Michael J. Shea

Free radicals and myocardial injury: pharmacologic implications.

A GROWING NUMBER of articles purport to demonstrate the importance of oxygen free radicals in a variety of pathophysiologic processes, including injury due to radiation, inflammation, and oxygen toxicity. The purpose of this essay is to examine the hypothesis that activated oxygen species may play a role in the extension of myocardial injury due to ischemia followed by reperfusion. Activated oxygen species include-superoxide anion, hydrogen peroxide, and hydroxyl radical. By virtue of

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.

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.

A randomized controlled trial of hospital discharge three days after myocardial infarction in the era of reperfusion.

To evaluate the feasibility and cost savings of hospital discharge three days after acute myocardial infarction, we screened 507 consecutive patients prospectively for clinical complications and exercise-test performance. Of 179 patients whose condition was classified as uncomplicated (no angina, heart failure, or arrhythmia 72 hours after admission), 126 underwent early exercise testing and 90 had no provocable myocardial ischemia. Eighty of these patients were randomly assigned to early (day 3) or conventional (days 7 to 10) hospital discharge. Seventy-six of them had received coronary reperfusion therapy (thrombolysis, angioplasty, or both). At six months of follow-up, there were no deaths or new ventricular aneurysms, and the early-discharge and conventional-discharge groups had similar numbers of hospital readmissions (6 and 10), reinfarctions (none and 5), and patients with angina (3 and 8). In the early-discharge group, 25 of 29 previously employed patients returned to work 40.7 +/- 21.9 days (mean +/- SD) after admission, as compared with 25 of 27 patients in the conventional-discharge group, who returned to work after a mean of 56.9 +/- 30.3 days (P = 0.054). The mean cumulative hospital and professional charges were

Free radicals in ischemic myocardial injury.

12,546 +/- 3,034 in the early-discharge group, as compared with

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

17,868 +/- 3,688 in the conventional-discharge group (P less than 0.0001). In carefully selected patients with uncomplicated myocardial infarction, hospital discharge after three days is feasible and leads to a substantial reduction in hospital charges. Before this strategy can be widely recommended, however, its safety must be confirmed in larger prospective clinical trials.

Prostaglandins and Prostaglandin Inhibitors in Ischemic Heart Disease

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.

Risk analysis for aortic surgery using hypothermic circulatory arrest with retrograde cerebral perfusion.

Summary: 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 < 0.05), or 24 h, 53.0 ± 6.1 (p < 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 > 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.

Beneficial effects of nafazatrom on ischemic reperfused myocardium

The evidence for a role of the prostaglandin system in myocardial ischemia and its consequences is still fragmentary. We review the factors that alter the relation between thromboxane A2 and prostacyclin production such that vasoconstriction, platelet aggregation, and the tendency toward thrombus formation are increased. Strategies to prevent platelet aggregation by interfering with the production of thromboxane A2 or by stimulation or administration of prostacyclin are currently under investigation in a number of centers. The ubiquity of the prostaglandin system and our incomplete understanding make careful long-term clinical trials and observations essential if we are to be sure that the net effect of these attempts is beneficial.

Exercise testing three days after onset of acute myocardial infarction

BACKGROUND Retrospective analysis of 144 patients undergoing aortic arch reconstruction using hypothermic circulatory arrest (HCA) with retrograde cerebral perfusion (RCP) for cerebral protection was performed. METHODS The diagnosis, procedure, and anatomic site of the arch anastomosis were analyzed to see if they were independent predictors of mortality or morbidity. In addition age, gender, HCA-RCP times, preoperative malperfusion (both treated and untreated), surgical status, and redo surgery status were also examined to determine their influence on the incidence of death and complications. Both multivariate and univariate analysis were performed using linear regression and cross-tabulation with either chi2 or Fishers exact test where appropriate. RESULTS Preoperative surgical status (emergent) and the presence of untreated preoperative malperfusion were the only variables that were significant independent predictors for mortality (p <0.05). No variable was significant for the prediction of stroke or other complications. The severity of surgery had no bearing on the patient outcome. CONCLUSIONS Complex aortic surgery using HCA-RCP can be performed with acceptable risk to the patients.