Cadmium and atherosclerosis: A review of toxicological mechanisms and a meta-analysis of epidemiologic studies

Environmental Research 162 (2018) 240–260

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Review article

Cadmium and atherosclerosis: A review of toxicological mechanisms and a meta-analysis of epidemiologic studies

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Alexey A. Tinkova,b,c, ,1, Tommaso Filippinid,1, Olga P. Ajsuvakovae, Margarita G. Skalnayab, Jan Aasethf,g, Geir Bjørklundh, Eugenia R. Gatiatulinai, Elizaveta V. Popovaj, Olga N. Nemereshinai, Pai-Tsang Huangk, Marco Vincetid, Anatoly V. Skalnya,b,l,m a

Yaroslavl State University, Yaroslavl, Russia Peoples' Friendship University of Russia (RUDN University), Moscow, Russia c Institute of Cellular and Intracellular Symbiosis, Russian Academy of Sciences, Orenburg, Russia d CREAGEN, Environmental, Genetic and Nutritional Epidemiology Research Center, University of Modena and Reggio Emilia, Modena, Italy e All-Russian Research Institute of Phytopathology, Odintsovo, Moscow Region, Russia f Faculty of Public Health, Inland Norway University of Applied Sciences, Elverum, Norway g Research Department, Innlandet Hospital Trust, Brumunddal, Norway h Council for Nutritional and Environmental Medicine, Mo i Rana, Norway i South-Ural State Medical University, Chelyabinsk, Russia j St. Joseph University in Tanzania, St. Joseph College of Health Sciences, Dar es Salaam, Tanzania k Wan Fang Medical Center, Taipei, Taiwan, ROC l Orenburg State University, Orenburg, Russia m Trace Element Institute for UNESCO, Lyon, France b

A R T I C L E I N F O

A B S T R A C T

Keywords: Cadmium Coronary heart disease Stroke Peripheral artery disease Lipid profile

Cadmium has been proposed to be the one of the factors of atherosclerosis development, although the existing data are still controversial. The primary objective of the present study is the review and the meta-analysis of studies demonstrating the association between Cd exposure and atherosclerosis as well as review of the potential mechanisms of such association. We performed a systematic search in the PubMed-Medline database using the MeSH terms cadmium, cardiovascular disease, atherosclerosis, coronary artery disease, myocardial infarction, stroke, mortality and humans up through December 20, 2017. Elevated urinary Cd levels were associated with increased mortality for cardiovascular disease (HR = 1.34, 95% CI: 1.07–1.67) as well as elevated blood Cd levels (HR = 1.78, 95% CI: 1.24–2.56). Analysis restricted to never smokers showed similar, though more imprecise, results. Consistently, we also observed an association between Cd exposure markers (blood and urine) and coronary heart disease, stroke, and peripheral artery disease. Moreover, Cd exposure was associated with atherogenic changes in lipid profile. High Cd exposure was associated with higher TC levels (OR = 1.48, 95% CI: 1.10–2.01), higher LDL-C levels (OR = 1.31, 95% CI 0.99–1.73) and lower HDL-C levels (OR = 1.96, 95% CI: 1.09–3.55). The mechanisms of atherogenic effect of cadmium may involve oxidative stress, inflammation, endothelial dysfunction, enhanced lipid synthesis, up-regulation of adhesion molecules, prostanoid dysbalance, as well as altered glycosaminoglycan synthesis.

1. Introduction Cardiovascular diseases (CVD) are the leading cause of death in the US (Benjamin et al., 2017) and European countries (Wilkins et al., 2017) accounting for 31% of all world-wide deaths or 17.7 million in 2016 (WHO, 2017) and 45% of all deaths or 3.9 million in Europe (Wilkins et al., 2017). Of these, about 50% were attributed to coronary

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heart disease (CHD), followed closely by stroke (Feigin et al., 2017), while peripheral vascular disease (PVD) contributed only 1–2% (Criqui and Aboyans, 2015). At the same time, the trends have been different between high-income countries and low-, medium-income countries. In particular, Western Europe, USA, and Australia show a dramatic decline in both CHD and stroke. Studies from Eastern Europe and Asia also report a decline in stroke mortality, whereas CHD mortality remains

Corresponding author at: Yaroslavl State University, Yaroslavl, Russia. E-mail address: [email protected] (A.A. Tinkov). These authors contributed equally to the research.

https://doi.org/10.1016/j.envres.2018.01.008 Received 22 December 2017; Received in revised form 5 January 2018; Accepted 10 January 2018 0013-9351/ © 2018 Elsevier Inc. All rights reserved.

Environmental Research 162 (2018) 240–260

A.A. Tinkov et al.

variable (Kelly and Fuster, 2010). In addition, American Heart Association reported that 92.1 million adults in USA have CVD. It was proposed that approximately 43.9% of the US people will have CVD by 2030 (Benjamin et al., 2017). Prevalence of CVD from European Social Survey 2014–2015 in for all European countries was 9.2% (ESS, 2015). According to WHO Mortality Database for global burden of disease estimates 2000–2011, the number of deaths from CVD vary from 40% for men (with 19% of CHD, 9% of stroke and 12% of the other CVD) to 49% (with 20% of CHD, 14% of stroke and 15% of the other CVD) for women (WHO, 2013). Recent studies have demonstrated that environmental pollution plays a significant role in CVD (Pope et al., 2004) and atherosclerosis in particular (Lawal, 2017). Moreover, it has been shown that an interaction between genetic and environmental factors may significantly contribute to atherosclerosis (Org et al., 2015). The mechanisms linking environmental pollution and atherosclerosis include oxidative stress, inflammation (Araujo, 2011), platelet activation (Poursafa and Kelishadi, 2010), and other pathways (Campen et al., 2012). Of organic pollutants, the most significant association with atherosclerosis was revealed for bisphenol A, phthalates (Lind and Lind, 2011), polychlorinated biphenyls, pesticides, dioxin (Lind et al., 2012a, 2012b). In turn, heavy metal ions as the major inorganic pollutants are also known to promote CVD and atherosclerosis (Prozialeck et al., 2007). In particular, an association between the incidence and mechanisms of atherosclerosis was demonstrated for arsenic (Simeonova and Luster, 2004). Cadmium was also proposed to be the one of the potential factors of atherosclerosis development (Messner et al., 2009). However, the existing data are still controversial (Santos-Gallego and Jialal, 2016). Although cadmium levels in the environment have been decreasing for the last 50 years due to improved emission control for fossil fuel combustion and improved technology for the production, use and disposal of cadmium and cadmium-containing products (Crea et al., 2013), the rate of Cd exposure is still high. In non-smoking and non-occupationally exposed population, the main source of Cd exposure is diet, with additional relevant contribution from air pollution (Vilavert et al., 2012; Filippini et al., 2016; Coudon et al., 2017). In particular, a more restrictive dietary intake guideline for Cd have been suggested in order to enhance the health protection (Satarug et al., 2017). Nevertheless, the estimated mean weekly intake of Cd in European population ranges from 1.9 to 3.0 µg/kg, in such cases exceeding the limit of 2.5 µg/kg suggested by the European Food Safety Authority (Nawrot et al., 2010; EFSA, 2012). Moreover, even low-dose Cd exposure is associated with increased mortality, as demonstrated in the recent meta-analysis (Larsson and Wolk, 2016). Therefore, the assessment of the toxicological effects of Cd exposure in general (Tinkov et al., 2017), including its role in atherosclerosis development, is of particular interest. The primary objective of the present study is to review the epidemiologic studies examining the association between Cd exposure and atherosclerosis, also addressing the biological plausibility of this possible association.

Fig. 1. Flow-chart of online search and selection.

exposure assessment (blood, urine or intake), the covariates adjusted for in the multivariable analysis, and eventually the odds ratios (OR), risk ratios (RR) or hazard ratios (HR) estimates and their 95% CI for the most adjusted model reported (Table 1 and 2). We used a random-effect model to account for heterogeneity (I2) in study-specific results. We performed stratified analysis according to Cd assessment methods and restricting to never smoker participants. In order to review the Cd-induced mechanisms of atherosclerosis we performed a search in PubMed-Medline database using the MeSH terms cadmium, atherosclerosis, lipid profile, lipoprotein, adhesion molecules, endothelial dysfunction, vascular inflammation. The latest search was dated as 20 December 2017. 3. Cadmium, cardiovascular diseases and coronary heart disease

2. Materials and methods

3.1. Cross sectional studies

We performed a systematic search in the PubMed-Medline database using the MeSH terms cadmium, cardiovascular disease, atherosclerosis, coronary artery disease, myocardial infarction, stroke, mortality and humans up through 20 December 2017. We performed a meta-analysis of retrieved observational studies assessing the incidence or mortality (cohort studies) or prevalence (cross-sectional studies) of cardiovascular outcome (i.e. cardiovascular diseases, coronary heart disease, and stroke) or cardiovascular risk factors (i.e. peripheral arterial disease and abnormalities in lipid profile) (Fig. 1). Generally, we compared the higher versus the lowest categories of Cd exposure using a methodology already specified in detail (Vinceti et al., 2016). The extracted data for meta-analysis included study design (i.e. cross-sectional or cohort), number, sex and country of participants, type of Cd

Examination of 948 men and 960 women (NHANES 2005) demonstrated that increased blood Cd levels were associated with a nearly 2fold higher prevalence of ischemic heart disease in a general cohort. The observed association was especially tight in women (OR = 2.28, 95% CI: 1.26–4.15) than in men (OR = 1.88, 95% CI: 0.96–3.69) (Lee et al., 2011). Correspondingly, a 50% increase in urine and especially blood Cd levels is associated with elevated prevalence of myocardial infarction and heart failure. After adjustment for smoking status (never smokers only) the association between heart failure and blood (OR = 1.10, 95% CI: 0.96–1.27) and urinary (OR = 1.02, 95% CI: 0.88–1.18) Cd concentration was found to be weaker (Peters et al., 2010). Higher urinary and blood Cd levels was also associated with increased prevalence rate (PR) of myocardial infarction in NHANES 2003–2012 241

2009

2008

CadmiBel (Cadmium in Belgium study)

NHANES III 1988–1994

Year

Population

13,956 (6558/ 7398

476 (216/ 260) LEA (215/265) 480 HEA

N (M/F)

Both

Both

Sex

Urine (μg/g creatinine)

Blood (nmol/L) Urine (nmol/L/ 24 h)

Specimen

GM: 0.28 M 0.40 F T3 (≥ 0.48) vs. T1 (< 0.21) M T3 (≥ 0.68) vs. T1 (< 0.29) F

GM (IQR): Low Exposure Area 10.6 (7.1–16.9) Blood 7.7 (5.4–11.9) Urine High Exposure Area 11.5 (6.8–19.6) Blood 11.7 (6.8–19.5) Urine

Cd levels

↑ CVD mortality ↑ CHD mortality

↑ CVD mortality↑ CHD mortality

Outcome Doubling of internal dose Blood CVD HR: 1.20 (95% CI: 0.90–1.60) HR: 1.29 (95% CI: 0.99–1.67) with smelters CHD HR: 1.19 (95% CI: 0.84–1.71) HR: 1.31 (95% CI: 0.95–1.81) with smelters Stroke HR: 0.83 (95% CI: 0.46–1.49) HR: 0.85 (95% CI: 0.49–1.47) with smelters Urine CVD HR: 1.07 (95% CI: 0.85–1.34) HR: 1.11 (95% CI: 0.89–1.38) with smelters CHD HR: 1.05 (95% CI: 0.79–1.40) HR: 1.09 (95% CI: 0.83–1.43) with smelters Stroke HR: 0.70 (95% CI: 0.59–0.98) HR: 0.61 (95% CI: 0.37–0.99) with smelters T3 vs. T1 CVD HR: 1.33 (95% CI: 0.69–2.56) M HR: 0.82 (95% CI: 0.47–1.42) F CHD HR: 2.48 (95% CI: 0.85–7.27) M HR: 0.45 (95% CI: 0.24–0.83) F 2-fold increase CVD

Risk assessment

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Menke et al. (2009)

Nawrot et al. (2008)

Age, sex, body mass index, smoking status, γglutamyltransferase (alcohol intake) and socio-economic status

Age, race/ethnicity, urban residence, annual household income, high school education, smoking status, pack-years, physical activity, diabetes, body mass index, alcohol consumption, C-reactive protein, total cholesterol, systolic blood pressure, blood pressure-lowering medication, blood lead, estimated glomerular filtration rate (and postmenopausal status in women)

Reference

Adjustments factors

Table 1 Association between Cd levels in the human organism and cardiovascular diseases (including risk factors for cardiovascular disease) in prospective studies included in meta-analysis.

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243

599

2012

2012

Women from Gothenburg (Sweden)

NHANES 1999–2004

8989

3119 (1403/ 1716)

2011

Kakehashi River basin in Japan

N (M/F)

Year

Population

Table 1 (continued)

Both

Women

Both

Sex

Blood (μg/L) Urine (μg/g creatinine)

Blood (μg/L) Urine (μg/g creatinine)

Urine (μg/g creatinine)

Specimen

GM: 0.44 Blood 0.28 Urine

Median (5th–95th) 0.34 (0.14–1.69) Blood 0.35 (0.14–1.01) Urine Q4 (≥ 0.58) vs. Q1 (≤ 0.22) Blood Q4 (≥ 0.57) vs. Q1 (≤ 0.24) Urine

GM (95% CI): 4.6 (4.4–4.7) M 7.2 (7.0–7.4) F Q4 (> 10) vs. Q1 (< 3)

Cd levels

↑ CVD, CHD and ischemic heart disease mortality

↑ carotid plaques prevalence ↑ plaque area

↑ CVD mortality

Outcome HR: 1.21 (95% CI: 1.07–1.36) M HR: 0.93 (95% CI: 0.84–1.04) F CHD HR: 1.36 (95% CI: 1.11–1.66) M HR: 0.82 (95% CI: 0.76–0.89) F CVD in never smokers HR: 1.30 (95% CI: 1.06–1.60) M HR: 0.93 (95% CI: 0.80–1.08) F Q4 vs. Q1 CVD mortality HR: 1.79 (95% CI: 1.02–3.12) M HR: 2.38 (95% CI: 1.11–5.07) F Stroke mortality HR: 1.0 (95% CI: 0.5–2.0) M HR: 3.6 (95% CI: 1.1–11.9) F Q4 vs. Q1 Large plaque prevalence at followup Blood OR: 4.6 (95% CI: 1.7–12.9) Urine OR: 2.7 (95% CI: 1.2–6.1) All (80th vs. 20th) Blood CVD HR: 1.69 (95% CI: 1.03–2.77) B HR: 1.74 (95% CI: 1.07–2.83) U CHD HR: 1.98 (95% CI: 1.11–3.54) B HR: 2.53 (95% CI: 1.54–4.16) U Ischemic Heart Disease HR: 1.73 (95% CI: 0.88–3.40) B HR: 2.09 (95% CI: 1.06–4.13) U Never smokers (80th vs. 20th)

Risk assessment

Tellez-Plaza et al. (2012)

Fagerberg et al. (2012)

Li et al. (2011)

Reference

(continued on next page)

Sex, education, annual household income, race/ethnicity, body mass index, blood lead, C-reactive protein, total cholesterol, HDL-C, cholesterol lowering medication use, hypertension, diabetes, estimated glomerular filtration rate, smoking status, cumulative smoking dose, serum cotinine (and menopausal status in women)

Pack-years of smoking, log HbA1c, systolic blood pressure, log ICAM-1, statin treatment, body mass index, apolipoprotein B/ apolipoprotein A-I ratio, log hsCPR, and plaque status at baseline

Age

Adjustments factors

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36,863

33,333

2013

Swedish Mammography Cohort

2013

489

2013

Women from Gothenburg (Sweden)

The cohort of Swedish men (COSM)

N (M/F)

Year

Population

Table 1 (continued)

Men

Women

Women

Sex

Intake (µg/day)

Intake (µg/day)

Blood (μg/L) Urine (μg/L)

Specimen

Mean (SD): 19 (3.7) Q4 (> 21) vs. Q1 (< 16)

Mean not reported Q4 (17) vs. Q1 (10)

Median (5th–95th): 0.33 (0.14–1.65) Blood 0.35 (0.14–0.96) Urine T3 (> 0.44) vs. T1 (< 0.25)

Cd levels

↔ CVD↔/↓ MI↔ Stroke

↔ CVD ↔ MI ↔ Stroke (total and subtypes)

↑ PAD risk (through ABI – ankle-brachial blood pressure index)

Outcome CVD HR: 1.17 (95% CI: 0.53–2.55) B HR: 1.98 (95% CI: 0.90–4.35) U T3 vs. T1 PAD Blood OR: 2.4 (95% CI: 0.9–6.3) Urine OR: 2.4 (95% CI: 1.0–5.5) Femoral plaque at baseline Blood OR: 3.8 (95% CI: 1.1–13-3) Urine OR: 2.4 (98% CI: 0.8–7.2) All (Q4 vs. Q1) CVD HR: 0.96 (95% CI: 0.85–1.09) MI HR: 1.07 (95% CI: 0.88–1.29) Stroke HR: 0.90 (95% CI: 0.76–1.05) Ischemic stroke HR: 0.89 (95% CI:0.74–1.06) Hemorrhagic stroke HR: 1.11 (95% CI: 0.68–1.80) Never smokers (Q4 vs. Q1) CVD HR: 0.89 (95% CI: 0.76–1.05) MI HR: 0.87 (95% CI: 0.67–1.14) Stroke HR: 0.90 (95% CI: 0.74–1.11) All (Q4 vs. Q1) CVD HR: 0.99 (95% CI: 0.91–1.09) MI HR: 0.93 (95% CI: 0.72–1.21)

Risk assessment

244

Julin et al. (2013b)

Julin et al. (2013a)

Fagerberg et al. (2013)

Reference

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Age, education, family history of myocardial infarction before the age of 60 years, high cholesterol, hypertension, ever use of aspirin, smoking status, body mass index, physical activity, alcohol consumption, energy intake, consumption of vegetables and whole grains

Age, education, family history of myocardial infarction before the age of 60 years, high cholesterol, hypertension, ever use of postmenopausal hormones, ever use of aspirin, smoking status, body mass index, physical activity, alcohol consumption, energy intake, consumption of vegetables and whole grains

Pack-years of smoking, current smoking, systolic blood pressure, HbA1c, apolipoprotein B/A-I ratio, statin treatment, stratification group at baseline (in relation to glucose tolerance and diabetes), ICAM-1

Adjustments factors

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Environmental Research 162 (2018) 240–260

Year

2013

Population

Strong Heart Study 1989–1991

Table 1 (continued)

3348

N (M/F)

Sex

Urine (μg/g creatinine)

Specimen

GM (IQR): 0.94 (0.61–1.45) Q4 > 1.45 vs. Q1 ≤ 0.61

Cd levels

↑ CVD mortality ↑ CHD mortality ↑ CVD incidence ↑ CHD incidence ↑ Stroke incidence ↑ HF incidence

Outcome Stroke HR: 1.03 (95% CI: 0.82–1.28) Never smokers (Q4 vs. Q1) CVD HR: 0.87 (95% CI: 0.75–1.02) MI HR: 0.75 (95% CI: 0.60–0.93) Stroke HR: 1.03 (95% CI: 0.82–1.28) All (Q4 vs. Q1) CVD mortality HR: 1.87 (95% CI: 1.34–2.60) CHD mortality HR: 1.51 (95% CI: 1.04–2.20) CVD incidence HR: 1.48 (95% CI: 1.21–1.80) CHD incidence HR: 1.33 (95% CI: 1.05–1.68) Stroke incidence HR: 1.87 (95% CI: 1.22–2.86) HF incidence HR: 1.61 (95% CI: 1.10–2.36) All (80th vs. 20th) CVD mortality HR: 1.43 (95% CI: 1.21–1.70) CHD mortality HR: 1.34 (95% CI: 1.10–1.63) CVD incidence HR: 1.24 (95% CI: 1.11–1.38) CHD incidence HR: 1.22 (95% CI: 1.08–1.38) Stroke incidence HR: 1.75 (95% CI: 1.17–2.59) HF incidence HR: 1.39 (95% CI: 1.01–1.94) Never smokers (80th vs. 20th) CVD mortality

Risk assessment

Tellez-Plaza et al. (2013c)

Reference

(continued on next page)

Sex, education, body mass index, total cholesterol, estimated LDL-C, hypertension, diabetes, estimated glomerular filtration rate, smoking status, cumulative smoking dose (and menopausal status in women)

Adjustments factors

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245

246

4378

4819

2015

2016

Malmö Diet and Cancer Study (MDSC)

2864

2013

Strong Heart Study (1989–91), examination visits (1993–1995 and 1997–1999)

Malmö Diet and Cancer Study (MDCS)

N (M/F)

Year

Population

Table 1 (continued)

Both

Both

Both

Sex

Blood (μg/L)

Blood (μg/L)

Urine (μg/g creatinine)

Specimen

GM (IQR): 0.31 (0.17–0.50) Q4 (≥ 0.50) vs. Q1 (< 0.17)

Median (range): 0.24 (0.02–5.07) M 0.27 (0.03–4.83) F Sex specific quartiles Q4 (≥ 0.50) vs. Q1 (< 0.15) M Q4 (≥ 0.50) vs. Q1 (< 0.18) F

GM (95% CI): 0.96 (0.90–1.02) T3 (> 1.23) vs. T1 (≤ 0.71)

Cd levels

↑ CHD incidence ↑ Stroke ↑ CVD mortality

↑/↔ HF ↔ AF

↑ PAD risk (through ABI – ankle-brachial blood pressure index)

Outcome HR: 1.26 (95% CI: 1.00–1.58) CHD mortality HR: 1.12 (95% CI: 0.86–1.45) CVD Incidence HR: 1.12 (95% CI: 0.95–1.32) CHD Incidence HR: 1.16 (95% CI: 0.96–1.39) Stroke Incidence HR: 0.90 (95% CI: 0.49–1.65) HF Incidence HR: 1.18 (95% CI: 0.68–2.05) All (T3 vs. T1) HR: 2.10 (95% CI: 1.16–3.53) Never smokers (T3 vs. T1) HR: 1.25 (95% CI: 0.83–1.80) All (20th vs. 80th) HR: 1.41 (95% CI: 1.05–1.81) Never smokers (20th vs. 80th) HR: 1.25 (95% CI: 0.83–1.80) All (Q4 vs. Q1) HF: HR: 1.95 (95% CI: 1.02–3.72) All HR: 3.91 (95% CI: 1.32–11.54) M HR: 1.18 (95% CI: 0.49–2.82) F HR: 2.87 (95% CI: 0.60–13.85) Never smokers (Q4 vs. Q1) AF HR: 1.02 (95% CI: 0.69–1.51) All All (Q4 vs. Q1) CHD incidence HR: 1.9 (95% CI: 1.2–2.9) MI HR: 1.8 (95% CI: 1.2–2.8) Stroke HR: 2.1 (95% CI: 1.3–3.2)

Risk assessment

Barregard et al. (2016)

Borné et al., 2015

Tellez-Plaza et al. (2013a)

Reference

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Sex, smoking, waist circumference, low education, low physical activity, alcohol intake, serum triglycerides, HbA1c, C-reactive protein, postmenopausal status, hormonal replacement, treatment for hypertension, diabetes, lipid-lowering medication, diastolic blood pressure, LDL, HDL,

Age, systolic blood pressure, use of blood pressure-lowering or lipids-lowering medications, diabetes, history of coronary heart disease, waist circumference, smoking status, alcohol intake, LDL-C, HDL-C, hsCRP, plasma creatinine, marital status, education status

Age at baseline, sex, education, location, body mass index, total cholesterol, estimated LDL-C, hypertension, diabetes, glomerular filtration rate, smoking status, cumulative smoking dose (and postmenopausal status in women)

Adjustments factors

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4156

2017

Malmö Diet and Cancer Study (MDCS)

Both

Sex

Blood (μg/L)

Specimen

Sex specific quartiles Q4 (≥ 0.47) vs. Q1 (< 0.15) M Q4 (≥ 0.49) vs. Q1 (< 0.18) F

Cd levels

↑ Ischemic Stroke

Outcome CVD mortality HR: 1.9 (95% CI: 1.1–3.2) Never smokers (Q4 vs. Q1) CHD incidence HR: 2.3 (95% CI: 1.0–5.1) MI HR: 2.4 (95% CI: 1.1–5.4) Stroke HR: 2.2 (95% CI: 1.0–4.8) CVD mortality HR: 2.6 (95% CI: 1.0–6.9) All (Q4 vs. Q1) HR: 1.66 (95% CI 1.01–2.72)

Risk assessment

Age, sex, waist circumference, smoking status, diabetes, blood pressure, medication, LDL-C, HDL-C, lipid lowering medication use, and C‐reactive protein

Adjustments factors

Borné et al. 2017

Reference

↑ – significant increase; ↓ – significant decrease; ↔ – no significant changes. ABI – ratio of the systolic blood pressures in the tibial and brachial arteries ≤ 0.9 in any artery; AF – atrial fibrillation; CHD – Coronary heart disease; CVD – cardiovascular disease; F – females; GM – geometric mean; HDL-C – high-density lipoprotein cholesterol; HF – heart failure; IQR – interquartile range; LDL-C – low-density lipoprotein cholesterol; M – males; MI – myocardial infarction; PAD – peripheral arterial disease; Q – quartile; Qi – quintile; SD – standard deviation; SE – Standard Error; T – tertile.

N (M/F)

Year

Population

Table 1 (continued)

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247

2010

2010

NHANES 1999–2006

NHANES 1999–2004

Year

Population

6456 (3333/ 3123)

12,049 (6121/5928)

N (M/F)

Both (M/F)

Both (M/F)

Sex

Blood (μg/ L) Urine (μg/g creatinine)

Blood (nmol/L) Urine (nmol/L)

Specimen

GM: 0.44 Qi5 ≥ 0.80 vs. Qi1 ≤ 0.26 GM: 0.31 Qi5 ≥ 0.69 vs. Qi1 ≤ 0.20

GM (SE): 3.8 (0.02) Blood 2.7 (0.03) Urine

Cd levels

↑ PAD risk (through ABI – ankle-brachial blood pressure index)

↑ Stroke prevalence ↑ HF prevalence ↑ MI prevalence

Outcome 50% level increase Blood Stroke OR: 1.38 (95% CI: 1.14–1.67) Heart failure OR: 1.48 (95% CI: 1.17–1.87) MI OR: 1.32 (95% CI: 1.13–1.54) Urine Stroke OR: 1.10 (95% CI: 1.00–1.20) Heart failure OR: 1.12 (95% CI: 1.04–1.21) MI OR: 1.12 (95% CI: 1.03–1.21) Never smokers (N = 5862) Stroke OR: 1.19 (95% CI: 1.02–1.37) B OR: 1.06 (95% CI: 0.93–1.21) U HF OR: 1.10 (95% CI: 0.96–1.27) B OR: 1.02 (95% CI: 0.88–1.18) U Qi5 vs. Qi1 Blood OR: 1.82 (95% CI: 0.82–4.05) M OR: 1.19 (95% CI: 0.66–2.16) F Urine OR: 4.90 (95% CI: 1.55–15.54) M OR: 0.56 (95% CI: 0.18–1.71) F 80th vs. 20th Blood OR: 1.95 (95% CI: 1.28–2.96) M OR: 3.04 (95% CI: 0.62–14.9) M never smokers OR: 1.47 (95% CI: 0.82–2.66) F

Risk assessment

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Tellez-Plaza et al. (2010)

Peters et al. (2010)

Reference

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Age, race/ethnicity, survey year, education, body mass index, blood lead, C-reactive protein, total cholesterol, HDL cholesterol, cholesterol-lowering medication, systolic blood pressure, blood pressure lowering medication, diabetes, and estimated glomerular filtration rate (and postmenopausal status for women)

Age, sex, race/ethnicity, education, body mass index, poverty income ratio, alcohol consumption, smoking status, diabetes, hypertension, hypercholesterolemia, chronic kidney disease (and coronary heart disease when applicable); urine also adjusted for urinary creatinine

Adjustments factors

Table 2 Association between Cd levels in the human organism and cardiovascular diseases (including risk factors for cardiovascular disease) in cross-sectional studies included in meta-analysis.

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249

3903

534

12,511

2015

2016

Health survey evaluation in Thailand

1908 (948/ 960)

2012

2011

KNHANES 2005

N (M/F)

KNHANES 2005, 2008, and 2009

Year

Population

Table 2 (continued)

Both

Both

Both

Both

Sex

Urine (μg/g creatinine)

Blood (μg/L)

Blood (μg/L)

Specimen

Mean (SD): 1.14 (1.18) (not exposed) vs. 9.76 (5.58) (exposed)

GM: 1.16 Qi5 > 1.89 vs. Qi1 ≤ 0.74

GM (SE): 1.53 (0.02)

Cd levels

↑ TG/HDL-C ratio ↓ HDL-C ↑ TG level

↑ risk of low HDL-C ↑ risk higher TG/ HDL-C ratio ↔ TC level ↔ LDL-C level ↔ TG level

↑ CHD prevalence ↑ Stroke prevalence

Outcome OR: 0.95 /95% CI: 0.49–1.86) women never smokers Urine OR: 3.28 (95% CI: 1.82–5.91) M OR: 1.67 (95% CI: 0.56–4.96) men never smokers OR: 0.65 (95% CI: 0.35–1.21) F OR: 0.47 (95% CI: 0.21–1.05) women never smokers IQR increase Both CHD OR: 2.10 (95% CI: 1.29–3.43) Stroke OR: 1.10 (95% CI: 0.79–1.54) Men CHD OR: 1.88 (95% CI: 0.96–3.69) Stroke OR: 1.26 (95% CI: 0.79–1.98) Women CHD OR: 2.28 (95% CI: 1.26–4.15) Stroke OR: 0.94 (95% CI: 0.50–1.75) Qi5 vs. Qi1 OR: 1.95 (95% CI: 1.54–2.46) OR: 1.41 (95% CI: 1.07–1.86) OR: 1.21 (95% CI: 0.78–1.87) OR: 1.19 (95% CI: 0.92–1.55) OR: 1.05 (95% CI: 0.77–1.45) Elevated Cd exposure OR: 3.78 (95% CI: 2.27–6.30) OR: 5.63 (95% CI: 3.33–9.53) OR: 2.81 (95% CI: 1.72–4.60) T3 vs. T1

Risk assessment

Tangvarasittichai et al. (2015)

Kim (2012)

Lee et al. (2011)

Reference

(continued on next page)

Sex, age, smoking status, body mass index, systolic and diastolic blood pressure, alcohol consumption, elevated oxidative stress, chronic kidney disease

Age, sex, body mass index, education, income, exercise, cigarette smoking, alcohol consumption, total energy intake, and total fat intake

Age, age2, education level, income, family hypertension history, systolic blood pressure, alcohol, smoking status, body mass index, waist circumference, blood lead

Adjustments factors

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Year

1489

N (M/F)

Both

Sex

(μg/

(μg/

Blood (μg/L)

Blood L) Urine L)

Specimen

Mean (SD): 3.61 (0.84) Q4 (> 5.99) vs. Q1 (< 3.96)

Median (IQR): 0.27 (0.10–0.49) Blood 0.18 (0.08–0.38) Urine

Cd levels

↑ ↑ ↑ ↑ ↑ Dyslipidemia High TC High TG Low HDL-C High LDL-C

Prevalence Rate (PR) of: ↑ CVD ↑ MI ↑ Stroke

Outcome CVD PR: 1.54 (95% 1.30–1.84) B PR: 1.92 (95% 1.22–3.02) U MI PR: 1.73 (95% 1.42–2.11) B PR: 2.02 (95% 1.08–3.80) U Stroke PR: 1.51 (95% 1.13–2.03) B PR: 2.16 (95% 1.17–4.00) U Never smokers CVD PR: 1.54 (95% 1.09–2.18) B PR: 1.85 (95% 0.91–3.75) U MI PR: 1.93 (95% 1.19–3.14) B PR: 2.42 (95% 0.81–7.18) U Stroke PR: 1.46 (95% 0.88–2.40) B PR: 1.60 (95% 0.76–3.40) U Q4 vs. Q1 OR: 1.83 (95% 1.32–2.28) OR: 1.67 (95% 1.24–2.21) OR: 1.58 (95% 1.36–2.11) OR: 1.66 (95% 1.06–2.23) OR: 1.63 (95% 1.16–2.22)

Risk assessment

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

CI:

Zhou et al. (2016)

Hecht et al. (2016)

Age, sex, income, diabetes, hypercholesterolemia, body mass index, smoking

Age, sex, body mass index, education, monthly income, smoking status, alcohol use, duration of exposure

Reference

Adjustments factors

↑ – significant increase; ↓ – significant decrease; ↔ – no significant changes. ABI – ratio of the systolic blood pressures in the tibial and brachial arteries ≤ 0.9 in any artery; CHD – Coronary heart disease; CVD – cardiovascular disease; F – females; GM – geometric mean; HDL-C – high-density lipoprotein cholesterol; HF – heart failure; IQR – interquartile range; LDL-C – low-density lipoprotein cholesterol; M – males; MI – myocardial infarction; PAD – peripheral arterial disease; Q – quartile; Qi – quintile; SD – standard deviation; SE – Standard Error; T – tertile; TG – triglycerides.

Health Survey on Cadmium Exposed Workers (HSCEW)

NHANES 2003–2012

Population

Table 2 (continued)

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HR for CVD and especially CHD were decreased. A two-fold elevation of creatinine-corrected urinary cadmium levels was associated with a significant increase in the hazard ratios for CHD only in men, but not in women. The observed associations were not changed after adjustment for smoking status (Menke et al., 2009). Nawrot et al. (2008) also detected an increase in the overall CVD and CHD mortality at higher blood Cd levels, whereas the association between urinary Cd and both parameters was weaker (Nawrot et al., 2008). Finally, the increased blood Cd levels (4th quartile) were associated with the increased 10year risk of coronary heart disease at OR = 6.87 (95% CI: 4.58–10.30) and OR = 4.30 (95% CI: 1.27–14.56) after adjustment for covariates including age, BMI, triglycerides (TG), and LDL-C, for men and women, respectively (Cho et al., 2015). Cd exposure was also associated with the values of intima-media thickness. In particular, a significant association between serum Cd levels and carotid artery intima–media thickness was also revealed in maintenance hemodialysis patients (Ari et al., 2011). A later follow-up study including 2589 participants demonstrated a significant association between toenail Cd levels and common, but not bulb and internal carotid intima-media thickness after adjustment for other clinical confounders (Xun et al., 2012). Neither in men nor in women Cd intake was associated with the risk of CVD in prospective studies. In particular, higher rate of Cd intake was associated neither with CVD, nor with CHD (Julin et al., 2013a, 2013b)

population (N = 12,511). The observed relationship was improved was improved after adjustment for smoking status, being more significant in never-smokers (Blood: PR = 1.93, 95% CI: 1.19–3.14; Urine: PR = 2.42, 95% CI: 0.81–7.18) (Hecht et al., 2016). Everett and Frithsen (2008) also revealed a relationship between urinary Cd levels and myocardial infarction that was improved after including only neversmokers into the analysis (OR = 1.85, 95% CI: 1.10–3.14). These observations are generally in agreement with data on intimamedia thickness. The results of a clinical study involving 195 young healthy females demonstrate that serum Cd levels were significantly associated with increased risk of high intima media thickness in a dosedependent manner (Messner et al., 2009). It is also notable that Cd was the only one from the list of 11 metals being significantly associated with the number of plaques in carotid arteries (p = 0.001) and intimamedia thickness (p = 0.005). However, after adjustment for clinical confounders both associations became insignificant (Lind et al., 2012a, 2012b). Correspondingly, a detailed study by Bergström et al. (2015) also demonstrated a significant relationship between blood Cd levels and area of atherosclerotic plaques. It is notable that the metal level was not interrelated with serum apolipoprotein (Apo)A1/ApoB values. Moreover, it has been observed that plaque Cd content is 50-fold higher than that in blood. The highest concentration of Cd in plaques was observed in the upstream sections of carotid plaques, being more than 2-fold higher than that in stenosis and downstream sections (Bergström et al., 2015).

3.3. Meta-analysis 3.2. Prospective studies We retrieved four cross-sectional studies assessing CHD prevalence, and seven cohort studies assessing CVD and CHD mortality. In metaanalysis of cross-sectional studies (Fig. 2A), a significant direct relationship between high blood Cd levels and CHD prevalence was observed with summary OR of 1.59 (95% CI: 1.24–2.04). Higher urinary Cd levels tended to be associated with increased CHD prevalence (OR = 1.34, 95% CI: 0.99–1.81). The analysis only on never smokers showed similar although not significant association between blood and urinary Cd levels and CHD (Fig. 2B). Meta-analysis of data from prospective studies (Fig. 3A) demonstrated that elevated urinary Cd levels are associated with increased CVD mortality (HR = 1.34, 95% CI: 1.07–1.67) as well as for elevated blood Cd levels (HR = 1.78, 95% CI: 1.24–2.56). Analysis restricted to never smokers showed similar results even the summary HRs include the unit using both urine (OR = 1.66, 95% CI: 0.76–3.60) and blood (HR = 1.66, 95% CI: 0.76–3.60) specimen (Fig. 3B). Conversely, summary HR of two studies using cadmium intake in never smokers did not showed an increase risk of CVD incidence. Meta-analysis of the prospective studies on the association between Cd exposure and CHD (Fig. 4A) demonstrated that higher blood Cd levels are associated with increased CHD mortality with HR of 1.60 (95% CI: 1.21–2.10). At the same time, increased urinary Cd concentrations were characterized by a slight positive although not significant association with higher mortality from CHD (HR = 1.27, 95% CI: 0.82–1.96). Adjustment for smoking status did not reveal any advanced outcome when overall studies were considered, even higher HR was demonstrated by two studies assessing Cd exposure alternatively through Cd blood or urine levels (Fig. 4B). In turn, Cd intake was not associated with increased CHD mortality neither in the general cohort (HR = 1.02, 95% CI: 0.88–1.30), nor in never-smokers (HR = 0.80, 95% CI: 0.67–0.94)

Several studies have shown a significant association between Cd exposure and atherosclerosis and related diseases. In particular, an earlier study has demonstrated that persons living in Cd-contaminated region of the Netherlands are characterized by a significantly higher incidence of atherosclerosis in comparison to the total country and region of reference values. In particular, the incidence of atherosclerosis in men aged 40–59 and 60–79 years living in Cd-polluted area was more than 2- and 3-fold higher than in those living in a region of reference (Houtman, 1993). Examination of 4639 Swedish middle-aged women and men in 1991–1994 also revealed a significant direct relationship between blood cadmium and the prevalence of atherosclerotic plaque in the right carotid artery after adjustment for potential confounders, including sex, age, smoking status, blood pressure, lipid spectrum, diabetes, treatment (Fagerberg et al., 2015). Both blood and urinary Cd concentrations were positively associated with the prevalence of carotid plaques and plaque area in a cohort of 64 y.o. Caucasian women. Moreover, the associations remained significant after adjustment for confounders both at baseline and prospectively (Fagerberg et al., 2012). Data analysis from NHANES 1999–2004 (8989 US adults) demonstrated an association between increased blood and urinary Cd levels and the risk of cardiovascular disease (CVD), heart disease, and coronary heart disease (CHD) mortality (Tellez-Plaza et al., 2012). Similarly, urinary Cd concentration was associated with increased CHD mortality in all models studied (Tellez-Plaza et al., 2013a, 2013b, 2013c). Correspondingly, in the Malmö Diet and Cancer Study the hazard ratio for coronary heart disease, acute coronary events (myocardial infarction), as well as CVD mortality in persons with the highest blood Cd levels were significantly increased as compared to the baseline (1st quartile of blood Cd levels) after adjustment for multiple confounders. Moreover, the observed association was even more expressed in never-smokers (Barregard et al., 2016). Correspondingly, elevation of urinary Cd levels was associated with increased hazard ratios for CVD mortality both in men and women (Li et al., 2011). At the same time, Menke et al. (2009) detected sex-specific associations between CVD and Cd exposure. In particular, the hazard ratios for CVD and CHD were significantly higher in men with elevated urinary Cd levels, whereas the

4. Cd and stroke 4.1. Cross-sectional studies The association between Cd exposure and the prevalence of stroke has been studied. It has been demonstrated that a 50% increase in blood 251

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more than 2-fold higher as compared to that in persons without PAD. At the same time, the association between Cd levels and the risk of PAD in women was U-shaped and was significantly affected by smoking status (Tellez-Plaza et al., 2010). Data obtained from NHANES 1999–2000 demonstrate that blood Cd levels are directly related to increased risk of peripheral arterial disease (Navas-Acien et al., 2004). Correspondingly, higher blood and urinary Cd levels in women from Gothenburg were associated with more than 2-fold higher risk of PAD as assessed by ankle-brachial blood pressure index (ABI). Moreover, after exclusion of femoral plaque at baseline, the association between blood Cd and higher ABI values was significantly improved (OR = 3.7, 95% CI: 1.05–13.3) (Fagerberg et al., 2013). The authors have later indicated that patients with peripheral artery disease were characterized by 36% higher urinary Cd levels in comparison to the controls. After adjustment for age, gender, race, education, smoking status and urinary creatinine concentration, the increased urinary Cd levels (75th vs. 25th percentiles) was associated with the higher risk of peripheral artery disease with OR of 3.05 (95% CI: 0.97–9.58) (Navas-Acien et al., 2005). However, another study using similar inclusion criteria demonstrated no significant relationship (p = 0.72) between 24-h urinary Cd excretion (Plusquin et al., 2005). A tight association between urinary Cd levels and the incidence of PAD was also demonstrated in adult American Indians (Tellez-Plaza et al., 2013a, 2013b, 2013c). It is also notable that adjustment for blood Cd and Pb levels significantly reduced the odds ratio for peripheral arterial disease in the highest quintile of homocysteine from 1.92 to 1.37, being indicative of the association between increased homocysteine and Cd and Pb levels (Guallar et al., 2006).

or urinary Cd levels is related to higher stroke OR. However, the association was more tight in the case of blood Cd. (Peters et al., 2010). Correspondingly, a recent study by Hecht et al. (2016) revealed increased prevalence rates for stroke at higher blood and especially urinary Cd levels (Hecht et al., 2016). Notably, adjustment for smoking status (never-smokers) revealed weaker interrelations between blood/ urinary Cd and stroke prevalence in both studies (Peters et al., 2010; Hecht et al., 2016). In contrast, Lee et al. (2011) did not observe a significant increase in stroke OR at higher blood Cd levels in a general cohort of the examinees. 4.2. Prospective studies Prospective studies demonstrated a more significant association between markers of Cd exposure and cerebrovascular events. In particular, a recent Malmö Diet and Cancer Study demonstrated a significantly increased stroke hazard ratio at higher blood Cd levels both in the general cohort and never-smokers (Barregard et al., 2016). In a recent study, the authors have also demonstrated that Cd levels in patients with carotid plaques were 26% higher as compared to the controls (Borne et al., 2017). It is notable that the prospective Strong Heart Study 1989–1991 involving 3348 subjects also demonstrated higher incidence of stroke in examinees with elevated urinary Cd levels. However, after adjustment for smoking status, no such relationship was observed in never-smokers (Tellez-Plaza et al., 2013a, 2013b, 2013c). Li et al. (2011) demonstrated a gender-specific association between Cd exposure and stroke mortality. In particular, women were characterized by a more than 3-fold higher mortality from stroke at higher urinary Cd levels, whereas in men Cd exposure did not seem to have a significant impact on stroke mortality (Li et al., 2011). At the same time, a prospective examination of 476 and 480 subjects living in low- and high-Cd areas, respectively, demonstrated the association between Cd exposure as assessed by blood and urinary metal levels with reduced cerebrovascular mortality irrespectively of the area (Nawrot et al., 2008). In a series of massive (33,333 and 36,863) prospective studies, Julin et al. (2013a, 2013b) assessed the impact of Cd intake on the risk of stroke, including the hemorrhagic and ischemic subtypes. At the same time, no significant association between dietary Cd exposure and the risk of stroke has been detected (Julin et al., 2013a, 2013b)

5.1. Meta-analysis Meta-analysis using highest vs. lowest quintile of Cd levels demonstrated that blood (OR = 1.54, 95% CI: 1.00–2.36) and urinary (OR = 1.97, 95% CI: 0.98–3.94) Cd levels were associated with higher PAD risk (Fig. 7A). The sensitivity analysis using 80th vs. 20th Cd levels shower similar relationship especially for blood Cd levels (Blood: OR = 1.83, 95% CI: 1.33–2.53; Urine: OR = 1.80, 95% CI 0.88–3.69). Notably, no associations between Cd exposure and PAD have been revealed in never-smokers (Fig. 7B).

4.3. Meta-analysis 6. Cd and lipid profile Meta-analysis (Fig. 5) of the three cross-sectional studies demonstrated that high blood Cd levels were positively associated with higher stroke risk (OR = 1.35, 95% CI: 1.17–1.57). In turn, urinary Cd concentrations were characterized by higher although not significant interaction with stroke risk (OR = 1.44, 95% CI: 0.75–2.74). After adjustment for the smoking status and inclusion of only never-smokers into the analysis, the studied relationship was confirmed, even though it was found to be weaker for both blood and urinary Cd levels. In turn, in six prospective studies (Fig. 6) both blood (RR = 1.36, 95% CI: 0.56–3.29) and urinary (RR = 1.27, 95% CI: 0.65–2.47) Cd levels tended to be associated with higher incidence of stroke. No additional information could be obtained after restricting analysis to never smokers. At the same time, no significant relationship between oral Cd exposure and stroke has been detected both in the general sample (RR = 1.00, 95% CI: 0.8801.14) and never-smokers (RR = 0.96, 95% CI: 0.82–1.11).

6.1. Clinical studies Certain clinical studies investigated the interaction between markers of Cd exposure and lipid spectrum. Particularly, examination of 1223 adult occupationally non-exposed men living in Rome, Italy, demonstrated a significant direct relationship between blood Cd levels and TG and non-HDL-C levels (Menditto et al., 1998). Analysis of data from 3903 participants of KNHANES (2005, 2008, 2009) also showed that blood Cd levels were significantly associated with the higher risk of low high-density lipoprotein cholesterol (HDL-C) levels and higher values of TG/HDL-C ratio. At the same time, no significant relationship between blood Cd levels, total cholesterol (TC), LDL-C, and TG was revealed (Kim, 2012). Similarly, examination of inhabitants of Cd-polluted villages and non-exposed controls revealed a significant association between urinary Cd levels and TG/HDL-C ratio. Multiple regression also demonstrated a tight relationship between TG and HDL-C levels and TG/HDL-C ratio (Tangvarasittichai et al., 2015). In a cross-sectional health survey on cadmium exposed workers involving 1489 subjects it has been revealed that increased blood Cd levels are associated with dyslipidemia, high total cholesterol and triglycerides, low HDL-C and high HDL-C (Zhou et al., 2016). Oppositely, Ettinger et al. (2014) demonstrated significantly reduced TG, TG/HDL ratio and HDLC levels at high blood Cd concentrations (Ettinger et al., 2014).

5. Cd and peripheral arterial disease (PAD) Examination of 6456 adults in NHANES 1999–2004 revealed a significant dose-dependent association between blood and urinary Cd concentrations and the risk of peripheral arterial disease (PAD) in men. Males with PAD were characterized by a significant more than 50% elevation of blood Cd levels, whereas urinary Cd concentration was 252

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and PON1P levels was observed (Pollack et al., 2014), generally being in agreement with the earlier in vitro studies (Costa et al., 2005). Therefore, Cd exposure and Cd body burden are associated with increased incidence of atherosclerosis and atherosclerosis-based diseases, being associated with a proatherogenic shift in lipid metabolism, proinflammatory state, and altered expression of adhesion molecules.

6.2. Meta-analysis The results of meta-analysis demonstrate that higher Cd exposure is associated with higher TC levels (OR = 1.48, 95% CI: 1.10–2.01), higher LDL-C levels (OR = 1.31, 95% CI 0.99–1.73) and lower HDL-C levels (OR = 1.96, 95% CI: 1.09–3.55), whereas Cd exposure tended to increase TG levels (OR = 1.29, 95% CI: 0.78–2.15) and TG/HDL-C ratio (OR = 1.57, 95% CI: 0.66–3.75) (Fig. 8).

8. Laboratory data 7. Cd and other laboratory parameters related to atherosclerosis

Several studies have demonstrated that Cd exposure is associated with altered lipid profile in experimental animals. In particular, administration of drinking water containing 5 and 50 mg/l Cd (as CdCl2) resulted in a significant dose-dependent increase in serum free fatty acids (FFA), TC, LDL, oxLDL, and F2-IsoP levels in rats. It is also notable that Zn treatment significantly reduced the observed Cd-induced effects (Rogalska et al., 2009). Correspondingly, a 3-month treatment of rats with 2.0 mg/l CdCl2 in drinking water resulted in a significant increase in serum TG, TC, and LDL-C levels, whereas the concentration of HDL-C was reduced in response to Cd exposure (Samarghandian et al., 2015). Intraperitoneal injection of 1 mg/kb b.w. CdCl2 for 21 days also resulted in a significant 37% increase in total cholesterol, 61% increase in TG, and a more than twofold elevation of LDL-C levels, whereas HDL-C concentration was significantly reduced (− 29%) in comparison to the control values (Mantur et al., 2014). Oral administration of 5 mg/kg b.w./day Cd2+ for four weeks resulted in a significant increase in TC, LDL-C, VLDL-C, FFA, TG, phospholipids, and HMG-CoA-reductase activity, whereas HDL-C concentration and LCAT activity were decreased when compared to the control values (Prabu et al., 2010). It is also interesting that a 7-week exposure of rats to 5 mg/kg b.w. Cd2+ resulted in a significant decrease in HDL2-C levels, whereas HDL3-C was significantly elevated (Skoczyńska, 2000). Serum lipid spectrum was similarly altered in rats intraperitoneally injected with 1.0 mg CdCl2/kg body weight for four weeks (Olisekodiaka et al., 2011). Subcutaneous injection of 3 mg/kg b.w./day for three weeks caused similar changes in rats’ serum and resulted in a significantly increased TC, TG, and FFA levels, as well as HMG-CoA-reductase activity in the liver in parallel with altered serum lipid spectrum (Murugavel and Pari, 2007). Chronic Cd exposure with drinking water resulted in a significant increase in serum cholesterol levels in rabbits (2 mg/kg b.w./day for 30 days) (Hristev et al., 2008). Of note, diabetic animals exposed to Cd via

Certain studies have investigated the relationship between Cd exposure and other laboratory makers of atherogenesis. In particular, it has been demonstrated that the observed atherogenic effect of Cd was not associated with overproduction of ICAM-1 from human endothelial cells (Fagerberg et al., 2013). A later study of the group also revealed that high blood Cd levels were associated with macrophage density (CD68) in bulb and internal carotid artery. At the same time, blood Cd levels were unrelated to lipid spectrum parameters and accumulation of CD14, an indicator of LPS-induced macrophage activation (Fagerberg et al., 2016). Cd exposure modulated specific metabolic pathways related to atherogenesis and further development of cardiovascular diseases. In particular, it has been shown that serum Cd levels significantly inversely correlated with flow-mediated dilatation. The association was also confirmed by linear regression analysis, being indicative of endothelial dysfunction (Kaya et al., 2012). A recent population study in Sweden also demonstrated a significant interrelationship between blood Cd levels and soluble urokinase plasminogen activator receptor, an inflammatory biomarker associated with atherosclerotic process (Fagerberg et al., 2017a, 2017b). It has been also demonstrated that chronic cadmium exposure in adult women resulted in increased platelet activation, associated with elevation of plasma P-selectin and CD40 ligand levels, ADP-induced platelet aggregation and glycoprotein IIb/IIIa expression, and platelet-neutrophil aggregation (Nontarach et al., 2016). Costa et al. (2005) revealed that blood Cd levels were differentially associated with PON activity by PON1 Q192R phenotype. In particular, Cd was associated with decreased PON1 arylesterase and PON1 paraoxonase (PON1P) activity in RR and QR phenotypes. At the same time, in QQ phenotype a positive relationship between blood Cd

Fig. 2. Meta-analysis of the odds ratio (OR) with 95% CI of coronary heart disease (CHD) mortality in cross-sectional studies in relation to markers of Cd exposure in all subjects (A) and in never smokers (B).

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Fig. 3. Meta-analysis of the hazard ratio (HR) with 95% CI of cardiovascular disease (CVD) in prospective studies in relation to markers of Cd exposure in all subjects (A) and in never smokers (B).

Fig. 4. Meta-analysis of the hazard ratio (HR) with 95% CI of coronary heart disease (CHD) in prospective studies in relation to markers of Cd exposure in all subjects (A) and in never smokers (B).

atherogenic activity (Kim et al., 2017). At the same time, another study demonstrated that lifetime low dose Cd exposure does not significantly affect serum cholesterol, triglyceride, and HDL-C levels in Wistar rats exposed to drinking water containing 20 µM CdCl2 (Almásiováá et al., 2012). Similarly, intraperitoneal injection of 8 mg Cd acetate for 12 weeks did not significantly affect serum lipid spectrum but was associated with reduced hepatic TG content (Barański et al., 1983). Correspondingly, prolonged 6-months treatment of rabbits with 8 mg/kg/day of Cd resulted in a significant increase in heart and kidney total lipids, cholesterol, triglyceride, and FFA content, and a significant decrease in these parameters in serum and liver (Subramanyam et al., 1991). Whole life Cd treatment (5 ppm from weaning to death) resulted in a significant increase in lipid deposition in rat aorta in comparison to the control values. At the same time, increased aortic lipid content in

subcutaneous injection were also characterized by significantly increased TC, TG, FFA, and PC levels in comparison to control animals (Senthilkumar et al., 2012). The observed Cd-induced changes in serum lipid spectrum (increased TG, TC, LDL-C, and very low-density lipoprotein cholesterol (VLDL-C)) were associated with decreased lipoprotein lipase activity. Moreover, Cd exposure through drinking water was also associated with increased hepatic TG, reduced cholesterol esters content, and intensified glycerol-3-phosphate acyltransferase mRNA expression. Increased fatty acid synthetase, isocitrate dehydrogenase activity, and [14C]-acetate incorporation were also indicative of hepatic fatty acid synthesis (Larregle et al., 2008). In a recent study Kim et al. (2017) demonstrated that Cd exposure resulted in a significant elevation of plasma TC and TG levels in zebrafish. In addition, Cd exposure induced structural modification and impaired anti-atherogenic functions of HDL3, whereas Cd-HDL3 was characterized by a pro254

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Fig. 5. Meta-analysis of the odds ratio (OR) with 95% CI of stroke in cross-sectional studies in relation to markers of Cd exposure in all subjects (A) and in never smokers (B).

exposure stimulated subendothelial LDL deposition in carotid artery of atherosclerosis-susceptible mice due to increased proteoglycan LDLbinding affinity (Kijani et al., 2017). In parallel with human studies, animal experiments demonstrated a significant role of adhesion molecules expression in Cd-induced atherogenesis. Thus, Cd-treated animals (100 mg/L CdCl2 in drinking water) were characterized by significantly higher plaque area, increased vascular cell adhesion molecule 1 (VCAM-1) and heat shock protein 60 (Hsp60) expression in ApoE-knockout mice (Knoflach et al., 2011). Cdtreated rats were also characterized by aortal intima thickening, increased lipid deposition, and smooth muscle cells proliferation, being associated with increased ICAM-1 expression. The observed changes were also accompanied by elevation of plasma ICAM-1 and reduced NO levels (Zhan et al., 2012). At the same time, another study failed to reveal any significant effect of Cd treatment (15 mg/kg/day Cd2+) on aorta morphology, whereas heart tissues were significantly affected (Ozturk et al., 2009). Maternal Cd exposure resulted in a significant

Cd-exposed animals was also associated with lower serum total cholesterol values (Schroeder and Balassa, 1965). These findings were confirmed by the results of a later study demonstrating that oral exposure to 0.88 and 8.8 mg CdCl2·2.5H2O for three months led to a significant increase in total cholesterol content in rats’ aorta (Janik, 1992). Being in agreement with the previous studies, the results of a detailed study by Messner and the coauthors demonstrated that administration of 100 mg/L of CdCl2 in drinking water to ApoE knockout mice fed a Western-type diet was associated with a significant increase in aortic plaque surface in comparison to the control values due to atherogenic lipid profile (Messner et al., 2009). It is also notable that pH significantly affected cardiovascular Cd toxicity at oral administration. In particular, exposure to 400 mg/L CdCl2 in drinking water at pH 5.0 and 7.0 significantly increased the appearance of fatty streaks in rat aorta to 46% and 50%, respectively. At the same time, no significant increase in the Cd-exposed group at pH = 8.0 and unexposed groups was observed (Nai et al., 2015). It has been also demonstrated that Cd

Fig. 6. Meta-analysis of the risk ratio (RR) with 95% CI of stroke in prospective studies in relation to markers of Cd exposure in all subjects (A) and in never smokers (B).

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higher morphological alterations and lower viability in response to Cd treatment (Kishimoto et al., 1991). A later study by the group revealed lower viability, altered proliferation, and migration of Cd-exposed HUVE cells (Kishimoto et al., 1996). However, low Cd treatment (< 10 µmol/L) in human umbilical vein endothelial cells (HUVECs) inhibited apoptosis but promoted autophagy, being associated with depression of integrin β4, caveolin-1 levels and phosphatidylcholinespecific phospholipase C (PLC) activity (Dong et al., 2009). It is notable that certain studies did not reveal toxic effect of Cd but even observed a stimulatory effect of Cd exposure on cell growth. In particular, it has been demonstrated that treatment of vascular smooth muscle cells with 10–200 nM cadmium did not result in LDH leakage being indicative for the absence of cell damage. Moreover, Cd exposure (10, 50, 100 nM) stimulated proliferation of bovine aortic smooth muscle cells as assessed by thymidine incorporation method (Fujiwara et al., 1998). A later study using ECV-304 endothelial cells demonstrated that reduced angiogenesis, cell migration, and tube formation is associated with altered actin polymerization and reduced NO production (Kolluru et al., 2006). Incubation of human umbilical vein endothelial cells with 15 and 100 µmol/L of cadmium resulted in a significant dose-dependent decrease in cell viability through induction of caspase-independent cell death, increase in vascular endothelial cell permeability, and inhibition of cellular proliferation (Messner et al., 2009). Tang et al. (2017) have demonstrated that p38 and ERK signaling may play a key role in Cd-induced apoptosis in endothelial cells (Tang et al., 2017). Another study also revealed a significant Cd-induced (10 μM) damage to vascular endothelial cells as assessed by elevated lactate dehydrogenase (LDH) levels (Fujiwara et al., 2011). These findings are in agreement with the results of the earlier study by Kaji et al. (1992) who demonstrated that cultivation of bovine endothelial cells with 0.5, 1.0, 2.0 or 5.0 μM CdCl2 for 24 or 72 h resulted in alteration of endothelial monolayer due to decreased number of endothelial cells and impaired cell proliferation in a dose-dependent manner (Kaji et al., 1992). It is notable that the observed Cd toxicity to endothelial cells was significantly enhanced by lead (Kaji et al., 1995). These data are generally in agreement with the observation of the relationship between Cd exposure and aortic aneurisms (Fagerberg et al., 2017a, 2017b). It has been demonstrated that HUVECs differentially respond to carious Cd concentrations (2.5–40 µM). In particular, low dose Cd treatment resulted in a significant increase in tube formation, being accompanied by increase vascular endothelial growth factor (VEGF)

increase in VCAM-1 and HO-1 expression in rat aorta, being associated with altered endothelium-dependent reactivity to acetylcholine and norepinephrine (Ronco et al., 2011). Proatherogenic effect of Cd was also shown to be at least partially related to altered arachidonic acid metabolite production. In particular, reduced vascular endothelium thromboresistance in Cd-exposed rabbits was supposed to be associated with inhibition of prostacyclin production (Grabowska-Maślanka et al., 1998). Intravenous injection of 0.25, 0.5, and 1 mg/kg/day Cd2+ for four days resulted in a dose-dependent increase in thromboxane B2 production, whereas the effect of Cd exposure on prostacyclin release varied from the dose (Caprino et al., 1982). Exposure to 50 and 100 ppm of Cd with drinking water for seven weeks resulted in a significant increase in total cholesterol, triglycerides, IL-2, IL-6, and TNFα levels, as well as reduced PON activity in a dose-dependent manner in rats. At the same time, both doses caused a significant twofold increase in oxLDL levels (Afolabi et al., 2012). In contrast to the clinical studies, prolonged ingestion of drinking water containing 15 ppm Cd2+ resulted in a significant increase in serum PON1 activity at 15, 30, and 60 days of treatment (Ferramola et al., 2011). It is worth mentioning that Cd exposure in cholesterol-fed rabbits prevented a diet-induced increase in serum and hepatic cholesterol levels, as well as reduced aortic plaque formation. Taking into account the observed decrease in serum ferritin accompanied by elevated transferrin levels the authors have proposed that the protective effect of Cd in the present animal model may be associated with reduced levels of free iron (Meijer et al., 1996). However, the observed interaction and its effect on lipid metabolism in normal conditions is questionable. Experimental studies using cell cultures reviewed in this section demonstrated the potential mechanisms of the influence of Cd exposure on atherosclerosis pathophysiology. However, certain mechanisms highlighted here are related not only to atherosclerosis but also to hypertension due to a tight relationship between these states (Zaheer et al., 2016). The earlier studies demonstrate that vascular endothelium is considered to be a target for Cd toxicity and Cd-induced endothelial dysfunction may be at least partially mediated via modulation of adhesion molecules expression (Prozialeck et al., 2006). In particular, human umbilical vein vascular endothelial cells are more sensitive to Cd toxicity in comparison to human fibroblasts, being characterized by

Fig. 7. Meta-analysis of the odds ratio (OR) with 95% CI of peripheral artery disease in relation to markers of Cd exposure in all subjects (A) and in never-smokers (B).

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interesting that Cd exposure decreased tissue plasminogen activator (PA) and PAI-1 release from smooth muscle cells but significantly increased PA production in fibroblasts without a significant effect on PAI1 production (Yamamoto et al., 1996). At the same time, in HUVECs Cd exposure significantly increased the release of PAI-1 but did not affect PA secretion (Yamamoto et al., 1995). In addition, Cd exposure with drinking water (15 ppm Cd for 2 months) significantly modified lipid metabolism in resident peritoneal macrophages. Briefly, Cd treatment resulted in increased stearic and arachidonic acid content, decreased palmitoleic and linoleic acid levels, and altered phospholipid spectrum (Ramirez and Gimenez, 2002). Direct modulation of lipid metabolism is also confirmed by the observation that Cd exposure (> 10−4 M Cd2+) significantly decreased lecithin-cholesterol acyltransferase reaction (Nakagawa et al., 1977). The existing data demonstrate that Cd exposure significantly affects vascular cell glycosaminoglycans (GAG). In particular, incubation of bovine aortic endothelial cells and HUVECs with increasing concentrations of Cd for 24 h resulted in a significantly increased GAG synthesis and heparin-like activity on the cell surface. The authors propose that the observed changes may be considered as a compensatory response to Cd-induced procoagulant state (Kaji et al., 1994). Later studies of the authors demonstrated that Cd treatment induces heparan sulfate proteoglycan synthesis in vascular endothelial cells (Ohkawara et al., 1997). Moreover, it has been proposed that Cd exposure may significantly affect proteoglycan composition in atherosclerotic plaques via induction of biglycan and decorin synthesis, being accompanied by inhibition of synthesis of other proteoglycans (Fujiwara et al., 2002). Moreover, 0.1 µM Cd exposure resulted in a significant reduction of GlcAβ1-3GalNAc formation in vascular smooth muscle cell layer. At the same time, in a cell culture Cd treatment significantly inhibited GlcAβ13GalNAc(4S) and GlcAβ1-3GalNAc(6S), but increased IdoAβ1-3GalNAc (4S) production (Fujiwara et al., 2003). It is also important to note that the dose-response effect of Cd toxicity may be nonlinear, as demonstrated by Renieri et al. (2017). This observation may explain certain differences and contradictions in the observed effects of Cd exposure on atherosclerosis. Taken together, the existing data demonstrate that cadmium-induced atherosclerosis may be mediated through multiple mechanisms acting simultaneously (Fig. 9). Hypothetically, enhanced hepatic lipid synthesis in parallel with atherogenic shifts in lipid profile results in dyslipidemia. In terms of Cd-induced oxidative stress, susceptibility of LDL to oxidation seems to be increased leading to formation of oxLDL. These alterations of lipid metabolism associated with Cd exposure ultimately lead to increased tissue lipid deposition. Endothelial dysfunction associated with proinflammatory and pro-oxidant effects of Cd results in increased expression of adhesion molecules and prostanoid dysbalance. Taken together with the overproduction of

Fig. 8. Meta-analysis of the odds ratio (OR) with 95% CI of altered lipid risk factors in relation to markers of Cd exposure.

section and the underlying up-regulation of MAPK, ERK, and JNK pathways. Oppositely, high-dose Cd exposure was associated with inhibition of tube formation in HUVECs and reduction of VEGF section, VEGF-R2 and MAPK activity (Kim et al., 2012). Treatment with 10, 50, and 100 µM Cd significantly reduced PMAinduced human dermal microvascular endothelial cell migration. At the same time, organization of microvascular ECs into tubes was inhibited already at lower concentrations of Cd (0.5–100 µM). Similarly, preincubation with the increasing doses of Cd (0.1 µM and higher) significantly decreased HUVEC tube formation, being associated with Cdinduced alteration of VE-cadherin localization (Woods et al., 2008). Similarly, exposure of CF-1 mice to 16.25, 32.5, 65 or 130 nM CdCl2 by intratracheal instillation resulted in a significant decrease in the level of VE-cadherin in vascular endothelial cells of the lung (Pearson et al., 2003). A study using bEnd.3 cells demonstrated that treatment with 3 and 10 µM CdCl2 resulted in a significant increase in VCAM-1 expression, being at least partially mediated via p38 and JNK pathways, as assessed by the use of specific inhibitors (Park et al., 2009). The results of a detailed study by Bernhard et al. (2006) demonstrated that in smokers Cd is associated with impaired arterial endothelial cells gene transcription. In particular, Cd upregulated expression of metal and oxidative defense genes and downregulated certain transcription factors as well as intermediate filament protein vimentin required for cellular shape maintenance (Bernhard et al., 2006). It has been also demonstrated that transforming TGF-β1 has a protective effect against Cd toxicity in endothelial cells (Kaji et al., 1994). Another study demonstrated that the majority of Cd-associated effects on endothelial dysfunction was shown to be related to impaired M1 cholinoreceptormediated response (Bilgen et al., 2003). Cd treatment (0.5, 1, 2 µM CdCl2) induced plasminogen activator inhibitor type 1 (PAI-1) synthesis through activation of protein kinase C in vascular endothelial cells, but not smooth muscle cells or fibroblasts (Yamamoto and Kaji, 2002), being in agreement with the earlier study of the authors (Yamamoto et al., 1993; Yamamoto, 2000). It is

Fig. 9. The potential mechanisms of proatherogenic effect of cadmium.

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proinflammatory signals, the latter results in increased migration of the leukocytes into the arterial wall. Generally, Cd-induced increase in lipid deposition, infiltration and altered GAGs synthesis play a significant role in atherosclerosis. It is also notable that certain mechanisms reviewed here may be also involved in the development of Cd-induced hypertension.

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