Abstract 13819: Circulating PON Lactonase Activity Predicts Major Adverse Cardiac Events in Subjects With Atherosclerotic Renal Artery Disease

Abstract

Introduction: Decreased plasma lactonase activity, catalyzed by high-density lipoprotein (HDL)-associated paraoxonase (PON), is associated with increased oxidant stress and cardiovascular risk in settings such as coronary artery disease as well as some etiologies of chronic kidney disease (CKD). However, whether circulating PON lactonase activity predicts outcomes in atherosclerotic renal artery stenosis (ARAS) is unknown. We sought to determine the prognostic value of circulating PON lactonase activity in subjects with ARAS, particularly in relation to established risk factors. Methods/Results: PON lactonase activity was measured in plasma of subjects with ARAS and either systolic hypertension while taking ≥2 antihypertensive drugs or CKD (n=718) enrolled in the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL) study as well as a cohort of apparently healthy, normotensive non-ARAS subjects (n=33). Participants with ARAS were prospectively followed for incident major adverse cardiac events (MACE, composite of cardiovascular death, nonfatal myocardial infarction, and stroke) over a median follow-up period of 43 months (interquartile range, 31 to 55). PON lactonase activity in ARAS subjects was significantly lower compared with that in non-ARAS control subjects [mean±SD, 2466±839 vs 3514±745 pmol/min/mL, P<0.001]. Next, participants were dichotomized based on the baseline plasma levels of PON lactonase activity, into high (> median) or low (≤ median) groups and were used to predict incident MACE at 3 years. Participants with lower PON lactonase activity had increased MACE at 3 years [67/359 (17%) vs 44/359 (12%), p<0.05]. Lower circulating PON lactonase activity (hazard ratio 1.26, 95% CI 1.0 to 1.53, p=0.016) was a predictor of MACE. After adjusting for traditional risk factors and medication use, lower PON lactonase activity (hazard ratio 1.22, 95% CI 1.01 to 1.50, p=0.04) still conferred an increased risk of MACE. Conclusions: In patients with ARAS, decreased circulating PON lactonase activity, a measure of diminished antioxidant properties of HDL, predicts higher risk of incident long-term adverse cardiovascular events in multivariate models adjusting for established clinical and biochemical risk factors.