P3490Intravenous administration of atorvastatin early after cardiac ischemia attenuates adverse left ventricular remodeling, ameliorates cardiac function and limits the deleterious effects of reinfarction
Authors: Vilahur G , Ben-Aicha S , Gutierrez M , Arzanauskaite M , Mendieta Badimon L G , Arderiu G , Casani L , Badimon L 
Published: October 2019

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