Background: Cardiac allograft vasculopathy (CAV) remains a major complication after heart transplantation (HT). Uric acid (UA) can stimulate T cells and has proatherogenic properties thus may play a role in CAV. Sirolimus (SRL) attenuates CAV but the mechanisms underlying its protective effect have not been fully elucidated. Objectives: To test whether UA is an independent predictor of CAV and whether conversion from calcineurin inhibitor (CNI) to SRL as primary immunosuppression modulates UA levels.
Methods: We analyzed a cohort of 224 patients who underwent HT between 2004 and 2015 and had serial coronary intravascular ultrasound (IVUS) studies for assessment of CAV. CAV progression was assessed by measuring the delta plaque volume corrected to segment length (dPV/L) and delta plaque index (dPI%) (PV/vessel volume ratio) between last follow-up and baseline IVUS. For multivariate analysis, a CAV event was defined as having a dPV/L ≥ 0.5 mm3/mm. All analyses were performed after adjustment for 9 potential confounders including creatinine.
Results: Elevated UA levels were associated with a significant increase in dPV/L (R=0.3, p=0.001) and dPI% (R=0.2, p=0.03). When segregated by baseline UA levels, patients with high (≥ the upper quartile cut-off of 7 mg/dl) compared with low (<7 mg/dl) UA had increased dPV/L (1.7±0.25 vs. 0.45±0.15 mm3/mm, p<0.0001) and dPI% (8.0±1.24 vs. 2.5±0.74%, p<0.001). In a multivariate analysis, elevated UA was associated with an increased risk of CAV (HR 2.1, 95% CI: 1.1-4.5, p=0.03). During follow-up, SRL resulted in decreased UA levels (5.8±1.4 vs. 5.2±1.5, p=0.003) and patients converted from a CNI to SRL and had low UA levels had the least progression in CAV (Figure).
Conclusions: UA is an independent predictor of CAV after HT. SRL results in decreased UA levels and this may be one of the mechanisms by which SRL attenuates CAV. Further studies are warranted to test whether directed UA-lowering therapy has an incremental role in mitigating CAV.