Reactive oxygen metabolites are closely associated with the diagnosis and prognosis of coronary artery disease

Abstract

Background: Reactive oxygen species (ROS) are associated with development of coronary artery disease (CAD). However, there's no useful biomarker of ROS in CAD.

Methods and results: We recruited 395 consecutive CAD patients who were performed coronary angiography (262 male and 133 female, age 70.2±10), and we measured serum derivatives of reactive oxidative metabolites (DROM) were measured. Two hundred twenty-seven non-CAD patients were also enrolled. We performed follow-up study in these 395 CAD patients and case-control study after risk factor and 1:1 pair matching (both, n=163). As subgroup analysis, DROM were also measured at the aortic root and the coronary sinus in 59 CAD patients. DROM were significantly higher in CAD patients (n=163, median [inter-quartile range, IQR]=338 [302 to 386]) than in risk factor-matched non-CAD patients (n=163, 311 [282 to 352.5], effect size=0.33, P<0.001). During a mean follow-up period of 20 months of 395 CAD patients, 83 cardiovascular events were recorded. Kaplan-Meier analysis showed a higher probability of cardiovascular events in the high-DROM group (>346 U.CARR) than in the low-DROM group (≤346 U.CARR) (P=0.001 [log-rank test]). Multivariate Cox hazard analysis identified ln-DROM as an independent predictor for cardiovascular events (hazard ratio: 10.8, 95% confidence interval: 2.76 to 42.4, P=0.001). The transcardiac gradient of DROM was significantly higher in CAD patients than in non-CAD patients (-2.0 [-9.0 to 9.0] versus 8 [-8.0 to 28.3], effect size=0.21, P=0.04), indicating that DROM production in coronary circulation is associated with development of CAD.

Conclusion: DROM are increased in CAD patients and associated with future cardiovascular events. DROM might provide clinical benefits for risk stratification of CAD.

Clinical trial registration url: http://www.umin.ac.jp/ctr/. Unique identifier: UMIN000012990.

Keywords: cardiovascular events; coronary artery disease; coronary circulation; follow‐up study; reactive oxygen species.

Figure 1.

Flow chart showing the protocol used for this study. CAD indicates coronary artery disease; DROM, derivatives of reactive oxygen metabolites.

Figure 2.

Serum DROM levels in CAD patients. A, Serum DROM levels in 163 CAD patients compared with 163 non‐CAD patients after risk matching for the number of patients, age, sex, and equal incidence of hypertension, DM, and dyslipidemia. B, Association between DROM levels with the severity of CAD. We classified CAD patients into SVD or MVD groups according to the number of diseased coronary vessels for evaluating the severity of CAD. Serum DROM levels were compared between 152 CAD patients with SVD and 243 CAD patients with MVD. C, Association between DROM levels with the complexity of CAD. We classified CAD patients into simple plaques or complex plaques groups according to the Ambrose criteria for evaluating the complexity of CAD. Plaques with concentric type and eccentric type I were distributed into simple plaques group, and eccentric type II and multiple irregularities were distributed into complex plaques group. Serum DROM levels were compared between 267 CAD patients with simple plaques and 128 CAD patients with complex plaques. The graphs show DROM using box‐and‐whisker plots. In these plots, lines within the boxes represent median values. The upper and lower lines of the boxes represent the 25th and 75th percentiles, respectively. The upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively. CAD indicates coronary artery disease; DM, diabetes mellitus; DROM, derivatives of reactive oxygen metabolites; MVD, multiple‐vessel disease; SVD, single‐vessel disease.

Figure 3.

Correlation between ln‐DROM and other biomarkers. A, Correlation between ln‐DROM and ln‐BNP. B, Correlation between ln‐DROM and ln‐hs‐CRP. BNP indicates B‐type natriuretic peptide; DROM, derivatives of reactive oxygen metabolites; hs‐CRP, high‐sensitivity C‐reactive protein.

Figure 4.

Receiver‐operating‐characteristic ana‐lysis. Significant positive correlation between DROM levels and the occurrence of cardiovascular events in CAD patients. AUC indicates area under the curve; CAD, coronary artery disease; DROM, derivatives of reactive oxygen metabolites.

Figure 5.

Follow‐up analysis in 393 CAD patients. A, Kaplan–Meier analysis for the probability of cardiovascular events in CAD patients with low‐ or high‐ln‐DROM (n=196, 197, respectively). CAD patients were divided into 2 groups using the median value of DROM (346 U.CARR). B, Serum ln‐DROM levels without or with cardiovascular events (n=310, 83, respectively). The graph shows DROM using box‐and‐whisker plots. In these plots, lines within the boxes represent median values. The upper and lower lines of the boxes represent the 25th and 75th percentiles, respectively. The upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively. CAD indicates coronary artery disease; DROM, derivatives of reactive oxygen metabolites.

Figure 6.

Production of DROM in the coronary circulation. DROM levels at the aortic root and the coronary sinus were measured in 31 non‐CAD patients and 59 CAD patients. A, Serum DROM levels at the aortic root in 31 non‐CAD patients and 59 CAD patients. B, Serum DROM levels at the coronary sinus in 31 non‐CAD patients and 59 CAD patients. C, Transcardiac gradients of DROM levels (ΔDROM=coronary sinus−aortic root) in 31 non‐CAD patients and 59 CAD patients. The graphs show DROM using box‐and‐whisker plots. In these plots, lines within the boxes represent median values. The upper and lower lines of the boxes represent the 25th and 75th percentiles, respectively. The upper and lower bars outside the boxes represent the 90th and 10th percentiles, respectively. CAD indicates coronary artery disease; DROM, derivatives of reactive oxygen metabolites.