What is the clinical evidence from this study?

Study design: Other. Population: Acute myocardial infarction (n=35). Intervention: Autologous porcine endothelial progenitor cells (EPC) or conditioned media vs. 0.9% normal saline. Primary outcome: Change in infarct-related territory (IRT) mass from baseline to 2 months (g) (p=<0.05).

June 18, 2008

Progenitor Cell Therapy in a Porcine Acute Myocardial Infarction Model Induces Cardiac Hypertrophy, Mediated by Paracrine Secretion of Cardiotrophic Factors Including TGFβ1

Q: What are the key findings of this study?

Intracoronary injection of autologous porcine endothelial progenitor cells or their conditioned media significantly increased infarct territory mass and improved regional systolic function at 2 months.

Key Result

Intracoronary injection of autologous porcine endothelial progenitor cells or their conditioned media significantly increased infarct territory mass and improved regional systolic function at 2 months.

Structured PICO

Does intracoronary injection of autologous endothelial progenitor cells or their conditioned media improve regional ventricular systolic function and infarct territory mass in a porcine model of acute myocardial infarction?

Population

35 Yorkshire pigs weighing 25 to 35 kg subjected to a closed-chest model of acute myocardial infarction and followed for 2 months.

Intervention

Intracoronary injection of autologous porcine endothelial progenitor cells (EPC) or conditioned media derived from autologous EPC

Comparator

Control

Outcome

Infarct territory mass and regional ventricular systolic function at 2 monthssurrogate

Endothelial progenitor cells improve regional function post-myocardial infarction in a porcine model via paracrine secretion of TGFbeta1, which induces cardiomyocyte hypertrophy.

Main Result

Absolute Event Rate: 19.6% vs 0%

p-value: p=<0.05

Limitations

Progenitor cell nomenclature is challenging in the porcine model due to a lack of specific antibodies.
The progenitor cells used were a heterogenous preparation, making the specific lineage contributing to secretion unclear.
The animals studied were healthy prior to infarction, unlike human patients who often have multiple risk factors.
Adjunctive post-infarction pharmacotherapy may interfere with the signaling pathways of the identified paracrine factors.
The study focused on cardiomyocyte size and LV mass changes, not traditionally studied parameters such as angiogenesis and scar formation.

Abstract

Administration of endothelial progenitor cells (EPC) is a promising therapy for post-infarction cardiac repair. However, the mechanisms that underlie apparent beneficial effects on myocardial remodeling are unclear. In a porcine model of acute myocardial infarction, we investigated the therapeutic effects of a mixed population of culture modified peripheral blood mononuclear cells (termed hereafter porcine EPC). Porcine EPC were isolated using methods identical to those previously adopted for harvest of EPC in human cell therapy studies. In addition the therapeutic effects of paracrine factors secreted by these cells was evaluated in vitro and in vivo. Intracoronary injection of autologous porcine EPC was associated with increased infarct territory mass and improved regional ventricular systolic function at 2 months compared to control. Treatment with conditioned media derived from autologous EPC was associated with similar improved effects on infarct territory mass and function. Histologic analysis of the infarct territory revealed significantly increased cardiomyocyte size in EPC and conditioned media treated groups, when compared to controls. A paracrine EPC effect was also verified in a pure myocardial preparation in which cardiomyocytes devoid of fibroblast, neuronal and vascular elements directly responded by increasing cell mass when exposed to the same conditioned media. Analysis of conditioned media revealed elevated levels of TGFbeta1 (human 267.3+/-11.8 pg/ml, porcine 57.1+/-6.1 pg/ml), a recognized mediator of hypertrophic signaling in the heart. Neutralizing antibodies to TGFbeta1 attenuated the pro-hypertrophic effect of conditioned media, and use of recombinant TGFbeta1 added to fresh media replicated the pro-hypertrophic effects of conditioned media in vitro. These data demonstrate the potential of paracrine factors secreted from endothelial progenitor cells to induce cardiomyocyte hypertrophy contributing to increased infarct territory LV mass, with favorable medium term effects on regional function following myocardial infarction.

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