Serum Urate and Incident Cardiovascular Disease: The Coronary Artery Risk Development in Young Adults (CARDIA) Study

<div><p>Objective</p><p>There is controversy about whether serum urate (sUA) predicts future cardiovascular disease (CVD) independently of classical risk factors, and the age at which any prediction starts. We studied the sUA-CVD association among generally healthy adults.</p><p>Methods</p><p>CARDIA recruited 5115 black and white individuals aged 18–30 years in 1985–1986 (year-0). Fatal and nonfatal CVD events by year 27 (n = 164) were ascertained during annual contacts and classified using medical records. The association with sUA (year-0, 10, 15 and 20) was modeled using Cox proportional hazards regression, pooling over gender-specific quartiles.</p><p>Results</p><p>Mean sUA concentration was higher in men than women, but increased over time in both genders. Those with elevated sUA had worse metabolic profiles that substantially deteriorated over time. Adjusting for demographic and lifestyle factors (the minimal model), baseline sUA concentration was positively associated with incident CVD (hazard ratio (HR) per mg/dL = 1.21; 95% confidence interval: 1.05, 1.39; P = 0.005). This positive association attenuated to nonsignificance in the full model accounting simultaneously for classical CVD risk factors (HR = 1.09; 0.94, 1.27; P = 0.24). Both the minimal and full models appeared to show stronger associations (than year-0 sUA) between year-10 sUA and incident CVD (HR = 1.27 and 1.12, respectively), but sUA was not statistically significant in the full model. Despite fewer events, year-15 sUA showed a significant sUA-CVD association pattern, with minimal model association magnitude comparable to year-10, and remained significant in the full model (HR = 1.19; 1.02, 1.40; P = 0.03). Hyperuricemia at year-15 strongly predicted CVD risk (HR = 2.11; 1.34, 3.33; P = 0.001), with some attenuation in the full model (HR = 1.68; P = 0.04).</p><p>Conclusions</p><p>sUA may be an early biomarker for CVD in adults entering middle age. The prediction of CVD by sUA appeared to strengthen with aging. The potential complex relation of sUA with deterioration of a cluster of metabolic abnormalities warrants future exploration.</p></div

Odds Ratios for Low eVO₂ max (≤31.98 mL/kg/minute) Across CDC/AAP Categories of Periodontitis, NHANES 1999–2004 (n = 2,760).

<p>Model 1: adjusted for age, race/ethnicity, gender, education, smoking, poverty-income ratio, BMI, MET-score, hypertension, diabetes, cholesterol, pulse.</p><p>Model 2: Model 1+ C-reactive protein and white blood cell count.</p

Longitudinal association between sUA and the incidence of any fatal or nonfatal CVD endpoints by year 27.

<p>sUA, serum urate; CVD, cardiovascular disease; Y, year; Q, quartile; BMI, body mass index; CI, confidence interval.</p><p>^a Model 1: adjusted for year 0 age, sex, race, clinic, education level, smoking status, physical activity and intakes of total calories, alcohol and protein.</p><p>^b Model 1 + year 0 BMI, systolic and diastolic blood pressure, anti-hypertension medication use (excluding those taking diuretics), diuretics use, and glomerular filtration rate.</p><p>^c Model 2: adjusted for age, sex, race, clinic, education level, smoking status and physical activity at year 10, and average intakes of total calories, alcohol and protein at years 0 and 7.</p><p>^d Model 2 + year 10 BMI, systolic and diastolic blood pressure, anti-hypertension medication use (excluding those taking diuretics), diuretics use, and glomerular filtration rate.</p><p>^e Model 3: adjusted for age, sex, race, clinic, education level, smoking status and physical activity at year 15, and average intakes of total calories, alcohol and protein at years 0 and 7.</p><p>^f Model 3 + year 15 BMI, systolic and diastolic blood pressure, anti-hypertension medication use (excluding those taking diuretics), diuretics use, and glomerular filtration rate</p><p>^g Hazard ratio (95% CI) for the incidence of any fatal or nonfatal CVD endpoints by the end of 2012 (year 25) across sUA tertiles, reference group is participants in the lowest tertile of sUA concentrations.</p><p>^h Hazard ratio (95% CI) for the incidence of any fatal or nonfatal CVD endpoints per mg/dL sUA when using continuous sUA variable.</p><p>ⁱ<i>P</i>-values for the association between sUA and CVD when using continuous sUA variables.</p><p>^j Values are presented as “hyperuricemia group (reference group)”. Numbers in the reference group (participants without hyperuricaemia, i.e. sUA <6.8 mg/dL) are given in parentheses.</p><p>^kHazard ratio (95% CI) for the incidence of any fatal or nonfatal CVD endpoints by the end of 2012 (year 25) for the hyperuricemia group.</p><p>Longitudinal association between sUA and the incidence of any fatal or nonfatal CVD endpoints by year 27.</p

Can Inconsistent Association between Hypertension and Cognition in Elders be Explained by Levels of Organochlorine Pesticides?

<div><p>The relation between hypertension and cognition in elders remains unclear, and studies on the effect of antihypertensive drugs on cognition have demonstrated conflicting results. This study was performed to evaluate if the association between hypertension and cognition in elders differed depending on serum concentrations of organochlorine (OC) pesticides, common neurotoxic chemicals. Participants were 644 elders aged 60–85 years who participated in the National Health and Nutrition Examination Survey 1999–2002 and were able to complete a cognitive test. We selected 6 OC pesticides that were commonly detected in the elderly. Cognition was assessed by the Digit Symbol Substitution Test (DSST), a relevant tool for evaluating hypertension-related cognitive function, and low cognition was defined by the DSST score < 25^th percentile. When OC pesticides were not considered in the analyses, elders with hypertension had about 1.7 times higher risk of low cognition than those without hypertension. However, in analyses stratified by serum concentrations of OC pesticides, the associations between hypertension and low cognition were stronger the higher the serum concentrations of p,p’-DDT, p,p’-DDE, β-hexachlorocyclohexane, and trans-nonachlor increased. Among elders in the 3^rd tertile of these pesticides, adjusted odds ratios were from 2.5 to 3.5. In contrast, hypertension was not clearly associated with the risk of low cognition in elders in the 1^st tertile of these pesticides. Similar patterns were observed for the continuous DSST score dependent variable. The difference in the association between hypertension and DSST scores according to the levels of OC pesticides suggest a key role of OC pesticides in the development of hypertension-related cognitive impairment and may help to identify hypertensive elders who are at a high risk of cognitive impairment.</p></div

Unadjusted participant characteristics (mean±SD or percent) of participants across exam years.

<p>^a Prevalent CVD endpoints and missing data on sUA or covariates at the year of sUA measurement were excluded from the analyses.</p><p>^b HOMA-IR was calculated as (glucose × insulin) / 405 [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0138067#pone.0138067.ref023" target="_blank">23</a>].</p><p>Unadjusted participant characteristics (mean±SD or percent) of participants across exam years.</p

Adjusted^* means of Digit Symbol Substitution Test score among all subjects or stratified by tertiles of serum concentrations of organochlorine pesticides.

<p>*Adjusted for age, sex, race-ethnicity, education, poverty income ratio, cigarette smoking, and body mass index.</p><p>Adjusted^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144205#t002fn001" target="_blank">*</a>} means of Digit Symbol Substitution Test score among all subjects or stratified by tertiles of serum concentrations of organochlorine pesticides.</p

Adjusted^* odds ratios (ORs) and 95% confidence intervals (CIs) between hypertension and the risk of low Digit Symbol Substitution Test score (<25^th% of study subjects) among all subjects or stratified by serum concentrations of organochlorine (OC) pesticides.

<p>*Adjusted for age, sex, race-ethnicity, education, poverty income ratio, cigarette smoking, and body mass index.</p><p>Adjusted^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0144205#t003fn001" target="_blank">*</a>} odds ratios (ORs) and 95% confidence intervals (CIs) between hypertension and the risk of low Digit Symbol Substitution Test score (<25^th% of study subjects) among all subjects or stratified by serum concentrations of organochlorine (OC) pesticides.</p

Does Mortality Risk of Cigarette Smoking Depend on Serum Concentrations of Persistent Organic Pollutants? Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) Study

<div><p>Cigarette smoking is an important cause of preventable death globally, but associations between smoking and mortality vary substantially across country and calendar time. Although methodological biases have been discussed, it is biologically plausible that persistent organic pollutants (POPs) like polychlorinated biphenyls (PCBs) and organochlorine (OC) pesticides can affect this association. This study was performed to evaluate if associations of cigarette smoking with mortality were modified by serum concentrations of PCBs and OC pesticides. We evaluated cigarette smoking in 111 total deaths among 986 men and women aged 70 years in the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) with mean follow-up for 7.7 years. The association between cigarette smoking and total mortality depended on serum concentration of PCBs and OC pesticides (P value for interaction = 0.02). Among participants in the highest tertile of the serum POPs summary score, former and current smokers had 3.7 (95% CI, 1.5–9.3) and 6.4 (95% CI, 2.3–17.7) times higher mortality hazard, respectively, than never smokers. In contrast, the association between cigarette smoking and total mortality among participants in the lowest tertile of the serum POPs summary score was much weaker and statistically non-significant. The strong smoking-mortality association observed among elderly people with high POPs was mainly driven by low risk of mortality among never smokers with high POPs. As smoking is increasing in many low-income and middle-income countries and POPs contamination is a continuing problem in these areas, the interactions between these two important health-related issues should be considered in future research.</p></div

Adjusted hazard ratios (HRs)^* and 95% confidence intervals (CIs) for all-cause mortality rate by summary measures^† of polychlorinated biphenyls (PCBs) or organochlorine (OC) pesticides, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

<p>*Hazard Ratios (HRs) adjusted for gender, BMI, exercise, and alcohol consumption.</p>†<p>Values of compounds belonging to in each summary measure were individually ranked; the rank orders of the individual POPs were summed to calculate summary measures and the summaries were divided into tertiles.</p

Adjusted^* serum concentrations (geometric means, ng/g lipid) of individual polychlorinated biphenyls (PCBs) or organochlorine (OC) pesticides according to the status of cigarette smoking, Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.

<p>*Adjusted for gender, BMI, exercise, and alcohol consumption.</p>†<p>POPs with dioxin activity.</p