Telmisartan in the diabetic murine model of acute myocardial infarction: dual contrast manganese-enhanced and delayed enhancement MRI evaluation of the peri-infarct region.

Ildiko Toma,Phillip C Yang,Paul J Kim,Michael V Mcconnell,Rajesh Dash,Phillip Harnish,Dwight Nishimura

doi:10.1186/s12933-016-0348-y

Abstract

Background A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI–DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model.Methods and resultsDual contrast MEMRI–DEMRI was performed on weeks 1, 2, and 4 following initiation of telmisartan treatment in 24 left anterior descendent artery ligated diabetic mice. The MRI images were analyzed for core infarct, peri-infarct, left ventricular end-diastolic, end-systolic volumes, and the left ventricular ejection fraction (LVEF). Transmission electron microscopy (TEM) and real-time PCR were used for ex vivo analysis of the myocardium. Telmisartan vs. control groups demonstrated significantly improved LVEF at weeks 1, 2, and 4, respectively (33 ± 7 %*** vs. 19 ± 5 %, 29 ± 3 %*** vs. 22 ± 4 %, and 31 ± 2 %*** vs 18 ± 6 %, ***p < 0.001). The control group demonstrated significant differences in the scar volume measured by MEMRI and DEMRI, demonstrating peri-infarct injury. Telmisartan group significantly salvaged the peri-infarct injury. The myocardial effects were validated by TEM, which confirmed the presence of the injured but viable cardiomyocyte morphology in the peri-infarct region and by flow cytometry of venous blood, which demonstrated significantly increased circulating endothelial progenitor cells (EPCs).ConclusionThe improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of EPCs to salvage the injured cardiomyocytes. Dual-contrast MEMRI–DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally.

Highlights

A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region
The improved cardiac function in ischemic cardiomyopathy of diabetic mice by telmisartan is attributed to the attenuation of the peri-infarct injury by the angiogenic effects of endothelial progenitor cell (EPC) to salvage the injured cardiomyocytes
Dual-contrast MEMRI–DEMRI technique tracked the therapeutic effects of telmisartan on the injured myocardium longitudinally

Summary

Introduction

A novel MRI technique, employing dual contrast manganese-enhanced MRI (MEMRI) and delayed enhancement MRI (DEMRI), can evaluate the physiologically unstable peri-infarct region. Dual contrast MEMRI–DEMRI enables comprehensive evaluation of telmisartan to salvage the peri-infarct injury to elucidate the underlying mechanism of restoring the ischemic cardiomyopathy in the diabetic mouse model. The. Angiotensin-converting enzyme inhibitors (ACE) has been repeatedly shown to decrease cardiovascular mortality in the diabetic population [5]. ACE inhibitors and have shown to reduce major cardiovascular disease outcomes [6]. Telmisartan, in particular, has been shown to be equivalent to ACE inhibitors in providing cardiovascular protection in high-risk heart failure patients, the diabetic population [7, 8]. The anti-apoptotic, anti-fibrotic and angiogenic effects of telmisartan with the modulatory role on peroxisome proliferator-activated receptor gamma (PPARγ) may contribute to the microvasculature of the periinfarct region to salvage the injured myocardium, reduce the remodeling of the myocardium and improve cardiac function [9]

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Conclusion