Acute Cellular Rejection and the Subsequent Development of Allograft Vasculopathy After Cardiac Transplantation

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 (OR = 0, 1R = 1, 2R = 2, 3R = 3) and any rejection score (ARS; calculated as OR = 0, 1R = 1, 2R = 1; 311 = 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. Conclusion: 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. J Heart Lung Transplant 2009;28:320-7. Copyright (C) 2009 by the International Society for Heart and Lung Transplantation.