The assessment of the results of heart transplantation.
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Heart Transplantation↗
Biomedical subjects
D K Cooper
Publications and source records attributed to D K Cooper.
Successful management of symptomatic cytomegalovirus disease with ganciclovir after heart transplantation.
In the 30-month period from January 1987 through June 1989, 57 patients underwent heart transplantation. Immunosuppressive therapy consisted of a combination of cyclosporine, azathioprine, low-dose methylprednisolone, and antilymphoblast globulin. Clinically significant, proven cytomegalovirus (CMV) disease has developed in no fewer than 22 patients (39%), involving the lung (n = 11), colon (n = 8), stomach (n = 4), and retina (n = 1). The diagnosis was confirmed by direct fluorescent antibody (DFA) (n = 14), histologic study (n = 6), and culture (n = 6) in all cases. The onset of CMV infection occurred at a mean of 5.7 months after heart transplantation (range, 3 weeks to 18 months). All patients were treated with ganciclovir until no sign of active CMV disease could be found. The length of treatment required varied from 2 to 8 weeks (mean, 3.5 weeks). Recurrence has occurred in only one patient, necessitating a further 26-week course of therapy. There were no deaths attributed definitely to CMV disease. There was a higher incidence of acute rejection in the first 3 posttransplant months (0.68 episodes/patient) in the CMV group than in those in whom CMV disease did not develop (0.34 episodes/patient; p less than 0.02). Of the CMV patients, 25% had significant features of graft atherosclerosis during the first posttransplant year, compared with only 8% of the non-CMV patients. In conclusion, (1) there was a high incidence of CMV disease with this immunosuppressive regimen, and we have subsequently discontinued routine antilymphoblast globulin therapy and instituted a triple therapy immunosuppressive protocol with prophylactic immunoglobulin and acyclovir; (2) CMV disease was successfully treated in all cases with ganciclovir alone; and (3) there was a trend toward an increased incidence of both acute rejection and accelerated graft atherosclerosis in the CMV group of patients.
Coronary Artery Disease↗
Risk of endocarditis in donor hearts.
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Adult↗
Histopathology of hyperacute rejection of the heart: experimental and clinical observations in allografts and xenografts.
The histologic findings in a total of 112 experimental heart transplants comprising allografts (baboon to baboon: n = 37), concordant xenografts (vervet monkey to baboon: n = 52), and discordant xenografts (pig to baboon: n = 23), in which the roles of ABO blood group incompatibility, corcordance, and immunosuppression were evaluated, are described. Hyperacute (vascular, humoral) rejection was characterized by disruption of the microcirculation, with interstitial hemorrhage and edema, rather than by intravascular thrombosis; the features were basically similar whether hyperacute rejection occurred in an ABO-incompatible allograft, concordant xenograft, or discordant xenograft. Hyperacute rejection was noted in all 23 discordant xenografts, in 12 to 52 concordant xenografts, and in four of 17 ABO-incompatible allografts. A unique mixture of acute and hyperacute rejection was observed in three ABO-incompatible allografts and in 10 concordant xenografts. Intensive antirejection therapy was associated with a reduced incidence of hyperacute rejection in corcordant xenografts but also with a significant number of fatal treatment-related complications.
ABO Blood-Group System↗
Cytoimmunologic monitoring after heart and heart-lung transplantation.
The ability of cytoimmunologic monitoring to detect acute rejection in heart and heart-lung transplant recipients was assessed. Seventeen heart and nine heart-lung transplant patients treated with cyclosporine as the primary immunosuppressive agent were monitored after operation. Seventeen acute rejection episodes occurred in the heart-only recipients and 12 in the combined heart-lung recipients. These acute rejection reactions were accompanied by increased numbers of "activated" lymphocytes in all but one case, providing cytoimmunologic monitoring a sensitivity of 100% in the heart-lung recipients and 94% in the heart recipients. The specificity was, however, low (68% in the heart recipients and 55% in the heart-lung recipients). Seventy-two percent of the false-positive results were associated with viral infections, particularly cytomegalovirus infections.
Adolescent↗
Clinical survey of heart transplantation between ABO blood group-incompatible recipients and donors.
A clinical survey of 4895 heart transplants performed at 66 centers worldwide revealed that eight patients (0.16%) had received ABO-incompatible donor hearts. Of these eight transplants, five hearts (63%) were hyperacutely rejected (vascular or humoral rejection), four within 24 hours and one (after treatment by plasmapheresis) at 13 days. Two patients died at the time of rejection; the remaining three underwent retransplantation. Two patients died (at retransplant and at 7 weeks, respectively), and one is alive 8 months later. Three ABO-incompatible hearts (37%) were not hyperacutely rejected; two of these patients remain alive 12 and 26 months later, and the third died at 11 months in an automobile accident. There was, therefore, an early mortality of four of eight patients (50%). Care should be taken to ensure ABO compatibility of the donor whenever heart transplantation is undertaken.
ABO Blood-Group System↗
Optimalization of immunosuppression after xenogeneic heart transplantation in primates.
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)
Animals↗
Does central nervous system toxicity occur in transplant patients with hypocholesterolemia receiving cyclosporine?
A syndrome of severe central nervous system toxicity (confusion, cortical blindness, quadriplegia, seizures, and coma) associated with cyclosporine therapy and a low serum cholesterol level in patients with liver transplants has been described. We present a case history of a patient who demonstrated several similar features after heart-lung transplantation. Possible cyclosporine neurotoxicity should be considered in any patients with hypocholesterolemia receiving this drug.
Adult↗
Right ventricular assist by a heterotopic left ventricle.
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Assisted Circulation↗
Triiodothyronine therapy for heart donor and recipient.
Both (1) brain-dead donors and (2) transplant recipients on cardiopulmonary bypass suffer a depletion in plasma-free triiodothyronine (T3), which leads to metabolic changes (from inhibition of mitochondrial function), resulting in myocardial energy store depletion. Replacement therapy with T3 reverses these changes in both donor and recipient. Donor heart energy stores and function will be maintained at optimum levels if T3 therapy is administered to both donor and recipient at the time of transplantation.
Cardiopulmonary Bypass↗
Prediction of acute cardiac rejection by changes in left ventricular volumes.
Sixteen patients underwent heart transplantation (11 orthotopic, five heterotopic). Monitoring for acute rejection was by both endomyocardial biopsy (EMB) and multigated equilibrium blood pool scanning with technetium 99m-labelled red blood cells. From the scans information was obtained on left ventricular volumes (stroke, end-diastolic, and end-systolic), ejection fraction, and heart rate. Studies (208) were made in the 16 patients. There was a highly significant correlation between the reduction in stroke volume and end-diastolic volume (and a less significant correlation in end-systolic volume) and increasing acute rejection seen on EMB. Heart rate and ejection fraction did not correlate with the development of acute rejection. Correlation of a combination of changes in stroke volume and end-diastolic volume with EMB showed a sensitivity of 85% and a specificity of 96%. Radionuclide scanning is therefore a useful noninvasive tool for monitoring acute rejection.
Biopsy↗
Acute pulmonary rejection precedes cardiac rejection following heart-lung transplantation in a primate model.
Twelve Chacma baboons underwent transplantation of the heart and both lungs from donor baboons matched for size and AB blood group. Cyclosporine was given daily orally, by twice daily intravenous injections, or by a single intravenous injection (together with oral azathioprine and, after 2 weeks, methylprednisolone); whole blood trough levels were inadequate in all groups. Survival was from 4 to 29 days, with death resulting from acute rejection of the lungs in 11 and from bronchopneumonia in one. In the 11 animals dying from rejection, histologic examination showed that the heart was spared from severe rejection in all cases but one. In the inadequately immunosuppressed baboon, therefore, acute rejection occurs earlier in the lungs than in the heart. We have now observed what we believe to have been acute pulmonary rejection in the absence of cardiac rejection on five occasions in three patients in our clinical transplantation program. We would suggest that pulmonary rejection must always be strongly suspected if there are any suggestive features, particularly pulmonary shadowing on chest radiographs, despite negative results of tests indicating rejection of the heart. In the absence of any easy method of confirming pulmonary rejection directly (other than open-lung biopsy, which is clearly contraindicated as a routine procedure), we suggest that more attention should be directed toward developing tests for rejection that are not organ specific, rather than relying on techniques that diagnose cardiac rejection only.
Animals↗
Successful orthotopic heart-lung transplantation in the baboon after five hours of cold ischemia with cardioplegia and Collins' solution.
En bloc transplantation of the heart and lungs was performed in 15 chacma baboons; the donor organs were stored between 4 and 6 hours before transplantation. The hearts were perfused in the donor animals with 15 ml/kg Wicomb's cardioplegic solution at 4 degrees C, the lungs with either 20 ml/kg 4 degrees C Collins' solution with an added 2.5% dextrose and 12 mEq magnesium sulfate (Collins' solution, group 1, n = 8), Collins' solution plus superoxide dismutase (40,000 U/L superoxide dismutase, group 2, n = 4), or Collins' solution plus superoxide dismutase plus peroxidase (5000 U/L peroxidase plus mannitol, group 3, n = 3). The pulmonary artery perfusion pressure was not allowed to exceed 50 cm water; the lungs were maintained at 30% to 50% inflation, and external cooling was applied. After explantation the thoracic organs were stored in 0.9% saline solution at 4 degrees C. In groups 1 (Collins' solution) and 2 (Collins' plus superoxide dismutase) all surviving baboons revealed normal blood gas values and normal light and electron microscopic histology at 24 hours. Three animals had further biopsies at intervals between 1 and 9 days, at which time the histology of the lungs proved normal and well preserved. All three baboons in group 3 (Collins' plus superoxide dismutase plus peroxidase) had grossly abnormal blood gas values from the time of operation, and all died within 9 hours; light microscopy of the lungs showed early lung infarctlike lesions and in one case pulmonary edema. These preclinical findings proved that storage of the lungs in Collins' solution with or without superoxide dismutase is possible for up to 5 hours; the addition of peroxidase had a detrimental effect.
Animals↗
Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon.
The problem of donor heart supply would be solved if hearts could be transplanted from readily available animals such as the pig or sheep. We have investigated heterotopic heart transplantation (in the neck) with the pig as donor and baboon as recipient. Five experimental groups were studied. Control hearts (group 1, n = 4) were rejected within 4 minutes to 8 hours. Splenectomy done before transplantation (group 2, n = 3) did not extend survival significantly (30 minutes to 8 hours). Donor heart survival in baboons receiving immunosuppressive therapy of cyclosporine and methylprednisolone (group 3, n = 5) was from 15 to 75 minutes only in four animals and for 5 days in one animal. Anti-pig antibody adsorption from baboon blood by pretransplant donor-specific kidney hemoperfusion (group 4, n = 7) resulted in cardiac function for 6 to 12 hours in three cases and from 4 to 5 days in four cases (p less than 0.02). A combination of pretransplant antibody adsorption and immunosuppression (group 5, n = 4) resulted in graft survival of 8 to 20 hours in three cases and of 4 days in one case (p less than 0.03). Histopathologic features of vascular (hyperacute) rejection were seen in all hearts except one (the 5-day survivor in group 3). Pretransplant adsorption of antibody clearly prolonged survival of discordant cardiac xenografts in some cases. Further exploration of this technique appears justified.
Adsorption↗
Hemodynamic and myocardial histologic and ultrastructural studies on baboons from 3 to 27 months following autotransplantation of hearts stored by hypothermic perfusion for 24 or 48 hours.
Hemodynamic and myocardial histologic studies have been made in four baboons, each of whom had undergone heart excision and storage, followed by autotransplantation. The excised baboon heart was stored by continuous hypothermic perfusion for 24 or 48 hours and then replaced orthotopically, the baboon being maintained alive in the interim by an orthotopic cardiac allograft. Follow-up of the autotransplanted baboons has been from 3 to 27 months. Cardiac catheterization revealed normal function both early and late after the period of storage. In three animals, myocardial histology was normal on light microscopy, although some dilation of the T tubules was seen on electron microscopy. In the fourth baboon, whose heart had been stored for 48 hours with follow-up for 13 months, light microscopy revealed some variation of staining of the myofibers and mild interstitial edema; ultrastructural studies showed mild intracellular edema, focal scanty loss of myofilaments, and a lack of dilation of the T tubular system. With this one possible exception, this study confirms that the system of hypothermic perfusion storage developed in our laboratory does not have any significant damaging effects on myocardial function or structure. There would appear, therefore, to be no contraindication to its use in clinical heart transplantation.
Animals↗
Hyperacute rejection in a discordant (pig to baboon) cardiac xenograft model.
Eight freshly excised pig hearts were hemoperfused by baboons in vivo. Cardiac function ceased in six hearts after a mean period of 90 minutes of perfusion (range 30 to 190 minutes). Two hearts continued functioning for the 4-hour study period. On microscopic examination, seven hearts, including one that continued beating, showed histopathologic features of hyperacute rejection. IgG, IgM, and C3 were strongly present on the myocardium in all cases. Hemoperfusion was associated with significant increases in heart mass (p less than 0.002) and circulating polymorphonuclear leukocytes (p less than 0.03) and reductions in coronary blood flow (p less than 0.0001), circulating lymphocytes (p less than 0.03), and C4 (p less than 0.03). Preformed circulating anti-pig antibodies disappeared in all but one baboon. Hyperacute rejection in this discordant xenograft model that used a nonhuman primate as "recipient" differs in few aspects from that seen in other experimental models. Possible methods of prolonging xenograft survival are discussed.
Animals↗
Regression of Kaposi's sarcoma after reduction of immunosuppressive therapy in a heart transplant patient.
The de novo development of Kaposi's sarcoma, confirmed by lymph node biopsy 17 months after heart transplantation in an 18-year-old patient, is described. Constitutional symptoms and axillary and inguinal lymphadenopathy were the presenting features. Surveillance for systemic involvement was negative, and the tumor seemed to be confined to the lymphoreticular system alone. Chemotherapy with vincristine and cyclophosphamide resulted in severe leukopenia and was discontinued. Immunosuppressive therapy, consisting of cyclosporine and methylprednisolone, was gradually reduced, resulting in regression of symptoms and lymphadenopathy. One year later the patient was symptom free, and only one extremely small inguinal lymph node was palpable. Microscopic examination of this node, however, revealed persistent Kaposi's sarcoma. The patient's immunosuppressed state would now appear to be sufficient to prevent acute rejection and yet insufficient to lead to growth and spread of the tumor.
Adolescent↗
Twenty years of heart transplantation at Groote Schuur Hospital.
Between December 1967 and July 1987, 110 heart transplantations (61 heterotopic and 49 orthotopic) and 12 heart-lung transplantations were done at Groote Schuur Hospital in Cape Town, South Africa. Twelve procedures were retransplantations, including two third interventions. The patients were divided into three groups: Group A (n = 55) from 1967 to 1982 received so-called conventional treatment of azathioprine, methylprednisolone, and antithymocyte globulin. Group B (n = 15) from 1983 to 1984 had cyclosporine in high dosages together with methylprednisolone. Group C (n = 30) received quadruple drug therapy of low-dosage cyclosporine, together with azathioprine, methylprednisolone in lower dosages, and antithymocyte globulin (for the first 4 to 6 days and rescue antithymocyte globulin for severe rejection). From Group A, nine of 55 patients are alive up to 17 years after transplantation. The main causes of death were acute rejections and infections (in 60% altogether). From group B, six of 15 patients are alive. Acute rejections and infections were the causes of death in 12% of the patients, but multiple organ failure was a major cause in 24% most probably because of the high dosages of cyclosporine. From group C, 23 of 30 patients have survived. In this group the results after heterotopic heart transplantation do not differ significantly from orthotopic transplantation, which justifies this procedure in particular situations. If all heterotopic and orthotopic transplantations are compared, orthotopic procedures have a substantially better outcome. With the modified immunosuppressive regimen (group C) combined with precise donor and recipient selection and more sophisticated rejection monitoring, the actuarial survival rate within the last 12 months is 94%.
Antilymphocyte Serum↗