BACKGROUND: The aim of the study was to assess temporal changes in plaque size and components after heart transplantation (HTx), and to evaluate the differences in treatment effects on plaque progression between sirolimus and calcineurin inhibitors (CNIs). METHODS: The study comprised 146 HTx recipients who were converted from CNIs to sirolimus as primary immunosuppressant (sirolimus group, n = 61) and those who were maintained on CNIs (CNI group, n = 85). A retrospective compositional analysis of serial virtual histology-intravascular ultrasound was performed. RESULTS: During a median follow-up of 2.8 years, there was a significant difference in plaque volume in favor of sirolimus between groups (p = 0.004). When subjects were sub-classified according to the time interval between HTx and study inclusion, those in the early group (<= 2 years after HTx) had a greater increase in plaque volume (p = 0.006), characterized by a higher progression rate of fibrous plaque volume (p = 0.01). The treatment difference between groups in plaque volume was identified in the early group in favor of sirolimus with attenuating effects on the progression of fibrous plaque component (both p = 0.03 for interaction). By contrast, there were significant differences in necrotic core and dense calcium volume (both p < 0.05 for interaction) in favor of CNIs in the late group (>= 6 years after HTx). CONCLUSIONS: Compared with continued CM therapy, sirolimus attenuated plaque progression in recipients with early conversion, but contributed to increases in necrotic core and dense calcium volume in those with late conversion. Our study supports the hypothesis that early initiation of sirolimus offers greater benefits in the treatment of CAV. J Heart Lung Transplant 2013;32:784-791 (C) 2013 International Society for Heart and Lung Transplantation. All rights reserved.