Opinions, hopes and concerns regarding pharmacogenomics: a comparison of healthy individuals, heart failure patients and heart transplant recipients.

It is not yet known whether healthy individuals and patients with a chronic disease have similar attitudes towards pharmacogenomics. Thus we conducted a survey of 175 healthy volunteers, 175 heart failure (HF) patients and 100 heart transplant recipients to compare their opinions on this subject. Most participants (>90%) stated that they would accept pharmacogenomic testing and expressed high hopes regarding its potential applications. Overall, interest for pharmacogenomics was shared equally among the three groups. In contrast, after adjusting for age, gender, education and income, healthy individuals were more likely to voice concerns about potential employment (P=0.008 vs HF, odds ratio (OR)=2.93, confidence interval (CI)=1.33-6.47; P=0.010 vs Transplant, OR=2.46, CI=1.24-4.90) and insurance discrimination (P=0.001 vs HF, OR=5.58, CI=2.01-15.48; P<0.001 vs Transplant, OR=4.98, CI=2.03-12.21) and were possibly more worried by confidentiality issues. These findings highlight the need for strict legislation and proper educational strategies directed at the general population to facilitate the clinical implementation of pharmacogenomics.

Comparison of cyclosporine and tacrolimus in combination with rabbit antithymocyte immunoglobulins as induction therapy in cardiac transplantation.

Induction with rabbit antithymocyte immunoglobulins (RATG) for cardiac transplantation allows reduction of calcineurin inhibitor and reduces the incidence of acute rejection episodes (ARE). We compared induction with RATG combined with either cyclosporine (CsA) or tacrolimus (FK) in regard to the number of ARE in the first year after transplantation. We transplanted 111 patients from 2000 to 2008 including 61 who received CsA-RATG, and 19, FK-RATG. At 3 months and 1 year the CsA group displayed 3.29 +/- 1.66 and 7.44 +/- 2.45 ARE per patient of grade at least 1R respectively. The FK group showed 3.21 +/- 1.71 and 8.13 +/- 2.07 episodes per patient (P = .86 at 3 months; P = .32 at 1 year). Among ARE 2R or greater, the CsA group displayed 0.51 +/- 0.70 and 0.91 +/- 0.95 episodes per patient at 3 months and 1 year, while the FK group showed 0.15 +/- 0.38 and 0.31 +/- 0.63 episodes, respectively (P = .09 at 3 months; P = .016 at 1 year). Among type 3R ARE, the CsA group showed 0.11 +/- 0.32 and 0.13 +/- 0.34 episodes, whereas the FK group experienced 0.05 +/- 0.23 and 0.05 +/- 0.23 episodes at 3 months and 1 year, respectively (P = .44 at 3 months, P = .35 at 1 year). The freedom rate from 1R, 2R, and 3R ARE was therefore similar between the two groups (P = .76, P = .14, and P = .23, respectively). Induction with FK-RATG tended to reduce the number of type 2R and greater rejection episodes per patient at 1 year after transplantation compared to CsA-RATG.

Sternal wound infection after heart transplantation: incidence and results with aggressive surgical treatment.

BACKGROUND: Sternal wound infection remains a significant complication. We reviewed the incidence and the treatment of sternal wound infection after heart transplantation. METHODS: Of 226 patients who had a heart transplantation, 20 (8.8%) underwent postoperative wound debridement for superficial or deep sternal wound infection. The incidence and the survival of patients with sternal wound infection were analyzed. RESULTS: The incidence of sternal wound infection was similar among patients treated with four protocols of immunosuppressive drugs: cyclosporine and prednisone (0 of 22; 0%); cyclosporine, prednisone, and azathioprine (2 of 24; 8.3%); cyclosporine, prednisone, azathioprine, and antithymocyte globulin (15 of 139; 10.8%); and cyclosporine, prednisone, mycophenolate mofetil, and antithymocyte globulin (3 of 41; 7.3%) (p = 0.4). Six-month and 5-year survival of patients with sternal wound infection averaged 85% +/- 8% and 74% +/- 10% compared with 92% +/- 2% and 82% +/- 3% in patients without wound infection (p = 0.15). Patients with deep sternal wound infection, debridement, and reconstruction had a 5-year survival averaging 80% +/- 10%. CONCLUSIONS: The incidence of sternal wound infection remains similar between patients treated with the triple drug therapy. Surgical debridement and reconstruction can result in long-term survival after heart transplantation.

A 10-year experience with intravenous thymoglobuline in induction of immunosuppression following heart transplantation.

BACKGROUND: Intravenous thymoglobuline (125 mg a day for 3 days, Institut Mérieux, France) has been used to induce immunosuppression following heart transplantation. Cyclosporine and prednisone, with and without azathioprine or mycophenolate mofetil were used as maintenance immunosuppression. OBJECTIVE: The objective of the study was to determine the clinical effect of antibody induction of immunosuppression following heart transplantation. METHODS: A retrospective analysis of the clinical experience at the Montreal Heart Institute. From 1988 to 1998, 163 patients were administered a 3-day course of intravenous thymoglobuline immediately following heart transplantation (Group 1). From 1983 to 1987 and during an isolated period in 1994, intravenous and oral cyclosporine was used immediately following heart transplantation in 48 patients (Group 2). Routine endomyocardial biopsies were performed in all patients and only moderate and severe rejection was treated. RESULTS: One, 5- and 10-year actuarial survival rate averaged 85%+/-3, 77%+/-4 and 67%+/-5 in Group 1 compared with 88%+/-5, 81%+/-6 and 76%+/-6 in Group 2 (p = 0.5). At 1 year, the freedom rate from an episode of acute rejection averaged 43%+/-4 in Group 1 and 30%+/-7 in Group 2 (p = 0.03) and the freedom rate from an episode of infection averaged 44%+/-4 in Group 1 and 31%+/-7 in Group 2 (p = 0.2). At 1, 5 and 10 years, the freedom rate from graft coronary artery disease averaged 93%+/-2, 68%+/-5 and 50%+/-7 in Group 1 compared with 93%+/-4, 58%+/-8 and 30%+/-8 in Group 2 (p = 0.1) and the freedom rate from cancer averaged 98%+/-1, 91%+/-3 and 67%+/-8 in Group 1 compared with 100%, 95%+/-3 and 77%+/-8 in Group 2 (p = 0.2). There was no side-effect related to the systemic injection of thymoglobuline. CONCLUSION: In a cyclosporine based protocol of immunosuppression, induction with an initial 3-day course of intravenous thymoglobuline is associated with a lower rate of acute rejection. Moreover, the risk of infection and of developing cancer is not increased whereas there was a trend towards a lower incidence of coronary atherosclerosis 5 and 10 years after transplantation.

Pharmacokinetic, hemodynamic, and metabolic effects of cyclosporine sandimmune versus the microemulsion neoral in heart transplant recipients.

BACKGROUND: Cyclosporine is a potent immunosuppressive agent that is, however, associated with systemic hypertension and renal dysfunction. The purpose of this investigation was to study the pharmacokinetic and long-term renal and hypertensive effects of Sandimmune (Sandoz) versus the new Neoral (Novartis) formulation of cyclosporine in heart transplant recipients. METHODS: Twenty heart transplant recipients with stable conditions and aged 54 +/- 9 years were studied in an open-labeled single-arm conversion protocol. Twelve-hour pharmacokinetic studies were performed on Sandimmune and after 4 weeks of treatment with Neoral at similar dosage. The 24-hour blood pressure monitoring, creatinine clearance, and complete biochemistry profile were studied simultaneously to the pharmacokinetic studies. Six-month follow-up with serial measurements of cyclosporine levels, and biochemistry profile was completed. RESULTS: Conversion to Neoral resulted in a 24% increase in area-under-the-curve in spite of no significant changes in cyclosporine trough levels (165 +/- 48 [Sandimmune] vs 169 +/- 32 nmol/L; p = 0.26). Respectively, 16%, 68%, and 16% were poor, average, and good absorbers on Sandimmune versus 26% and 74% being average or good absorbers on Neoral. Averaged systolic and diastolic blood pressure were not affected by Neoral, but blood pressure readings increased in 20% of patients previously known as having hypertension. The 24-hour blood pressure data yielded no significant changes with Neoral, but the nocturnal drop in systolic blood pressure was attenuated by Neoral. Twenty-four-hour creatinine clearance was not affected by Neoral, but serum magnesium levels decreased significantly at 6 months. CONCLUSIONS: Neoral resulted in 24% increase in cyclosporine exposure without significant changes in trough levels, and improved absorption status. This greater drug exposure is well tolerated and resulted in a slight increase in blood pressure in a subset of patients and some decrease in magnesium levels, but it had no effect on renal function.

Comparison of Neoral and Sandimmune cyclosporine for induction of immunosuppression after heart transplantation.

OBJECTIVE: To compare the efficacies of Neoral cyclosporine (N-CSA [Sandoz]) and Sandimmune cyclosporine (S-CSA [Sandoz]) in induction of immunosuppression immediately after heart transplantation. DESIGN: A prospective and a retrospective cohort. SETTING: Patients who underwent heart transplant operations at the Montreal Heart Institute, Montreal, Quebec. PATIENTS: To evaluate the results of both formulations of cyclosporine (CSA), a cohort of 20 consecutive patients who underwent heart transplant operations between 1994 and 1995, and who were administered N-CSA, azathioprine, prednisone and intravenous CSA (10 patients) or rabbit antithymocyte globulin (RATG) (10 patients) were compared with 21 patients who underwent heart transplant operations between 1993 and 1994, and were treated with RATG, S-CSA, azathioprine and prednisone. Preoperative patient characteristics were similar in all groups. RESULTS: There were no significant differences in daily CSA doses after the fourth day following transplantation. Higher trough levels of CSA were observed during the first four days, from days 12 to 14 and one month after transplantation in the two groups that were administered N-CSA. Serum levels of creatinine were significantly higher three to five days after transplantation in both groups who received N-CSA. Creatinine levels were also higher between days 13 and 14 in patients who received N-CSA and intravenous CSA. Oral administration of N-CSA was stopped temporarily in two patients (20%) who received intravenous CSA because of a sudden decrease in urine output and rise in serum creatinine. Three months after transplantation actuarial freedom rate from acute rejection averaged 33 +/- 10% in the S-CSA group, 10 +/- 9% in patients treated with N-CSA and intravenous CSA and 24 +/- 15% in patients treated with N-CSA and RATG (P = 0.25). The risk (hazard) of early rejection was higher in the group that received intravenous CSA and N-CSA. CONCLUSIONS: While similar averaged doses of N- and S-CSA were administered early after transplantation, the use of N-CSA resulted in higher blood levels of CSA. N-CSA appears to be well absorbed early after cardiac transplantation, but renal toxicity remains a significant concern.

Effect of pentoxifylline on renal toxicity of cyclosporine: results of a clinical trial after heart transplantation.

BACKGROUND: Pentoxifylline was suggested to prevent the renal release of endothelin caused by cyclosporine. METHODS: We studied the renal-sparing effect of pentoxifylline in 44 patients who underwent heart transplantation between 1991 and 1994 and were randomized to a group treated with pentoxifylline (400 mg three times daily) or to a control group. All patients were treated according to the same immunosuppression protocol, including induction with perioperative rabbit anti-thymocyte antibody and maintenance with azathioprine, cyclosporine, and prednisone. Five patients withdrew voluntarily because of lack of compliance, and five patients died during the first month of the study. RESULTS: There was no difference between the two groups in regard to age, sex, initial cardiopathy, the number of acute rejections, and the number of infection episodes. Urinary clearance of creatinine averaged 1.1 +/- 0.1 ml/sec, 1.3 +/- 0.1 ml/sec, and 1.3 +/- 0.1 ml/sec in the control patients (n = 16) and 1.2 +/- 0.1 ml/sec, 1.4 +/- 0.1 ml/sec, and 1.3 ml/sec in patients treated with pentoxifylline (n = 18) at initiation, 12 months, and 24 months of the study (p > 0.05), respectively. At these three times, the serum creatinine levels averaged 106 +/- 4 mmol/L, 119 +/- 4 mmol/L, and 126 +/- 5 mmol/L in the control group and 94 +/- 4 mmol/L, 114 +/- 4 mmol/L, and 127 +/- 5 mmol/L in patients treated with pentoxifylline, respectively (p > 0.05). Trough levels of cyclosporine throughout the study period averaged 212 +/- 8 mmol/L and 206 +/- 8 mmol/L in the control and treated groups, respectively (p > 0.05). Endothelin blood levels averaged 0.4 +/- 0.2 pg/ml for nine control patients and 0.4 +/- 0.1 pg/ml for a group of 10 patients treated with pentoxifylline (p > 0.05). CONCLUSIONS: Pentoxifylline in association with cyclosporine did not result in a significant improvement in renal function during the first 2 years after heart transplantation.

Risk factors for early, cumulative, and fatal infections after heart transplantation: a multiinstitutional study.

BACKGROUND AND METHODS: By multivariable analysis, risk factors were identified for initial infection of any type, cumulative infections during the first 6 months and fatal infection among 2210 heart transplant recipients at 30 institutions. RESULTS AND CONCLUSIONS: Of the 1218 infections in 695 patients, bacterial infections were most frequent (47%), followed by viral (42%), fungal (8%), and protozoal (4%). Risk factors for earlier infection included older recipient age (p < 0.0001), ventilator support at time of transplant (p < 0.0001), ventricular assist device at time of transplant (p = 0.02), OKT3 induction therapy (p < 0.0001), donor black race (p = 0.0007), and positive donor cytomegalovirus serology (for cytomegalovirus infection) (p = 0.0007). Cumulative infections during the first 6 months were increased by older recipient age (p < 0.0001), ventilator support at transplant (p = 0.0004), ventricular assist at transplant (p = 0.009), Black donor (p = 0.03), female donor (p = 0.03), and OKT3 induction therapy (p = 0.005). The actuarial freedom from fatal infection was 96% at 1 year and 95% at 3 years. Risk factors for death from infection included very old (p = 0.002) and very young recipients (p = 0.004), ventilator support at time of transplant (p = 0.004), older donor (p < 0.0001), and longer donor ischemic time (p = 0.02). The risk of death from infection within the first 3 months exceeded 20% among older recipients (> 55 years) on ventilator support at time of transplantation who received an older (> 50 years) donor heart.

Antithymocyte globulin and methotrexate therapy of severe or persistent cardiac allograft rejection.

BACKGROUND: The treatment of severe or persistent acute rejection remains difficult despite newer immunosuppressive agents available. METHODS: To evaluate the effectiveness of rabbit antithymocyte globulin and methotrexate as therapy for severe or persistent acute cardiac allograft rejection, we conducted a retrospective analysis of clinical and laboratory data from 150 consecutive heart transplant recipients between 1983 and 1994. RESULTS: Thirteen episodes of severe or refractory acute rejection were treated with rabbit antithymocyte globulin in 10 patients. Rabbit antithymocyte globulin (125 mg/day for 3 consecutive days) was effective in 90% of patients. Therapy was well tolerated, and contributed to one infectious complication, no malignancy, and long-term survival in 8 of 10 patients. Recurrent rejection developed in 60% of patients. Methotrexate (7.5 to 15 mg/wk for 16 weeks) was administered to 8 patients with persistent rejection documented on three consecutive endomyocardial biopsies. Therapy was effective in 6 of the 8 patients, with one infectious complication and no malignancy on follow-up. White blood cell count decreased significantly during therapy (p = 0.008). Seven of the 8 patients in the methotrexate group are long-term survivors. CONCLUSIONS: Rabbit antithymocyte globulin is a valuable alternative in patients with severe or refractory acute rejection. Methotrexate is an important adjunct in patients with persistent rejection unresponsive to conventional immunosuppressive regimens.

Mediastinal and pericardial complications after heart transplantation. Not-so-unusual postoperative problems?

Of a total of 133 patients who underwent heart transplantation, 16(12%) had pericardial and mediastinal complications. Non-infectious pericardial complications, pericardial effusion and constriction were noted in ten patients, and infectious pericarditis or mediastinitis in six. Cardiac echocardiography, catheterization and magnetic resonance imaging were useful in assessing these problems. All patients underwent surgical treatment, pericardial drainage, pericardectomy or muscle flap closure. Twelve (75%) of these 16 patients are long-term survivors. In conclusion, pericardial and mediastinal complications are common after heart transplantation, and aggressive surgical treatment is most often effective in their control.

Cytomegalovirus after heart transplantation. Risk factors for infection and death: a multiinstitutional study. The Cardiac Transplant Research Database Group.

Cytomegalovirus infection is a major cause of morbidity and rehospitalization after heart transplantation. To assess its incidence and risk factors in the current era of heart transplantation, we analyzed cytomegalovirus infection data in 1553 patients from 26 institutions (Cardiac Transplant Research Database Group) undergoing primary heart transplantation between Jan. 1, 1990, and June 30, 1992. There were 230 treated cytomegalovirus infections in 200 patients, of which 16 were fatal (6%; 70% confidence limits 5% to 9%). Actuarial freedom from cytomegalovirus infection was 98% 1 month, 88% 3 months, and 83% 24 months after transplantation, with a peak incidence of initial infection at 2 months. Twenty-five (12%) of 200 patients with cytomegalovirus infection had recurrent cytomegalovirus infection during a mean follow-up of 13.9 months. The primary location of cytomegalovirus infection was blood in 100 infections (43%), lung in 69 (30%), gastrointestinal tract in 54 (23%), and other sites in seven patients (3%). Cytomegalovirus pneumonia exhibited the highest mortality rate (13%). Risk factors by multivariate analysis for earlier development of cytomegalovirus infection included pretransplantation cytomegalovirus serology (positive donor, negative recipient [p < 0.0001]; positive donor, positive recipient [p = 0.0002]; and negative donor, positive recipient [p = 0.02]) and cytolytic induction therapy (p = 0.05). A cytomegalovirus-positive recipient with a cytomegalovirus-positive donor had a 15% chance of having cytomegalovirus infection, whereas a cytomegalovirus-negative recipient with a cytomegalovirus-positive donor had a 24% chance. Ganciclovir treatment was administered in 227 (99%) of 230 infections. By multivariable analysis, the likelihood of a fatal cytomegalovirus infection was increased with a higher number of infections of any type during the first post transplantation month (p < 0.0001). There was no increased mortality rate in cytomegalovirus infections associated with cytomegalovirus-positive donor and cytomegalovirus-negative recipient (6% mortality rate) versus all other cytomegalovirus infections (6% mortality rate) (p = 0.9) or with OKT3 induction therapy (0% mortality rate) versus all others (noninduction and induction with other than OKT3) (1.4%) (p = 0.03). In conclusion, the biggest determinant of cytomegalovirus infection is donor and recipient pretransplantation cytomegalovirus serologic results with cytolytic induction therapy adding a small additional risk. The overall mortality rate from cytomegalovirus infections is low (7%) in the current era with rapid culture techniques and ganciclovir therapy. Cytomegalovirus infections are more likely to be fatal if there are more frequent preceding infections of any type, but mortality rates are not increased by OKT3 induction or with a cytomegalovirus-positive donor organ transplanted into a cytomegalovirus-negative recipient.

Cholesterol-lowering intervention and coronary artery disease after cardiac transplantation.

Allograft coronary artery disease is a major threat to long-term survival after cardiac transplantation. It has been suggested that hyperlipidemia plays a major role in allograft coronary disease. The objective of the present study was to evaluate the effect of a lipid-lowering intervention with diet and drug therapy after cardiac transplantation. Forty-six patients who underwent transplantation between 1988 and 1991 and who were treated with the American Heart Association phase 1 diet and an HMG coenzyme A reductase inhibitor (lovastatin or simvastatin) when low-density lipoprotein cholesterol levels were higher than 3.4 mmol/L were compared with 35 untreated patients having transplantation between 1983 and 1988. Annual coronary angiograms were obtained in both groups. Cholesterol, triglyceride, and low-density lipoprotein levels were significantly lower in the treated group. Actuarial survival and event-free survival (survival free from allograft coronary artery disease) were similar in both groups. Low-density lipoprotein levels lower than 3 mmol/L at the last follow-up had a positive effect on event-free survival. The cholesterol-lowering intervention was not effective in decreasing the prevalence of allograft coronary artery disease. This study suggests that more aggressive measures to lower low-density lipoprotein levels may be necessary to significantly affect allograft disease. Clinical trials should be developed to address this hypothesis.

Induction of immunosuppression with rabbit antithymocyte globulin: five-year experience in cardiac transplantation.

Perioperative induction of immunosuppressive treatment with rabbit antithymocyte globulin (RATG) and late introduction of cyclosporine was used in a group of 77 patients to prevent early renal dysfunction related to cyclosporine. Peak value in plasma creatinine during hospitalization for transplantation averaged 148 +/- 49 mmol/L in patients treated with RATG compared with 215 +/- 21 mmol/L in 39 patients initially treated without RATG induction (P = 0.01). Of patients treated with RATG, 65 +/- 6% remained free from acute rejection at six months versus 40 +/- 8% of untreated patients (P = 0.03). Rates of freedom from infection, from allograft coronary artery disease and from cancer are similar in both groups. Actuarial survival rates were identical in the two groups. The total number of lymphocytes, the percentage of T lymphocytes and of helper T cells were significantly lower when RATG was used. In conclusion, RATG prophylaxis given immediately after transplantation was well tolerated without complication and resulted in adequate immunosuppression to allow delayed introduction of maintenance treatment with cyclosporine.

Prevention of herpes simplex virus infection by oral acyclovir after cardiac transplantation.

Infection with herpes simplex virus is common among immunosuppressed patients. In an attempt to prevent such infection, 58 patients (group 1) who underwent cardiac transplantation between 1987 and 1990 were given acyclovir (200 mg orally three times a day) prophylactically throughout their postoperative hospital stay (mean 22 days +/- 1 day). The patients' immunosuppressive protocol included cyclosporine, azathioprine and prednisone. The course of these patients was compared to that of 24 patients (group 2) who underwent cardiac transplantation between 1983 and 1986 but were not given prophylactic antiviral treatment postoperatively. The immunosuppressive protocol in these patients consisted of cyclosporine and prednisone. Herpes infection developed during the 1st year in 5 patients (9%) in group 1 and in 11 patients (46%) in group 2 (p < 0.05). The actuarial rates of freedom from herpes infection at 1, 6 and 12 months after transplantation were 100%, 98% +/- 2% and 95% +/- 3%, respectively, in group 1 and 82% +/- 7%, 58% +/- 11%, 53% +/- 11% in group 2. All viral infections were cutaneous or mucosal, except for one, which developed in a patient with pneumonia. All infections responded well to treatment, although one patient with an infected cornea was left with a permanent visual deficit. The authors conclude that prophylaxis of herpes simplex virus infection with acyclovir administered orally in the early postoperative period is effective in preventing viral infections during the 1st year after cardiac transplantation.

Syncope: a symptom of coronary artery spasm after cardiac transplantation.

Two cases of coronary spasm in cardiac transplant recipients in which the presenting symptom was syncope without chest pain are reported. Diagnosing coronary spasm in transplant patients appears to be important because, based upon the few cases in the literature, prognosis is very poor. Coronary spasm may be related to accelerated atherosclerosis occurring in the transplanted heart.

Clinical and angiographic features and prognostic significance of early postinfarction angina with and without electrocardiographic signs of transient ischemia.

PURPOSE: The goal of the study was to characterize the clinical and angiographic characteristics and the prognostic significance of early postinfarction angina associated or unassociated with ST-T changes. PATIENTS AND METHODS: Four hundred forty-nine consecutive patients surviving an acute myocardial infarction and catheterized before hospital discharge were included. They were closely monitored in the coronary care unit and a 12-lead electrocardiogram (ECG) was promptly obtained before the administration of nitroglycerin whenever chest pain suggestive of ischemia occurred. Complete follow-up information was obtained for all patients a mean of 14 +/- 8 months after the qualifying infarction. RESULTS: Early postinfarction angina occurred in 164 patients. Transient ST-T changes were documented during pain in 79 patients and were absent in 85. Compared with patients without postinfarction angina, patients with angina without ST-T changes were older and had a more frequent past history of angina (42% versus 28%, p = 0.01). They also more often had a non-Q-wave myocardial infarction with lower peak creatine kinase blood level elevation. At angiography, patients with angina had more extensive coronary artery disease (1.9 +/- 0.8 diseased vessels per patient versus 1.6 +/- 0.8, p less than 0.05) and more left ventricular segments at jeopardy by a significant coronary artery stenosis (1.5 +/- 1.1 versus 1.2 +/- 1.1, p less than 0.05). The presence of ST-T changes during chest pain was associated with a further increase in the severity of coronary artery disease (2.1 +/- 0.8 diseased vessels per patient, p less than 0.05) and with a less well-developed collateral circulation (18% versus 34% of patients, p = 0.01) that was more often compromised by a coronary artery stenosis (22% versus 8% of patients, p = 0.008). In-hospital infarct extension occurred in 2% of patients without angina, 3.5% of patients with angina without ECG changes, and 28% of patients with angina and ST-T changes (p less than 0.01). The 2-year survival was similar in the first two groups (90% and 96%), and poorer (83%, p = 0.02) in patients with ST-T changes. Survival rates without myocardial infarction were respectively 80%, 78%, and 67% (p less than 0.004). CONCLUSION: A gradient in the severity of coronary artery disease and in the extent of myocardium at jeopardy exists from patients with no postinfarction angina to patients with angina and to patients with angina accompanied by ECG signs of ischemia. The presence of ST-T changes during pain indicates a much less favorable clinical outcome.

[The effect of cyclosporin on renal function following cardiac transplantation: should one lessen the toxicity?]. / Effet de la cyclosporine sur la fonction rénale après transplantation cardiaque: peut-on diminuer la toxicité?

Between 1983 and 1988, 50 patients underwent cardiac transplantation at the Institut de Cardiologie de Montréal. During this period, four immunosuppression protocols were used, each including cyclosporine. A combination of cyclosporine and prednisone was used in the first 24 patients (group 1). Triple combination immunosuppression (cyclosporine, prednisone and azathioprine) was given perioperatively in 13 patients (group 2). The prophylactic use of rabbit antithymocyte globulin and late administration (4 days postoperatively) of cyclosporine to prevent early renal failure associated with cyclosporine therapy was chosen in 13 other patients (group 3). Owing to serious deterioration of renal function in 15 of the 24 group 1 patients, the serum creatinine levels reaching 255 +/- 51 mmol/L and the creatinine clearance 34 +/- 2 ml/min between 6 months and 4 years after transplantation, immunosuppression was modified to triple-combination therapy by the addition of azathioprine and a reduction of the serum levels of cyclosporine (group 4). Twelve of the 15 patients showed a substantial improvement in renal function from 3 to 18 months after these changes were introduced. No patient in groups 2 and 3 had late renal insufficiency, and in all group 3 patients renal function remained normal as in the immediate postoperative period. In conclusion, important modifications in protocol permitted a reduction of early and late renal failure due to cyclosporine after cardiac transplantation.