Intracoronary delivery of mesenchymal stem cells at high flow rates after myocardial infarction improves distal coronary blood flow and decreases mortality in pigs

Abstract

Objectives: Evaluate the effects of pressure and duration of intracoronary (IC) infusion of mesenchymal stem cells (MSCs) on delivery efficiency and safety after myocardial infarction (MI).

Background: Standard IC delivery of MSCs can lead to intravascular plugging and reduced coronary blood flow. The optimal delivery pressure and duration is unknown.

Methods: Immediately after MI pigs were randomized to 1 of 3 delivery protocols of 5 x 10(7) iron-fluorescent microspheres labeled MSCs, control received 2 ml infusions at 1 ml/min (five times), very high flow rate (VHFR) a single 10 ml infusion at 60 ml/min and the high flow rate (HFR) group a single 10 ml infusion at 20 ml/min. TIMI grade flow was assessed throughout the procedure and at sacrifice (day 14). MSCs distribution was analyzed in isolated hearts by 4.7T MRI. Delivery efficiency was quantified via fluorescent microsphere recovery using a magnetic separation technique and by light microscopy.

Results: TIMI grade flow did not change following MI (all groups TIMI 3). However, following MSCs delivery only 18% (2/11) of control animals had TIMI 3 blood flow vs. 56% (5/9) in VHFR and 67% (4/6) in HFR (P = 0.03). As a consequence, 63% of control animals died within 24 hr, 33% in VHFR and none in HFR (P = 0.02). MSCs delivery in the infarct tissue did not differ between the groups (P = 0.06).

Conclusions: A single MSCs infusion at 20 ml/min resulted in improved coronary blood flow and decreased mortality, without sacrificing delivery efficiency.

(c) 2008 Wiley-Liss, Inc.

Figures

Fig. 1

Delivery of mesenchymal stem cells (MSCs) at 60 ml/min (VHFR) and 20 ml/min (HFR) was associated with improved TIMI flow rates after infusion. VHFR, very high flow rate; HFR, high flow rate; MI, myocardial infarction.

Fig. 2

TIMI grade flow following mesenchymal stem cells (MSCs) infusion after infarction. Delivery at either 60 ml/min (n = 9) or 20 ml/min (n = 6) resulted in a higher percentage of animals exhibiting TIMI 3 grade flow following MSCs infusion compared to the control group (n = 11) (P = 0.03).

Fig. 3

Representative MRI examples showing the presence of iron-labeled cells (dark areas) 14 days following delivery in the three groups. Transversal slice imaging shows cells located in the approximate infarct region fed by the mid and distal LAD (anterior and septal walls).

Fig. 4

Intracoronary delivery of mesenchymal stem cells (MSCs) in infarct tissue was similar across the groups (control vs. experimental P = 0.06). Lines represent mean values for each group. *Shows animal with persistent occlusion of LAD following MSCs delivery, associated with the highest retention of cells.

Fig. 5

Concentration of Prussian blue-positive cells in the infarct and normal zones detected by histology. Upper panel: There was no significant difference in particle concentration in the infarct tissue among the 3 groups (P = 0.71). Results are expressed as mean ± SEM. Lower panel: (A) ×100 magnification of the infarct tissue showing Prussian Blue-positive mesenchymal stem cells following delivery at 60 ml/min (B) ×400 magnification of the black box in panel A. Bar indicates 100 μm. [Color figure can be viewed in the online issue, which is available at www.interscience.wiley.com.]