BACKGROUND: The aim of this study was to determine whether epicardial structural disease may affect the manifestation of a longitudinal decrease in myocardial blood flow (MBF) or MBF difference during hyperemia in cardiovascular risk individuals, and its dependency on the flow increase. METHODS AND RESULTS: In 54 cardiovascular risk individuals (at risk) and in 26 healthy controls, MBF was measured with (13)N-ammonia and PET/CT in mL/g/min at rest and during dipyridamole stimulation. Computed tomography coronary angiography (CTA) was performed using a 64-slice CT of a PET/CT system. Absolute MBFs during dipyridamole stimulation were mildly lower in the mid-distal than in the mid-LV myocardium in controls (2.20 +/- .51 vs 2.29 +/- .51, P < .0001), while it was more pronounced in at risk with normal and abnormal CTA (1.56 +/- .42 vs 1.91 +/- .46 and 1.18 +/- .34 vs 1.51 +/- .40 mL/g/min, respectively, P < .0001), resulting in a longitudinal MBF difference that was highest in at risk with normal CTA, intermediate in at risk abnormal CTA, and lowest in controls (.35 +/- .16 and .22 +/- .09 vs .09 +/- .04 mL/g/min, respectively, P < .0001). On multivariate analysis, log-CCS and mid-LV hyperemic MBF increase, indicative of microvascular function, were independent predictors of the observed longitudinal MBF difference (P