Background: A fairly immediate reduction in angina pectoris symptoms after cholesterol lowering has been described. Our previous findings in rabbits and in a four-patient human pilot study indicated the existence of an RBC membrane barrier to oxygen (O2) transport in the presence of hypercholesterolemia. Our current objective was to determine whether, and to what extent, the plasma cholesterol concentration is an influencing factor in RBC O2 release and cellular O2 availability. Study Design: In an unique O2 diffusion analysis system, blood samples from 100 patients referred for lipid modification were analyzed. After 1 to 2 minutes of mixing in our diffusion analysis system, the next 1 to 2 minutes of circulation is comparable with 1 to 2 seconds of myocardial capillary flow. RBC O2 diffusion was defined by the depletion rate of total O2 content in blood from full O2 saturation (98%) to desaturation (approximately 60%). Relative tissue O2 availability was defined as the percentage decrease in O2 availability between the high-cholesterol group and the lowcholesterol group. Results: The 100 patients were divided almost equally into two groups on the basis of plasma cholesterol ranges of 175 to 229mg/dL (n=49) and 230 to 299 mg/dL (n = 51). The mean cholesterol concentrations and percentage increases in the high-cholesterol group over the low-cholesterol group were: for plasma, 206 ± 0.3 and 256 ± 0.4mg/dL, 24.3% (p<0.001); for RBCs, 93 ± 0.2 and 106 ± 0.2mg/dL, 14.0% (p <0.001); and for RBC membranes, 41 ± 0.1 and 54 ± 0.2mg/dL, 31.7% (p < 0.001). The blood O2 diffusion curves were distinctly different between the high- and the low-cholesterol groups (p < 0.05). Blood O2 diffusion, defined by the blood O2 diffusion curves, was inversely proportional to the plasma, RBC, and RBC-membrane cholesterol concentrations. The relative tissue O2 availability after a circulation period of more than 3 minutes in the diffusion system, showed a decrease of 17.5% (p < 0.05) between the plasma cholesterol groups, in comparing the two plasma cholesterol concentration extremes of less than 200 mg/dL (n = 14) and greater than 275 mg/dL (n = 11) after a circulation period of more than 3 minutes in the diffusion system, we found a decrease in relative tissue O2 availability of 35.8% (p < 0.05). Conclusions: The plasma cholesterol concentration may be an influencing factor in RBC-membrane cholesterol content, which, in turn, may regulate RBC-membrane O2 transport, RBC O2 release, and cellular O2 availability. The implications of this work include the addition of angina pectoris control to the indications for appropriate lipid modification and the development of an in vitro blood stress test to replace patient cardiac stress testing. (C) 2000 by the American College of Surgeons.