The influence of ABO blood groups on the incidence of cardiac allograft rejection in males.
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Biomedical subjects
Publications and source records attributed to A H Balk.
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In a consecutive series of 146 kidney transplant recipients treated with cyclosporin A a strong correlation between matching for the HLA-A, HLA-B, and HLA-DR loci specificities and outcome of the grafts was observed in male recipients with non-O blood groups. Such a beneficial effect of matching was not found in female patients or male patients with blood group O. In these patients survival of the grafts at one year was good irrespective of the number of HLA-A, B, and DR mismatches. Also in 47 male heart transplant recipients immune responsiveness against mismatched HLA antigens was related to blood group. A significantly higher incidence of rejection episodes was observed in male patients with non-O blood groups (n = 32) than in those with blood group O (n = 15). Matching for HLA-DR reduced the number of acute rejection episodes in male patients with non-O blood. These findings may help explain the controversial reports about the importance of HLA matching in organ transplantation. Furthermore, as most candidates for heart transplantation are male and not of blood group O, the higher incidence of graft rejection in these patients underscores the need for an exchange strategy of donor hearts.
Plasma atrial natriuretic factor (ANF) concentrations were measured, and relationships to intracardiac pressures and atrial dimensions were assessed in a series of 17 heart transplant recipients undergoing cardiac catheterization during their annual evaluation. Despite excellent cardiac function (normal filling pressures, adequate cardiac output, ejection fraction above 60%), plasma levels of ANF were elevated. Step-up levels across the heart were consistent with increased cardiac secretion, whereas both the metabolic clearance rate and plasma half-life were normal. Correlations between plasma concentrations of ANF at different cardiac sites and atrial filling pressures were low. However, right and left atrial dimensions in our patients were greatly enlarged. These findings suggest that increased atrial size (by virtue of the atrial anastomoses) and augmented wall stress (law of Laplace) rather than pressure per se are responsible for the increased ANF production after heart transplantation.
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Coronary arteriography, performed for recent anterior wall myocardial infarction in a 29 year old man, showed multiple aneurysms of the distal branches of the left coronary artery without evidence of obstructions in the major branches, and two clusters of abnormal vessels, supplying tumors in the right ventricle and the left atrium. At operation and histologic examination both tumors appeared to be myxomas. In addition, two myxomas, located elswhere in the body, could be proven histologically.
We analyzed the results of passive immunization against CMV in 146 heart transplant recipients. The 65 seronegative recipients were prophylactically treated with anti-CMV immunoglobulins during and after the operation. Twenty-nine of these 65 patients received a seropositive donor heart. CMV infection occurred in 21/65 seronegative and in 40/81 seropositive recipients (difference not significant). The incidence of CMV infection in seronegative recipients of a CMV-matched donor heart (3/34) was significantly lower than in seronegative recipients of a positive donor heart and lower than in seropositive recipients, but no significant difference in infection rate was found between the two latter groups (18/29 vs. 40/81). Although primary infection more frequently resulted in CMV disease than secondary infection (11/21 vs. 10/40) no difference in incidence of disease was noted between seronegative and seropositive patients (11/65 vs. 10/81), nor was there a difference in the severity of symptoms following primary or secondary infection. There was a higher incidence of CMV disease in all patients who received a heart from a seropositive donor versus a seronegative donor. However, after transplantation of a heart from a seropositive donor the incidence (27%) of CMV disease observed in our passively immunized seronegative patients was the same as in the patients with naturally acquired seropositivity. There was no difference in the prevalence of coronary artery disease between patients with and without CMV infection or disease. We conclude that using the current passive immunization scheme the occurrence of CMV infection and disease is largely dependent on the serostatus of the donor.
The aim of this study was to analyze whether left ventricular dysfunction affects the safety and feasibility of high-dose dobutamine-atropine stress echocardiography. We examined the results of the test in 318 consecutive patients who were referred for high-dose dobutamine-atropine stress echocardiography and also underwent diagnostic cardiac catheterization. Forty-four patients had a left ventricular ejection fraction of 25% or less (mean, 21%; range, 15% to 25%). In the entire group of 318 patients, no serious complications (death, myocardial infarction, or ventricular fibrillation) occurred. The overall feasibility of completing the test was excellent (97%). A trial fibrillation occurred in four patients, nonsustained ventricular tachycardia in 12, and sustained ventricular tachycardia in one. A decrease in systolic blood pressure of greater than 40 mm Hg or a peak systolic pressure of less than 80 mm Hg was present in eight cases. In the group with an ejection fraction of 25% or less, there was a higher rate of significant tachyarrhythmias (14% versus 5%; p = 0.03), whereas the feasibility of the test was slightly lower (89%; p < 0.01), but no difference for hypotension was found. By multivariate analysis, a history of tachyarrhythmias was the only predictor of stress-induced arrhythmias. Advanced left ventricular dysfunction does not represent a contraindication for dobutamine-atropine stress testing.
To evaluate the efficacy of myocardial T2 values in the assessment of allograft rejection, we performed magnetic resonance (MR) imaging at 0.5 T serially in seven cardiac transplant recipients and singly in seven normal volunteers. Cardiac-gated multi-echo spin echo images were obtained; T2 values were estimated by a two-point method from regions of interest in the myocardium. Patients underwent MR and cardiac biopsy at various times after transplantation. Forty-two patient exams were performed. All biopsies showed either no rejection or early stages of rejection: grade 0 in 8 examinations, grade 1 in 28, and grade 2 in 6. Myocardial T2 values in patients in early stages of cardiac rejection were slightly higher (but not statistically significant) than those in non-rejecting patients and normal volunteers. Although this study did not allow prospective detection of cardiac rejection in our patient group, it demonstrated a trend toward higher T2 values at higher biopsy grades that may indicate an ability to assess more severe stages of transplant rejection.
BACKGROUND: Anti-interleukin-2 receptor monoclonal antibodies have been used successfully in the prevention of rejection in cardiac allografts in several animal models. METHODS: In an open randomized study murine monoclonal CD3 antibody and BT563, a murine anti-interleukin-2 receptor monoclonal antibody, were given as rejection prophylaxis during the first week after heart transplantation. Cyclosporine therapy was initiated at the third postoperative day. RESULTS: In half the BT563-treated patients an early rejection was histologically shown at week 1, whereas heart transplant recipients treated with murine monoclonal CD3 antibody had a rejection incidence at week 1 of only 9%. During BT563 treatment CD25-positive cells (i.e., cells bearing the interleukin-2 receptor) were not detectable in peripheral blood. However, immunohistologic studies of endomyocardial biopsy specimens taken 1 week after transplantation showed the presence of CD25-positive cells within these specimens in 8 of 10 (80%) of patients with rejection. In patients without rejection CD25-positive cells were present in the biopsy specimens of only two of nine patients (22%). Reverse-transcriptase polymerase chain reaction studies on biopsy material showed the presence of messenger RNA for the interleukin-2 receptor in all and for interleukin-2 in three of five (60%) of biopsy specimens of rejecting grafts. CONCLUSIONS: Although CD25-positive cells were not detectable in peripheral blood during BT563 treatment, these cells were at the same time found to be present within 80% of the endomyocardial biopsy specimens from the rejecting grafts. By initiating cyclosporine treatment at day 0, the synergistic effect of combining cyclosporine and anti-interleukin-2 receptor monoclonal antibodies may result in a lower rejection incidence.
The value of pulsed-wave transmitral Doppler for the diagnosis of moderate acute rejection was examined in a total of 347 Doppler recordings obtained in 32 consecutive cardiac allograft recipients. Serial Doppler examinations (median, 11 per patient; range, 1 to 23) were performed simultaneously with endomyocardial biopsies from the first week after heart transplantation to a follow-up of 186 days (median; range, 10 to 395 days after transplantation). Pulsed-wave transmitral Doppler did not allow noninvasive diagnosis of moderate acute rejection in individual patients. Peak filling rate normalized for mitral stroke volume, early diastolic velocity, and mean diastolic velocity were significantly increased, whereas diastolic filling period was decreased during moderate acute rejection compared to other biopsy classes. The wide overlap of measurements in individual recipients with or without rejection may be due, however, to a variety of hemodynamic factors after transplantation affecting diastolic function, which are superimposed on the restrictive left ventricular filling pattern caused by persistent mild acute rejection and left ventricular hypertrophy. These hemodynamic factors include pulmonary hypertension, perioperative ischemia, reperfusion injury, and changes in both blood pressure and loading conditions caused by hypertension and its treatment. Differences between studies with regard to the detection of moderate acute rejection by transmitral Doppler may be caused by chance, because most studies were relatively small. Differences in methods, patient selection, duration of follow-up, prevalence of hypertension and left ventricular hypertrophy, and differences in antihypertensive drug regimens may also play a role. Furthermore differences in the incidence of mild acute rejection, its treatment, and the type of maintenance immunosuppressive regimen used may have influenced the outcome of these studies considerably.
The increasing numbers of long-term survivors after heart transplantation make yearly coronary arteriography, used by most centers to study the development of transplant coronary artery disease, less practical. Therefore the prevalence and clinical relevance of coronary artery disease in 119 one-year survivors of heart transplantation were studied. Visual analysis revealed two main patterns of vascular changes: abnormalities of the epicardial vessels and their major branches and abnormalities of the tertiary branches. The prevalence of all abnormalities in the coronary vascular tree increased from 34% after 1 year to 79% after 5 years. The prevalence of anatomically significant lesions (more than 50% stenosis in the epicardial branches or abrupt ending/proximal occlusion of tertiary branches) was only 11% after 5 years. During follow-up of 25 to 87 (median, 43) months, no significant coronary artery disease developed in the 101 patients who showed normal epicardial vessels or abnormal tertiary branches only at their first year angiography, and none of the patients died of ischemic heart disease. Of the 18 patients with abnormal epicardial vessels, three patients died of ischemic heart disease; one of these patients was treated with atherectomy and is alive at the moment of this report, and two patients showed progression of discrete lesions without evidence of ischemia until now. Based on these findings, a schedule for timing of arteriography was developed depending on the first-year coronary findings.
BACKGROUND: Cytokines play an important role in allograft rejection. The local production of cytokines by T-helper 2 cells within an allograft could influence the induction of graft rejection. METHODS: Therefore we studied the in vitro production of cytokines by cells infiltrating the graft. graft-infiltrating cell cultures derived from human endomyocardial biopsy specimens more often produced interleukin-2 (p < 0.001), interferon-gamma (p < 0.001), interleukin-4 (p = 0.02), and interleukin-6 (p = 0.04) after stimulation with a B-cell line obtained from the heart donor than after stimulation with a third-party B-cell line. Furthermore, the levels of these cytokines were significantly higher after donor stimulation than after third-party stimulation (p < 0.001). RESULTS: Within the first 90 days after heart transplantation, significantly higher levels of interleukin-2 (p = 0.050 and interferon-gamma (p = 0.02) were produced by donor-stimulated lymphocyte cultures derived from biopsy specimens taken during a rejection episode compared with cultures from biopsy specimens taken during a period without rejection. After 90 days, the levels of T-helper 1 cytokine (interleukin-2 and interferon-gamma) production were, irrespective of the rejection grade, comparable with those found in the cultures from rejection biopsy specimens taken early after transplantation. With regard to T-helper 2 cytokines (interleukin-4 and interleukin-6), no relation was found with the presence of rejection at any time after transplantation. CONCLUSIONS: These data suggest that in the first 3 months after heart transplantation, acute rejection is associated with the production of increased levels of T-helper 1 cytokines but not of T-helper 1 cytokines but not of T-helper 2 cytokines by donor stimulated graft-infiltrating lymphocytes. Thereafter, the T-helper 1 cytokine production of graft-infiltrating lymphocytes remained high, suggesting a continuous state of immunologic activity even in the absence of rejection.