Background:
Intracoronary infusion of bone marrow (BM) mononuclear cells (BM-MNCs) late after acute myocardial infarction (AMI) has shown no improvement in global or regional left ventricular (LV) function (LateTIME and SWISS-AMI). Studies in experimental AMI models suggest a possible cytokine-related depression of progenitor cell function. Furthermore, BM cell content is correlated with the LV functional response. Accordingly, we hypothesize that inflammatory cytokines associated with the late phase of AMI may impair BM function and alter progenitor cell subsets.
Method:
Patients with previous AMI (n=87) were recruited in a multicenter cell therapy trial by the Cardiovascular Cell Therapy Research Network (CCTRN LateTIME, NCT00684060). BM and peripheral blood (PB) were collected 2-3 weeks after AMI and examined for cell phenotypes and progenitor capacities as well as PB inflammatory and angiogenic cytokines in a core laboratory. Multiple regression analyses were conducted and correlations between cytokine levels and cell phenotypes, cell functions, and post-MI cardiac function were determined. BM from healthy donors, handled in the same manner, was used as a reference.
Result:
Of 26 cytokines analyzed, IL-6 showed a negative correlation with ECFC colony maximum in BM (estimate±SE (SEE) -0.13±0.04 P=0.007, multivariableR2: 0.59) and Healthy BM showed decreased ECFC colony outgrowth in the presence of IL-6 (P <0.05), in a dose-dependent manner. PDGF-BB positively correlated with CFU-EC colony maximum in BM (SEE 0.006± 0.002, P=0.023, R2: 0.22), MSC colony maximum in BM (SEE 0.006±0.002, P=0.023, R2: 0.17) and MSC colony maximum in PB (SSE 0.018±0.005, P=0.00005, R2:0.24). No significant correlations were found between cardiac function after AMI and PB cytokine levels.
Conclusions:
At 2-3 weeks after AMI, PB levels of the angiogenic cytokine, PDGF-BB and the pro-inflammatory cytokine, IL-6, were associated with BM cell phenotype and function. IL-6 has the potential to impair endothelial progenitor cell capacity; inhibiting IL-6 may be a target for improving the regenerative capacity of BM cells after AMI.
Secretome of apoptotic peripheral blood cells (APOSEC) confers cytoprotection to cardiomyocytes and inhibits tissue remodelling after acute myocardial infarction: a preclinical study