Predicting Coronary Artery Disease Risk Research Articles

Both Paraoxonase-1 Genotype and Activity Do Not Predict the Risk of Future Coronary Artery Disease; the EPIC-Norfolk Prospective Population Study

BackgroundParaoxonase-1 (PON1) is an antioxidant enzyme, that resides on high-density lipoprotein (HDL). PON1-activity, is heavily influenced by the PON1-Q192R polymorphism. PON1 is considered to protect against atherosclerosis, but it is unclear whether this relation is independent of its carrier, HDL. In order to evaluate the atheroprotective potential of PON1, we assessed the relationships among PON1-genotype, PON1-activity and risk of future coronary artery disease (CAD), in a large prospective case-control study.Methodology/Principal FindingsCases (n = 1138) were apparently healthy men and women aged 45–79 years who developed fatal or nonfatal CAD during a mean follow-up of 6 years. Controls (n = 2237) were matched by age, sex and enrollment time. PON1-activity was similar in cases and controls (60.7±45.3 versus 62.6±45.8 U/L, p = 0.3) and correlated with HDL-cholesterol levels (r = 0.16, p<0.0001). The PON1-Q192R polymorphism had a profound impact on PON1-activity, but did not predict CAD risk (Odds Ratio [OR] per R allele 0.98[0.84–1.15], p = 0.8). Using conditional logistic regression, quartiles of PON1-activity showed a modest inverse relation with CAD risk (OR for the highest versus the lowest quartile 0.77[0.63–0.95], p = 0.01; p-trend = 0.06). PON1-activity adjusted for Q192R polymorphism correlated better with HDL-cholesterol (r = 0.26, p<0.0001) and more linearly predicted CAD risk (0.79[0.64–0.98], p = 0.03; p-trend = 0.008). However, these relationships were abolished after adjustment for HDL (particles-cholesterol-size) and apolipoproteinA-I (0.94[0.74–1.18], p-trend = 0.3).Conclusions/SignificanceThis study, shows that PON1-activity inversely relates to CAD risk, but not independent of HDL, due to its close association with the HDL-particle. These data strongly suggest that a low PON1-activity is not a causal factor in atherogenesis.

A Convenient Tool to Profile Patients for Generalized Cardiovascular Disease Risk in Primary Care

The early identification of and intervention in patients with increased risk factors for generalized cardiovascular disease greatly reduces their long-term mortality from hard coronary artery disease (CAD) events and other related co-morbidities. Thus, a number of multivariate risk factor analyses based on large-scale population studies have led to various risk-scoring models aimed at screening for those at high risk for CAD. These assessment systems, by virtue of novel diagnostic markers and better population data, have become increasingly adept at accurately predicting CAD risk in individual patients. Nevertheless, their practical application in the setting of primary care has lagged, because of a reluctance of many primary care physicians to adopt these methods. An effective risk assessment system should not only encompass the risk for hard CAD events but also include risks for related co-morbid conditions, such as stroke and heart failure, and be simple and accurate enough to be efficiently used in primary care clinics. In conclusion, in an attempt to simplify 1 of the more effective risk assessment devices for generalized cardiovascular disease risk that meets all these requirements, the investigators strongly support the model proposed by D'Agostino and colleagues and provide here a commentary on its utility in identifying patients at high risk for cardiovascular disease.

Abstract 3451: Risk for Coronary Artery Disease at the 9p21.3 Locus Is Abolished by a Protective Locus at 8p21.3 Identified by a Genome-Wide Association Study

Background : Coronary artery disease (CAD) is the leading cause of death in the western world. The only common genetic risk locus identified to date by us and others in genome wide association studies (GWAS) resides at 9p21.3. Methods: The Ottawa Heart Genomic Study compared genotypes of 1,542 early onset CAD patients (average 49y) and 1,455 elderly control Caucasians (average 75y). Results: Here, we report two protective haplotypes in the 3′ region of the lipoprotein lipase (LPL) gene at 8p21.3. LPL promotes lipolysis of circulating triglycerides (TG) and increases levels of atheroprotective high density lipoprotein (HDL) cholesterol. Since the 8p21.3 haplotypes are protective, we tested their interaction with the 9p21.3 risk allele. The rs10503669 haplotype associated with elevated TG and HDL levels but did not affect risk from 9p21.3. In contrast, the rs17411031 haplotype was not associated with TG or HDL levels and showed a significant interaction that abolished 9p21.3 risk independent of known risk factors. The interaction was confirmed using data of the Wellcome Trust Case Control Consortium. Excluding carriers of the interacting allele, accuracy of 9p21.3 to predict CAD risk is dramatically improved. Conclusion: Identification of the first modifier gene of the 9p21.3 risk locus for CAD improves CAD risk assessment and provides novel insight into coronary atherosclerosis. This protective 8p21.3 locus may provide a target for novel therapy.

Retinol-Binding Protein 4 and Prediction of Incident Coronary Events in Healthy Men and Women

Recent studies reported that retinol-binding protein 4 (RBP4) has a causal role in insulin resistance and suggested that its circulating levels may predict cardiovascular disease. However, the latter assumption has not yet been tested. We assessed the value of RBP4 measurement in the prediction of incident coronary artery disease (CAD). We conducted a nested case-control study of incident CAD (n = 1036 cases vs. n = 1889 controls) selected from among 25,336 participants of the EPIC-Norfolk study. Healthy men and women, aged between 45 and 79 yr, were recruited from age-sex registers of general practices in Norfolk. Participants completed a baseline questionnaire survey between 1993 and 1997, attended a clinic visit, and were followed for an average of 6 yr. Cases (n = 1036) were participants who developed CAD during the follow-up. Controls (n = 1889) matched by age, sex, and enrollment time remained free of any CAD during follow-up. Risk of incident fatal or nonfatal CAD according to RBP4 quartiles was assessed. RBP4 levels were higher in cases than in controls. RBP4 levels correlated weakly with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, and total and low-density lipoprotein-cholesterol and were inversely associated with C-reactive protein concentrations. The strongest correlation was found with triglycerides. The risk of incident CAD was associated with increasing quartiles of RBP4 levels (P = 0.03). However, adjustment for cardiovascular risk factors abolished this association. Measurement of serum RBP4 does not provide added value for predicting CAD risk beyond traditional risk factors.

Excess coronary artery disease risk in South Asian immigrants: can dysfunctional high-density lipoprotein explain increased risk?

Coronary artery disease (CAD) is the leading cause of mortality and morbidity in the United States (US), and South Asian immigrants (SAIs) have a higher risk of CAD compared to Caucasians. Traditional risk factors may not completely explain high risk, and some of the unknown risk factors need to be explored. This short review is mainly focused on the possible role of dysfunctional high-density lipoprotein (HDL) in causing CAD and presents an overview of available literature on dysfunctional HDL. The conventional risk factors, insulin resistance parameters, and metabolic syndrome, although important in predicting CAD risk, may not sufficiently predict risk in SAIs. HDL has antioxidant, antiinflammatory, and antithrombotic properties that contribute to its function as an antiatherogenic agent. Recent Caucasian studies have shown HDL is not only ineffective as an antioxidant but, paradoxically, appears to be prooxidant, and has been found to be associated with CAD. Several causes have been hypothesized for HDL to become dysfunctional, including Apo lipoprotein A-I (Apo A-I) polymorphisms. New risk factors and markers like dysfunctional HDL and genetic polymorphisms may be associated with CAD. More research is required in SAIs to explore associations with CAD and to enhance early detection and prevention of CAD in this high risk group.

Combined Influence of Body Mass Index and Waist Circumference on Coronary Artery Disease Risk Factors Among Children and Adolescents

In adult populations, it is recognized widely that waist circumference (WC) predicts health risk beyond that predicted by BMI alone; current recommendations for adults are that a combination of BMI and WC be used to classify obesity-related health risk. For children and adolescents, however, little is known about the combined influence of BMI and WC on health outcomes. The objectives of this study were to determine whether BMI and WC predict coronary artery disease (CAD) risk factors independently for children and adolescents and to assess the clinical utility of using WC in combination with BMI to identify CAD risk. Subjects included 2597 black and white, 5- to 18-year-old, male and female youths. Outcome measures included 7 CAD risk factors. In the first analysis step, BMI and WC were used as continuous variables to predict CAD risk factors. In the second analysis step, participants were placed into normal-weight, overweight, and obese BMI categories and, within each BMI category, CAD risk factors were compared for groups with low and high WC values. When BMI and WC were included in the same regression model to predict CAD risk factors, the added variance above that predicted by BMI or WC alone was minimal, which indicated that BMI and WC did not have independent effects on the risk factors. For example, for systolic blood pressure, BMI alone explained 7.3% of the variance, WC alone explained 7.7% of the variance, and the combination of BMI and WC explained 8.1% of the variance. When BMI and WC values were categorized with a threshold approach, WC provided information on CAD risk beyond that provided by BMI alone, particularly when the categories were used to predict elevated CAD risk factor levels. For instance, in the overweight BMI category, the high-WC group was approximately 2 times more likely to have high triglyceride levels, high insulin levels, and the metabolic syndrome, compared with the low-WC group. These findings provide some evidence that a combination of BMI and WC should be used in clinical settings to evaluate the presence of elevated health risk among children and adolescents.

Sex Differences in Coagulation and Fibrinolysis in Subjects with Coronary Artery Disease

Women with coronary artery disease (CAD) have a prognosis at least as bad and possibly worse than men. Differences in classical risk factors do not fully account for these findings and there is evidence that circulating levels of haemostatic factors may predict CAD risk. In this study sex differences in haemostatic risk factors were examined in relation to coronary stenosis. 609 (420 men, 69%) subjects admitted for coronary angiography for suspected CAD were recruited. Levels of Factor VII:C (FVII:C), fibrinogen, plasminogen activator inhibitor-1 (PAI-1) and von Willebrand factor (vWF) were estimated in 296 subjects from one centre. Of these, women (n = 107) had higher levels of FVII:C (134% vs 117%, p < 0.0005), and fibrinogen (3.4 g/l vs 3.2 g/l p = 0.01) than men (n = 189) and these differences remained after adjusting for other covariates. In subjects with angiographically significant atheroma these differences in haemostatic factors (n = 50 for women vs n = 147 for men) were exaggerated, (FVII:C 139% vs 117, p < 0.0001, fibrinogen 3.7 g/l vs 3.3 g/l p = 0.003), PAI-1 (26.2 ng/ml vs 19.7 ng/ml, p = 0.02) with a trend towards higher levels of vWF in the women. Women with significant atheroma at angiography (n = 50) had higher levels of PAI-1 (25.0 ng/ml vs 13.4 ng/ml p < 0.0001) and vWF (1.25 IU/ml vs 1.06 IU/ml, p = 0.02) and a trend towards higher levels of both fibrinogen and FVII:C than women with normal or in significant coronary vessel disease (n = 57). Elevated circulating levels of PAI-1, vWF, fibrinogen and FVII:C in women with angiographically proven CAD may contribute to an adverse cardiovascular risk factor profile and the poorer prognosis in females than male patients with proven coronary artery disease.