Abstract
BackgroundIntracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC), after acute myocardial infarction (AMI), has been shown to improve myocardial function. However, therapeutic efficacy is limited, possibly because cell retention rates are low, suggesting that optimization of cell retention might increase therapeutic efficacy. Since retention of injected BMMNC is observed only within infarcted, but not remote, myocardium, we hypothesized that adhesion molecules on activated endothelium following reperfusion are essential. Consequently, we investigated the role of vascular cell adhesion molecule 1 (VCAM-1) in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion.Methods and resultsVCAM-1 expression in the infarct and remote region was quantified at 1, 3, 7, 14, and 35 days, post-reperfusion (n≥6 swine per group). Since expression levels were significantly higher at 3 days (2.41±0.62%) than at 7 days (0.98±0.28%; p<0.05), we compared the degree of cell retention at those time points in a follow-up study, in which an average of 43·106 autologous BMMNCs were infused intracoronary at 3, or 7 days, post-reperfusion (n = 6 swine per group) and retention was histologically quantified one hour after intracoronary infusion of autologous BMMNCs. Although VCAM-1 expression correlated with retention of BMMNC within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3±1.3% vs. 3.1±1.4%, p = 0.72). This was not due to the composition of infused bone marrow cell fractions (analyzed with flow cytometry; n = 5 per group), as cell composition of the infused BMMNC fractions was similar.ConclusionThese findings suggest that VCAM-1 expression influences to a small degree, but is not the principal determinant of, BMMNC retention.
Highlights
Cell therapy with autologous bone marrow-derived cells generally yields statistically significant, but rather modest, improvements in myocardial function after acute myocardial infarction (AMI) [1,2,3]
vascular cell adhesion molecule 1 (VCAM-1) expression correlated with retention of bone marrow-derived mononuclear cells (BMMNC) within each time point, overall BMMNC retention was similar at day 3 and day 7 (2.3±1.3% vs. 3.1±1.4%, p = 0.72)
The major findings were that: (i) vascular cell adhesion molecule 1 (VCAM-1) expression is upregulated in the microcirculation of infarct-impaired myocardial tissue in a transient manner with VCAM-1 presence peaking at 3 days (~12- fold) and 7 days (~5-fold) post-AMI, with normalization to baseline values within 14 days post-AMI; (ii) VCAM-1 expression correlated with the magnitude of cell retention both at 3 days and 7 days post-AMI, but average cell retention was not different at 3 days vs. 7 days, indicating that cell retention was primarily independent of VCAM-1 presence; (iii) composition of the mononuclear fraction was not different 3 or 7 days post-AMI and selected cell types individually did not correlate with retention
Summary
Cell therapy with autologous bone marrow-derived cells generally yields statistically significant, but rather modest, improvements in myocardial function after acute myocardial infarction (AMI) [1,2,3]. As measured with immunofluorescence, was observed only within the infarcted region, whereas no cells were retained when cells were injected selectively into the non-occluded left anterior descending coronary artery (LAD). The latter findings suggest that cell adherence and retention are active processes, occurring exclusively in the reperfused infarct-zone, and not just physical entrapment of the cells due to cell size. Intracoronary infusion of autologous bone marrow-derived mononuclear cells (BMMNC), after acute myocardial infarction (AMI), has been shown to improve myocardial function. We investigated the role of vascular cell adhesion molecule 1 (VCAM-1) in BMMNC retention in swine undergoing reperfused AMI produced by 120 min of percutaneous left circumflex coronary occlusion
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