Influence of the extent of the zone at risk on the effectiveness of drugs in reducing infarct size.

Abstract

SUMMARY The goal of this study was to examine whether the effectiveness of a drug in protecting ischemic myocardium depends on the size of the hypoperfused zone (the area at risk) measured immediately after coronary artery occlusion (CAO). Methoxy-verapamil (D600), a potent calcium antagonist, was used to test this hypothesis. In 68 dogs, 1 minute after CAO, 8 mCi of technetium-99m-labeled albumin microspheres were injected into the left atrium for later assessment of the hypoperfused zone by autoradiography. Eighteen dogs were treated with D600 (0.8 mg/kg as a bolus 15 minutes after CAO and 0.2 mg/kg/ hour as a continuous infusion for 6 hours). After 6 hours, the hearts were excised and the left ventricles cut into 3-mm-thick slices and stained with triphenyltetrazolium chloride. The extent of myocardial damage was measured by planimetry of the unstained areas. Thereafter, the same slices were autoradiographed and the extent of the hypoperfused zones measured by planimetry of the "cold spots."Both the treated and control dogs were classified according to the amount of the left ventricle that was hypoperfused: small (< 25%), medium (25-30%), and large (> 30%). In control dogs with small, medium and large hypoperfused zones, the percentages of the hypoperfused zone that evolved to infarction were 95.9 + 3.5% (mean ± SEM), 90.8 3.5%, and 93.1 ± 2.6%, respectively; in the D600-treated dogs, 31.9 ± 8.3%, 53.8 ± 3.0%, and 61.3 9.2%, respectively. Thus, the dogs with the smallest areas at risk had the most extensive reduction in damage (67%); the effectiveness of treatment was intermediate in those with medium areas at risk (41%) and treatment had the least effect in those with the largest area at risk (34%). Thus, the size of the area at risk, determined in vivo immediately after CAO, is an important factor in determining the effectiveness of a drug in reducing myocardial damage.NUMEROUS INTERVENTIONS are effective in reducing the extent of myocardial damage after experimental coronary artery occlusion.'-5 However, it is not known whether, besides the beneficial properties of the intervention, the degree of effectiveness depends upon the initial size of the area at risk of infarction, i.e., the hypoperfused zone (HZ). The goal of this investigation was to determine whether methoxy-verapamil (D600), a potent calcium antagonist,6"'reduces myocardial damage to the same extent in areas of hypoperfusion of different magnitudes. To assess the zone of hypoperfusion, 2 x 106 highly radioactive (8 mCi) albumin microspheres, 20 u in diameter (3M Company), were injected into the left atrium 1 minute after coronary artery occlusion.8 9Fifteen minutes after occlusion, the dogs were randomized into two groups, 50 to a control group and 18 to a D600-treated group. In the latter, D600 was administered intravenously: 0.8 mg/kg as a bolus, followed by a continuous infusion of 0.2 mg/kg/hour until 6 hours after coronary artery occlusion.Six hours after coronary artery occlusion, the dogs were killed and the left ventricle (LV) was diss...

Hydrogen peroxide contrast--enhanced two-dimensional echocardiography: real-time in vivo delineation of regional myocardial perfusion.

“…Close correlation between area of risk, as demonstrated by MB staining, and area of infarction, as shown by TTC staining, has previously been demonstrated after 6 hr of occlusion without a myocardial salvaging intervention. 17 18 Thus, the extent of infarction also correlated well with that of ECD in our series in which no attempt was made at salvage. The extent of the ECD was a considerably more accurate indicator of the state of The correlation is higher and the estimating error is smaller for percent circumferential extent of abnormality at all levels for ECD vs MB than for ECD vs TTC, indicating that ECD corresponds to malperfusion rather than infarction.…”

Comparative effects of nicardipine, a new calcium antagonist, on size of myocardial infarction after coronary artery occlusion in dogs.

“…Data from three dogs (all in the pretreatment group) with hypoperfused zones smaller than 10% of the left ventricle were excluded from the analyses of the effects of nicardipine on the incidence of ventricular arrhythmias and on myocardial infarct size after coronary artery occlusion, because it has been demonstrated that both the occurrence of ventricular arrhythmias and the effectiveness of an intervention to reduce infarct size depend on the extent of the hypoperfused zone, and that the smaller the hypoperfused zone, the less frequent the ventricular arrhythmia and the more effective the treatment.34 41 Ventricular arrhythmias and mortality. Ventricular fibrillation did not occur during reperfusion after temporary (5 min) coronary artery occlusion.…”

Effects on infarct size of reperfusion and pretreatment with β-blockade and calcium antagonists

“…In the present study in anaesthetised dogs this principle has been applied, but a number of problems were encountered, this experience led us to redefine the most appropriate method for our purpose, as existing experimental procedures in dogs are not very reproducible or economical. Large numbers of animals have been required (31,43), and the results with drug treatments controversial (28,34,48,55). Previous work has emphasised the important difference between permanent coronary artery occlusion and temporary occlusion followed by reperfusion (41).…”