Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties

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Abstract

Direct intramyocardial injection of mesenchymal stem cells (MSCs) improves left ventricular ejection fraction (LVEF) and may increase ventricular arrhythmia in hearts with myocardial infarction (MI). We hypothesized that intravenous MSCs given early after acute MI would engraft in injured myocardium, improve LV function, and result in pro-arrhythmic electrical remodeling. We created an apical infarction in swine by balloon occlusion/reperfusion, administered diI-labeled allogeneic bone marrow derived MSCs intravenously 30 min post-reperfusion and measured LVEF and wall thickness at baseline, 1 month, and 3 months. Epicardial effective refractory periods (ERPs) were determined before sacrifice. At 3 months, treated pigs [n = 7] had significantly higher LVEF than controls [n = 8] (49 ± 2% vs. 44 ± 3%, P = 0.015)and significantly less wall thickening of non-infarcted myocardium. ERPs were significantly shorter than controls at all pacing cycle lengths (P  0.002), suggesting a pro-arrhythmic potential. DiI was found in the lungs, in infarct, and peri-infarct myocardium. Conclusion: IV infusion of MSCs soon after acute MI in swine improves LVEF and limits wall thickening in the remote non-infarcted myocardium, consistent with a beneficial effect on post-MI ventricular remodeling. Since there is no need for immune suppression or clinical expertise, IV infusion of MSCs may expand the potential clinical application of stem cell therapy.

Introduction

Despite the clinical success of reperfusion therapy, a large proportion of patients develop myocardial necrosis, ventricular remodeling and resultant congestive heart failure after acute myocardial infarction (MI). Stem cell therapy may represent one approach to attenuate remodeling and thus improve clinical outcome.

Adult mesenchymal stem cells (MSCs) have multilineage potential.[1] They are not immunogenic and allogeneic transplantation does not require immunosupression [2], [3]. Direct intramyocardial injection of MSCs improves left ventricular (LV) function compared to controls in small animal and porcine models of sub-acute and chronic infarction.[2], [4] In humans, however, direct intramyocardial injection of MSCs has practical limitations to widespread clinical use. If efficacious, the intravenous (IV) infusion of MSCs has clear practical advantages.

We sought to examine the effects of MSC therapy in a porcine model of acute MI that is clinically relevant in the era of reperfusion therapy: IV delivery very early after reperfusion of a culprit artery. We hypothesized that intravenously infused MSCs would home to the zone of injury and attenuate post-infarct remodeling. We have previously shown that direct MSC injection induces nerve sprouting, suggesting a potential pro-arrhythmic effect [5]. We thus sought to determine through electrophysiological testing whether IV MSC therapy could create an arrhythmogenic substrate.

Section snippets

MSC preparation

Porcine mesenchymal stem cells were isolated and cultured as previously described [1]. The MSCs were labeled with a cross-linkable membrane dye, DiI (Molecular Probes, Inc, Eugene, OR) following the manufacturer's protocol, and then frozen and thawed for use.

Infarct model

Farm pigs (n = 23, mean weight 20 ± 9.5 kg) were premedicated with amiodarone (400 mg/day for 7 days preoperatively, then 200 mg/day for 3 days), and treated with atenolol (25 mg), ASA (325 mg) and plavix (75 mg) three days prior to infarction

Infarct model

Eleven animals were enrolled into the control arm, and twelve into the IV-MSC arm. Three animals in the control group and three animals in the IV-MSC group expired within three days of infarct induction. One animal in the IV-MSC group expired the day prior to 3-month follow-up and sacrifice, and another in the IV-MSC group was euthanized early at two weeks post-infarction because of clinical signs of severe heart failure. Pathology of the latter animal demonstrated a larger infarct size than

Discussion

The most important finding in this study is that the IV infusion of allogeneic MSCs soon after the induction of acute MI results in a significantly greater LVEF and less eccentric hypertrophy compared to untreated animals at 3 months follow-up.

Three months after therapy, the magnitude of difference in LVEF was nearly 5% compared to controls. This difference was significant using a single-tailed test, which was used because prior stem cell studies have consistently indicated a beneficial effect

Conclusions

Intravenous delivery of allogenic mesenchymal stem cells early after reperfused acute MI in a porcine model led to significantly greater LVEF, less eccentric hypertrophy, global shortening of ERPs and increased slope of restitution curves at 3 months follow-up compared to controls. Therefore, intravenous MSC may alter electrical and mechanical ventricular remodeling post-MI. Our study supports the concept that systemic MSC administration after successful primary reperfusion for acute MI may

Acknowledgement

This study was funded by a grant from Osiris Therapeutics, Inc.

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