Jonathan D. Newman

Metal pollutants and cardiovascular disease: Mechanisms and consequences of exposure

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.

Association between arsenic exposure from drinking water and longitudinal change in blood pressure among HEALS cohort participants

Background Cross-sectional studies have shown associations between arsenic exposure and prevalence of high blood pressure; 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 2 years after baseline. Mixed-effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with annual change in blood pressure during follow-up (median, 6.7 years). Result In the HEALS population, the median water arsenic concentration at baseline was 62 μg/L. Individuals in the highest quartile of baseline water arsenic or urinary creatinine-adjusted arsenic had a greater annual increase in systolic blood pressure compared with those in the reference group (β = 0.48 mmHg/year; 95% CI: 0.35, 0.61, and β = 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 diastolic blood pressure for water arsenic and urinary creatinine-adjusted arsenic, (β = 0.39 mmHg/year; 95% CI: 0.30, 0.49, and β = 0.45 mmHg/year; 95% CI: 0.36, 0.55, 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. Citation Jiang J, Liu M, Parvez F, Wang B, Wu F, Eunus M, Bangalore S, Newman JD, Ahmed A, Islam T, Rakibuz-Zaman M, Hasan R, Sarwar G, Levy D, Slavkovich V, Argos M, Scannell Bryan M, Farzan SF, Hayes RB, Graziano JH, Ahsan H, Chen Y. 2015. Association between arsenic exposure from drinking water and longitudinal change in blood pressure among HEALS cohort participants. Environ Health Perspect 123:806–812; http://dx.doi.org/10.1289/ehp.1409004

Association between fine particulate matter exposure and subclinical atherosclerosis: A meta-analysis

Background Epidemiological studies in humans that have evaluated the association between fine particulate matter (PM2.5) and atherosclerosis have yielded mixed results. Design In order to further investigate this relationship, we conducted a comprehensive search for studies published through May 2014 and performed a meta-analysis of all available observational studies that investigated the association between PM2.5 and three noninvasive measures of clinical and subclinical atherosclerosis: carotid intima media thickness, arterial calcification, and ankle-brachial index. Methods and results Five reviewers selected studies based on predefined inclusion criteria. Pooled mean change estimates and 95% confidence intervals were calculated using random-effects models. Assessment of between-study heterogeneity was performed where the number of studies was adequate. Our pooled sample included 11,947 subjects for carotid intima media thickness estimates, 10,750 for arterial calcification estimates, and 6497 for ankle-brachial index estimates. Per 10 µg/m3 increase in PM2.5 exposure, carotid intima media thickness increased by 22.52 µm but this did not reach statistical significance (p = 0.06). We did not find similar associations for arterial calcification (p = 0.44) or ankle-brachial index (p = 0.85). Conclusion Our meta-analysis supports a relationship between PM2.5 and subclinical atherosclerosis measured by carotid intima media thickness. We did not find a similar relationship between PM2.5 and arterial calcification or ankle-brachial index, although the number of studies was small.

Activated Platelets Induce Endothelial Cell Activation via an Interleukin-1β Pathway in Systemic Lupus Erythematosus

Objective— Systemic lupus erythematosus (SLE) is associated with the premature development of cardiovascular disease. The platelet–endothelium interaction is important in the pathogenesis of cardiovascular disease. In this study, we investigated the platelet phenotype from patients with SLE and matched controls, and their effect on endothelial cells. Approach and Results— Platelet aggregability was measured in 54 SLE subjects off antiplatelet therapy (mean age 40.1±12.8 years; 82% female; 37% white) with age- and sex-matched controls. Platelets were coincubated with human umbilical vein endothelial cells (HUVECs) and changes to gene expression assessed by an RNA array and quantitative reverse transcription polymerase chain reaction. SLE disease activity index ranged from 0 to 22 (mean 5.1±3.9). Compared with controls, patients with SLE had significantly increased monocyte and leukocyte–platelet aggregation and platelet aggregation in response to submaximal agonist stimulation. An agnostic microarray of HUVECs cocultured with SLE platelets found a platelet-mediated effect on endothelial gene pathways involved in cell activation. Sera from SLE versus control subjects significantly increased (1) activation of control platelets; (2) platelet adhesion to HUVECs; (3) platelet-induced HUVEC gene expression of interleukin-8, and intercellular adhesion molecule 1; and (4) proinflammatory gene expression in HUVECs, mediated by interleukin-1&bgr;–dependent pathway. Incubation of SLE-activated platelets with an interleukin-1&bgr;–neutralizing antibody or HUVECs pretreated with interleukin-1 receptor antibodies attenuated the platelet-mediated activation of endothelial cells. Conclusions— Platelet activity measurements and subsequent interleukin-1&bgr;–dependent activation of the endothelium are increased in subjects with SLE. Platelet–endothelial interactions may play a role in the pathogenesis of cardiovascular disease in patients with SLE.

Particulate air pollution and carotid artery stenosis

Outdoor fine particulate air pollution (mass concentration of particles <2.5 μm in diameter [PM2.5]) exposure is ubiquitous and is associated with cardiovascular mortality and ischemic heart disease events (1). PM2.5 exposure also increases the risk for ischemic stroke (2). The vascular and hemodynamic effects of PM2.5 may explain some, but not all, of this increased risk (2). However, it is unknown whether PM2.5 is associated with prevalent clinical atherosclerosis, such as carotid artery stenosis (CAS), a lesion critical to the pathophysiology of ischemic stroke (3). To achieve this objective, we examined PM2.5 and prevalent CAS among more than 300,000 residents of New York, New Jersey, and Connecticut.

Diabetes mellitus is a coronary heart disease risk equivalent for peripheral vascular disease

Background Diabetes mellitus (diabetes) is associated with significantly increased risk of peripheral vascular disease. Diabetes is classified as a coronary heart disease (CHD) risk equivalent, but it is unknown whether diabetes is a CHD risk equivalent for peripheral vascular disease. The objective was to evaluate the odds of peripheral arterial disease (PAD) or carotid artery stenosis (CAS) among participants with diabetes, CHD, or both, compared with participants without diabetes or CHD, in a nationwide vascular screening database. We hypothesized that diabetes and CHD would confer similar odds of PAD and CAS. Methods A cross‐sectional analysis of all eligible Life Line Screening Inc participants age 30 to 90 years with ankle brachial indices for PAD (ankle brachial index <0.9 in either leg) and carotid artery duplex ultrasonographic imaging for CAS (internal CAS ≥50%) was performed (N = 3,522,890). Results Diabetes and CHD were present in 372,330 (10.7%) and 182,760 (5.8%) of participants, respectively; PAD and CAS were present in 155,000 (4.4%) and 130,347 (3.7%) of participants. After multivariable adjustment, PAD odds were 1.56 (95% CI 1.54‐1.59) and 1.69 (95% CI 1.65‐1.73) for participants with diabetes or CHD, respectively. Participants with both diabetes and CHD had 2.75‐fold increased odds of PAD (95% CI 2.66‐2.85). Findings were similar for CAS; compared with no diabetes or CHD, CAS odds increased for participants with diabetes alone (1.53, 95% CI 1.50‐1.56), CHD alone (1.72, 95% CI 1.68‐1.76), and both diabetes and CHD (2.57, 95% CI 2.49‐2.66). Findings were consistent for women and men. Conclusion In a large database of more than 3.5 million self‐referred participants, diabetes was a CHD risk equivalent for PAD and CAS, and participants with comorbid diabetes and CHD had an especially robust association with PAD and CAS. Counseling regarding screening and prevention of peripheral vascular disease may be useful for patients with diabetes. Graphical abstract Peripheral vascular disease risk for diabetes and CHD. Figure. No caption available.

Gene–arsenic interaction in longitudinal changes of blood pressure: Findings from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh

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 is lacking. In this study, we used mixed effect 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.

The Recent National Lipid Association Recommendations: How Do They Compare to Other Established Dyslipidemia Guidelines?

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.

Low-moderate urine arsenic and biomarkers of thrombosis and inflammation in the Strong Heart Study

The underlying pathology of arsenic-related cardiovascular disease (CVD) is unknown. Few studies have evaluated pathways through thrombosis and inflammation for arsenic-related CVD, especially at low-moderate arsenic exposure levels (<100 μg/L in drinking water). We evaluated the association of chronic low-moderate arsenic exposure, measured as the sum of inorganic and methylated arsenic species in urine (ΣAs), with plasma biomarkers of thrombosis and inflammation in American Indian adults (45–74 years) in the Strong Heart Study. We evaluated the cross-sectional and longitudinal associations between baseline ΣAs with fibrinogen at three visits (baseline, 1989–91; Visit 2, 1993–95, Visit 3, 1998–99) using mixed models and the associations between baseline ΣAs and Visit 2 plasminogen activator inhibitor-1 (PAI-1) and high sensitivity C-reactive protein (hsCRP) using linear regression. Median (interquartile range) concentrations of baseline ΣAs and fibrinogen, and Visit 2 hsCRP and PAI-1 were 8.4 (5.1, 14.3) μg/g creatinine, 346 (304, 393) mg/dL, 44 (30, 67) mg/L, and 3.8 (2.0, 7.0) ng/mL, respectively. Comparing the difference between the 75th and the 25th percentile of ΣAs (14.3 vs. 5.1 μg/g creatinine), ΣAs was positively associated with baseline fibrinogen among those with diabetes (adjusted geometric mean ratio (GMR): 1.05, 95% CI: 1.02, 1.07) not associated among those without diabetes (GMR: 1.01, 95% CI: 0.99, 1.02) (p-interaction for diabetes = 0.014), inversely associated with PAI-1 (GMR: 0.94, 95% CI: 0.90, 0.99), and not associated with hsCRP (GMR: 1.00, 95% CI: 0.93, 1.08). We found no evidence for an association between baseline ΣAs and annual change in fibrinogen over follow-up (p-interaction = 0.28 and 0.12 for diabetes and non-diabetes, respectively). Low-moderate arsenic exposure was positively associated with baseline fibrinogen in participants with diabetes and unexpectedly inversely associated with PAI-1. Further research should evaluate the role of prothrombotic factors in arsenic-related cardiovascular disease.

The benefits of neighborhood racial diversity: Neighborhood factors and its association with increased physical activity in ACS patients

Regular physical activity reduces the risk of adverse events after an acute coronary syndrome (ACS).1 Physical activity level is influenced by neighborhood factors such as racial diversity in the general population,2,3 but the impact of neighborhood factors on physical activity after an ACS is unknown. We therefore prospectively evaluated the relationship of post-ACS physical activity assessed by continuous activity monitors with neighborhood characteristics, including ethnic density, income, female headed households, and racial diversity, in patients enrolled in the Prescription Use, Lifestyle, and Stress Evaluation (PULSE) Study. We included 107 patients enrolled in the PULSE study from February 1, 2009 to June 30, who were monitored with an Actical® (Philips – Respironics, Inc, Bend, Oregon) accelerometer device during the first 45 days following discharge from their ACS. For this analysis, physical activity level was operationalized as the mean maximum 6 minutes of activity during the day (M6m), which has previously been employed in studies of patients with chronic heart failure to summarize the patients’ peak activity level.4, 5 Because the trajectory of physical activity is expected to change after hospital discharge, we calculated the M6m measure at 7, 14, 21, and 28 days post-discharge. Characteristics of neighborhood in which patients resided were determined by geocoding mailing addresses using the ArcGISSM (Arc Geographic Information System) software to map individual patients to census tracts (Figure 1). Twenty patients were excluded, at random, as to not violate an assumption of independence when analyzing nested individual-level and neighborhood-level data. Patients were distributed across 87 census tracts. The current analysis therefore included 87 PULSE patients. From the Census American Community Survey 2005-2009 we extracted four neighborhood characteristics corresponding to each census tract: Neighborhood racial diversity, Hispanic ethnic density, percentage female headed household, and median income.6,7 Neighborhood Racial Diversity Index is derived from the calculated variance of four racial/ethnic categories, Black, White, Asian, and Hispanic, summed together to compute the generalized measure of variance (GV), where higher values reflect a higher degree of racial/ethnic diversity. 8 The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Institutional Review Board of Columbia University Medical Center and all patients provided informed consent. Figure 1 Demographic mapping of neighborhood racial diversity for Post ACS patients (N = 87). Darker colors indicate census tracts with increased racial heterogeneity. All neighborhood measures were investigated as continuous measures, with exception of neighborhood racial diversity, which was also categorized into quartiles with the highest quartile as reference. Using growth curve model as a base, neighborhood measures and all other covariates were individually added to the model to assess their bivariate associations with estimated physical activity (M6m) at each time point. Subsequent models assessed the independent association of neighborhood diversity with Day 7, 14, 21, and 28 physical activity after adjusting for demographic (age, gender, ethnicity, race, medicaid insurance, and education) clinical (Charlson comorbidity index, the Global Registry of Acute Coronary Events (GRACE) risk score, left ventricular ejection fracture [LVEF], body mass index, and diagnosis of diabetes mellitus) and the above-described neighborhood level predictors. Because day 7 physical activity may differ from patients Day 14, 21, and 28 physical activity, we tested for the interaction of time and time-squared with each of the significant predictors of physical activity. The mean age of participants was 61.8 years, and the self-identified racial-ethnic composition of the patient sample is 62% White, 32% Hispanic, 19% Black, 3% Asian, 14% Other, and 2% multiple race (Table 1). The average GV index was 0.40, indicating that, on average, there is approximately a 40% chance that two randomly selected patients in the “average neighborhood” would belong to different racial-ethnic subgroups. After adjustment for all demographic, clinical, and neighborhood predictors, the linear association between neighborhood racial diversity and predicted peak physical activity remained significant across all time points (p < .008). Table 1 Baseline Characteristics of Study Participants (N=87) and their Bivariate Correlations with Predicted Day 7 Peak Daytime Physical Activity Categorical analyses indicated that the predicted peak physical activity on day 28 post-ACS was on average 41.3% greater for patients living in neighborhoods in the upper quartile of neighborhood racial diversity. In the fully adjusted model, predicted peak physical activity in the most racially diverse neighborhoods was 40.6%, 42.5%, 39.6%, and 32.4% greater compared to that in neighborhood in the lower three quartiles of racial diversity, at Days 7, 14, 21, and 28 post-ACS discharge, respectively. The interaction effect of racial diversity with post-discharge day (both linear and quadratic terms) was statistically significant, indicating that the effect of neighborhood diversity on predicted peak physical activity is not constant over time. The principal finding of this study is that neighborhood racial diversity was independently associated with higher physical activity after an ACS. On average, across all four time-points, the upper quartile of neighborhood racial diversity had greater physical activity outcome than the bottom three quartiles of neighborhood racial diversity. Previous studies have been inconclusive in identifying neighborhood factors associated with physical activity. Some studies suggest that lower census tract income is associated with decreased physical activity.2 On the other hand, high population density has been shown to be positively associated with physical activity. 3 Also, increased residential racial segregation has been found to be associated with decreased physical activity both in the United Kingdom and in the US.3,10 Our results confirm a different association for ACS patients, increased neighborhood level of racial diversity is associated with increased peak physical activity in a largely urban area. Reasons for this association include the possibility that patients who live in racially diverse neighborhoods have differential access to facilities for physical activity, 9 or that their exercise habits are positively influenced by exposure to the physical activity patterns of individuals of varying race and ethnicity. This study was limited to a small number of participants recruited from a single center and only a subset of enrolled patients wore accelerometers. However, there were no differences across baseline characteristics between patients who enrolled in the actigraphy study versus those who did not enroll. In conclusion, these findings suggest that the environment may play an important role in post ACS activity level and merits attention when caring for patients after an ACS.