Endothelial dysfunction, impaired endogenous fibrinolysis, and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction.
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BACKGROUND: Effective endogenous fibrinolysis requires rapid release of tissue plasminogen activator (tPA) from the vascular endothelium. Smoking is a known risk factor for arterial thrombosis and myocardial infarction, and it causes endothelial dysfunction. We therefore examined the effects of cigarette smoking on substance P-induced tPA release in vivo in humans. METHODS AND RESULTS: Blood flow and plasma fibrinolytic factors were measured in both forearms of 12 smokers and 12 age- and sex-matched nonsmokers who received unilateral brachial artery infusions of substance P (2 to 8 pmol/min). In both smokers and nonsmokers, substance P caused dose-dependent increases in blood flow and local release of plasma tPA antigen and activity (P<0.001 for all) but had no effect on the local release of plasminogen activator inhibitor type 1. Compared with nonsmokers, increases in forearm blood flow (P=0.03) and release of tPA antigen (P=0.04) and activity (P<0.001) caused by substance P were reduced in smokers. The area under the curve for release of tPA antigen and activity decreased by 51% and 53%, respectively. CONCLUSIONS: Cigarette smoking causes marked inhibition of substance P-induced tPA release in vivo in humans. This provides an important mechanism whereby endothelial dysfunction may increase the risk of atherothrombosis through a reduction in the acute fibrinolytic capacity. (+info)
Tissue expression and immunolocalization of tumor necrosis factor-alpha in postinfarction dysfunctional myocardium.
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BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) is markedly elevated in advanced heart failure. It is not known whether tissue TNF-alpha is elevated in the common setting of myocardial infarction leading to heart failure and what the source of TNF-alpha is. To determine this, we studied the expression and protein localization of TNF-alpha and its 2 main receptors (TNF-R1/R2) in a rat model of large infarction. METHODS AND RESULTS: Male rats were randomized to proximal left anterior descending ligation. The animals were killed on days 1, 3, 10, and 35 after ligation to examine gene expression and protein production of TNF-alpha and TNF-R1/R2 from the infarct, peri-infarct, and contralateral zones of infarcted heart. There was increased TNF-alpha mRNA production throughout the myocardium at day 1, and detectable expression persisted to day 35 after myocardial infarction. The expression of this cytokine is not confined strictly to the infarct or peri-infarct zones but is expressed by cardiac myocytes within the myocardium in the contralateral normal zone. Changes in gene expression are mirrored initially by augmented protein production within the myocytes. Levels of TNF-alpha protein in the infarct and peri-infarct zones rose early to 8- to 10-fold above normal levels and rose to 4- to 5-fold in the contralateral zone. Finally, expression of the TNF-R1 mRNA transcripts was upregulated at days 3 and 10 after ligation in the infarct and peri-infarct zones, suggesting that the signal transduction pathways necessary for TNF-alpha in the heart remain intact as TNF-alpha biosynthesis increases. CONCLUSIONS: TNF-alpha is present early in a model of large myocardial infarction and is sustained into the later stage within the myocardium. Expression of this cytokine is not only confined strictly to the infarct or peri-infarct zone but is expressed by cardiac myocytes within the myocardium contralateral to the infarct. Therefore TNF-alpha production forms a part of an important intrinsic myocardial stress response system to injury. (+info)
Interaction between neutral endopeptidase and angiotensin converting enzyme inhibition in rats with myocardial infarction: effects on cardiac hypertrophy and angiotensin and bradykinin peptide levels.
(51/19124)
Combined inhibition of neutral endopeptidase 24.11 (NEP) and angiotensin converting enzyme (ACE) is a candidate therapy for hypertension and cardiac failure. Given that NEP and ACE metabolize angiotensin (Ang) and bradykinin (BK) peptides, we investigated the effects of NEP inhibition and combined NEP and ACE inhibition on Ang and BK levels in rats with myocardial infarction. We administered the NEP inhibitor ecadotril (0, 0.1, 1, 10, and 100 mg/kg/day), either alone or together with the ACE inhibitor perindopril (0.2 mg/kg/day) by 12-hourly gavage from day 2 to 28 after infarction. Ecadotril increased urine cyclic GMP and BK-(1-9) excretion. Perindopril potentiated the effect of ecadotril on urine cyclic GMP excretion. Neither perindopril nor ecadotril reduced cardiac hypertrophy when administered separately, whereas the combination of perindopril and 10 or 100 mg/kg/day ecadotril reduced heart weight/body weight ratio by 10%. Administration of ecadotril to perindopril-treated rats decreased plasma Ang-(1-7) levels, increased cardiac BK-(1-9) levels, and increased Ang II levels in plasma, kidney, aorta, and lung. These data demonstrate interactions between the effects of NEP and ACE inhibition on remodeling of the infarcted heart and on Ang and BK peptide levels. Whereas increased cardiac BK-(1-9) levels may contribute to the reduction of cardiac hypertrophy, the reduction in plasma Ang-(1-7) levels and increase in Ang II levels in plasma and tissues may compromise the therapeutic effects of combined NEP/ACE inhibition. (+info)
Short left coronary artery trunk as a risk factor in the development of coronary atherosclerosis. Pathological study.
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The relation between the length of the main left coronary artery and the degree of atherosclerosis in its branches was studied by postmortem examination in 204 subjects aged 20 to 90 years. The findings suggest that in cases with a short main left coronary artery the atherosclerotic lesions in the anterior descending and circumflex branches appear earlier, progress faster at higher levels of severity, and lead more frequently to myocardial infarction, than in cases with a long left coronary artery trunk. In cases over the age of 50 years, where disease is expected to have developed, it was shown that the degree of atherosclerosis in the left anterior descending and circumflex branches was inversely related to the length of the main left coronary artery. The correlation coefficients were -0-527 and -0-428, respectively, and in either case a test for zero correlations was significant (P less than 0-001). The possible changes in the haemodynamic and mechanical conditions associated with the variations of the anatomical pattern of the coronary arteries and their influence in the development of atherosclerosis are discussed. It is suggested that the length of the main left coronary artery is a congenital anatomical and possibly hereditary factor influencing the rate of development of atherosclerosis in the branches of the main left coronary artery. (+info)
Discriminant function analysis of factors related to myocardial infarction in male patients on antihypertensive therapy.
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Records of 367 male patients who began attending the Dunedin Hospital Hypertension Clinic between 1959 and 1969 were coded up to the end of 1972. Of these patients, 60 had their first myocardial infarction, or sudden cardiac death without previous evidence of myocardial infarction, while they were attending the clinic. This infarct group was compared with a control group of 120 which was chosen from the remaining patients so that the two groups would be comparable with regard to their age and year of first attendance. A stepwise discriminant function analysis showed that the basal systolic and diastolic pressures measured when patients started attending the clinic were the variables with the most significant difference. Further analysis showed that inclusion of the average casual standing systolic pressure when patients were receiving antihypertensive therapy improved the discrimination between the groups. The average casual standing diastolic pressure during antihypertensive therapy also improved the discrimination, but, curiously enough, with a negative sign in the discriminant function. Quetelet's index of obesity similarly improved the discrimination, obese subjects having less risk of infarction or sudden death. Serum cholesterol, however, was not related to prognosis. (+info)
Plasma zinc in acute myocardial infarction. Diagnostic and prognostic implications.
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Zinc is a metal component of many important enzymes, and its availability controls the rate of synthesis of nucleic acids and protein. Serum zinc levels have been shown to fall after acute tissue injury, including myocardial infarction. The purpose of this clinical study was to examine the value of plasma zinc measurements in a coronary care unit. Studies were made in 188 patients: 88 with unequivocal myocardial infarction, 52 controls, and 48 in a borderline group. Patients with myocardial infarction showed a fall in plasma zinc within the first three days, whereas patients in the other two groups did not. The difference in the mean minimum zinc levels between the groups with and without infarction was highly significant. In patients with myocardial infarction there was good correlation between the minimum plasma zinc level and the peal value of plasma enzymes, and also with some clinical estimators of prognosis. A fall in plasma zinc is a reliable diagnostic test for acute myocardial infarction, and the extent of the fall has prognostic implications. (+info)
Isoprenaline-induced changes in regional myocardial perfusion in the pathogenesis of myocardial necrosis.
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Isoprenaline in a single dose induces impairment in perfusion of the subendocardial myocardium of the rat left ventricle. This defect in perfusion persists for up to 150 min and corresponds in distribution to the myocardial necrosis produced by similar doses of isoprenaline. It is mediated by the beta-receptors as it is prevented by beta-blockade with propranolol. It is considered that isoprenaline-induced myocardial necrosis represents myocardial infarction. (+info)
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)