Coronary risk factors adversely affect coronary resistance vessel dilation to acetylcholine, but little is known about the effect of risk factors on coronary blood flow (CBF) responses to physiologic stimuli. CBF was derived from Doppler flow velocity (0.018-inch Doppler wire) and coronary diameter (quantitative angiography) in response to rapid atrial pacing in 50 patients (mean age 52 +/- 12 years). Patients were prospectively divided into 3 groups based on their angiograms: group 1 (n = 17), normal coronary arteries; group 2 (n = 18), 1-vessel coronary artery disease (CAD) with a smooth study artery; group 3 (n = 15), 1-vessel CAD and an irregular study artery (<20% stenosis). Pacing produced a significant increase in CBF compared with baseline in groups 1 and 2 (34 +/- 40%, 42 +/- 35%, p < 0.0001), respectively, but not in group 3 (21 +/- 33%), but there was no difference in the pacing response among the 3 groups. The increase in CBF to pacing was inversely related to serum cholesterol (p = 0.01) and triglycerides (p = 0.06) and directly related to the increase in heart rate-blood pressure product (p = 0.007). By multivariate analysis, total cholesterol and the increase in double product were the only factors related to the increase in CBF. Increases in CBF to atrial pacing are inversely related to serum total cholesterol and are not related to the angiographic presence of atherosclerosis in patients with mild CAD.