Increased creatine kinase-MB levels and ST-segment depression are well-known prognostic factors in the setting of non-ST-elevation acute coronary syndrome (ACS). We hypothesized a relationship between virtual histology intravascular ultrasound (VH-IVUS) findings and these prognostic factors. We performed "whole vessel" VH-IVUS analysis in culprit arteries of 225 patients with ACS and measured the 4 basic VH-IVUS coronary plaque components--fibrous, fibrofatty, dense calcium (DC), and necrotic core (NC)--and calculated a NC/DC ratio. Patients' age was 62 +/- 11 years; 72% were men and 23% had diabetes. Only the NC/DC ratio had a positive association with creatine kinase-MB levels (r = 0.21, p = 0.03), and it was significantly higher for patients with ST-depression compared with those with non-ST-depression ACS (1.97 +/- 1.46 vs 1.58 +/- 1.10, p = 0.02). Sensitivity and specificity curves determined that a NC/DC value > or =2 (odds ratio 3.8, p = 0.01) and percentage of NC > or =6 (odds ratio 3.1, p = 0.04) were thresholds that best separated patients with high-risk non-ST-elevation ACS from those without abnormal creatine kinase-MB or ST depression. Patients with both predictors had significantly higher total cholesterol (204.7 +/- 60.5 vs 173.6 +/- 44.3 mg/dl, p = 0.01), higher low-density liprotein cholesterol (132.5 +/- 49.8 vs 101.3 +/- 33.2 mg/dl, p = 0.02), and more myocardial injury (creatine kinase-MB value of 42 +/- 38 vs 12 +/- 21, p = 0.01) than patients with no predictors. In conclusion, VH-IVUS analysis showed that the percentage of NC and its ratio to DC in diseased coronary segments are positively associated with a high-risk ACS presentation.