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Arsenic exposure promotes the emergence of cardiovascular diseases

  • Christiana Karachaliou EMAIL logo , Argyro Sgourou , Stavros Kakkos and Ioannis Kalavrouziotis
Published/Copyright: July 12, 2021
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Reviews on Environmental Health
From the journal Reviews on Environmental Health Volume 37 Issue 4

Abstract

A large number of studies conducted in the past decade 2010–2020 refer to the impact of arsenic (As) exposure on cardiovascular risk factors. The arsenic effect on humans is complex and mainly depends on the varying individual susceptibilities, its numerous toxic expressions and the variation in arsenic metabolism between individuals. In this review we present relevant data from studies which document the association of arsenic exposure with various biomarkers, the effect of several genome polymorphisms on arsenic methylation and the underling molecular mechanisms influencing the cardiovascular pathology. The corresponding results provide strong evidence that high and moderate-high As intake induce oxidative stress, inflammation and vessel endothelial dysfunction that are associated with increased risk for cardiovascular diseases (CVDs) and in particular hypertension, myocardial infarction, carotid intima-media thickness and stroke, ventricular arrhythmias and peripheral arterial disease. In addition, As exposure during pregnancy implies risks for blood pressure abnormalities among infants and increased mortality rates from acute myocardial infarction during early adulthood. Low water As concentrations are associated with increased systolic, diastolic and pulse pressure, coronary heart disease and incident stroke. For very low As concentrations the relevant studies are few. They predict a risk for myocardial infarction, stroke and ischemic stroke and incident CVD, but they are not in agreement regarding the risk magnitude.

Keywords: arsenic exposure; cardiovascular disease; endothelial dysfunction; hypertension; peripheral arterial disease; prenatal exposure

Introduction

Arsenic (As) is a widespread element in the earth’s crust and biosphere. Regarding elemental toxicities, As is considered as one of the major clinical concerns. Human populations are exposed to arsenic mainly through food and drinking water [1] and in a lesser degree through soil and ambient air contaminated wine, tobacco, additive in agents of preventive wood conservation and industrial and occupational exposure. Many epidemiological studies have shown that chronic exposure to As is related to increased risk for cardiovascular disease (CVD) and mortality in As-endemic regions. Furthermore, clinical evidence has shown that As causes a variety of adverse effects on human health and the risk of all-cause and chronic-disease mortality is raised with increasing arsenic exposure [2], [3], [4], [5], [6].

Arsenic concentrations in water have been categorized as high for values exceeding 150 ppb (150 μg/L), moderate between 150 and 50 ppb, and low below 50 ppb. The World Health Organization (WHO) and the European Union have set the limit of 10 μg/L for arsenic concentrations in drinking water to ensure that its consumption will be safe for humans during lifetime. However, there are two opposing views with respect to the low-dose effects regarding safety, and arguments focus on whether the threshold limit should be at levels lower than 10 μg/L [7].

In this work, we review a number of relevant studies of the past decade on the effect of As exposure on the cardiovascular system. Our analysis includes a careful assessment of the possible effects as they are inferred from comparisons of the results presented in each study. The objective of the present review is to summarize the updated knowledge that associates the arsenic exposure with certain biomarkers and with the potential role, favorable or adverse, of several genome polymorphisms on arsenic methylation and their effect on the development of CVDs including hypertension, atherosclerosis, coronary heart disease, myocardial infarction, stroke, peripheral blood circulation, pregnancy, prenatal and postnatal effects.

To systematically review the literature on As and CVD, we searched for articles published and catalogued in “Scopus”, “Web of Science”, “Pub Med” and “Google Scholar” databases from 2010 onwards, using the key words ‘Arsenic’ and ‘CVD’ and combinations of the terms ‘atherosclerosis’, ‘endothelium’, ‘stroke’, ‘hypertension’ and ‘biomarkers’. Published articles other than on the effect of As on cardiovascular system were not considered relevant. Studies that were carried out on this subject in vitro, in animal models, or in human tissues were also considered in this review as an unseparated part of research exploring the biological mechanisms of the CVD pathology. Furthermore, the references cited in the collected list of articles were also searched for additional relevant studies. In total, 516 publications were downloaded and further narrowed down after careful revision and evaluation (Figure 1). Exclusion criteria were set for 213 articles on other pathologies than CVDs or referring to As-exposure harm in general. From the remaining 305 articles, 89 were excluded after review of abstract and 21 after detailed evaluation of full text. One hundred ninety three articles are finally reviewed.

Figure 1: Flow diagram of the article selection process.
Figure 1:

Flow diagram of the article selection process.

Arsenic metabolic pathways within cells

Arsenic enters the human body in its inorganic (iAs) state. As is metabolized first in the intestine and then in the liver [8] accomplishing downstream biochemical reactions of the oxidative and reductive methylation pathways. Scientific research has revealed common strategies of As metabolism patterns between organisms, from the simplest to the most composite. Understanding the pathways of As metabolism may reveal mechanisms through which the ingested As and its intermediate metabolic products affect the human body and as a further step may lead to effective medical treatments.

Experimental studies on animals based on a range of effects related to oxidative stress and vascular inflammation suggest that the arsenic penetration through cell membrane is efficient by the utilization of the phosphate carrier system. This assumption is justified by the fact that As and phosphorus expose similar physicochemical properties as they belong to the same group of the periodic table. In the blood glutathione serves as an electron donor for the reduction of arsenate iAsV (pentavalent state) to arsenite iAsIII (trivalent state). Further metabolic steps comprise oxidative methylation during which, S-adenosylmethionine acts as a methyl group transporter to form mono-methylarsenate, which is subsequently reduced to mono-methylarsonous acid (MMAIII, MMAV), by thioredoxin or glutathione. Accordingly, both MMA forms undergo partial methylations by arsenic methyltransferase enzymes and produce dimethylarsinic acid (DMAV) and dimethylarsinous acid (DMAIII) [9], [10], [11]. A lucid description of the methylation process is given by Thomas et al. [12] and more recently in Ref. [13].

Inorganic arsenic and its methylated products are distributed within the body and excreted mostly in the urine. Inorganic As is toxic to the majority of organ systems with the degree of toxicity depending on dose and individual susceptibility. In particular, in its pentavalent form it replaces the phosphate in glycolytic and cellular respiration pathways, whereas in its trivalent form it inhibits numerous other cellular enzymes through sulfhydryl group binding and alters the phenotype of the endothelial cells [9, 14, 15].

As metabolites differ in their biological effects. There is experimental evidence that the trivalent metabolites MMAIII and DMAIII are related with carcinogenesis, cardiovascular diseases, skin disorders and gangrene (known as blackfoot disease) and various other adverse health effects [9]. In particular, MMAIII and DMAIII, are the most toxic forms and their concentration in urinary or blood serum indicates the degree of toxicity derived from their ability to cause epigenetic modifications and increase the risk of As-associated diseases in exposed individuals [16], [17], [18].

Various biological samples have been used to internally assess As intake in humans, including serum, urine, saliva, nail, and hair [19, 20]. In the urine, arsenic is excreted as a mixture of iAs, MMA and DMA, having a half-life of approximately four days [20] and the total arsenic concentration, defined as the sum tAs = iAs + MMA + DMA per urine liter stands as an index of inorganic As (iAs) effect. The concentrations and relative percentages of iAs metabolites detected in the urine of chronically exposed populations vary among individuals, in which total urinary As is comprised of ∼10–20% iAs, ∼10–20% MMAs, and ∼60–80% DMAs [21, 22] and reflect the effect of cumulative and chronic exposures to arsenic intake from various sources, mainly from food and drinking water. In urine, As can be expressed either as percentages of the arsenic metabolites (i.e., iAs, MMA, DMA%) or as primary and secondary methylation ratios (PMI and SMI) indicating methylation capacity and defined as follows:

PMI = MMA % / iAs %
SMI = DMA% / MMA%

Lower methylation capacity is manifested by higher urine levels of MMA%, lower levels of DMA%, increased PMI, and decreased SMI. For higher methylation capacity the exact opposite values are observed.

The risk of iAs-caused diseases is associated with both exposure levels and methylation efficiency in the human body. The As metabolism is complicated because it can be influenced by various factors which depend on the environment and are subjected to individual variability. The factors influencing As exposure level and susceptibility are nutrition, smoking and drinking habits, place of residence and ethnicity, age, sex, pregnancy and lactation and genetic polymorphisms that are potentially related with the inter-individual variation of urine and plasma biomarkers [10, 23], [24], [25], [26].

Also, different studies provide evidence that arsenic susceptibility exhibits two profiles to the microbes that are endemic to the human intestinal tract, which generate arsenic metabolites with not well characterized toxicity [19, 27, 28]. Sulfate-reducing bacteria from the human gastrointestinal system are reported to participate in the thiolation of the pentavalent MMA and partially convert it into monomethyl monothioarsonate and iAS arsenous acid (iAsIII) [29]. Analogous experiments in mice have demonstrated that the ingested As affects the plurality of the gut microbiome [30].

In general, methylation of inorganic arsenic differs among humans as well as between species. In most mammalian species the methylated products MMA and DMA of iAs are excreted in urine more rapidly than AsIII. In the majority of experimental animal species the secondary methylation ratio SMI takes values much bigger than the corresponding values for humans [31].

As methylation efficiency in humans is partially determined by gender and age

Men are reported to methylate As less efficiently than women [32]. Urinary samples from men showed higher MMA% and lower DMA% and SMI than urinary samples from women. In a Tibetan region with high concentration in drinking water (average conc. 969 μg/L), urinary samples from males contained iAs and MMA each one exceeding by 21% the corresponding species in females [33]. Males also exhibited lower DMA and SMI by 16 and 28% respectively compared to females, whereas PMI differences between genders were insignificant. These results are in agreement with three separate studies conducted to determine As methylation capacity profiles among adult individuals subjected to chronic As exposure via drinking water in Inner Mongolia, China [10, 34] with As concentrations ranging from medium to high, and in USA [35] with As concentrations regulated at 10 μg/L. The results demonstrated that males had higher iAs and MMA% in urine and lower DMA% than females, implying a more efficient As metabolism and excretion rate for females. This difference can be partially explained by the effect of estrogens, that facilitate the excretion of As via the “one-carbon metabolism” [36]. Conflicting results came from a nationally representative cross-sectional study conducted by the National Health and Nutrition Examination Survey (NHANES) in US [37], which found that tAs and DMA were higher among men than women, whereas a recent study [38] among subjects in Inner Mongolia, China, explored pathways of chronic As exposure with regard to As contents in daily food and showed that males had lower tAs concentration in urine than females, but PMI and SMI were the same for both genders.

Metabolite profiles of males and females unequivocally differ and, specific genetic variants in metabolism-related genes depict a sexual dimorphism. Studies, applying metabolomics approaches that cover metabolites from all major parts of human metabolism, reported gender-differentiated results. Gender differences assessed, were further corrected against age and body mass index (BMI) as cofactors [39]. Of the most illuminating differences between genders is the evolutionarily conserved distribution of the main energy storage organ, the white adipose tissue. Considering the key role of adipose tissue, with the simultaneous endocrine and storage functions in mammals, the more efficient response to high As concentrations justified in females can be attributed to adipocytes’ repository capacity for the “useless” metabolic products. In this context, it is possible that subproducts of As metabolism can be withdrawn by the adipose tissue and thus, are not detectable in both bloodstream and urine, contributing to a more favourable symptom manifestation of CVD in women.

Regarding the relation of the methylation capacity with age, the afore mentioned studies [10, 32, 34, 38] reported that tAs concentration and PMI in urine increased with age suggesting a more productive As metabolic activity for elder subjects than younger ones, whereas SMI remained practically invariable due to a possibly improved secondary As methylation capacity, not particularly associated with age. A meta-analysis by Shen et al. [32], showed that among subjects aged ≤50 years, iAs% was higher whereas, MMA% and PMI were lower than among elder subjects. Another study [33] including ages varying between 0 and 72 years, concluded that children 0–12 years and adults 53–72 years had lower urine iAs and MMA and higher DMA and SMI compared to subjects with intermediate ages. Furthermore, if children were excluded, DMA, PMI and SMI were all increasing with age.

Arsenic methylation capacity is usually stimulated during pregnancy, mainly in the first trimester. Pregnant women show an increased efficiency to metabolize As and excrete in their urine excessive amounts iAs and MMA% [40]. This observation was verified in a study conducted to evaluate the association between As methylation capacity and dietary intake of protein and folate in pregnant women in Bangladesh [41].

Correlation of metabolic syndrome to high As concentrations

Metabolic syndrome is referred to the occurrence of at least two of the following medical conditions: increased systolic (SBP) or diastolic blood pressure (DBP), abdominal obesity, high fasting plasma glucose, high serum triglycerides, and low serum high-density lipoprotein (HDL) and/or high serum low-density lipoprotein (LDL). The association between metabolic syndrome and urinary As metabolites has been the objective of different studies. High water As concentrations, higher than 400 μg/L, were associated with the presence of metabolic syndrome [42]. Analysis of the urinary As metabolites showed an increased odds ratio of MS subjects with lower PMI and higher SMI levels. Moreover, As concentration limits to 10 μg/L (considered safe by the world health organization, WHO) in drinking water, were negatively correlated with metabolic syndrome [35].

Obesity reflects a complex MS condition, subsequently manifesting more of the symptoms already mentioned for MS and beyond these, the insulin resistance is mostly pronounced. Obesity is characterized by the value of the body mass index, which is defined as the weight (in kilograms) divided by the square of height (in meters). Body mass index above 30 is generally considered within the obese scale. The association between BMI and urinary As metabolites is not clear and the results from different studies do not concur. Thus, high body mass index is associated with low % MMA [32], low % MMA and high SMI [43] and with lower mean %iAs, lower mean %MMA and higher mean %DMA [35, 44]. The explanation supplied by the authors is that this could be attributed to possible mechanisms associated with increased fat content of the subjects and the suppressed expression of several genes, such as the Arsenic 3 methyltransferase gene (As3MT) [43] or to reduced muscle mass using creatinine as a mediator of chronic inflammation [44]. In contrast to the preceding findings, results from a recent study suggest that the urinary PMI and SMI are not affected by the body mass index [38].

Methylation capacity has been also associated with obesity and high insulin levels in adolescence. The urinary levels MMA and DMA% among obese, insulin-impaired adolescents were higher and lower respectively than among obese adolescents with normal insulin levels [45].

The effect of arsenic on cardiovascular system

In humans, persistent exposure to As has been associated with a multiplicity of As-induced adverse health effects [46], [47], [48], [49], [50], which include the generation of oxidative stress, endothelial dysfunction, the formation of various epigenetic aberrations, modification in enzymes’ activity and dysregulation of signaling pathways (Figure 2). All the above determine an increased risk for cardiovascular diseases, including coronary artery disease, stroke (with or without carotid atherosclerosis), hypertension, left ventricular hypertrophy, cardiomyopathy, myocardial infarction, alteration in cardiac ion channels and microvascular abnormalities (arteriosclerosis and gangrene/blackfoot disease) as well as cancer [18, 21, 51], [52], [53], [54], [55], [56]. The effect of the chronic As exposure on CVD development depends on the As uptake and is affected by the interaction with nutritional and genetic factors and personal habits (drinking, smoking etc.) [57].

Figure 2: Schematic representation of As mechanisms of action within cell and consequences affecting blood vessel atheromatous plaque formation. Metabolism within hepatocytes lead mainly to ROS formation and inflammation pathways up-regulation. Cellular responses are illustrated within a “typical” cell representing pathways of both hepatocytes and endothelial cells. Oxidative stress possibly interferes in epigenetic defects across the genome, among other harmful effects attributed to ROS production. This implies a mechanism responsible for the As-mediated increased DNA methylation and cholesterol efflux inhibition. Aberrant DNA methylation frequently occurs in both global and specific gene promoter CpG islands and/or shores, resulting in genomic instability and the transcription upregulation of pro-atherogenic genes. To this end, induction of inflammation factors expression, further modulate the activity of endothelium on the arterial wall deteriorating vasodilation, downstream biochemical pathways disturbances that promote endothelial apoptosis. Long-term exposure accelerates blood vessel tissue damage and is associated with high risk for cardiovascular diseases.
Figure 2:

Schematic representation of As mechanisms of action within cell and consequences affecting blood vessel atheromatous plaque formation. Metabolism within hepatocytes lead mainly to ROS formation and inflammation pathways up-regulation. Cellular responses are illustrated within a “typical” cell representing pathways of both hepatocytes and endothelial cells. Oxidative stress possibly interferes in epigenetic defects across the genome, among other harmful effects attributed to ROS production. This implies a mechanism responsible for the As-mediated increased DNA methylation and cholesterol efflux inhibition. Aberrant DNA methylation frequently occurs in both global and specific gene promoter CpG islands and/or shores, resulting in genomic instability and the transcription upregulation of pro-atherogenic genes. To this end, induction of inflammation factors expression, further modulate the activity of endothelium on the arterial wall deteriorating vasodilation, downstream biochemical pathways disturbances that promote endothelial apoptosis. Long-term exposure accelerates blood vessel tissue damage and is associated with high risk for cardiovascular diseases.

As exposure leads to arterial vessel wall injury

In the vasculature, the most sensitive target of arsenic toxicity is the endothelium. Endothelial dysfunction causes an imbalance between vasoconstricting and vasodilating factors, which is an initiating precursor to the development of chronic vascular abnormalities related to atherosclerosis and cardiovascular diseases [58], [59], [60].

Arsenic exposure decreases the cardiac glutathione-1 by binding to the sulfhydryl group of GSH, and leads to ROS accumulation. Arsenic-induced ROS include superoxide anion ( O 2 − ), hydroxyl radical (OH), hydrogen peroxide ( H 2 O 2 ) and peroxyl radicals via activation of a specific nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, which deteriorates vasodilation by decreasing NO and raising angiotensin II (ANGII) levels. Elevation of angiotensin II induces metalloproteinase expression (including MMP-2 and MMP-9) and imbalances the interconnection of endothelium with the underlying vascular smooth muscle thus, contributing to the arterial stiffening [61].

In the liver arsenic promotes capillarization of the sinusoidal endothelium and perturbs the liver X receptor/retinoid X receptor signaling axis that controls cholesterol levels in tissues and influences lipid homeostasis, factors that potentially promote the pathogenic mechanism underlying As-related vascular diseases [62, 63].

Peripheral blood vessels are a major target of arsenic toxicity. High levels of chronic arsenic exposure increase arterial stiffness and systolic blood pressure and reduce diastolic blood pressure, results that are associated with the development of gangrene (black foot disease), a severe form of peripheral arterial disease (PAD). A possible mechanism of arsenic associated PAD risk is endothelial toxicity, a precursor leading to the development of vascular dysregulation. There is a quasi-linear relation between As concentration in water and in urine for long-term exposure to low- moderate As concentrations. Measurements of urinary As and association with the ankle brachial index (ABI) >1.4 but not with ABI <0.9 has been reported together with a linear association between urine As levels and PAD incident [64]. As exposure also promotes the formation of carotid atheromatous plaque from early childhood. In a cohort study the concentration of tAs in urine, (35–70 or >70 μg/L) was significantly associated with plasma asymmetric dimethylarginine (ADMA), an inhibitor of nitric oxide synthase and possible predictor of increased carotid intima-media thickness [65]. In a recent experimental study [66] it was demonstrated that As induces cytoskeletal changes and shape changes of human platelets ultimately contributing to increased thrombosis.

Experiments οn animals and cultured human endothelial cell monolayers provide strong evidence that As exposure alternates also Ca2+ intracellular regulation leading to ventricular arrhythmias and contractile dysfunctions [52]. It increases Ca2+ flux into the cytosol by activating the expression of various inflammatory molecules, such as calpains and caspases [14, 15, 52, 67], [68], [69], [70], and furthermore, inhibits key regulators of lipid homeostasis [70]. Following events to progressing calcification are the premature arterial aging [71] and endothelial dysfunction that promote the initiation of CVD development. Other experiments on animals have shown that exposure to As reduces enzymatic antioxidants like vitamins C and E [72], glutathione-S-transferase, glutathione peroxidase, increases oxidized glutathione (GSS) [72, 73], malondialdehyde and C-reactive protein [74] and induces cardiac toxicity. A low-dose administration of As2O3 (≤5 μmol/L) to rats, for a period <48 h [75], activated ROS accumulation and up-regulated NADPH oxidase and the expression of transforming growth factor beta 1, a regulatory protein that controls cell growth, cell proliferation, cell differentiation, and apoptosis. Analogous experiments on ApoE−/− mice exposed to NaAsO2 through drinking water showed that vessel plaque composition was altered, generating atherosclerotic lesions, less stable and more vulnerable [76]. In addition, it was observed that lower As concentrations were more atherogenic than the higher and that As promoted the initiation of atherosclerosis at drinking water concentrations as low as 10 μg/L [77] by increasing monocyte adhesion to endothelial cells, changing the peripheral lymphocyte proliferation and decreasing extracellular matrix proteins in fibroblasts. As can produce vascular disease progression in mice, characterized by smooth muscle cell decrease, vessel wall remodeling and platelet-derived growth factor production [78].

Furthermore, arsenic induces oxidative stress in human vascular smooth muscle cells by altering antioxidant activity and increasing inflammation [79, 80]. It is known that cell to cell junctions in the endothelium control different features of vascular homeostasis in function of organ-specific requirements. Arsenic-induced disturbances can lead to disorganization of these features and promote endothelial cell growth and apoptosis [51, 81], [82], [83], [84], [85], [86]. Investigation of the association between arsenic exposure and serum vascular endothelial growth factor (VEGF) levels in an As-endemic area in Bangladesh showed dose–response relationships with water, hair and nail As concentrations. Mean vascular endothelial growth factor levels in <10, 10.1–50 and >50 μg/L groups were 91.84, 129.54, and 169.86 pg/mL, respectively [87].

The evidence supports that constant exposure to As is associated with atherosclerosis [15, 61, 69, 71]. The aorta and the main arteries lose their compliance by becoming stiffer. This implies increased effort by the left ventricle to pump out blood into the aorta and the arteries and results in left ventricular hypertrophy [56].

As exposure promotes hypertension

Hypertension is characterized by structural changes in the vasculature that cause increased arterial stiffness and resistance to flow and manifests itself by increased systolic blood pressure (SBP) and reduced diastolic blood pressure (DBP). Elevated concentrations combined with cumulative arsenic ingestion and inefficient or low arsenic methylation capacity, increase susceptibility to hypertension in humans [23, 37, 54]. Experimental animal studies confirm corresponding studies in humans and provide strong evidence for the onset of hypertension, due to As exposure. Thus, rats continuously exposed to arsenic at increasing doses of sodium arsenite ( NaAsO 2 ) through drinking water for 90 days, exhibited dose-dependent increase in systolic, diastolic and mean arterial blood pressure by increasing angiotensin II levels, aortic miRNA expression levels, NADPH oxidase activity and ROS generation [88]. Furthermore, mice exposed to As developed an hypertrophic left ventricle [89], indicating oncoming chronic hypertension due to arterial wall remodeling.

Constant exposure to increased water As is correlated to augmented blood pressure. The association of hypertension with arsenic in people residing in areas of high groundwater contamination has been reported by numerous studies. In particular, in a 13-year follow-up study, from 1990 to 2003, among residents in the As-endemic area of southwestern Taiwan in which mean water As concentration was very high (>500 μg/L), the incidence of hypertension was positively associated with augmented concentration of urinary As(V) [90]. The same results were observed in Bangladesh [91] and in a cross-sectional study in Iran [92]. In a functional assessment of blood pressure reactivity due to arsenic exposure in drinking water conducted in two towns in Romania [93], one with low-moderate levels of As concentration and the other with negligible levels, the exposed groups expressed a 4-fold probability of blood pressure hypertension than the unexposed groups (47.4 vs. 12.5%). Analysis of data from a population-based cancer case control study in northern Chile, where the subjects were divided into distinct categories of low As concentration (<60 μg/L), middle (60–623 μg/L) and upper (>623 μg/L), showed that the middle and the upper categories had adjusted hypertension ORs of 1.49 and 1.65, respectively [94].

As exposure affects blood pressure from early life. In a cohort study among children, high tAs exposure >70 μg/L, compared to tAs <35 μg/L, was significantly associated with increased DBP and SBP, increased left ventricular mass and lower left ventricular ejection fraction [65]. In a US cohort study between women during pregnancy, arsenic exposure, with range of arsenic level in drinking water 0–147.7 μg/L, was related to greater monthly increases in SBP and pulse pressure (PP), over the course of pregnancy. The selected women were subgrouped by urinary tAs (0.35–2.54 μg/L), (2.54–5.34 μg/L) and (5.34–288.5 μg/L) and each 5 μg/L increase in urinary tAs was associated with a 0.15 and 0.14 mmHg elevation per month in SBP and PP respectively, over the course of pregnancy [49]. Finally, in a cross-sectional study in an As-endemic area of Inner Mongolia, China that aimed to evaluate the possible relationship between chronic water As exposure and the prevalence of hypertension, the subjects were divided into three groups depending on As exposure: <10, 10–50 and >50 μg/L. The SBP of the >50 μg/L group was significantly higher and the OR for hypertension for the 10–50 μg/L group was 1.417, compared to 1.937 for the >50 μg/L group [95].

The impact of chronic exposure to low water As concentrations (WAs) on blood pressure, pulse pressure (PP) and mean arterial blood pressure (MAP), was explored in a cross-sectional study among villagers in an area of Inner Mongolia, China, in which the concentration of WAs was <50 μg/L. Τhe odds ratios showed a 1.45-fold increase of blood pressure in the group with >30–50 years of arsenic exposure and a 2.95-fold increase in the group with >50 years exposure (baseline <30 year) [96]. The preceding results are supported by a meta-analysis of 11 cross-sectional studies, which showed an increasing trend in the odds of hypertension with increasing arsenic exposure [97]. Another study reported a low prevalence of hypertension (6.6%), among participants in Bangladesh with arsenic exposure >50 μg/L, but suggested a strong association for a prolonged duration of exposure (≥10 years). Additional analysis by gender revealed an association for diastolic hypertension in males and increased pulse pressure in females [98].

The relationships between arsenic exposure, arsenic methylation capacity, and blood pressure were also investigated in a cohort study conducted among residents in Inner Mongolia, China. The concentrations of arsenic species in the subjects’ urine with DBP>90 mmHg or with SBP>140 mmHg or with PP >55 mmHg were higher than for control subjects [99]. Similarly, the WAs and urinary concentrations of As metabolites, were positively associated with hypertension and higher contents of WAs, iAs and MMA raised the incidence of hypertension [100]. Results from an analogous study showed that participants with the lower methylation capacity were at higher risk for hypertension [101]. Also, 2009–2012 data from NHANES, revealed that higher urinary dimethylarsinic acid and trimethylarsine oxide concentrations were associated with and accounted for 5.4 and 19.0% of the population attributable risk for high blood pressure with odds ratio OR 1.38 and 2.56, respectively [54]. In contrast to the preceding results, the 2003–2008 data derived from NHANES on the effect of low As concentrations among US population, showed that DMA and total urinary arsenic concentrations were not associated with the incidence for hypertension, SBP and DBP [37].

Tissues rich in thiol groups (e.g., skin, hair, nails) are reliable indicators of the chronic exposure to As and hypertension is positively linked to their As content. In West Bengal a significant dose response relationship was observed between As levels in scalp hair and hypertension in a region with a well-water As concentration varying between 3 and 326 μg/L, compared to subjects in a region with <3 μg/L. Higher hair As concentrations were associated with an elevated hypertension risk, with odds ratio 2.87 for the exposed group and 29.10 for subjects beyond 60 years [102]. Similar were the results from a study among hypertensive and non-hypertensive women exposed to chronic low As intake from various local food types in China [103]. The median hair As concentration of the hypertensive women was 0.211 μg/g, whereas in the controls did not exceeded 0.101 μg/g. Elevated hair As concentrations were again associated with an elevated hypertension risk, with an adjusted odds ratio of OR=2.55. In a cross-sectional analysis of possible associations between toenail metals and blood pressure among elder men from the Normative Aging Study in US [104], the results showed an interquartile range increase in toenail arsenic (0.06 μg/g) associated with higher SBP (0.93 mmHg) and PP (0.76 mmHg).

In contrast to the preceding findings, other studies concluded that no association exists between As exposure and hypertension. A study in Turkey [105] aiming to assess cardiac autonomic function among occupationally As-exposed in metal recycling and chemical manufacturing industry and non-exposed subjects, (median blood arsenic 24 μg/dL among the first vs. 0.3 μg/dL among the second and urinary arsenic levels 73 μg/L vs. 0.9 μg/L), reported insignificant differences between the two groups in SBP, DBP, PP and in various blood and urine biomarkers. In another study among women living at Argentinian Andes [23] the median arsenic concentration in urine was 200 μg/L (range 22–545 μg/L). Despite the fact that some of them were at advanced age and chronically exposed to high levels of arsenic, their triglycerides levels were low, they did not exhibit signs of inflammation, and the urinary arsenic concentrations were inversely associated with SBP and DBP and with a normal ratio οf apolipoproteins B/A. The authors provided as a possible explanation that ethnicity could be an important factor contributing to the efficiency of arsenic metabolism, to an analogous way that their cardiovascular system was adapted to environmental conditions of low oxygen pressure over time, at high altitudes.

Regarding the effects of very low As concentration (<10 μg/L) in hypertension, the existing studies do not support any association between As ingestion and hypertension. An ecological study conducted in Saskatchewan, Canada [106], where mean values across areas for public WAs varied between 0.8 and 7.5 μg/L, justified this non-association. This observation is in agreement with previous experiments in mice, according to which the systematic exposure to identical low arsenic doses did not reveal any significant differences from control mice, for the mean arterial pressure [78].

As metabolites and biomarkers related to hypertension

The association of arsenic exposure with urinary creatinine-adjusted arsenic and their relation to changes in blood pressure was investigated among a large number of participants during the Health Effects of Arsenic Longitudinal Study (HEALS) [107]. The results showed that WAs concentrations within the range from 0.1 to 864 μg/L and urinary arsenic concentration varying from 1 to 2,273 μg/L, have a direct effect to blood pressure. Subjects in the highest quartile of WAs (>148 μg/L) or urinary creatinine-adjusted arsenic (>352 μg/g) had a greater annual increase in SBP (0.48 and 0.43 mmHg/year, respectively), compared with the reference group. Likewise, the annual values of DBP had a greater increase for the subjects in the highest quartile of WAs (0.39 mmHg/year). In another cross-sectional study investigating the incidence of hypertension among subjects in a county of China [108], where arsenic concentration ranged from 0 to 650 μg/L, the results revealed a significant trend for increasing risk for hypertension with elevating levels of urinary creatinine-adjusted MMA or DMA or tAs. Subjects in the highest quartile of these urinary indices (MMA >37.89 μg/g creatinine, DMA >181.85, tAs >250.61) showed a higher risk for hypertension than those in the lowest quartile (MMA <11.28 μg/g creatinine, DMA <66.70, tAs <93.77) with odd ratios OR: 1.776, 1.812 and 1.893 respectively.

Comparison of blood pressure levels between subjects living in As-endemic areas (WAs 192.05 ± 161.54 μg/L) and in non-As-endemic areas (WAs 3.19 ± 2.99 μg/L), during a cross sectional study in Bangladesh, showed that in the As-endemic areas Big endothelin-1 and plasma uric acid (PUA) levels were significantly higher among the hypertensive group (0.96 ± 0.19 vs. 0.80 ± 0.23 fmol/mL, p<0.001) [91, 109]. In addition, it was found that there was a dose-response relationship between PUA levels and WAs.

As exposure is strongly associated with the CVDs development in a dose- related mode

Epidemiological studies in areas with high and very high levels respectively to WAs [53, 110] provide solid evidence in favor of higher risk and increased mortality from cardiovascular disease (CVD) related to dose-dependent As concentrations. Experiments on rats showed that arsenic induces dose-dependent structural and ultrastructural remodeling of cardiac tissue [111]. Measurement of tAs concentrations in cardiovascular tissues’ samples derived from As-exposed and unexposed coronary heart disease patient groups, showed that the auricle tissue behaves as an arsenite (AsIII) and arsenate (AsV) depository, increasing the risk for cardiovascular mortality [112].

Moderate WAs concentrations are also associated with CVDs. Evidence of this association is provided by a case control study [113], in which the risk for CVDs was four times higher and directly related to the water As concentration.

The mortality rate from CVD in a population with WAs concentrations <12.0 μg/L was estimated as 214.3 per 100,000 person per year, whereas in people with ≥12.0 μg/L was 271.1 per 100,000 person per year, indicating a 26.5% increase [114]. The same study showed a dose–response relation between As exposure and mortality from heart disease. When As exposure was accompanied by smoking, the hazard ratio on mortality from ischemic heart disease increased by 50% [114, 115].

Three other studies among participants in US exposed to moderate levels of arsenic (<100 μg/L) [47, 50, 116] reported a strong positive association between As exposure or urinary arsenic and CVD, coronary heart disease and stroke mortality. Analogous was the outcome of a nested case-control study in a cohort in China, conducted to explore the association between plasma As concentrations and incident coronary heart disease, which showed a significant interrelation QR=1.78 [117]. The conclusion from these studies was that the hazard ratio for these diseases was increasing with either increasing creatinine in urinary arsenic concentrations or with increasing duration of WAs exposure.

Among children and adolescents, moderate-high exposure to As increases the hazard ratios for mortality due to cerebrovascular and cardiovascular disease in a dose-response relationship. In a follow-up cohort study among children 5–18 years old in Bangladesh, during 2003–2010, it was shown that girls were at a higher risk than boys [118] and adolescents were at a higher risk than children [119].

Chronic exposure to arsenic at low-moderate doses is suspected to increase mortality from CVD, acute coronary syndrome and cerebrovascular disease [50]. An ecological study in Spain reported that mortality rates for cardiovascular, coronary and cerebrovascular disease were increased in municipalities exposed to WAs >10 μg/L. Comparison between WAs concentrations >10 μg/L and lower than 1 μg/L, showed that CVD mortality rates were increased by 2.2% [46].

The incidence of acute coronary syndrome upon As exposure has been demonstrated in a study between subjects from two areas in Serbia [120], in which median WAs concentration was 80 and 1 μg/L, respectively. It was shown that the average five-year incidence rate for CVD in the first area was almost twice as high as the corresponding rate in the other area (237.00/100,000 and 124.40/100,000).

Subjects already suffering from hypertension, are prone to develop atherosclerotic cardiovascular disease (ASCVD) upon As exposure even at low levels. In a US study among adults with hypertension, men had higher risk to develop ASCVD than women and the highest quartiles of WAs (>21.57 μg/L) and urine arsenic (39.0 μg/L) exhibited a higher risk (ASCVD=1.22) than in the lowest quartiles (WAs <4.92 μg/L, urine arsenic 9.2 μg/L) [121].

Persistent arsenic exposure is associated with cardiac arrhythmia and is responsible for an increased risk for cardiovascular mortality in humans. Experiments with a dose-controlled administration of As2O3 to animals [70] showed that it induces among others, electrocardiogram abnormalities, such as torsade de pointes, QRS (graphical deflections of a typical electrocardiogram) widening, QT (time between the start of the Q wave to the end of the T wave in a typical electrocardiogram) prolongation, ST depression (the trace in the ST segment in a typical electrocardiogram is abnormally low, below the baseline), T-wave flattening, cardiac arsenic accumulation and histopathological changes. Rats and guinea pigs administered with As2O3 or NaAsO2 exhibited prolonged QT interval and cardiac fibrosis together with myocardial damage [74, 122], [123], [124], [125], [126], [127], [128].

The administration of As2O3 to patients with acute promyelocytic leukemia has been implicated to cardiac abnormalities induction, including long QT syndrome and torsades de pointes, which can result in life-threatening arrhythmias [129, 130]. Arsenic exposure increases QT interval and activates mechanisms for cardiac arrhythmias and increased CVD risk. In a study with participants in a highly-exposed area of Taiwan [131], cumulative arsenic exposure was associated with As-dose dependent QT and with coronary artery disease and carotid atherosclerosis. Similarly, a five-years follow-up study among adults by the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh with mean arsenic exposure levels 95 μg/L, (range 0.1–790 μg/L) demonstrated a positive relationship between long-term arsenic exposure and QTc prolongation [132]. Analogous were the findings for low-moderate As exposure (<100 μg/L). A cross-sectional association was identified between baseline arsenic exposure and QTc interval. In addition, higher methylation capacity was also associated with QTc prolongation at baseline [133].

Cumulative low-moderate As exposure, with mean exposure 19.3 μg/L (range 0.5–80.4 μg/L) and average exposure duration 39.5 years, was positively associated with a risk of ischemic heart diseases and stroke and with an increased risk of myocardial infarction (HR=2.94) and PAD (HR=2.44) [134]. Another experiment [81], conducted to assess the effect of sodium arsenite (NaAsO2) on human umbilical vein endothelial cells (HUVECs), showed that cells’ exposure to sodium arsenite concentrations ≤10 μM (1μΜ=10−6 As mol/L=130 μg/L) increased mitochondrial membrane potential, stimulated human umbilical vein endothelial cells growth and increased vascular tubular formation. However, higher concentrations (≥20 μM) altered the ROS levels, caused cytotoxicity, inhibited angiogenesis, increased cell apoptosis and decreased mitochondrial membrane potential in a dose-dependent manner. In the same study, two other As compounds, the arsenic trioxide (As2O3) and the tetra arsenic oxide (As4O6), were implicated to the proliferation inhibition of human umbilical vein endothelial cells.

Growing evidence suggests that lower levels of As exposure is also critical issue for CVD development. Experimental studies on animals [76, 77] have shown that As can elicit adverse cardiovascular effects at doses much lower than those required to induce cancer. In a recent study [50] it was shown that lifetime exposure to inorganic As in drinking water (10–100 μg/L) was associated with increased risk for coronary heart disease and for every 15 μg/L increase in water As concentration, the risk for CHD increased by 38%. Low water As concentrations (lower than 50 μg/L) were found associated with hypertension, and pulse pressure [96], coronary heart disease [116] and incident stroke [135]. Lower concentrations in the range 0.6–17.1 μg/L were related with increased systolic and diastolic blood pressure [37]. In a dose-response meta-analysis of the relationship between cardiovascular disease (CVD) and As exposure at drinking water [136], an overall positive association between CVD risks and low level (1–10 μg/L) As concentration was suggested. Subjects exposed to water As concentrations of 10 μg/L were modelled to have 50% CHD and 17%CVD greater risk compared with subjects exposed to concentrations of 1 μg/L.

The effect of relatively low As concentration on myocardial infarction was the subject of a cohort study among subjects in two areas in Denmark [137]. With respect to the incidence of myocardial infarction, the higher arsenic concentration quartile (WAs 2.21–25.34 μg/L) was associated with an incidence rate ratio (IRR) 1.48 when compared with baseline concentrations (WAs 0.05–1.83 μg/L).

As exposure promotes the formation of carotid atheromatous plaque from early childhood. An indicator of atherosclerosis and a measure to diagnose the extent of the atheromatous plaque is carotid intima-media thickness (cIMT). In a cohort study the concentration of tAs in urine, (35–70 or >70 μg/L) was significantly associated with plasma asymmetric dimethylarginine, an inhibitor of nitric oxide synthase and possible predictor of increased carotid intima-media thickness [65]. A strong association between urinary MMA and risk for ischemic stroke was reported in a study using data from the US national REGARDS (Reasons for Geographic and Racial Differences in Stroke) study. It was found that for MMA levels ranging between 0.01 and 0.77 μg/g creatinine, and during a gradual increase of urinary MMA on a log-scale, the ischemic stroke risk increased nearly 2-fold [138].

The association between As exposure and carotid intima-media thickness (cIMT) and stroke was investigated in three studies among subjects, in Taiwan [139], Bangladesh [140] and Italy [141]. The first showed an elevated risk for carotid atherosclerosis in subjects with arsenic exposure ≥50 μg/L and mainly in those who carried the genotypes of purine nucleoside phosphorylase A–T haplotype and either of the As3MT risk polymorphism or glutathione S-transferase omega risk haplotypes (Odds Ratio: 6.33). The second study concluded that the simultaneous presence of a level of well-water arsenic ≥40.4 μg/L and the As3MT GG genotype (rs3740392) was associated with increased cIMT. The third observed an increase of cIMT in the elderly males and, to a lesser extent, in females. In addition, it was found that subjects with a high urinary As level (≥3.86 μg/L) being carriers of the Glutathione S-Transferase T1 had higher cIMT than those with a low urinary As level. A positive relationship between urinary MMA% and cIMT was also observed in a study that was carried out to examine the association between past arsenic intake and urinary arsenic and stroke in a given population exposed to a mean well-water arsenic concentration 102.0 μg/L for at least three years [142]. Urinary DMA% was inversely associated with cIMT but there was no apparent association of urinary iAs%, PMI, or SMI with cIMT. Analogous were the findings in another study among American Indians in three States [143].

With respect to the incidence of stroke, the results from a cohort among subjects in two areas in Denmark [137] showed that the higher arsenic concentration quartile was associated with an IRR 1.79. Subjects chronically exposed to10 μg/L or more through WAs, resulted in an IRR at 1.44 for all strokes and 1.63 for ischemic strokes [144]. Even at lower concentrations (median WAs, 7.78 μg/L), an analysis suggested a relationship between As and ischemic stroke in hospital admissions in Michigan, USA, and stroke was associated with a relative risk of 1.03 for each μg/L increase in As [135]. Similarly, another research among adults in Bangladesh, using well-water with arsenic concentrations <10, 10–49, and ≥50 μg/L, indicated an increased risk (mean HR 1.20 and 1.35) of overall stroke mortality among men and women with increasing arsenic concentration [145].

A meta-analysis of 18 epidemiological studies [53] (WAs >50 μg/L), estimated that the pooled relative risks were 1.32 for CVD, 1.89 for coronary heart disease (CHD), 1.08 for stroke and 2.17 for PAD. At low-moderate As levels, the evidence was inconclusive. In a more recent meta-analysis [146], comparing WAs exposures of 20 μg/L with baseline concentration 10 μg/L, the reported pooled relative risk was 1.09 for CVD incidence, 1.11 for CHD and 1.08 for incident stroke. Comparison between 50 with 10 μg/L exhibited higher relative risk. CVD: 1.21, CHD: 1.27 and stroke: 1.20. The results of a meta-regression analysis [147] in which the level of As concentration regarding the non-observable adverse effects was 50 μg/L, indicated that an escalating increase by 1μg/L in WAs concentration resulted in a 0.1% significant increase in risk for CVDs, in two distinct regions in Vietnam.

Analysis of the preceding studies suggests that the risk for CVDs increases with higher WAs concentration and with lower As methylation capacity. Regarding the effect of WAs concentration on various blood biomarkers, recent studies conducted in a Native American population revealed that a mean annual WAs intake 0.490 mg (equivalent daily intake 1.35 μg), was positively associated with oxidized LDL [148] and with increased atherosclerosis and abnormal proliferation of VSMCs [149, 150]. In another study [151] it was estimated that mean daily intake for a 60 kg man with WAs concentration 100 μg/L, which was the equivalent to a dose of 9 μg/bw or 540 μg/day. This corresponds to a daily consumption of 5.4 L from drinking and cooking. On the assumption that the As intake is proportional to WAs concentration, a daily intake of 1.35 μg implies a WAs concentration much less than 1 μg/L, suggesting that there is no safe threshold value for As exposure [152].

Genetic and epigenetic defects associated with As exposure

There is strong evidence associating the urinary As metabolite levels with genetic and epigenetic changes across genome. Genetic polymorphisms frequently occurring within As metabolism related genes impact As metabolism and suggest a potential mechanism associated with variation in As metabolic capabilities among humans [57, 153], [154], [155], [156]. It has been shown in numerous cohort and cross-sectional studies that arsenic methylation efficacy is affected by the metabolic action of the arsenic [3] methyltransferase gene (As3MT) via oxidative methylation and glutathione S-transferase via reductive methylation and that there is an association between genetic polymorphisms of the As3MT gene with the response to iAs toxicity and As metabolites in populations exposed to moderate–high arsenic levels [33, 157,158]. The metabolic activity of As3MT is also considered to have an association with the chronic and slow intoxication of the human body and consequently with variable susceptibility to As toxic effects [10, 116, 159]. Metabolism of arsenite to DMAV by As3MT promotes clearance [8], but it also produces trivalent intermediates that are potential toxicants. Human As3MT polymorphisms are linked to differential arsenic methylation efficacy. Different ethnicities with numerous existing pool variants contribute to a wide range of enzymatic activity observed [11, 21, 160], [161], [162], [163]. In children, As3MT variation influences arsenic methylation efficiency to a lesser degree than in adults [164]. Furthermore, there is experimental evidence for genetic linkage between arsenic metabolites and chromosomes 5, 9 and 11, suggesting that both heritability and environmental factors cooperate in inter-individual arsenic metabolism and excretion [165, 166].

Regarding the possible relationship between As related elevation in blood pressure and single nucleotide polymorphisms, a study conducted over seven years of follow-up [167] to investigate whether genetic susceptibility can modify the association between blood pressure and As, found that 44 single nucleotide polymorphisms interfere with the As related elevation in blood pressure parameters and among them, the presence of rs3794624 single nucleotide variation was associated with a 2.23 mmHg greater annual increase in pulse pressure. Besides, a 100 μg/L elevation in baseline water As concentration was related to a greater increase in annual systolic blood pressure (0.22 mmHg), diastolic blood pressure (1.10 mm Hg) and pulse pressure (0.13 mmHg). Other genetic polymorphisms can also modify the associations between CVD and arsenic exposure. In a prospective case-cohort study it was shown that two single nucleotide polymorphisms, rs281432 in intercellular adhesion molecule-1 (ICAM1) and rs3176867 in vascular adhesion molecule-1 (VCAM1), were related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction leading to CVD with hazard ratio 1.82 and 1.34, respectively [168], [169], [170].

Clinical evidence also, highlights epigenetic alterations, such as the modified genomic CpG methylation in the long interspersed nuclear element-1 (LINE-1), that are implicated in many types of disorders, including cardiovascular disease. In a recent study in which the association between arsenic exposure and LINE-1 methylation levels was evaluated [171], the average LINE-1 methylation levels in female participants were lower than those of the subjects living in non-endemic areas. In the same study male participants showed insignificant differences in LINE-1 genomic methylation profiles. Decreased levels of LINE-1 methylation might be involved in the arsenic-induced elevation of systolic blood pressure.

Other studies have shown that there is a marked association between urinary As levels and serum expression levels of a specific cluster of microRNAs (miRNAs), another component of the epigenetic machinery. miRNAs contribute to critical cellular processes and their normal profile is a prerequisite for the cardiac function as well. miRNAs’ aberrant expression can disturb cellular homeostasis and may lead to the As-induced diseases, such as cancer, CVD and diabetes [18, 172].

An important role of miRNAs estimation is their prognostic value on risk stratification in cardiovascular diseases. Several studies raise the possibility that various circulating miRNAs could be proposed as prognostic biomarkers of pathologies associated with myocardial infarction and cardiomyopathy [173], diastolic dysfunction [174], heart failure [175, 176] and atherosclerosis [31]. In this context, six circulating miRNAs were significantly correlated with elevated plasma MMA (miRs-423-5p, -142-5p -2, -423-5p +1, -320c-1, -320c-2 and -454-5p) [177], three (miR-3135b, miR-3908 and miR-5571-5p) with heart failure [176] and two (miR-155 and miR-126) with the onset and development of As induced cardiovascular diseases [178].

In a study conducted to explore the association between gene polymorphisms and the efficiency of arsenic biomethylation among women living at Argentinian Andes where the median arsenic concentration in urine was 200 μg/L (range 22–545 μg/L) and was suggested that genetic variants of N-6 adenine-specific DNA methyltransferase 1 (N6AMT1) had a significant effect in the variability obtained for the urinary MMA levels [179]. Previous and subsequent experimental evidence corroborates the preceding suggestion, that N6AMT1decreases cytotoxicity of MMAIII and is able to convert it to the less toxic DMAV [180, 181].

Prenatal and postnatal As effects

Exposure to As during pregnancy is a matter of great concern due to the vulnerability of the mother and the fetal development to the arsenic toxicity and can have a profound effect on the development of cardiovascular diseases in later life [40]. Experimental studies on animals support that arsenic exposure in utero alters the fetal developmental programming mainly due to DNA methylation modifications [41]. Furthermore, experiments on ApoE−/− mice have demonstrated that the arsenic exposure over gestation alters hepatic development in the offspring and accelerates atherosclerosis [182].

Prenatal exposure can affect the miRNA expression of newborn. In a genome-wide miRNA expression analysis of newborn cord blood, investigating for possible miRNA expression changes associated with in utero arsenic exposure, it was demonstrated that prenatal exposure to As, changes the profile of 12 circulating miRNAs, namely let-7a, miR-107, miR-126, miR-16, miR-17, miR-195, miR-20a, miR-20b, miR-26b, miR-454, miR-96, and miR-98 and was positively associated with the maternal urinary tAs [183].

Prenatal exposure is also associated with various biomarkers. In a cohort study of US women and their newborns, in which the associations between prenatal As exposure and infant cord blood levels of inflammation biomarkers were investigated, the results showed that the tertile group with the highest As urinary concentration (5.30–288.5 μg/L), was positively related to infant cord blood level of ICAM1 and VCAM1 compared with the tertile group with the lowest urinary concentration (0.20–2.38 μg/L) [184]. Thus, the association between prenatal As exposure and the expression of various miRNAs and biomarkers can be used as a potential prognostic tool to pathways related to future cardiovascular pathologies.

Epidemiological studies among residents in As endemic areas in Chile with elevated levels of As in the water, indicate an association between in utero arsenic exposure and the development of adult diseases [185]. Adults 30–49 years old who had been subjected to prenatal and/or childhood exposure via high levels of WAs (average level, 860 μg/L) in northern Chile, between 1958 and 1970, exhibited increased mortality rates from acute myocardial infarction [186], [187], [188], whereas a similar study in Taiwan [189] found that As exposure in utero was associated with higher LDL later, at ages 2–15 years. Α study in Bangladesh, investigated positive association between blood pressure abnormalities among infants with the maternal urine-As concentrations during pregnancy. Results showed that each 1 mg/L increase in maternal urinary As was associated with a 3.7 mm Hg increase in child systolic blood pressure and a 2.9 mm Hg in diastolic blood pressure [190, 191]. Exploration of the possible associations between water As concentration and prevalence of some congenital heart defects has led to results showing an increased risk, OR=1.41, among infants whose mothers during pregnancy ingested water with As concentration higher than 10 μg/L [192].

The synergistic effect of arsenic and cadmium on heart defects in offspring was investigated in a cohort study among congenital heart defect (CHd)-affected pregnancies and control women, in China. The median levels of hair arsenic and cadmium of women with CHd-affected pregnancies were significantly higher than the corresponding levels in the control group (p<0.05). As concentrations ≥117.80 ng/g-hair were associated with a 5.62-fold increase in the risk of any CHd subtype, with a dose-response relationship. In addition, it was observed that cadmium may have an enhancing effect on the association between arsenic and the risk (OR 1.96) for CHds in the offspring [193].

Conclusion

Chronic exposure to high concentrations in drinking water results in increased morbidity and mortality. Moderate-high As concentrations in drinking water are consistently associated with increased risk for CVDs. High As exposure and lower methylation capacity implies increased health risk. Divergent results are obtained between genders and among different age groups. The observed differences attributed to gender and age should be investigated and correlated with both the genetic and epigenetic background and the adipose tissue accumulation. The properties of adipose tissue to function as a metabolic waste repository should also be correlated with variations in levels of blood and urine biomarkers, associated with As metabolism.

Growing experimental evidence shows that genetic polymorphisms of enzymes involved in As metabolism is a possible mechanism that favors decreased capabilities of As methylation and excretion among individuals.

The odds ratio for increased BP is raised upon increasing As uptake. Similarly, the risk for coronary heart disease, heart attack and stroke increases with increasing As concentration. Low arsenic concentrations in the urine (<20 μg/L) or in drinking water (<< 50 μg/L) are not associated with the prevalence of hypertension or with SBP or DBP. However, experimental evidence indicates that, even at insignificant (<1 μg/L) to moderately low (<25 μg/L) As concentrations, the risk for heart attack and stroke is significant and their manifestation is associated with high blood pressure. A possible explanation to this effect is that even at low exposure where hypertension has not yet manifested, As enhances the formation of unstable atherosclerotic lesions.

Maternal As exposure during pregnancy may have an effect on inflammatory pathways and/or endothelial dysfunction in the offspring and positively results in a higher risk for CVDs and mortality at later life. Exposure over gestation and early childhood is associated with increased SBP and DBP and an increased risk of child mortality from myocardial infarction.

Perspectives for future research

Most of the conducted investigations refer to water As concentrations varying in a range between values lower than 10 μg/L and higher than 150 μg/L and present results for mean concentrations. Few studies refer to low concentrations (lower than 50 μg/L) and even less, to very low concentrations (lower than 10 μg/L). Low water As concentrations are associated with increased systolic, diastolic and pulse pressure, coronary heart disease and incident stroke. Experimental evidence indicates that, even at insignificant (<1 μg/L) to moderately low (<25 μg/L) As concentrations, the risk for heart attack and stroke is significant and their manifestation is associated with high blood pressure. A solid knowledge regarding the As exposure to water As concentrations less than 10 μg/L necessitates further research. This includes (1): further experimentation on animal models with water As concentration lower than 10 μg/L, to significantly correlate the arsenic exposure association with various biomarkers, the effect of several genome polymorphisms on arsenic methylation under such low dosages and the potential mechanisms influencing the cardiovascular pathology. (2) Corresponding epidemiological studies to investigate the possible relationship between chronic As exposure (lower than 10 μg/L) and hypertension, myocardial infarction, carotid intima-media thickness and stroke, ventricular arrhythmias and peripheral arterial disease. (3) Epidemiological studies to investigate the possible relationship between As exposure (lower than 10 μg/L) during pregnancy and postnatal effects among children.

Corresponding author: Christiana Karachaliou, School of Science and Technology, Lab. of Sustainable Waste Technology Management, Hellenic Open University, Patras, Greece, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: The local Institutional Review Board deemed the study exempt from review.

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Received: 2021-01-14
Accepted: 2021-06-11
Published Online: 2021-07-12
Published in Print: 2022-12-16

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review Articles
  3. Arsenic exposure promotes the emergence of cardiovascular diseases
  4. Glyphosate effects on the female reproductive systems: a systematic review
  5. Association between mobile phone use and hearing impairment: a systematic review and meta-analysis
  6. Neurological susceptibility to environmental exposures: pathophysiological mechanisms in neurodegeneration and multiple chemical sensitivity
  7. Effects of non-ionizing electromagnetic fields on flora and fauna, Part 3. Exposure standards, public policy, laws, and future directions
  8. Study of solid waste (municipal and medical) management during the COVID-19 pandemic: a review study
  9. Health effects associated with phthalate activity on nuclear receptors
  10. Environmental impact assessment of plastic waste during the outbreak of COVID-19 and integrated strategies for its control and mitigation
  11. Cancer risk assessment of polycyclic aromatic hydrocarbons in the soil and sediments of Iran: a systematic review study
  12. Letter to the Editor
  13. Coherent MM-wave EMFs produce penetrating effects via time-varying magnetic fields: response to Foster & Balzano
  14. Book Review
  15. Arnold R. Eiser: Preserving brain health in a toxic age: new insights from neuroscience, integrative medicine and public health
https://doi.org/10.1515/reveh-2021-0004
Keywords for this article
arsenic exposure; cardiovascular disease; endothelial dysfunction; hypertension; peripheral arterial disease; prenatal exposure

Articles in the same Issue

  1. Frontmatter
  2. Review Articles
  3. Arsenic exposure promotes the emergence of cardiovascular diseases
  4. Glyphosate effects on the female reproductive systems: a systematic review
  5. Association between mobile phone use and hearing impairment: a systematic review and meta-analysis
  6. Neurological susceptibility to environmental exposures: pathophysiological mechanisms in neurodegeneration and multiple chemical sensitivity
  7. Effects of non-ionizing electromagnetic fields on flora and fauna, Part 3. Exposure standards, public policy, laws, and future directions
  8. Study of solid waste (municipal and medical) management during the COVID-19 pandemic: a review study
  9. Health effects associated with phthalate activity on nuclear receptors
  10. Environmental impact assessment of plastic waste during the outbreak of COVID-19 and integrated strategies for its control and mitigation
  11. Cancer risk assessment of polycyclic aromatic hydrocarbons in the soil and sediments of Iran: a systematic review study
  12. Letter to the Editor
  13. Coherent MM-wave EMFs produce penetrating effects via time-varying magnetic fields: response to Foster & Balzano
  14. Book Review
  15. Arnold R. Eiser: Preserving brain health in a toxic age: new insights from neuroscience, integrative medicine and public health
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