Copper Dysregulation and Cardiovascular Disease: A Review of Underlying Mechanisms and Therapeutic Targets

Cardiovascular diseases account for one-third of global deaths, yet their underlying mechanisms remain incompletely understood. Copper is essential to cardiovascular physiology, influencing mitochondrial respiration, antioxidant defense, and connective tissue integrity. Emerging evidence identifies that copper dysregulation plays a role in the development of chronic cardiac conditions, including atherosclerosis, cardiomyopathy, and heart failure. This review evaluates clinical and preclinical studies on copper dysregulation in cardiovascular disease. Literature was sourced from PubMed and the Cochrane Database of Systematic Reviews, focusing on mechanistic insights, population-level associations, and therapeutic strategies. Several studies implicate copper deficiency in mitochondrial dysfunction via disrupted chaperone networks (eg, SCO1, CTR1), reduced cytochrome c oxidase activity, and maladaptive cardiac remodeling. In contrast, copper overload increases oxidative stress, lipid peroxidation, and vascular dysfunction. Additionally, cuproptosis, a newly recognized form of copper-induced cell death, contributes to myocardial injury. Epidemiological data show U-shaped associations between serum copper levels and cardiovascular mortality, with both extremes linked to elevated risk. Genetic and observational studies suggest copper may serve as both a biomarker and modifiable risk factor. Therapeutic strategies-including copper chelation, supplementation, and modulation of copper transport proteins-have shown promise in preclinical models. While preclinical and observational data underscore the role of copper in cardiovascular health, translational research and interventional trials are critically needed. Targeted modulation of copper pathways may offer a novel therapeutic strategy for cardiovascular disease in copper-imbalanced states.