Human carcinomas variably express the complement inhibitory proteins CD46 (membrane cofactor protein), CD55 (decay-accelerating factor), and CD59 (protectin).

Normal human tissues express membrane-associated complement inhibitory proteins that protect these tissues from damage by autologous complement. To determine whether neoplasms also express these proteins, we examined the distribution of the complement inhibitors decay-accelerating factor (DAF), CD59 (protectin), and membrane cofactor protein in frozen samples of human breast, colon, kidney, and lung carcinomas and in adjacent non-neoplastic tissues, using immunohistochemistry. All samples were also studied for deposition of C3 fragments and activated C5b-9. Differences between normal tissues and the corresponding neoplasms were often observed, with loss or gain of expression of one or more inhibitors. Ductal carcinomas of the breast showed the most variation in phenotype; some tumors expressed only one inhibitor while others expressed different combinations of two or three inhibitors. Colon carcinomas, by contrast, stained intensely for all inhibitors. Renal cell carcinomas had weak to moderate expression of one to three inhibitors, generally DAF and CD59, whereas non-small cell carcinomas of the lung usually expressed CD59 and membrane cofactor protein with variable DAF immunoreactivity. The two small cell carcinomas of the lung showed little or no staining for any inhibitor. Activated C5b-9 deposition was seen adjacent to tumor nests in a minority of carcinomas and showed no correlation with complement inhibitor expression. C3 fragment deposition was minimal. Our results demonstrate that most carcinomas, with the exception of small cell carcinomas of the lung, do express one or more complement inhibitors at a level likely to inhibit complement-mediated cellular damage. Unexpectedly, large quantities of DAF and CD59 were often observed in tumor stroma, with only limited deposition in normal connective tissue. This suggests that carcinomas may supplement the activity of membrane-associated complement inhibitors by release of soluble forms of DAF and CD59 into the surrounding extracellular matrix.

Cathepsin B in angiogenesis of human prostate: an immunohistochemical and immunoelectron microscopic analysis.

BACKGROUND: Angiogenesis (or neovascularization) is required for the growth of solid organ tumors and precedes invasion of the adjacent stroma by neoplastic cells. We investigated the relative density and distribution of cathepsin B (CB) immunostained microvessels (i.e., small blood vessels and capillaries) in benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and prostatic adenocarcinoma (CAP) by immunocytochemical localization of an antibody directed against a cathepsin B-derived synthetic peptide (Syn-CB). METHODS: We studied 16 formalin-fixed, prostatectomy specimens that were embedded in paraffin/paraplast for histological examination by hematoxylin and eosin and immuno-localization of the Syn-CB antibody. Selected paraformaldehyde-fixed specimens were embedded in K4M Lowicryl or LRWhite resins. We localized the antibody in thin sections using immunoelectron microscopy techniques. RESULTS: Eight patients had BPH [4 patients with BPH alone, 2 with BPH and PIN, and 2 with BPH and CAP]. Ten cancer cases included one with Gleason histologic score 4, two with score 6, four with score 7, and three with score 8. In CAP cases, Gleason score 6 and 7 tumors had more microvessels than the score 4 or 8 tumors. In both BPH and CAP cases, the antibody was localized chiefly in the endothelial cells of microvessels, but occasionally in ductal and glandular epithelial cells. Ultrastructurally, CB-immunoreactive gold particles were markedly increased at the luminal and basal plasma membrane surfaces and folds of endothelial cells in neoplastic prostate, but not in the endothelial cells of BPH. Furthermore, the presence of CB localizing gold particles in collagen and smooth muscle fibers near the microvessels indicated leakage of the enzyme in prostatic stroma of neoplastic prostate. Similar leakage was not observed in BPH. Morphometric analysis showed that the relative density of microvessels increased two to three times in cancer patients when compared to patients with BPH alone. Our study also indicated that BPH associated with PIN or CAP had an increased density of microvessels when compared to BPH alone. CONCLUSIONS: Our study showed that the relative density and distribution of microvessels are the most important features of neovascularization in prostatic tumors. The relative density of microvessels increased in PIN and CAP when compared to BPH alone. Although the localization of CB is associated with lysosomes of endothelial cells in both BPH and CAP, there is a greater association of CB with the plasma membranes of endothelial cells in CAP than BPH. Immunoelectron microscopy provided evidence that CB might be involved in dissolution of basement membranes in neoplastic tumors during angiogenesis. CB localization has the potential of defining a role for this protease in degradation of extracellular matrix constituents during early steps of angiogenesis.

Myocardial lipid composition in turkeys with dilated cardiomyopathy.

OBJECTIVE: The aim was to determine if reduced heart lipid peroxidation in turkeys with two forms of dilated cardiomyopathy, previously reported, was related to an alteration in the lipid composition of the ventricle. METHODS: Myocardial lipid composition was measured in turkeys with two types of dilated cardiomyopathy. Twenty six turkeys with naturally occurring dilated cardiomyopathy, six with furazolidone induced dilated cardiomyopathy, and 18 age matched control birds were used at 1 day, 9-10 days, and 38-78 days of age. Left ventricular fatty acid composition of the phospholipid, triglyceride, free fatty acid, and cholesterol ester fractions was analysed using gas chromatography. RESULTS: Significant age related changes were identified in the fatty acid composition of the heart. In the phospholipid fraction, linoleic acid (18:2 omega 6) values increased with age, while arachidonic acid values decreased. The saturated to unsaturated fatty acid ratio in control hearts was unchanged as a function of age in the phospholipid fraction. In the triglyceride fraction, however, this ratio decreased substantially between newly hatched and nine day old birds and then markedly increased in two month old controls. There was a striking alteration in the saturated to unsaturated fatty acid ratio in the triglyceride fraction of 2 month old cardiomyopathic birds; this ratio was markedly increased in the furazolidone induced cardiomyopathic turkey hearts (5.14 v 2.79 in controls) and markedly diminished (ie, 0.97 to 1.21) in the spontaneously cardiomyopathic turkeys. A significant increase in myristic (14:0) and decrease in linoleic (18:2 omega 6) acid concentration in the furazolidone group v control and a marked decrease in myristic and increase in linoleic acid concentrations in the spontaneously cardiomyopathic group v controls was present. CONCLUSIONS: (1) There is an age related alteration in the fatty acid composition of control turkey hearts. (2) Previously identified reduced lipid peroxidation in furazolidone induced and spontaneous cardiomyopathy in turkeys does not appear to be related to reduced concentration of polyunsaturated fatty acids. (3) The two forms of dilated cardiomyopathy are associated with markedly disparate alterations in the concentration of polyunsaturated fatty acids in the triglyceride fraction of 1-2 month old turkey hearts. The changes may be related, in part, to the pathogenesis in these two different forms of dilated cardiomyopathy.

Catecholamines in turkeys with alcohol-induced cardiomyopathy.

Although alcoholic cardiomyopathy has been difficult to reproduce in animals, turkeys fed 5% ethanol develop a dilated congestive cardiomyopathy. We therefore used this model to examine the adrenergic response to left ventricular dysfunction induced by alcohol. In normal turkeys, norepinephrine in kidneys decreased markedly with age from 1 day to 2 mo, with a similar but less dramatic decrease in cardiac norepinephrine. By 2 mo, chronic alcohol ingestion depleted cardiac norepinephrine compared with controls (217 +/- 22 vs. 316 +/- 41 ng/g, P < 0.05), even though cardiac norepinephrine is relatively low in turkeys compared with many other animals and humans. Norepinephrine in aorta was also decreased with alcohol administration, but kidney norepinephrine was unaffected. Dopamine was unaltered in any of the organs studied. Plasma norepinephrine is normally high in turkeys with arterial levels greater than venous (2,898 +/- 746 vs. 1,987 +/- 531 pg/ml at 2 mo). Venous plasma norepinephrine did not differ from control (2,595 +/- 547 pg/ml) after 2 mo of alcohol. Thus, as in humans, cardiomyopathy in alcohol-fed turkeys is associated with reduced cardiac norepinephrine, but unlike humans with cardiomyopathy, circulating norepinephrine remains normal.

Reversible effects of ethanol in utero on cardiac sarcoplasmic reticulum of guinea pig offspring.

STUDY OBJECTIVE: The aim was to investigate the effects of chronic ethanol exposure in utero on the sarcoplasmic reticulum of the developing heart. DESIGN: Pregnant guinea pigs were given 2.5% ethanol in their drinking water and guinea pig lab chow from day 30 to the end of pregnancy. Control pregnant guinea pigs received regular drinking water and lab chow. Ethanol was discontinued at delivery. Cardiac calcium transport function was evaluated in isolated sarcoplasmic reticulum from offspring of ethanol treated and control guinea pigs killed at 1-3 d and 3-5 months of age. EXPERIMENTAL SUBJECTS: The study group consisted of 28 Camm-Hartley guinea pigs. There were 24 controls of the same species. MEASUREMENTS AND MAIN RESULTS: Maternal deaths, litter size, number of stillborns, newborn body weight, and heart weight were not different in ethanol treated and control guinea pigs and their offspring. Ca2+ uptake, Ca2+ binding, and Ca2+ stimulated ATPase activity in isolated sarcoplasmic reticulum were all reduced in 1-3 d old offspring from ethanol treated mothers when compared to age matched control offspring (p less than 0.05). By 3-5 months, calcium transport in cardiac sarcoplasmic reticulum of ethanol treated offspring was similar to that of age matched control offspring. CONCLUSIONS: Moderate ethanol exposure in utero produced functional cardiac alterations in the newborn which were slowly reversible with abstinence from ethanol.

Reduced heart lipid peroxidation precedes cardiac dilatation in turkeys with naturally occurring cardiomyopathy.

STUDY OBJECTIVE: The aim of the study was to determine if reduced heart lipid peroxidation in 1-2 month old turkeys with furazolidone induced dilated cardiomyopathy is drug related and model dependent, a non-specific characteristic of the dilated turkey heart, or if alterations of heart lipid peroxidation can occur prior to onset of cardiac dilatation, and therefore may be involved in its pathogenesis. DESIGN: Ventricular lipid peroxidation capacity and superoxide dismutase activity were measured in controls and in turkeys with spontaneous cardiomyopathy at various ages (newly hatched, 7-10 d, and 1-2 months) and stages of the disease. SUBJECTS: 46 turkeys with naturally occurring dilated cardiomyopathy and 29 age matched controls were used at hatch, 7-10 d, and 1-2 months of age. MEASUREMENTS AND MAIN RESULTS: Heart lipid peroxidation, measured by thiobarbituric acid reactive substances (malondialdehyde), was found to be reduced not only in the dilated hearts of 1-2 months old cardiomyopathic turkeys [114(SEM 10) v 176(21) nmol.100 mg-1 protein, p = 0.023] but also in the non-dilated hearts of 9-10 day old cardiomyopathic turkeys [135(17) v 274(35) nmol.100 mg-1 protein, p = 0.004]. Ventricular superoxide dismutase activity was similar in control and cardiomyopathic turkeys at all stages and there was the expected increase with age. In control turkeys ventricular superoxide dismutase activity in 1-2 month old birds, at 718(52) nitrite units.100 mg-1 protein, was significantly higher than values in 7-10 day old turkeys [398(31) nitrite units.100 mg-1 protein, p = 0.001]. CONCLUSIONS: Decreased lipid peroxidation capacity is present in the dilated hearts of spontaneously cardiomyopathic turkeys. However, it is also decreased in cardiomyopathic turkeys at 9-10 d (the time of highest mortality) prior to the onset of cardiac dilatation. Therefore, alterations in heart lipid composition may be involved in the pathogenesis of this cardiomyopathy and not simply a result of the cardiac dilatation/hypertrophy process.

Amyloidosis.

The authors present a review of amyloidosis and its classification and clinical presentations. They also discuss its diagnosis and treatment, and present a case of amyloid deposition in the plantar weightbearing aspects of the feet, which exemplifies the classic clinical findings.

Renal injury in DOCA-salt hypertensive C5-sufficient and C5-deficient mice.

We induced hypertension by uninephrectomy and treatment with desoxycorticosterone (DOCA) and 1% NaCl in the drinking water in congenic mice that differ in the single gene locus responsible for the presence or absence of the complement component C5 and compared them to uninephrectomized normotensive (no DOCA-NaCl) mice. In contrast to C5-sufficient (C5S) mice. C5-deficient (C5D) mice can neither generate C5a nor assemble C5b-9. After four weeks of treatment, DOCA-C5S and -C5D mice developed similar degrees of hypertension; mice receiving no DOCA remained normotensive. Only hypertensive mice developed glomerular injury. Hypertensive DOCA-C5D mice developed more glomerular capillary loop dilatation and larger glomerular capillary tuft volumes than DOCA-C5S mice (1.0 +/- 0.1 vs. 0.7 +/- 0.03 X 10(6) microns 3, respectively, P less than 0.05). However, DOCA-C5S mice, compared to DOCA-C5D mice, had significantly more glomerular cell proliferation (64.5 +/- 2 vs. 42 +/- 3 nuclei/glomerulus), cell necrosis (injury score 22 +/- 1 vs. 17 +/- 1), extracapillary proliferation (26 +/- 4 vs. 2.5 +/- 2% of glomeruli) and proteinuria (5.9 +/- 0.8 vs. 3.7 +/- 0.5 mg/24 hr; all P less than 0.05). By immunofluorescence microscopy both DOCA-C5S and -C5D had mesangial C3 deposits but only DOCA-C5S mice had C9 deposits. After 16 weeks of DOCA-NaCl C5S mice, in comparison to C5D mice, had more severe glomerulosclerosis (injury score 50 +/- 6 vs. 12 +/- 4), proteinuria (16.6 +/- 0.1 vs. 9 +/- 0.1 mg/24 hr), and renal insufficiency (serum creatinine 0.25 vs. 0.15 mg/dl), all P less than 0.05. These changes occurred despite levels of hypertension that were similar in DOCA-NaCl C5S and C5D throughout the whole study period. We conclude that C5a and/or C5b-9 may play an important role in hypertensive glomerular injury. Moreover, these studies demonstrate that differences in host responses may determine target organ susceptibility to similar injurious mechanisms.

Accelerated idioventricular rhythm complicating atrioventricular junction ablation for automatic atrial tachycardia.

A 13-year-old male with histologic evidence of cardiomyopathy, drug-refractory primary atrial tachycardias, and deteriorating left ventricular function underwent transcatheter His bundle ablation to control ventricular rate. Following an initial successful ablation at the level of the atrioventricular node, the patient exhibited an accelerated escape rhythm of apparent junctional origin (ventricular cycle length = 470 msec, HV = 100 msec) with complete heart block. A second ablation procedure was undertaken, following which an accelerated idioventricular rhythm (cycle length = 500 msec) became apparent and has persisted (follow-up 15 months). Thus, findings in this patient suggest that attempts to control refractory rapid ventricular responses in cardiomyopathy patients with primary atrial tachycardias may be complicated by the potential for junctional and idioventricular sites to exhibit similar abnormally accelerated subsidiary pacemaker function.

Immunohistochemical localization of laminin in the basement membranes of normal, hyperplastic, and neoplastic human prostate.

We examined the effects of fixatives and antibody sources on the immunohistologic localization of laminin in normal and cancer-containing human prostates and studied the localization patterns in carcinomas of varying degrees of histologic differentiation. Two different polyclonal antibodies were localized in paraffin-embedded or cryostat sections of fixed (alcohol, formalin, and paraformaldehyde) or unfixed tissue, using the immunofluorescence (IF) or immunoperoxidase (IP) techniques, with positive and negative controls. We found that the IF reactions were more intense in unfixed or alcohol-fixed sections than in paraformaldehyde-fixed specimens. IP reactions were very weak or absent in fixed and paraffin-embedded sections, but pepsin treatment of these sections resulted in more intense and uniform IP reaction products, stronger than in unfixed or ethanol-fixed cryostat sections. With the IP technique, laminin localization was intense and uniform in the basement membranes (BM) of acini, blood vessels, smooth muscle, and nerve fibers in normal prostate, benign hyperplasia (BPH), and well-differentiated carcinomas. The BM of poorly differentiated carcinomas showed widespread absence of laminin reactivity. In normal BPH and well-differentiated tumors, occasional epithelial cells and their surface and acinar lumina had laminin reactivity. However, in higher grade tumors, numerous neoplastic cells had laminin reactivity in cytoplasm, their surface, and secretory material. Some macrophages and neutrophils also contained laminin reactivity, presumably of degraded laminin. In some moderately and poorly differentiated tumors, the BM of small capillaries did not contain laminin. The BM of larger vessels always had laminin reactivity, even in the higher grade tumors.

Reduced lipid peroxidation in dilated hearts of cardiomyopathic turkeys.

Adverse pulmonary reactions to some nitrofuran antibiotics are thought, in part, to involve production of reactive oxygen radicals. Furazolidone, a nitrofuran antibiotic, causes a dilated cardiomyopathy in domestic turkeys. The mechanism of this drug induced cardiomyopathy is unknown. We investigated the possible role of free radical injury in this heart failure model. Left ventricular lipid peroxidation capacity, assessed by two methods (the thiobarbituric acid reactive substances and lipid hydroperoxides assays respectively), was investigated in five 5-8 week old cardiomyopathic turkeys with severe cardiac dilatation, left ventricular dysfunction and systemic hypotension, and in five control birds. Superoxide dismutase activity, total and manganese, was also measured in the crude left ventricular homogenates. Both lipid peroxidation products were reduced in the myopathic hearts: thiobarbituric acid reactive substances (malondialdehyde) 70(SEM 4) v 86(3) nmol.100 mg protein-1 in controls, p less than 0.02; and lipid hydroperoxides 29(7) v 74(14) nmol.100 mg protein-1, p less than 0.02. Total superoxide dismutase activity was similar in cardiomyopathic and control hearts: 670(26) v 657(105) nitrite units.100 mg protein-1. Although total superoxide dismutase activity was unchanged, we found decreased manganese superoxide dismutase in the dilated hearts compared with controls (54% v 84% of total activity, p less than 0.02). In separate in vitro experiments furazolidone (2-10 mg.g wet weight-1) did not increase malondialdehyde production in turkey (or rat) left ventricular homogenates. These results indicate that cardiomyopathy induced by furazolidone is associated with decreased myocardial lipid peroxidation. Although as yet unexplained, the decrease may be due to a diminished amount of heart lipid susceptible to peroxidation accompanying the process of cardiac hypertrophy and dilatation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal cholesterol metabolism in renal clear cell carcinoma.

The clear cell form of renal cell carcinoma is known to derive its histologic appearance from accumulations of glycogen and lipid. We have found that the most consistently stored lipid form is cholesteryl ester. Clear cell cancer tissue contained 8-fold more total cholesterol and 35-fold more esterified cholesterol than found in normal kidney. Cholesteryl ester appeared to be formed intracellularly since it was not membrane-bound and since oleate was the predominant form, as opposed to linoleate in lipoprotein cholesteryl esters. The cholesterol in clear cell tumors did not appear to be a result of excessive synthesis from acetate since HMG-CoA reductase (EC 1.1.1.34) activity was lower in cancer tissue than in normal kidney (2.9 +/- 0.8 vs. 7.2 +/- 1.2 pmol/mg of protein per min). In contrast, intracellular activity of fatty acyl-coenzyme A:cholesterol acyl transferase (ACAT, EC 2.3.1.26) was higher in tumor tissue than in normal kidney (2405 +/- 546 vs. 1326 +/- 301 pmol/mg of protein per 20 min) while cytosolic cholesteryl ester hydrolase activity appeared normal. Cholesteryl ester storage in clear cell renal cancer may be a result of a primary abnormality in ACAT activity or it may be a result of reduced release of free cholesterol (relative to cell content) with a secondary elevation in ACAT activity.

Cardiac and skeletal muscle abnormalities in cardiomyopathy: comparison of patients with ventricular tachycardia or congestive heart failure.

Results of cardiac muscle and skeletal muscle biopsies were compared in 22 patients with cardiomyopathy; 11 patients presented with symptoms secondary to ventricular tachycardia (Group 1) and 11 had symptoms of severe congestive heart failure (Group 2). No patient had structural or ischemic cardiac disease. In Group 1 patients, hemodynamic abnormalities were subtle, but invasive study demonstrated dilated cardiomyopathy in two patients and restrictive cardiomyopathy in nine. In Group 2, eight patients had dilated cardiomyopathy and three had restrictive cardiomyopathy. Cardiac biopsy results were abnormal in all 22 patients and the abnormalities were similar for the two groups. Cardiac histologic study revealed a spectrum of abnormalities including fibrosis, dilated sarcoplasmic reticulum, increased numbers of intercalated discs and mitochondrial abnormalities. Histologic abnormalities of skeletal muscle were similar in each group, consisting of endomysial fibrosis and increased lipid deposits. Slightly more than half of the Group 1 and Group 2 patients also had a low concentration of skeletal muscle long chain acylcarnitine. These data demonstrate that abnormalities of both cardiac and skeletal muscle are common in patients with cardiomyopathy; abnormalities are similar whether initial symptoms are due to ventricular tachycardia or congestive heart failure. It is suggested that these patients with cardiomyopathy may have a generalized myopathy.

Beta-adrenergic function in a congestive cardiomyopathy model.

We investigated the cardiac beta-adrenergic-adenylate cyclase (AC) system in turkeys inbred for congestive cardiomyopathy (CCM) and the relation of this system to echocardiographically determined left ventricular shortening fraction (LVSF) in individual 56-day-old birds. The isoproterenol (Iso)-stimulated, NaF-stimulated, and basal AC activities in CCM birds were decreased to 69, 72, and 86%, respectively, of control values, P less than 0.05. By linear regression analysis there was significant direct correlation of initial LVSF in CCM birds with each of the following: change in heart rate (HR) after Iso function; Iso-stimulated, NaF-stimulated, and basal AC activities, and density of beta-adrenergic receptors. In addition, we investigated the effect of Iso infusion (0.4 microgram X kg-1 X min-1) on systemic hemodynamics. In CCM birds the initial LVSF was 72% of the control value, P less than 0.01; the initial HR was 112% of the control value, P less than 0.01. During Iso infusion both the LVSF and HR in control birds were increased, whereas in CCM turkeys with marked cardiac dilatation neither of these parameters changed. In 10-day-old CCM turkeys, which show no cardiac dilatation, NaF-stimulated AC activity was reduced to 70% of the control values, whereas basal and Iso-stimulated AC activities were unchanged. Thus an abnormality in the beta-adrenergic-adenylate cyclase system is present in CCM birds before development of cardiac dilatation; when cardiac dilatation is severe, a global defect in this system can be directly related to depressed inotropic and chronotropic responsiveness to Iso infusion in individual turkeys.

Role of the unstirred layer in protecting the murine gastric mucosa from bile salt.

Bile salts disrupt a functional gastric mucosal barrier which normally minimizes back-diffusion of H+ into mucosa. Our previous studies have shown that ionized bile salts disrupt the barrier to H+ by dissolving membrane lipids. The presence of an unstirred water layer on the surface of the gastric mucosa could protect against bile salt injury either by creating a concentration gradient of bile salt from lumen to mucosal surface or by slowing diffusion of lipid-laden mixed micelles away from the mucosal surface. In the present study we investigated this possibility in the anesthetized rat. Measurements of H+ back-diffusion and Na+ forward-diffusion across the gastric mucosa were made before and after exposure to a bile salt solution that was either unmixed or mixed by continuous withdrawal and injection. Using carbon monoxide diffusion, we observed this method of mixing to decrease the unstirred layer thickness from 880 to 448 micron (p less than 0.02). Mixing increased mean H+ back-diffusion induced by a 10 mM mixture of six conjugated bile salts from -2.58 to -4.11 microEq/min (p less than 0.01) and increased mean forward-diffusion of Na+ from 1.81 to 3.27 microEq/min (p less than 0.01). Mixing also increased efflux of mucosal phospholipid (32.7 to 52.2 nmol/min, p less than 0.05) and of cholesterol (4.89 to 8.87 nmol/min, p less than 0.05) into the bile salt solution. Addition of saturation amounts of lecithin and cholesterol to the bile salt solution completely prevented disruption of the barrier whether the solution was mixed or not. Mixing also increased mucosal uptake of bile salt from 74.6 to 221.3 nmol/min (p less than 0.01) when no lipids were added. In the presence of lecithin and cholesterol, mixing increased absorption of bile salt from 63.5 to 165.6 (p less than 0.02). These findings further support the hypothesis that bile salts disrupt the gastric mucosal barrier by dissolution of mucosal membrane lipids, and provide evidence that the unstirred water layer helps protect the gastric mucosa from bile salt injury.

Arachidonic acid metabolism in thrombocytes and vascular tissues of turkeys.

Turkeys are hypertensive compared to mammals of similar size. In vitro synthesis of thrombocyte thromboxane B2 (TxB2), 12L-hydroxy-5,8,10 heptadecatrienoic acid (HHT), 12L-hydroxy-5,8,10,14-eicosatetraenoic acid (HETE) and aortic prostaglandin (PG) production was studied in one to ten month old domestic white turkeys. Compared to normal human platelets, TxB2 production was increased (55.4 vs. 31.4%) and HETE production was markedly reduced (6.5 vs. 34.6%) in control thrombocytes. Similar to human platelets in which cyclooxygenase inhibition with aspirin results in an increase in HETE production, block of the thrombocyte enzyme with aspirin doubled the production of HETE. In vitro conversion of radiolabeled arachidonic acid (AA) showed that the primary PG produced by turkey aorta was PGE2. A 6-keto immunoreactive PG was present which comigrated with authentic 6-keto PGF1 alpha, but failure of the aortic supernatant to inhibit adenosine diphosphate or AA induced platelet aggregation suggested that PGI2 was not produced. The vasodepressor potency of PGE1, PGE2 and PGI2 was altered in awake turkeys with PGE1 and PGE2 having five times the hypotensive effect as PGI2. In addition, conversion of AA to PGE2 by aorta in one month turkeys was greater (17.3 vs. 9.2%) than in ten month old turkeys. Systemic arterial pressure was increased in the ten month old turkeys (188 mmHg) compared to one month old turkeys (143 mmHg). Thus, both vascular AA metabolism and the vasodepressor potencies of PGE2 and PGI2 are altered and the activity of the lipoxygenase pathway in thrombocytes is limited in the turkey.

Carnitine alterations in spontaneous and drug-induced turkey congestive cardiomyopathy.

Carnitine and acylcarnitines were measured in plasma and tissues of control turkeys, turkeys with an inbred spontaneous cardiomyopathy, and turkeys with furazolidone-induced cardiomyopathy. Heart failure was evident in both types of cardiomyopathy from decreased systemic blood pressure and cardiac dilatation compared to controls. Plasma free carnitine, short-chain acylcarnitine, and long-chain acylcarnitine were significantly elevated by 76 to 614% (p less than 0.01) in the two cardiomyopathy models compared to control. The highest carnitine levels were found in the most hypotensive turkeys. Liver free carnitine and short-chain acylcarnitine levels were also elevated by 45 to 537% (p less than 0.05) in both types of cardiomyopathy. Free carnitine was elevated by 126% in left ventricle and by 54% in skeletal muscle of the furazolidone-treated turkeys (p less than 0.05). We speculate that hepatic synthesis of carnitine may be increased in response to hypotension and progressive cardiac dysfunction in cardiomyopathic turkeys. Such an increase may be useful to promote beta-oxidation of fatty acids as a cardiac energy source.

Inducible ventricular arrhythmias in a naturally occurring model of cardiomyopathy.

This study examined inducibility of ventricular tachyarrhythmias in turkeys with and without naturally occurring dilated cardiomyopathy. Using a transvenously positioned electrode catheter, 32 cardiomyopathy and 12 control unsedated turkeys aged 2 to 4 months were studied by right ventricular endocardial extrastimulus testing at basic pacing cycle lengths of 200 and 170 ms with both 1 and 2 extrastimuli and burst pacing at progressively shorter cycle lengths (200 to 100 ms). Following study, a dilatation index (determined as the ratio of left ventricular endocardial and epicardial diameter at level of the apex-base midpoint) was utilized to assess the functional severity of cardiomyopathy. All control turkeys had a dilatation index less than 0.3. In cardiomyopathic turkeys, dilatation index was normal (less than 0.3) in 3/32, showed mild to moderate dilatation in 25/32 (0.3 to 0.6), and severe dilatation in 4/32 (greater than 0.6). Results showed no difference in right ventricular effective or functional refractory periods between control and cardiomyopathic turkeys. Control turkeys had no inducible ventricular tachyarrhythmias, but 16/32 cardiomyopathic turkeys (p less than 0.005) had inducible ventricular tachyarrhythmias, consisting most frequently of two beats of rapid ventricular tachycardia supervened by ventricular fibrillation. In the cardiomyopathic turkeys, inducible tachyarrhythmias occurred in 1/3 with normal dilatation index, in 11/25 with mild to moderate dilatation, and in 4/4 with severe dilatation. Thus, inducibility of ventricular tachyarrhythmias in cardiomyopathic turkeys is closely associated with increasing ventricular dilatation, but does not correlate with altered right ventricular refractoriness. This model may be suitable for studying the relationship between ventricular tachyarrhythmias and cardiomyopathy.

Effect of early propranolol treatment in an animal model of congestive cardiomyopathy. II. beta-adrenergic receptors and left ventricular function.

Young turkeys inbred for congestive cardiomyopathy (CCM) were treated with propranolol prior to the development of cardiac enlargement. One-day-old inbred CCM and commercial turkeys received 2 mg X kg-1 X day-1 of propranolol for 1 month and were compared with untreated age matched inbred CCM and commercial turkeys. Heart weight, body weight, and binding characteristics of cardiac beta-adrenergic receptors, using (-)3H-dihydroalprenolol as a ligand, were determined at 10 and 28 days. Left ventricular shortening fraction was determined at 28 days and at 32 days, 4 days after propranolol was discontinued, in treated and untreated inbred CCM and commercial turkeys. Propranolol did not prevent the development of cardiac hypertrophy in inbred CCM turkeys at 28 days of age and did not effect body weight or heart weight in either inbred CCM or commercial turkeys at 10 or 28 days of age. In the inbred CCM turkeys, the maximum number of binding sites (Bmax) and the binding affinity (Kd) of beta-adrenergic receptors were not changed by propranolol treatment. In the propranolol-treated commercial turkeys, Bmax the of beta-receptors was increased at 28 days of age compared with untreated age matched controls, 382 vs 194 fmol X mg-1 (p less than 0.05). Untreated inbred CCM turkeys when compared with untreated age matched commercial turkeys show a significant reduction of binding affinity of beta-receptors at both 10 and 28 days of age, Kd = 10.4 vs 6.2 nmol X litre-1 at 10 days and 11.3 vs 5.2 nmol X litre-1 at 28 days (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute necrotising eosinophilic myocarditis.

Löffler's endocarditis is a recognised complication of diseases associated with eosinophilia. Eosinophilic heart disease is usually chronic, but there is a rare acute variety. Three patients with an unusual form of eosinophilic heart disease characterised by acute necrotising eosinophilic myocarditis after a possible initial viral infection and underlying allergic diathesis are reported. In contrast to previously reported cases of acute Löffler's endocarditis there was no notable extracardiac pathology.