The Effects of CYP3A5 Genetic Polymorphisms on Serum Tacrolimus Dose-Adjusted Concentrations and Long-Term Prognosis in Chinese Heart Transplantation Recipients.

BACKGROUND AND OBJECTIVES: Effective management of immunosuppressants is extemely important to improve prognosis of heart transplant recipients. We aim to investigate the effects of cytochrome P450 (CYP) 3A5 (rs776746) single nucleotide polymorphisms (SNPs) on serum tacrolimus concentrations/doses (C/Ds, ng/mL per mg/kg) and long-term prognosis in Chinese heart transplant recipients. METHODS: We detected the CYP3A5 SNPs of 203 consecutive Chinese heart transplant recipients between August 2005 and July 2012, and 55 of them who received tacrolimus-based immunosuppressive therapy were enrolled in this study. The tacrolimus C/Ds at 1, 3, 6, 12, 24 and 36 months after transplantation were routinely calculated. X-ray-guided endomyocardial biopsies (EMBs) were performed at 1, 3 and 6 months after heart transplantion to evaluate acute rejection degrees. All participants were then followed up annually until May 2018. The designed primary endpoint was all-cause mortality. RESULTS: In 55 heart transplant recipients (43 males and 12 females), CYP3A5 non-expressors (CYP3A5*3/*3, n = 40) had significantly higher tacrolimus C/Ds than expressors (CYP3A5*1/*3, n = 15) at all time points (P < 0.001). Chi-squared test showed no significant differences in EMB-proven acute rejections between the two groups within 6 months after heart transplantion. The median follow-up period was 94.7 months, and eight patients died. Kaplan-Meier analysis showed CYP3A5 expressors tend to have higher mortality than non-expressors (20% vs 12.5%, log-rank: P = 0.314). CONCLUSIONS: CYP3A5 SNPs affect tacrolimus pharmacokinetics in Chinese heart transplant recipients, and non-expressors have higher tacrolimus C/Ds. In addition, expressors tend to have a worse long-term prognosis than non-expressors.

Late onset radiation-induced constrictive pericarditis and cardiomyopathy after radiotherapy: A case report.

INTRODUCTION: Radiation-induced heart disease (RIHD) is a serious side effect of cancer treatment, including coronary artery disease, valvular cardiac dysfunction, cardiomyopathy, aortopathy, and chronic constrictive pericarditis. Herein, this case we present was diagnosed as radiation-induced constrictive pericarditis and cardiomyopathy by means of cardiac magnetic resonance (CMR) and transthoracic echocardiogram, finally confirmed by pathology after performing heart transplant operation. CONCLUSIONS: This case supports a notion that RIHD often causes multiple heart impairment and CMR is helpful to diagnose cardiomyopathy after radiation.

[Risk factors for hypertension and impact of postoperative hypertension on medium survival after heart transplantation].

OBJECTIVE: To access the prevalence and risk factors for hypertension after heart transplantation (HT), and the impact of post-transplant hypertension on medium-term survival among HT patients. METHODS: Data from 265 consecutive patients underwent HT between June 2004 and May 2012 in Fuwai hospital and survived for at least 6 months were retrospectively analyzed. Hypertension was defined as systolic pressure ≥ 140 mm Hg (1 mm Hg = 0.133 kPa) and/or diastolic pressure ≥ 90 mm Hg or current treatment with antihypertensive drugs. Patients were divided into post-HT hypertension group and non-hypertension group. Logistic regression analysis was used to determine preoperative and postoperative risk factors for hypertension after HT. Kaplan-Meier method and log rank test were used for survival analysis. RESULTS: Hypertension was present in 17.4% (46/265) patients before HT and in 57.4% (152/265) patients post HT. The median follow-up time was 37 months (20 - 57 months). Logistic regression analysis showed that male gender (OR: 2.27, 95%CI: 1.16 - 4.42, P < 0.05), history of pre-HT hypertension (OR: 2.22, 95%CI: 1.05 - 4.71, P < 0.05), and cyclosporine A based immunosuppressive therapy (OR: 2.54, 95%CI: 1.51 - 4.29, P < 0.01) were independent risk factors for the development of post-HT hypertension. At the end of 1, 3, 5 years, the survival rate of heart transplant patients by Kaplan-Meier method estimation were 100%, 97.2%, 86.7% in post-HT hypertension group; 98.1%, 93.8%, 93.8% in non-hypertension group. Log rank test displayed that there was no significant difference between the two survival curves (P > 0.05). CONCLUSIONS: Hypertension is a frequent comorbidity after HT. Male gender, pre-HT hypertension together with cyclosporine A based immunosuppressive therapy are independent predictors for the development of post-HT hypertension. By adjusting the controllable risk factors and active control of blood pressure, the medium-term survival is similar between patients with or without postoperative hypertension in this cohort.

[Sirolimus use in heart transplantation recipients with chronic renal dysfunction].

OBJECTIVE: To observe the effect of sirolimus-based immunosuppression administered on heart transplant recipients with chronic renal dysfunction. METHODS: From June 2004 to December 2008, standard calcineurin inhibitors (CNI)-based immunosuppressive regimen was changed to reduced-dose CNI plus sirolimus due to CNI-related chronic renal dysfunction in 20 out of 138 cardiac transplant recipients at Fuwai Hospital. The standard immunosuppressive regimen included steroid, CNI (cyclosporine or tacrolimus), and mycophenolate mofetil or azathioprine. Sirolimus was started at 0.75 - 1.50 mg/d with titration to achieve levels of 5 - 15 µg/L, and CNI dose was reduced gradually to 1/2-2/3 of the baseline level. Patients were followed for changes in renal function, lipid level and clinical side effects related to immunosuppressive therapy. Endomyocardial biopsy (EMB) was performed routinely at 3 weeks, 3, 6 and 12 months after transplantation. EMB was also performed at 3 months after regimen change within 1 year post-transplantation or when rejections were suspected in patients beyond 1 year post-transplantation. Echocardiography was performed for monitoring purpose. RESULTS: The mean follow-up after regimen change was (7.9 ± 6.3) months. Final sirolimus dose was (0.89 ± 0.22) mg/d and blood drug level was (7.6 ± 3.8)µg/L. Cyclosporine dose was reduced from (191.7 ± 60.0) mg/d to (123.6 ± 34.8) mg/d, with blood drug concentration reduced from (175.5 ± 58.0) µg/L to (111.9 ± 56.0) µg/L in 18 patients (P < 0.01). Tacrolimus average dose was reduced from 4.25 mg/d to 3.00 mg/d, with blood drug concentration reduced from 13.5 µg/L to 10.5 µg/L in 2 patients. Serum creatinine level fell from (160.4 ± 25.5) µmol/L to (134.4 ± 26.8) µmol/L (P < 0.01) and urea nitrogen fell from (13.8 ± 4.7) µmol/L to (10.4 ± 3.0) µmol/L (P < 0.01) at one month after regimen change. Twenty two EMBs were performed in 11 patients within 1 year post-transplant, there were 4 episodes of acute rejected (ISHLT grade 2). Twenty patients are all alive and cardiac function was normal. The most common side effect was hyperlipidemia, and triglycerides, total cholesterol and low density lipoprotein levels were significantly increased at 1 month post regimen change (P < 0.05 or P < 0.01). Leukocyte, hemoglobin and platelet as well as liver function remained unchanged at 1 month post regimen change (all P > 0.05). CONCLUSION: Our results show that change from CNI-based immunosuppressive regimen to reduced-dose CNI plus sirolimus is an effective and safe approach for the management of patients with CNI-related chronic renal dysfunction, leading to an improvement in renal function without compromise in anti-rejection efficacy and with tolerable side effects.

[Safety analyses from 439 patients underwent endomyocardial biopsy via the right internal jugular vein approach].

OBJECTIVE: Primary indications for endomyocardial biopsy (EMB) include heart transplant rejection surveillance and identifying cardiomyopathy or myocarditis. EMB procedures have not yet gained widespread acceptance because of concerns about possible complications associated with EMB procedures. In this single-center retrospective study, we analyzed the incidence of major and minor EMB procedure-related complications of 439 EMBs during the past 4.5 years. METHODS: From May 2004 to November 2008, 15 patients with cardiomyopathy and 1 patient with suspected cardiac tumor underwent 16 EMB procedures and 131 heart transplant recipients underwent 423 EMB procedures with the use of a modified Cordis bioptome. All EMB procedures were made via the right internal jugular vein approach and RV septum EMBs were performed under fluoroscopic guidance without additional echocardiographic monitoring. Operators were allowed to perform EMB procedure alone if a minimum of 50 EMB procedures had been previously supervised by a senior operator and all EMBs were performed by 4 operators. All patients underwent a 12-lead electrocardiogram (ECG), 12-hour continuous ambulatory ECG monitoring, chest X-ray and transthoracic echocardiography before and after EMB procedures to obtain a detailed evaluation of the incidence of conduction abnormalities, arrhythmias, pericardial effusions and worsening valve insufficiency. RESULTS: There was no major complications like cardiac tamponade, hemothorax and pneumothorax. Minor complications such as conduction abnormalities including temporary RBBB (lasting < 24 h after EMB procedures) were found in 2 cases (0.47%) and sustained RBBB (> 24 h) was evidenced in 1 case (0.23%). There were no A-V block, complex ventricular arrhythmias or episodes of atrial fibrillation during and post procedure. In addition, 4 cases (0.91%)of EMB induced mild-moderate tricuspid regurgitation during the procedure were diagnosed by echocardiography. CONCLUSION: The EMB procedure via the right internal jugular vein approach under fluoroscopic guidance is safe and associated with a very low complication rate when performed by experienced operators.

[Extracorporeal membrane oxygenation in the peri-operative period of heart transplantation].

OBJECTIVE: To summarize and analyze clinical outcomes and experience about using extracorporeal membrane oxygenation (ECMO) in supporting heart transplant patients in the peri-operative period of in Fuwai Hospital retrospectively. METHODS: We performed 131 orthotopic heart transplantations from June 2004 to December 2008. Fourteen cases used veno-artery ECMO (Medtronic Ltd) for mechanical circulatory support in the peri-operative period of heart transplantation. Active clotting time(ACT) was maintained between 160 - 200 seconds, mean blood flow was 1.8 - 3.3 L/min during ECMO assistant period. RESULTS: Twelve survivals discharged with NYHAI, two patients died of multiple orgen failure with severe infection and complication of central nervous system. The ECMO time was 75 - 824 h and mean time 149 h. 12 survivals with ECMO assistance decreases the dose of vasoactive drugs, after bedside UCG evaluating heart function recovery with stable circulation, ECMO could be weaned off uneventfully after 100 h. Five patients with seven times bleeding complication and one patient with catheter-associated arterial thrombosis of distal limb, all ECMO patients with low-albuminemia and hyperbilirubinemia at some degree, eleven patients with increasing blood creatine and five patients were treated with continous renal replacement therapy, one patient with pertinacious hyperbilirubinemia was treated with plasma exchange and molecular absorbent recirculating system. Seven patients were extension incision healing and six patients were tracheotomy. CONCLUSIONS: ECMO can bridge patients with end-stage heart failure to heart transplant, and extend the use of marginal donors, grasp the ECMO indication and timing of application, avoiding irreversible dysfunction of the vital organs and preventing complication during ECMO, ECMO may decrease mortality of severe patients in the peri-operative period of heart transplantation.

Adult endothelial progenitor cells from human peripheral blood maintain monocyte/macrophage function throughout in vitro culture.

Mononuclear cells (MNCs) isolated from peripheral blood by density gradient centrifugation were plated on human fibronectin-coated culture plates and cultured in EGM-2 medium. Attached spindle-shaped cells, reported as endothelial progenitor cells (EPCs) by some investigators, had elongated from adherent round cells, but had not proliferated from a small number of cells as supposed previously. The growth curve of the primary EPCs showed that the cells had little proliferative capacity. Flow cytometry analysis showed that the cells could express some of the endothelial lineage markers, while they could also express CD14, which is considered a marker of monocyte/macrophage lineages throughout culture. In endothelial function assays, the cells demonstrated a lower level of expression of eNOS than mature endothelial cells in the reverse transcription-polymerase chain reaction and did not show an ability to develop tube-like structures in angiogenesis assay in vitro. In this study, we identified the monocytoid function of EPCs by the combined Dil-labeled acetylated low-density lipoprotein (Dil-Ac-LDL) and Indian ink uptake tests. All the cells were double positive for Dil-Ac-LDL and Indian ink uptake at days 4, 14 and 28 of culture, which means the EPCs maintained monocytoid function throughout the culture. Therefore, although adult EPCs from peripheral MNCs have some endothelial lineage properties, they maintain typical monocytic function and have little proliferative capacity.