Oxidative Stress Biomarkers and Incidence of Postoperative Atrial Fibrillation in the Omega-3 Fatty Acids for Prevention of Postoperative Atrial Fibrillation (OPERA) Trial

Abstract

Background: Animal study results point to oxidative stress as a key mechanism triggering postoperative atrial fibrillation (PoAF), yet the extent to which specific biomarkers of oxidative stress might relate to PoAF risk in humans remains speculative.

Methods and results: We assessed the association of validated, fatty acid-derived oxidative stress biomarkers (F2-isoprostanes, isofurans, and F3-isoprostanes) in plasma and urine, with incident PoAF among 551 cardiac surgery patients. Biomarkers were measured at enrollment, the end of surgery, and postoperative day 2. PoAF lasting ≥30 seconds was confirmed with rhythm strip or electrocardiography and centrally adjudicated. Outcomes were assessed until hospital discharge or postoperative day 10, whichever occurred first. Urine level of each oxidative stress biomarker rose at the end of surgery (2- to 3-fold over baseline, P<0.001) and subsequently declined to concentrations comparable to baseline by postoperative day 2. In contrast, plasma concentrations remained relatively stable throughout the perioperative course. Urine F2-isoprostanes and isofurans at the end of surgery were 20% and 50% higher in subjects who developed PoAF (P≤0.009). While baseline biomarker levels did not associate significantly with PoAF, end of surgery and postoperative day 2 isoprostanes and isofurans demonstrated relatively linear associations with PoAF. For example, the end of surgery extreme quartile multivariate adjusted OR (95% CI) for urine isofurans and F3-isoprostanes were 1.95 (1.05 to 3.62; P for trend=0.01) and 2.10 (1.04 to 2.25, P for trend=0.04), respectively. The associations of biomarkers with PoAF varied little by demographics, surgery type, and medication use (P≥0.29 for each).

Conclusions: These novel results add to accumulating evidence supporting the likely key pathogenic role of elevated oxidative stress in PoAF.

Clinical trial registration: URL: Clinicaltrials.gov Unique identifier: NCT00970489.

Keywords: atrial fibrillation; cardiac surgery; isofurans; isoprostanes; oxidative stress.

© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Figures

Figure 1

Plasma oxidative stress biomarkers concentration (pg/mL) at baseline (recruitment), end of surgery (at time of closure), and postoperative day 2. Data shown are mean±SE. The white and gray bars represent subjects without and with incident postoperative atrial fibrillation (PoAF), respectively. *Mean plasma level of F2-isoprostanes were ≈20% higher in patients who developed PoAF than in those who did not (P=0.05, adjusted for end of surgery F2-isoprostane concentrations).

Figure 2

Urine creatinine-adjusted concentration of oxidative stress biomarkers (ng/mg) at baseline (recruitment), end of surgery (at time of closure), and postoperative day 2. Data shown are mean±SE. The white and gray bars represent subjects without and with incident postoperative atrial fibrillation (PoAF), respectively. *Mean urine F2-isoprostane and isofuran levels were ≈20% and ≈50% higher in subjects who subsequently developed PoAF (P≤0.009, adjusted for baseline concentrations).

Figure 3

Multivariable-adjusted association of plasma (A) isofuran at end of surgery (B) isofuran at postoperative day 2 and (C) F2-isoprostanes at postoperative day 2 with postoperative atrial fibrillation (PoAF), evaluated by restricted cubic splines and logistic regression. Biomarkers underwent log-transformation before analyses as they were right-skewed, and analyses adjusted for age (years), sex (male/female), country (US, Italy, Argentina), body mass index (kg/m2), prevalent hypertension (yes/no), prevalent diabetes (yes/no), prevalent coronary heart disease (yes/no), prevalent chronic renal failure (yes/no), prevalent heart failure (yes/no), smoking (never or former/current), dyslipidemia (yes/no), statin medication use (yes/no), ejection fraction (%), and logistic Euroscore (continuous). The solid red line and shaded areas represent the OR and 95% CIs, respectively, in comparison to the reference level representing the median value of the lowest quartile (12.5th percentile). Dotted vertical lines correspond to the 10th, 25th, 50th, 75th, and 90th percentiles of the log biomarker concentrations. There was overall linear association for each biomarkers with PoAF (P≤0.02) but little evidence of nonlinearity (P≥0.83).

Figure 4

Multivariable-adjusted association of end of surgery (A) urine isofurans and (B) urine F3-isoprostanes with postoperative atrial fibrillation (PoAF), evaluated by restricted cubic splines and logistic regression. Biomarkers underwent log-transformation before analyses as they were right-skewed, and analyses adjusted for age (years), sex (male/female), country (US, Italy, Argentina), body mass index (kg/m2), prevalent hypertension (yes/no), prevalent diabetes (yes/no), prevalent coronary heart disease (yes/no), prevalent chronic renal failure (yes/no), prevalent heart failure (yes/no), smoking (never or former/current), dyslipidemia (yes/no), statin medication use (yes/no), ejection fraction (%), and logistic Euroscore (continuous). The solid red line and shaded areas represent the OR and 95% CIs, respectively, in comparison to the reference level representing the median value of the lowest quartile (12.5th percentile). Dotted vertical lines correspond to the 10th, 25th, 50th, 75th, and 90th percentiles of the log biomarker concentrations. Both biomarkers associated linearly overall with PoAF (P=0.02 for each) but showed little evidence of nonlinearity (P≥0.26 for each).