Comparative effects of cortisone, dianabol and enovid on isoprenaline-induced myocardial infarction in arteriosclerotic vs nonarteriosclerotic rats.
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Male and female nonarteriosclerotic (virgin) and arteriosclerotic (breeder) Sprague-Dawley rats were subjected to acute myocardial infarction with isoprenaline. When myocardial necrosis was most intense, animals were given cortisone (high and low doses), Dianabol, or Enovid. Animals receiving large doses of cortisone manifested the best survival rate during the early stages of myocardial infarction. Although their serum enzyme levels were least elevated and their hearts showed tha least amount of damage, these animals had undergone the most intense body weight loss and began to die suddenly during the later stages of the experiment. These animals also manifested hyperlipidaemia, hyperglycaemia, septicaemia, severe disuse atrophy of their adrenal glands, and reduced Cmpd. B production. Animals treated with low doses of cortisone or with the anabolic and androgenic steroid, Dianabol, manifested none of the myocardial pretective effects of the larger dose of cortisone. These animals displayed a high incidence of left ventricular aneurysm formation concomitant with extensive cartilaginous metaplasia within the aneurysmal sites. Treatment with the contraceptive drug, Enovid, caused body weight loss, hyperlipidaemia, hyperglycaemia, gonadal atrophy and reduction of Cmpd. B production. Although the high dose of cortisone exercised definite salutary effects during early myocardial infarction, chronic treatment led to adrenal disuse atrophy and hypoadrenocorticism associated with sudden death during the later stages of myocardial repair. These findings indicate that proper adjustment of the dose and chronicity of corticosteroids used for treating the crisis of acute myocardial infarction must be made in order to provide effective protection against untoward pathophysiological conditions, acceleration of myocardial repair, but without suppression of adrenal function. (+info)
Peripheral blood flow rates and microvascular responses to orthostatic pressure changes in claudicants before and after revascularisation.
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OBJECTIVES: To study the effect of arterial reconstruction for occlusive atherosclerotic disease with intermittent claudication on blood flow rate during rest and on microvascular responses to orthostatic pressure changes in the pulp skin of the first toe where arteriovenous anastomoses are numerous. MATERIAL: Eleven patients with Fontaine IIa claudication (ankle blood pressure index > 0.30) before and 7 (range: 2-11) months after intervention. METHODS: Blood flow rate was measured by the heat washout method with the toe at heart level and after passive lowering to 50 cm below this level using a Clark type electrode with thermostatically controlled cap that was fixed to the pulp of the first toe by adhesive tape. RESULTS: At heart level, blood flow rate was lower in claudicants before reconstruction as compared to a group of previously published control subjects (p = 0.0076, Wilcoxon), blood flow rate increased in claudicants from before to after intervention (p = 0.0128), and postoperative blood flow rate was like that of normals (N.S.). Before surgery, blood flow rate in claudicants increased in median with a factor of 1.79 during lowering (p < 0.0051). CONCLUSIONS: The disturbance of the microcirculatory responses to orthostatically induced pressure changes in claudicants reverted towards normal after arterial reconstruction. (+info)
Inhibition by a coantioxidant of aortic lipoprotein lipid peroxidation and atherosclerosis in apolipoprotein E and low density lipoprotein receptor gene double knockout mice.
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Antioxidants can inhibit atherosclerosis in animals, though it is not clear whether this is due to the inhibition of aortic lipoprotein lipid (per)oxidation. Coantioxidants inhibit radical-induced, tocopherol-mediated peroxidation of lipids in lipoproteins through elimination of tocopheroxyl radical. Here we tested the effect of the bisphenolic probucol metabolite and coantioxidant H 212/43 on atherogenesis in apolipoprotein E and low density lipoprotein (LDL) receptor gene double knockout (apoE-/-;LDLr-/-) mice, and how this related to aortic lipid (per)oxidation measured by specific HPLC analyses. Dietary supplementation with H 212/43 resulted in circulating drug levels of approximately 200 microM, increased plasma total cholesterol slightly and decreased plasma and aortic alpha-tocopherol significantly relative to age-matched control mice. Treatment with H 212/43 increased the antioxidant capacity of plasma, as indicated by prolonged inhibition of peroxyl radical-induced, ex vivo lipid peroxidation. Aortic tissue from control apoE-/-;LDLr-/- mice contained lipid hydro(pero)xides and substantial atherosclerotic lesions, both of which were decreased strongly by supplementation of the animals with H 212/43. The results show that a coantioxidant effectively inhibits in vivo lipid peroxidation and atherosclerosis in apoE-/-;LDLr-/- mice, consistent with though not proving a causal relationship between aortic lipoprotein lipid oxidation and atherosclerosis in this model of the disease. (+info)
Endothelial cytotoxicity mediated by serum antibodies to heat shock proteins of Escherichia coli and Chlamydia pneumoniae: immune reactions to heat shock proteins as a possible link between infection and atherosclerosis.
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BACKGROUND: Growing evidence suggests that an immunological reaction against heat shock proteins (HSPs) may be involved in atherogenesis. Because HSPs show a high degree of amino acid sequence homology between different species, from prokaryotes to humans, we investigated the possibility of "antigenic mimicry" caused by an immunological cross-reaction between microorganisms and autoantigens. METHODS AND RESULTS: Serum antibodies against the Escherichia coli HSP (GroEL) and the 60-kDa chlamydial HSP (cHSP60) from subjects with atherosclerosis were purified by use of affinity chromatography. Western blot analyses and competitive ELISAs confirmed the cross-reaction of the eluted antibodies with human HSP60 and the bacterial counterparts. The cytotoxicity of anti-GroEL and anti-cHSP60 antibodies was determined on human endothelial cells labeled with 51Cr. A significant difference (40% versus 8%) was observed in the specific 51Cr release of heat-treated (42 degrees C for 30 minutes) and untreated cells, respectively, in the presence of these anti-HSP antibodies and complement. This effect was blocked by addition of 100 microg/mL recombinant GroEL. In addition, seropositivity against specific non-HSP60 Chlamydia pneumoniae antigens is more prominent among high-anti-HSP titer sera than low-titer sera. CONCLUSIONS: Serum antibodies against HSP65/60 cross-react with human HSP60, cHSP60, and GroEL; correlate with the presence of antibodies to C pneumoniae and endotoxin; and mediate endothelial cytotoxicity. These findings suggest that humoral immune reactions to bacterial HSPs, such as cHSP60 and GroEL, may play an important role in the process of vascular endothelial injury, which is believed to be a key event in the pathogenesis of atherosclerosis. (+info)
Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort.
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BACKGROUND AND PURPOSE: Although stroke mortality rates in the United States are well documented, assessment of incidence rates and case fatality are less well studied. METHODS: A cohort of 15 792 men and women aged 45 to 64 years from a population sample of households in 4 US communities was followed from 1987 to 1995, an average of 7. 2 years. Incident strokes were identified through annual phone contacts and hospital record searching and were then validated. RESULTS: Of the 267 incident definite or probable strokes, 83% (n=221) were categorized as ischemic strokes, 10% (n=27) were intracerebral hemorrhages, and 7% (n=19) were subarachnoid hemorrhages. The age-adjusted incidence rate (per 1000 person-years) of total strokes was highest among black men (4.44), followed by black women (3.10), white men (1.78), and white women (1.24). The black versus white age-adjusted rate ratio (RR) for ischemic stroke was 2.41 (95% CI, 1.85 to 3.15), which was attenuated to 1.38 (95% CI, 1.01 to 1.89) after adjustment for baseline hypertension, diabetes, education level, smoking status, and prevalent coronary heart disease. There was a tendency for the adjusted case fatality rates to be higher among blacks and men, although none of the case fatality comparisons across sex or race was statistically significant. CONCLUSIONS: After accounting for established baseline risk factors, blacks still had a 38% greater risk of incident ischemic stroke compared with whites. Identification of new individual and community-level risk factors accounting for the elevated incidence of stroke requires further investigation and incorporation into intervention planning. (+info)
Mild carotid artery atherosclerosis: assessment by 3-dimensional time-of-flight magnetic resonance angiography, with reference to intravascular ultrasound imaging and contrast angiography.
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BACKGROUND AND PURPOSE: Our aim was to evaluate the usefulness of 3-dimensional time-of-flight magnetic resonance angiography (3-D TOF MRA) in detection and quantification of mild atherosclerotic changes of carotid arteries with reference to intravascular ultrasound (IVUS) and contrast angiography. METHODS: TOF MRA at 1.5 T, IVUS, and selective digital subtraction angiography were performed on 31 extracranial carotid arteries of 27 patients (mean age, 52 years; age range, 17 to 75 years) undergoing neuroendovascular interventions. The atherosclerotic lesions were registered, and quantitative measurements of plaque thickness, luminal diameters, and diameter stenosis were independently performed for the imaging modalities. RESULTS: Among 170 arterial segments analyzed, IVUS revealed a total of 48 atherosclerotic lesions (mean diameter stenosis, 17%; range, 4% to 40%), only 25 of which were depicted on digital subtraction angiography. Analysis of the axial source images of TOF MRA resulted in sensitivity of 77% to 83% and specificity of 71% to 80% in lesion depiction for the 2 readers with reference to IVUS. The values of diameter stenosis measured from MRA and IVUS were closely interrelated (r=0.53 to 0.61, P<0.001). CONCLUSIONS: Three-dimensional TOF MRA is feasible and moderately accurate for evaluation of mild atherosclerotic changes of carotid arteries. (+info)
Insulin sensitivity in subjects with type 2 diabetes. Relationship to cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study.
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OBJECTIVE: Among nondiabetic subjects, insulin resistance has been associated with increased cardiovascular risk factors, including dyslipidemia, hypertension, impaired fibrinolysis, and coagulation. Less is known about the relationship between insulin resistance and cardiovascular risk factors in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: To examine this issue, we determined insulin sensitivity (SI) in 479 type 2 diabetic subjects by minimal model analyses of frequently sampled intravenous glucose tolerance tests in the Insulin Resistance Atherosclerosis Study (IRAS), a large multicenter study of insulin sensitivity and cardiovascular disease in African-Americans, Hispanics, and non-Hispanic whites. We defined insulin-sensitive subjects as having SI > or = 1.61 x 10(-4) min-1.microU-1.ml-1 (above median in nondiabetic subjects of all ethnic groups in the IRAS). Using this definition, only 37 type 2 diabetic subjects were insulin sensitive, and the remaining 442 were insulin resistant. RESULTS: After adjustment for age, sex, ethnicity, and clinic, insulin resistance was significantly correlated with total triglycerides, VLDL cholesterol, VLDL triglyceride, fibrinogen, PAI-1, and fasting glucose, and was inversely correlated with HDL cholesterol level and LDL size. Carotid intimal-medial thickness was greater in insulin-resistant than in insulin-sensitive subjects, but this difference was not statistically significant. After further adjustment for waist circumference (marker of visceral adiposity), insulin-resistant subjects continued to have higher plasminogen activator inhibitor 1 and VLDL triglyceride levels, lower HDL cholesterol levels, and smaller LDL particle size than did insulin-sensitive subjects. After further adjustment for fasting glucose levels, these results were very similar. CONCLUSIONS: We conclude that insulin-resistant type 2 diabetic subjects have more atherogenic cardiovascular risk factor profiles than insulin-sensitive type 2 diabetic subjects and that this is only partially related to increased obesity and an adverse body fat distribution. (+info)
Proatherogenic and antiatherogenic effects of probucol and phytosterols in apolipoprotein E-deficient mice: possible mechanisms of action.
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BACKGROUND: The effects of probucol and a phytosterol mixture (FCP-3PI) on atherosclerotic lesion formation, plasma lipoproteins, hepatic and lipoprotein lipase activities, antioxidant enzyme activities, and plasma fibrinogen were investigated in apolipoprotein E-knockout (apoE-KO) mice. METHODS AND RESULTS: Three groups of 8 mice were fed a diet containing 9% (wt/wt) fat (controls) or the foregoing diet supplemented with either 1% (wt/wt) probucol (the probucol group) or 2% (wt/wt) FCP-3PI (the FCP-3PI group) for 20 weeks. Compared with controls, atherosclerotic lesion size was 3 times greater in the probucol group, whereas it was decreased by half in the FCP-3PI group. Probucol treatment resulted in high plasma probucol concentrations, which correlated (r=0.69) with the lesion area. HDL cholesterol was reduced (>75%) in the probucol group and slightly increased (14%) in the FCP-3PI-treated group. Postheparin lipoprotein lipase (LPL) activity was significantly reduced in both treatment groups, but only FCP-3PI significantly decreased hepatic lipase activity. Plasma fibrinogen was increased 42% by probucol and decreased 19% by FCP-3PI relative to controls. Probucol significantly increased plasma glutathione reductase, glutathione peroxidase, and superoxide dismutase activities (P<0.05). In contrast to findings in apoE-KO mice, there was no probucol-induced atherosclerosis in their wild-type counterparts fed the same dose for the same period of time. CONCLUSIONS: Antiatherogenic activity of FCP-3PI in apoE-KO mice is associated with an increase in HDL cholesterol concentration along with decreases in hepatic lipase activity and plasma fibrinogen concentrations. Proatherogenic effects of probucol may be related to increased plasma fibrinogen, decreased HDL cholesterol concentrations along with decreased LPL activity, or its direct "toxicity" due to very high plasma concentration. Our studies demonstrate that the antioxidant and cholesterol-lowering properties of probucol do not prevent atherogenesis in this particular animal model. (+info)