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.