The measurement of coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography (TTDE) with invasive intracoronary Doppler flow wire technique (ICD) was validated and the pathological factors which influence CFVR in patients with angiographically normal coronary arteries were analyzed. CFVR was determined successfully in left anterior descending artery (LAD) in 37 of 40 patients with angiographically normal coronary arteries (men 22, women 15, age 20-75 years, mean age 54 +/- 12 years). Coronary flow velocity was measured in the distal LAD by TTDE with contrast enhancement at baseline and during intravenous adenosine infusion of 140 microg/kg per min within 48 h after ICD technique. Average peak velocity at baseline (APVb), average peak velocity during hyperemia (APVh) and CFVR determined from TTDE were correlated closely with those from ICD measurements (APVb: y = 0.64x + 5.04, r = 0.86, P < 0.001; APVh: y = 0.63x + 14.36, r = 0.82, P < 0.001; CFVR: y = 0.65x + 0.92, r = 0.88, P < 0.001). For CFVR measurements, the mean differences between TTDE and ICD methods were 0.12 +/- 0.39. CFVR in patients with history of hypertension was significantly lower than that in patients without history of hypertension (P < 0.05). Intravascular ultrasound (IVUS) was performed in 34 patients. Plaque formation was found in LAD by IVUS in 17 (50%) patients. No significant difference in CFVR was found between the patients without plaque formation (3.11 +/- 0.49) and those with plaque formation (2.76 +/- 0.53, P = 0.056). It is suggested that TTDE with contrast enhancement provides reliable measurement of APV and CFVR in the distal LAD. The early stage of atherosclerosis could be detected by IVUS, which may be normal in angiography. CFVR is impaired in patients with history of hypertension compared with that in patients without history of hypertension.