Faculty Bibliography

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide and mounting evidence indicates that toxicant exposures can profoundly impact on CVD risk. Epidemiologic studies have suggested that arsenic (As) exposure is positively related to increases in blood pressure (BP), a primary CVD risk factor. However, evidence of whether genetic susceptibility can modify the association between As and BP are lacking. In this study, we used mixed effects models adjusted for potential confounders to examine the interaction between As exposure from well water and potential genetic modifiers on longitudinal change in BP over approximately 7years of follow-up in 1137 subjects selected from the Health Effects of Arsenic Longitudinal Study (HEALS) cohort in Bangladesh. Genotyping was conducted for 235 SNPs in 18 genes related to As metabolism, oxidative stress and endothelial function. We observed interactions between 44 SNPs with well water As for one or more BP outcome measures (systolic, diastolic, or pulse pressure (PP)) over the course of follow-up. The interaction between CYBA rs3794624 and well water As on annual PP remained statistically significant after correction for multiple comparisons (FDR-adjusted p for interaction=0.05). Among individuals with the rs3794624 variant genotype, well water As was associated with a 2.23mmHg (95% CI: 1.14-3.32) greater annual increase in PP, while among those with the wild type, well water As was associated with a 0.13mmHg (95% CI: 0.02-0.23) greater annual increase in PP. Our results suggest that genetic variability may contribute to As-associated increases in BP over time.

BACKGROUND: Cross-sectional studies have shown associations between arsenic exposure and prevalence of high BP; however, studies examining the relationship of arsenic exposure with longitudinal changes in blood pressure are lacking. METHOD: We evaluated associations of arsenic exposure in relation to longitudinal change in blood pressure in 10,853 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). Arsenic was measured in well water and in urine samples at baseline and in urine samples every two years after baseline. Mixed effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with blood pressure annual change during follow-up (median, 6.7 years). RESULT: In the HEALS population, the median water arsenic concentration at baseline was 62 microg/L. Individuals in the highest quartile of baseline water arsenic or urinary creatinine-adjusted arsenic had a greater annual increase in SBP compared with those in the reference group (beta=0.48 mmHg/year; 95% CI: 0.35-0.61, and beta=0.43 mmHg/year; 95% CI: 0.29-0.56) for water arsenic and urinary creatinine-adjusted arsenic, respectively) in fully adjusted models. Likewise, individuals in the highest quartile of baseline arsenic exposure had a greater annual increase in DBP (beta=0.39 mmHg/year; 95% CI: 0.30, 0.49, and beta=0.45 mmHg/year; 95% CI: 0.36, 0.55) for water arsenic and urinary creatinine-adjusted arsenic, respectively) compared with those in the lowest quartile. CONCLUSION: Our findings suggest that long-term arsenic exposure may accelerate age-related increases in blood pressure. These findings may help explain associations between arsenic exposure and cardiovascular disease.

The National Lipid Association (NLA) recently released recommendations for the treatment of dyslipidemias. These recommendations have commonalities and differences with those of other major societies with respect to risk assessment, lifestyle therapy, targets of therapy, and the use of non-statin agents. In this review, we compare the basic elements of the guidelines from each major society to provide clinicians with a comprehensive document reviewing the key principles of each.

INTRODUCTION: There is epidemiological evidence that metal contaminants may play a role in the development of atherosclerosis and its complications. Moreover, a recent clinical trial of a metal chelator had a surprisingly positive result in reducing cardiovascular events in a secondary prevention population, strengthening the link between metal exposure and cardiovascular disease (CVD). This is, therefore, an opportune moment to review evidence that exposure to metal pollutants, such as arsenic, lead, cadmium, and mercury, is a significant risk factor for CVD. METHODS: We reviewed the English-speaking medical literature to assess and present the epidemiological evidence that 4 metals having no role in the human body (xenobiotic), mercury, lead, cadmium, and arsenic, have epidemiologic and mechanistic links to atherosclerosis and CVD. Moreover, we briefly review how the results of the Trial to Assess Chelation Therapy (TACT) strengthen the link between atherosclerosis and xenobiotic metal contamination in humans. CONCLUSIONS: There is strong evidence that xenobiotic metal contamination is linked to atherosclerotic disease and is a modifiable risk factor.

BACKGROUND: Troponin elevation is a risk factor for mortality in patients with non-ST-segment-elevation acute coronary syndromes. However, the prognosis of patients with troponin elevation and nonobstructive coronary artery disease (CAD) is unknown. Our objective was therefore to evaluate the impact of nonobstructive CAD in patients with non-ST-segment-elevation acute coronary syndromes and troponin elevation enrolled in the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. METHODS AND RESULTS: In the ACUITY trial, 3-vessel quantitative coronary angiography was performed in a formal substudy of 6921 patients presenting with non-ST-segment-elevation acute coronary syndromes. Patients with elevated admission troponin levels were stratified by the presence or absence of obstructive CAD (any lesion with quantitative diameter stenosis >50%). Propensity score matching was performed to adjust for baseline characteristics. Of 2442 patients with elevated troponin, 197 (8.8%) had nonobstructive CAD. Maximum diameter stenosis was 87.4 (73.2, 100.0) versus 22.6 (19.2, 25.7; P<0.0001) in patients with versus without obstructive CAD, respectively. Propensity matching yielded 117 patients with nonobstructive CAD and 331 patients with obstructive CAD, with no significant baseline differences between groups. In the matched cohort, overall 1-year mortality was significantly higher in patients with nonobstructive CAD (5.2% versus 1.6%; hazard ratio [95% confidence interval]=3.44 [1.05, 11.28]; P=0.04), driven by greater noncardiac mortality. Conversely, recurrent myocardial infarction and unplanned revascularization rates were significantly higher in patients with obstructive CAD. CONCLUSIONS: Patients with non-ST-segment-elevation acute coronary syndromes and elevated troponin levels but without obstructive CAD, while having low rates of subsequent myocardial infarction and unplanned revascularization, are still at considerable risk for 1-year mortality from noncardiac causes. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00093158.

Background: Patients with moderate or severe ischemia have a heightened risk for myocardial infarction and cardiovascular death. Geographic variation in the proportion of stress myocardial perfusion imaging (MPI) and echocardiography (echo) with at least moderate ischemia is unknown. Methods: De-identified monthly MPI and stress echo screening logs from sites participating in the NHLBI-funded ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) Trial were reviewed for site-specific number of studies with site-interpreted moderate or severe ischemia. Data are reported as site-weighted medians (interquartile range [IQR]). Results: 97 sites contributed 448 months totaling 46,530 studies. Of 34,463 MPI and 12,067 stress echo studies, 1,308 (3.9% [IQR: 1.2, 8.0]) and 466 (3.2% [IQR: 0.0, 10.0]), respectively, had at least moderate ischemia (P=0.74). Median age was 66 years (IQR: 59, 73); 29.5% were female. Regional variation in study proportion with at least moderate ischemia was observed for both MPI and stress echo (P<0.001 for both, Table) and age (P<0.001), but not for sex (P=0.22). Compared to outside-US, US studies were less likely to have at least moderate ischemia (P<0.001). Conclusions: Regional variations exist in the proportion of stress imaging studies with moderate or severe ischemia. Moderate or severe ischemia was lowest among US studies, suggesting inter-country variability in the clinical assessment of ischemia. (Figure Presented)

Systolic blood pressure (SBP) often varies between clinic visits within individuals, which can affect estimation of cardiovascular disease (CVD) risk. We analyzed data from participants with two clinic visits separated by a median of 17 days in the Third National Health and Nutrition Examination Survey (n = 808). Ten-year CVD risk was calculated with SBP obtained at each visit using the Pooled Cohort Equations. The mean age of participants was 46.1 years, and 47.3% were male. The median SBP difference between the two visits was -1 mm Hg (1st to 99th percentiles: -23 to 32 mm Hg). The median estimated 10-year CVD risk was 2.5% and 2.4% at the first and second visit, respectively (1st to 99th percentiles -5.2% to +7.1%). Meaningful risk reclassification (ie, across the guideline recommended 7.5% threshold for statin initiation) occurred in 12 (11.3%) of 106 participants whose estimated CVD risk was between 5% and 10%, but only in two (0.3%) of 702 participants who had a 10-year estimated CVD risk of <5% or >10%. SBP variability can affect CVD risk estimation, and can influence statin eligibility for individuals with an estimated 10-year CVD risk between 5% and 10%.