Low-level cadmium exposure and cardiovascular outcomes in elderly Australian women: A cohort study

https://doi.org/10.1016/j.ijheh.2017.12.007Get rights and content

Highlights

  • Urinary cadmium associated with increased risk of heart failure in elderly women.

  • Reduced odds of carotid focal plaque in those with higher urinary cadmium.

  • Increased heart failure mortality associated with cadmium exposure in never smokers.

Abstract

Background

Cadmium has been associated with increased risk of cardiovascular disease (CVD) in observational studies, however there has been a limited focus on this relationship in women.

Objectives

This study investigated the association of urinary cadmium (UCd) concentrations with CVD outcomes and all-cause mortality in elderly Western Australian (WA) women.

Methods

UCd excretion was measured at baseline in 1359 women, mean age 75.2 ± 2.7 years and 14.5 years of atherosclerotic vascular disease (ASVD) hospitalisations and deaths, including both the principle cause of death and all associated causes of death. Health outcome data were retrieved from the Western Australian Data Linkage System. Cox regression analysis was used to estimate hazard ratios of ASVD and all-cause mortality. UCd was ln-transformed and models were adjusted for demographic and CVD risk factors.

Results

Median (IQR) concentration of UCd was 0.18 (0.09–0.32) μg/L. In multivariable-adjusted analyses per ln unit (equivalent to ∼2.7 fold) increase in UCd, there was a 36% increase in the risk of death from heart failure and 17% increase in the risk of a heart failure event, respectively (HR = 1.36, 95% CI 1.11–1.67; HR = 1.17, 95% CI 1.01–1.35). When analyses were restricted to never smokers the relationship between UCd and death from heart failure remained (HR 1.29, 95% CI 1.01–1.63).

Conclusions

This study suggests that even at low levels of exposure cadmium may be associated with heart failure hospitalisations and deaths in older women, however given the dilute nature of these urine samples, the results must be interpreted with caution.

Introduction

Cadmium is a widespread heavy metal released in industrial and agricultural processes and has been associated with many serious chronic diseases (Nawrot et al., 2010). Environmental exposure to cadmium is mainly due to exposure to tobacco smoke and diet, with diet being the main source of cadmium in non-smokers (Nawrot et al., 2010). Low environmental exposure to cadmium has been found to increase the risk of adverse health outcomes including decreased bone mineral density (Gallagher et al., 2008), impaired kidney function (Olsson et al., 2002) and various cancers (Åkesson et al., 2012; McElroy et al., 2006). An Australian study by Hinwood et al. (2013), examined exposure in 173 pregnant women and reported that one third had urinary cadmium concentrations ≥1 μg/g creatinine, which indicated an increased risk of health effects in this population. In older Australian women lower concentrations of urinary cadmium were reported, however, an association between urinary cadmium and decreased bone mineral density was still present at this low level of exposure (Callan et al., 2015).

A limited number of longitudinal studies of cadmium exposure, all-cause mortality and cardiovascular disease have been conducted, with most studied cohorts residing in the United States (Menke et al., 2009, Tellez-Plaza et al., 2013a; Tellez-Plaza et al., 2013b; Tellez-Plaza et al., 2012) or Japan (Nakagawa et al., 2006; Suwazono et al., 2014).

A recent meta-analysis calculated overall HRs for all-cause mortality (6 studies) and CVD mortality (5 studies) associated with increased urinary cadmium to be 1.44 (95% CI 1.25, 1.64) and 1.57 (95% CI 1.27, 1.95), respectively (Larsson and Wolk, 2015). When the analysis was restricted to the four studies that had undertaken subgroup analysis by sex, the HR for all-cause mortality for women in the highest vs lowest category of urinary cadmium concentration was 1.50 (95% CI 1.08, 2.08) (Larsson and Wolk, 2015). A US study using the NHANES cohort concluded that cadmium exposure was associated with an increased risk of all-cause and cardiovascular disease mortality among men, but not women (Menke et al., 2009). An analysis of the 1999–2004 NHANES cohort found no differences in the association between cadmium exposure all-cause and CVD mortality by sex (Tellez-Plaza et al., 2012). A more recent systematic review of populations with low to moderate levels of cadmium exposure, however, found similar associations between cadmium exposure and cardiovascular disease between men and women, but the relationship was not significant for women (Tellez-Plaza et al., 2013c). Conversely, a longitudinal study conducted in a cadmium contaminated area of Japan suggested that high levels of exposure to cadmium led to excess risk of mortality among women but not in men (Uetani et al., 2007). Whilst sex specific risk was suggested in these studies the results were inconsistent and the differential associations by sex may represent chance findings. Barregard et al. (2016) investigated the relationship between blood cadmium and incident cardiovascular disease (CVD) in men and women in Sweden and found increased hazard ratios for all CVD events for participants in the highest exposure quartile.

Mechanistically, cadmium exposure has been shown to elicit endothelial damage both in vitro and in murine models, with accelerated plaque formation observed (Knoflach et al., 2011; Messner et al., 2009). Cadmium exposure was found to be associated with the development of atherosclerotic plaques in 64 year old Swedish women after a 5 year follow up (Fagerberg et al., 2012), thus providing evidence of the pro-atherogenic potential effects of cadmium exposure.

Longitudinal studies of cadmium exposure and mortality are scarce, particularly in those with low levels of exposure. Given that women are known to have higher levels of cadmium exposure (Vahter et al., 2007) the contradictory results regarding the association between cadmium exposure and all-cause and CVD mortality in women, suggests that more studies focussed on women are warranted, especially older women. Furthermore, there have been limited studies on the relationship between cadmium exposure and non-fatal cardiovascular events.

CVD remains the number one cause of mortality in Australia and globally (Australian Bureau of Statistics, 2014; World Health Organization, 2013). Therefore, it is important to identify factors that increase the risk of developing CVD. The objective of this study was to examine the association between cadmium exposure and the incidence of mortality, cardiovascular mortality and (non-fatal) cardiovascular events in 14.5 year follow up of 1359 elderly Western Australian women. Coronary heart disease (CHD), stroke or cerebrovascular accident (CVA), heart failure (HF) and peripheral arterial disease (PAD), collectively known as atherosclerotic vascular disease (ASVD), were examined, as well as all-cause mortality.

Section snippets

Study population

Participants of this study (n = 1500) were women randomly recruited in the Perth metropolitan region from the Australian electoral roll in 1998. They were initially randomised into a 5-year, double-blinded, placebo-controlled calcium intervention trial of 1.2 g of elemental calcium in the form of two tablets of calcium carbonate taken daily, or an identical placebo (Prince et al., 2006). Participants were aged ≥70 years, ambulant and expected survival of at least 5-years. Participants were then

Results

Urinary cadmium concentrations were low in this cohort with a mean concentration of 0.38 μg/L and median of 0.18 μg/L (Table 1). Cadmium concentrations were below the limit of detection in 13.8% of participants. Only 18 participants had urinary cadmium concentrations ≥2 μg/L. Urine samples were second morning void samples collected when the participants were well hydrated and were dilute, with 73% of samples having a urinary creatinine concentrations of <0.3 g/L. Urinary specific gravity was

Discussion

In this cohort of elderly Australian women, urinary cadmium concentrations were associated with increased risk of heart failure hospitalisations and mortality, independent of age, smoking history and diabetes. The robustness of this association was confirmed in a sensitivity analysis excluding women with prevalent ASVD. However, attempts to adjust for urinary dilution weakened the associations between urinary cadmium and cardiovascular outcomes in this cohort.

The concentrations of urinary

Conclusions

In this cohort of elderly women with low cadmium exposure, increased urinary cadmium was associated with increased heart failure mortality and non-fatal heart failure events over a 14.5 year follow up period, although adjustment for urinary specific gravity or creatinine attenuated these relationships, therefore the results must be interpreted with caution. The relationship with heart failure mortality was observed in never smokers, although residual confounding by second hand smoke exposure

Sources of support

The Longitudinal Study of Ageing Women (LSAW) study formerly known as the CAIFOS/CARES study was supported by Healthway (the Health Promotion Foundation of Western Australia) and by project grants 254627, 303169 and 572604 from the National Health and Medical Research Council of Australia. The salary of Dr Lewis is supported by a National Health and Medical Research Council of Australia Career Development Fellowship (1107474). None of these funding agencies had any role in the conduct of this

Acknowledgements

The authors wish to thank the staff at the Data Linkage Branch, Hospital Morbidity Data Collection and Registry of Births, Deaths and Marriages for their work on providing the data for this study and Mark Bannister (School of Science, Edith Cowan University) for his assistance with urinary metals analysis.

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