Heavy metal poisoning and cardiovascular disease

Cardiovascular disease (CVD) is an increasing world health problem. Traditional risk factors fail to account for all deaths from CVD. It is mainly the environmental, dietary and lifestyle behavioral factors that are the control keys in the progress of this disease. The potential association between chronic heavy metal exposure, like arsenic, lead, cadmium, mercury, and CVD has been less well defined. The mechanism through which heavy metals act to increase cardiovascular risk factors may act still remains unknown, although impaired antioxidants metabolism and oxidative stress may play a role. However, the exact mechanism of CVD induced by heavy metals deserves further investigation either through animal experiments or through molecular and cellular studies. Furthermore, large-scale prospective studies with follow up on general populations using appropriate biomarkers and cardiovascular endpoints might be recommended to identify the factors that predispose to heavy metals toxicity in CVD. In this review, we will give a brief summary of heavy metals homeostasis, followed by a description of the available evidence for their link with CVD and the proposed mechanisms of action by which their toxic effects might be explained. Finally, suspected interactions between genetic, nutritional and environmental factors are discussed.

1. Introduction

The potential association between chronic heavy metal exposure and cardiovascular disease (CVD) has a number of implications. Although the cardiovascular system is not typically viewed as a primary target of heavy metal toxicity, review articles covering their role as cardiovascular toxicant are scant, and the prime concern of most reviews has focused on the imbalance in the antioxidant protective mechanisms leading to oxidative stress in the cells as a major effect of their environmental exposure. Altered gene expression by environmental influence, particularly dietary components over gene regulation is expected to be responsible for heavy metal toxicity.

In this paper, we will give a brief summary of heavy metals homeostasis, followed by a description of the available evidence for their link with CVD and the proposed mechanisms of action by which their toxic effects might be explained. Finally, suspected interactions between genetic, nutritional, and environmental factors are discussed.

2. The Prevalence of CVD and Its Risk Factors

Despite recent significant advances in the treatment of CVD, it remains the number one cause of death in the developed world and accounts for almost one million fatalities each year in United States alone [1]. CVD also accounts for 82% of deaths in the developing countries [2]. The annual mortality rate of CVD is expected to reach 23.6 million deaths by 2030 [3]. The traditional risk factors for CVD do not account for all deaths [4]. Environmental, dietary, and lifestyle factors appear to be important, accounting for the dramatic recent changes in prevalence and would be of wide public health significance.

Confounding variables effects are being now evaluated as potential mediators (i.e., in the biological causal pathway), moderators (i.e., risk modifiers), direct causes, or otherwise parts of complex causal pathways [5]. These pathways can include connections between individual-level indicators (e.g., age, sex, race/ethnicity, socioeconomic status); behavioral risk factors (e.g., dietary habits); biological factors (e.g., genetics); social factors; heavy metals dose (i.e., both recent and cumulative); health conditions (e.g., diabetes, heart disease, and hypertension); other biological markers predictive of disease (e.g., homocysteine levels) that may be thought of as either outcomes by themselves or as intermediate pathological states that result in other conditions (e.g., renal dysfunction, cognitive declines).

The spectrum of risk factors for CVD ranges from purely genetic to behavioural and environmental factors in the broadest sense (Table 1). CVD is initiated by a coincidence of different risk factors. The latter two already show that behaviour and the environment (including the composition of nutrition) play an essential role in the majority of CVD. Patients differ in the time of onset, dynamics, and outcomes of CVD, indicating the complex pathophysiology of CVD. Different, genetically determined susceptibilities to environmental risk factors, interactions of the cardiovascular system with other organs like the immune system, and possible interactions between these risk factors within an individual are the likely causes of those differences. Despite an increasing understanding of genes, proteins, signalling pathways, cell-cell interactions, and systemic processes involved in CVD (initiation, progression, and outcome), the relevance of environmental factors is hardly investigated.

CategoryExamplesReferencesNonmodifiable risk factors(i) Advancing age
(ii) Male gender
(iii) Family history/genotype(i) [6]
(ii) [7]
(iii) [8]Metabolic risk factors(i) Hypertension
(ii) Diabetes mellitus/glucose intolerance
(iii) Metabolic syndrome
(iv) Hyperlipidemias
(v) Obesity/overweight(i) [9]
(ii) [10]
(iii) [11]
(iv) [12]
(v) [13]Lifestyle risk factors(i) Smoking
(ii) Physical activity
(iii) Diet(i) [14]
(ii) [15]
(iii) [16, 17]Novel risk factors(i) Lipoprotein (a)
(ii) Homocysteine
(iii) Inflammatory markers (e.g., C-reactive protein)
(iv) Prothrombotic factors (e.g., fibrinogen)
(v) Trace elements (e.g., selenium, zinc, copper, chromium)
(vi) Heavy metals (e.g., arsenic, lead, cadmium, mercury)(i) [18]
(ii) [19]
(iii) [20–2