Abstract
Hypertension is a leading contributor to cardiovascular morbidity and mortality. Trace elements such as cadmium (Cd), copper (Cu), iron (Fe), magnesium (Mg), selenium (Se), and zinc (Zn) modulate blood pressure through oxidative stress, endothelial dysfunction, and metabolic regulation. Although previous studies have largely focused on individual elements, the combined effects of trace elements remain poorly understood. This systematic review summarizes observational evidence regarding associations between blood trace element concentrations and hypertension, and evaluate potential interactive effects among multiple trace elements. We systematically searched PubMed, Wiley, Google Scholar, and Web of Science for studies published between 1970 and 2025 reporting blood trace element concentrations in hypertensive and normotensive adults. Sixteen studies met the inclusion criteria. Pooled mean differences (MD) and standardized mean differences (SMD) were calculated using random-effects models. Heterogeneity, publication bias, and potential interactions among trace elements were assessed. A value p < 0.05 was considered statistically significant. Cd and Cu concentrations were higher in hypertensive individuals (Cd: MD = 4.67, 95% CI: 0.25-9.10; SMD = 2.48, 95% CI: 0.18-5.25; I(2) = 99.4%; Cu: MD = 19.18, 95% CI: 4.48-33.87; SMD = 0.86, 95% CI: 0.26-1.46; I(2) = 99.6%), although heterogeneity was extremely high. No consistent associations were observed for Zn, Fe, Mg, or Se. Very few studies assessed interactions between multiple trace elements. Evidence suggested no significant difference in the Zn/Cu ratio between hypertensive and normotensive groups.. Elevated blood concentrations of Cd and Cu are statistically associated with adult hypertension; however, these association should be considered hypothesis-generating, as evidence for other trace elements remains inconclusive. The limited research on co-exposures highlights the need for future studies employing multivariate and interaction models to better understand the role of trace element interactions in hypertension.