Effect of acute rosuvastatin administration on myocardial ischemia/reperfusion injury and MMP-2 activity under normo and hypercholesterolemic conditions.

VERÓNICA D'ANNUNZIO; MARTÍN DONATO; BRUNO BUCHHOLZ; LUKAS ERNI; VERÓNICA MIKSZTOWICZ; GABRIELA BERG; LAURA SCHREIER; NIDIA BASSO

Buenos Aires

Congreso; XVI World Congress of Cardiology.; 2008

World Heart Federation

Rosuvastatin pre-treatment reduces infarct size and improves ventricular dysfunction. However, no information is available on the putative beneficial effects of rosuvastatin when given during reperfusion. Thus, the main objective was to determine whether rosuvastatin administered during this condition can modify both the infarct size and the recovery of postischemic ventricular function in hearts from normo and hypercholesterolemic rabbits. Simultaneously, the role played by the activation of MMP-2 in these hearts was also evaluated. Isolated and isovolumic rabbit hearts were perfused according to Langendorff technique. The following groups were studied: 1- In normocholesterolemic rabbits: G1, 30 min of global ischemia and 120 min of reperfusion were performed; G2 similar to G1 but rosuvastatin (50µM) was administered during reperfusion. 2.-In hypercholesterolemic animals, fed with an enriched-cholesterol (1%) diet for 4 weeks, G3 was similar to G1 and G4 to G2. Total cholesterol before diet was 59.6±9.3 mg/dl, after diet was 185.4±21.4 mg/dl (p<0.05). Samples of the coronary effluent were collected in basal situation, 2, 5 and 30 min of the reperfusion period and the activity of MMP-2 measured itself for quantitative zimography, and there were quantified the gelatinolytic areas as relative areas (AR) and expressed  as percentage of basal value. After 2 hours of reperfusion, the hearts were frozen, and cut into slices from the apex to the base. Sections were incubated for 20 minutes in 1% triphenyltetrazolium chloride, and then immersed in 10% formalin. The infarct size was expressed as a percentage of the left ventricular area. Rosuvastatin improved LVDP and LVEDP only in hypercholesterolemic animals. The infarct size in G1 and G3 was 16.6±2.6% and 25.6±2.7%, respectively. Rosuvastatin administration reduced infarct size: in G3 was 4.5±1.1, and in G4 was 5.5±1.6 (p<0.05).Rosuvastatin also significantly decreased MMP-2 activity compared with the baseline coronary effluent sampled during aerobic perfusion both in normo and hypercholesterolemic rabbit hearts. The area under the curve (AUC, arbitrary units) of MMP-2 activity during the first 30 minutes of reperfusion was calculated in both experimental groups. Rosuvastatin significantly reduced AUC, in both normocholesterolemic and hypercholesterolemic animals. In normocholesterolemic animals the mean of AUC was 1873±286, the administration of rosuvastatin decreased AUC to 441±229, which represents a 76.4% reduction (p<0.05). Similarly, in hypercholesterolemic animals the AUC decreased from 1859±240 in control group to 1015±224 in rosuvastatin group, representing a 45.4% reduction (p<0.05). These groups present a relationship between MMP-2 activity at 2 minutes of reperfusion and infarct size considering all experimental groups. There is a positive and significant correlation between both variables (r2=0.97, p<0.01). This correlation suggests that MMP-2 activity could determine, at least in part, myocardial reperfusion injury.We concluded that rosuvastatin administration during reperfusion reduces infarct size in hearts from normo and hypercholesterolemic rabbits and improves the recovery of ventricular function in hypercholesterolemic animals. The attenuation of MMP-2 activity in rosuvastatin groups during reperfusion, and the correlation between MMP-2 and infarct size suggest that MMP-2 could plays an important role in myocardial reperfusion injury