P3490Intravenous administration of atorvastatin early after cardiac ischemia attenuates adverse left ventricular remodeling, ameliorates cardiac function and limits the deleterious effects of reinfarction

Abstract

Abstract Background Statins have shown to attenuate reperfusion-induced myocardial injury. However, whether statins directly target ischemia-related cardiac damage attenuating adverse left ventricular (LV) remodeling and post-myocardial infarction (MI) complications remains unknown. Purpose We examined the impact of a single intravenous administration of IV-STATIN early after ischemia onset on LV remodeling and reinfarction in a dyslipidemic pig model by serial CMR. Methods Diet-induced hypercholesterolemic pigs (N=14; cholesterol: 394±61mg/dL) were subjected to 90min of ischemia (MI-induction by LAD-coronary balloon occlusion) and further reperfusion. One group of pigs received an intravenous bolus of IV-STATIN (a modified preparation of atorvastatin; 0.3mg/kg) at 15min of ischemia (IV-STATIN-ISCH; n=7) whereas the other was orally treated with atorvastatin shortly post-MI (ATORVA-POST-MI; n=7). 40 days thereafter animals underwent a second MI-induction (reinfarction) and were sacrificed at day43. All animals remained post-MI and until sacrifice on p.o. atorvastatin treatment and a high-cholesterol diet. Serial CMR analysis was performed at day3 (early LV remodeling), prior-reinfarction (late LV remodeling; day40) and post-reinfarction (day43) for the assessment of global anatomical and functional parameters and segmental motility. Myocardial tissue was collected for molecular and histological analyses of cell death-, inflammatory-, and angiogenic-related markers. Results CMR revealed 3 days post-MI an absolute 6% reduction on infarct size in IV-STATIN-ISCH pigs as compared to ATORVA-POST-MI pigs (18.0±0.8% LV vs. 23.9±1.9% LV; p<0.05) with the resultant 25% increase in myocardial salvage (p<0.05). These infarct size-limiting effects remained up to day40 and lead to 30% smaller scars vs. ATORVA-POST-MI pigs (9.9±0.8% LV vs. 13.9±1.9% LV; respectively; p=0.06). Interestingly, reinfarction did not expand the damage produced by MI in IV-STATIN-ISCH animals whereas it increased by 13% the scar size of ATORVA-POST-MI pigs (p<0.05). These IV-STATIN-ISCH- related benefits detected throughout the study were associated with a significant global improvement in stroke volume and LVEF as well and less regional wall motion abnormalities and dysfunctional segments in the jeopardized region (p<0.05 vs. ATORVA-POST-MI). The scar of reinfarcted IV-STATIN-ISCH pigs showed lower apoptosis execution and MCP-1 expression and higher vessel density vs. ATORVA-POST-MI (p<0.05). Lipids levels and liver/renal parameters remained unchanged in all animals throughout the study. Conclusions This is the first study to prove that intravenous administration of IV-STATIN early after MI improves structural and functional cardiac remodeling and limits the worsening effects of reinfarction. The potential cardiac benefits afforded by CardioshieldTM infusion early after MI-diagnosis (i.e., out-of-hospital and/or cath lab setting) deserves to be clinically investigated. Acknowledgement/Funding Fundaciό Investigaciό Marato TV3 #20154310; PNS 2015-71653-R and PNS SAF2016-76819-R MINECO, ISCIII; CIBERCV CN16/11/00411