Serum myeloperoxidase/paraoxonase 1 ratio as potential indicator of dysfunctional high-density lipoprotein and risk stratification in coronary artery disease.

OBJECTIVE: Granular leukocyte-derived myeloperoxidase (MPO) promotes oxidation of lipoproteins, while paraoxonase 1 (PON1) has antioxidant properties for high-density lipoprotein (HDL). We evaluated their effects on coronary risk stratification and function of lipoproteins. METHODS AND RESULTS: A total 158 patients who had previously undergone percutaneous coronary intervention and who had been hospitalized for coronary re-angiography were enrolled. Coronary lesions (restenosis or de novo lesion) were observed in 84 patients but not associated with conventional lipid profile. In contrast, serum MPO levels and PON1 activities were significantly associated with the prevalence of coronary lesions. The high MPO/PON1 ratio, when cutoff values were set at 1.59, was independently correlated with restenosis (odds ratio 6.4, 95% CI 2.2-19.3, P = 0.001) and de novo lesions (odds ratio 3.5, 95% CI 1.3-9.4, P = 0.014). We isolated HDL from patients with high or low MPO/PON1 ratio, and compared anti-inflammatory properties of HDL. Human umbilical vein endothelial cells were stimulated with inflammatory cytokine, and the expression of vascular cell adhesion molecule-1 (VCAM-1) was evaluated. HDL isolated from patients with low serum MPO/PON1 ratio inhibited VCAM-1 expression significantly greater than that with high MPO/PON1 ratio. We also demonstrated that the cholesterol efflux capacity of apolipoprotein B-depleted serum from patients with high MPO/PON1 ratio was significantly decreased than that with low MPO/PON1 ratio. CONCLUSIONS: MPO/PON1 ratio could be a useful marker for secondary prevention of coronary artery disease through modulation of HDL function.

Fasting serum concentration of apolipoprotein B48 represents residual risks in patients with new-onset and chronic coronary artery disease.

BACKGROUND: To identify new therapeutic targets for coronary artery disease (CAD), we investigated whether fasting serum concentration of apolipoprotein (apo) B48 could be a marker for CAD. METHODS: Patients with CAD were divided into those with new-onset CAD [i.e., those receiving percutaneous coronary intervention (PCI) for the first time] and those with chronic CAD (i.e., those receiving follow-up coronary angiography). Fasting serum biochemical analyses were performed on admission and 6 months after the PCI. RESULTS: On admission, serum LDL-C concentrations in patients with chronic CAD (n=138), presumably receiving statin treatment, were lower than in patients with new-onset CAD (n=50, p<0.02) or without CAD (n=71, p<0.001). Nevertheless, apoB48 was higher in CAD patients than in those without CAD (p<0.001). After adjusting for classic cardiovascular risk factors, multivariate logistic regression analyses showed apoB48 to be an independent predictor of coronary risk in new-onset or chronic CAD, irrespective of the LDL-C levels. Moreover, apoB48 was markedly increased during the follow-up period in CAD patients having new lesion progression after the prior PCI. CONCLUSION: Fasting serum apoB48 concentration could be a marker of new onset as well as chronic CAD, and predict new lesion progression in secondary prevention.

Effect of cytochrome P450 2C19 polymorphism on target lesion outcome after drug-eluting stent implantation in japanese patients receiving clopidogrel.

BACKGROUND: Cytochrome P450 (CYP) 2C19 polymorphism is associated with reduced responsiveness to clopidogrel and poor clinical outcome after drug-eluting stent (DES) implantation, but its contribution to lesion outcome after DES implantation is unclear. METHODS AND RESULTS: The study included 160 Japanese patients who received clopidogrel and underwent DES implantation with follow-up angiography. Patients were divided into 3 groups by CYP2C19 polymorphism: extensive metabolizers (EM), intermediate metabolizers (IM), and poor metabolizers (PM). The incidence of major adverse cardiac events (MACE) and target lesion revascularization (TLR) were compared among the 3 groups. Optical coherence tomography (OCT) was performed for 120 patients to evaluate the incidence of intra-stent thrombi. Of the 160 patients, the proportion of EM, IM, and PM was 37.5%, 48.1%, and 14.4%, respectively. The incidence of TLR and MACE was more frequent in IM and PM than EM (TLR: 18.2% and 26.1% vs. 3.3%, P=0.008, MACE: 22.1% and 30.4% vs. 5.0%, P=0.005). Among the 120 patients who underwent follow-up OCT, intra-stent thrombi were more frequently detected in IM and PM than in EM (45.6% and 63.2% vs. 20.5%, P=0.005). The incidence of TLR was significantly higher in patients with than in those without intra-stent thrombi (27.7% vs. 6.8%, P=0.003). CONCLUSIONS: CYP2C19 loss-of-function polymorphism might be associated with the incidence of MACE and TLR in association with intra-stent thrombi.

Impact of cytochrome P450 2C19*2 polymorphism on intra-stent thrombus after drug-eluting stent implantation in Japanese patients receiving clopidogrel.

BACKGROUND: The cytochrome P450 (CYP) 2C19*2 polymorphism is associated with reduced responsiveness to clopidogrel and poor clinical outcome after stent implantation. Despite the high frequency of this polymorphism in Japanese patients, its contribution to cardiac events and stent thrombi after drug-eluting stent (DES) implantation is not clear in this population. METHODS AND RESULTS: One hundred Japanese patients received clopidogrel and underwent follow-up optical coherence tomography (OCT) after DES implantation. The patients were divided into 2 groups: those with at least one CYP2C19*2 allele (*2 carriers) and non-carriers. The incidence of stent thrombosis and major adverse cardiac events (MACE; ie, death, myocardial infarction, and target vessel revascularization) was compared between the 2 groups. In addition, OCT was used to evaluate the incidence of intra-stent thrombus, defined as a mass protruding into the lumen with significant attenuation. Of the 100 patients, 42 were *2 carriers. No remarkable differences in the baseline characteristics were noted. Although MACE did not differ significantly between the 2 groups, a subclinical intra-stent thrombus was detected more frequently in *2 carriers than in non-carriers (52.3% vs. 15.5%, P=0.0002). Multivariate logistic regression analysis showed that the presence of the CYP2C19*2 polymorphism was the only independent predictive factor for intra-stent thrombus (P=0.00006). CONCLUSIONS: From these results it is suggested that CYP2C19*2 polymorphism is associated with subclinical thrombus formation among Japanese patients receiving clopidogrel. (Circ J 2011; 75: 99-105).