Intravenous mesenchymal stem cell therapy early after reperfused acute myocardial infarction improves left ventricular function and alters electrophysiologic properties
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.
References (38)
- et al.
Mesenchymal stem cells are capable of homing to the bone marrow of non-human primates following systemic infusion
Exp Hematol
(2001) - et al.
Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction
J Am Coll Cardiol
(2003) The time course of left ventricular remodeling after acute myocardial infarction
Am J Cardiol
(1997)- et al.
Nonhematopoetic mesenchymal stem cells can be mobilized and differentiate into cardiomyocytes after myocardial infarction
Blood
(2004) - et al.
Mesenchymal stem cells promote engraftment of human umbilical cord blood-derived CD34(+) cells in NOD/SCID mice
Exp Hematol
(2002) - et al.
Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo
Exp Hematol
(2002) - et al.
Upstream stimulation versus downstream stimulation: arrhythmogenesis based on repolarization dispersion in the human heart
J Am Coll Cardiol
(2002) - et al.
Autologous bone-marrow stem–cell transplantation for myocardial regeneration
Lancet
(2003) - et al.
Catheter-based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease: a feasibility study
J Am Coll Cardiol
(2003) - et al.
Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up
J Am Coll Cardiol
(2003)