Randomized 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

Abstract

Background

For transcoronary progenitor cells’ administration, injections under flow arrest (over-the-wire balloon technique, OTW) are used universally despite lack of evidence for being required for cell delivery or being effective in stimulating myocardial engraftment. Flow-mediated endothelial rolling is mandatory for subsequent cell adhesion and extravasation.

Methods

To optimize cell directing toward the coronary endothelium under maintained flow, the authors developed a cell-delivery side-holed perfusion catheter (PC). Thirty-four patients (36-69 years, 30 men) with primary stent-assisted angioplasty-treated anterior MI (peak TnI 151 [53-356]ng/dL, mean[range]) were randomly assigned to OTW or PC autologous ⁹⁹Tc-extametazime-labeled bone marrow CD34⁺ cells (4.34 [0.92-7.54] × 10⁶) administration at 6-14 days after pPCI (LVEF 37.1 [24-44]%). Myocardial perfusion (^99mTc-MIBI) and labeled cells’ activity were evaluated (SPECT) at, respectively, 36-48 h prior to and 60 min after delivery.

Results

In contrast to OTW coronary occlusions, no intolerance or ventricular arrhythmia occurred with PC cells’ administration (P < .001). One hour after delivery, 4.86 [1.7-7.6]% and 5.05 [2.2-9.9]% activity was detected in the myocardium (OTW and PC, respectively, P = .84). Labeled cell activity was clearly limited to the (viable) peri-infarct zone in 88% patients, indicating that the infarct core zone may be largely inaccessible to transcoronary-administered cells.

Conclusions

Irrespective of the transcoronary delivery method, only ≈5% of native (i.e., non-engineered) CD34⁺ cells spontaneously home to the injured myocardium, and cell retention occurs preferentially in the viable peri-infarct zone. Although the efficacy of cell delivery is not increased with the perfusion method, by avoiding provoking ischemic episodes PC offers a rational alternative to the OTW delivery.

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.