Hypercholesterolemia is common after pediatric heart transplantation: initial experience with pravastatin.

BACKGROUND: Coronary allograft vasculopathy (CAV) is a progressive complication after cardiac transplantation and limits survival. Hyperlipidemia is a known risk factor for CAV, and pravastatin is effective in decreasing cholesterol levels in adults after transplantation. However, few data exist regarding lipid profiles and statin use after pediatric heart transplantation. We evaluated the prevalence of hyperlipidemia in pediatric heart transplant recipients and assessed the efficacy and safety of pravastatin therapy. METHODS: We performed a retrospective chart review of lipid profiles > or =1 year after surgery in 50 pediatric cardiac transplant recipients to assess the incidence of hyperlipidemia. Twenty of these patients received pravastatin for hypercholesterolemia. Their primary immunosuppression therapy was cyclosporine/prednisone plus either azathioprine or mycophenolate mofetil. We reviewed serial lipid profiles, creatinine phosphokinase, and liver enzymes. RESULTS: Overall, 36% of the patients (n = 50) had total cholesterol (TC) concentrations > 200 mg/dl and 52% had low-density lipoprotein (LDL) >110 mg/dL beyond 1 year after transplantation. Of the 20 treated with pravastatin, TC (236 +/- 51 vs 174 +/- 33 mg/dl) and LDL levels (151 +/- 32 vs 99 +/- 21 mg/dl) decreased significantly with therapy (p <.0001). We found no symptoms; however, 1 patient had increased creatinine phosphokinase. Liver enzyme concentrations remained normal in all. CONCLUSIONS: Hypercholesterolemia is prevalent in pediatric cardiac transplant recipients. Pravastatin therapy is effective in decreasing TC and LDL levels, seems to be safe, and is tolerated well. Further studies are necessary to determine whether pravastatin treatment is beneficial in decreasing CAV.     

Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients.

BACKGROUND: Hyperlipidemia is common after cardiac transplantation and it is a risk factor for post-transplantation coronary artery disease. Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia. Pravastatin, a HMG-CoA reductase inhibitor, has been shown to be effective and safe for cholesterol reduction in adult heart transplant recipients. To our knowledge the safety and efficacy of pravastatin therapy in pediatric and adolescent heart transplant populations have not been previously analyzed. Therefore, we evaluated lipid profiles, liver transaminases, rejection data, and possible side effects in pediatric and adolescent cardiac transplant recipients treated with pravastatin. METHODS: The study group consisted of 40 cardiac transplant recipients 10 to 21 years old (mean age 16.9 years). Twenty-two patients received pravastatin in addition to an immunosuppressive regimen of either cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone. Serial determinations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides were available for all pravastatin-treated patients. Pre-treatment lipid values and hepatic transaminases were compared with those measured after therapy with pravastatin. Comparison of pravastatin-induced lipid reduction between groups treated with cyclosporine vs tacrolimus was also made. RESULTS: Patients receiving pravastatin experienced a mean 32 mg/dl decrease in TC (p < 0.005) and a mean 31 mg/dl decrease in LDL (p < 0.005), regardless of their immunosuppressive regimen. No statistical differences occurred in the magnitude of mean lipid reduction induced by pravastatin between the groups treated with cyclosporine vs tacrolimus. No significant changes in hepatic transaminase levels were noted, and no clinical evidence of pravastatin-induced myositis occurred in any subjects. CONCLUSION: Pravastatin therapy is effective and safe when used in pediatric and adolescent cardiac transplant recipients. Although the pravastatin-induced reduction in TC and LDL was more pronounced in patients receiving cyclosporine, the reduction was not statistically different from that in the tacrolimus group. No evidence of hepatic dysfunction or rhabdomyolysis in patients treated with pravastatin was noted. Long-term studies are required to evaluate the effect of pravastatin therapy on the incidence of accelerated coronary atherosclerosis in this population.     

Cardiac allograft vasculopathy in pediatric heart transplant recipients

Metabolic parameters for coronary allograft vasculopathy (CAV) have not been well defined in children. CAV (by angiography or autopsy) was studied in 337 heart recipients on a cyclosporine-based steroid-sparing regimen. Freedom from CAV for all was 79% at 10 years. Fifty-nine patients (18%) developed CAV at a mean of 6.5 +/- 3 years post-transplant. First year rejections were significantly higher in CAV, mean 2.3 vs. 1.4, P = 0.003, odds ratio (OR) 1.8. Rejection with hemodynamic compromise beyond 1 year post-transplant was associated with CAV, P < 0.001, OR 8.4. There was no significant correlation among human leukocyte antigen DR (HLA DR) mismatch, pacemaker use or homocysteine levels and the development of CAV. Maximum cholesterol and low density lipoprotein (LDL) levels were not significantly different. Neither diabetes nor hypertension was significant predictors of CAV on multivariate logistic regression analysis. In conclusion, frequent and severe rejection episodes may predict pediatric CAV. Neither glucose intolerance nor lipid abnormalities appeared to alter risk for CAV in this population.     

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.     

Rejection with heart failure after pediatric cardiac transplantation.

BACKGROUND: Rejection associated with heart failure or death occurs after pediatric cardiac transplantation but has had limited analysis. METHODS: We analyzed the records of 96 consecutive pediatric cardiac transplant recipients who survived to hospital discharge. RESULTS: Eighteen patients (19%) experienced 23 episodes of heart failure or death associated with rejection. Univariate analysis demonstrated black race (p = 0.041), transplantation after 12 months of age (p = 0.032), later time after transplantation (p = 0.037), rejection episode in the first year after transplantation (p = 0.001), and history of two or more rejection episodes (p < 0.001) were significantly associated with rejection seen with heart failure. A multivariate regression analysis identified two or more rejection episodes to be the only independent risk factor for the development of rejection with heart failure (odds ratio 20; 95% confidence limits, 4-104; p < 0.0001). CONCLUSIONS: This study identified pediatric heart transplant recipients with a history of previous rejection episodes to be at a higher risk for symptomatic or fatal rejection. Further studies are needed to determine if intensification of maintenance immunosuppression, long-term rejection surveillance, or both in patients with multiple rejection episodes could reduce morbidity and mortality from rejection.     

Late rejection episodes more than 1 year after pediatric heart transplantation: risk factors and outcomes.

BACKGROUND: Little is known about late rejection episodes after pediatric heart transplantation. We determined the frequency of late rejection episodes (>1 year) after pediatric heart transplantation, defined risk factors for its occurrence, and evaluated outcome after late rejection. METHODS: We analyzed data from 685 pediatric recipients (<18 years at transplantation) who underwent transplantation between January 1, 1993, and December 31, 1997, at 18 centers in the Pediatric Heart Transplant Study (PHTS). Probability of freedom from late rejection was determined and risk factors for late rejection and for death after late rejection were sought using univariate and multivariate analyses. RESULTS: We followed 431 patients for >1 year (median follow-up, 32.9 months) of whom 106 (24.6%) experienced 1 or more late rejection episodes (total of 178 episodes, 27 with severe hemodynamic compromise). Probability of freedom from first late rejection was 73% at 3 years and 66% at 4 years after transplantation. Risk factors (multivariate analysis) for first late rejection were >1 episode of rejection in the first year (p = 0.009), recipient black race (p = 0.0002), and older age at transplantation (p = 0.0003). Only 4 of 325 (1.2%) children who survived beyond 1 year without late rejection died compared with 26 of 106 (24.6%) with late rejection (p < 0.0001). Nine of these 26 died within 1 month of the first late rejection episode, and 17 died subsequently: 5 of acute rejection, 3 of sudden unexplained deaths, 3 of documented coronary artery disease, and 6 of other causes. Severe hemodynamic compromise with late rejection was identified as a risk factor for death among children with 1 or more episodes of late rejection. CONCLUSIONS: Approximately 25% of pediatric recipients in the PHTS who survived beyond 1 year experienced late rejection episodes. Late rejection is associated with poor survival, especially when associated with hemodynamic compromise. Absence of late rejection episodes is associated with very low risk of death during medium-term follow-up after pediatric heart transplantation. Determining the risk factors for late rejection will help to identify a cohort of patients who may benefit from enhanced rejection surveillance and treatment.     

Differential Effect of Everolimus on Progression of Early and Late Cardiac Allograft Vasculopathy in Current Clinical Practice

Randomized trials showed that mTOR inhibitors prevent early development of cardiac allograft vasculopathy (CAV). However, the action of these drugs on CAV late after transplant is controversial, and their effectiveness for CAV prevention in clinical practice is poorly explored. In this observational study we included 143 consecutive heart transplant recipients who underwent serial intravascular ultrasound (IVUS), receiving either everolimus or mycophenolate as adjunctive therapy to cyclosporine. Ninety‐one recipients comprised the early cohort, receiving IVUS at weeks 3–6 and year 1 after transplant, and 52 the late cohort, receiving IVUS at years 1 and 5 after transplant. Everolimus independently reduced the odds for early CAV (0.14 [0.01–0.77]; p = 0.02) but it did not appear to influence late CAV progression. High‐dose statins were found to be associated with reduced CAV progression both early and late after transplant (p ≤ 0.05). Metabolic abnormalities, such as high triglycerides, were associated with late, but not with early CAV progression. By highlighting a differential effect of everolimus and metabolic abnormalities on early and late changes of graft coronary morphology, this observational study supports the hypothesis that everolimus may be effective for CAV prevention but not for CAV treatment, and that risk factors intervene in a time‐dependent sequence during CAV development.     

Atrial tachyarrhythmias and permanent pacing after pediatric heart transplantation.

BACKGROUND: Atrial tachyarrhythmias have been reported in as high as 50% of adult heart recipients. Limited information is available on arrhythmias in pediatric transplant patients. Our objective was to determine the prevalence and significance of atrial tachyarrhythmias and permanent pacing following pediatric heart transplantation. METHODS: A retrospective review of the medical records, electrocardiograms, and Holter recordings of all consecutive patients following heart transplantation at Children's Hospital, Boston (n = 104) and Lucile Packard Children's Hospital, Stanford (n = 123) was performed. The study group consisted of 227 patients with a median age at transplant of 10.2 yrs (1 day-23.3 yrs). RESULTS: Atrial tachyarrhythmias occurred in 32 patients (14%) at a median of 15 days post-transplant (1 day-9.2 yrs) and included atrial flutter (n = 13), atrial fibrillation (n = 7), ectopic atrial tachycardia (n = 5), atrioventricular reciprocating tachycardia or atrioventricular node reentry (n = 5), and other (n = 2). Atrial flutter was the only tachyarrhythmia associated with allograft rejection (6/13 atrial flutter vs. 0/7 atrial fibrillation vs. 0/5 ectopic atrial tachycardia, p = 0.03). Patients with atrial fibrillation had a 2.5 fold (95%CI 1.7-3.5) higher risk of death or retransplant compared to patients without atrial fibrillation. Ectopic atrial tachycardia tended to occur in younger recipients compared to atrial fibrillation and flutter (2.7 yrs vs 18.6 yrs and 8.5 yrs respectively, p = 0.06) and was associated with a benign clinical course. There was no association between atrial tachyarrhythmias and graft ischemic time, surgical technique, or coronary artery disease. Pacemakers were required in 12 patients (5.2%), 7 with sinus node dysfunction and 5 for intermittent complete atrioventricular block. There was no consistent association between the need for permanent pacing and coronary artery disease, rejection, or surgical technique. CONCLUSIONS: Atrial tachyarrhythmias and permanent pacing were uncommon in this cohort of pediatric heart transplant recipients. Association with cardiac rejection, clinical course, and mortality varied depending on the tachyarrhythmia mechanism.     

心脏移植术后移植物血管病:阜外医院单中心长期随访结果总结

目的 总结心脏移植术后心脏移植物血管病变(CAV)的发生情况及其对患者长期存活的影响.方法 回顾性分析1006例心脏移植受者的临床资料,48例CAV患者中4例因缺失影像学证据未纳入分析.1002例受者中,根据CAV发生情况分为CAV组(44例)和无CAV组(958例).总结CAV的发生情况,比较两组患者的临床资料,分析...     

Changes in coronary endothelial function predict progression of allograft vasculopathy after heart transplantation.

OBJECTIVE: Coronary endothelial dysfunction may be an early marker for cardiac allograft vasculopathy (CAV) in orthotopic heart transplant recipients. We used serial studies to evaluate changes in coronary endothelial function in patients with and without clinically evident CAV. BACKGROUND: In serial studies with intravascular ultrasound (IVUS) and Doppler flow wire measurements, we previously demonstrated that annual decrements in coronary endothelial function are associated with progressive intimal thickening. METHODS: We studied 45 patients annually, beginning at transplantation until pre-specified end-points (angiographic CAV or cardiac death) were reached. At each study, we measured coronary endothelial function using intracoronary infusions of adenosine, acetylcholine, and nitroglycerin. We simultaneously recorded IVUS images and Doppler velocities. RESULTS: Of the 45 patients studied, 9 reached end-points during the study (6 had CAV and 3 died). The mean annual change in area response to acetylcholine was -4.5% +/- 3.0% in patients who reached end-points and -0.9% +/- 1.5% in those who did not (p = 0.04). The mean annual decrement in flow response to acetylcholine was greater in patients who reached end-points (-31% +/- 11% vs -5% +/- 5%, p = 0.08). Responses to adenosine and nitroglycerin did not differ. CONCLUSIONS: When serial responses were evaluated, patients with end-points had more rapid decreases in endothelial function. The rate of disease progression may be more important than the absolute degree of intimal thickening in early CAV. These data implicate endothelial dysfunction in the development of clinically significant vasculopathy and suggest that serial studies of endothelial function may provide important prognostic information about the development of CAV after heart transplantation.     

Total lymphoid irradiation for refractory rejection in pediatric heart transplantation

BACKGROUND: We evaluated the role of total lymphoid irradiation (TLI) in the management of refractory rejection among pediatric heart transplant patients. METHODS: Eleven of 298 patients underwent TLI at 6 to 195 months of age and were divided into subgroups: those who survived (group A, n = 7) and those who did not survive beyond 1 year after TLI (group D, n = 4). Non-TLI recipient data were considered as the controls. RESULTS: Six out of 11 patients died eventually (54%). TLI was initiated 3 to 107 months after transplantation with a dosage of 600 to 840 cGy. The pre-TLI rejection rate (0.62 +/- 0.40 per month) was higher (p < 0.0001); however, the post-TLI rejection rate (0.24 +/- 0.65 per month) showed no significant difference from the control rejection rate. The Cox proportional hazard model found significance for TLI as a risk factor for development of posttransplant coronary artery disease (relative risk, 4.8; 95% CI, 1.1 to 21.3) and posttransplant lymphoproliferative disease (relative risk, 47.9; 95% CI, 1.6 to 1,475.3), respectively. Although the rejection rate decreased after TLI in both groups (group A pre/post, 0.51 +/- 0.31/0.06 +/- 0.08 per month; group D pre/post, 0.82 +/- 0.49/0.57 +/- 1.09 per month), significance was obtained only in group A (p = 0.018). CONCLUSIONS: TLI was an effective adjunct for reversal of refractory rejection in pediatric heart transplantation by reducing the rejection rate. Great care must be taken for the risk of development of coronary artery disease or lymphoproliferative disease.     

Is bridging to transplantation with a left ventricular assist device a risk factor for transplant coronary artery disease?

BACKGROUND: Left ventricular assist device (LVAD) support is associated with coagulopathy, bleeding, increased blood transfusion, and increased anti-HLA antibody production. Increased anti-HLA antibody production is associated with early transplant rejection, transplant coronary artery disease (CAD), and decreased post-transplant survival rates. We asked whether bridging to transplantation with an LVAD increases the risk of transplant CAD. METHODS: We reviewed data for all adults (>18 years old) who underwent heart transplantation at our institution between 1988 and 2000. After exclusion of transplant recipients who survived <3 years, we divided the remaining cohort into 2 groups: those bridged to transplantation with LVADs (mean duration of support, 149 +/- 107 days, n = 29) and those in United Network for Organ Sharing Status 1 bridged to transplantation without LVADs (controls, n = 86). We compared groups in terms of disease cause, age, sex, donor age, panel-reactive antibody testing, crossmatching, pre- and post-transplant cholesterol concentrations, diagnosis of diabetes mellitus or treated hypertension, infections, calcium channel blocker use, transplant rejection, ischemic time, cytomegalovirus infection, pre-transplant transfusion, and incidence of transplant CAD (defined as any coronary lesion identified by coronary angiography). We considered p < 0.05 to be significant. RESULTS: The bridged and control groups were similar in all respects except mean ischemic time (217 +/- 58 minutes vs 179 +/- 67 minutes, p = 0.007), post-transplant cholesterol concentration (212 +/- 55 mg/dl vs 171 +/- 66 mg/dl, p = 0.007), and pre-transplant transfusion incidence (100% vs 22%, p < 0.001). The incidence of transplant CAD was similar in both groups during a 3-year follow-up period (28% vs 17%, p = 0.238) and during total follow-up (34% vs 35%, p = 0.969). Multivariate logistic regression analysis identified cholesterol concentration at 1 year after transplantation as a significant predictor of CAD at 3 years after heart transplantation (p = 0.0029, odds ratio = 0.984). CONCLUSIONS: Bridging to transplantation with an LVAD does not increase the risk of transplant CAD. Nevertheless, aggressive prophylactic therapy to minimize potential risk factors for transplant CAD, such as increased cholesterol concentration, is warranted in all transplant recipients.     

Diastolic performance assessed by tissue Doppler after pediatric heart transplantation.

BACKGROUND: Diastolic performance, indexed by tissue Doppler imaging (TDI), has been reported to predict cellular rejection in adult heart recipients, but the predictive value of TDI after pediatric heart transplantation is unknown. METHODS: TDI-derived diastolic performance was studied in 37 pediatric (median age 2.54 years) heart recipients in the absence and presence of rejection. Maximum velocities in diastole of the left ventricular posterior wall thinning (diastvelLVPWmax) and medial mitral valve annulus (MVA) were determined in 160 echocardiograms from recipients who experienced either no rejection (Group 1, n = 22) or >or=1 rejection episode(s) (Group 2, n = 14) during the study interval (2 years). There was 1 death in the immediate post-transplant period not included in the analyses. RESULTS: The diastvelLVPWmax determined by TDI in Group 1 increased during the first 90 days post-transplant (r = 0.31; p = 0.05), was heart-rate-dependent (r = 0.591; p < 0.001), and was significantly lower than the veILVPWmax determined from digitized M-mode tracings (116 +/- 31 vs 135 +/- 44 mm/s; p < 0.05). In a sub-group of children transplanted during the study and followed for >or=1 year (n = 9), diastvelLPWmax, determined by TDI, was lower in infant recipients (n = 6; 106.5 +/- 22 mm/s) than in older recipients (n = 3; 135 +/- 36 mm/s; p = 0.015). With rejection, diastvelLVPWmax, determined by M mode (147 +/- 13 vs 104 +/- 11 mm/s; p < 0.05), was decreased compared with baseline recipient studies prior to rejection. In contrast, rejection did not significantly change diastvelLVPWmax, as determined by TDI. MVA E/A (peak early-to-late diastolic velocity ratio) was significantly decreased with rejection (1.37 +/- 0.23 vs 0.92 +/- 0.22; p < 0.05). As a single parameter, an MVA E/A <1.1 was predictive of rejection in 4 of 10 recipients with MVA E/A >or=1.1 pre-rejection. CONCLUSIONS: TDI-derived diastvelLVPWmax varied with age at transplant, heart rate and time post-transplant. A decrease in TDI-derived MVA E/A, but not diastvelLVPWmax, can be of additional predictive value in non-invasive surveillance for rejection in pediatric heart recipients.     

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.     

The Influence of Race and Common Genetic Variations on Outcomes After Pediatric Heart Transplantation

Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow‐up was 6.25 years. Unadjusted 5‐year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8–19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes.     

Dobutamine stress echocardiography in the assessment of cardiac allograft vasculopathy in asymptomatic recipients

PURPOSE: Cardiac allograft vasculopathy (CAV) is the most important cause of late mortality among cardiac allograft recipients. Dobutamine stress echocardiography (DSE) is considered a safe and cost-effective method to screen these patients who remain free of angina most of the time. We evaluated DSE results in a series of cardiac allograft recipients. METHODS: The DSE was performed on a yearly basis. From 2004 to 2006, twelve DSEs were performed on 8 patients, including 7 men, and overall mean age of 36 +/- 12 years. Dobutamine infusion begun at 5 microg/kg/min was titrated at 3-minute stages to 10, 20, 40, and 50 microg/kg/min to achieve the target heart rate. In addition, at every stage, we performed a 12-lead EKG, heart rate, and blood pressure recording. The DSE results were compared with coronary angiograms and endomyocardial biopsies. RESULTS: Two patients displayed mildly and 1 patient a severely abnormal DSE test. The severely abnormal DSE test was associated with severe coronary artery stenosis, including inexperiment of the left main coronary artery. The second patient with an abnormal DSE had contour irregularities and distal cut-off of the right coronary artery as well as 2R cellular rejection. The third patient had a normal angiogram and no rejection. None of the patients with normal DSE experienced a cardiac event, coronary lesions, or rejection. CONCLUSION: Use of DSE appears to be a sensitive method to detect CAV in asymptomatic recipients. However, mild wall motion abnormalities can be detected in patients without stenosing coronary lesions. The value of DSE in predicting CAV must be examined in larger series with long-terms of follow-up.     

Efficacy and safety of pravastatin vs simvastatin after cardiac transplantation.

Prior studies of cardiac transplant recipients have shown that pravastatin reduces 12-month rejection and mortality after cardiac transplantation and simvastatin reduces 4-year mortality, low-density lipoprotein (LDL) cholesterol levels, and intimal thickening.In a 12-month observational study, cardiac transplant recipients received open-label pravastatin 40 mg (n = 42) or simvastatin 20 mg daily (n = 45) on an alternating basis from the time of transplantation. Lipid levels, safety, and post-transplant outcomes were compared.We found no significant differences in total LDL or high-density lipoprotein cholesterol, triglycerides, linearized infection or rejection rates, liver function tests, or immunosuppressant dosages between groups at 1, 3, 6, or 12 months. Rhabdomyolysis or myositis occurred only in patients on simvastatin (n = 6, 13.3%) with no episodes for patients on pravastatin (p = 0. 032). Survival at 12 months on an actual treatment basis was 97.6% for patients on pravastatin and 83.7% for those on simvastatin (p = 0.078). Immunosuppression-related deaths occurred in only 2.4% (1 patient) on pravastatin vs 15.6% (n = 7) on simvastatin (p = 0.06). Pravastatin and simvastatin resulted in comparable lipid profiles. Pravastatin use was however free from the high rates of rhabdomyolysis and myositis seen with simvastatin use. Pravastatin was additionally associated with a trend toward superior survival, attributable to fewer immunosuppression-related deaths. For safety and pharmacokinetic reasons, pravastatin should be considered the statin of choice after heart transplantation.     

Tumor necrosis factor gene polymorphism and cardiac allograft vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) limits survival after cardiac transplantation. Tumor necrosis factor-alpha (TNF-alpha) may be a key factor in the development of CAV. Two bi-allelic polymorphisms associated with high TNF-alpha production have been identified in the TNF gene locus, TNFA1/2, at position -308 and TNFB1/2 at +252. We hypothesized that recipient TNFA2 and TNFB2 homozygosity is associated with the development of CAV after heart transplantation. METHODS: TNF gene polymorphisms were analyzed by multiplex fluorescent solid-phase mini-sequencing in 70 cardiac transplant recipients. Recipients homozygous for TNFA2 or TNFB2 (Group A, n = 29) were compared with recipients heterozygous or homozygous for TNFA1 and TNFB1 (Group B, n = 41). Coronary arteriography was performed annually or when indicated. Cumulative freedom from CAV and survival was calculated according to the Kaplan-Meier test. RESULTS: Mean follow-up was 3.8 +/- 0.3 years. In Group A, 11 of 29 recipients (38%) developed CAV compared with 9 of 41 (22%) in Group B (p = 0.12). Cumulative freedom from CAV at 3 years was 42% in Group A and 80% in Group B (p = 0.043). In Group A, 11 of 29 recipients (38%) died during follow-up compared with 4 of 41 (10%) in Group B (p = 0.006). Cumulative survival at 3 years was 72% in Group A and 93% in Group B (p = 0.003). CONCLUSIONS: The results suggest that TNFA2 and TNFB2 allele homozygosity is associated with cardiac allograft vasculopathy and mortality in heart transplant recipients.     

Lipoprotein-associated phospholipase A2 predicts progression of cardiac allograft vasculopathy and increased risk of cardiovascular events in heart transplant patients

BACKGROUND: Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk factor for coronary artery disease (CAD) in nontransplant patients. We evaluated the association between Lp-PLA2, cardiac allograft vasculopathy (CAV) assessed by 3D intravascular ultrasound, and incidence of cardiac adverse events in heart transplant recipients. MATERIALS AND METHODS: Fasting blood samples were obtained and stored from a cross-section of 112 cardiac transplant recipients attending the Mayo cardiac transplant clinic in 2000 to 2001, mean of 4.7 years after transplant. Lp-PLA2 was measured in plasma aliquots using an enzyme-linked immunoassay. Fifty-six of these patients subsequently underwent two 3D intravascular ultrasound studies in 2004 to 2006 12 months apart. Cardiovascular (CV) events included percutaneous coronary intervention, coronary artery bypass grafting (CABG), reduction in left ventricular ejection fraction (LVEF) < or =45% secondary to CAV and CV death. RESULTS: High Lp-PLA2 level was associated with increase in plaque volume (r=0.43, P=0.0026) and percent plaque volume (r=0.45, P=0.0004). The association remained significant after adjusting for clinical and lipid variables. During follow-up of 5.1+/-1.6 years, 24 CV adverse events occurred in 15 of 112 (13%) heart transplant patients. Lp-PLA2 level>236 ng/mL (higher tertile) identified a subgroup of patients having a 2.4-fold increase of relative risk for combined endpoint of CV events (percutaneous coronary intervention, CABG, LVEF<45%, and CV death; 95% CI 1.16-5.19, P=0.012) compared with patients with Lp-PLA2< or =236 ng/mL. CONCLUSIONS: Lp-PLA2 is independently associated with progression of CAV and predicts a higher incidence of CV events and CV death in transplant patients. This finding supports the concept that systemic inflammation is an important mediator of CAV. Lp-PLA2 may be a useful marker for risk of CAV and a therapeutic target in posttransplant patients.     

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.