Lack of association between endomyocardial evidence of rejection in the first six months and the later development of transplant-related coronary artery disease.

The development of transplant-related coronary artery disease (TCAD) is the major determinant of long-term heart transplant survival. To test the hypothesis that TCAD might be related to cellular myocardial rejection, the grades of rejection seen at all biopsies performed in the first 6 months after heart transplantation were analyzed in 108 patients who survived more than 6 months. The development of TCAD was assessed at routine follow-up coronary angiography in 101 patients and at necropsy in seven patients. This data was analyzed with Kaplan-Meier survival curves and Cox proportional hazard regression analysis. No significant association was found between either moderate rejection or any level of rejection and the later development of TCAD, nor did the absence of any rejection protect against its development.

Some prognostic factors for the development of transplant-related coronary artery disease in human cardiac allografts.

The study of endomyocardial biopsy specimens taken in the first 130 days after transplantation has yielded no histologic features predictive of later development of transplant-related coronary artery disease. This study, however, indicated that a combination of the following factors might be predictive in cyclosporine-treated patients: untreated histologically proven episodes of rejection, infection with cytomegalovirus or reactivation of infection, ischemic heart disease in the recipient as the reason for heart transplantation, and possibly HLA-B5 or -B8 mismatch.

The correlation of various features of rejection in myocardial biopsies after human heart transplantation.

1571 specimens taken at 493 occasions for endomyocardial biopsy in 30 selected heart transplant patients were reexamined in order to assess (a) the difference between conventional (steroid, azathioprine and antithymocyte globulin) and cyclosporine with low-dose steroid immunosuppression regimes, and (b) the relationship of myocardial rejection to endocardial infiltrates, the Quilty lesion, and changes in the small intramyocardial blood vessels. The incidence of all histological changes discussed were related to the severity of the myocardial rejection and therefore the endocardial and vascular changes may be used as adjuvants to make good any technical deficiencies in the myocardial part of the biopsy. Cyclosporine therapy is associated with the Quilty effect and with changes in small vessels.

Toxoplasmosis in heart and heart and lung transplant recipients.

Of the first 250 heart and 35 heart and lung transplant recipients at Papworth Hospital, Cambridge, who survived for more than one month after transplantation, 217 heart and 33 heart and lung patients were investigated serologically for evidence of Toxoplasma gondii infection. Six patients acquired primary T gondii infection, most probably from the donor organ. Five patients experienced T gondii recrudescence, two of whom had recovered from primary infection a few years earlier. Two patients died from primary T gondii infection and the severity of symptoms in the other patients with primary infection was related to the amount of immunosuppressive treatment. Prophylaxis with pyrimethamine (25 mg a day for six weeks) was introduced for T gondii antibody negative transplant recipients who received a heart from a T gondii antibody positive donor after the first four cases of primary toxoplasmosis. Of the seven patients not given pyrimethamine, four (57%) acquired primary T gondii infection. This compared with two of the 14 patients (14%) given prophylaxis.

Lack of association between cytomegalovirus infection of heart and rejection-like inflammation.

Serial myocardial biopsy specimens, taken up to the time of serological evidence of primary cytomegalovirus (CMV) infection in 22 heart transplant patients, were examined and compared with those taken over similar times after transplantation in 21 patients who did not develop CMV infection. None of these 43 patients had serological evidence of CMV infection before their heart transplantation. There was no evidence of an increased cellular infiltrate in the myocardium at the time of the active CMV infection, even though the donor heart is the likeliest source of infection, nor was there any change in myocyte, interstitial cell, or vascular endothelial cell nuclei to identify active CMV infection.

Effect of donor heart damage on survival after transplantation.

Evaluation of the functional condition of the heart prior to its removal from the donor or after transport to the recipient is difficult. Biopsies of the myocardium allow serial assessments to be made throughout this period, but suffer from the disadvantage that the average analysis of biopsies has only a tenuous connection with physiological function. Quantitative birefringence measurements (QBM), on the other hand, assess the ability of myocardial fibres to respond to ATP and calcium and have been shown to correlate well with measurements of cardiac function (P less than 0.001). A prospective study of myocardial biopsies before excision, after transport and again after transplantation, using quantitative birefringence measurement of biopsies of the heart has recently been completed. These studies have shown evidence of impaired myocardial function in 73 (43%) of 172 donor hearts studied prior to excision, with a further 27% showing significant deterioration during storage and transport to the recipient. Biopsy assessments therefore indicated that at the moment of implantation, only 30% of the donor hearts were normal. Functional assessment of the biopsies by QBM correlated with early clinical outcome of transplantation (P less than 0.001). Longer term follow-up of the recipients (up to 5 years) has shown that the mortality of recipients of hearts with impaired function before transplantation is significantly increased (44% of 120) compared with that of recipients of undamaged hearts (6% of 52, P less than 0.001).

Cyclosporine-associated nephropathy in patients with heart and bone marrow transplants.

The morphology of kidneys from heart (n = 55) and bone marrow (n = 112) transplant recipients treated either with cyclosporine (CSA) or conventional immunosuppression was investigated at autopsy. The major findings were: In the bone marrow transplant recipients glomerular collapse, tubular atrophy, interstitial fibrosis, striped form, CSA-associated arteriolopathy and thrombi in glomeruli and/or arterioles were more often found in the CSA group as compared to conventional immunosuppression. In the heart transplant recipients glomerular collapse and obsolescence, tubular atrophy and intimal fibrosis in arteries were more frequent in the CSA group. Vascular interstitial toxicity known to be associated with CSA treatment from renal transplant patients was found in 54% (25% severe) of the bone marrow and 19.5% (9.7% severe) of the the heart transplant recipients. The prevalence of vascular interstitial toxicity in bone marrow versus heart transplant recipients is possibly due to higher CSA dosage and pretreatment with cytostatic drugs and irradiation. Analyses of the lesions from early stages to the full picture of vascular interstitial toxicity suggests that CSA causes a form of thrombotic microangiopathy with focal glomerular and/or arteriolar thrombosis followed by typical CSA-associated arteriolopathy which results in interstitial fibrosis with tubular atrophy.

Effects of cyclosporine on the transplanted human heart.

The possible short-term effects of cyclosporine on the heart were studied in 42 endomyocardial biopsies taken at the time of high levels of cyclosporine in the blood, in 20 biopsies at low blood cyclosporine levels, and in 44 biopsies taken from patients on a conventional (before cyclosporine) regimen of azathioprine and steroids after heart transplantation. More long-term effects were studied in postmortem heart sections from 11 liver transplant patients, six of whom had received cyclosporine immunosuppression therapy. The weight of transplanted hearts at necropsy and at retransplantation were analyzed, and in each of the groups of rejectors and nonrejectors, the hearts treated with cyclosporine were significantly heavier than the hearts treated with azathioprine and steroids. Cyclosporine is associated with a higher incidence of interstitial edema and fibrosis than other forms of immunosuppression therapy, and these changes are probably aggravated by rejection.

Transvenous lung biopsy in the pig.

At present there is no satisfactory technique for repeated lung biopsy in recipients of heart-lung transplants. A new technique for lung biopsy, which might be adopted for this purpose, has been developed. A Teflon sheath is inserted through the jugular vein into the pulmonary artery with the aid of a balloon catheter. A flexible biopsy forceps is then introduced through the sheath into the pulmonary arterial tree and advanced into the periphery of the lung, where biopsy samples are taken. The procedure was attempted in 14 pigs. Initially crocodile jaw (two pigs) and fenestrated cups forceps (five pigs), which are currently in use for transbronchial lung biopsy, were used. Subsequently the biopsy forceps was modified and the jaws were replaced by a cutting needle mechanism (six pigs). Out of the 13 animals in which the procedure was technically possible, lung parenchyma was obtained from nine and pulmonary arterial wall from 11. One animal died shortly after the procedure. The cause of death could not be determined with certainty at postmortem examination. There was, however, a small tear on the surface of the lung, which could have produced a tension pneumothorax. The other 12 animals recovered from the procedure. They were killed 24 hours later and postmortem examination was carried out. One animal in which the crocodile jaw forceps had been used had a haematoma in the lower lobe (3 X 3 X 4 cm) and 100 ml of blood in the pleural cavity. In the other 11 animals, in which the fenestrated cups or the cutting needle forceps had been used, the intrapulmonary haematomas were 1-2 cm in diameter and the pleural surface was intact. It is concluded therefore that transvenous lung biopsy is feasible and that this procedure might find an application in monitoring rejection in recipients of heart-lung transplants.

Fatal heart block due to mesothelioma of the atrioventricular node.

A fit young man of 23 was symptom free until the time of his death despite a narrow complex complete heart block, with resting heart rates down to 35 beats/min, that was first diagnosed when he was 10. The clinical diagnosis remained congenital heart block. Necropsy showed extensive infiltration of the atrioventricular node and proximal bundle by mesothelioma tissue. Pacing had not been advised because of his excellent exercise tolerance.

Conduction tissue in the transplanted human heart.

Eleven orthotopically transplanted human hearts have been examined at retransplantation or necropsy. They were selected to cover the period up to 3 years after transplantation. The recipient SA node was examined in six, the donor SA node in eight and the AV conduction tissue in all eleven. Each of these areas has been examined by serial sectioning. All the conduction tissue is discretely involved in rejection and this involvement is no more severe than in the adjacent myocardium. In the AV tissue there is a tendency for the peripheral parts to be more frequently involved than the proximal. There is little evidence of permanent structural damage to the AV tissues by recurrent episodes of mild to moderate rejection. In the atrial nodes there is about a 50 per cent chance of surgical or procurement damage to both the recipient and the donor tissue.

Surgical pathology of the thymus: 20 years' experience.

Fifty five patients underwent thymic surgery at Papworth Hospital from April 1964 to March 1984. The number presenting and the percentage with symptoms annually remained unchanged during this period. Forty four of these 55 patients had tumours. Twenty eight had thymomas (18% of whom had myasthenia gravis and 7% red cell aplasia), nine Hodgkin's disease, four germ cell tumours, and three secondary carcinomatous tumours. Five tumours were cystic. Six further patients had non-tumourous cystic lesions (four simple, one foregut, one lymphangiectatic). The remaining five patients had follicular hyperplasia; all of these had myasthenia gravis. Complete excision was performed in 41 of the 55 patients. So far survival is 100% in those with benign lesions other than benign thymomas, where the survival was 70% at five years. Those with malignant thymomas had a 60% survival rate at five years and those with Hodgkin's disease 29%.

Significance of donor transmitted disease in cardiac transplantation.

Infectious complications constitute a major cause of morbidity and mortality after heart transplantation. Those infections transmitted with the transplanted heart are potentially avoidable. Cytomegalovirus infections and toxoplasmosis occupy a prominent position in this category. The outcome of transplanting hearts from donors previously exposed to these infections depends largely on the existing immune status of the recipient. This paper is a retrospective study on the incidence of Toxoplasma gondii and cytomegalovirus infections in patients undergoing heart and heart-lung transplantation at Papworth Hospital, Cambridge.

Coronary sinus type atrial septal defect in a child with pulmonary atresia and Ebstein's anomaly.

At birth an infant was found to have an unusual series of abnormalities with a coronary sinus type atrial septal defect complicating pulmonary atresia with an intact ventricular septum and Ebstein's anomaly. The functionally important anomalies were diagnosed by echocardiography and cardiac catheterisation. The coronary sinus defect and Ebstein's anomaly were detected only at necropsy. Although only a single case, the features of this heart favour Bull's revised classification of pulmonary atresia.

Heart transplant pathology: the British experience.

An account of human heart transplantation as seen by the histopathologists involved at the two UK transplant centres is presented. Between January 1979 and July 1984 179 patients received 186 hearts and 124 are still alive up to four years after operation. Cyclosporin A based immunosuppression has been used in the last 120 patients. Four patients developed neoplastic lesions. The commonest reason for transplantation was ischaemic heart disease (63%), followed by congestive cardiomyopathy (35%). The seven retransplants were for acute or chronic rejection. The monitoring of rejection by endomyocardial biopsies is described, and the causes of death and necropsy findings are presented.

Disseminated toxoplasmosis in cardiac transplantation.

The first case of disseminated toxoplasmosis following cardiac transplantation in the UK is described, with details of Toxoplasma antibody tests made on other cardiac transplant patients. Sixteen of 40 (39%) of recipients had Toxoplasma antibody before operation. Eleven of 30 (37%) of donors had Toxoplasma antibody. The were four occasions when a negative recipient received a heart from a positive donor. Three survived the immediate postoperative period and two became infected with toxoplasmosis. The implications of this are discussed. Disseminated toxoplasmosis appears much more often when heart muscle from a dye test positive donor is given to a dye test negative recipient. Antibiotic therapy is limited by the fact that the antitoxoplasma drugs available are static in their effect, and need to be given for prolonged periods postoperatively.