The hemodynamic responses to upright exercise after orthotopic cardiac transplant.

The study was undertaken to examine the heart rate (HR) and stroke volume (SV) responses to upright exercise in patients after orthotopic cardiac transplantation (Group A). The findings were compared to data obtained from post-coronary artery bypass surgery patients (Group B) and from healthy subjects (Group C). All three groups (n = 12 in each group) were matched for age and gender. The preexercise HR and blood pressure were significantly higher in Group A (p < 0.05), whereas the SV was significantly lower (41 +/- 4mL.beat-1 vs 63 +/- 3 and 65 +/- 2 mL.beat-1 in Group B and C respectively, p < 0.05). In Group A, at submaximal work loads, the SV was consistently lower than in Groups B and C. During the early phases of exercise, the HR was consistently higher in Group A also. Systemic vascular resistance remained significantly higher in Group A throughout exercise (p < 0.05).

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.

Risk factor analysis for the major hazards following heart transplantation--rejection, infection, and coronary occlusive disease.

This study demonstrates the importance of analyzing survival by cause of death in order to achieve a better understanding of the prognostic indicators involved. It further emphasizes the need for analysis of risk factors in both univariate and multivariate models, and the danger of making judgements based on premature analysis of data on follow-up after heart transplantation. Survival following transplantation is characterized by the major hazards of early death due to infection and rejection and late graft loss due to coronary occlusive disease (COD). This study summarizes the first-graft survival experience for 323 transplant patients at Papworth Hospital, and assesses a number of potential risk factors for (1) early mortality, (2) late mortality from COD, and (3) development of COD. The potential risk factors considered for all hazards are donor and recipient age, sex, blood group, and matching of these factors; donor cause of death and recipient immunosuppression; inotropic support; waiting time; preoperative diagnosis and previous cardiac surgery; ischemic time; and extubation time. In addition, for development of, and graft loss from, COD, perioperative rejection and cytomegalovirus infection; hypertension at discharge; and cholesterol, triglycerides, and lipids at two years were assessed as risk factors. Advances in immunosuppression were observed to have increased overall survival rates and decreased mortality from infection, rejection, and COD, as well as decreasing morbidity from COD. Fatal rejection was found to be more likely in female recipients, recipients over 40 years, recipients of grafts from donors over 30 years old, patients who were transplanted for valvular heart disease, and patients who waited less than three months for their transplant. Male recipients of female donor organs were more likely to lose their grafts as a result of COD. Patients older than 50 and hearts from donors older than 40 conferred a high risk of development of and loss from COD. Patients transplanted for ischemic heart disease were more likely to develop COD. High cholesterol, low HDL, high LDL, and high triglycerides at two years after transplant showed some evidence of high risk for the subsequent development of COD, although these relationships are not statistically significant at this stage. Contrary to other recent studies, cytomegalovirus infection was not found to be a risk factor for the development of COD.

Early abdominal complications following heart and heart-lung transplantation.

In the first 11 years of the heart and heart-lung transplantation programme at Papworth Hospital, Cambridge, 356 patients underwent heart transplantation, and 73 patients received both heart and lungs. Out of 429 patients 41 (9.5 per cent) developed abdominal complications within the first 30 days, and 20 of the 41 required surgery. The complications included pancreatitis (10), peptic ulceration (8), and pseudo-obstruction (8), in addition to colonic perforation and small bowel obstruction. When laparotomy was performed it was well tolerated. This paper supports the view that successful management of abdominal complications following transplantation requires prompt diagnosis and treatment. Where doubt exists in the presence of an acute abdomen, laparotomy is the appropriate way to establish a definitive diagnosis.

Combined renal and cardiac transplantation for severe left ventricular dysfunction in end-stage renal failure.

Successful treatment of severe cardiac failure in a patient with end-stage renal failure by combined renal and cardiac transplantation is described. The possible causes of myocardial disease in the dialysis population are discussed.

Durability of porcine bioprosthetic valves.

Between 1975 and 1979 140 cardiac bioprostheses were implanted in 133 patients (mean age 60 years) at Papworth Hospital, Cambridge, England. Of these 85 remained available for analysis in the mid- and long term. Incidence of thromboembolism, bleeding, and infectious endocarditis were 2.1% +/- 0.6% (Standard error of mean), 0.2% and 0.8% +/- 0.4% per patient-year respectively. Primary valve failure occurred in only 5 patients. Freedom from primary valve failure was 98.3-r +/- 0.3% at 10 years and 82.3 +/- 4.5% at 12 years after replacement. Many patients died of old age before valve failure could occur. Therefore the percentage of tissue failure compared with the original number of patients operated on is even lower. Low incidence of valve failure, lack of need for long-term anticoagulation, and low incidence of thromboembolism make the bioprosthesis a good choice for valve replacement in older patients.

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.

Malignant tumors after heart transplantation.

Three hundred-thirteen heart transplant procedures were performed in 303 patients in the 10 years between January 1979 and December 1988. The incidence, histologic type, and site of malignant disease have been analyzed in the 275 patients (91%) who survived more than 1 month after heart transplantation. Four immunosuppressive regimens have been used during this period. Patients 1 through 29 received azathioprine and steroids with 28 days of intravenous antithymocyte globulin. Patients 30 through 89 received cyclosporine and low-dose steroids; the next 61 patients were randomized between cyclosporine and low-dose steroids and cyclosporine and azathioprine; and after patient 150 we have used triple therapy. All cyclosporine-based regimens have included a short course of prophylactic antithymocyte globulin. Eleven malignant tumors have been diagnosed, between 2 months and 6 years after the transplant procedure, and these have been treated by a variety of means. These tumors were two squamous cell carcinomas of the skin; a malignant anal wart that recurred after excision and radiotherapy and necessitated abdominoperineal resection: two small-cell carcinomas of the lung: one squamous cell carcinoma of the esophagus and one of the larynx; two carcinomas of the kidney were found at postmortem examinations; and there were two malignant lymphomas, one of which disseminated rapidly, whereas the other has had prolonged remissions with reduction in immunotherapy with acyclovir. These 11 tumors were responsible for four deaths. No relationship has been demonstrated between type of immunosuppression and tumor development. All patients who are immunosuppressed remain at increased risk for malignant changes. Close surveillance is needed to detect tumors at an early stage.

Validation of impedance cardiography measurements of cardiac output during limited exercise in heart transplant recipients.

Twenty-one patients were studied at rest and during exercise after heart transplantation to compare cardiac output measured by thermodilution and impedance cardiography. Exercise was performed on a bicycle ergometer over a limited range of work load (25 and 50 watt) whilst metabolic gas exchange was recorded. One patient was studied at rest whilst his circulation was maintained by a Jarvik-7 artificial heart. The values of cardiac output measured by impedance cardiography corresponded closely with the flow rate from the artificial heart. There was also close agreement between the impedance and thermodilution measurements of cardiac output at rest and during exercise. Both measurements followed the changes in heart rate and oxygen consumption. Both thermodilution and impedance cardiography methods elicited good reproducibility of cardiac output measurements at rest and during exercise. These observations suggest that the noninvasive and continuous record of cardiac output obtained by impedance cardiography can be used for the postoperative monitoring of heart transplant recipients.

Management of rejection in heart transplant recipients: does moderate rejection always require treatment?

Triple-drug immunosuppression with cyclosporine, azathioprine, and steroids was introduced at Papworth Hospital in 1986. The management of rejection episodes in the first 40 patients receiving this regimen was reviewed for a minimal follow-up period of 18 months. Routine endomyocardial biopsy specimens were taken and classified into nil, minimal, mild, moderate, and severe rejection categories. Management was dependent on the biopsy result, in addition to the clinical state of the patient. In the early postoperative period (day 0 to 30) 2% of biopsy results showed severe rejection and 27% showed moderate rejection; all but one of the latter patients received augmentation of immunosuppression. In the intermediate period (days 31 to 90) severe rejection was present in 1% and moderate rejection in 36 (31%) of biopsies. Immunosuppression was augmented in 13 symptomatic patients, but in 23 asymptomatic patients additional therapy was withheld and the biopsy was repeated in 5 to 7 days. If moderate rejection was still present (11 cases), immunosuppression was augmented. Later (3 to 12 months) augmentation of immunosuppression was given on only four occasions. When the histologic criteria for diagnosis of moderate rejection are present during the early period after transplantation, we recommend augmented immunosuppression. In cases of later rejection we suggest that the decision be based on the biopsy result and the clinical condition of the patient; however, a prospective controlled trial will be required to confirm that this policy is correct.

Intensive care management of children following heart and heart-lung transplantation.

We report the intensive care management of 23 children (age 3-15 years) following orthotopic heart (HT) and combined heart and lung transplantation (HLT) performed at our 2 institutes between February 1985 and August 1989. Cyclosporin A, azathioprine and steroids were given as routine immunosuppression, whilst anti-thymocyte globulin (ATG) was used for the first 3 post-operative days. Mean ventilation time was 24.6 h (range 4-74 h). Cardiovascular support comprised isoprenaline infusions in all patients (mean period 65.7 h) whilst dopamine and other inotropic agents were used less frequently. Sequential atrioventricular pacing was required more often in the HT patients (n = 9) than in the HLT patients (n = 4). Fluid input was restricted to maintain a plasma osmolality of 290-300 mosm/kg. There were 2 perioperative deaths both due to acute right heart failure. Other post-operative complications included: bleeding (n = 3); acute graft rejection (n = 4); infection (n = 3); systemic hypertension (n = 6); neurological abnormalities (n = 2); renal dysfunction (n = 6) and hyperglycaemia (n = 6).

A comparative study of prostacyclin infusion given before and during cardiopulmonary bypass to assess the first pass effect of the circuit on platelet number and function.

Platelet damage during cardiopulmonary bypass (CPB), although proportional to the duration of bypass, may result in significant dysfunction after the initial contact with an extracorporeal circuit, the so-called 'first pass' phenomenon. The platelet sparing effect of prostacyclin (PGI2) infusion was studied in a double-blind randomized trial on male patients undergoing coronary artery bypass grafts to assess the effect of the 'first pass' through the CPB circuit. Prostacyclin infusion was begun before the onset of CPB or during CPB in two groups which were compared to a placebo control group. A standardized anaesthetic, surgical and perfusion technique were used. Preoperatively and during surgery at pre-set intervals, whole blood platelet aggregation was studied using ADP and collagen agonists. Platelet numbers and function measured by ADP aggregation were conserved in the two PGI2 groups. There was no significant difference between the treated groups. We conclude, therefore, that the initial contact of platelets with the CPB circuit, in the absence of PGI2 did not irreversibly affect platelet function. In addition, the hypotensive action of PGI2 was easier to control once on bypass. It may therefore be preferable to delay PGI2 infusion until CPB has been established.

Bacterial endocarditis in a transplanted heart.

A 51-year-old man presented with an abscess in his sternotomy scar 33 months after orthotopic heart transplantation. After surgical drainage he developed a febrile illness which led to renal and pulmonary failure. Twenty-three days after the illness began, blood cultures grew Staphylococcus aureus and he died 11 days later. Post-mortem examination revealed acute bacterial endocarditis with dense colonies of gram-positive cocci on the mitral valve leaflets and microabscesses in the myocardium of the transplanted heart.

Chronic relapsing pericarditis and dilated cardiomyopathy: serological evidence of persistent enterovirus infection.

By means of two different IgM-capture assays, enterovirus-specific IgM responses were shown in 9 of 14 (64%) patients with chronic relapsing pericarditis. This finding suggests persistent enterovirus infection, particularly coxsackie B virus infection. IgM responses persisted for at least 1 year and for up to 10 years after onset of symptoms. In contrast, patients with acute enterovirus infections, including acute pericarditis, had transient responses. Among patients with acute pericarditis, the level of IgM antibody was significantly higher in those who subsequently relapsed (mean 1.21, range 0.6-2.0 optical density [OD] units) than in those who did not (0.4, 0.2-0.9 OD units; p less than 0.01). Of 86 patients with dilated cardiomyopathy, 28 (33%) showed enterovirus-specific IgM responses which were present for up to 19 months before transplantation and persisted up to 4 years afterwards. Although the distribution of HLA types in these patients was similar to that in the general population, the frequency of the HLA A2 haplotype was significantly higher in those who were IgM positive. IgM antibody was significantly more common in those who had had symptoms for longer than a year before transplantation than in those with a shorter duration of symptoms (1 of 21 vs 8 of 23; p less than 0.02). Persistent virus-specific serum IgA responses were also shown in patients with chronic cardiac disease.

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.

Heart and heart-lung transplantation, Papworth Hospital, 1979-1989.

The quality of life for those who survive the first 3 months after transplantation is generally good (10). The duration of hospital stay and the cost of transplantation per patient has been reduced during the last 3 years. Cardiologists are coming to appreciate the therapeutic potential of both heart and heart-lung transplantation. One of the chief logistical problems now being faced is that of increasing the provision of transplant services to match the increasing demand. It was said in an earlier edition of this book that this would be donor organ limited and that pattern already seen in the United States is becoming apparent in the United Kingdom. The broad principles of management of heart and heart-lung recipients have been established. Further improvements in medium and long-term results can be anticipated as a result of refining immunosuppression and defining the cause of chronic donor organ related damage (small vessel coronary occlusive disease in heart transplants and chronic obliterative bronchiolitis in heart-lung transplants). Heart transplantation has become firmly established as a therapeutic option for life threatening heart disease. It is probably too early to attribute this label to heart-lung transplantation which continues through its developmental phase with acceptable short-term results. Improvements in chronic damage characteristic of long-term survival in both heart and heart-lung transplant recipients will be a significant clinical step forward in this field.