From the Department of Medicine, College of Medicine, University of Florida, Gainesville (M.S., E.W., J.J.S., J.Z., C.J.P., C.R.C.); Regenerative Medicine Research, Texas Heart Institute, CHI St. Luke’s Health Baylor College of Medicine Medical Center, Houston (M.R., D.A.T.); Department of Medicine, University of Louisville, KY (R.B.); Department of Cardiovascular Sciences, Methodist DeBakey Heart and Vascular Center, the Houston Methodist Research Institute, TX (J.P.C.); Interdisciplinary Stem Cell Institute, University of Miami School of Medicine, FL (J.M.H., A.K.); Department of Medicine, Cedars-Sinai Heart Institute, Los Angeles, CA (T.D.H.); Department of Cardiology, Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, MN (J.H.T.); and Department of Cardiovascular Medicine, Stanford University, School of Medicine, CA (P.C.Y.).
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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-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 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.