Rationale: Intracoronary infusion of bone marrow mononuclear cells (BM-MNCs) after acute myocardial infarction (AMI) has led to limited improvement in left ventricular (LV) function. Although experimental AMI models have implicated cytokine-related impairment of progenitor cell function, this response has not been investigated in humans. Objective: To test the hypothesis that peripheral blood (PB) cytokines predict bone marrow (BM) endothelial progenitor cell (EPC) colony outgrowth and cardiac function after AMI. Methods and Results: BM and PB samples were collected from 87 participants 14-21 days after AMI and BM from healthy donors was used as a reference. Correlations between cytokine concentrations and cell phenotypes, cell functions, and post-AMI cardiac function were determined. PB IL-6 negatively correlated with endothelial colony forming cell (ECFC) colony maximum in the BM of AMI patients (estimate ± SE (ESE) -0.13±0.05, P=0.007). BM from healthy individuals showed a dose-dependent decrease in ECFC colony outgrowth in the presence of exogenous IL-1β or IL-6 (P <0.05). Blocking the IL-1R or IL-6R reversed cytokine impairment. In AMI study participants, the angiogenic cytokine platelet-derived growth factor BB glycoprotein (PDGF-BB) correlated positively with BM-derived CFU-EC colony maximum (ESE 0.01 ± 0.002, P<0.001), multipotent mesenchymal stromal cell (MSC) colony maximum (ESE 0.01±0.002, P=0.002) in BM, and MSC colony maximum in PB (ESE 0.02±0.005, P<0.001. Conclusions: Two weeks after AMI, increased PB PDGF-BB was associated with increased BM function, while increased IL-6 was associated with BM impairment. Validation studies confirmed inflammatory cytokine impairment of BM that could be reversed by blocking IL-1R or IL-6R. Together, these studies suggest that blocking IL-1 or IL-6 receptors may improve the regenerative capacity of BM cells after AMI.Clinical Trial Registrations: clinicaltrials.gov Identifiers: NCT00684060.
- Journal Article