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.     

Prognostic value of contractile response during high-dose dipyridamole echocardiography test in heart transplant recipients.

BACKGROUND: Coronary allograft vasculopathy (CAV) remains a main factor limiting long-term survival after heart transplantation (HTX). The diagnosis of CAV is still based on serial coronary angiography. In this study, we evaluated the prognostic value of high-dose dipyridamole echocardiography in HTX. METHODS: Sixty-eight patients underwent dipyridamole echocardiography within 48 hours of their scheduled annual coronary angiography. Coronary allograft vasculopathy was defined as CAV 1 (focal or diffuse stenosis <50%) or CAV 2 (focal or diffuse stenosis >or=50%). Wall-motion score index (WMSI) was evaluated at rest and after dipyridamole administration. RESULTS: Results of coronary angiography were normal in 43 patients (63%), showed CAV 1 in 11 (16%), and showed CAV 2 in 14 (21%). Rest wall motion was normal in 39 patients and abnormal in 29. After dipyridamole administration, wall motion remained normal in all 39 (Group 1, no CAV in 34 and CAV 1 in 5). Of 29 patients with rest wall-motion abnormalities, all reversed to normal after dipyridamole in 8 patients (Group 2, no CAV in 7 and CAV 1 in 1) and remained or worsened in 21 (Group 3, CAV 2 in 14 and no CAV or CAV 1 in 7). During follow-up (6 +/- 3 years), 15 patients had major cardiac events: 11 occurred in Group 3, whereas 4 occurred in Groups 1 and 2. Wall motion at rest and after dipyridamole administration and CAV were independent predictors for cardiac events; only dipyridamole WMSI >1 remained significant (p < 0.0001) at multivariate analysis. CONCLUSIONS: Dipyridamole echocardiography is a simple, non-invasive test that after HTX may identify patients with altered wall motion who deserve stricter surveillance.     

Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha), a key factor in the inflammatory cascade, has been implicated in coronary artery disease. Two biallelic polymorphisms in the TNF gene locus (TNFA at position -308 and TNFB at +252) may influence TNF-alpha production. Individuals with the rare TNFA2 allele or TNFB2 homozygosity have augmented TNF-alpha production. We investigated the genotypes associated with increased TNF-alpha production in coronary artery bypass grafting (CABG) patients and if these genotypes influence the magnitude of the postoperative inflammatory response. METHODS: TNF gene polymorphisms were analyzed by multiplex fluorescent solid-phase minisequencing in 86 CABG patients. Plasma concentrations of TNF-alpha, IL-6 and C3a and C-reactive protein (CRP) were analyzed before and after surgery in 45 of the patients and compared with genetically high and low TNF-alpha producers. RESULTS: Thirty percent of the patients carried the TNFA2 allele and 45% were TNFB2 homozygous. The allelic frequencies were TNFA1/TNFA2 = 0.84/0.16 and TNFB1/TNFB2 = 0.32/0.68. Pre- and postoperative levels of TNF-alpha, IL-6, C3a and CRP did not differ significantly between genetically high and low TNF-alpha producers. CONCLUSIONS: The frequency of high TNF-alpha producing genotypes in a CABG population was comparable to that previously reported from normal populations. Furthermore, we found no evidence that the investigated TNF-alpha gene polymorphisms influence postoperative inflammatory response after uncomplicated coronary surgery.     

Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha), a key factor in the inflammatory cascade, has been implicated in coronary artery disease. Two biallelic polymorphisms in the TNF gene locus (TNFA at position -308 and TNFB at +252) may influence TNF-alpha production. Individuals with the rare TNFA2 allele or TNFB2 homozygosity have augmented TNF-alpha production. We investigated the genotypes associated with increased TNF-alpha production in coronary artery bypass grafting (CABG) patients and if these genotypes influence the magnitude of the postoperative inflammatory response. METHODS: TNF gene polymorphisms were analyzed by multiplex fluorescent solid-phase minisequencing in 86 CABG patients. Plasma concentrations of TNF-alpha, IL-6 and C3a and C-reactive protein (CRP) were analyzed before and after surgery in 45 of the patients and compared with genetically high and low TNF-alpha producers. RESULTS: Thirty percent of the patients carried the TNFA2 allele and 45% were TNFB2 homozygous. The allelic frequencies were TNFA1/TNFA2=0.84/0.16 and TNFB1/TNFB2=0.32/0.68. Pre- and postoperative levels of TNF-alpha, IL-6, C3a and CRP did not differ significantly between genetically high and low TNF-alpha producers. CONCLUSIONS: The frequency of high TNF-alpha producing genotypes in a CABG population was comparable to that previously reported from normal populations. Furthermore, we found no evidence that the investigated TNF-alpha gene polymorphisms influence postoperative inflammatory response after uncomplicated coronary surgery.     

The experimental study of cardiac allograft vasculopathy and myocardial fibrosis in rats

We sought to analyze the development of myocardial fibrosis and cardiac allograft vasculopathy (CAV) as a theoretical basis for the prevention and treatment of rejection. Heterotopic cardiac transplantation was performed from Wistar rats to Sprague-Dawley rats. The recipients pretreated with donor splenocyte (SPC) infusion followed by cyclophosphamide (CP) were divided into 3 groups: Control animals without immunosuppression (Group 1; n = 10); Group 2, CsA treatment (n = 10) with euthanasia 2-3 months posttransplantation; and Group 3 (n = 20), CP plus SPC treatment with 10 recipients euthanized at 2 weeks posttransplantation and 10 animals monitored for at least 1 year posttransplantation. Histological studies were performed to evaluate myocardial fibrosis and CAV; 2-3 days after transplantation, there was abundant infiltration of collagenous fibers in the adventitia and intima of the coronary arteries in Group 1 allografts. Group 2 allografts demonstrated abundant infiltration of collagenous fibers in the adventitia and intima of arteries and arterioles resulting in significant luminal stenosis. In contrast, pretreatment of animals with SPC and CP induced long-term allograft survival; myocardial fibrosis and CAV were dramatically reduced in Group 3 compared with Groups 1 and 2. The infiltration of collagenous fibers in coronary arteries was one of the major causes of CAV. Preconditioning of recipients with SPC followed by CP not only induced immune tolerance but also alleviated myocardial fibrosis and CAV in allografts.     

Does cytomegalovirus status influence acute and chronic rejection in heart transplantation during the ganciclovir prophylaxis era?

BACKGROUND: The effect of cytomegalovirus (CMV) status on acute rejection in heart transplantation is not well understood. Furthermore, there is some evidence to suggest that CMV antibody positivity is associated with cardiac allograft vasculopathy (CAV). METHODS: This study compared the effect of CMV antibody status in heart transplant donors (D) and recipients (R) on acute and chronic rejection episodes during the ganciclovir prophylaxis era. RESULTS: All heart transplant recipients at Papworth Hospital during the ganciclovir prophylaxis era were included (n = 374). They were grouped according to recipients and their respective donor CMV serology: R(-)/D(-) (n = 82); R(+)/D(-) (n = 114); R(-)/D(+) (n = 73); and R(+)/D(+) (n = 105). Ganciclovir prophylaxis was administered to the R(-)/D(+) group. The mean (SD) recipient and donor ages were 46 (11), 51 (9), 47 (11) and 52 (8) years (p < 0.001), and 32 (11), 33 (14), 36 (12) and 38 (14) years (p = 0.01), respectively, for the CMV groups. The mean number of acute rejection episodes (as confirmed by cardiac biopsy) per 100 patient-days was 0.13 (0.36), 0.11 (0.34), 0.12 (0.34) and 0.12 (0.34), respectively (p > 0.05) There was no statistical difference in the development of CAV as assessed by angiography (p = 0.92). At 2 years, the "freedom from CAV" rates were 96%, 97%, 97% and 98%, respectively. The 5-year post-operative survival rates were 83%, 79%, 67% and 73% (p = 0.08 overall). CONCLUSIONS: CMV status of heart transplant recipients and their respective donors does not influence acute or chronic rejection in terms of cardiac allograft vasculopathy.     

Does University of Wisconsin solution harm the transplanted heart?

BACKGROUND: University of Wisconsin solution (UW) has been shown to be an effective preservative for the cardiac allograft. Recently, the high potassium content of UW has been implicated in causing coronary endothelial damage, allegedly contributing to development of cardiac allograft vasculopathy (CAV) and eventually to poorer survival. METHODS: We examined our experience using UW for preservation of cardiac allografts between 1990 and 1994 (n = 94), and compared these to hearts preserved with the lower potassium-containing Stanford solution used at our center between 1986 and 1990 (n = 65). Indices of graft function, ischemic injury, CAV incidence, CAV severity, and survival were evaluated. RESULTS: The 2 groups were similar in age, gender, diagnosis, donor inotropic support, donor-recipient weight ratio, incidence of acute graft failure, and cytomegalovirus seroconversion. UW-preserved hearts came from older donors (30.5 vs 24.1 years, p < .001), and were transplanted into more status 1 recipients (56% vs 22%, p < .001), consistent with current trends. Mean ischemic time of UW-preserved hearts was significantly longer (184 vs 155 minutes, p < .005) although time required to wean from bypass was less (45.5 vs 73.8 minutes, p < .001) and there was a trend towards less inotropic requirement. CPK-MB release was less with UW preservation (63 vs 87 microg/ dL, p = .001). Three years after transplantation, both groups were similar in the incidence of CAV (UW, 27.3%; STNF, 37.5%; p = 0.27), and also the severity of CAV (p = 0.78). Deaths attributed to CAV were equal in each group (UW, 11.4% vs STNF, 10.7%; p = 0.79). Kaplan-Meier survival analysis revealed equivalent survival curves (p = 0.26). CONCLUSIONS: We conclude that UW is a safe and effective myocardial preservative, allowing longer ischemic times with equivalent graft function. Our data suggest that when UW is used for cardiac allograft preservation, both CAV and survival are comparable to the experience with other preservatives containing lower concentrations of potassium.     

Correlation of chlamydia pneumoniae infection and severity of accelerated graft arteriosclerosis after cardiac transplantation

BACKGROUND: Chlamydia pneumoniae has been associated with atherosclerosis, although its role in the process is not clearly defined. Heart transplant recipients are known to have high titers of antibodies to C. pneumoniae, and the organism has been recovered from the coronary arteries of both transplant recipients and donors. This study evaluated association between C. pneumoniae infection and accelerated graft arteriosclerosis (AGA), also known as cardiac allograft vasculopathy (CAV), after cardiac transplantation. METHODS: A case-control study was performed with 54 heart transplant recipients at the Johns Hopkins Hospital. Severe cases had >50% luminal narrowing on cardiac catheterization, mild cases <50% narrowing, and controls were free of arteriosclerotic disease. Blood specimens were examined for C. pneumoniae serology and DNA detection by polymerase chain reaction (PCR) assays. RESULTS: For every twofold increase in geometric mean C. pneumoniae immunoglobulin (Ig)G titer, the odds ratio for severe AGA versus controls was 3.13 (P=0.03) and for mild AGA versus control patients was 1.61 (P=0.45). On Kaplan-Meier survival analysis there was a nonsignificant trend toward faster development of CAV in patients with higher C. pneumoniae antibody titers. Overall, 29% of heart transplant patients evaluated had evidence of circulating C. pneumoniae DNA by PCR, without a statistical difference between groups. CONCLUSIONS: C. pneumoniae IgG titer correlates with severity of allograft arteriosclerosis after cardiac transplantation. Circulating C. pneumoniae DNA is detectable by PCR in up to 30% of cardiac transplant recipients, but this does not correlate with severity of allograft vasculopathy.     

Retransplant and Medical Therapy for Cardiac Allograft Vasculopathy: International Society for Heart and Lung Transplantation Registry Analysis

Cardiac retransplantation for heart transplant recipients with advanced cardiac allograft vasculopathy (CAV) remains controversial. The International Society for Heart and Lung Transplantation Registry was used to examine survival in adult heart recipients with CAV who were retransplanted (ReTx) or managed medically (MM). Recipients transplanted between 1995 and 2010 who developed CAV and were either retransplanted within 2 years of CAV diagnosis (ReTx) or alive at ≥2 years after CAV diagnosis, managed medically (MM), without retransplant, constituted the study groups. Donor, recipient, transplant characteristics and long‐term survival were compared. The population included 65 patients in ReTx and 4530 in MM. During a median follow‐up of 4 years, there were 24 deaths in ReTx, and 1466 in MM. Survival was comparable at 9 years (55% in ReTx and 51% in MM; p = 0.88). Subgroup comparison suggested survival benefit for retransplant versus MM in patients who developed systolic graft dysfunction. Adjusted predictors for 2‐year mortality were diagnosis of CAV in the early era and longer time since CAV diagnosis following primary transplant. Retransplant was not an independent predictor in the model. Challenges associated with retransplantation as well as improved CAV treatment options support the current consensus recommendation limiting retransplant to highly selected patients with CAV.     

Delayed occurrence of cardiac allograft vasculopathy in Chinese heart transplant recipients compared with their western counterparts

Cardiac allograft vasculopathy (CAV) is a leading limiting factor to long-term survival after cardiac transplantation. We investigated the prevalence of CAV and its associated factors in Chinese heart transplant recipients. From July 1987 to July 2000, we performed 140 consecutive heart transplantations at the National Taiwan University Hospital. Of the 140 patients, 98 who were > or = 17-yr old at the time of transplantation, had survived for more than 1 yr after transplantation, and who had normal findings at the 1-month coronary angiogram study, were included in this study. Group I consisted of 25 patients who eventually developed CAV in the follow-up, and group II consisted of 73 patients who were free from CAV in the follow-up. CAV was defined by coronary angiogram study.The donor and recipient characteristics were not statistically different between the two groups except the older donor age (p = 0.02), higher first-year mean rejection score (p = 0.03) and more prevalent cytomegalovirus infection rate (p = 0.03) in group I. Multivariate Cox regression analysis revealed that only higher first-year mean rejection score (p = 0.01), and older donor age (p = 0.04) were important risk factors for developing CAV. The 1-5 yr of actuarial freedom from the presence of CAV were 97, 93, 86, 80 and 69% in our study patients. In summary, these data show that CAV occurred later in Chinese heart transplant recipients in comparison with their western counterparts, but the risk factors for developing CAV were not different.     

Lack of Effect of MICA Antibodies on Graft Survival Following Heart Transplantation

Little is known about the effect of MICA antibodies (Abs) on cardiac allograft function and survival. Pretransplant and posttransplant serum from 491 and 196 adult cardiac allograft recipients, respectively, has been investigated for MICA Abs, donor specificity and the effect of MICA Abs on graft survival, acute rejection episodes (AR) and cardiac allograft vasculopathy (CAV). Patients with HLA Abs (11.6%) were excluded from the analysis. A total of 11.8% of patients had MICA Abs, without HLA Abs, before their transplant. Actuarial graft survival demonstrated slightly better survival of patients with donor-specific MICA Abs at 1 and 5 years (88.9% and 83.3%) than patients negative for MICA Abs (72% and 63.7%, p = 0.051). After transplantation, 15.8% of patients produced MICA Abs, and in 17 patients these were produced de novo . There was no effect of pretransplant or posttransplant production of MICA Abs on numbers of AR episodes in year 1, or CAV assessed at years 3 and 5. Immunocytochemistry of cardiac biopsies from 11 patients did not demonstrate a presence of MICA. Sera from only 4/69 patients with MICA Abs fixed complement prior to transplantation and from 7/38 patients following transplantation. In conclusion, this study suggests that MICA Abs do not adversely affect the outcome of cardiac transplantation.     

Heart retransplantation for heart allograft failure in Chinese heart transplant recipients: NTUH experience

We investigated the short- and long-term results after heart retransplantation in terms of different causes of heart allograft failure. We sought to establish the data of heart retransplantation in Chinese compared with Western counterparts due to differences in heart allograft vasculopathy. From March 1995 to May 2005, eight heart transplantation recipients with allograft failure underwent retransplantation. Heart allograft failure was due to coronary vasculopathy (CAV) in six patients (75%) and acute rejection in two patients (25%). The mean interval to retransplantation was 32 to 84 months (mean 54.3 months). There were five patients who survived after heart retransplantation for CAV and no patient survived after an earlier diagnosis of acute rejection. Heart retransplantation is a feasible method with acceptable long-term survival rate for heart allograft failure. After careful pretransplant evaluation, retransplantation is acceptable. The survival after retransplantation for CAV is notably great than that after acute rejection. Heart retransplantation is the only way for patients who have cardiac allograft failure to achieve long-term survival.     

心脏移植后存活时间超过10年者的临床分析

目的 总结单中心13例心脏移植后存活超过10年受者的治疗及随访情况.方法 13例受者在1995年8月至2001年6月期间接受心脏移植,前8例受者采用环孢素A+硫唑嘌呤+皮质激素的经典免疫抑制方案,后5例在该方案基础上进行了免疫诱导,有6例在吗替麦考酚酯(MMF)上市后将硫唑嘌呤替换为MMF.围手术期对主要并发症及时进行防治,术后对受者进行定期随访,建立个人长期随访档案,监测急性排斥反应(AR)和移植物血管病(CAV)发生情况,采用生存质量调查表分析生活状况.结果 13例存活超过10年的受者占同期心脏移植总例数的48.1%(13/27),术后受者心理状态较好,生存质量良好,均能够正常的学习、生活及工作.术后近期(1年内)发生的并发症包括AR 3例、感染4例、肾功能不全3例、移植物右心功能不全5例、移植后新发糖尿病2例及肝功能不全5例,经对症治疗后均好转;术后远期(1年后)发生的并发症包括CAV 2例、AR 4例、高胆固醇血症5例、高血压病4例、高尿酸血症10例及慢性肾功能损害3例等.1例受者于移植后13年因并发肝癌死亡.结论 心脏移植受者长期存活与其心理状态、经济条件、依从性及良好的随访制度等密切相关,并受社会因素的影响.

Abstract：

Objective To retrospectively analyze the clinical management and follow-up of 13 recipients with survival of over ten years after cardiac transplantation. Methods Thirteen male recipients underwent orthotopic heart transplantation between August 1995 and June 2001 in our center and received standard immunosuppressive therapy protocols (8 cases) or induction therapy protocols (5 cases). Cyclosporine, azathioprine or mycophenolate mofetil, and prednisolone were applied as maintenance immunosuppressive regimens. Six recipients switched from azathioprine to mycophenolate mofetil when mycophenolate mofetil was available. Perioperative complications were prevented and treated. After operation, the recipients were followed up regularly to set up personnel long-term follow-up files. The incidence of acute rejection (AR) and (cardiac allograft vasculopathy (CAV) was monitored. Results The 13 survived recipients accounted for 48. 1 % of the total number in the corresponding period (13/27). All survivals recovered well and had a good quality of life. The recent (1 year) complications included acute allograft rejection (3 cases), infection (4 cases), renal insufficiency (3 cases), allograft right ventricular dysfunction (5 cases), post-transplant diabetes (2 cases) and liver dysfunction (5 cases). The long-term (1 year later) complications included acute allograft rejection (2 cases), CAV (2 cases), hypercholesterolemia (5 cases), hypertension (4 cases), hyperuricemia (10 cases) and chronic renal impairment (3 cases). One hepatitis B virus carrier died of liver cancer 13 years after transplantation. Conclusion The long-term survival of cardiac allograft recipients is closely associated with psychological state, financial condition, compliance and follow-up medical system, while the sociological and environmental factors may play important roles.     

Comparison of combined prophylaxis of cytomegalovirus hyperimmune globulin plus ganciclovir versus cytomegalovirus hyperimmune globulin alone in high-risk heart transplant recipients

BACKGROUND: Seronegative heart transplant recipients who receive an allograft from seropositive donors have a higher risk of developing cytomegalovirus (CMV) disease and cardiac allograft vasculopathy (CAV) and dysfunction. Neither CMV-specific hyperimmune globulin nor ganciclovir as sole CMV prophylaxis is sufficient to prevent CMV disease in high-risk patients. We retrospectively evaluated the efficacy of CMV-hyperimmune globulin with and without ganciclovir in 207 D+/R- heart transplant recipients. METHODS: The study population was divided into two groups: Group A was composed of 96 patients who received CMV hyperimmune globulin as sole CMV prophylaxis, and group B was composed of 111 patients who received combined CMV prophylaxis. All recipients were subjected to quadruple cytolytic immunosuppression. Primary and secondary end points included prevention of CMV-associated death, CMV disease and productive infection, CAV, and overall infection. RESULTS: There was no difference in overall survival between the two groups. Four patients in the group A died of CMV sepsis, whereas no CMV-associated death was observed in group B (P =0.0326). The actuarial incidence of CMV disease was significantly lower in patients who received double CMV prophylaxis (32.29 vs. 11.71, P =0.0003). Although no difference was observed with regard to productive CMV infection (53.12 vs. 65.77, P =not significant), CAV and overall infection rates were significantly higher in the first group (7.29 vs. 0.9, P =0.0157 and 70.83 vs. 62.16, P =0.03, respectively). CONCLUSIONS: Double CMV prophylaxis consisting of CMV hyperimmune globulin and ganciclovir is able to abolish CMV death and prevent CMV disease in high-risk heart transplant recipients. Therefore, the use of a combination regimen is recommended for seronegative recipients with seropositive donors.     

Neointimal inflammation and adventitial angiogenesis correlate with severity of cardiac allograft vasculopathy in pediatric recipients.

BACKGROUND: Chronic inflammation and angiogenesis have been implicated in the pathogenesis of both cardiac allograft vasculopathy (CAV) and age-related vasculopathy. Because concurrent atherosclerosis does not complicate assessment of CAV in children, we sought to characterize the spectrum of coronary lesions in this population and determine whether inflammatory infiltrates and angiogenesis correlate with severity of CAV. METHODS: In 18 pediatric heart specimens CAV was graded 1 to 4 (none to severe). Each case was assigned to either: Group I, no inflammation; Group II, perivascular inflammation; or Group III, perivascular and neointimal inflammation. Inflammatory infiltrates were immunophenotyped using anti-CD3, anti-CD20 and HAM 56. Angiogenesis was assessed by determining microvascular density (MVD) in 5 high-power fields (HPFs) per section. RESULTS: CAV was evident in 94% of cases, and inflammation in 61%. Cases with neointimal inflammation had significantly more severe CAV compared with cases without inflammation (2.7 +/- 0.16 vs 1.9 +/- 0.2, p = 0.002). MVD was significantly higher in both inflammation groups (Groups II and III) compared with Group I (4.1 +/- 0.5 per HPF and 5.9 +/- 0.5 vs 3.1 +/- 0.7, p = 0.018 and p = 0.002) and correlated with the degree of CAV (p = 0.007). The perivascular infiltrates (Group II, n = 5) contained lymphocytes, macrophages and plasma cells, and 67% of neointimal infiltrates (Group III, n = 6) also contained eosinophils. CONCLUSIONS: CAV in children is more common than previously reported. Our data indicate that CAV is often associated with inflammation and that adventitial angiogenesis correlated with the severity of CAV.     

Influence of tumor necrosis factor-alpha gene-308 polymorphism on the development of coronary vasculopathy after cardiac transplantation.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) has been implicated in cardiovascular disease. Polymorphism of the TNF-alpha gene promoter region (position -308) influences an individual's production of TNF-alpha. This affects susceptibility to acute rejection after cardiac transplantation. Because the highest serum levels of TNF-alpha have been found in recipients with cardiac transplant vasculopathy and because TNF-alpha blockade can prevent the disease in rabbits, we investigated the effect of TNF-alpha promoter polymorphism on the development of vasculopathy in human cardiac allograft recipients. METHODS: Using sequence-specific primers to the TNF-alpha gene and polymerase chain reaction, the genotypes of 147 cardiac transplant recipients and 134 heart donors were identified. An association was sought between the presence of high-producing (A homozygotes, GA heterozygotes) or low-producing (G homozygotes) TNF-alpha genotype and the development of coronary vasculopathy, diagnosed by routine surveillance coronary angiography. RESULTS: We found that 31.9% of recipients and 27.0% of donors were high TNF-alpha producers. The presence of the high-producing TNF-alpha allele led to an earlier diagnosis of vasculopathy; 3.42 years (+/- 91.3 days) vs 3.84 years (+/- 76.3 days) for high- and low-producing cardiac graft recipients, respectively; 3.52 years (+/- 87.3 days) vs 3.78 years (+/- 77.4 days) for high- and low-producing donor grafts, respectively. However, neither of these differences were significant. By Kaplan Meier actuarial analysis and log-rank test, TNF-alpha polymorphism had no effect on the freedom from vasculopathy when considering either recipient (p = 0.99) or donor (p = 0.86) TNF-alpha genotype. Multivariate analysis identified increasing donor age and the number of acute rejection episodes of International Society for Heart and Lung Transplantation grade 3 or greater as independent risk factors for vasculopathy in both the recipient and donor cohorts. CONCLUSIONS: Polymorphism at position -308 in the promoter region of the TNF-alpha gene fails to predict the development of cardiac transplant-related vasculopathy and cannot be used as a genetic risk marker. This may be because of the effects of immunosuppressive treatment.     

Non-invasive diagnostic of cardiac allograft vasculopathy by 31P magnetic resonance chemical shift imaging.

BACKGROUND: Coronary angiography is still the gold standard for the diagnosis of cardiac allograft vasculopathy (CAV) for which alternative non-invasive diagnostic approaches are currently investigated. In this study, we assessed whether 31P magnetic resonance chemical shift imaging can diagnose CAV by studying variations in cardiac high-energy phosphates in a population of adult heart transplant recipients. METHODS AND RESULTS: CAV was defined by coronary angiography as the presence of diffuse coronary irregularities with significant concentric narrowing on epicardial or distal coronary arteries. Eight patients with CAV (group A), and 18 patients without CAV (group B) were included in this study and compared to nine healthy volunteers (group C). Patients and volunteers underwent 31P three-dimensional chemical shift imaging to determine the ratio of phosphocreatine (PCr) and adenosine tri-phosphate (ATP). PCr/ATP was significantly lower in group A (1.51+/-0.50) than in groups B and C (1.98+/-0.53 (p=0.003) and 2.14+/-0.31 (p=0.001)), respectively. Time from transplant, number of episodes of acute rejection, and left ventricular ejection fraction (LVEF) were not significantly different between patient groups. A PCr/ATP value of 1.59 was the optimal cut-off value to predict CAV (specificity and sensitivity of 100% and 72%, respectively). CONCLUSION: Clinically, in vivo 31P chemical shift imaging is a promising, non-invasive method to detect the potential modifications of high-energy phosphates related to CAV and to better screen indications for coronary angiograms. This may be relevant for coronary angiography follow-up and adjustments of immunotherapy regimen.     

T-cell depletion eliminates the development of cardiac allograft vasculopathy in mice rendered tolerant by the induction of mixed chimerism

We previously demonstrated that cardiac allografts to fully tolerant chimeric mice developed cardiac allograft vasculopathy (CAV). Here we begin to examine which components of the immune system are responsible for the pathogenesis of CAV in such tolerant recipients. B10.A/B6 mixed chimeric mice were created by receiving injections of bone marrow cells from B10.A (H-2k) mice given to C57BL/6 (B6; H-2b) mice with some preparations. B10.A skin grafts were first placed onto B10.A/B6 mixed chimeric recipients. When the donor strain skin grafts had survived perfectly for at least 56 days, B10.A hearts were transplanted heterotopically into B10.A/B6 mixed chimeric recipients. Hearts were examined for the presence of CAV 56 days later. To determine the effector cells that contribute to the development of CAV, they were treated weekly with a combination of anti-CD4/CD8 monoclonal antibodies (mAbs) or anti-NK1.1 mAb continuing until 56 days. 14 B10.A cardiac transplants of 18 otherwise untreated B10.A/B6 chimeric recipients developed CAV; concurrent B6 isografts were unaffected (0/7). In chimeric recipients treated with anti-CD4/8 mAbs, the prevalence of CAV was greatly reduced (0/6, P < .01 compared to the untreated group). Anti-NK1.1 mAb was not effective in the prevention of CAV (4/5). These data suggest that T cells may contribute in some way to the development of CAV that occurs in those fully tolerant recipients. Host T cells that may still be responsive to non-major histocompatability complex antigens, including tissue-specific antigens presented not on skin but on heart, may also be responsible for the development of CAV in tolerant animals.     

Coronary Microvascular Dysfunction Correlates With the New Onset of Cardiac Allograft Vasculopathy in Heart Transplant Patients With Normal Coronary Angiography

Coronary microvascular dysfunction is emerging as a strong predictor of outcome in heart transplantation (HT). We assessed the validity of microvascular dysfunction, defined by means of a reduced coronary flow reserve (CFR), as a factor associated with new onset epicardial cardiac allograft vasculopathy (CAV) or death. We studied 105 patients at 4 ± 1 years post‐HT with a normal coronary angiography (CA). New onset CAV was assessed by CA. CFR was assessed in the left anterior descending (LAD) coronary artery by transthoracic Doppler echocardiography and calculated as the ratio of hyperaemic to basal blood flow velocity. A CFR ≤ 2.5 was considered abnormal. Epicardial CAV onset or death was assessed during a follow‐up of 10 years. New onset CAV was diagnosed in 30 patients (28.6%) (Group A), and the CA was normal in the remaining 75 patients (71.4%) (Group B). Group A had reduced CFR compared with group B (2.4 ± 0.6 vs. 3.2 ± 0.7, p < 0.0001). A CFR ≤ 2.5 was independently associated with a higher probability of new onset CAV (p < 0.0001) and a higher probability of death, regardless of CAV onset (p < 0.01). Microvascular dysfunction is independently associated with the onset of epicardial CAV, and associated with a higher risk of death, regardless of CAV onset.     

The effect of thymectomy on tolerance induction and cardiac allograft vasculopathy in a miniature swine heart/kidney transplantation model.

BACKGROUND: We have previously demonstrated that MHC class I disparate hearts transplanted into miniature swine treated with a short course of cyclosporine developed florid cardiac allograft vasculopathy (CAV) and were rejected within 55 days. However, when a donor-specific kidney is cotransplanted with the heart allograft, recipients become tolerant to donor antigen and accept both allografts long-term without the development of CAV. In the present study, we have investigated the role of the host thymus in the induction of tolerance and prevention of CAV in heart/kidney recipients. METHODS: Total thymectomies were performed in six animals (postoperative day [POD]-21), which on day 0 received either an isolated MHC class I disparate heart allograft (n=3) or combined class I disparate heart and kidney allografts (n=3), followed in both cases by a 12-day course of cyclosporine (POD 0-11). Graft survival and the development of CAV in these thymectomized recipients were compared to the same parameters in non-thymectomized, cyclosporine-treated recipients bearing either class I disparate heart allografts (n=5) or heart and kidney allografts (n=4). RESULTS: In the group of animals bearing isolated class I disparate heart allografts, the thymectomized recipients rejected their allografts earlier (POD 8, 22, 27) than the non-thymectomized recipients (POD 33,35,45,47,55). The donor hearts in both the thymectomized and non-thymectomized animals developed florid CAV. In the group of animals bearing combined class I disparate heart and kidney allografts, the nonthymectomized recipients accepted both donor organs long term with no evidence of CAV. In contrast, none of the thymectomized heart/kidney recipients survived >100 days, and they all developed the intimal proliferation of CAV. CONCLUSION: Thymic-dependent mechanisms are necessary for the induction of acquired tolerance and prevention of CAV in porcine heart/kidney recipients.