Systematic Review and Meta-analysis of Environmental Toxic Metals Contaminants and Risk of Ischemic Stroke

doi:10.21203/rs.3.rs-1540330/v1

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Systematic Review and Meta-analysis of Environmental Toxic Metals Contaminants and Risk of Ischemic Stroke

https://doi.org/10.21203/rs.3.rs-1540330/v1

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Background

Stroke is the second largest cause of mortality (WHO 2014) and long-lasting disability worldwide. Many risk factors are associated with stroke: age, gender, chronic illnesses, cardiovascular disease, lifestyle, and smoking. With global industrialisation, the roles of environmental contaminants and their association with stroke are still unclear and have attracted much more attention.

Methodology

We conducted a systematic review on environmental toxic metals contaminants and the risk of ischemic stroke. A comprehensive literature search was carried out till 30th June 2021 from databases such as PubMed, Science Direct, Embase and Scopus. The quality of all the articles which met our inclusion criteria was assessed using Newcastle-Ottawa scaling, and four eligible studies were included for our systematic review.

Result

The serum and urine cadmium concentrations were positively associated with the risk of ischemic stroke. There is an inverse association of serum and urine concentration of Mercury (Hg), serum concentration of gold and cerium with ischemic stroke, and the serum and urine concentration of Lead (Pb) had no association with ischemic stroke risk.

Conclusion

The study showed strong associations between heavy metals and ischemic strokes, but more studies are required to prove the associations.

Heavy Metals

Ischemic Stroke

Systematic Review

Stroke

Metal Contaminants

Meta-analysis

A very debilitating illness, stroke is currently one of the most common causes of health impairment worldwide (Mensah et al. 2015). In 2019, the global prevalence of stroke was 101.5 million people, but the prevalence of ischemic stroke was 77.2 million people, with 3.3 million people dying from ischemic stroke (Viran et al. 2021). The risk of stroke is linked to myriad of factors, including age, gender, chronic illnesses (diabetes, hypertension), cardiovascular disease, lifestyle variables (obesity, stress), and smoking (Tan et al. 2018; Guzik and Bushnell 2017; Turin et al. 2016). Although, Stroke can be either Ischemic or haemorrhagic, which can be distinguished by the blockage or rupture of blood vessels, followed by tissue damage or sometimes cell death. Ischemic stroke accounts for approximately 85 per cent of all recorded instances, with haemorrhagic stroke accounting for the remaining 15 per cent (Mergenthaler et al. 2004). Ischemic stroke is a significant cause of disability and mortality globally, owing to the high sensitivity to even short (minutes) blood flow disruptions of the brain parenchyma.

The environment is constantly subjected to various chemical loads originating from natural and human sources. The release of these compounds from anthropogenic sources continues to rise due to growing industrialisation and urbanisation in many parts of the world. Heavy metals are a class of non-biodegradable environmental pollutants widespread in nature. Though the negative consequences of their exposure, such as lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As), are well-recognized, their use and quantities in the environment are growing day by day (Alloway 2013).

Furthermore, recent studies have linked persistent intoxication in humans to cardiovascular effects such as elevated blood pressure (Hu et al. 2018). Heavy metal toxicity may also be linked to an increased risk of stroke because elements such as Pb, Cd and Hg disrupt the vascular system (Houston 2011; Lin et al. 2018). In reality, exposed people have a high frequency of non-communicable illnesses like hypertension and diabetes (Arrifano et al. 2018). The later circumstances can be recognised as risk factors for ischemic stroke. For instance, the mortality rate owing to Ischemic stroke grew by 28 per cent in Brazil's northern area but reduced by 13–25 per cent in the country's south-eastern parts during the 2000–2010 year (Baena et al.2014).

The pieces of evidence of involvement of heavy metal in ischemic stroke can be cited from different clinical and preclinical studies. Chronic exposure to Pb causes deficiency of antioxidants and disturbs the antioxidants activity by replacing their active cofactor metals (Pachauri et al. 23012). It is also found that the direction of Pb in childhood results in a region-specific reduction in adult grey matter volume of participants, which is strongly linked with the small vessel disease (Cecil et al.2008; Kim et al. 2016). Hg exposure may result in cerebral vasospasm, reduced NO bioavailability, increased oxidative stress, neuro-inflammation, amyloid plaque formation, cholinergic and serotonergic transmission disturbances (Wiggers et al. 2016; Bjørklund et al. 2019). The major contributor to cadmium toxicity is cellular oxidative damage. In a study conducted in an animal model, 24 h exposure of Cd in the brain exhibited alteration of oxidative stress markers and brain inflammatory markers (Zheng et al. 2016).

Although numerous studies on the toxicity of specific metals on biological systems in the environment have also been conducted, a comprehensive and systematic study investigating the association between heavy metal exposure and risk of Ischemic stroke is highly scarce. To our knowledge, this will be the first systematic study to analyse and evaluate the association between heavy metals and Ischemic stroke risk.

Literature Search

The systematic literature search for the review was done by the investigators (P.D, P.G.) on 30th June 2021. The databases used were PubMed, Embase, Scopus and Science Direct, the MESH terms used for the search were heavy metals [TIAB] AND cerebral stroke [TIAB] OR ischemic stroke [TIAB]. Out of 182 results from PubMed, 30 were found relevant; three articles were included for the systematic review; other articles were excluded as they fell under exclusion criteria. The search in the Science Direct database provided 83 results, out of which one article was included for the systematic review and others were excluded due to insufficient information and duplication. The search by Embase database showed 30 results, out of which two were relevant but was excluded due to repetition. The search by Scopus resulted in 40 results, out of which 1 article was relevant but excluded due to duplication. All the articles were included from 1998 to 2021 (Fig.1). The systematic review has been registered to PROSPERO with registration ID: CRD42021267391.

Inclusion and Exclusion Criteria

The inclusion criteria for the search were all the case-control studies conducted in human adults (age above 18 years) and the studies that gave a direct link between Ischemic stroke and heavy metals. All the preclinical studies, model studies, reviews, case reports, newsletters and the studies from which the association between ischemic stroke and heavy metals cannot be extracted were excluded. The search was restricted to articles in the English language.

Study Selection and Data Extraction

The two investigators (PD, PG) independently searched for suitable studies in four databases. The systematic search was well assisted with the thoroughly defined inclusion and exclusion criteria. After screening for population, abstract, and title of the study, each article's relevant information was added to the well-defined table for further easy analysis and understanding. The table included the information like author's name, year of publishing, duration of the study, study design, sample size, age and sex, heavy metals, sample collection, assay method, confounders adjusted, the conclusion from the study, relevant result and limitation of the study.

Quality Assessment

Newcastle-Ottawa scale is an easy and convenient tool to calculate the quality of the non-randomized studies, including case-control and cohort studies. The reviewers (PD, PG) ensured the quality of all the case-control studies included in the systematic review by Newcastle-Ottawa scaling.

Through the systematic search, 335 records were gathered from a different database. Out of which, four records seemed to link to the topic directly and were chosen for the systematic review. The general characteristics of included studies are described in Table 1. Out of 4 studies, two were nested case-control, and 2 were case-control design. All the studies were published between 2005 to 2020.

Two studies focused on the heavy metal Cd among the four eligible studies.

In the studies conducted by Borne et al. 2017, Cd levels were measured in 4156 subjects (39.2% men; mean SD age 57.35.9 years) without a history of stroke. The patients were followed up for the mean of 16.7 years, where 221 patients developed ischemic stroke. The result showed a positive association between serum Cd concentration and Ischemic stroke (HR: 1.66; 95% CI, 1.01–2.72). Incidence of ischemic stroke was associated both with carotid plaque (hazard ratio 1.44, 95% confidence interval, 1.09–1.90, P=0.009) and Cd (hazard ratio for quartile [Q] 4 versus Q1–3: 1.95, confidence interval, 1.33–2.85, P=0.001), after adjustment for risk factors. There was a significant interaction between Cd and plaque concerning the risk of ischemic stroke (P=0.011). After adjustment for risk factors, subjects with plaque and Cd in Q4 had a hazard ratio of 2.88 (CI 1.79–4.63) for ischemic stroke, compared with those without plaque and Cd in Q1 to Q3 (Borné et al. 2017).

The other study conducted by Chen et al., 2018 investigated the relationship between urine Cd concentration and risk of Ischemic stroke. For the study, 660 patients of ischemic stroke and 2540 participants in a randomly selected subcohort. This case-control population was chosen from a REGARDS study cohort (Reasons for Geographic and Racial Differences in Stroke). This study showed that the creatinine corrected urine Cd concentration was significantly associated with ischemic stroke (HR 1.82, 95% CI 1.06–3.11). The adjustment with the cofounders was significantly related to the p-value of 0.0004 (Chen et al. 2018).

The study conducted by Estévez et al., 2020 analysed 45 inorganic elements to find their relationship with stroke. The study was done in 92 patients and 86 controls. The study concluded a positive association of Pb with Ischemic stroke in univariate and multivariate analysis (OR = 1.65 (95% CI, 1.09–2.50) and OR = 1.91 (95% CI, 1.20–3.04), respectively. They also suggested an inverse association of gold (Au) and cerium (Ce) with Ischemic stroke in multivariate analysis (OR = 0.81 (95% CI, 0.69–0.95) and OR = 0.50 (95% CI, 0.31–0.78) (Medina-Estévezet al. 2020).

While the case-control study by Lin et al., 2018 showed the inverse association of serum and urine levels of Hg with Ischemic stroke patients (p-value 0.032, 0.006 respectively). They also suggested no significant difference in serum and urine Pb (S-Pb), As (S-As) levels in either group (Lin et al.2018). Thirty-three patients selected were the first-ever acute ischemic stroke patients, while 39 healthy controls were selected.

Pathogenesis:

Cd has been associated with pro-inflammatory effects in experimental and human studies. It has been shown to increase the necrosis and apoptosis in macrophages exposed to increased cd levels. Additionally, Cd inhibits fibroblast proliferation and collagen synthesis in vascular cells. These effects could severely impair the function of endothelial cells and reduce the stability of the carotid plaque (Olszowski et al. 2012, 2015).Cadmium is supposed to be genotoxic and promotes DNA damage, along with gene deletion and adverse transcriptional and cytoplasmic changes in various rodent cultured cells such as ovarian, myoblasts, liver cells, and osteoblasts. These changes could lead to enhanced apoptosis along with impaired proliferation and differentiation (Verougstraete et al. 2002; Schwerdtle et al 2010).

However, other heavy metals like Pb and Hg seem to have a protective role on endothelial function. However, metal like lead also causes cell damage, apoptosis, and chromosomal abnormalities at toxic dosage. The dichotomy of having a protective role in vascular endothelium on one hand to cellular damage on the other may be dose-dependent and the latter being obvious at toxic dosages (Goyer et al. 1973; Valentino et al. 1991).In vitro studies have demonstrated that the impairment of vascular endothelial layer caused by Cd toxicity is antagonized by Zinc (Zn) through prevention of Cd-induced deendothelialised area formation along with a detachment of [3H] thymidine-labelled endothelial cells. Zn further reduces the incorporation of [3H] thymidine into the growing cells, and it also prevents Cd-induced cell damage indicated by the activity of lactate dehydrogenase. In animal models, Zn supplementation has been shown to have anti-oxidative effects mainly by preventing the Cd-induced changes in lipid peroxidation and other lipid compounds. Additionally, Zinc causes decreased Cd accumulation, thereby reducing the Cd-induced apoptosis by 1.5-2 folds (Toshiyuki et al. 1993).

Meta-analysis:

In the association between heavy metals and ischemic stroke analysis, we observed a 17% reduction in the risk of heavy metal for ischemic stroke 0.83(0.76 to 0.90). In the subgroup with the measure of association, we observed a significantly higher hazard ratio (HR 1.67, 95% CI 1.20 to 2.15); however, a protective effect was noted in the pooled odds ratio analysis OR 0.81; 95% CI 0.74 to 0.88) figure 2

To the best of our knowledge, this is the first systematic review and metanalysis to assess and integrate the scientific data from epidemiological research on the association between heavy metals exposure and stroke risk. Atherosclerotic plaque is a well-known and crucial factor for cerebral ischemic stroke. In numerous investigations, Cd has been proven to cause vascular disorders in animals, such as atherosclerosis. The presence of Cd in the environment has been linked to a substantial increase in the incidences of stroke (Fagerberg et al. 2015; Peters et al. 2010). Experimental evidence revealed that Cd could affect endothelial function at doses lower than the reference values (Angeli et al. 2013). Heavy metals have differed in their effect on the risk of stroke. Cadmium hurts endothelial function, while other heavy metals like zinc and lead have a protective effect and antagonize the adverse impact of cadmium on endothelial function (Olszowski et al. 2012, 2015; Fagerberg et al. 2015). The study conducted born et al hurt which was followed over some time the study confirmed that both large artery address chlorosis and small artery occlusion seem to be associated with presence of plaque and high cadmium and hi cadmium. However, there was a nonsignificant association of plaque with cadmium in cardio embolic stroke. Smoking is known to increase cadmium exposure. Although the study adjusted for smoking status, there still could be residual confounding for the same. However, the number of pathogenic subtypes where small and the result of specific subtypes must be interpreted with caution.

In another study done by Estevez at all of case-control type, the authors tried to investigate the role of 45 inorganic elements with stroke in 92 patients and 83 controls. Blood levels of lead were significantly higher and associated with stroke patients, while gold and cerium were higher in control and were inversely related to ischemic stroke. Modifiable risk factors were different between the groups, the sample size was small. Similarly, the study tried to investigate 45 inorganic elements, and the combined effect of these elements is unknown.

Chen et al. conducted the case-cohort study including 680 incident ischemic stroke out of 2540 participants. After adjustment for confounders, urinary cadmium was associated with an increased incidence of ischemic stroke. However, the observed association was more pronounced among participants in the lowest tertile of serum Zinc values. Still, this effect was attenuated and found to be nonsignificant in the never smokers. However, urinary cadmium in the present study only measured at the baseline and within-person, variation may affect the findings of the study. Moreover, like other observational studies, residual confounding factors from dietary and environmental factors cannot be ruled out.

Lin et al. investigated relationship between the amount of heavy metals and stroke incidence. The consecutive patients of acute ischemic stroke onset within one week were selected. The serum levels of lead, mercury, arsenic, and cadmium were determined. The study found low levels of urinary serum mercury in the first-ever ischemic stroke while nonsignificant difference in urinary or serum levels of lead, arsenic, and cadmium was found. The study had several limitations including a small sample size, the possibility of recall bias for covariates like alcohol consumption, smoking habits, and fish consumption. Also, a single blood urine sample does not reflect the total body burden.

There are a few strengths of our review and metanalysis. First and foremost, this is the first systemic review to compile all the published literature linking heavy metals and their association with ischemic stroke. Our study also highlighted the plausible pathogenic mechanism of heavy metal causing ischemic stroke, which mostly comes from the studies published on animal models.

There are several limitations of the present review and metanalysis. First, the studies are too few (only four) to draw conclusive evidence from the review. Secondly, two of the four included studies carried out by Estevez and Chin et al. were carried out in a small number of patients, 92 and 33, respectively, which were the significant limitations of the included studies. Third, only one of the studies done by Borne et al. was done prospectively where the patients were followed up for significant duration till they developed ischemic stroke and the Cd levels were measured. At the same time, all the other studies were case-control studies done in a relatively small sample size, which would challenge the external validity of the published studies. Fourth, two studies have used the patients’ serum while the other two have used urine to estimate the heavy metals. Different mediums of measurement can lead to a discrepancy in the result interpretation.

Previous studies from different cohorts have reported a link between Cd in the blood and cardiovascular illness, particularly carotid plaque (Barregard et al. 2016; Tellez-Plaza et al. 2016). Even though causality cannot be established in the study, there are numerous negative consequences of Cd that may raise the risk of stroke. The current findings by Borne et al., 2017, demonstrated that Cd and carotid plaque have a synergistic effect on the risk of Ischemic stroke in the future. Because the whole population is exposed to Cd through their diets and Cd is very slowly removed from the human body, this finding might have significant public health consequences (Borné et al. 2017).

The relationship between Cd exposure and the risk of Ischemic stroke was maintained in stratified analyses among ever smokers and significantly reduced among never smokers, even though the interaction test was not statistically significant. Aside from the comparatively low amount of Cd exposure among never smokers, the discrepancy might be explained that non-smokers usually lead healthier lifestyles, including eating nutritious food. In addition, detailed information on smoking was collected in the present study, which enabled us to reduce the residual confounding and study the effect modification by smoking status.

To our knowledge, the study conducted by Chen et al., 2018 is the first long-term study that links urinary Cd and the risk of ischemic stroke (Chen et al. 2018). Although previous studies have been done, they have focused on all strokes, and hence there was a lack of information on stroke types and measured Cd concentration in the diet. Urinary Cd has been shown to represent long-term exposure and total body load in studies (Tellez-Plaza et al. 2012), which is essential for understanding the health effects of Cd exposure in the average population. The current study is noteworthy since it is the first to show that Zn has an inhibitory impact on Cd toxicity in humans. Because bioaccumulation of Cd in the human body is challenging to eliminate effectively (Nordberg and Kjellström 1979), this result has significant clinical and public health implications.

Exposure to toxicological heavy metals including Pb, Hg, As, and Cd is progressively related to cardiovascular and stroke risks (Kaji 2004; Prozialeck et al. 2008; Mitra et al.2014). For example, various epidemiological studies have shown that higher Pb levels are associated with an increased risk of Ischemic stroke (Kim et al. 2013; Møller and Kristensen 1992). Furthermore, Pb exposure has been linked to an increase in the incidences of cardiovascular disease as well as stroke (Navas-Acien et al. 2004; Schober et al. 2006). Since few studies are available on different databases, our review was solely based on observational data that unmeasured confounders might affect. Therefore, further conclusive trials and research are needed to validate the study in the general population. This will also help us know the risk of adverse health consequences even at relatively low exposure to these toxic metals. This will guide setting up appropriate legislation, preventive strategies, and standards to tackle the global determinant of ischemic stroke.

Serum and urine Cd concentrations are positively associated, while serum and urine Hg concentrations are inversely related to the risk of Ischemic stroke. A single study revealed that the serum and urine concentration of Pb had no association with ischemic stroke risk. However, more extensive prospective cohort studies are required in larger populations to further establish the causal association of metals with acute ischemic stroke.

Acknowledgement: We would like to acknowledge the Institute of Medical Sciences for its infrastructural and technical support.

Disclaimer: Priya Gupta and Archisman Mahapatra will share the 2^nd authorship.

Conflict of interest: The authors have no relevant financial or non-financial interests to disclose.

Data availability: The authors confirm that the data supporting the findings of this study are available within the article.

Funding sources: This research was not supported by any funding institution.

Disclaimer: Priya Gupta and Archisman Mahapatra will share the 2^nd authorship.

Author contributions:

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Priya Dev, Abhishek Pathak and Amit Kumar. The first draft of the manuscript was written by Priya Dev, Priya Gupta, Archisman Mahapatra and Mareena Cyriac, and all authors commented on previous versions of the manuscript. Vijaya Nath Mishra and Varun Kumar Singh were involved in the manuscript editing. All authors read and approved the final manuscript.

Alloway BJ. Sources of heavy metals and metalloids in soils. InHeavy metals in soils 2013 (pp. 11-50). Springer, Dordrecht.
Angeli JK, Pereira CA, de Oliveira Faria T, Stefanon I, Padilha AS, Vassallo DV. Cadmium exposure induces vascular injury due to endothelial oxidative stress: the role of local angiotensin II and COX-2. Free Radic. Biol. Med. 2013 Dec 1;65:838-48.
Arrifano GP, Alvarez-Leite JI, Souza-Monteiro JR, Augusto-Oliveira M, Paraense R, Macchi BM, et al. In the heart of the Amazon: noncommunicable diseases and apolipoprotein E4 genotype in the riverine population. Int. J. Environ. Res. 2018 Sep;15(9):1957.
Baena CP, Olandoski M, Younge JO, Buitrago-Lopez A, Darweesh SK, Campos N, et al. Effects of lifestyle-related interventions on blood pressure in low and middle-income countries: systematic review and meta-analysis. J. Hypertens. 2014 May 1;32(5):961-73.
Barregard L, Sallsten G, Fagerberg B, Borné Y, Persson M, Hedblad B, et al. Blood cadmium levels and incident cardiovascular events during follow-up in a population-based cohort of Swedish adults: the Malmö Diet and Cancer Study. Environ. Health Perspect. 2016 May;124(5):594-600.
Bjørklund G, Tinkov AA, Dadar M, Rahman M, Chirumbolo S, Skalny AV, et al. Insights into the potential role of mercury in Alzheimer’s disease. J. Mol. Neurosci. 2019 Apr;67(4):511-33.
Borné Y, Fagerberg B, Persson M, Östling G, Söderholm M, Hedblad B, et al. Cadmium, carotid atherosclerosis, and incidence of ischemic stroke. J. Am. Heart Assoc. 2017 Dec 2;6(12):e006415.
Cecil KM, Brubaker CJ, Adler CM, Dietrich KN, Altaye M, Egelhoff JC, et al. Decreased brain volume in adults with childhood lead exposure. PLoS Med. 2008 May;5(5):e112.
Chen C, Xun P, Tsinovoi C, McClure LA, Brockman J, MacDonald L, et al. Urinary cadmium concentration and the risk of ischemic stroke. Neurology. 2018 Jul 24;91(4):e382-91.
Fagerberg B, Barregard L, Sallsten G, Forsgard N, Östling G, Persson M, et al. Cadmium exposure and atherosclerotic carotid plaques–Results from the Malmö diet and Cancer study. Environ. Res. 2015 Jan 1;136:67-74.
Goyer RA, Rhyne BC. Pathological effects of lead. Int. J. Exp. Pathol. 1973;12:1-77.
Guzik A, Bushnell C. Stroke epidemiology and risk factor management. Continuum (Minneap Minn). 2017 Feb 1;23(1):15-39.
Houston MC. Role of mercury toxicity in hypertension, cardiovascular disease, and stroke. J. Clin. Hypertens. 2011 Aug;13(8):621-7.
Hu XF, Singh K, Chan HM. Mercury exposure, blood pressure, and hypertension: A systematic review and dose–response meta-analysis. Environ. Health Perspect. 2018 Jul 31;126(07):076002.
Kaji T. Cell biology of heavy metal toxicity in vascular tissue. Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan. 2004 Mar 1;124(3):113-20.
Kim JH, Byun HM, Chung EC, Chung HY, Bae ON. Loss of integrity: impairment of the blood-brain barrier in heavy metal-associated ischemic stroke. Toxicol. Res. 2013 Sep;29(3):157-64.
Kim YJ, Kwon HK, Lee JM, Cho H, Kim HJ, Park HK, et al. Gray and white matter changes link cerebral small vessel disease to gait disturbances. Neurology. 2016 Mar 29;86(13):1199-207.
Lin CH, Hsu YT, Yen CC, Chen HH, Tseng CJ, Lo YK, et al. Association between heavy metal levels and acute ischemic stroke. J. Biomed. Sci. 2018 Dec;25(1):1-8.
Mensah GA, Norrving B, Feigin VL. The global burden of stroke. Neuroepidemiology. 2015;45(3):143-5.
Medina-Estévez F, Zumbado M, Luzardo OP, Rodríguez-Hernández Á, Boada LD, Fernández-Fuertes F, et al. Association between Heavy Metals and Rare Earth Elements with Acute Ischemic Stroke: A Case-Control Study Conducted in the Canary Islands (Spain). Toxics. 2020 Sep;8(3):66.
Mergenthaler P, Dirnagl U, Meisel A. Pathophysiology of stroke: lessons from animal models. Metab. Brain Dis. 2004 Dec;19(3):151-67.
Mitra J, Vasquez V, Hegde PM, Boldogh I, Mitra S, Kent TA, et al. Revisiting metal toxicity in neurodegenerative diseases and stroke: therapeutic potential. Neurol. Res. Ther. 2014;1(2).
Møller L, Kristensen TS. Blood lead is a cardiovascular risk factor. Am. J. Epidemiol. 1992 Nov 1;136(9):1091-100.
Navas-Acien A, Selvin E, Sharrett AR, Calderon-Aranda E, Silbergeld E, Guallar E. Lead, cadmium, smoking, and increased risk of peripheral arterial disease. Circulation. 2004 Jun 29;109(25):3196-201.
Nordberg GF, Kjellström T. Metabolic model for cadmium in man. Environ. Health Perspect. 1979 Feb;28:211-7.
Olszowski T, Baranowska-Bosiacka I, Gutowska I, Piotrowska K, Mierzejewska K, Korbecki J, et al. The effects of cadmium at low environmental concentrations on THP-1 macrophage apoptosis. Int. J. Mol. Sci. 2015 Sep;16(9):21410-27.
Olszowski T, Baranowska-Bosiacka I, Gutowska I, Chlubek D. Pro-inflammatory properties of cadmium. Acta Biochim. Pol. 2012 Dec 13;59(4).
Pachauri V, Dubey M, Yadav A, Kushwaha P, Flora SJ. Monensin potentiates lead chelation efficacy of MiADMSA in rat brain post chronic lead exposure. Food Chem. Toxicol. 2012 Dec 1;50(12):4449-60.
Peters JL, Perlstein TS, Perry MJ, McNeely E, Weuve J. Cadmium exposure in association with the history of stroke and heart failure. Environ. Res. 2010 Feb 1;110(2):199-206.
Prozialeck WC, Edwards JR, Nebert DW, Woods JM, Barchowsky A, Atchison WD. The vascular system is a target of metal toxicity. Toxicol. Sci. 2008 Apr 1;102(2):207-18.
Schober SE, Mirel LB, Graubard BI, Brody DJ, Flegal KM. Blood lead levels and death from all causes, cardiovascular disease, and cancer: results from the NHANES III mortality study. Environ. Health Perspect. 2006 Oct;114(10):1538-41.
Schwerdtle T, Ebert F, Thuy C, Richter C, Mullenders LH, Hartwig A. Genotoxicity of soluble and particulate cadmium compounds: impact on oxidative DNA damage and nucleotide excision repair. Chem. Res. Toxicol. 2010 Feb 15;23(2):432-42.
Tan YF, Zhan LX, Chen XH, Guo JJ, Qin C, Xu E. Risk factors, clinical features and prognosis for subtypes of ischemic stroke in a Chinese population. Curr. Med. Sci. 2018 Apr;38(2):296-303.
Tellez-Plaza M, Guallar E, Howard BV, Umans JG, Francesconi KA, Goessler W, et al. Cadmium exposure and incident cardiovascular disease. Epidemiology (Cambridge, Mass.). 2013 May;24(3):421.
Tellez-Plaza M, Navas-Acien A, Menke A, Crainiceanu CM, Pastor-Barriuso R, Guallar E. Cadmium exposure and all-cause and cardiovascular mortality in the US general population. Environ. Health Perspect. 2012 Jul;120(7):1017-22.
Toshiyuki K, Atsushi M, Chika Y, Michiko S, Hiroshi K. Zinc protection against cadmium-induced destruction of the monolayer of cultured vascular endothelial cells. Toxicol. Lett. 1993 Mar 1;66(3):247-55.
Turin TC, Okamura T, Afzal AR, Rumana N, Watanabe M, Higashiyama A, et al. Hypertension and lifetime risk of stroke. J. Hypertens. 2016 Jan 1;34(1):116-22.
Valentino M, Governa M, Marchiseppe I, Visona I. Effects of lead on polymorphonuclear leukocyte (PMN) functions in occupationally exposed workers. Arch. Toxicol. 1991 Oct;65(8):685-8.
Verougstraete V, Lison D, Hotz P. A systematic review of cytogenetic studies conducted in human populations exposed to cadmium compounds. Mutat Res Rev Mutat Res. 2002 Mar 1;511(1):15-43.
Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. Heart disease and stroke statistics—2021 update: a report from the American Heart Association. Circulation. 2021 Feb 23;143(8):e254-743.
Wiggers GA, Furieri LB, Briones AM, Avendaño MS, Peçanha FM, Vassallo DV, et al. Cerebrovascular endothelial dysfunction induced by mercury exposure at low concentrations. Neurotoxicology. 2016 Mar 1;53:282-9.
Zheng JL, Yuan SS, Wu CW, Lv ZM, et al. Acute exposure to waterborne cadmium-induced oxidative stress and immunotoxicity in the brain, ovary, and liver of zebrafish (Danio rerio). Aquat. Toxicol. 2016 Nov 1;180:36-44.

Table1: General characteristics of included studies

S.N.

Author’s name

Study duration

Heavy metal analyzed

Study design

Case-control sample size

Sex and age

Method of exposure assessment (blood, urine, diet)/ assay method

Confounders adjusted

Conclusion

Result

Limitations

Newcastle - Ottawa

Sensitivity

Specificity

Borne et al

2017

(Sweden)

1991 to 2010

Cadmium

Nested case control

221 IS patients/ 3935 non ischemic stroke patients

Male and female

Blood/ inductively coupled plasma mass spectrometry

Age, sex, waist circumference, smoking status, diabetes mellitus, blood pressure (BP), BP-lowering drugs, low-density lipoprotein, high-density lipoprotein, lipid-lowering drugs, and C-reactive protein.

The cadmium concentration was relatively high for the IS patients and the association remained significant after adjustment for age sex and other risk factors. Carotid plaque was also associated with ischemic stroke, after adjustments for risk factors. When the plaque and cadmium are combined and simultaneously adjusted for risk factors they exhibited a significant association.

There was a significant interaction between cadmium and plaque with respect to risk of ischemic stroke

Some of the risk factors are changed during long follow up which may affect the cadmium concentration.

Chen et al

2018

( USA)

January 2003 to October 2007

cadmium

Nested case control

680 IS patients 1860 control

Male and female

≥45 years of age

Urine

/ National Health and Nutrition Examination Survey (NHANES) method with a NEXION 300X quadrupole inductively coupled plasma mass spectrometry

age, sex, race (black or white), age-sex and age-race interactions, and region (Stroke Buckle, the rest of Stroke Belt, or non–Stroke Belt region)

This study showed that the creatinine corrected urine cadmium concentration is significantly associated with ischemic stroke.

This study suggested that cadmium exposure may be an independent risk factor for ischemic stroke.

Urinary cadmium concentration was measured only at baseline. The study didn’t consider the within-person variation.

Lin et al

2018

(Taiwan)

2012–2013

Pb, Hg, As, and Cd,

Case control

33 acute ischemic stroke patients /39 healthy control

Male and female

Serum and urine/ inductively coupled plasma–mass spectrometry

Study proved the positive association of lead with stroke in univariate and multivariate analysis. Also suggested an inverse association of gold and cerium with stroke in multivariate analysis.

Study found low levels of serum and urine Hg in first-ever patients with AIS, providing new evidence of dysregulated heavy metals in patients with AIS.

The study was conducted in a single center with relatively small sample size.

Estévez et al

2020

( Spain)

April 2017 and April 2018.

Ag, As, Ba, Be, Cd, Co, Cu, Hg, Mn, Pb, Pd, Se, Sb, Sr, Th, U, V, Zn, Au, Bi, Ce, Dy, Er, Eu, Fe, Ga, Gd, Ho, In, La, Lu, Nb, Nd, Os, Pr, Pt, Ru, Sm, Sn, Ta, Tb, Tm , Y, Yb.

case-control study

92 IS patients /83 healthy controls

Male and female

≥18 years of age

Blood

smoking, arterial hypertension, dyslipidemia and coronary cardiopathy

There is an inverse association of serum and urine level of Hg with the ischemic stroke (p value 0.032, 0.006 respectively). Also suggested that there was no significant difference in serum Pb (S-Pb), As (S-As), and Cd (S-Cd) levels and urine Pb (U-Pb), As (U-As) and Cd (U-Cd) levels in either group.

These findings provided new evidence of the potential association of dysregulated heavy metals and other elements in patients with stroke, whose ability to cross the blood brain barrier has been previously suggested.

The study didn’t provide any information about mechanism of these elements in stroke.

*Ag (silver), As (arsenic), Au (gold), Ba (barium), Be (beryllium), Bi (bismuth), Cd (cadmium), Ce (cerium), Co (cobalt), Cu (copper), Dy (dysprosium), Er (erbium), Eu (europium), Fe (iron), Ga (gallium), Gd(gadolinium), Hg (mercury), Ho (holmium), In (indium) La (lanthanum), Lu (lutetium), Mn (manganese), Nb (niobium), Nd(neodymium), Ni (nickel), Os (osmium), Pb (lead, Pd (palladium), Pr (praseodymium), Pt (platinum), Ru (ruthenium), Se (selenium) c, Sb (antimony), Sn (tin), Sr (strontium), Ta (tantalum), Tb (terbium), Th (thorium), Tm (thulium), U (uranium), V (vanadium), Y (yttrium), Yb (ytterbium), Zn (zinc).

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Systematic Review and Meta-analysis of Environmental Toxic Metals Contaminants and Risk of Ischemic Stroke

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