Myocardial Release of Stromal Derived Factor-1 and Stem Cell Factor and Cardiac Uptake of Progenitor Cells

Abstract

Introduction: Activation of cytokines and their signaling pathways play a key role in the pathogenesis of myocardial injury and the subsequent response. It has been suggested that cytokine-mediated mobilization of CD34+ progenitor cells (PCs) is an important response to acute myocardial injury. This paradigm has been inadequately evaluated in chronic HF. Hypothesis: That the failing heart insufficiently produces CD34+ cell mobilizing cytokines, and there is no net cardiac uptake of PCs. Methods: We aimed to characterize cytokine secretion by the failing human heart and by neonatal rat cardiomyocytes in response to various stresses. In HF patients (n=19, NYHA class III) and age matched healthy controls (n=8), we performed right heart catheterization, and coronary sinus, peripheral venous and arterial sampling to determine levels of stromal derived factor−1 (SDF−1) and stem cell factor (SCF). We sought to determine the abundance of peripheral CD34+PCs and subsets with assessment of co-expression of the SDF−1 receptor, CXCR4, and the stem cell factor (SCF) receptor, CD117, utilizing FACS. SDF−1 and SCF secretion in vitro by isolated neonatal rat cardiomyocytes in response to norepinephrine, atrial natriuretic peptide and angiotensin II (AII) was also examined. Results: Isolated neonatal rat cardiomyocytes constitutively secreted both SDF−1 and SCF, and only AII (100 nM) induced a rise in SDF−1 secretion (2.5 fold; p<0.05 vs NE and ANP), but not SCF. Peripheral plasma levels of SDF−1 were significantly greater in HF (2491 ± 302 vs 1796 ± 121, p<0.05) whilst SCF levels did not differ. Plasma SDF−1 correlated significantly with right atrial pressure (r=0.86, p<0.01) and pulmonary capillary wedge pressure (r=0.71, p<0.01). A very significant relationship between transcardiac gradients of both SDF and SCF−1 (r=0.99, p<0.001) existed. In peripheral blood, there was a correlation between CD34+ cell levels and SDF−1 (r=0.50, p<0.05) and SCF (r=0.468, p=0.058), however no link was found between CD34+ cell co-expression of CXCR4 or CD117 and the corresponding cytokines. Further, we explored the relation between circulating cytokine levels and the abundance of CD34+ progenitor cells. There was no transcardiac gradient of progenitor cells. Conclusion: Cardiomyocytes and the failing heart have some capacity for cytokine secretion, responsive to both hemodynamic and neurohormonal stressors and linked to CD34+ cell mobilization.