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Coronary artery disease (CAD) is the leading killer in the United States. Patients with severe CAD and ischemia have worse prognosis. Therefore expansion of biomarker research, to identify at-risk individuals and explain the complex biology between cardiovascular growth factors and atherosclerosis is needed. Neuregulin-1β (NRG-1β) is a myocardial stress activated growth and survival factor released from endocardial and endothelial cells. NRG-1β is essential for cardiovascular development and a regulator of angiogenesis. We postulated that plasma and serum levels of NRG-1β would vary in relation to CAD severity and the presence of stress-induced ischemia.We measured serum and plasma levels of NRG-1β and vascular endothelial growth factor (VEGF) in 60 patients undergoing cardiac catheterization. CAD severity was calculated from angiographic results using a modified Duke jeopardy score.Serum NRG-1β (sNRG-1β), plasma NRG-1β (pNRG-1β), serum VEGF, and plasma VEGF were detectable in the majority of patients. The pNRG-1β levels were approximately two-fold higher than sNRG-1β. Both sNRG-1β and pNRG-1β correlated inversely with CAD severity. pNRG-1β levels were statistically higher in patients with stress-induced ischemia denoted by a positive myocardial perfusion imaging study that correlated with angiographic findings (P=0.02).Both sNRG-1β and pNRG-1β correlated inversely with angiographic severity of CAD. pNRG-1β levels were two-fold higher than serum and were higher in patients with stress-induced ischemia. Therefore we conclude that plasma is the optimal source for the further exploration of the biological significance of NRG-1β as a biomarker of CAD severity and ischemia.