Circulating copper levels and the risk of cardio-cerebrovascular diseases and cardiovascular and all-cause mortality: A systematic review and meta-analysis of longitudinal studies

Copper is an essential trace element in the human body; its relationship with cardio-cerebrovascular diseases (CCVDs) remains unclear. This study aimed to comprehensively investigate the association between circulating copper concentrations and CCVD risk and mortality. We searched the PubMed, Cochrane Library, Embase, Scopus, and Web of Knowledge databases for cohort studies reporting associations between circulating copper concentrations and cardiovascular diseases and mortality published up to August 23, 2023. Effect sizes were pooled using random-effects models. We graded the certainty of the evidence by the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. Our analysis included 47,813 patients across 17 cohort studies. Elevated circulating copper levels were linked to the risk of stroke (OR = 1.52; 95% CI 1.30–1.78), coronary artery disease mortality (RR = 2.77; 95% CI 1.82–4.19), cardiovascular mortality (RR = 1.79; 95% CI 1.52–2.11), and all-cause mortality (RR = 1.56; 95% CI 1.35–1.79) but not the risk of acute myocardial infarction (RR = 2.01; 95% CI 0.63–6.47). Continuous analysis (per 20 μg/dl increase) showed consistent results regarding the association between copper levels and stroke incidence (OR = 1.23; 95% CI 1.14–1.33), cardiovascular mortality (HR = 1.28; 95% CI 1.07–1.53) and all-cause mortality (HR = 1.22; 95% CI 1.04–1.44). Except for the low certainty of evidence of acute myocardial infarction incidence, all outcomes had moderate certainty of evidence. Excessive circulating copper levels are associated with stroke, coronary artery disease mortality, cardiovascular mortality, and all-cause mortality with moderate certainty.