Therapeutic potential of tacrolimus on acute myocardial infarction in minipigs: analysis with serial cardiac magnetic resonance and changes at histological and protein levels.

Sheung-Fat Ko,Jiunn-Jye Sheu,Min-Chi Chen,Chung-Cheng Huang,Steve Leu,Hon-Kan Yip,Shu-Hang Ng,Cheuk-Kwan Sun,Chia-Chang Lee,Chen-Chang Lee

doi:10.1155/2014/524078

Abstract

This study investigates the therapeutic potential of intracoronary tacrolimus against acute myocardial infarction (AMI) in minipigs with serial cardiac magnetic resonance (CMR) and changes at histological and protein levels. Twelve minipigs subjected to permanent left anterior descending artery ligation were randomized as tac-treated group (n = 6, with intracoronary tacrolimus treatment) and controls (n = 6). CMR with cine and late gadolinium enhancement (LGE) studies were performed on postoperative days 2, 5, and 21. There were no significant differences in left ventricular function (LVF), contractility, and LGE between the two groups on day 2. On day 5, the tac-treated group showed a significantly higher ejection fraction, smaller infarct, and lower day-5/day-2 infarct ratio than controls. On day 21, the controls demonstrated further deterioration of LVF and infarct. Contrastingly, the tac-treated animals demonstrated preservation of LVF, contractility, significantly smaller infarct, and lower day-21/day-2 infarct ratios compared with those on day 5 and controls. The in vivo CMR results were correlated with in vitro findings on histology, immunostaining, and Western blotting which revealed significantly less fibrosis, higher vascularities, less CD68+ and CD40+ inflammatory cells, lower expressions of inflammatory (MMP-9, NF-κB, and TNF-α), and apoptotic (Bax, Caspase-3, c-PARP) biomarkers, respectively, in tac-treated AMI minipigs than controls.

Highlights

Ischemic heart disease is one of the leading causes of death worldwide [1]
The present study investigates the therapeutic potential of intracoronary tacrolimus administration in minipigs after permanent left anterior descending (LAD) artery ligation using serial cardiac magnetic resonance (CMR) with detailed in vivo assessment of left ventricular changes
On postoperative day 2, there were no significant differences between the control and tac-treated groups in left ventricular (LV) mass/body weight (BW) ratio, LVED, and LVES volume/BW ratios, stroke volume (SV) and ejection fraction (EF), and the infarct extent on late gadolinium enhancement (LGE)

Summary

Introduction

Reperfusion of the jeopardized myocardium remains the most common approach to treating acute myocardial infarction (AMI) [2]. Recent studies have proposed that inflammatory and immune reactions play important roles in AMI and that administrating immunosuppressive drugs to block such reactions could potentially salvage the myocardium. Experimental and clinical studies have reported that cyclosporine, a potent immunosuppressant, can reduce left ventricular (LV) infarct size and preserve LV function (LVF) after AMI [6, 7]. Two recent studies reported preserved LVF in minipigs with AMI treated by intracoronary administration of tacrolimus using echocardiographic assessment [9, 10]. The present study investigates the therapeutic potential of intracoronary tacrolimus administration in minipigs after permanent left anterior descending (LAD) artery ligation using serial CMR with detailed in vivo assessment of left ventricular changes. The findings from in vitro histopathologic, immunostaining, and Western blot studies of the explanted heart were used for confirming the in vivo observations

Material and Methods

Cardiac Magnetic Resonance

Results

Discussion

Conflict of Interests