Identification and characterization of two genes (MIP-1beta, VE-CADHERIN) implicated in acute rejection in human heart transplantation: use of murine models in tandem with cDNA arrays.

BACKGROUND: Genes and mechanisms of action involved in human acute rejection after allogeneic heart transplantation remain to be elucidated. The use of a murine allograft model in tandem with cDNA arrays and quantitative real-time polymerase chain reaction (Q-PCR) can greatly help in identifying key genes implicated in human heart acute rejection. METHODS AND RESULTS: Hearts from Balb/c mice were either not transplanted or transplanted heterotopically in the abdomen of Balb/c (isografts) and C57BL/6 (allografts) mice. Histological analysis showed acute rejection only in allografts. Total RNA was extracted from isografts (n=3), allografts (n=4), and not transplanted hearts (n=4); reverse transcribed; and labeled with P32. Each probe was hybridized to cDNA macroarrays. Eight genes were overexpressed and 7 genes were underexpressed in allografts compared with isografts. Macrophage inflammatory protein-1beta (MIP-1beta), an overexpressed gene, and VE-cadherin, an underexpressed gene, were validated by immunohistochemistry and Q-PCR in the murine models. Genes of interest, validated in the 3 murine groups, were then investigated in human heart tissues. Immunohistochemistry and Q-PCR performed on endomyocardial biopsies after heart transplantation showing no rejection (n=10) or grade IB (n=10) or IIIA (n=10) rejection, according to International Society of Heart and Lung Transplantation criteria, confirmed the results obtained from the murine model. CONCLUSIONS: We have demonstrated that the upregulation of MIP-1beta and downregulation of VE-cadherin may strongly participate in human acute heart rejection.

Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.

BACKGROUND: The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. METHODS: A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. RESULTS: After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. CONCLUSIONS: The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.

Thiopurine S-methyltransferase gene polymorphism is predictive of azathioprine-induced myelosuppression in heart transplant recipients.

Azathioprine (AZA) is metabolized via the cytosolic enzyme thiopurine S-methyltransferase (TPMT). TPMT activity exhibits genetic polymorphism with four prevalent (75%) mutant alleles TPMT*2 (G238C) and TPMT*3 (A719G and/or G460A) and a wild-type allele TPMT*1. To test the hypothesis that presence of these mutations is associated with greater toxicity of AZA in heart transplant recipients, 30 consecutive patients treated with AZA were followed up for the first month after heart transplant. Mutation of TPMT gene (mutation-specific polymerase chain reaction-based methods) was observed in four patients (A719G: n = 2; A719G plus G460: n = 2). Agranulocytosis did not occur in patients with the wild genotype. It occurred in the two patients with mutation A719G and there was a 40% drop in neutrophils in the two other patients. Discontinuation of AZA in the four mutant patients corrected for the drop. Presence of TPMT mutations is associated with a greater likelihood of agranulocytosis. Determination of these mutations could reduce the risk for hematological side-effects.

Safety, tolerability and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil based formulation of cyclosporine--results at six months after transplantation.

BACKGROUND: The introduction of cyclosporine has resulted in significant improvement in the survival of cardiac allograft recipients due to decreased mortality from infection and rejection. The original oil-based cyclosporine formulation exhibits variable and unpredictable bioavailability that correlates with an increased incidence of acute and chronic rejection in those patients in whom this is most pronounced. The primary objectives of this prospective, multicenter, randomized, double-blind study in cardiac transplant patients were: to compare the efficacy of cyclosporine microemulsion (CsA-NL) with oil-based cyclosporine (CsA-SM) as measured by cardiac allograft and recipient survival and the incidence and severity of acute rejection episodes; and to assess the safety and tolerability of CsA-NL compared with CsA-SM in this population. This report represents the analysis of results 6 months after transplantation. METHODS: A total of 380 patients undergoing their first cardiac transplant at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial examining the safety and efficacy of CsA-NL versus CsA-SM. Rejection was diagnosed using endomyocardial biopsy and were graded according to standardized criteria of the International Society of Heart and Lung Transplantation (ISHLT). Clinical parameters were monitored during the study. Survival and freedom from were used for analysis as was Fisher's exact test for comparisons between groups. RESULTS: At 6 months after transplantation, allograft and patient survival were the same for both groups. The frequency of ISHLT grade 3A or greater episodes in the two groups was identical. Fewer CsA-NL patients (5.9%) required antilymphocyte antibody (ATG or OKT-3) therapy for rejection compared with the CsA-SM-treated patients (14.1%, P=0.01). Females with ISHLT rejection grade > or = 3A treated with CsA-NL had a 46% lower incidence of rejection compared with the CsA-SM-treated group (31.3% vs. 57.6%, P=0.032). Fewer infections were seen in the CsA-NL. With the exception of baseline and 1 week posttransplant creatinines which were higher in the CsA-NL group, the overall creatinine was not significantly different between the two groups. CONCLUSIONS: This multicenter, randomized study of cardiac transplant recipients documented less severe rejection (in particular those requiring antibody therapy) and a lower incidence of infection in CsA-NL-treated patients. Results from the female subgroup analysis suggest that the improved bioavailability of CsA-NL might reduce the frequency of rejection episodes in female patients. The use of CsA-NL was not associated with an increased risk of adverse events.

[Reversible graft dysfunction after cardiac transplantation]. / Dysfonction réversible du greffon après transplantation cardiaque.

The authors report 3 cases of major graft dysfunction after cardiac transplantation which recovered completely with biventricular mechanical assistance in 4 to 8 days. All three cases were primary biventricular graft failures in patients with normal preoperative pulmonary resistances. These early dysfunctions (with no signs of myocardial infarction on electro- or echocardiography and in the absence of abnormal increased peri-operative enzyme levels) associated with total functional recovery conforming to the definition of the phenomenon of myocardial stunning. These results argue in favour of aggressive management of primary graft dysfunction.

A randomized active-controlled trial of mycophenolate mofetil in heart transplant recipients. Mycophenolate Mofetil Investigators.

BACKGROUND: After heart transplantation, 1-year and 5-year survival rates are 79% and 63%, respectively, with rejection, infection, and allograft coronary artery disease accounting for the majority of deaths. Mycophenolate mofetil (MMF), an inhibitor of the de novo pathway for purine biosynthesis, decreases rejection in animals and in human renal transplantation. METHODS: In a double-blind, active-controlled trial, 28 centers randomized 650 patients undergoing their first heart transplant to receive MMF (3000 mg/day) or azathioprine (1.5-3 mg/kg/day), in addition to cyclosporine and corticosteroids. Rejection and survival data were obtained for 6 and 12 months, respectively. Because 11% of the patients withdrew before receiving study drug, data were analyzed on all randomized patients (enrolled patients) and on patients who received study medications (treated patients). RESULTS: Survival and rejection were similar in enrolled patients (MMF, n=327; azathioprine, n=323). In treated patients (MMF, n=289; azathioprine, n=289), the MMF group compared with the azathioprine group was associated with significant reduction in mortality at 1 year (18 [6.2%] versus 33 deaths [11.4%]; P=0.031) and a significant reduction in the requirement for rejection treatment (65.7% versus 73.7%; P=0.026). There was a trend for fewer MMF patients to have > or = grade 3A rejection (45.0% versus 52.9%; P=0.055) or require the murine monoclonal anti-CD3 antibody or antithymocyte globulin (15.2% versus 21.1%; P=0.061). Opportunistic infections, mostly herpes simplex, were more common in the MMF group (53.3% versus 43.6%; P=0.025). CONCLUSIONS: Substitution of MMF for azathioprine may reduce mortality and rejection in the first year after cardiac transplantation.

Long conservation organs in heart transplantation: postoperative results and long-term follow-up in fourteen patients.

Between 1988 and 1995, 14 heart transplantations were performed after a long preservation period (10 to 13 hours). The transplantation procedure (Shumway) was standard, and our results were achieved through the implementation of a very strict reperfusion technique that included low pressure and low cardiopulmonary bypass output for the first 10 minutes. Three patients died during the postoperative period, and the survival rate was 75% at 1 year and 71% at 5 years. The results obtained with hearts stored for such long periods are comparable to the results obtained with hearts stored for less than 4 hours.

High prevalence of thromoembolic complications in heart transplant recipients. Which preventive strategy.?

Consecutive patients transplanted between January 1984 and December 1988 were followed until August 1992 to detect fatal and nonfatal thromboembolic complications, including sudden death, acute and chronic myocardial infarction, pulmonary and peripheral embolisms, stroke, and thrombophlebitis. The probability of developing such complications was 9.86 per 100 patients per year. The probability of fatal complications was 3.97% per year; the mean interval between transplant and death was 1247 days versus 29.5 days for nonthromboembolic deaths. Thromboembolic deaths represented 5.1% of total mortality at the first year posttransplant but 57, 30, 67 and 73% at the second, third, fourth, and fifth years, respectively. Among the prognosis factors that were analyzed, none was significant predictor of thromboembolic complication. This high prevalence of thromboembolic complications suggests that effective antithrombotic strategy should be defined in heart transplant recipients.

Comparative epidemiologic study of premalignant and malignant epithelial cutaneous lesions developing after kidney and heart transplantation.

BACKGROUND: Cutaneous carcinomas are the most frequent cancers in organ transplant recipients. OBJECTIVE: Our purpose was to compare the epidemiologic data of cutaneous premalignant and malignant epithelial lesions in kidney and heart transplant recipients. METHODS: A total of 580 kidney and 150 heart transplant recipients were examined for the presence of premalignant and malignant epithelial lesions. RESULTS: A twofold increase in incidence of premalignant and malignant epithelial lesions was found in heart compared with kidney transplant recipients. Heart transplant recipients were older at transplantation, received more intense immunosuppressive treatment, and had a shorter delay from transplantation to the development of the first lesion. The squamous cell carcinoma/basal cell carcinoma ratio was 2.37:1 in kidney and 1.08:1 in heart transplant recipients. The extracephalic location represented 60% of the premalignant and malignant epithelial lesions in kidney and 30% in heart transplant recipients. CONCLUSION: Cutaneous premalignant and malignant epithelial lesions in kidney and heart transplant recipients show epidemiologic differences that can tentatively be explained by the older age and the more intense immunosuppressive treatment of heart transplant recipients.

[Value of coronary angiography in the diagnosis of coronary artery disease of the transplanted heart. Coronary angiography and arteriosclerosis of the graft]. / Valeur de la coronarographie dans le diagnostic de la maladie des artères coronaires du greffon après transplantation cardiaque. Coronarographie et athérosclérose du greffon.

The diagnostic value of coronary angiography, a widespread method of detection of transplant coronary artery disease, was studied in 17 cardiac transplant patients with reference to histological examination. In the 6 coronary segments studied, the only significant but weak correlation that was found was for the distal left anterior descending artery: the correlations were not statistically significant in the other 5 segments. Coronary angiography underestimated lesions and false negative results were frequently reported (66 and 27% respectively). The limitations of coronary angiography may be explained by the technical artefacts related to both methods of evaluation and the anatomically diffuse and distal nature of transplant coronary artery atherosclerosis. A more reliable diagnostic method would seem to be required in view of the clinical importance of this pathology.