The cumulative effect of acute rejection on development of cardiac allograft vasculopathy.

Background: Acute rejection increases the inflammatory burden of the transplanted organ and predisposes to cardiac allograft vasculopathy (CAV). In this study we aim to determine the magnitude of the association, and to differentiate between the effects of mild vs severe rejection episodes.

Methods: Between 1988 and 2003, 489 1-year survivors of heart transplantation underwent 1,435 angiograms. These patients were classified as having no CAV (0% stenosis), mild/moderate CAV (<70%) or severe CAV (>70%). Acute rejection was considered either mild (Grades 1A, 1B and 2 untreated) or moderate/severe (Grade 2 treated on a clinical basis and Grades 3A, 3B and 4). We used multi-state Markov models to examine risk factors for the onset of CAV.

Results: Expressed as relative risk, the onset of CAV was significantly increased by donor age (1.26 per 10 years, 95% confidence interval [CI] 1.12 to 1.42), male recipient (1.72, 95% CI 1.01 to 2.94), pre-transplant recipient ischemic disease (1.53, 95% CI 1.14 to 2.06) and cumulative number of moderate/severe rejections (1.10 per episode, 95% CI 1.03 to 1.18). Human leukocyte antigen (HLA) and cytomegalovirus (CMV) matching, donor gender, recipient age, smoking, cumulative CMV infections and mild rejections were not significant risk factors. Estimated annual onset rate of CAV was 11.3% for patients with no moderate/severe rejection, rising to 13.6% for those with two and 18.0% for those with five such rejections.

Conclusions: Acute moderate/severe cellular rejection has a cumulative impact on CAV onset, whereas mild, untreated rejection is not associated with CAV.