Effect of pharmacologic immunosuppression on donor heart survival in a closely related nonhuman primate xenograft model.
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Biomedical subjects
Publications and source records attributed to B Reichart.
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Between September 1984 and June 1988, 46 patients (8 traumatic rupture, 10 acute and 11 chronic dissection, 17 true aneurysms) with lesions of the thoracic aorta were managed surgically. Four patients died after surgery for acute dissection, 2 after management of chronic aneurysm and 1 after replacement of the descending aorta for a chronic degenerative aneurysm. In 2 patients the operation was complicated by paraplegia.
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Between December, 1967 and August, 1988, 147 heart transplants (64 orthotopic, 68 heterotopic procedures; 15 heart-and-lung replacements) were performed on 128 patients. In the majority of the recipients, dilated cardiomyopathy or end-stage ischaemic heart disease was diagnosed. From 1985 to the present, 70 transplants (45 orthotopic, 11 heterotopic and 14 heart-lung) took place. Seventeen of these patients (mean age 46.6 years) suffered from end-stage disabling (NYHA IV) coronary artery disease; in each case the angiogram verified severe stenosis or occlusion of the three main coronary artery systems. Their histories revealed a total of 22 previous myocardial infarctions; 8 patients needed a total of 9 surgical revascularization procedures. The left ventricular ejection fraction (LVEF) ranged from 9% to 24% (mean 15.3%). Before transplantation three patients required intraaortic balloon pump (IABP) support. Fourteen of the 17 patients are at present still alive with post operative periods ranging from 8 weeks to 3.5 years (the actuarial 90-days and 1-year-survival rates being respectively 91.7% and 81.5%). Twelve of the patients are in NYHA class I; 2 are in class II. Three late deaths occurred: one from pneumocystic carinii/cytomegalovirus pneumonia, a second from atypical pneumonia and a third from chronic graft rejection. Radionuclide ventricular studies demonstrated postoperative left ventricular ejection fractions ranging from 54%-81% (mean 71%).(ABSTRACT TRUNCATED AT 250 WORDS)
A reliable method has been developed to produce stenosis of the right coronary artery of baboons as a consequence of electrostimulation of the vessel at a chosen position. At that site a pair of electrodes were implanted and activated with a train of 9-volt pulses (length: 10 ms, separation: 100 ms) for 30 min, 5 days/week, up to 6 weeks. 13 animals were included in the experiment, 2 of those served as controls. Pathohistologically the structure of the artificially produced constrictions is similar to atherosclerotic lesions. On average the stenoses occupied 55% of the available lumen; total occlusion and no stenosis were observed in 1 case each.
Adenosine is a potential cardioplegic agent by virtue of its specific inhibitory properties on nodal tissue. We tested the hypothesis that adenosine could be more effective than potassium in inducing rapid cardiac arrest and enhancing postischemic hemodynamic recovery. Isolated rat hearts were perfused with Krebs-Henseleit buffer or cardioplegic solutions to determine the time to cardiac arrest and the high-energy phosphate levels at the end of cardioplegia. Cardioplegic solutions contained adenosine 10 mmol/L, potassium 20 mmol/L, or adenosine 10 mmol/L + potassium 20 mmol/L and were infused at a rate of 2 ml/min for 3 minutes at 10 degrees C. Both time taken and total number of beats to cardiac arrest during 3 minutes of cardioplegia were reduced by adenosine 10 mmol/L and adenosine 10 mmol/L + potassium 20 mmol/L when compared with potassium 20 mmol/L alone (p less than 0.001). Tissue phosphocreatine was conserved by adenosine 10 mmol/L when compared with potassium 20 mmol/L, being 7.1 +/- 0.2 (mumol/gm wet weight (n = 7) and 6.0 +/- 0.3 mumol/gm wet weight (n = 5), respectively (p less than 0.05). Postischemic hemodynamic recovery was tested in isolated working rat hearts. After initial cardiac arrest, the cardioplegic solution was removed with Krebs-Henseleit buffer at a rate of 2 ml/min for 3 minutes at 10 degrees C, and thereafter total ischemia was maintained for 30 or 90 minutes at 10 degrees C before reperfusion. Adenosine 10 mmol/L enhanced recovery of aortic output when compared with potassium 20 mmol/L or adenosine 10 mmol/L + potassium 20 mmol/L, the percentage recovery after 30 minutes of ischemia being 103.0% +/- 4.4% (n = 6), 89.0% +/- 5.8% (n = 6), and 86.6% +/- 4.3% (n = 6), respectively (p less than 0.05 for comparison between adenosine 10 mmol/L and potassium 20 mmol/L). Thus adenosine cardioplegia caused rapid cardiac arrest and improved postischemic recovery when compared with potassium cardioplegia and with a combination of these two agents.
The role of ABO blood group compatibility on graft survival when transplantation is performed between closely related animal species is uncertain. Heart transplants (in the neck) were performed between donor vervet monkeys and recipient baboons; no immunosuppressive therapy was given. Survival in ABO-compatible pairs (group 1, n = 9) was for a mean of 10.3 (+/- 5.2) days, which was not significantly different from that in ABO-incompatible pairs (group 2, n = 9: mean survival 7.3 +/- 5.6 days). In group 2, however, three hearts were rejected hyperacutely within 60 minutes, whereas in group 1 only one heart was rejected within 24 hours (not significant). Preformed anti-vervet monkey antibody was present in only one of 18 baboons, but developed in eight others. ABO-specific antibodies were present in all nine group 2 baboons and increased in titer in six cases. Histopathologic features of vascular (humoral) rejection, sometimes associated with cellular infiltration, were seen in a majority of hearts in both groups. Though the number of animals in this study was small, ABO-incompatibility would not appear to be a major factor in cardiac xenograft survival when transplantation is performed between closely related primate species, though early hyperacute rejection would seem more likely to occur when blood group incompatibility is present.
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27 patients who underwent heart transplantation one to five years ago, were evaluated concerning psychological and social adjustment after heart transplantation. Prior to cardiac transplantation, predictors for good rehabilitation status were absence of psychopathology, clear motivation, good social background, advanced physical debility (being bedridden as opposed to ambulatory), absence of a history of excessive alcohol consumption. Age was not found to be a predictor of outcome. Criteria for good rehabilitation status after cardiac transplantation were absence of psychopathology, good compliance, social reintegration, return to work, psychological well-being, satisfaction with the quality of life and good exercise capacity. The criteria for good rehabilitation correlate positively with the predictors specified and with each other. Psychopathology after cardiac transplantation was related to psychopathology prior to the intervention, motivation, social background, postoperative compliance, social reintegration, return to work, psychological well-being and satisfaction with the quality of life. Compliance was related with the predictors motivation, social background, history of excessive alcohol consumption, psychopathology after transplantation and return to work. Social reintegration was correlated with social background and post-transplantation psychopathology. Return to work was related to motivation, post-transplantation psychopathology and compliance. While physical well-being was not associated with the predictors except motivation, it was related to the rehabilitation factors of post-transplantation psychopathology, social reintegration, and return to work. Satisfaction with the quality of life correlated with only the rehabilitation factors of post-transplantation psychopathology and psychological well-being. Physical exercise capacity was related to psychological well-being after transplantation.
A patient with a ruptured heart as a result of severe blunt trauma is described. There was also a false angiographic appearance of a ruptured aorta due to a ductal diverticulum. The association of aortic and cardiac rupture is discussed.
Twenty-one neonates and infants less than 3 months old undergoing cardiac surgery for an obstructed right ventricular outflow tract, intact ventricular septum and a small or hypoplastic right ventricle were retrospectively analyzed, in order to assess the effects of a change in management protocol. Seven of the 8 patients with critical pulmonary stenosis survived surgery using a transannular outflow patch, whereas only 1 of the 8 patients with pulmonary atresia survived the same operation. Two patients in the latter group died 2 and 3 months after surgery but with complications arising from surgery. Of 5 patients with pulmonary atresia who had a modified Blalock Taussig shunt, 3 patients survived the surgery and were discharged home. These results significantly indicate that there is an unacceptably high mortality for the relief of pulmonary atresia (with intact septum) using a transannular outflow patch, and a Blalock Taussig shunt is the preferred operation. The transannular outflow patch is a safe operation for neonates with critical pulmonary stenosis, irrespective of the size of the right ventricle.
Seven baboons underwent autotransplantation of the heart or heart and both lungs (group A). Eleven allografts were performed (group B) (nine orthotopic heart transplants and two en bloc transplants of the heart and both lungs). Radionuclide ventriculography was performed both pretransplant and at intervals posttransplant in all animals, and provided measurements of ejection fraction (EF) and left ventricular volumes (LVv) (end-diastolic volume [EDV], end-systolic volume [ESV], and stroke volume [SV]). In seven animals, a total of 20 endomyocardial biopsies were taken. Correlation was made between histopathological features of acute rejection seen on endomyocardial biopsy and changes in EF and LVv measured by radionuclide imaging. A significant increase of 12% in the EF (P less than 0.01) and significant falls in the LVv were observed in all animals (groups A and B) on the first posttransplant day, presumably a result of total cardiac denervation. EDV was reduced by 50% (P less than 0.005), ESV by 62% (P less than 0.0001), and SV by 43% (P less than 0.0001). In autografted baboons (group A) EF and LVv showed no further changes until reinnervation of the heart had occurred, when they reverted to pretransplant levels. In the allografted baboons (group B) further significant reductions in the LVv occurred as acute cardiac rejection progressed. From the first post-transplant day to the time of the final study before the animals' death, the EF decreased by 10% (P less than 0.01), the EDV by 38% (P less than 0.005), and SV by 73% (P less than 0.003): the decrease in ESV did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)
Heart transplantation is, today, an accepted and recommended modality in the management of selected patients suffering from terminal heart disease. However, acute rejection and infection remain the major complications of this operation. Serial endomyocardial biopsy (EB), considered as the standard for diagnosis of cardiac rejection, is an invasive and delicate operation, not free of complications, even when done by skilled personnel in specialized centers. The object of this study was to compare and correlate between radionuclide ventriculography (RNV) and the histologic findings of EB. Furthermore, to validate the use of nuclear cardiology techniques that allow noninvasive, reliable, and rapid quantitation of ventricular function and myocardial perfusion for the diagnosis and management of rejection in patients with heart transplants. Radionuclide studies of left ventricular function were performed in 3 heterotopic heart transplant patients (HHT) with long term survival and early after the operation in 5 patients with HHT, 12 orthotopic heart transplants (OHT) and in 2 heart and lung transplants (HLT). Simultaneous EBs were performed in the early posttransplant patients and a histologic score for acute rejection was obtained. First pass (FP) and multigated equilibrium blood pool ventriculography, using the in vivo 99mTc-labelling of RBCs was used to measure left ventricular volumes (LVV) such as stroke volume (SV), end-diastolic volume (EDV), end-systolic volume (ESV), and both global and regional ejection fraction (EF, REF). The histological grading of acute rejection was classified into four groups: (1) no rejection, (2) mild rejection, (3) moderate rejection, and (4) severe rejection. The median of each LVV parameter was calculated and correlated with the EB using a nonparametric one way analysis of variance. A percentage change of LVVs was used rather than the difference of the calculated LVVs. During moderate acute rejection, SV had the highest correlation in P less than 0.004, followed by the EDV (P less than 0.05), and finally ESV (P less than 0.02). During severe acute rejection the correlation was SV (P less than 0.0008), EDV (P less than 0.001), and ESV (P less than 0.006). Myocardial perfusion scintigraphy using 201T1 was performed in the HHT patients, although, at this stage we have not attempted a correlation with the histologic findings. In one patient with long term survival OHT, increased 131I-metaiodobenzylguanidine (MIBG) myocardial uptake was evident during a rejection episode.
Between February 1983 and July 1987, twelve patients underwent heart-lung transplantation at the University of Cape Town and the University of Munich. The patients included eight men and four women, whose ages ranged from 15 to 49 years (mean, 27 years). The underlying pathologic condition was idiopathic primary pulmonary hypertension in five cases, Eisenmenger's syndrome in four cases, idiopathic pulmonary fibrosis in one case, diffuse fibrosing alveolitis in one case, and chronic emphysema in one case. The immunosuppressive regimen consisted of cyclosporine A, azathioprine, and rabbit antithymocyte globulin (RATG) during the first 2 postoperative weeks; RATG was subsequently replaced by methylprednisolone. Pulmonary rejection frequently occurred in the absence of cardiac rejection; in one case, however, this situation was reversed. Two patients required retransplantation, which was undertaken for caseating pulmonary tuberculosis with obliterative bronchiolitis after 1 year in one case and for early pulmonary insufficiency after 2 days in the other case. There were no operative deaths, but three early deaths occurred, owing to respiratory insufficiency of unknown origin (10 days postoperatively), multiorgan failure (10 days postoperatively), and acute liver dystrophy (11 days postoperatively). Five weeks after operation, a fourth patient died of multi-organ failure. There were five late deaths, all of which resulted from infectious complications. Three patients, including one who underwent retransplantation, remain alive and well, 10 to 36 months postoperatively.
Between August 1981 and February 1987, 67 orthotopic heart transplants and three heart-lung transplants were performed in 69 patients at the University of Munich Hospital. The immunosuppressive regimen consisted of cyclosporine A, azathioprine, and prednisone. The diagnosis of acute rejection was based on cytoimmunologic monitoring, frequency analysis of fast Fourier transformed surface electrocardiograms (FFT-ECGs), and two-dimensional echocardiography. The results of these diagnostic methods were compared to the findings provided by endomyocardial biopsies, which were performed simultaneously with the noninvasive studies. Seventy patients underwent cytoimmunologic monitoring. In 88% of all rejection episodes, this technique revealed activated lymphocytes and lymphoblasts in the mononuclear concentrate of the peripheral blood samples; the presence of such cells is known to be an extremely early sign of acute rejection. Twenty-six patients were monitored by means of FFT-ECG. In 20 of the 21 cases of rejection, this method disclosed significant changes in the frequency spectrum of the QRS complex in the 70- to 110-Hz range; in 12 cases, these changes were the earliest sign of acute rejection. Therefore, FFT-ECG had a sensitivity of 95%. All of the QRS changes were reversible with rejection therapy. Forty-five patients were subjected to two-dimensional echocardiography. In 31 of the 35 cases of rejection, the echocardiogram showed a significant increase in the left ventricular wall thickness and a decrease in the left ventricular cross-sectional area during mild rejection. Moderate or severe rejection was characterized by an increase in the diastolic area, as well as a decrease in the systolic area change and in the diastolic maximum velocity of area change. Thus, two-dimensional echocardiography had a sensitivity of 89%. In the recent cases, the diagnosis of rejection was based on noninvasive methods alone. After rejection therapy had been instituted, endomyocardial biopsies were performed to assess the effectiveness of the treatment. With noninvasive rejection monitoring, the number of endomyocardial biopsies performed during the first three postoperative months was only 2.8 per patient; in comparison with invasive rejection monitoring, noninvasive follow-up was associated with a 75% reduction in the need for biopsy.
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Systemic and pulmonary hemodynamics were studied in two groups of Chacma baboons following the induction of brain death. Group A was a control group of 11 animals who underwent brain death. They showed significant increments of mean systemic arterial, left atrial, and pulmonary arterial pressures; of systemic vascular resistance, heart rate, and pulmonary artery blood flow; and a reduction in aortic blood flow during the induction of brain death. As a result of increased sympathetic nervous system activity, areas of myocardial cell necrosis occurred in 73% of the animals and pulmonary edema in 36%. Group B consisted of five animals that were pretreated with verapamil hydrochloride infused over a period of 30 minutes prior to the induction of brain death (mean dosage, 0.26 mg/kg). Except for a rise in heart rate, no significant changes occurred in systemic or pulmonary hemodynamics, and no myocardial or pulmonary histopathological changes were seen. These findings would indicate that verapamil hydrochloride prevents both the peripheral and central hemodynamic changes that result from increased sympathetic activity associated with the induction of brain death, and thus prevents myocardial structural damage, which may be associated with increased calcium uptake by the myocyte.