In contrast, late outgrowth endothelial cells appear after 14 to 21 days of culture. Early EPCs and OECs originate from different bone marrow-derived mononuclear cell populations. Advances in coronary guide wire technology have facilitated the development of physiologic indices to allow accurate assessment of coronary epicardial arteries and the microcirculation. The fractional flow reserve and index of microvascular resistance are specific measures of epicardial disease and integrity of the microcirculation respectively, whereas coronary flow reserve provides a functional measure of both levels of the circulation. Given the different biological characteristics between EPC populations, we hypothesized that distinct EPC populations may play different roles in atheroprotection, and therefore explored whether the different EPC populations would be related to key measures of coronary epicardial and microvascular disease in humans by combining cellular, angiographic and physiologic assessments. In addition, there was no correlation between EPC number and function and the state of the coronary microcirculation. Interestingly, the relationship between epicardial CAD severity and OEC function, but not number, persisted after adjusting for age, raising the hypothesis that progenitor cell function plays a more important role in protection from epicardial vessel disease than the actual number of OECs. These findings are consistent with an earlier study reporting that patients with chronic ischemic cardiomyopathy had impaired function, but not levels, of bone-marrow derived progenitor cells, compared with normal healthy controls. The role of EPCs in atheroprotection remains poorly understood and controversial. Experiments using animal models of atherosclerosis have yielded conflicting results. In one study, longterm treatment with bone marrow-derived EPCs from young nonatherosclerotic Apolipoprotein E knockout mice prevented atherosclerosis progression in ApoE knockout recipients despite persistent hypercholesterolemia. However, other studies reported contrasting results, and found that transplantation of EPCs increased atherosclerotic plaque progression and lesion size in ApoE knockout mice. Likewise, previous studies exploring the relationship between EPC levels and epicardial CAD severity in humans have also yielded conflicting results. Consistent with our findings, Kunz et al reported an inverse correlation between EPC colony forming unit levels and CAD severity. However, studies assessing the noncoronary circulation have reported a similar association with our study and findings by Kunz et al, whereby lower EPC levels were associated with more severe peripheral vascular disease and greater carotid intima-media thickness. A recent study assessing the biological function of OECs also reported results consistent with our study.