Environmental toxic metal contaminants and risk of cardiovascular disease: systematic review and meta-analysis

Selection criteria

We included studies if they met the following initial search criteria: were prospective cohort, case-control, or nested case-control in design; had sampled from healthy (ie, participants or referents, where appropriate, were based on initially healthy participants) or general populations (ie, populations with both healthy and prevalent cases of cardiovascular disease at baseline); assessed toxic metal exposure at individual level rather than aggregate level (eg, individual-level exposure to arsenic in drinking water); or reported risk estimates for cardiovascular disease, coronary heart disease, or stroke, for at least one toxic metal. We excluded studies for the following reasons: they only reported on mean levels and standard deviations of toxic metals in cases and non-cases; they only assessed exposure to toxic metals using a self reported dietary measure; or were cross-sectional or ecological in design. Two independent reviewers screened the search results to assess conformity with selection criteria, with disagreement resolved with a third reviewer. In cases of multiple publications from a single study, we used the most up to date information.

Data extraction and quality assessment

Data on the following characteristics were extracted independently by two investigators using standardised protocols: sample size; study design; sampling population; location (defined as Europe, North America, and the Asia-Pacific region); year of baseline survey; study design; age range of participants at baseline; sex; mean levels of environmental contaminants at baseline; sample type (serum, plasma, or adipose tissue), storage temperature, assay methods; duration of follow-up; numbers of disease outcomes of interest and reported effect estimates with each marker for each outcome; and degree of statistical adjustment used (defined as ‘+’ when relative risks were adjusted for age and sex only; ‘++’ when adjusted for established vascular risk factors (eg, age, sex, smoking status, lipids, hypertension, history of cardiometabolic disease); and ‘+++’ when adjusted other additional factors (eg, social status)). Adequate adjustments for these factors are essential to control for the potential confounding effect by these factors in influencing both levels of toxic metals and the risk of cardiovascular disease, resulting in a spurious association. Two independent reviewers used the Newcastle-Ottawa scale to assess the quality of the included studies.²⁴ This scale uses a star system (with a maximum of nine stars) to assess the quality of a study in three domains: selection of participants; comparability of study groups; and the ascertainment of outcomes of interest. Studies that scored nine stars were considered to be of high quality, studies that scored seven or eight stars were considered to be of medium quality, and studies that scored less than seven stars were considered to be of low quality.

Data synthesis and analysis

To enable a consistent approach to meta-analysis and interpretation of findings in this review, relative risk estimates for the association of toxic metals and cardiovascular disease, coronary heart disease, and stroke were transformed to consistently correspond to the comparison of the top versus bottom third of the distribution in each study, using methods previously described.²⁵ Briefly, log risk estimates were transformed assuming a normal distribution, with the comparison between top and bottom thirds being equivalent to 2.18 times the log relative risk for a 1 standard deviation increase (or equivalently, as 2.18/2.54 times the log relative risk for a comparison of extreme quarters). Standard errors of the log relative risks were calculated using published confidence limits and were transformed in the same way. For example, the study by Kromhout et al reported a relative risk of cardiovascular disease of 1.06 (95% confidence interval 0.47 to 2.37) comparing the top versus bottom quartile of lead exposure, corresponding to a log relative risk of 0.058 and standard errors (log relative risk) of 0.41.²⁶ The conversion of risk estimates to top versus bottom third exposure of lead in this study is performed as follows: log relative risk_{(top v bottom third)}=(2.18/2.54)*0.058=0.05 and standard errors log relative risk _{(top v bottom third)}=(2.18/2.54)*0.41=0.35.

We calculated summary relative risks by pooling the study-specific estimates using a random- effects model that included between study heterogeneity (parallel analyses used fixed-effect models). We assessed the consistency of findings across individual studies by standard χ² tests and the Ι² statistic.²⁷ We assessed heterogeneity between observational cohorts by comparing results from studies grouped according to prespecified study level characteristics (such as study design, location, year of baseline survey, duration of follow-up, numbers of outcomes recorded, outcome definition, degree of statistical adjustment used, and sample type) using meta-regression. In particular, for studies investigating the association of arsenic with cardiovascular disease outcomes, the impact of the measurement source (biomarker v water) on risk estimates was assessed in subgroup analyses. We assessed evidence of publication bias across studies using funnel plots and Egger test for outcomes where at least three studies were available.²⁸

We performed dose-response meta-analyses using generalised least-squares trend estimation (GLST) analysis as described by Greenland and Longnecker.²⁹ We estimated study-specific slopes (linear trends) from the correlated natural logs of the relative risks across toxic metal exposure categories. Only studies that reported the number of cases, non-cases, person years of follow-up, and the relative risks with the variance estimates for at least three quantitative exposure categories were included. The median or mean level of the toxic metal in the original scale was assigned to the corresponding relative risk for each exposure category. If data were not available, we estimated the median using the midpoint of each category. When the highest or lowest category was open, we assumed it to be of the same amplitude as the adjacent category. Potential nonlinear dose-response relations were examined by modelling levels of toxic metals using restricted cubic splines.³⁰ A P value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second spline is equal to zero. All statistical tests were two sided and used a significance level of P<0.05. We performed all analyses using Stata version 12 (StataCorp, College Station, TX).

Associations between environmental contaminants and the risk of cardiovascular disease outcomes

Thirty five studies were included in the meta-analysis of environmental contaminants and cardiovascular disease outcomes. Six studies (one reporting on arsenic, two on cadmium, three on mercury) which did not use an appropriate assessment of heavy metal exposure (ie, use of cadmium levels in toenails) or did not adjust for important confounders of heavy metal exposure (eg, smoking for cadmium or seafood intake for mercury) were excluded from the analysis (table 1). In total, 14 706, 12 033, and 3613 cases of cardiovascular disease, coronary heart disease, and stroke, respectively, across 35 contributing studies were included in the meta-analysis. The total follow-up duration ranged from five to 36 years in the prospective studies. Twenty three studies adjusted for conventional risk factors for cardiovascular disease including age, sex, and sociodemographic factors (ethnicity, education, income) as well as additional risk factors such as smoking status, blood pressure, lipids, and medical history. Thirteen studies adjusted for age, sex, and sociodemographic factors. Three studies adjusted for age and sex only. Figure 2 shows the summary plot for cardiovascular disease, coronary heart disease, and stroke comparing participants in the top third with those in the bottom third of various environmental contaminants. Figure 3, figure 4, and figure 5 show the forest plots for each separate outcome.

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Fig 2

Summary of the association of environmental contaminants with cardiovascular outcomes. Pooled risk estimates were calculated using random effects meta-analyses. The relative risk compares the risk for each outcome in individuals in the top third with those in the bottom third of baseline levels of the environmental contaminants (ie, extreme thirds). Risk estimates from separate studies were typically adjusted for basic demographics (eg, age, sex, systolic blood pressure, smoking, history of diabetes, etc)

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Fig 3

Association between environmental contaminants and cardiovascular disease. NR=not reported; +=minimally adjusted (typically adjusted for age and sex only); ++=adjusted for at least one non blood based cardiovascular risk factor (eg, systolic blood pressure, body mass index, history of diabetes, etc); +++=additionally adjusted for at least one blood based cardiovascular risk factor (eg, total cholesterol, c-reactive protein, etc)

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Fig 4

Association between environmental contaminants and coronary heart disease. NR=not reported; +=minimally adjusted (typically adjusted for age and sex only); ++=adjusted for at least one non blood based cardiovascular risk factor (eg, systolic blood pressure, body mass index, history of diabetes, etc); +++=additionally adjusted for at least one blood based cardiovascular risk factor (eg, total cholesterol, c-reactive protein, etc)

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Fig 5

Association between environmental contaminants and stroke. NR=not reported; +=minimally adjusted (typically adjusted for age and sex only); ++=adjusted for at least one non blood based cardiovascular risk factor (eg, systolic blood pressure, body mass index, history of diabetes etc); +++=additionally adjusted for at least one blood based cardiovascular risk factor (eg, total cholesterol, c-reactive protein, etc)

Arsenic, lead, cadmium, and copper were significantly associated with the risk of coronary heart disease, with respective relative risks of 1.23 (95% confidence interval 1.04 to 1.45), 1.85 (1.27 to 2.69), 1.29 (0.98 to 1.71), and 2.22 (1.31 to 3.74). There was no association of mercury levels with coronary heart disease, relative risk of 0.99 (0.65 to 1.49). There was evidence of heterogeneity in coronary heart disease estimates across studies for most environmental contaminants (I²=78%, P<0.001 for arsenic; I²=66%, P=0.005 for lead; I²=52%, P=0.08 for cadmium; I²=85%, P<0.001 for mercury; and I²=67%, P=0.03 for copper).

Similar to the risk of coronary heart disease, arsenic, lead, cadmium, and copper levels were also associated with an increased risk of cardiovascular disease (respective relative risks of 1.30, 95% confidence interval 1.04 to 1.63; 1.43, 1.16 to 1.76; 1.33, 1.09 to 1.64; and 1.81, 1.05 to 3.11). There was no evidence of an association of mercury levels with the risk of cardiovascular disease (0.94, 0.66 to 1.36). However, there was significant evidence of heterogeneity in cardiovascular disease estimates across studies (I² ranging from 68%, P=0.001 for lead to 84%, P<0.001 for mercury).

Lead and cadmium were also associated with a significantly increased risk of stroke (respective relative risks of 1.63, 95% confidence interval 1.14 to 2.34 and 1.72, 1.29 to 2.28) with no evidence of heterogeneity across studies (I²=0%, P=0.76 and I²=10%, P=0.33). There was no evidence of an association of arsenic with risk of stroke, with little to no evidence of heterogeneity in stroke estimates across studies for either contaminant (I²=56%, P=0.08).

Dose-response meta-analyses

The dose-response relations between levels of toxic metals and cardiovascular outcomes, based on available relevant data are shown in supplementary materials, figure S1. Only two studies reporting on exposure to arsenic in drinking water, three studies reporting on exposure to cadmium, and four studies reporting on exposure to lead, provided sufficient information to perform the dose-response analysis. In summary, for baseline arsenic levels in well water and risk of cardiovascular disease, there was evidence of a linear association across the full spectrum of arsenic levels (0 μg/L to 369.5 μg/L, P=0.31 for nonlinearity; see supplementary material, fig S1A). Similarly, there was evidence of a linear association between lead levels in blood and the risk of coronary heart disease (P=0.677 for nonlinearity; see supplementary material, fig S1B), with a pooled relative risk for risk of coronary heart disease per 5 μg/dL increment in lead levels being 1.07 (95% confidence interval 1.04 to 1.10). By contrast, for the association between cadmium levels in urine and the risk of cardiovascular disease, an initial steep increase in risk (within urine cadmium levels of 0.11 μg/g to 1.41 μg/g) was followed by a weaker increase in risk beyond 1.41 μg/g. The relative risk of cardiovascular disease for each 0.75 μg/g increment of cadmium was 1.21 (95% confidence interval 1.09 to 1.33, P=0.656 for nonlinearity; see supplementary materials, fig S1C). There was a significant linear association between cadmium levels in urine and the risk of coronary heart disease (P=0.865 for nonlinearity; see supplementary materials, fig S1D).

Comparison with other studies

Findings observed in this review may have several potential explanations. We found a positive association of arsenic, an environmental toxic metal found in large quantities in rice and groundwater in many parts of the world, with the risk of coronary heart disease.^{76 77} Arsenic exposure has been reported to accelerate and exacerbate atherosclerosis in apolipoprotein E-knockout mice.^{78 79} Clinical and experimental studies of arsenic exposure have reported the production of reactive oxygen species in endothelial cells,⁸⁰ up regulation of inflammatory signals,⁸¹ and higher blood pressure.^{82 83 84} These findings extend several previous epidemiological studies that reported striking associations with Blackfoot disease (a severe peripheral vascular disease) in people exposed to extremely high cumulative doses of arsenic.^{85 86}

Although circulating levels of lead seem to be in decline in the developed world,⁸⁷ owing principally to the concomitant decrease in the usage of leaded gasoline and leaded paint, lead exposure remains considerably high in many areas.^{5 88} The strong positive association found in our review between lead and the risk of cardiovascular disease, reinforces lead exposure as a major public health concern.⁸⁹ Two key pathways by which lead has been implicated in the risk of cardiovascular disease are mediation through accelerated systolic blood pressure and damage to renal function.⁹⁰ Previous studies have also suggested an association of lead with atherosclerosis as a result of lead-induced oxidative stress and inflammation after exposure.^{11 15}

The present review also shows a positive association of copper with cardiovascular disease, as suggested in previous studies.^{91 92} While copper is an essential trace element, excess copper can induce oxidative stress by generation of reactive oxygen species.¹¹ Copper-mediated lipid peroxidation has been demonstrated in several in vivo and in vitro studies.²¹ Another possible mechanism for the potential deleterious effects of copper is through a copper-homocystein complex which have been suggested to induce endothelial dysfunction and vascular injury.⁹³ For both arsenic and copper, albeit based on limited data, the potentially linear dose-response relation that we have observed indicates that even at lower average exposure levels (common in many global regions), these toxic metals may have a detrimental impact on vascular health.

We also observed a positive association between levels of cadmium and cardiovascular disease, which was independent of several potential risk of cardiovascular disease factors (including smoking status). Cadmium's adverse effects on the vascular system are thought to be mediated by oxidative stress, inflammation, and endothelial cell damage, which can result in atherosclerosis. This is important as cadmium is widely prevalent in groundwater and common plant-based foods (eg, rice and vegetables).⁹⁴

Conversely, mercury, a potentially toxic trace metal that humans are exposed to primarily through fish consumption,⁹⁵ was not significantly associated with the risk of cardiovascular disease in the current review. Although some individual studies have observed inverse relations between mercury levels and the risk of cardiovascular disease,^{62 66} there is currently no accepted biological explanation that supports such a link.⁶⁶

Strengths and limitations of the study

Strengths and limitations of this work merit careful consideration. This is the first comprehensive meta-analysis of several key environmental toxic metals in relation to the risk of cardiovascular disease. We have focused solely on individual-level assessments of exposure to toxic metals, and performed our analyses based primarily on toxic metals measured directly using an objective biomarker or well established measures of individual level exposure such as arsenic in drinking water. However, it should be noted that the biological determinants, precision of measurements and ability to reflect long term exposure may differ across various biomarkers.⁹⁶ Therefore, to ensure consistent long term exposure assessment, the use of repeated measurements over time that accounts for any potential individual variation in levels (ie, regression dilution)⁹⁷ should be considered in future studies.⁵⁵ Furthermore, most studies that measured arsenic and cadmium levels in urine were based on spot or first morning void samples, which might be limited by the fact that they reflect the hydration status of the individual at the time of collection, and therefore, may differ markedly in dilution owing to differences in urinary flow rate,⁹⁸ and differences in stability and reproducibility of metals measured in them. Additionally, although over half the risk estimates for urinary arsenic and cadmium from all included studies were creatinine adjusted, some were unadjusted for any marker of urinary dilution. While this review is limited to published findings, the use of individual participant data, in future large-scale primary studies, would allow a more detailed and specific assessment of the association between the considered environmental toxic metals and cardiovascular disease, including: assessing the role of routes of exposure (eg, environmental v occupational); a standardised adjustment for confounders (eg, smoking status); reduce heterogeneity resulting from meta-analysis of diverse study populations; and a more consistent characterisation of any potential dose-response relation. Such comprehensive assessments are currently underway.^{99 100} Equally, our review was solely based on observational data which might be affected by unmeasured confounders – making a causal inference difficult. In this regard, an earlier randomised trial, based on people with pre-existing cardiovascular disease, suggested that moderate reduction of cardiovascular events occured after intravenous chelation therapy (which facilitates urinary excretion of heavy metals)¹⁰¹ compared with placebo. However, further conclusive trials, especially those involving general populations, are needed. Additionally, the identification of polymorphisms influencing circulating levels of these toxic metals which can be used as proxies for circulating levels (such as polymorphisms near AS3MT, MT1A/B),^{102 103 104} may also allow future investigations of potential causal associations with disease using instrumental variable analysis (ie, mendelian randomisation analyses).¹⁰⁵

Implications for clinicians and policy makers

Our findings may have important policy and scientific implications. Firstly, these findings highlight the importance of environmental toxic metals in enhancing cardiovascular risk, beyond the roles of conventional behavioural risk factors (such as tobacco use and unhealthy diet). These results may have a key policy implication given that current global noncommunicable disease prevention strategies (eg, WHO 2018 Report)¹⁰⁶ are focused primarily on tackling behavioural determinants. Recognising environmental factors (such as toxic metals) as additional priorities, therefore, will help gain wider sociopolitical support for setting up appropriate legislation, preventive strategies and standards, and investment to tackle these major global determinants of cardiovascular diseases. Secondly, the observed associations appeared approximately linear for arsenic, lead, and cadmium levels with cardiovascular disease outcomes, indicating the risk of adverse health consequences even at a relatively low exposure of these toxic metals. Nonetheless, these current findings warrant further detailed research to reliably quantify suboptimal levels to define individuals at risk and to trigger appropriate clinical action. Presently, in clinical practice, toxicity for these metals, if suspected, are established through a range of diagnostic investigations including blood and 24-hour urinary analyses and typically involving an inductively coupled plasma mass spectrometry analytical technique for elemental determinations.¹⁰⁷ Treatment options for heavy metal toxicity include various antidotes and chelating agents (which enhance the elimination of metals from the body) such as succimer (DMSA), unithiol (DMPS), sodium calcium edetate, and dimercaprol.¹⁰⁸ However, since efficacy and response of these therapies vary greatly,¹⁰⁹ primary prevention, by developing evidence based public health guidelines and innovative low cost, scalable interventions to reduce human exposure to these contaminants, should be prioritised.