Received for publication April 30, 2004.
Revised September 10, 2004.
Accepted for publication September 16, 2004.

Apolipoprotein A-I_Milano and 1-Palmitoyl-2-oleoyl phosphatidylcholine Complex (ETC-216) Protects the In Vivo Rabbit Heart from Regional Ischemia-Reperfusion Injury

Abstract

Ex vivo studies demonstrated that a synthetic HDL comprised of a complex of recombinant apolipoprotein A-I_Milano and 1-palmitoyl-2-oleoyl phosphatidylcholine protects the isolated rabbit heart from reperfusion injury. Therefore, we sought to determine if a pharmaceutical preparation of this complex, ETC-216, was cardioprotective in an in vivo model of left anterior descending artery (LAD) occlusion and reperfusion. Initially, ETC-216 (100 mg/kg) was tested in acute (one treatment) and chronic (two-treatments) IV administrations. ETC-216-treated rabbits developed smaller infarcts expressed as percent of area at risk (p<0.01) compared to vehicle treatments. No differences were noted between chronic and acute administration. Therefore next, ETC-216 (10, 3 or 1 mg/kg) or equivalent vehicle volumes were acutely infused. Compared to vehicle, ETC-216 reduced infarct size as a percent of the area at risk at 10 (p<0.0005) and 3mg/kg (p< 0.05). No significant differences occurred at 1 mg/kg. To determine if ETC-216 could protect the heart after initiation of ischemia, the synthetic HDL (10 mg/kg) was infused intravenously beginning 5 minutes prior to the end of 30 minutes of LAD occlusion. Infarct size as percent of the area at risk was 31.6±3.0 (ETC-216) versus 49.5±2.5 (vehicle), (p<0.001); and as percent of left ventricle was 19.7±1.6 (ETC-216) versus 34.1±2.3 (vehicle) (p<0.0005). Electron microscopy demonstrated that ETC-216 prevented irreversible cardiac damage as assessed by mitochondrial granulation and sarcomere contraction band formation. These findings suggest ETC-216 reduces reperfusion injury and may have utility for coronary artery revascularization procedures.

Key words: electron microscopy, infarct size, plasma lipoprotein, reperfusion injury, synthetic HDL, unesterified cholesterol

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