Initial experience with FK 506 as an immunosuppressant for nonhuman primate recipients of cardiac allografts.
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Biomedical subjects
Publications and source records attributed to M Billingham.
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Hypertension and cardiomyopathy are prominent findings in humans and rats harboring pheochromocytomas, tumors that can secrete enormous quantities of catecholamines. We have previously found that alpha- and beta-adrenergic receptor antagonists may ameliorate the hypertension and cardiomyopathy found in New England Deaconess Hospital rats implanted with pheochromocytoma. The present studies were designed to determine the possible action of the angiotensin converting enzyme inhibitor captopril on these changes in rats harboring pheochromocytomas. Rats were implanted with transplantable pheochromocytomas and treated with captopril dissolved in the drinking water (1 mg/ml) for 4-6 weeks. Systolic blood pressure was monitored by using the tail-cuff technique. In the rats with pheochromocytoma, blood pressure progressively increased to 184 +/- 3 mm Hg after the tumor was implanted. However, in rats with pheochromocytoma treated with captopril in the drinking water before the development of hypertension, blood pressure did not increase (137 +/- 3 mm Hg). In rats with pheochromocytoma with established hypertension, captopril normalized the systolic blood pressure. Plasma norepinephrine was markedly elevated to a similar extent in both groups compared with unimplanted control rats. Plasma renin activities were slightly lower in rats with pheochromocytoma compared with unimplanted control rats. Treatment with captopril of rats with pheochromocytoma did not modify contraction of isolated rings of thoracic aorta exposed in vitro to either phenylephrine or angiotensin II. Treatment with captopril markedly attenuated the cardiomyopathy induced by pheochromocytoma. These results demonstrate that captopril prevents the development of hypertension despite markedly elevated concentrations of catecholamines. In addition, captopril attenuates catecholamine-induced cardiomyopathy in pheochromocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)
We describe the findings at autopsy in a patient who underwent Rotablator atherectomy of the right coronary artery. During the procedure, the artery became occluded. Despite attempts to reopen the vessel with balloon angioplasty and emergency coronary artery bypass grafting, the patient developed irreversible cardiac failure and expired 2 days after the Rotablator procedure. At autopsy, the right coronary artery was found to be occluded by thrombus. No evidence of dissection or perforation of the vessel wall was seen. Small intramyocardial arteries and arterioles, downstream from the treated vessel, were embolized by pulverized atheroma.
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The automatic implantable cardioverter/defibrillator is tested intraoperatively to ensure effectiveness by performing a number of induced fibrillation-defibrillation trials. The temporal stability of defibrillation energy requirements and the histopathologic effects of multiple defibrillating shocks were studied in 12 dogs chronically instrumented with an internal spring-patch lead system identical to that used in humans. Dogs were studied on days 1, 11, 18, 25 and 32. Data were analyzed by logistic regression and the energy required for 50% (E50) and 80% (E80) success was compared. On day 32 the dogs were killed and the heart was removed for gross and microscopic pathologic examination. There was a significant decrease in energy requirements from day 1 to day 11, as the E50 decreased from 6.9 +/- 4.5 to 4.9 +/- 2.5 J (p less than 0.02) and the E80 decreased from 8.5 +/- 5.2 to 6.1 +/- 3.4 J (p less than 0.02). The energy requirements then remained stable over the remainder of the experiment. The dogs were administered 209 +/- 18 shocks (range 1 to 24 J) for a total cumulative dose of 1,524 +/- 571 J. In all cases, both grossly and microscopically, there was no evidence of pathologic changes in the myocardium or coronary vessels. In all cases there was a fibrous plaque beneath the patch electrodes, at times containing an area of patchy hemorrhage; in a single specimen a mixed inflammatory infiltrate accompanied the hemorrhage. Endothelialization of the spring electrode with mild right atrial endocardial fibrosis was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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Diagnosis of rejection after cardiac transplantation is currently made by right ventricular endomyocardial biopsy. To evaluate antimyosin imaging as a noninvasive means of detecting human cardiac rejection, the Fab fragment of murine monoclonal antimyosin antibodies was labeled with indium-111 and given intravenously to 18 patients (age 45 +/- 12 years) in 20 studies 7 days to 9 years after transplantation. Endomyocardial biopsy specimens were obtained at the time of each imaging study. Eight patients had positive scans confirmed by biopsy as rejection, and eight patients had negative scans and no evidence of rejection on biopsy. Discordance was observed in four studies, two with positive scans and no rejection on biopsy and two with negative scans and positive biopsy. The sensitivity, specificity, and overall accuracy of the technique were each 80%. Imaging with radiolabeled antimyosin antibody Fab fragments may be of value in the noninvasive identification of rejection in the cardiac transplant recipient.
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A new noncatheter method for measuring pressures of the right side of the heart uses specially manufactured microbubbles of carbon dioxide injected into the peripheral venous system. Sudden expansion of these bubbles in the cardiac chambers causes bubble oscillations at a frequency that is primarily a function of surrounding pressure. The oscillations are recordable by a microphone on the chest wall. The preliminary experience has been in dogs and further development is needed before we can begin clinical testing of the method. In its current form, the potential for measuring higher systolic pressures seems better than that for lower diastolic pressures.
The necessity for conscious animal models in the study of cardiac physiology has been established for hemodynamics. The characterization of the electrophysiologic properties of the heart has not been performed in a serial fashion in a conscious animal model. Implanted telemetry sensing devices for recording atrial, ventricular, and His electrograms and stimulation systems for both atrium and ventricle allowed serial evaluation of eight dogs for up to 4 months. There were significant fluctuations in some electrophysiologic variables with time, particularly heart rate, sinus node recovery time, and pacing rate for induction of Wenckebach block. This variability did not appear to deviate with time after implantation, and no significant differences in the basal electrophysiologic state were found between the period early after surgery (0 to 2 1/2 weeks) and later (3 to 8 weeks).
Seventeen patients received combined heart and lung transplants at Stanford University between March 1981 and December 1983. All recipients were suffering from end-stage pulmonary hypertension. Five patients died within the first few postoperative weeks, but the remainder were well between 2 and 35 months after operation. Immunosuppression consisted of cyclosporine with an initial course of rabbit antithymocyte globulin, and azathioprine was given for the first 2 postoperative weeks. Maintenance immunosuppression was achieved with cyclosporine and prednisone. Rejection, as diagnosed by cardiac biopsy, was treated with intravenous methylprednisolone. The functional status of the survivors has been good, and upon discharge from the hospital, all returned to normal activity. Our preliminary experience indicates that cardiopulmonary transplantation represents a realistic therapeutic approach for patients with end-stage pulmonary disease.
Combined heart and lung transplantation was carried out in thirteen patients at Stanford University between March 1981 and May 1983. The recipients were between 22 and 45 years old. All patients were suffering from end-stage pulmonary hypertension; nine patients had Eisenmenger's syndrome; the remaining four were transplanted for primary pulmonary hypertension. Three patients died within one month of surgery. The remainder are well at between 22 months and three weeks from operation. The duration of stay in the hospital for the surviving patients ranged from 38 to 85 days. The immunosuppressive protocol has been essentially the same for all recipients, and has consisted of cyclosporine with an initial course of rabbit antithymocyte globulin (RATG) with azathioprine given for the first two weeks, and then replaced with prednisone. Rejection, as diagnosed by cardiac biopsy, was treated with pulses of methylprednisolone. Early complications included bleeding that necessitated reexploration (five patients); damage to the vagus, recurrent laryngeal, or phrenic nerves (three patients); and failure of the donor lungs (one patient). Modifications of technique that have developed include removal of the recipient heart and lungs separately, and preservation of the lungs with a modified Collins' solution instead of a cardioplegic solution. The results of this operation are considerably superior to clinical efforts in lung transplantation. The combined operation may be preferable for the following reasons: All diseased tissue is removed, thus eliminating recurrent infection, and also perfusion/ventilation disparity. Transplantation of the entire heart and lung block preserves coronary-tracheal vascular anastomoses and makes airway dehiscence less likely. Diagnosis of rejection by cardiac biopsy seems to be a satisfactory method of diagnosis and treatment of pulmonary rejection.
A fatal myocardial infarction in a 22-year-old man with hemophilia A and a factor VIII inhibitor is described. The catastrophic event occurred while the patient was receiving high doses of unactivated prothrombin complex concentrates. Autopsy examination revealed myocardial hemorrhage with no evidence of coronary artery disease or thrombosis. There also was postmortem evidence of previous myocardial infarctions. This is the fourth documented case of myocardial infarction occurring in a young hemophiliac patient using unactivated prothrombin complex concentrates. It is concluded that utilization of prothrombin complex concentrates in hemophiliac patients must be limited and closely monitored. Therapeutic guidelines are recommended.
Combined heart and lung transplantation was carried out in ten patients at Stanford University Medical Center between March, 1981, and December, 1982. All patients had end-stage pulmonary hypertension. 7 of them had Eisenmenger's syndrome and 3 primary pulmonary hypertension. 3 patients died within a month of operation, but the remaining recipients are well 2 months to 2 years after transplantation. The hospital stay of the survivors ranged from 38 to 85 days. All survivors have returned to normal activity. The results of heart and lung transplantation have thus been considerably superior to those reported previously for lung transplantation. It is suggested that cardiopulmonary replacement is suitable treatment for end-stage pulmonary hypertension with or without associated congenital heart disease and that its application to other forms of advanced pulmonary failure may be warranted.
Rest myocardial 201T1 scintigraphy was undertaken in 15 males mean age 39 years (22-54) who had been accepted for cardiac transplantation. Complete pathological correlation was obtained in 14 after transplantation and in 1 who died before a suitable donor heart became available. The average time from scintigraphy to pathological evaluation was 42 days (9-103). All the 201T1 images were grossly abnormal and on the basis of these studies it was not possible to differentiate ischemic from idiopathic cardiomyopathy. Each of the three views of the 201T1 study was divided into three segments, therefore 135 areas were available for comparison (3 x 3 x 15). Eighty-eight of these were abnormal on scan and 78 of these were abnormal pathologically. The right ventricle was seen on all rest images but the degree of uptake bore no relationship to the measured thickness of the right ventricular wall. Structures such as the atrial wall and the enlarged papillary muscle were visualized in some patients. In two patients there was an improvement of the rest 201T1 image in delayed views and histologically these areas showed a mixture of muscle and fibrous tissue. The sensitivity of 201T1 imaging in this study was 89% and there was close correlation of the images with gross and microscopic pathological findings.
The arrhythmogenic and inotropic effects of digoxin were studied in normokalemic controls, chronically hypokalaemic, and potassium-repleted dogs instrumented to maintain heart rate, mean aortic pressure, mean left atrial pressure and autonomic tone constant. The duration of digoxin infusion needed to produce ventricular tachycardia (VT) was 56.7 +/- 3.6 min in depleted dogs, 69.0 +/- 2.7 min in controls (P less than 0.005 compared with depleted dogs), and 60.5 +/- 3.0 min in repleted dogs. Baseline left ventricular dP/dt (LV dP/dt) was similar in all groups. After digoxin, LV dP/dt increased more in controls and repleted dogs than in chronically hypokalaemic dogs; eg, after 45 min of digoxin infusion LV dP/dt increased 12.7 +/- 4.4% in hypokalaemic dogs; eg, after 45 min of digoxin infusion LV dP/dt increased 12.7 +/- 4.4% in hypokalaemic dogs, 43.8 +/- 3.3% in controls (P less than 0.025) and 39.3 +/- 8.5% in repleted dogs (P less than 0.025). The inotropic response to isoprenaline was also attenuated in the chronically hypokalaemic dogs. Plasma digoxin was similar in all groups. LV digoxin was also similar in control and depleted dogs. Although inhibition of Na+, K+-ATPase and the initial velocity of 3[H]-ouabain specific binding was less in depleted dogs at VT than in controls (P less than 0.05), the magnitude of this difference was not sufficient to explain the attenuated inotropic response. No histological abnormalities were seen on light or electron microscopy in any of the groups. Therefore chronic hypokalaemia has two deleterous effects. It increases sensitivity to the arrhythmogenic effects of digoxin and impairs the inotropic response to digoxin, and isoprenaline.