Circulating Serum Copper Is Associated with Atherosclerotic Cardiovascular Disease, but Not Venous Thromboembolism: A Prospective Cohort Study

Abstract

<b><i>Background and Objective:</i></b> Serum copper has been linked to the risk of atherosclerotic cardiovascular disease (CVD). However, the potential association between serum copper and venous thromboembolism (VTE) is not known. The principal aim was to evaluate the potential prospective association between serum copper and VTE risk. A secondary aim was to confirm or refute previously reported associations between serum copper and atherosclerotic CVD. <b><i>Methods:</i></b> Serum copper was measured at baseline using atomic absorption spectrometry in 2,492 men aged 42–61 years without a history of VTE in the Kuopio Ischemic Heart Disease prospective cohort study. Cox regression models were used to calculate hazard ratios (HRs) with 95% confidence interval (CI) for VTE. <b><i>Results:</i></b> During a median follow-up of 27.0 years, 166 VTE events occurred. The risk of VTE per 1 standard deviation increase in serum copper in age-adjusted analysis was HR: 1.02; 95% CI: 0.88–1.20, which was attenuated to HR: 0.99; 95% CI: 0.82–1.19, following further adjustment for several established and emerging risk factors. Comparing the top versus bottom tertiles of serum copper, the corresponding adjusted HRs were 1.16 (95% CI: 0.80–1.66) and 1.11 (95% CI: 0.74–1.68), respectively. In 1,901 men without a history of coronary heart disease (CHD), the multivariable-adjusted HR for CHD was 1.32 (95% CI: 1.10–1.59) comparing extreme tertiles of serum copper. <b><i>Conclusion:</i></b> In middle-aged Finnish men, we confirmed previously reported associations between high serum copper levels and increased risk of atherosclerotic CVD, but serum copper was not associated with future VTE risk. Other large-scale prospective studies conducted in women, other age-groups, and other populations are needed to confirm or refute these findings.

Plasma Metallomics Reveals Potential Biomarkers and Insights into the Ambivalent Associations of Elements with Acute Myocardial Infarction

“…50,51 However, there has also been contradicting reports on elevated circulating Cu found in CHD patients in large-scale studies from the USA and Finland, as well as in a smaller study in Iran. [53][54][55][56] The results from our study agree with these reports (Table 3).…”

“…Interestingly, when comparing between these studies as well as present work, it seemed that the elevated Cu was consistently seen in both prospective and cross-sectional studies. [53][54][55][56] This indicates that Cu concentrations were elevated in CHD patients when measured both before and after atherosclerotic events. This allows us to conclude that elevated circulating Cu is likely a causal/risk factor.…”

No evidence of a prospective relationship between serum zinc and venous thromboembolism in Caucasian men: a cohort study

“…The adjustment for confounders were based on four models: (Model 1) age; (Model 2) Model 1 plus systolic blood pressure (SBP), body mass index (BMI), total cholesterol, triglycerides, smoking status, history of type 2 diabetes (T2D), history of coronary heart disease (CHD), medication for dyslipidaemia, alcohol consumption, physical activity, and socioeconomic status (SES); (Model 3) Model 2 plus high sensitivity C-reactive protein (hsCRP) and history of cancer; and (Model 4) a model comprising dietary factors including serum magnesium, total energy intake, intake of processed and unprocessed red meat, and intake of fruits, berries and vegetables. The confounders selected were based on their previously established roles as risk factors for VTE, evidence from previous research, previously published associations with VTE in the KIHD study (Kunutsor et al 2021 , 2019a ; Kunutsor and Laukkanen 2021 ), or their potential as confounders based on known associations with VTE outcomes and observed associations with serum zinc using the available data (Groenwold et al 2011 ). Given the long-follow-up of the cohort, we explored the potential for regression dilution bias by conducting sensitivity analysis that was restricted to the first 10 years of follow-up.…”

Single and Combined Associations of Plasma and Urine Essential Trace Elements (Zn, Cu, Se, and Mn) with Cardiovascular Risk Factors in a Mediterranean Population

“…The ability of Mn to enhance oxidative stress is due to the transition of its oxidative state +2 to +3, which increases its pro-oxidant capacity [ 65 ]. However, the current emphasis is on the chronic effect of moderately high concentrations of these elements, given the growing evidence of an increased risk of cardiometabolic diseases such as diabetes, hypertension, dyslipidemias, and some cardiovascular outcomes [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 ]. Despite the large number of studies [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ] that show a direct relationship between Se, Cu, Zn, or Mn and cardiovascular risk factors, there are other studies that show no associations or even an inverse relationship [ 51 , 78 , 79 , 80 , 81 , 82 , 83 , 84 ].…”