and the frequency of allograft rejection (biopsy Grade > or =2) in patients with the TNFA2 allele (Group A, n = 15) was compared with TNFA1 homozygotes (Group B, n = 42). Overall survival and time to rejection episodes also were compared between groups. RESULTS: The frequency of allograft rejection was similar between groups (Group A, 8/15 [56%]; Group B, 22/42 [52%]; p = 0.77). Time to rejection also was comparable (Group A, 17 +/- 11 days; Group B, 20 +/- 20 days, p = 0.74). Overall post-transplant survival was similar between groups (1- and 2-year percentage survival: Group A, 87% and 78%, Group B, 88% and 82%, p = 0.35). CONCLUSION: The TNFA2 allele was not associated with increased risk of rejection in adult cardiac transplant recipients. The impact of this polymorphism on overall post-transplant outcomes will require investigation in larger multicenter studies.     

Simplified Parsonnet risk scale identifies limits to early patient discharge

BACKGROUND: Fast-track recovery after coronary artery bypass surgery has influenced patient care positively. Predicting patients who fall off track and require prolonged (> or =7 days) hospitalization remains uncertain. The Parsonnet risk assessment score is effective in predicting length of stay, but is limited by inaccurate subdivision of risk categories. We simplified the Parsonnet risk scale to better identify patients eligible for fast-track recovery. METHOD: The cases of 604 consecutive patients who underwent isolated coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) were reviewed retrospectively. A rapid recovery protocol emphasizing reduced CPB time, preoperative intra-aortic balloon pump (IABP) criteria, and atrial fibrillation prophylaxis was applied to all patients. The five original divisions of the Parsonnet risk scale were reduced to three risk categories: Low (0-10; Group A), Intermediate (11-20; Group B), High (> 20; Group C). Comparisons of progressive risk categories were analyzed to identify predictive factors associated with fast-track outcomes. RESULTS: The thirty-day operative mortality for the entire group was 3.6%. Three clinical features were identified that distinguished risk progression-female gender, reoperative CABG, and increased age. Additionally, the presence of diabetes (p < 0.05), congestive heart failure (p < 0.01), and peripheral vascular disease (p < 0.001) distinguished Groups A and B, while acute myocardial infarction (p < 0.05) influenced outcomes in Group C. Group A (48%) mean risk score 5.9+/-3.2 was compared to Group B (34%) 14.8+/-2.6, which was further compared to Group C (18%) 26.4+/-2.8. The mean length of stay for Group A (5.3+/-4.1 days) was notably less than Group B (6.1+/-4.7 days; p < 0.05); however, both groups responded favorably to fast-track techniques. Group C did not respond comparably (9.2+/-9.2 vs 6.1+/-4.7 days; p < 0.001) and experienced prolonged recovery. The simplified Parsonnet risk scale did not identify differences in operative mortality and revealed only pneumonia (p < 0.05) and atrial fibrillation (p < 0.01) to be greater in Group C. As risk increased, significantly less revascularization was performed (Group A 3.6+/-1.2 grafts/patient vs Group B 3.3+/-1.2 [p < 0.01]; Group B 3.3+/-1.2 vs Group C 2.5+/-1.0 [p < 0.001]). CONCLUSION: A simplified Parsonnet risk scale (three categories) is an effective tool in identifying factors limiting fast-track recovery. Low- and intermediate-risk patients represent the majority (82%) and respond well to fast-track methods. High-risk patients (18%) are limited by a greater percentage of female patients, reoperative CABG, and the very elderly, resulting in fast-track failure. Strategies to improve recovery in high-risk patients may include evolving off-pump techniques.     

The utility of cyclosporine weaning in renal transplantation.

Abrupt conversion of cyclosporine immunosuppression to conventional treatment with azathioprine and prednisone avoids long-term cyclosporine nephrotoxicity, albeit at the cost of a 20% to 40% rejection rate. The authors investigated the benefits and risks of a cyclosporine weaning protocol in 24 cadaveric and 9 live donor kidney recipients treated with a sequential quadruple immunosuppressive protocol. In cadaver kidney recipients, slow tapering of cyclosporine resulted in a 19% (p less than 0.001) improvement in the glomerular filtration rate, as estimated by the inverse ratio of the plasma creatinine concentration. Cadaver kidney recipients were stratified according to graft function (GFR ratio greater than 0.76, less than 0.76) at the of cyclosporine discontinuation. In 12 patients with well-functioning grafts, a 24% improvement was observed, whereas in 12 patients with poor graft function, the gain was limited to 13%. Patients with limited graft function tended to have more acute rejection episodes before cyclosporine weaning (0.92 +/- 0.64 versus 0.42 +/- 0.64, not significant). When the 24 cadaver kidney recipients were stratified according to onset of graft function after transplantation (days to plasma creatinine of 250 mumol/L), need for dialysis, panel reactive antibodies (PRA), and duration of cyclosporine treatment, no significant differences in graft function were observed at the onset or end of cyclosporine weaning. Acute graft rejection before cyclosporine weaning was the only variable associated with a significantly lower estimated glomerular filtration rate ratio at the end of cyclosporine treatment (0.83 +/- 0.11 versus 0.67 +/- 0.16, p less than 0.01). Weaning of cyclosporine was associated with a minimal risk of acute graft rejection. A single patient with stable graft function at the onset of the weaning process experienced an acute but reversible rejection episode 2 months after cyclosporine was discontinued. In summary, gradual weaning of cyclosporine improves graft function, and eliminates the excessive risk of acute graft rejection without the need for additional corticosteroid treatment.     

The effects of preprimed oxygenators on gas transfer efficiency

Cancellation of on-pump coronary artery bypass grafting after the circuit is primed may result in the discarding of unused circuits. In some off-pump cases, a surgeon may request that the circuit be primed, but complete the surgical procedure without utilizing the circuit. The major concerns about the unused circuit are its sterility and the performance of the oxygenator after it has been primed for a long period of time. The goal of this study is to determine whether prepriming of the circuit with and without albumin has an effect on the gas transfer efficiency of oxygenators during simulated cardiopulmonary bypass. Monolyth integrated membrane lungs (Sorin Biomedical, Arvada, CO) were used to deoxygenate and oxygenate the bovine blood. Oxygenators were preprimed for 72 (N = 6) and 24 (N = 6) hours before testing. In control group (N = 6), oxygenators were tested immediately (0 h) after they were primed. Three different priming solutions were used: physiological saline solution (Group A); 1.25% of human albumin (Group B); and 5% human albumin (Group C). The blood was modified to the American Association of Medical Instrumentation Standards before testing. The blood flow through the oxygenators was set at 2 Lpm and 4 Lpm, with gas (FiO2 at 1.0) to blood flow ratio at 1:1. Cultures were also obtained from preprimed oxygenators to test circuit sterility. Oxygen transfer in oxygenators primed for 0 h at blood flow of 4 Lpm were 203 mL/min +/- 9.7 (Group A), 263.1 mL/min +/- 52.9 (Group B), and 270.5 mL/min +/- 13.1(Group C, p < .01 vs. Group A). In oxygenators preprimed for 72 h, the CO2 transfers were 135.0 mL/min +/- 21.8 (Group A), 104.9 mL/min +/- 2.4 (Group B), and 148.9 +/- 26.6 (Group C, p < .006 vs. Group B). In addition, the pressure drops were 56.5 mmHg +/- 5.5 (Group A), 82.6 mmHg +/- 13.4 (Group B), and 67.6 mmHg +/- 15.3 (Group C, p < .05 vs. Group B). In group A, O2 transfer were 203.5 mL/min +/- 9.7 (0 h), 272.4 mL/min +/- 66.6 (24 h), and 260.8 mL/min +/- 31.1 (72 h, p < .01 vs. 0 h). In group B, O2 transfer were 263.1 mL/min +/- 52.0 (0 h), 302.7 mL/min +/- 77.4 (24 h), and 235.2 mL/min +/- 16.5 (72 hr, p < .02 vs. 24 hr). Cultures obtained from 12 preprimed oxygenators presented no organism growth for up to 5 days. In conclusion, oxygen transfer increases in oxygenators preprimed with albumin immediately after they were primed. However, gas transfer decreased after they were primed with albumin for 72 h. Oxygenators preprimed for 24 h and 72 h with 0.9% saline had better O2 transfer than those primed for 0 h.     

Intrathymic immune modulation prevents acute rejection but not the development of graft arteriosclerosis (chronic rejection)

BACKGROUND: We showed previously that our intrathymic immune modulation protocol induces virtually permanent graft survival of simultaneously transplanted cardiac allografts in MHC-incompatible rat strain combinations. It is, however, unknown whether this procedure prevents the development of graft arterial disease (GAD). METHODS: Male AO recipient rats were intrathymically inoculated with 2.5x10(7) PVG splenocytes immediately followed by heterotopic transplantation of a PVG cardiac allograft (day 0). Immunosuppression consisted of 1 ml of antilymphocyte serum i.p. (day 0) and cyclosporine i.m. (15 mg/kg body weight) on days 1, 2, and 3 posttransplantation. Histological analysis, mixed lymphocyte reactions, and intragraft cytokine mRNA expression were performed at several time points after engraftment. RESULTS: Histological analysis revealed that GAD was already present 14 days after transplantation. At 200 days, virtually all vessels were affected and over 80% of the vessels showed severe intimal lesions. Infiltrate analysis displayed massive parenchymatous infiltrates (CD8+ cells and ED1+ macrophages) 2 weeks after transplantation. At later time points, infiltrates became epicardial and/or blood vessel associated and mainly consisted of CD4+, CD8+, and B cells. Mixed lymphocyte reactions showed nonspecifically decreased responses at 60 days but complete restoration of these responses at later time points (120 to 280 days). Intragraft cytokine mRNA expression showed decreased interleukin-2/interferon-gamma and sustained interleukin-10 expression 2 weeks after transplantation. Transforming growth factor-beta mRNA expression was increased >200 days after transplantation. CONCLUSIONS: Intrathymic immune modulation does not abolish alloreactivity, and despite induction of long-lasting graft survival, this procedure does not prevent and may even facilitate the development of GAD.     

Effects of fish oil on graft arteriosclerosis and MHC class II antigen expression in rat heterotopic cardiac allografts.

The effect of fish oil on accelerated graft coronary arteriosclerosis was assessed in Lewis to Brown-Norway rat heterotopic cardiac allografts. Twelve Brown-Norway rats were supplemented with 2 ml/kg/day of fish oil (68.3 mg eicosopentaenoic acid and 47.5 mg decosahexaenoic acid per milliliter). Eleven additional animals, receiving an isocaloric amount of safflower oil, served as control. All diets began 1 week before operation. Immunosuppression was obtained with low-dose cyclosporine (2 mg/kg/d). When killed (100 days), there were no significant differences in percentage weight gain, graft function, or histologic rejection score. Although lipid profiles were comparable, total cholesterol:high-density lipoprotein ratio was marginally higher in animals treated with fish oil (p = 0.069). Mean percentage luminal occlusion (before and after correcting for differences in size between coronary vessels analyzed) and average intimal thickness were similar between animals treated with fish oil and safflower oil as assessed by computer-assisted digitized, morphometric planimetry. In all allografts, donor interstitial dendritic cells were repopulated with recipient dendritic cells. The major histocompatibility complex class II cell density in the fish oil group did not differ significantly from rats supplemented with safflower oil (1.48 +/- 0.68 vs 1.48 +/- 0.65 cells per mm2, p = 0.995). In conclusion, fish oil did not exert any beneficial effect over safflower oil in terms of graft coronary arteriosclerosis, histologic rejection, or plasma lipids.(ABSTRACT TRUNCATED AT 250 WORDS)