title: Attenuation of cardiac allograft vasculopathy by sirolimus: Relationship to time interval after heart transplantation.
abstract: 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 CNI 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.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Andrew
authors.initials: A
authors.lastname: Cassar
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshino
authors.forename: Andreas J
authors.initials: AJ
authors.lastname: Flammer
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.forename: Rajiv
authors.initials: R
authors.lastname: Gulati
authors.forename: Yan
authors.initials: Y
authors.lastname: Topilsky
authors.forename: Eugenia
authors.initials: E
authors.lastname: Raichlin
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Lennon
authors.forename: Lilach O
authors.initials: LO
authors.lastname: Lerman
authors.forename: Charanjit S
authors.initials: CS
authors.lastname: Rihal
authors.forename: Sudhir S
authors.initials: SS
authors.lastname: Kushwaha
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
mesh_terms: D005260:Female; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000209:etiology / Q000517:prevention & control; D012189:Retrospective Studies; D020123:Sirolimus / Q000627:therapeutic use*; D013997:Time Factors; D014184:Transplantation, Homologous; D014652:Vascular Diseases / Q000209:etiology* / Q000517:prevention & control*
chemical_list: D007166:Immunosuppressive Agents; D020123:Sirolimus
keywords: calcineurin inhibitors; cardiac allograft vasculopathy; intravascular ultrasound; plaque composition; plaque progression; sirolimus; virtual histology