Original ArticleRandomized transcoronary delivery of CD34+ cells with perfusion versus stop-flow method in patients with recent myocardial infarction: Early cardiac retention of 99mTc-labeled cells activity
Introduction
Progenitor cell transplantation is anticipated to complement current revascularization strategies in acute myocardial infarction (MI) by stimulating endogenous repair and, potentially, by replacing part of the damaged microvascular and myocardial tissue. Initial reports of successful small-animal experiments led to direct, rapid attempts of their translation in the clinical setting. Today, transcoronary transfer of autologous bone marrow cells has been performed in more than 1,500 patients with a recent MI who were included in over 20 clinical studies.1, 2, 3 Meta-analyses of those studies indicate, disappointingly, that the long-term benefit is clinically minimal or absent.1,2
Efficient delivery of progenitor cells to the recent infarct injury zone is a pre-requisite for any effect of cell therapy.4,5 For transcoronary cell administration, past and current clinical studies have universally1, 2, 3 adopted a “stop-flow” technique, using the central lumen of an inflated over-the-wire balloon catheter positioned in the stent in infarct-related artery (IRA).6,7 Injecting the cells under flow arrest has been assumed to “allow for adhesion and potential transmigration of the infused cells through the endothelium”7, 8, 9 or “prolong contact time for cellular migration to the damaged tissue”.10 Interestingly, the stop-flow method was never shown to be required for progenitor cell delivery or to be effective in enhancing myocardial retention of the cells.6,11
Evaluation of different transcoronary cell administration techniques in man has been considered essential for further development of cellular therapies.6,11, 12, 13
Evidence indicates that, similar to leukocytes, flow-mediated undisturbed “physiological” rolling in contact with endothelium is a primary, mandatory step in progenitor cells trafficking.5 Progenitor cells endothelial rolling (mediated largely by selectins) is a “primer” for integrin-mediated downstream adhesion to the activated endothelium, and chemokine-mediated transendothelial diapedesis (extravasation) and migration to the injured tissue.4,5 In addition, blood flow-related hydrodynamic forces are known to play an important role in the cell rolling and adhesion process by interacting, for instance, with the selecin bonds.14 This suggested that cell administration under maintained coronary flow might be more effective than the coronary-occlusive delivery.
The perfusion technique, including the employment of side-holed catheters, has been in clinical use since 1990s for transcoronary drug administration under maintained coronary flow.15,16 More recently, the perfusion technique was found effective in transcoronary gene delivery in the pig heart in situ.17 Initially, in a pilot study the authors tested the feasibility of autologous bone marrow cell delivery through a perfusion catheter intended for intracoronary drug administration.4 Currently, the authors have developed a side-holed perfusion catheter (PC) dedicated to cell delivery under maintained coronary flow and, in a randomized study in man, the authors have quantified early myocardial uptake of autologous CD34+ cells administered with the stop-flow versus perfusion technique.
Section snippets
Cell-Delivery Perfusion Catheter
The side-hole design of the perfusion catheter was chosen because this design was previously shown to be optimal for towards-the-wall delivery.15,16 For bench testing, the authors designed PCs with the following parameters: (1) lumen size of 0.9 or 1.2 mm; (2) side-hole number of 8, 10, 12, 15, or 20; and (3) side-hole diameter of 0.10, 0.15, or 0.20 mm. All PCs were designed in rapid exchange (RX) system, with two independent lumens (one, RX, for a 0.014 inch guide-wire, and the other for
Results
Thirty-four patients (30 men) aged 36-69 years were recruited. The OTW- and PC-group were similar with respect to demographic, clinical, and laboratory characteristics (Table 1). The CD34+ cell number, and the labeled cells’ viability and activity were also similar (Table 2). Labeling efficiency, defined as the fraction of label retained by the cells, was 65.4 ± 2.1% (43.7-77.8%) and was not different between the study groups (64.6 ± 3.2% vs 66.1 ± 2.6%). The number of CD34+ cells correlated
Discussion
This study is the first human study on visualization and quantification of early retention of CD34+ cells delivered transcoronary with a non-occlusive technique. Our principle findings are as follows. First, in contrast to OTW coronary-occluding technique, no intolerance or ventricular arrhythmia occur in patients with a recent MI with cell administration through side-holed perfusion catheter dedicated to cell delivery. Secondly, irrespective of the transcoronary delivery method, early
Acknowledgments
We thank Professor M.Z. Ratajczak of the Institute of Regenerative Medicine, Stem Cell Biology Program, University of Louisville, KY, USA for his tutorials on the biology of progenitor cell trafficking and for his contribution to the study concept. We thank Professors M. Tendera and W. Wojakowski of Medical University of Silesia, Katowice, Poland for their support to the study set-up and execution.
The authors indicated that they have no financial conflicts of interest.
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Parts of this work have been presented to the Transcatheter Cardiovascular Therapeutics (Novel Concepts and Innovative Devices—Invited Faculty Session) and to the European Society of Cardiology (Young Investigator Awards).
Supported by Ministry of Science and Higher Education (Poland) (project PBZ-KBN-099/P05/2003) and ‘For the Heart Foundation’ in Kraków, Poland. AZ was a recipient of the City of Krakow Research Scholarship.