Background-Most myocardial infarctions are caused by the rupture of small rather than large plaques in the arteries of the heart that are beyond the detection limit of current technologies. Methods and Results-Recently, optical coherence tomography (OCT) has demonstrated considerable potential as a method for high-resolution assessment of vulnerable plaque. However, intravascular OCT imaging is complicated by the need to remove blood from the imaging field because blood results in substantial signal attenuation. This work examines index matching as a method for increasing penetration. Index matching is based on the hypothesis that the predominant source of scattering in blood is the difference in refractive index between the cytoplasm of erythrocytes and serum. By increasing the refractive index of serum to a value near that of the cytoplasm, or index matching, scattering can be substantially reduced. The concept was tested with a system that pumped blood in vitro through transparent tubing. The test compounds, dextran and intravenous contrast agent, both led to significant improvements in penetration (69Ϯ12% and 45Ϯ4%). No significant effect was seen with the saline control. For dextran, the effect could not be attributed to reductions of red cell number or volume because changes in these parameters were not different from the control. In the case of intravenous contrast, a small but significant relative reduction in red cell volume was seen. Conclusions-This study demonstrates the feasibility of index matching for improving OCT imaging through blood.Future studies are required to identify compounds for effective index matching in vivo. Key Words: tomography Ⅲ plaque Ⅲ myocardial infarction Ⅲ blood Ⅲ imaging M yocardial infarction, commonly known as heart attack, is the leading cause of death in the industrialized world. 1 Most myocardial infarctions result from the rupture of small, thin-walled plaques in the coronary arteries. When these plaques rupture, they release lipid into the blood, a clot forms, and the vessel occludes. 2,3 Most of these plaques are below the detection limit of currently available imaging technologies. 4 Therefore, a true clinical need exists for an imaging technology capable of identifying these plaques before rupture.A recently developed, high-resolution imaging technology, optical coherence technology (OCT), has demonstrated considerable potential as a method for imaging vulnerable plaque. [5][6][7][8] OCT is analogous to ultrasound, measuring the intensity of back-reflected infrared light rather than sound. 9 Initial in vitro OCT imaging of cardiovascular tissue was conducted with postmortem human aorta. 5 In these studies, OCT was shown to identify structural features such as lipid collections, thin intimal caps, and fissures characteristic of plaque vulnerablity. OCT has also been directly compared with high-frequency intravascular ultrasound, the current clinical technology with the highest resolution. 6,7 The superior resolution of OCT has been confirmed both quantitatively and...