Basic Science Research
Shock Wave-Pretreated Bone Marrow Cells Further Improve Left Ventricular Function After Myocardial Infarction in Rabbits

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Background

We tested whether shock wave (SW) offers additional benefits in improving left ventricular (LV) function after acute myocardial infarction (AMI) in rabbits receiving SW-treated autologous bone marrow-derived mononuclear cells (BMDMNCs) transplantation.

Methods and Results

Saline (750 μL; group 2), BMDMNCs (1.0 × 107; group 3), or preimplant SW-treated BMDMNCs (group 4) were implanted into the infarct area of male rabbits 15 minutes after left coronary artery ligation, whereas eight rabbits without AMI served as controls (group 1; n = 8 per group). The results showed that in infarct area of LV, protein expressions of Cx43 and cytochrome C in mitochondria and endothelial nitric oxide synthase mRNA expression were lower in group 2 than in other groups, and decreased in group 3 as compared with groups 1 and 4 (all p values < 0.01). Conversely, mRNA expressions of endothelin-1 and matrix metalloproteinase-9, mitochondrial oxidative stress, and total fibrotic area were higher in group 2 than in other groups (all p values < 0.05). Furthermore, 6-month LV function by 2-D echo/angiogram showed significant impairment in group 2 than in other groups and in group 3 than in groups 1 and 4 (all p values < 0.005).

Conclusions

Application of SW-treated autologous BMDMNCs is superior to BMDMNCs alone for preserving LV function after AMI.

Introduction

Acute myocardial infarction (AMI) remains the leading cause of death in patients hospitalized for cardiovascular disease.1, 2 Numerous clinical studies have demonstrated that the achievement of brisk thrombolysis in myocardial infarction grade 3 flow immediately after thrombolytic therapy or primary percutaneous coronary intervention in AMI is effective in minimizing the effect of ischemic insult to myocardium, preserving left ventricular (LV) function, and improving overall survival.3, 4, 5, 6 However, there is limited benefit of reperfusion therapy if medical attention is delayed.7, 8 Additionally, despite application of reperfusion therapy,3, 4, 5, 6 nonviable cardiomyocytes after MI cannot be regenerated. Therefore, LV dilatation and remodeling from poor regional and global contractile function mainly account for poor clinical outcomes.9, 10, 11, 12, 13 Therefore, restoring lost myocardium is desirable in treating AMI.

Increasing evidence shows that bone marrow stem cell (SC) therapy seems highly advantageous in improving ischemia-induced or infarct-related cardiac dysfunction.14, 15, 16 Clinical observational studies have further established that the improvement in LV function is mainly because of angiogenesis after SC transplantation.17, 18 Moreover, in vitro studies indicate that extracorporeal shock wave therapy not only can upregulate the expression of vascular endothelial growth factor in cultured human umbilical vein endothelial cells19, 20 and in rat bone marrow cells,21but it can also promote bone marrow cells to develop endothelial phenotype.21 Accordingly, this study tested the hypothesis that autologous transplantation of shock wave (SW)-treated culturing bone marrow-derived mononuclear cells (BMDMNCs) into infarct LV myocardium is superior to BMDMNC therapy alone in improving LV function in a rabbit model of AMI.

Section snippets

Ethics

All experimental procedures had been approved by the Institute of Animal Care and Use Committee at our hospital and performed according to the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, National Academy Press, Washington, DC, revised 1996).

Animals, Protocol, and Procedure

Pathogen-free, male New Zealand rabbits, weighing 2.5-2.8 kg were used in this study. Rabbits were anesthetized by mixture of intraperitoneal ketamin (25 mg/kg) and rompon (12 mg/kg). After being shaved on the chest, each

Body Weight, Echocardiographic, and Angiographic Findings and Mortality (Table I)

The initial and final body weight did not differ among the four groups. Additionally, echocardiographic study demonstrated no differences in terms of initial LVEF, left ventricular end-systolic dimension (LVESD), and LVEDD. By day 30 after AMI induction, the echocardiographic examination revealed that LVEDD was similar among the four groups. However, the echocardiographic findings showed that LVESD was significantly higher, whereas LVEF was significantly lower in groups 2-4 as compared with

An Additional Benefit of Preimplantation SW Application to Culturing BMDMNCs for Improving LV Function and Attenuating LV Remodeling

Both experimental and clinical observational studies have established that bone marrow stem cell therapy improves ischemia- or infarct-related LV dysfunction.14, 15, 16, 17, 18, 19, 24 The present study, using a rabbit AMI model, also revealed that BMDMNC implantation into IA improved 120-day LV function. Therefore, the results of the current study strengthen the findings of those previous studies.

In fact, although growing evidence indicates that various types of cellular therapy improve LV

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    Cheuk-Kwan Sun contributed equally to this study compared with the first author.

    Steve Leu contributed equally to this study compared with the corresponding author.

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