Animal models for protecting ischemic myocardium: results of the NHLBI Cooperative Study. Comparison of unconscious and conscious dog models.

Abstract

The Animal Models for Protecting Ischemic Myocardium Study was undertaken for the purpose of developing reproducible animal models that could be used to assess interventions designed to limit infarct size. This paper describes the results obtained in an unconscious dog model and in a conscious dog model, developed in three participating laboratories. The unconscious dog model, involving reperfusion after 3 hours of ischemia in open-chest dogs, was intended to determine whether therapy followed by early reperfusion would limit infarct size more than reperfusion alone. The conscious dog model used chronically instrumented dogs and permanent coronary occlusion to better mimic myocardial infarction in man. In both models, the proximal circumflex artery was occluded, and the primary experimental endpoint was infarct size, as measured by histological techniques 3 days after the initial occlusion. Infarct size was analyzed in relation to baseline variables including the anatomic area at risk, collateral blood flow to the subepicardial zone of ischemia and hemodynamic determinants of myocardial metabolic demand. Most of the variation in infarct size in control dogs could be related to variation in the area at risk, collateral blood flow, and rate pressure product. Using multivariate analysis and groups of 15 dogs, an intervention that limited infarct size by 10-13% of the area at risk would have been detected 50% of the time. Larger treatment effects would be detected more readily, and smaller effects often would be missed, unless group sizes were larger. Two drugs, verapamil and ibuprofen, were evaluated in both models, with experimental group sizes averaging 13 and 20 dogs, in the unconscious and conscious models, respectively. Three of 15 verapamil-treated dogs in the unconscious model study had much smaller infarcts than expected from baseline parameters. With these exceptions, neither drug limited infarct size in either model.

Neuroprotective antioxidant STAZN protects against myocardial ischemia/reperfusion injury

“…Thus, in experimental studies of myocardial infarction, measurement of the area at risk is often presented as a necessary control for each animal [32], with the infarct size being normalized and expressed as a percentage of the area at risk. Because of large inter-animal variation in infarct size in canine models, the normalization to area at risk appears reasonable in this species [33]. In humans, while the size of the occluded coronary vascular bed is a determinant of infarct size, the difficulty of measuring the size of the riskzone in humans [34] precludes defining or normalizing clinical infarct size as a percentage of the area at risk.…”

Comparison of the effects of EXP3174, an angiotensin II antagonist and enalaprilat on myocardial infarct size in anaesthetized dogs

“…Furthermore, in order to assess regional myocardial blood flow and infarct size, we followed the recommendations of the NHLBI cooperative study (Reimer et al, 1985 'O'Ru or "4"Ce (New England Nuclear, Boston, Massachusetts, U.S.A.), were injected through the catheter into the left atrial appendage, followed by a 10 ml saline flush. Beginning just before and continuing for 60 s after injection, a reference sample of arterial blood was withdrawn from the femoral artery at a rate of 9 ml min-'.…”

Effect of duration of ischaemia on reduction of myocardial infarct size by inhibition of neutrophil accumulation using an anti‐CD18 monoclonal antibody

“…The absence of measurements of myocardial blood flow in many of these studies has been suggested as a possible reason for the contradictory results reported in the literature (Reimer et al, 1989) since there could be differences in the level of collateral blood flow in control and treated groups. This was not considered to be a problem in our study since rabbits have been shown to have negligible coronary collateral blood flow (Maxwell et al, 1987 protection was reported with anti-neutrophil interventions were characterized by a shorter duration of coronary artery occlusion (Litt et al, 1989;de Lorgeril et al, 1989;Simpson et al, 1990), compared with most of those reporting no effect (Reimer et al, 1985;Chatelain et al, 1987). Furthermore, Jolly et al (1986) have previously reported that protection with anti-neutrophil antiserum in a canine model of acute myocardial infarction was lost when the duration of ischaemia was extended from 90 min to 4 h. Thus, there appears to be a difference between dogs and rabbits regarding the duration of ischaemia which can be tolerated.…”