Peripheral Blood Cytokine Levels After Acute Myocardial Infarction: IL-1ß- and IL-6-Related Impairment of Bone Marrow Function.

ABSTRACT

RATIONALE Intracoronary infusion of bone marrow (BM) mononuclear cells after acute myocardial infarction (AMI) has led to limited improvement in left ventricular 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 BM endothelial progenitor cell colony outgrowth and cardiac function after AMI. METHODS AND RESULTS: BM and PB samples were collected from 87 participants 14 to 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 interleukin-6 (IL-6) negatively correlated with endothelial colony-forming cell colony maximum in the BM of patients with AMI (estimate±SE, -0.13±0.05; P=0.007). BM from healthy individuals showed a dose-dependent decrease in endothelial colony-forming cell colony outgrowth in the presence of exogenous IL-1ß 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 correlated positively with BM-derived colony-forming unit-endothelial colony maximum (estimate±SE, 0.01±0.002; P<0.001), multipotent mesenchymal stromal cell colony maximum (estimate±SE, 0.01±0.002; P=0.002) in BM, and mesenchymal stromal cell colony maximum in PB (estimate±SE, 0.02±0.005; P<0.001). CONCLUSIONS: Two weeks after AMI, increased PB platelet-derived growth factor BB glycoprotein was associated with increased BM function, whereas 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 URL http//www.clinicaltrials.gov. Unique identifier NCT00684060.