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

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Abstract
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). Methoxyverapamil (D600), a potent Ca antagonist, was used to test this hypothesis. In 68 dogs, 1 min after CAO, 8 mCi of 99mTc-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 min after CAO and 0.2 mg/kg per h as a continuous infusion for 6 h). After 6 h, 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. 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 that was hypoperfused in the left ventricle: 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 [standard error of the mean]), 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. 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%). 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.