title: Acute cellular rejection and the subsequent development of allograft vasculopathy after cardiac transplantation.
abstract: BACKGROUND
  Cardiac allograft vasculopathy (CAV) is primarily immune-mediated. We investigated the role of cellular rejection in CAV development.
  
  
  METHODS
  The study comprised 252 cardiac transplant recipients (mean age, 49.02 +/- 17.05 years; mean follow-up, 7.61 +/- 4.49 years). Total rejection score (TRS) based on the 2004 International Society of Heart and Lung Transplantation R grading system (0R = 0, 1R = 1, 2R = 2, 3R = 3) and any rejection score (ARS; calculated as 0R = 0, 1R = 1, 2R = 1; 3R = 1, or the number of rejections of any grade) were normalized for the total number of biopsy specimens. CAV was defined as coronary stenosis of 40% or more and/or distal pruning of secondary side branches. Thirty-two patients had undergone 3-dimensional intravascular ultrasound (IVUS) at baseline and with virtual histology (VH) IVUS at 24 months.
  
  
  RESULTS
  In univariate analysis, 6-month TRS (hazard ratio [HR], 1.9; 95% confidence interval [CI], 0.99-3.90, p = 0.05) and ARS (HR, 2.22; 95% CI, 1.01-4.95; p = 0.047) were associated with increased risk of CAV. In multivariate analysis, 6-month TRS (HR, 2.84; 95% CI, 1.44-6.91, p = 0.02) was significantly associated with increased risk of CAV onset. The 12- and 24-month rejection scores were not risk factors for the onset of CAV. By Kaplan-Meier analysis, 6-month TRS exceeding 0.3 was associated with a significantly shorter time to CAV onset (p = 0.018). There was direct correlation (r = 0.44, p = 0.012) between TRS at 6 months and the percentage of necrotic core demonstrated by VH-IVUS at 24 months.
  
  
  CONCLUSIONS
  Recurrent cellular rejection has a cumulative effect on the onset of CAV. The mechanism may be due to increased inflammation resulting in increased plaque burden suggesting a relationship between the immune basis of cellular rejection and CAV.
authors.affiliation: William J. von Liebig Transplant Center, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Raichlin
authors.forename: Brooks S
authors.initials: BS
authors.lastname: Edwards
authors.forename: Walter K
authors.initials: WK
authors.lastname: Kremers
authors.forename: Alfredo L
authors.initials: AL
authors.lastname: Clavell
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodeheffer
authors.forename: Robert P
authors.initials: RP
authors.lastname: Frantz
authors.forename: Naveen L
authors.initials: NL
authors.lastname: Pereira
authors.forename: Richard C
authors.initials: RC
authors.lastname: Daly
authors.forename: Christopher G
authors.initials: CG
authors.lastname: McGregor
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.forename: Sudhir S
authors.initials: SS
authors.lastname: Kushwaha