Effects of methotrexate on acute rejection and cardiac allograft vasculopathy in heart transplant recipients.

BACKGROUND: In heart transplant recipients methotrexate has been shown to reverse recurrent/persistent acute rejection refractory to intensified conventional immunosuppression. This study sought to determine whether methotrexate produces a sustained decline of heart allograft rejection rates and renders rejection rates of patients with a history of recurrent/persistent rejection similar to those of heart transplant recipients without such history. METHODS: Rejection, infection, and cardiac allograft vasculopathy were compared in 35 patients treated with methotrexate (12 +/- 9 mg/week for 34 +/- 54 weeks) and 236 patients never given methotrexate. Because the mean time from transplantation to initiation of methotrexate was 9.4 months, patients treated without methotrexate were analyzed for events < or = 9.4 versus > 9.4 months after heart transplantation. RESULTS: Demographics, perioperative and maintenance immunosuppression, and postoperative follow-up time (58 +/- 32 vs 57 +/- 33 months) were similar in the two groups. Rejection rates decreased in both groups but remained significantly higher in the patients treated with methotrexate after initiation of therapy than in the patients treated without methotrexate more than 9.4 months after transplantation (0.15 +/- 0.16 vs 0.06 +/- 0.12 episodes/patient/month; p = 0.0014). Infection rates were higher in patients after methotrexate initiation than in patients treated without methotrexate more than 9.4 months after heart transplantation (0.17 +/- 0.24 vs 0.06 +/- 0.13 episodes/patient/month; p = 0.015). At the end of the follow-up period methotrexate- and non-methotrexate-treated groups did not differ in the percentage of patients with angiographically detectable cardiac allograft vasculopathy (17.1% and 21.2%, respectively) and survival (71.4% and 64.0%, respectively). CONCLUSIONS: Even after reversal of rejection by methotrexate, patients requiring methotrexate for the treatment of persistent/recurrent rejection continued to have higher rejection rates than patients not requiring methotrexate. In spite of persistently higher rejection rates, patients treated with methotrexate did not have higher rates of cardiac allograft vasculopathy. This finding raises the question whether methotrexate provides a protective influence on the development of cardiac allograft vasculopathy in this high-risk group.

Factors associated with the development of persistently depressed cardiac output during the first year after cardiac transplantation.

The purpose of this study was to determine factors associated with the development of a persistently depressed cardiac output during the first year after cardiac transplantation. With this aim in mind, the records of 133 consecutive patients undergoing orthotopic cardiac transplantation and surviving for > or = 1 year after transplantation were reviewed. For each patient, the mean cardiac index for each of the 3-month periods, 0-3, 4-6, 7-9, and 10-12 months after transplantation was calculated. Of the 133 patients, 19 (14%) had a mean cardiac index < 2.4 l/min/m2 during > or = 3 of these 3-month periods. The pre- and post-transplantation clinical, immunologic, and hemodynamic data of these 19 patients (study group) were compared with the remaining 114 patients (control group). Compared with the control group, the patients in the study group were older (56 +/- 5 vs. 46 +/- 15 years; p = 0.0001), more frequently had ischemic heart disease as the original diagnosis (58 vs. 37%; p < 0.05), had a lower preoperative cardiac index (1.91 +/- 0.53 vs. 2.71 +/- 1.0 l/min/m2; p = 0.0001), more frequently did not receive perioperative anti-T cell therapy (47 vs. 25%; p = 0.046), and had a greater median number of infections during the first year after transplantation (5 vs. 3; p = 0.027). However, only one factor--a low preoperative cardiac index--emerged as an independent predictor of the development of a persistently depressed cardiac index during the first year after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Risk/benefit ratio of perioperative OKT3 in cardiac transplantation.

To evaluate the risk/benefit ratio of perioperative OKT3 in cardiac transplant patients receiving triple-drug immunosuppression, patients who underwent cardiac transplantation between July 1, 1988 and December 31, 1989 (n = 33) and who received perioperative OKT3 were retrospectively compared with patients who underwent transplantation between January 1, 1990 and June 30, 1991 (n = 46), and who received no perioperative anti-T cell therapy. To allow similar follow-up, data were analyzed through June 30, 1990 for the OKT3 group and through December 31, 1991 for the no anti-T cell therapy group. Patients in the no anti-T cell therapy group waited longer for a donor organ; other pretransplant characteristics did not differ. The azathioprine dose 1 month after transplant was higher in the no anti-T cell therapy group (144 +/- 63 mg vs 109 +/- 55 mg, p = 0.016); other post-transplant immunosuppression was similar. The incidence of total and treated rejection and the time to the first rejection did not differ between the groups. The OKT3 group had a higher number of infections (0.8 +/- 0.9 vs 0.3 +/- 0.3, p = 0.006) and intravenously treated infections (0.5 +/- 0.6 vs 0.1 +/- 0.2, p = 0.004) per patient per month. Cytomegalovirus infection developed in 46% of the OKT3 group versus 22% of the no anti-T cell therapy group (p = 0.025). Patient survival did not differ between the groups. Thus, an immunosuppressive regimen that includes perioperative OKT3 increases infections, especially cytomegalovirus infections, without decreasing or delaying rejection or increasing survival.

Heart transplantation as a treatment option for end-stage heart disease in patients older than 65 years of age.

Because of the critical donor organ shortage for heart transplantation, selection of recipients should be based on the potential for maximum benefit. To evaluate the effects of advancing age on outcome after heart transplantation, we compared the clinical variables of 12 recipients aged 65 years or older (66.1 +/- 0.9 years [x +/- standard deviation]; range, 65 to 67 years) with those of 57 patients aged 55 to 64 years (59.3 +/- 2.7 years) at the time of the procedure. The two study groups were similar in sex, race, pretransplantation heart disease, immunocompatibility, maintenance immunosuppression, and length of first hospitalization at the time of the procedure. Groups were also similar regarding the incidence of malignancies, fractures, diabetes, neurologic complications, and renal dysfunction occurring over the follow-up period. Patients 65 years of age or older had a significantly higher number of hospital days (36 +/- 29 versus 15 +/- 18 days; p < 0.02) and increased frequency of infections/month (0.7 +/- 0.3 versus 0.3 +/- 0.4 infections/month; p < 0.03) during the first postoperative year. Older patients had a higher incidence of cytomegalovirus infections (50% versus 19%; p < 0.06), lower rates of rejection at 1 and 6 months after operation (p < 0.03), and more severe functional limitation (p < 0.002) than patients aged 55 to 64 years. One-year actuarial survival was not significantly different in the two groups. The results of our study suggest that, because of lower rejection and higher infection rates, heart transplantation recipients older than 65 years of age should receive less intense immunosuppression.(ABSTRACT TRUNCATED AT 250 WORDS)

High-risk cardiac operation: a viable alternative to heart transplantation.

To determine if high-risk heart operation with circulatory support standby is an acceptable alternative to direct heart transplantation, we reviewed 21 patients who were accepted as heart transplant candidates but offered a heart operation because of the availability of circulatory support. Preoperative left ventricular ejection fraction was 0.25 +/- 0.08 (mean +/- standard deviation), and New York Heart Association functional class was 3.4 +/- 0.7. The patients underwent 16 bypass graft operations, 4 mitral and 2 aortic valve replacements, and 4 defibrillator implantations (combined procedures in 5 patients). An intraaortic balloon pump was placed in 12 patients. One patient required biventricular assist device support but was weaned in 11 days. Twenty patients were discharged 14.8 +/- 11.5 days postoperatively. One patient died 15 days postoperatively of amiodarone-induced respiratory failure, and 1 died suddenly 2 months postoperatively. At 10.5 +/- 6 months postoperatively, 19 patients (90%) are alive. Mean functional class is 1.9 +/- 0.9. None of the patients has undergone transplantation, but 2 are awaiting donor organs. We conclude that in selected heart transplant candidates high-risk heart operation is a viable alternative to direct heart transplantation.

Photopheresis versus corticosteroids in the therapy of heart transplant rejection. Preliminary clinical report.

BACKGROUND: Photopheresis is a technique in which reinfusion of mononuclear cells exposed to UV-A light ex vivo after in vivo treatment with 8-methoxypsoralen initiates host-immunosuppressive responses. METHODS AND RESULTS: To determine if photopheresis safely reverses International Society for Heart and Lung Transplantation (ISHLT) rejection grades 2, 3A, and 3B without hemodynamic compromise, 16 heart transplant patients with ISHLT rejection grades 2, 3A, and 3B were randomized to photopheresis or corticosteroid therapy. The average number of mononuclear cells treated with each photopheresis procedure was 9.8 +/- 9.1 x 10(9) (mean +/- SD). Photopheresis and corticosteroids reversed eight of nine and seven of seven episodes of rejection, respectively. The median time from initiation of treatment to rejection reversal was 25 days (range, 6-67 days) in the photopheresis group and 17 days (range, 8-33 days) in the corticosteroid group. Hemodynamics were normal before either treatment and did not change after reversal of rejection. No adverse reactions occurred with photopheresis, and all patients in either treatment group are alive. CONCLUSIONS: These preliminary, short-term results in prospectively randomized patients indicate that photopheresis may be as effective as corticosteroids for treating ISHLT rejection grades 2, 3A, and 3B. The apparently low toxicity and potential efficacy of photopheresis warrant further analysis of its role in the prevention and treatment of heart transplant rejection.

Successful treatment of heart transplant rejection with photopheresis.

Photopheresis is a potential therapy for rejection in which reinfusion of mononuclear cells exposed to ultraviolet-A light ex vivo, after treatment with 8-methoxypsoralen in vivo, initiates host immune responses that specifically inhibit the cytotoxicity of the photomodulated mononuclear cells. Between May 1990 and January 1991, 7 heart transplant (HT) patients (age 42.2 +/- 16.7 [mean +/- SD] years) on triple immunosuppression (cyclosporine, corticosteroids, and azathioprine) had 9 episodes of non-hemodynamically compromising moderate rejection that were treated with photopheresis. These episodes of rejection occurred at an average of 114.4 +/- 180.5 (range 8-575) days after HT. After oral administration the mean serum level of 8-methoxypsoralen achieved was 129.0 +/- 72.4 ng/ml. An average of 10.4 +/- 9.6 x 10(9) mononuclear cells were treated with each photopheresis procedure. Photopheresis was performed twice when less than 5 x 10(9) mononuclear cells had been treated with the first procedure. Of 9 rejection episodes treated with photopheresis, 5 required 1 procedure and 4 required 2 procedures. Photopheresis was used to treat a single episode of rejection in 5 pts. and 2 separate rejection episodes in 2 additional pts. Eight of 9 episodes of rejection were successfully reversed by photopheresis as assessed by endomyocardial biopsy (EMB) performed 7 days after treatment. Immunohistochemical analysis of EMB samples revealed that postphotopheresis cell counts for T cells, B cells, and macrophages were reduced compared to pretreatment values and correlated with the histopathologic resolution of rejection. Hemodynamics were normal prephotopheresis and remained unchanged at the time when the postphotopheresis EMB showed no evidence rejection No adverse effects have been observed with photopheresis. Over a follow-up period of 5.3 +/- 4.0 months, rejection and infection rates/pt./follow-up months were 0.3 +/- 0.4 and 0.04 +/- 0.07, respectively. The preliminary, short term results of this pilot study indicate that photopheresis may be efficacious in the treatment of moderate rejection in hemodynamically stable HT patients and thus may be an alternative to corticosteroid pulses.