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Biomedical subjects

M E Billingham

Publications and source records attributed to M E Billingham.

At least 253 records · Page 14Linked to original sources
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Features of mildly dilated congestive cardiomyopathy compared with idiopathic restrictive cardiomyopathy and typical dilated cardiomyopathy.

Congestive cardiomyopathy was recognized in eight patients with only mildly dilated ventricles (an echocardiographic ventricular diastolic dimension index of less than 10% to 15% above the normal range) but with other features typical of end-stage congestive cardiomyopathy. Such patients with mildly dilated cardiomyopathy (MDCM) represented 5% of heart transplant recipients with cardiomyopathy, who were analyzed by us. The clinical, echocardiographic, and hemodynamic data, as well as the gross and microscopic pathologic findings of the hearts in this group were compared with similar data in five patients with idiopathic restrictive cardiomyopathy (IRCM) and 10 patients with typical dilated cardiomyopathy (DCM). Compared with IRCM and DCM, patients with MDCM had a higher incidence of familial cardiomyopathy (p less than 0.009). The echocardiographic features of patients with MDCM and DCM were virtually identical, showing globular hearts with predominant left ventricular dilation and diffuse poor left ventricular contraction. Patients with IRCM had marked atrial dilation but less abnormality of left ventricular size and contraction parameters. On the basis of echocardiographic data, patients with IRCM and MDCM could be well segregated. Cardiac index and light microscopic examinations were similar in the three groups. However, electron microscopy showed a lack of myofibrillar loss in patients with IRCM, little or no myofibrillar loss in those with MDCM, and almost total myofibrillar loss in those with DCM. Patients with MDCM have a high prevalence of familial cardiomyopathy. Absolute heart size and electron microscopic features of the MDCM group were intermediate between IRCM and DCM, but other clinical, echocardiographic and hemodynamic findings were similar to typical DCM.

Adolescent↗
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Acute and chronic cardiovascular effects of doxorubicin in the dog: the cardiovascular pharmacology of drug-induced histamine release.

We evaluated the acute hemodynamic effects of doxorubicin in the open-chest dog. Doxorubicin at doses of 1-4 mg/kg administered over 2 min produced profound hemodynamic changes that were similar to those produced by histamine. These changes persisted despite administering the drug as a slow infusion. Histamine release in peripheral tissues was documented by a marked increase in venous histamine levels following doxorubicin administration. The heart extracted histamine during a period when arterial levels were increased, as indicated by consistently low coronary sinus/aortic ratios. Secondary catecholamine release occurred in response to histamine and histamine-mediated hemodynamic effects. Immunoreactive prostaglandins E and F were increased in coronary sinus blood beginning 30 min after the initiation of a continuous infusion of doxorubicin, and increased slowly thereafter. H1- and H2-receptor blockade with diphenhydramine and cimetidine prevented the early (2-30 min postinfusion) effects of doxorubicin, and combined histaminergic and adrenergic blockade prevented the late effects. A dose of doxorubicin (1 mg/kg) that released histamine and catecholamines produced primary cardiac effects acutely and a cardiomyopathy when administered chronically. The release of vasoactive substances could be part of the pathogenetic mechanism of anthracycline cardiomyopathy.

Animals↗
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Mediation of subacute anthracycline cardiotoxicity in rabbits by cardiac histamine release.

We tested the hypothesis that cardiac histamine release mediates subacute doxorubicin (DXR) cardiotoxicity in rabbits. New Zealand white rabbits given DXR 20 mg/kg i.v. over 30 min developed myocardial damage 24 h later that was similar to that observed in humans. In isolated heart preparations, DXR produced dose-related cardiac histamine release at DXR concentrations of 1, 5, and 25 micrograms/ml given as 1-min exposures. Prior exposure of isolated hearts to 10 microM cromolyn sodium completely prevented histamine release from 5 micrograms/ml DXR. Pretreatment of animals with cromolyn produced significant protection against DXR-mediated subacute cardiotoxicity. We conclude that the release of cardiac histamine may be involved in the pathogenesis of anthracycline cardiotoxicity.

Animals↗
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The cytodiagnosis of malignant lymphomas and Hodgkin's disease in cerebrospinal, pleural and ascitic fluids.

One hundred twenty-six fluids from 98 patients with malignant lymphomas have been examined cytologically. The overall accuracy was 88 per cent with only one false positive in 126 fluids. False negatives were highest in the cerebrospinal fluid, which may reflect poor exfoliation of malignant lymphoma cells when the leptomeninges are involved. We have found exfoliative cytology to be an accurate method of diagnosing lymphomatous involvement of the leptomeninges, pleura and peritoneum and when a cytologic diagnosis of involvement by lymphoma is made it is almost as accurate as a histologic diagnosis. Nuclear characteristics and selected histochemical methods will allow classification of many types of lymphoma in bytologic preparations.

Ascitic Fluid↗
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Sustained myocardial hypertrophy seven years or more after heart transplantation: a morphometric study of endomyocardial specimens.

Myocyte hypertrophy is typical in transplanted hearts at 3 years. Because chronic hypertrophy may, if severe enough, increase the risk of infarction or gradual heart failure, our goal was to document the time course of its development and to look for signs of cellular changes in long-term survivors. We used light microscopic morphometry to estimate myocyte width in right ventricular endomyocardial biopsy specimens taken from 18 patients 1 week, 1 year, and 7 years after transplantation, and we used electron microscopic morphometry to estimate myocyte myofibril volume fractions and myocardial blood vessel length per unit volume in 10 patients at 7 to 12 years. Controls were pretransplant right ventricular biopsy specimens from 10 disease-free donor hearts. Myocyte width at 1 week (mean, 21.4 microns; SD, 2.7) was significantly greater than control (11.8, 2.2, p less than 0.01). By 1 year there was a small but significant regression (19.1, 2.4, p less than 0.05), but there was no significant change between 1 and 7 years (20.2, 2.5). Myocardial blood vessel length per unit volume at 7 to 12 years (1128 mm/mm3; SD, 259) was not significantly different from controls (1355, 298); myofibril volume fraction, however, (0.43, 0.04) was significantly lower than in controls (0.48, 0.03, p less than 0.01) but was not lower than in a different group of transplant patients studied previously at 3 years (41.4, 0.03). Myocyte hypertrophy occurs immediately after transplantation and is maintained indefinitely, with normal myocardial vascularity. There is a small reduction of myofibril content, which appears to be stable in long-term survivors.

Biopsy↗
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Assessment of cardiac allograft rejection with electrophysiology of the conduction system and histopathology of the ventricle.

Correlation between the effective refractory period of the conduction system and the histopathologic grade of the ventricle was examined in the rat cardiac allograft during acute rejection. Lewis rats were recipients of intraabdominal heart grafts from brown Norway rats (allogeneic group, n = 42) or Lewis rats (syngeneic group, n = 15). No immunosuppressant was given. The effective refractory period of the conduction system was measured by the programmed atrial extrastimulus method (basic cycle length, 150 msec) just before the time of death. Specimens of the transplanted hearts were examined histopathologically and the histopathologic grade of rejection was scored according to the standardized grading system of the International Society for Heart and Lung Transplantation. The effective refractory period of the allogeneic heart was significantly longer starting on the third day after transplantation (p less than 0.01). The effective refractory period of the allogeneic heart was more prolonged as the severity of rejection increased. The correlation between the effective refractory period (Y) and the histopathologic grade (X) of the allogeneic group was statistically significant (r = 0.955; Y = 10.3X + 81.0; p less than 0.01). The effective refractory period of all syngeneic hearts and allogeneic hearts of postoperative day 1 and 2 were statistically equivalent to the period of native rat hearts (81.0 +/- 2.0 msec; n = 6). The histopathologic grade of the conduction system was the same as that of the ventricle. We conclude that the effective refractory period of the conduction system could be a useful measure to predict the histopathologic grade of cardiac allograft rejection.

Abdomen↗
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Bovine pericardial valves. Nine-year clinical experience with the Novacor left ventricular assist system.

The Novacor electrically powered left ventricular assist system (LVAS), currently used in a bridge-to-transplant (BTT) clinical trial, incorporates bovine pericardial (BP) valves (Edwards CVS Division, Baxter Healthcare Corporation). In preclinical evaluation in the adult sheep, BP valves exhibited severe calcific stenosis as early as 8 weeks postimplant (longest implant 158 days, elective termination for calcific deposit). The clinical experience, however, has been in sharp contrast. Eighty-one patients have been supported for a cumulative duration of 9.1 years (two currently on LVAS). Thirty-five (43%) patients were supported for longer than 30 days, and of these, 29 (85%) were transplanted. The longest implant duration was 370 days (alive, 8 months posttransplant). There was no evidence of calcific degeneration of these valves for durations to 370 days. These results are encouraging for ultimate chronic clinical application.

Animals↗
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Effects of fish oil on graft arteriosclerosis and MHC class II antigen expression in rat heterotopic cardiac allografts.

The effect of fish oil on accelerated graft coronary arteriosclerosis was assessed in Lewis to Brown-Norway rat heterotopic cardiac allografts. Twelve Brown-Norway rats were supplemented with 2 ml/kg/day of fish oil (68.3 mg eicosopentaenoic acid and 47.5 mg decosahexaenoic acid per milliliter). Eleven additional animals, receiving an isocaloric amount of safflower oil, served as control. All diets began 1 week before operation. Immunosuppression was obtained with low-dose cyclosporine (2 mg/kg/d). When killed (100 days), there were no significant differences in percentage weight gain, graft function, or histologic rejection score. Although lipid profiles were comparable, total cholesterol:high-density lipoprotein ratio was marginally higher in animals treated with fish oil (p = 0.069). Mean percentage luminal occlusion (before and after correcting for differences in size between coronary vessels analyzed) and average intimal thickness were similar between animals treated with fish oil and safflower oil as assessed by computer-assisted digitized, morphometric planimetry. In all allografts, donor interstitial dendritic cells were repopulated with recipient dendritic cells. The major histocompatibility complex class II cell density in the fish oil group did not differ significantly from rats supplemented with safflower oil (1.48 +/- 0.68 vs 1.48 +/- 0.65 cells per mm2, p = 0.995). In conclusion, fish oil did not exert any beneficial effect over safflower oil in terms of graft coronary arteriosclerosis, histologic rejection, or plasma lipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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Sensitivity and specificity of diastolic indexes for rejection surveillance: temporal correlation with endomyocardial biopsy.

Although acute diastolic dysfunction is an early sequela of the rejecting heart, reported sensitivities and specificities have varied widely when Doppler echocardiography is used for rejection surveillance. This study examines the temporal relationship between changes in Doppler echocardiographic indexes of diastolic function and sequential endomyocardial biopsies to identify possible factors accounting for false-positive and false-negative results. A total of 114 Doppler echocardiographic studies and biopsies were performed weekly in 39 patients aged 14 to 59 years during the initial 3 months after heart transplantation. All Doppler examinations were within 24 hours of biopsy and were analyzed in a blinded fashion. Onset of restrictive physiology, defined as a 15% decrease in either isovolumic relaxation time or pressure half-time, was determined by analysis of the Doppler mitral flow velocity curve.

Adolescent↗
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Dilemma of variety of histopathologic grading systems for acute cardiac allograft rejection by endomyocardial biopsy.

From the International Society for Heart Transplantation Registry, it can be seen that more than 2000 hearts are now being transplanted per year and that this number is likely to continue to rise. Because the leading causes of death in the first year after heart transplantation are infection and acute rejection, it is clear that the problem of managing heart recipients becomes that of correctly diagnosing acute rejection. For many years the endomyocardial biopsy has provided a safe, reliable, morphologic index of acute rejection. Notwithstanding the drawback of an invasive technique and sampling error, the endomyocardial biopsy has prevailed as the single most reliable method for diagnosing acute rejection. In 1974 a grading system for the diagnosis of acute rejection from biopsy material was first described. Since then, the grading system has been updated, and over the years many different grading systems have evolved to accommodate better the style of managing heart recipients in different centers worldwide. Although this is satisfactory for individual centers, it has become clear that there is difficulty in comparison of different treatment regimens from transplant centers using different grades. For continued improvement of survival in heart recipients, multicenter trials using different treatment and management protocols must be tried. To accomplish this, direct comparisons between one regimen and another must be made. For this purpose, a universal grading system has been suggested. This article makes an initial attempt to point out the weaknesses and strengths of the current grading systems and an initial attempt to define the criteria that would be accepted in a universal, or standard, grading system.

Biopsy↗
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Pathologic features in long-term cardiac allografts.

Pathologic conditions of six long-term orthotopic heart transplant survivors (11 to 17 years) was compared with a group of six similar heart transplant recipients surviving only 2 years. The two groups were matched as far as possible for age and sex of both recipients and donors and for immunosuppressive therapy (azathioprine and prednisone). Ischemic time, HLA-A, -B typing, acute rejection episodes, lipid profiles, and coronary angiograms were investigated in both groups. None of these parameters correlated with survival or disease of the graft. Graft coronary disease was present in 10 of 12 cases and caused graft failure in 8 of 12. All six long-surviving grafts and four of six surviving only 2 years showed occlusive coronary disease. The major difference in the two groups was in the pathologic condition of the coronary arteries in the long-term survivors, which more resembled that of naturally occurring atherosclerosis than the characteristic concentric graft coronary disease present in grafts surviving 2 years. Although the histopathologic features were different in the two groups, no investigated factor was useful in predicting graft disease and survival.

Adult↗
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The spectrum of coronary artery pathologic findings in human cardiac allografts.

Coronary artery morphologic features of 61 human cardiac allografts of short- and long-term survival were correlated with coexisting myocardial pathologic findings and cause of death. On the basis of distribution of coronary lesions, allografts were divided into two broad groups: those with fibrous or atherosclerotic lesions confined to the proximal region of epicardial arteries and those with diffuse necrotizing vasculitis or atherosclerosis of the entire coronary arterial system. Within the two groups, coronary artery morphologic features varied in a time-dependent fashion. Disease in the proximal region began as concentric fibrous intimal thickening, with atheromatous lesions observed after 1 year after transplantation. Five of 10 (50%) patients with atheromatous plaques in the proximal region of arteries died or underwent retransplantation because of coronary disease, as compared to only 1 of 29 (3%) patients with fibrous intimal thickening only in the proximal region. The earliest form of diffuse disease was a necrotizing vasculitis, which was invariably associated with acute myocardial rejection. Long-term survivors with diffuse disease showed severe fibrous or fibrofatty intimal lesions of the large and small epicardial and intramyocardial arteries. In some, diffuse disease may have resulted from healing of necrotizing vasculitis. Eight of nine (89%) long-term survivors with diffuse coronary artery disease died or required retransplantation because of coronary vascular disease. The coronary artery disease of human cardiac allografts is a heterogeneous phenomenon with variable distribution, morphologic features, severity, clinical significance, and, possibly, pathogenesis.

Adolescent↗