Showing papers in "The Journal of heart transplantation in 1989"

Vascular (humoral) rejection in heart transplantation: pathologic observations and clinical implications.

Abstract: We prospectively studied 551 sequential endomyocardial biopsies from 36 consecutive cardiac allografts. With the use of a combination of light microscopy (including careful evaluation of vascular changes) and immunofluorescence to detect the deposition of immunoglobulin and complement, we identified three patterns of allograft rejection, designated as cellular rejection, vascular (humoral) rejection, and mixed rejection. Cellular rejection was diagnosed with modified Billingham criteria. Vascular rejection was diagnosed by finding the combination of prominent endothelial cell swelling and/or vasculitis on light microscopy and the vascular deposition of immunoglobulin and complement by immunofluorescence. In such patients, cellular lymphoid infiltrates were uniformly absent at the time the vascular changes were detected. Mixed rejection consisted of findings of both cellular and vascular rejection occurring simultaneously. Twenty of 36 allografts exhibited cellular rejection; seven allografts showed vascular rejection, and nine allografts developed mixed rejection. The vascular (humoral) pattern of rejection was important to identify because the patients with this type of rejection had a significantly decreased survival compared with that of patients with cellular rejection (p less than 0.05). Survival in the mixed rejection category was intermediate. Positive donor-specific cross-match and/or panel-reactive antibody greater than or equal to 5% and systolic dysfunction were seen in three of the seven allografts with vascular (humoral) rejection but not in the other types. In the early period after transplant (up to 3 weeks after transplant), the only reliable identifying characteristics of patients with vascular (humoral) rejection were the presence of vascular immunoglobulin and complement assessed by immunofluorescence and endothelial cell swelling and interstitial edema as confirmed by histologic examination. We conclude that immunofluorescence should be routinely done on all heart biopsies for the first month after transplantation. Patients with vascular (humoral) rejection cannot be reliably identified by any other means.

The spectrum of coronary artery pathologic findings in human cardiac allografts.

Abstract: Coronary artery morphologic features of 61 human cardiac allografts of short- and long-term survival were correlated with coexisting myocardial pathologic findings and cause of death. On the basis of distribution of coronary lesions, allografts were divided into two broad groups: those with fibrous or atherosclerotic lesions confined to the proximal region of epicardial arteries and those with diffuse necrotizing vasculitis or atherosclerosis of the entire coronary arterial system. Within the two groups, coronary artery morphologic features varied in a time-dependent fashion. Disease in the proximal region began as concentric fibrous intimal thickening, with atheromatous lesions observed after 1 year after transplantation. Five of 10 (50%) patients with atheromatous plaques in the proximal region of arteries died or underwent retransplantation because of coronary disease, as compared to only 1 of 29 (3%) patients with fibrous intimal thickening only in the proximal region. The earliest form of diffuse disease was a necrotizing vasculitis, which was invariably associated with acute myocardial rejection. Long-term survivors with diffuse disease showed severe fibrous or fibrofatty intimal lesions of the large and small epicardial and intramyocardial arteries. In some, diffuse disease may have resulted from healing of necrotizing vasculitis. Eight of nine (89%) long-term survivors with diffuse coronary artery disease died or required retransplantation because of coronary vascular disease. The coronary artery disease of human cardiac allografts is a heterogeneous phenomenon with variable distribution, morphologic features, severity, clinical significance, and, possibly, pathogenesis.

Interleukin-1-induced myocardial depression in an isolated beating heart preparation.

Abstract: Myocyte necrosis and interstitial edema seen with severe cardiac allograft rejection are probable major contributors to associated cardiac dysfunction. The monokine interleukin-1 (IL-1), although important in recruitment of the immunologic response, stimulates release of a variety of vasoactive compounds, including prostaglandin E2. In addition, IL-1 has been shown to alter protein metabolism in both skeletal and cardiac atrial muscle. IL-1 was infused into the aortas of isolated perfused rat hearts to test the hypothesis that it might directly induce myocardial dysfunction. Heart rate, generated force, creatine phosphokinase release, and lactate production were measured serially. Compared with the control group, there was a significant reduction of force (expressed as percentage of baseline) in the IL-1--treated group (for example 87% +/- 7% versus 77% +/- 11% at 60 minutes, p = 0.016; 65% +/- 11% versus 50% +/- 14% at 180 minutes, p = 0.018). IL-1--treated and control groups did not differ in heart rates, lactate production, or creatine phosphokinase release. In this model, IL-1 produces a depression in myocardial force that does not appear to be due to myocardial cell necrosis or to a change from aerobic to anerobic metabolism.

Acute rejection and coronary artery disease in long-term survivors of heart transplantation.

Abstract: The development of acute rejection and coronary artery disease (CAD) was studied in 173 patients who survived at least 1 year after orthotopic heart transplantation. There were 20 late deaths. The incidence of acute rejection found on endomyocardial biopsies after 1 year was 5.6%. Alteration in the immunosuppressive regimen accounted for 77% of the rejection episodes (chi-square = 9.3, F less than 0.01). Acute rejection without alteration in immunosuppressive therapy occurred only 1.4% of the time. CAD developed in 28 patients (16.2%). The prevalence of CAD was 5.8% at 1 year, 15.5% at 2 years, and increased to 66% at 6 years. Patients developing CAD had 0.5 (+/- 0.8) rejection episodes after 1 year as opposed to 0.2 (+/- 0.5) rejection episodes in patients with no CAD (S1 less than 0.01 by Mann-Whitney). There was no difference in the number of rejection episodes during the first year. The total number of rejection episodes was 1.9 (+/- 1.6) and 1.2 (+/- 1.2) in patients with and without CAD, respectively (S1 less than 0.03 by Mann-Whitney). Diabetes mellitus was present in 25% of patients with CAD and 16.5% of patients without CAD (chi-square = 3.14, F less than 0.1). Acute rejection rarely occurs after 1 year and is usually caused by an alteration in the immunosuppressive regimen. CAD develops with increasing frequency and is correlated with rejection episodes and diabetes mellitus.

Arterial hypertension in heart transplant recipients treated with triple-drug immunosuppressive therapy.

Abstract: Arterial hypertension occurs in the majority of heart transplant recipients treated with high dosages of cyclosporine. The incidence of hypertension with lower loading and maintenance dosages of cyclosporine, as used with triple-drug immunosuppressive therapy is unknown. Fifty-six patients who had transplantation at the University of Minnesota, Minneapolis, from December 1983 through December 1986, received low loading (6 to 10 mg/kg) and maintenance dosages of cyclosporine in addition to azathioprine (2 to 2.5 mg/kg/day) and prednisone. Two weeks after transplantation 68% of the patients were hypertensive (blood pressure greater than 140/90 mm Hg) despite normal serum creatinine levels (1.14 +/- 0.33 mg/dl). The number of patients requiring treatment for hypertension increased progressively, with 92% of the patients being hypertensive by 6 months. No correlation was found between blood pressure values, serum creatinine levels, and cyclosporine levels in the blood. Systemic vascular resistances were elevated 1 year after transplantation, whereas cardiac output and ventricular filling pressures were normal. Circulating norepinephrine levels, abnormally elevated before transplantation, normalized after operation. In 13 heart recipients in whom sequential measurements were obtained, plasma norepinephrine levels decreased within 2 weeks after transplantation. These data indicated that hypertension develops in almost all patients after heart transplantation despite the lower dosage of cyclosporine used with the triple-drug immunosuppressive therapy and the absence of significant renal impairment with this regimen, and probably it is not the result of activation of the sympathetic nervous system.

Hypercholesterolemia after heart transplantation: amelioration by corticosteroid-free maintenance immunosuppression.

Abstract: Most heart transplant recipients develop hypercholesterolemia, the cause of which is poorly understood. To test the hypothesis that corticosteroids contribute to the hypercholesterolemia, we reviewed 117 consecutive heart transplant recipients who survived more than 4 months, of whom 51 (44%) required and 66 (56%) did not require maintenance corticosteroids, chronic immunosuppression maintained with cyclosporine and azathioprine only. Fasting serum cholesterol levels were measured every 3 months and were found to be 21% to 26% lower during the first 18 months after heart transplantation in the group that did not require chronic corticosteroid administration (p less than 0.001). Beginning 3 months after transplantation, average serum cholesterol levels ranged from 199 +/- 8 mg/dl to 211 +/- 9 mg/dl in the corticosteroid-free group compared with 262 +/- 8 mg/dl to 272 +/- 8 mg/dl in patients requiring corticosteroid maintenance immunosuppression. Because serum cyclosporine levels did not differ between the groups, a contribution by cyclosporine to posttransplant hypercholesterolemia could not be substantiated. Although the hypercholesterolemia that occurs after heart transplantation is undoubtedly multifactorial, corticosteroid administration contributes importantly to its development.

Hyperlipidemia after clinical heart transplantation.

Abstract: Accelerated coronary atherosclerosis is a major cause of morbidity and death in the cardiac transplant recipient. Hypercholesterolemia has been implicated as a contributing risk factor. Because of this we reviewed lipoprotein profiles from transplant recipients from 1968 to 1986 in an attempt to identify the risk factors for the development of lipid disorders after transplantation. Patients were divided into three groups based on their immunosuppressive protocols. Group 1 consisted of 10 patients receiving azathioprine and prednisone. Group 2 consisted of 24 patients receiving cyclosporine and prednisone with or without azathioprine. Group 3 consisted of 18 patients receiving cyclosporine and azathioprine without prednisone. Total cholesterol levels at 1 year were highest in group 2 (266 mg/dl versus 236 mg/dl for group 1 [p = 0.16] and 223 mg/dl for group 3 [p = 0.005]). High-density lipoprotein cholesterol levels were lowest in group 3 (38 mg/dl versus 51 mg/dl for group 1 [p = 0.025] and 54 mg/dl for group 2 [p = 0.0001]). Subgroup analysis with multivariate and univariate analysis found that prednisone and preoperative coronary artery disease are the major contributors to the posttransplant lipid abnormalities.

Heart transplantation in children.

Abstract: Heart transplantation in children is being performed with increasing frequency. As experience has accrued, problems of rejection, graft atherosclerosis, and growth have been noted. Seventeen children (seven boys and 10 girls) between the ages of 5 months and 14 years have undergone heart transplantation since 1981. The preoperative diagnosis was cardiomyopathy in 13 children, congenital heart disease in two, and endocardial fibroelastosis in two. Immunosuppressive therapy has included a tapering schedule of cyclosporine, azathioprine, and prednisone. There are 13 children alive, with four hospital deaths (two of infection, one of rejection, and one of graft failure). Rejection occurs as frequently in children as in adults. Two children have undergone retransplantation for rejection. Long-term hemodynamics are normal. Growth has been delayed in two of five children who are younger than age 10 years. Kidney function remains stable. Rehabilitation is 100% among the discharged patients. Heart transplantation in children represents an effective therapeutic modality. Heart transplantation in the young has emphasized morbidity caused by current immunosuppressive agents.

Magnetic resonance imaging of human orthotopic heart transplantation: correlation with endomyocardial biopsy.

Abstract: The ability of magnetic resonance imaging (MRI) to detect allograft rejection was studied concomitantly in two centers. In 29 patients MR images performed on a 0.5 T imager were compared with pathologic findings obtained by transvenous right ventricular endomyocardial biopsies. Eight patients had grade 1 or 2 acute rejection, and their myocardium thickness was increased significantly compared with values obtained in normal volunteers, in normal heart allograft patients, and in patients during the resolving phase of an acute rejection episode, whereas no abnormal signal intensity was found in the myocardium of heart allograft patients with acute rejection. This finding is quite in opposition to what was found in experimental models. This could be the result of the immunosuppressive regimen of those patients including cyclosporine, whereas few experimental studies included cyclosporine treatment. For chronic rejection or fibrosis, MRI did not allow the diagnosis because the MRI appearance was close to normal. Finally, MRI appears as a complementary technique to B-mode ultrasound in detecting nonimmunologic complications such as pericardial effusions and endocavitary processes. These data suggest that MRI could be used in the future to monitor rejection, to guide the timing of endomyocardial biopsy, and to assess the response after immunosuppressive treatment.

Psychologic assessment of candidates for heart transplantation: toward a normative data base.

Abstract: Psychologic variables appear to play a role in mediating outcome of heart surgery and organ transplantation. Psychologic data, therefore, can be useful in providing optimal care for transplant candidates during hospitalization and recovery. Psychologic assessment of transplantation candidates is difficult because of the lack of normative data specific to this population. This problem is addressed in the present article. A standard protocol for the assessment of heart transplant candidates is described and some preliminary normative data on the tests used in this protocol are presented.

Relation between recipient: donor body size match and hemodynamics three months after heart transplantation.

Abstract: Cardiac allograft hemodynamics were compared with respect to donor and recipient body weights to determine whether recipient: donor body size match played a significant role in subsequent recipient hemodynamics. Thirty-four stable outpatients underwent resting right-sided cardiac catheterizations 3 months after heart transplantation. As expected, resting cardiac output correlated positively with recipient body weight (r = 0.50, p = 0.002), and mean cardiac index (2.7 +/- 0.6 L/min/m2) was normal. There was, however, only a weak and statistically insignificant correlation between recipient body weight and stroke volume (r = 0.31, p = 0.072). There was a statistically significant negative correlation between donor: recipient body weight ratio and right arterial pressure (r = 0.41, p = 0.017), pulmonary wedge pressure (r = 0.38, p = 0.027), and heart rate (r = 0.39, p = 0.024). These data demonstrate that although cardiac output is maintained at levels appropriate for recipient size after heart transplantation, patients who receive small hearts rely on an increased heart rate and elevated filling pressures to achieve this end. These data suggest that the cardiac allograft may not adapt to recipient body size by 3 months after transplantation.

Heterotopic heart transplantation: a reliable option for a select group of high-risk patients.

Abstract: From July 1982 through February 1988, 229 patients underwent heart transplantations at the Texas Heart Institute, Houston, 11 of whom had heterotopic transplantations. Indications for the heterotopic procedure included pulmonary hypertension (eight patients) and marked body-weight mismatch (greater than or equal to 20%) between the recipient and donor (three patients). The 1-year actuarial survival rate for the heterotopic group is 80.4% compared with 77.9% for the orthotopic group. Despite similar immunosuppressive regimens, the incidence of advanced rejection within 60 days after transplantation was 9.1% (one of 11 patients) for the heterotopic patients and 33.7% (68 of 202 patients) for the orthotopic group. The one heterotopic patient who experienced rejection in this period had a positive retrospective lymphocyte crossmatch. Seven patients who had heterotopic heart transplantations had right pleural effusions; three of these required tube thoracotomy. Two others experienced angina of the native heart, but the symptoms abated with cessation of native heart function. Despite anticoagulant therapy, one patient had reversible neurologic events caused by emboli. Some of the patients had pulmonary and embolic complications, but all of these problems were readily manageable and resolved without permanent sequelae. In orthotopic transplantation, the presence of pulmonary hypertension can compromise donor heart function in the intraoperative or immediate postoperative periods. Patients with this problem, previously considered unsuitable candidates for transplantation, may have a successful transplantation with the heterotopic technique. Although heterotopic heart transplantation is technically more demanding and may be associated with complications that do not occur in orthotopic transplantation, our experience has shown that it is a reliable surgical option for these high-risk patients.

Significance of asymptomatic biliary tract disease in heart transplant recipients.

Abstract: Biliary disease in conjunction with heart transplantation was encountered in 13 of 33 patients: in the past history (three patients), at pretransplant evaluation (nine patients), and appearing de novo after transplantation (one patient). Four patients with asymptomatic cholelithiasis underwent transplantation: biliary complications requiring emergency and/or urgent surgery occurred in all, with two deaths. Potentially complicating factors included (1) untoward effects of steroids on tissue healing and infection and (2) interaction between liver dysfunction and/or external bile loss and cyclosporine metabolism. Therapeutic lessons learned from this experience involve (1) selection of monoclonal antibodies over methylprednisolone for rejection control, (2) return of drained bile to the gastrointestinal tract, and (3) careful cyclosporine level and dosage monitoring. Five candidates with asymptomatic cholelithiasis underwent elective pretransplant biliary surgery; despite their compromised heart function, all patients had an uncomplicated postoperative course. We conclude that asymptomatic biliary disease is frequent in transplant candidates, can lead to serious morbidity and/or mortality after transplantation, and ideally can and should be treated before transplantation.

Cyclosporine and azathioprine immunosuppression without maintenance steroids: a prospective randomized trial.

Abstract: Since the commencement of the St. Vincent's Transplant Programme, 41 patients have undergone orthotopic heart transplantation, with low-dose cyclosporine and prednisolone as maintenance immunosuppression. An actuarial survival rate of 75% at 1 year resulted. To reduce early rejection-related death, azathioprine was chosen as an augmenting immunosuppressive agent to be administered as a prospective randomized trial. Sixty patients were randomized; 29 received low-dose cyclosporine plus azathioprine plus prednisolone (group A). Thirty-one patients received cyclosporine and azathioprine alone (group B). Both groups received a 7-day course of antithymocyte gamma globulin. One group B patient who underwent retransplantation was not analyzed. Actuarial survival for group A was 92% and group B 93%. The overall incidence of rejection for group A was 1.1 per patient and group B, overall, 2.3 episodes per patient. Group B patients who had persistent rejections were converted to group A protocol. Nine group B patients (30%) required conversion to maintenance steroids (group C). The overall incidence of infection was 1.6 episodes per patient and 1.3 episodes per patient for group A and group B, respectively. Two early deaths in group B and one in group A were unrelated to immunosuppressive protocol. One group A patient died at day 280 of multiorgan failure. There were no rejection- or infection-related deaths in the series. Hypertension occurred with equal frequency in both study groups. The cyclosporine and azathioprine protocol produces actuarial survival and morbidity rates comparable to those of a matched triple-therapy group. Thirty percent of patients in this protocol, however, will require maintenance steroids.

Oxygen free radical scavengers to prevent pulmonary reperfusion injury after heart-lung transplantation.

Abstract: Oxygen free radical scavengers, such as superoxide dismutase (SOD) and catalase (CAT), have been shown to reduce effectively myocardial reperfusion injury. No such data have been reported for cold global pulmonary ischemia, which is required in heart-lung transplantation. Heterotopic heart-left lung allotransplantation was performed in 18 dogs after single-flush perfusion of the lungs with Euro-Collins solution (60 ml/kg), cardioplegic arrest, and 6 hours of cold global ischemia. Six dogs served as controls. In six other dogs prostacyclin (PGI2) was administered both into the pulmonary artery (20 ng/kg/min) and to the Euro-Collins solution (15 mg/L) before explantation (group A). Grafts in six other dogs were preserved with Euro-Collins solution plus SOD (40,000 U/L) and CAT (100,000 U/L)(group B). In addition, SOD (1 mg/kg) and CAT (1.5 mg/kg) were given intravenously during the first 20 minutes of reperfusion. There was no significant difference in cardiac output, right and left atrial pressures, nor pulmonary arteriolar resistance among the groups. In contrast, left atrial oxygen pressure (PO2) values were best in group B. At all times, PO2 values in animals in groups A and B exceeded those in control animals. Compared with control animals with Euro-Collins solution preservation alone, animals with both PGI2 and SOD/CAT preservation had significantly improved pulmonary function after heart-lung transplantation. Better oxygenation in the SOD/CAT group (group B) suggests an important impact of oxygen free radicals during reperfusion.

Optimalization of immunosuppression after xenogeneic heart transplantation in primates.

Abstract: Xenogeneic heart transplantation is becoming increasingly attractive because of the shortage of suitable donor organs. In small infants and neonates, for whom suitable human grafts are difficult to obtain, this may play a particularly important role. To evaluate the optimal immunosuppressive regimen after xenogeneic transplantation, cervical heterotopic heart transplantation was performed with vervet monkeys as donors and chacma baboons as recipients. The following groups were investigated: group 1 (n = 9): control, no immunosuppressive medication; group 2 (n = 5): cyclosporine in combination with azathioprine and methylprednisolone; group 3 (n = 6): cyclosporine, azathioprine, and methylprednisolone in combination with antithymocyte globulin for postoperative days 0 to 9; group 4 (n = 7): cyclosporine, azathioprine, and methylprednisolone in combination with 15-deoxyspergualin for postoperative days 0 to 9. Because of severe treatment-related side effects that were observed in group 4, further immunosuppression was modified as follows: group 5 (n = 5): 15-deoxyspergualin was combined with cyclosporine and methylprednisolone only. Acute rejection episodes were diagnosed by cytoimmunologic monitoring on alternate days and weekly myocardial biopsies and were treated with 500 mg methylprednisolone intravenously for 3 to 5 consecutive days. The graft survival after xenogeneic heart transplantation was best in group 3 with 43.3 days compared with 10.3 days in the control group. Still 2.3 acute rejections occurred, which in most cases led to graft failure in these animals. In group 4 the graft survival was prolonged to 20.1 days on average. Only 0.5 acute rejections per animal occurred, but severe gastrointestinal complications and infections were observed that made further experiments necessary to minimize these treatment-related complications.(ABSTRACT TRUNCATED AT 250 WORDS)

Orthotopic total artificial heart bridge to transplantation: preliminary results.

Abstract: A detailed summary of seven patients who received eight total artificial heart implants, including one Phoenix heart, two Jarvik 7-100 ml hearts, and five Jarvik 7-70 ml hearts, and nine heart transplants, reveals that bleeding, hemolysis, and thromboembolic and infectious problems are not the limiting factors. Size of the patient and the requirement for adequate space to permit adequate systemic and pulmonary venous filling seem to be the major limitations. Patients with a reasonable expectation of receiving a transplantation within 3 weeks are the best candidates for a bridge to transplantation. After this adhesions were found to cause severe technical problems at reoperation.

Heterotopic heart transplantation: current status in 1988.

Abstract: Among the 480 patients who underwent heart transplantation in our institution (since 1968), 40 patients received an allograft in the heterotopic position. The recipients were evaluated by using hemodynamics and Doppler echocardiography before and after surgery. Ten to 30 days after surgery, preoperative pulmonary artery pressure, pulmonary artery wedge pressure, and pulmonary vascular resistance (PVR) decreased significantly (p less than 0.005). Cardiac output increased significantly (p less than 0.0001). Postoperative Doppler echocardiography showed that heterotopic hearts had an excellent ejection fraction (mean 73% +/- 11%). No improvement occurred in the left ventricular function of the native heart. Among the factors affecting short-term prognosis of heterotopic heart transplantation (HHT) recipients. PVR seems to be the most important determinant of survival. HHT does not seem to improve the prognosis of patients with elevated PVR. HHT, however, is still indicated in large patients and in emergency situations in which an available donor heart appears unable to support the recipient's circulation if used in the orthotopic position.

The role of indium-111 antimyosin (Fab) imaging as a noninvasive surveillance method of human heart transplant rejection

Abstract: The identification of rejection after heart transplantation in patients receiving cyclosporine immunosuppressive therapy requires the endomyocardial biopsy, an invasive method associated with a finite morbidity. To evaluate the role of indium-111 antimyosin (Fab) scintigraphy as a noninvasive surveillance method of heart transplant rejection, the Fab fragment of murine monoclonal antimyosin antibodies labeled with indium-111 was administered intravenously in 30 scintigraphic studies to 10 consecutive heart transplant recipients. Endomyocardial biopsy specimens were obtained 72 hours after each scintigraphic study. Nineteen scintigraphic studies had negative findings; no false negative finding was obtained. Eleven antimyosin scintigraphic studies had positive findings, and in these studies endomyocardial biopsy revealed mild rejection in two cases, moderate acute rejection with myocyte necrosis in two cases, myocyte necrosis as a consequence of ischemic injury in six cases, and possibly cytotoxic damage in one case. Antimyosin scintigraphy may represent a reliable screening method for the surveillance of heart transplant patients. In the presence of a negative finding from antimyosin scintigraphy, it may be possible to avoid endomyocardial biopsy. Conversely, in patients who have a positive finding from antimyosin scintigraphy, the endomyocardial biopsy is mandatory to establish the definitive diagnosis by histologic examination of the myocardium.

An avoidable pitfall in donor selection for heart transplantation. Utah Heart Transplant Program.

Abstract: Evaluation of potential donors for heart transplantation is an important part of any heart transplantation program. Standard guidelines are being refined constantly to expand the donor pool. We present a case of carbon monoxide poisoning that led to severe myocardial damage in the transplanted heart.

Sequential analysis of monomorphic and polymorphic major histocompatibility complex antigen expression in human heart allograft biopsy specimens.

Abstract: Changes in major histocompatibility complex (MHC) antigen expression after heart transplantation were investigated in 233 cardiac allograft biopsy specimens of 33 patients by means of immunohistologic examination. The altered tissue expression was related to histopathologic and clinical diagnoses. A panel of monoclonal antibodies directed to monomorphic determinants was used for the analysis of MHC antigens, class I (human leukocyte antigens [HLA]-A, B, C, and beta 2 microglobulin) and class II (HLA-DR, HLA-DP, HLA-DQ). Donor and recipient MHC antigen expression (HLA-A and HLA-B) was studied by use of monoclonal antibodies directed to polymorphic epitopes. It was found in 57 of 78 rejection episodes that the induction of class I MHC antigens on the normally negative myocyte membranes was related to the rejection process. Usually the induction was focally associated with lymphocytic infiltrates but in severe rejection was generalized on all myocyte membranes. After effective rejection treatment the class I induction was reversed. Class II (HLA-DR) MHC antigens were induced on most vessel endothelia. During rejection MHC antigens HLA-DP and HLA-DQ also were coexpressed on the endothelia of a few vessels. Donor HLA-A and HLA-B antigens were expressed by endothelial and interstitial cells in comparable density but only in low amounts on myocyte membranes. Recipient interstitial cells infiltrated around vessels with time after transplantation. Most interstitial cells between myofibrils, however, remained those of the donor type until 1 year after transplantation. These results show that cardiac allografts undergo remarkable changes in the expression of MHC antigens during clinical complications after transplantation. Furthermore, the changes in alloantigen composition may influence the clinical course.

Dyslipoproteinemias after heart and heart-lung transplantation: potential relation to accelerated graft arteriosclerosis.

Abstract: Plasma lipid, lipoprotein lipid, and low-density lipoprotein (LDL) apolipoprotein B (Apo B) levels were measured in 34 patients who had undergone heart transplantation and in two patients who had undergone heart-lung transplantation. In contrast to initial reports, atherogenic dyslipoproteinemias were common, with 14% of patients having increased LDL cholesterol levels, 16.7% increased triglyceride levels, 8.3% decreased high-density lipoprotein (HDL) cholesterol levels, and 22.2% increased LDL Apo B levels. Of interest, 14% of patients had an HDL cholesterol level greater than the 95th percentile of the general population. In four patients coronary arteriosclerosis developed after transplantation. All had an atherogenic dyslipoproteinemia. One had type II hypercholesterolemia, and one had isolated low HDL cholesterol levels. Two had hyperapobetalipoproteinemia, one of whom also had low HDL cholesterol levels. The results establish that atherogenic dyslipoproteinemias are frequent in patients after heart transplantation and suggest that these dyslipoproteinemias, along with rejection, may play a role in the pathogenesis of arteriosclerosis after transplantation.

Reversal of rejection-induced coronary vasculitis detected early after heart transplantation with increased immunosuppression

Abstract: Four patients who underwent heart transplantation, in whom coronary obstruction was seen early after transplantation, are described. Repeated acute rejection episodes were detected within the first 2 months in each patient. Coronary obstruction or ischemia was shown through a combination of T1-201 isotopic study findings, evidence of vasculitis of a small coronary arteriole seen at endomyocardial biopsy, or coronary angiographic results. Vigorous treatment for rejection (antithymocyte globulin and bolus methylprednisolone) was given, and coronary artery lesions or myocardial ischemia resolved after treatment. Rejection-induced coronary obstruction should be considered in patients with repeated acute rejection episodes who are predisposed to the development of vascular rejection. Early after transplantation such obstruction is caused by diffuse vasculitis of small and medium-sized vessels and may be reversed with increased immunosuppression.

Extended cardiopulmonary preservation for heart-lung transplantation: a comparative study of superoxide dismutase.

Abstract: We examined an 8-hour cardiopulmonary preservation technique and the role of free radical-induced injury during cardiopulmonary preservation and transplantation. Hence, donor dogs were placed on cardiopulmonary bypass, rapidly cooled to 15 degrees C, and heterotopic heart-unilateral left lung transplantations were performed. In group 1 (n = 5), hearts and lungs were transplanted immediately after core-cooling and cardioplegic arrest. In groups 2 to 5 (n = 5 in each group), heart-lung blocks were excised and stored at 4 degrees C for 8 hours before transplantation. During preservation hearts were perfused (20 mm Hg) with oxygenated extracellular solution (pH 7.4, 410 m0sm/L) and the lungs immersed in the same solution. In groups 3 through 5 recombinant human superoxide distumase (r,h-SOD, total 40 mg/kg) was administered during either donor cooling, donor preservation, or just before and during reperfusion, respectively. Load independent analysis of myocardial function was assessed by determining the ratio of the end-systolic pressure to end-systolic dimension. Pulmonary preservation was evaluated by determination of extravascular lung water of the implanted left lung, arterial oxygenation on 40% inspired oxygen, and pulmonary vascular resistance. Although arterial oxygenation was similar in each group, pulmonary vascular resistance was increased in groups 2 through 4 after implantation. Furthermore, in groups 2 and 4 impaired myocardial function and increased extravascular lung water were observed. Administration of r,h-SOD, however, just before and during reperfusion significantly enhanced cardiopulmonary preservation. These results indicate that free radical-induced injury is primarily the result of reperfusion. Thus the best time for administration of r,h-SOD is before and during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Neopterin as a new marker to detect acute rejection after heart transplantation.

Abstract: Neopterin is excreted at high levels in the course of activation of the immunologic system during allograft rejection or viral infection. This pteridine therefore may be considered as a specific indicator of T cell-mediated immunity. With radioimmunoassay we analyzed both serum and urine levels of neopterin in 43 patients after orthotopic heart transplantation. These data were correlated to the histologic finding at routine endomyocardial biopsies (EMB). In case of rejection (that is, grades I to II or more in EMB) serum levels of neopterin increased about 156% +/- 94% within 1 week before EMB, whereas urine levels increased about 215% +/- 137%. The most marked increase was seen 2.8 days before the corresponding EMB. The predictive value theory was used to elaborate the reliability of the correlation between an increase of neopterin levels and the occurrence of an acute rejection episode. With regard to serum levels, sensitivity and specificity were 0.872 and 0.815, respectively. The positive predictive value was 0.41 and the negative predictive value was 0.977. We found similar results in urine levels.

Posttransplantation diabetes mellitus in heart transplant recipients.

Abstract: This study was undertaken to investigate the impact of diabetes, which develops after heart transplantation, on infection and patient survival. Nondiabetic patients (366) underwent heart transplantation at our institution between June 1, 1980 and January 12, 1988. Of these patients, 29 (8%) developed posttransplantation diabetes (PTD), defined as a continued need for hypoglycemic agents. The PTD group did not differ significantly from the nondiabetic recipients in age, sex, or human leukocyte antigen type. The average age in the PTD group was 49 years. Average length of follow-up was 21 months (range 4 to 46 months). Eighteen patients are maintained on insulin. Eight patients are on oral hypoglycemic agents. Three patients died while on insulin. The average prednisone dosage in this group is 0.23 mg/kg/day. There have been 18 minor infections and four potentially serious nonlethal infections in the 27 PTD recipients. One lethal infection occurred 33 months after heart transplantation. The only other fatality was related to metastatic bladder cancer. This lethal infection rate of 3% compares with a rate of 11% in all nondiabetic recipients who have follow-up for 21 months. The 3-year actuarial survival of the PTD group is 75%, which compares favorably with the survival of nondiabetic patients. PTD cannot be predicted by sex, age, or human leukocyte type before transplantation, and it does not significantly increase the incidence of mortality or serious infection.

Extracardiac surgical complications in heart transplant recipients

Abstract: As the population of patients undergoing orthotopic heart transplantation increases, more patients are likely to develop surgical complications unrelated to the transplant procedure. This article reviews 38 extracardiac surgical complications sustained in 18 of 48 patients undergoing orthotopic heart transplantation at our institution over a 4-year period. Twenty-seven complications (71.1%) required operative intervention most commonly in an urgent or emergent manner (59.3%). Three patients underwent six laparotomies. Infection was the cause in almost half of all complications and in 65% of those requiring surgery. Gastrointestinal hemorrhage was common and successfully managed nonoperatively in all cases. The overall operative mortality was 11% with only two deaths related to a surgical complication. The satisfactory outcome in these patients can be attributed to the early diagnosis of complications, timely therapeutic intervention, careful adjustment of immunosuppressive agents, and close patient follow-up with the transplant institution.