July 2010 | Vol 7 | N.º 7 | CNIC-22 [PDF (687KB)]

Cadmium as a novel cardiovascular risk factor: Supportive evidence and future directions

María Téllez-Plaza, Ana Navas-Acién and Eliseo Guallar*
Correspondence to:
María Téllez-Plaza, Departamento de Epidemiología y Genética de Poblaciones, Centro Nacional de Investigaciones Cardiovasculares Carlos III, C/ Melchor Fernández Almagro, 3, 28029 Madrid (Spain)
Email mtellez@cnic.ess

Competing interests
The authors declare no competing interests.

Abstract
In addition to secondary preventive strategies in high-risk patients, which are common in clinical practice, population-based primary preventive strategies are critical to reducing the cardiovascular disease burden in the population. Environmental toxicants are widespread, and the general population is exposed to them through air, water and food. Some environmental toxicants may cause cardiovascular disease. Because exposure to them is preventable, there are substantial opportunities for population-based cardiovascular preventive strategies. Given the limited performance of current cardiovascular disease risk-stratification equations, insufficient access to the healthcare system, and incomplete individual adherence to high-risk preventive interventions, efforts to uncover the cardiovascular effects of preventable environmental exposures are urgently needed. In this commentary, we present the example of cadmium, a non-essential toxic metal, with increasing evidence that supports its role in atherosclerosis initiation and progression. Overall, the epidemiologic evidence supports the plausibility of cadmium as a cardiovascular risk factor at low chronic exposure levels, which are relevant for most populations worldwide. Future prospective studies assessing cadmium-related cardiovascular end-points should include fatal and non-fatal events. In addition, research investigating the genetic determinants of cadmium metabolism and toxicity and the relevant mechanisms for cadmium toxicity, including the role of DNA methylation alterations, is needed.

Importance of research on novel cardiovascular risk factors
Cardiovascular disease is the major cause of mortality and morbidity worldwide. It is estimated that the coronary heart disease burden will rise from 47 million disability-adjusted life years (DALY) in 1990 to 82 million DALY in 2020.¹ The effectiveness of high-risk secondary preventive strategies, common in clinical practice, is affected by the limited performance of risk-stratification equations,² insufficient access to the healthcare system, and incomplete individual adherence to high-risk secondary preventive interventions.³ As a consequence, there is a need to identify preventable cardiovascular risk factors for which population-based primary preventive strategies can be implemented.⁴

Exposure to environmental toxicants through air, water and food is widespread in the population.⁵ Some environmental toxicants may contribute to the development of cardiovascular disease.⁶-⁹ Because exposure to environmental toxicants is preventable, the opportunity for population-based cardiovascular preventive strategies is substantial. For instance, meta-analyses of studies conducted in several countries have reported that the incidence of acute myocardial infarction decreased by almost 20% following the implementation of comprehensive smoke-free legislations that regulated bars and restaurants.¹⁰-¹²

The importance of environmental toxicants in terms of population exposure and their potential for prevention justify the conduct of focused research. In this review, we present the case of cadmium, a toxic metal, as an example of a widespread and preventable environmental exposure with mounting evidence on its role in cardiovascular disease. Additionally, we comment on potential directions for future research.

Widespread exposure to cadmium
Cadmium is a non-essential metal widely distributed in the environment.¹³, ¹⁴ A by-product from mining, smelting and refining of zinc, lead and copper ores, cadmium production and use has substantially increased, particularly in nickel-cadmium batteries, fertilisers, coatings and plastic stabilisers.¹³ The environmental impact of non-recycled nickel-cadmium batteries and of cadmium-containing fertilisers on human exposure through soil and diet is a major concern.¹³, ¹⁵ Indeed, leafy or root vegetables and grains bioconcentrate cadmium from the soil,¹³, ¹⁵ resulting in a major cadmium exposure pathway through the diet and smoking. Acidic soils are associated with increased cadmium transfer to plants compared to alkaline soils.¹⁶ Ambient air can also contribute to exposure, particularly in urban areas and in the vicinity of industrial sources.¹³, ¹⁵

Cadmium metabolism and biomarkers
After exposure, cadmium is incorporated into the body through the respiratory and digestive tracts using transporters like those used by essential divalent metals (e.g., zinc, iron, manganese, and calcium) such as ZIP-8 and DMT-1.¹⁵, ¹⁷, ¹⁸ In patients with low iron stores, increased expression of the divalent metal transporter (DMT-1) in human enterocytes may increase cadmium uptake through the digestive tract.¹⁵

In blood, under conditions of chronic exposure, cadmium is transported bound mainly to metallothioneins (MTs). MTs are a low molecular weight family of proteins with a high heavy-metal-binding capacity.¹⁹, ²⁰ MTs bind metals through the thiol (-SH) group of Cys residues. They have been associated with protection against toxic metals and with the homeostasis, storage and transport of physiological metals such as zinc and copper.¹⁹, ²⁰ In the kidney, cadmium-MT compounds are completely and quickly filtered by the glomerulus. Cadmium-MT compounds are then transported into the proximal tubule cells by endocytosis, where they bioaccumulate.¹⁵ The biological half-life of cadmium in humans is very long (15–30 years), and it progressively accumulates with age in the kidney (the site of half of the body’s burden), liver, pancreas and central nervous system.¹⁵

In epidemiologic studies, cadmium concentrations in blood and urine are established biomarkers of cadmium exposure and internal dose.¹³, ¹⁵, ¹⁷, ²¹Urine cadmium reflects kidney cadmium and, consequently, has been considered a biomarker of cumulative body burden. Blood cadmium is more dependent on daily fluctuations in exposure and has been considered a marker of ongoing exposure. However, in cadmium-exposed workers, the half-life of blood cadmium showed a fast component (3-4 months) and a slow component (10 years); supporting the suggestion that, after long-term exposure, blood levels of cadmium may also reflect the body’s burden of cadmium.¹⁵, ²¹

Biological plausibility for cadmium as a cardiovascular risk factor
Experimental evidence²², ²³ suggests that cadmium could directly induce atherosclerosis initiation and progression. In vitro, cadmium causes endothelial dysfunction, and in vivo, it accelerates atherosclerotic plaque formation.²³ Several mechanisms have been suggested to explain the role of cadmium in promoting atherosclerosis. First, cadmium, a divalent cation that binds to sulphhydryl group-containing enzymes, could indirectly increase reactive oxygen species formation²², ²⁴ and interfere with anti-oxidative stress responses by binding metallothionein,¹⁹ a low molecular weight protein that regulates zinc homeostasis and acts as a free radical scavenger.²⁰, ²², ²⁵ Second, cadmium may inhibit the cell cycle by altering cell signalling pathways and induce an atypical form of apoptosis involving necrotic rupture of the endothelial cell plasma membrane, with subsequent attraction and activation of macrophages.²³ Third, cadmium may partly contribute to atherosclerosis formation through vasopressor mechanisms such as direct vasoconstrictor action, inhibition of vasodilator substances such as nitric oxide, or activation of the sympathetic nervous system.²⁶, ²⁷ In the kidney, cadmium may induce salt retention and volume overload, which may produce hypertension.²⁸ It is also possible that cadmium, a well-known nephrotoxicant in occupational settings,¹³, ¹⁵, ¹⁷, ²¹ contributes to systemic hypertension and atherosclerosis partly by producing injury to the kidney, a key organ in blood pressure regulation.

Other mechanisms, such as cadmium-related estrogenic activity²⁹ and epigenetic changes³⁰-³², could be involved in cadmium cardiovascular toxicity. However, the contribution of these mechanisms to human atherosclerosis has not been explored in epidemiologic studies. Importantly, DNA methylation alterations, which result in changes in gene expression, are mitotically and meiotically heritable.³³ Given that cadmium has been associated with DNA methylation alterations³⁰, ³¹, ³² and the fact that reproductive tissues are target organs for cadmium exposure,¹⁵ parental cadmium exposure burden may be heritable across generations.

In summary, some experimental evidence provides biological plausibility for cadmium as a cardiovascular risk factor. However, the relevance of these mechanisms to human atherosclerosis is uncertain.

Cadmium and cardiovascular end-points in epidemiologic studies
Early epidemiologic evidence on the association of cadmium exposure with atherosclerosis end-points was published between the 1960s and the early 1990s.³⁴-³⁸ Ecologic studies reported increased cardiovascular mortality rates with elevated cadmium levels in air in the US34 and with soil and water in the Netherlands.³⁵ Autopsy studies found associations between tissue cadmium levels and atherosclerotic lesions.³⁵-³⁸ A small case-control study measured higher blood cadmium concentrations in subjects with myocardial infarction or coronary heart disease compared to controls.³⁹

In environmentally and occupationally exposed populations from Japan and Belgium, prospective evidence also supports the link between cadmium and cardiovascular disease mortality.⁴⁰, ⁴¹ In a Japanese population, urine cadmium concentrations at baseline were prospectively associated with increased heart failure mortality (multivariable-adjusted hazard ratio 1.97 [1.06, 3.66] for men and 1.59 [1.03, 2.46] for women).⁴⁰ In both men and women, blood and urine cadmium levels were associated with a moderate increase in cardiovascular mortality, although the multivariable-adjusted hazard ratios were not statistically significant, possibly owing to a limited sample size (hazard ratio for a doubling of cadmium levels at baseline 1.20 [0.90–1.60] for blood cadmium and 1.07 (0.85–1.34) for urine cadmium).⁴¹ Chronic kidney disease is another end-point related to cardiovascular disease that has been related to cadmium exposure in cadmium-polluted areas in prospective studies from Japan and Sweden.⁴², ⁴³ In general populations living in non-polluted areas, however, few epidemiologic studies have evaluated the association between low chronic cadmium exposure and cardiovascular end-points.

The National Health and Nutrition Examination Survey (NHANES) is a major program of the U.S. National Center for Health Statistics. A complex, multistage, probability sampling design is used to select participants that are representative of the civilian non-institutionalised U.S. population.⁴⁴ Accumulating evidence from NHANES reports associations of cadmium biomarkers with different cardiovascular related end-points including blood pressure levels,⁴⁵, ⁴⁶ kidney disease,⁴⁷ diabetes,⁴⁸ peripheral arterial disease,⁴⁹, ⁵⁰ electrocardiogram (ECG)-diagnosed myocardial infarction,⁵¹ and self-reported history of stroke, heart failure and myocardial infarction.⁵² These findings are remarkable given the relatively low levels of cadmium exposure in the US (geometric means of 0.41 μg/L and 0.26 μg/g creatinine in blood and urine, respectively, in NHANES 1999-2006 participants 20 years old or older) compared to other populations.¹⁶, ¹⁷, ²¹ In Figures 1 and 2, we present dose-responses of blood cadmium and cardiovascular end-points using public data available in NHANES 1999-2006. Most of these findings have been previously reported for different NHANES subsamples with consistent findings.⁴⁶, ⁴⁹, ⁵²

Strengths of the NHANES studies include the large sample size, the availability of information on multiple risk factors for cardiovascular end-points, the careful standardisation of study protocols and extensive quality control for the examination and laboratory procedures, and, importantly, the representative nature of the general population. An important limitation, however, is the cross-sectional design. Nonetheless, a prospective study on urine cadmium levels in NHANES III (1988-1994) with an overall average follow-up of 7 years found increasing urine cadmium concentrations to be associated with increased cardiovascular mortality among men but not women.⁵³ These results suggest that gender differences in cadmium-related cardiovascular end-points at low levels of exposure, which are seldom evaluated in general population studies, are possible.
Finally, in a recent epidemiologic study conducted in young Austrian women, serum cadmium was associated with increased carotid intima-media thickness (multivariable-adjusted odds ratios for intima media thickness exceeding the 90th percentile comparing the two highest cadmium tertiles versus the lowest one were 5.2 (1.2, 22.4) and 6.4 (1.2, 33.4), respectively).²³ These findings support the hypothesis that cadmium exposure may be involved in early subclinical atherosclerosis.

Cadmium exposure prevention
In smokers, tobacco is the main source of cadmium exposure. In non-smoking general populations living in non-polluted settings, second-hand smoke and certain foods are the main sources of exposure.¹³ Because individual-based strategies are limited to effectively decrease personal exposure to cadmium, population-based strategies and interventions aiming to decrease environmental exposure are critical.⁴ For instance, major strategies that can reduce exposure to cadmium include tobacco-control policies such as promoting public and private smoke-free environments, reviewing food safety policies and cadmium safety standards, and limiting cadmium industrial releases into the environment such as ensuring the adequate handling of cadmium-nickel batteries. In populations living in the vicinity of industrial settings and in some urban areas, air and dust ingestion are the relevant routes of cadmium exposure. In highly polluted settings, in addition to population-based strategies (such as soil remediation or limiting cadmium industrial releases), individual-based high-risk strategies could contribute to reduce exposure. The following preventive recommendations for individuals have been reviewed by Nawrot and co-workers: 1) quitting smoking, 2) replacing carpets with floor coverings that can be washed, 3) using vacuum cleaner with a HEPA filter capable of retaining particles <3 μm, 4) employing soil pH testing and modification and 5) increasing iron intake and stores.¹⁶

However, for most of these strategies, there is no epidemiologic or experimental evidence available on the effectiveness of such interventions in decreasing cadmium biomarker levels over time or, ultimately, decreasing rates of cadmium-related outcomes.

Future directions
The consistency of the association between low chronic cadmium exposure and cardiovascular end-points must be evaluated in sufficiently powered studies in non-polluted areas in different regions of the world. Given insufficient prospective data, future prospective studies will be very important in assessing the temporality of the associations between cadmium and cardiovascular end-points, including fatal and non-fatal events. Epidemiologic studies on the cardiovascular effects of cadmium should systematically evaluate differences between men and women. Finally, studies with comprehensive evaluations of subclinical atherosclerosis can provide information on the early effects of cadmium exposure and relevant pathways for its cardiovascular effects.

Given the important role of metallothioneins in cadmium metabolism, investigating the role of metallothioneins as confounders or effect modifiers of cardiovascular-related cadmium toxicity is important. Determination of the levels of metallothioneins in biological samples is challenging.⁵⁴ The development of metallothionein quantification techniques suitable for large-scale epidemiologic studies is needed. Another major area of research is the evaluation of genetic loci related to cadmium levels in the human body as well to cadmium toxicity. The evaluation of genetic determinants of cadmium metabolism and toxicity could contribute to 1) discovering novel biological pathways for cadmium metabolism, 2) using a Mendelian randomisation approach⁵⁵ to test and discuss the causality of cadmium exposure as a cardiovascular risk factor and 3) identifying risk subgroups to target preventive interventions.

Finally, further experimental research is needed to disentangle the role of different mechanisms mediating the relationship of cadmium with different cardiovascular end-points. Importantly, novel mechanisms for cadmium toxicity should be explored, such as DNA methylation alterations that could partially mediate cadmium toxicity. In addition to mechanistic research investigating the epigenetic effects of cadmium, population-based studies should be conducted to investigate the role of global hypomethylation and gene-specific methylation alterations in the relationship between cadmium toxicity and cardiovascular end-points including subclinical atherosclerosis.

Conclusion
Increasing evidence indicates that cadmium, a widespread and preventable environmental exposure, may cause cardiovascular disease. Prospective studies evaluating cardiovascular disease development in populations exposed to a wide range of cadmium exposure levels are needed. Understanding the role of cadmium in cardiovascular disease could substantially improve cardiovascular health as cadmium exposure can be monitored and controlled.