Randomized transcoronary delivery of CD34(+) cells with perfusion versus stop-flow method in patients with recent myocardial infarction: Early cardiac retention of ⁹⁹(m)Tc-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 (⁹⁹(m)Tc-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.

Figure 1

Ventricular tachycardia (VT) associated with infarct-related artery (LAD)—occlusive cell delivery (2nd OTW-balloon inflation, man 53 years, day 7 after pPCI, LVEF 37%, ECG recording at 25 mm/s coupled to the angiocardiograph, Siemens Axiom Artis). Immediately prior to VT the patient reported increasing chest pain (note ST-segment elevation in I and aVL; this was progressive during the balloon inflation). Ischemia is a well-known trigger of ventricular arrhythmias in the setting of a forming myocardial scar which constitutes an arrhythmic substrate

Figure 2

Whole-body gamma-emission scans at 60 min after transcoronary delivery of ^99mTc-extametazime-labeled autologous CD34⁺ cells. Examples are from a patient with a large anterior MI (4th quartile, A, left, note two peaks of myocardial activity) and a relatively small anterior MI (1st quartile, B, right, note diffuse activity that may correspond to the anterior wall). LV is delineated in red. Myocardial activity was 6.52% (A) and 2.21% (B) of whole-body gamma emission. Detailed tomographic (SPECT) images from these two patients are shown in Figure 3I (left panel) and II (right panel), respectively

Figure 3

Box-plot presentation of % early myocardial retention of radioactivity 60 min after transcoroary delivery of ^99mTc-extametazime-labeled autologous CD34⁺ cells with coronary-occlusive (OTW, n = 13) versus non-occlusive perfusion (PC, n = 21) technique at 6-14 days after anterior MI (random assignment on a 1:2 basis). The median value was 4.32% and 5.03% respectively (P = .84 for difference between the groups). Myocardial activity uptake was expressed as % total body activity and it was taken as an index of early myocardial engraftment

Figure 4

SPECT images of myocardial perfusion (day 7 after MI; standard projections in A1-A3) and early myocardial uptake of radioactivity (^99mTc-extametazime-labeled autologous CD34⁺ cells, day 9 after MI, B1-B3 are same projections as A1-A3) in the OTW (left panel) and PC (right panel) group. Integrated images combining the activity of labeled cells and myocardial perfusion are shown in (C). Black arrows (top) indicate the peri-infarct zone. Note the lack of perfusion in septum, anterior wall and apex. Pink arrows (bottom) indicate the maintained (albeit impaired) perfusion in the septum, anterior wall and apex. Examples of the peri-infarct uptake of ^99mTc-labeled cells activity (typical early engraftment pattern, seen in 88% study patients) are in Figure 4I. Figure 4II shows representative examples of a diffuse infarct activity uptake that was seen in only 12% subjects who experienced a relatively small ischemic injury (infarct size in the 1st quartile and the LVEF in the 4th quartile by both echo and G-SPECT)