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S W Werns

Publications and source records attributed to S W Werns.

31 records · Page 2Linked to original sources
PubMed1989

Myocardial ischemia and reperfusion: the role of oxygen radicals in tissue injury.

Thrombolytic therapy has gained widespread acceptance as a means of treating coronary artery thrombosis in patients with acute myocardial infarction. Although experimental data have demonstrated that timely reperfusion limits the extent of infarction caused by regional ischemia, there is growing evidence that reperfusion is associated with an inflammatory response to ischemia that exacerbates the tissue injury. Ischemic myocardium releases archidonate and complement-derived chemotactic factors, e.g., leukotriene B4 and C5a, which attract and activate neutrophils. Reperfusion of ischemic myocardium accelerates the influx of neutrophils, which release reactive oxygen products, such as superoxide anion and hydrogen peroxide, resulting in the formation of a hydroxyl radical and hypochlorous acid. The latter two species may damage viable endothelial cells and myocytes via the peroxidation of lipids and oxidation of protein sulfhydryl groups, leading to perturbations of membrane permeability and enzyme function. Neutrophil depletion by antiserum and inhibition of neutrophil function by drugs, e.g., ibuprofen, prostaglandins (prostacyclin and PGE1), or a monoclonal antibody, to the adherence-promoting glycoprotein Mo-1 receptor, have been shown to limit the extent of canine myocardial injury due to coronary artery occlusion/reperfusion. Recent studies have challenged the hypothesis that xanthine-oxidase-derived oxygen radicals are a cause of reperfusion injury. Treatment with allopurinol or oxypurinol may exert beneficial effects on ischemic myocardium that are unrelated to the inhibition of xanthine oxidase. Furthermore, the human heart may lack xanthine oxidase activity. Further basic research is needed, therefore, to clarify the importance of xanthine oxidase in the pathophysiology of reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary Disease↗
PubMed1989

Implications for patient triage from survival and left ventricular functional recovery analyses in 500 patients treated with coronary angioplasty for acute myocardial infarction.

The in-hospital course of 500 consecutive patients treated with coronary angioplasty for acute myocardial infarction was reviewed in relation to their clinical and angiographic presentation and angioplasty outcome to determine which patients benefit most from successful angioplasty in this setting. Patient age was 56 +/- 11 years (mean +/- SD) and 78% were men; 46% had anterior myocardial infarction, 49% received concomitant intravenous thrombolytic therapy, left ventricular ejection fraction was 47 +/- 11% and median time to angioplasty was 4.7 h (range 1 to 24). Angioplasty was successful in 78% of patients and partially successful in 7% of patients; the overall in-hospital mortality rate was 10.2%. Multivariate analysis found six independent correlates (p less than 0.05) of in-hospital mortality: left ventricular ejection fraction less than or equal to 30%, lack of postangioplasty infarct artery patency, age greater than 65 years, recurrent ischemia after successful angioplasty, emergency bypass surgery and arterial pressure on admission to the catheterization laboratory less than 100 mm Hg. After consideration of these predictors of survival in multivariate analyses, angioplasty success still was independently correlated with improved in-hospital survival for patients with cardiogenic shock (p = 0.002) and anterior myocardial infarction (p = 0.007). A trend toward an independent beneficial effect of successful angioplasty on survival was also noted in patients with inferior wall infarction and precordial ST segment depression (p = 0.063) and for all patients who were hypotensive on admission to the catheterization laboratory, regardless of the infarct site (p = 0.057).(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon↗
PubMed1989

Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease.

Acetylcholine causes endothelium-dependent dilation of normal arteries in most animal species. The effect of acetylcholine on normal human coronary arteries is controversial. Pathologic studies and epicardial echocardiography have shown that diffuse atherosclerosis is often present despite angiographic evidence of discrete coronary artery disease (CAD). Therefore, we postulated that acetylcholine would cause vasoconstriction of coronary arteries that are angiographically normal in patients with CAD. Coronary artery diameter, measured by automated quantification of digitized cineangiograms, was determined before and after the intracoronary infusion of 0.2 mM acetylcholine at 0.8-1.6 ml/min. The diameter of stenotic or irregular segments of six atherosclerotic coronary arteries decreased from 1.80 +/- 0.42 mm before acetylcholine to 1.26 +/- 0.46 mm after acetylcholine (p = 0.0025). Acetylcholine had a significantly different effect on the diameter of two groups of coronary arteries that are angiographically normal. Acetylcholine caused a 0.16 +/- 0.09-mm increase in the diameter of 14 normal coronary arteries in patients without CAD, whereas it caused a 0.26 +/- 0.12-mm decrease in the diameter of 14 normal coronary arteries in patients with CAD (p less than 0.01). Thus, the normal response to intracoronary acetylcholine is vasodilation, suggesting that endothelium-derived relaxing factor is released from normal human coronary endothelium. The vasoconstrictive effect of acetylcholine in the angiographically normal coronary arteries of patients with CAD suggests the presence of a diffuse abnormality of endothelial function.

Acetylcholine↗
PubMed1988

Leukocytes, oxygen radicals, and myocardial injury due to ischemia and reperfusion.

Ischemic myocardium generates stimuli for neutrophil chemotaxis before the final extent of irreversible ischemic injury is attained. Reperfusion accelerates the infiltration of ischemic myocardium by neutrophils. Oxygen radicals released by the activated neutrophils may exacerbate the tissue damage caused by ischemia. Neutrophil depletion by antiserum was shown to limit infarct size in dogs undergoing coronary occlusion for 90 minutes followed by reperfusion for 6 or 72 hours, but not in dogs undergoing occlusion for 4 hours. Prostacyclin, which inhibits the generation of superoxide anions by neutrophils, also limited canine myocardial injury despite no effect on collateral blood flow. Iloprost, an analogue of prostacyclin that inhibits neutrophils also reduced infarct size, while SC39902, an analogue that does not inhibit neutrophils, did not alter infarct size. The results suggest that oxygen radicals released by activated neutrophils play a role in the pathophysiology of myocardial injury due to ischemia followed by reperfusion.

Animals↗
PubMed1988

Sustained limitation by superoxide dismutase of canine myocardial injury due to regional ischemia followed by reperfusion.

This study was performed to evaluate the effects of superoxide dismutase, a scavenger of superoxide anions, on leukocyte accumulation and myocardial injury in a canine preparation of myocardial infarction. Dogs underwent occlusion of the left circumflex coronary artery for 90 min, followed by a reperfusion for 6 or 24 h. The dogs received either saline or superoxide dismutase (5 mg/kg), beginning 15 min before coronary occlusion and ending 15 min after coronary reflow. Myocardial infarct size, expressed as a percentage of the area at risk, was significantly less in superoxide-dismutase-treated dogs that underwent reperfusion for 6 h, 17.5 +/- 1.7, or 24 h, 25.8 +/- 3.6, compared to saline-treated dogs that underwent reperfusion for 6 h, 42.7 +/- 4.4 (p less than 0.05), or 24 h, 53.0 +/- 6.1 (p less than 0.05). The differences in infarct size were not due to differences in myocardial oxygen demand. Superoxide dismutase had no effect on regional myocardial perfusion of the ischemic bed. Accumulation of 111indium (In)-labeled autologous leukocytes within the area at risk was similar in control and superoxide-dismutase-treated dogs (p greater than 0.05). The results suggest that oxygen radicals play a role in the extent of injury due to regional myocardial ischemia followed by reperfusion, and the protective effect of free radical scavengers may be sustained beyond the expected plasma half-life of the administered agent.

Animals↗
PubMed1988

Protection of reperfused ischemic canine myocardium by CI-922, a new inhibitor of leukocyte activation.

There is increasing evidence that activated neutrophils cause myocardial injury during reperfusion of ischemic myocardium. This study was performed to assess the effect of Ci-922, an inhibitor of neutrophil activation, in a canine preparation of myocardial infarction. Dogs received 15-min infusions of CI-922 1 mg/kg or 5% dextrose beginning 30 min before occlusion of the left circumflex coronary artery. After occlusion for 90 min and reperfusion for 6 h, infarct size was determined by ex vivo perfusion of the left circumflex coronary artery with triphenyltetrazolium chloride. The percentage of the area at risk infarcted was: control, 42 +/- 5; and CI-922, 23 +/- 4 (p less than 0.05 vs. control). There were no significant inter-group differences in heart rate or mean arterial pressure, and CI-922 did not enhance collateral blood flow to the ischemic bed. After incubation with CI-922 (100 microM), production of superoxide anions by canine neutrophils activated by opsonized zymosam decreased from 3.5 +/- 0.2 to 2.0 +/- 0.4 nmol/10 min/10(6) cells (p less than 0.05). Thus, inhibition of neutrophil-mediated damage may explain the cardioprotective effect of CI-922.

Animals↗
PubMed1987

Superoxide dismutase does not cause scar thinning after myocardial infarction.

Previous studies demonstrated that treatment with superoxide dismutase, a scavenger of superoxide anions, limits the extent of myocardial injury in a canine preparation of regional myocardial ischemia and reperfusion. Little is known, however, about the effects of superoxide dismutase on the healing of a myocardial infarct. Therefore, this study was performed to determine whether treatment with superoxide dismutase during myocardial ischemia impairs formation of scar tissue after infarction. Dogs received 2 hour infusions of superoxide dismutase or albumin (controls) by way of the left atrium beginning 15 minutes before and ending 15 minutes after a 90 minute occlusion of the left circumflex coronary artery. Six weeks later the animals were killed. Two-dimensional echocardiography was performed before surgery and before induced death. Wall thickening in the central ischemic zone was decreased at 6 weeks compared with baseline studies (p less than 0.05), but the decrease was similar for both groups. The hydroxyproline concentrations (microgram/mg dry weight) of the scar tissue in the superoxide dismutase and control groups, respectively, were 35.3 +/- 3.8 and 28.7 +/- 5.0 (p less than 0.05). The ratios of the scar thickness to normal wall thickness were superoxide dismutase 0.91 +/- 0.03 and control 0.89 +/- 0.03 (p greater than 0.05). Thus, superoxide dismutase had no adverse effect on wall thickening or scar formation assessed 6 weeks after myocardial infarction, and may be useful to limit oxygen radical-mediated damage during reperfusion of the ischemic myocardium.

Animals↗
PubMed1986

Reduction of the size of infarction by allopurinol in the ischemic-reperfused canine heart.

This study was performed to assess the effect of allopurinol in a canine preparation of myocardial infarction. Dogs underwent occlusion of the left circumflex coronary artery for 90 min, followed by reperfusion for 6 hr. Three groups were studied: (1) control, (2) dogs receiving 25 mg/kg allopurinol 18 hr before occlusion and 50 mg/kg 5 min before occlusion, and (3) dogs receiving allopurinol as above plus 5 mg/kg superoxide dismutase over 1 hr beginning 15 min before reperfusion. Infarct size expressed as a percentage of the area at risk was 40 +/- 4 in the control group, 22 +/- 5 in the allopurinol group (p less than .05 vs control), and 17 +/- 4 in the allopurinol plus superoxide dismutase group (p less than .05 vs control). The differences in infarct size were not due to differences in myocardial oxygen supply or demand. Neutrophil superoxide anion production was not altered by allopurinol treatment. The results suggest that myocardial xanthine oxidase may generate oxygen radicals that play a role in myocardial injury due to ischemia and reperfusion.

Allopurinol↗
PubMed1985

Free radicals in ischemic myocardial injury.

Myocardial ischemia causes release of chemotactic factors, migration of neutrophils, peroxidation of lipids, and depletion of free radical scavengers. The invading neutrophils may injure the myocardial vasculature and sarcolemma by generating oxygen free radicals. Several agents that affect neutrophils or oxygen radicals were evaluated in a canine model of regional myocardial ischemia and reperfusion. Anesthetized dogs underwent occlusion and reperfusion of the left circumflex coronary artery. Infarct zone, area at risk of infarction, and total left ventricle were quantified by gravimetric and planimetric analysis. Limitation of infarct size by ibuprofen was associated with marked suppression of leukocyte accumulation within the ischemic myocardium. Neutrophil depletion by antiserum resulted in similar reductions of infarct size and was accompanied by a reduction in leukocyte infiltration. A combination of oxygen radical scavengers, superoxide dismutase plus catalase, decreased myocardial injury whether infusion began before occlusion or 75 min after occlusion. None of the treatments significantly altered hemodynamic indices of myocardial oxygen demand. Reduction of infarct size by ibuprofen, neutrophil antiserum, and free radical scavengers indicates that neutrophils and oxygen radicals participate in producing the irreversible damage to the myocardium during ischemia and reperfusion.

Animals↗
PubMed1985

The independent effects of oxygen radical scavengers on canine infarct size. Reduction by superoxide dismutase but not catalase.

Previous studies demonstrated a significant reduction of ultimate infarct size in the canine heart by the combined administration of superoxide dismutase plus catalase. This study was performed to assess the independent effects of each enzyme on ultimate infarct size due to ischemia/reperfusion. Dogs received 2-hour infusions of superoxide dismutase, catalase, or albumin (controls) via the left atrium beginning 15 minutes before and ending 15 minutes after a 90-minute occlusion of the left circumflex coronary artery. The dogs were killed 6 hours after reperfusion. After histochemical staining, infarct and risk area masses were calculated by gravimetric and planimetric analysis. Infarct size expressed as a percentage of the area at risk was: superoxide dismutase, 19 +/- 5; catalase, 30 +/- 5; and controls, 40 +/- 3. Infarct size in the superoxide dismutase group, but not the catalase group, was significantly less than in controls (P less than 0.05). No significant differences in hemodynamics or area at risk were observed that could explain the differences in infarct size. The results indicate that superoxide dismutase alone protects reperfused ischemic myocardium as well as does the combination of superoxide dismutase and catalase. The beneficial effect of superoxide dismutase and insignificant effect of catalase suggest that tissue damage during ischemia and reperfusion may be mediated largely by superoxide anion but not by hydrogen peroxide.

Animals↗