Cardiovascular diseases, including cardiac arrhythmias, atherosclerosis and heart failure (HF), are diseases of the circulatory system and are a leading cause of morbidity and mortality worldwide (1). According to the World Health Organization, cardiovascular disease accounts for 31% of the deaths worldwide (2). Despite the numerous therapeutic interventional methods, cardiovascular diseases account for approximately one-third of all deaths worldwide (3). Cardiovascular diseases aggravate healthcare costs and are a significant economic burden (4). Currently, the present understanding of the mechanisms and risk factors underlying the pathogenesis of cardiovascular diseases is limited, although there is increasing interest in the role of trace elements in cardiovascular diseases (5). Therefore, it is crucial to elucidate the composition of trace elements in cardiovascular diseases relative to physiological levels and provide valuable insights into treatment strategies for cardiovascular diseases.

Copper is primarily obtained from the consumption of vegetables, shellfish, meat, seeds and nuts (6), and plays a crucial role as a trace element in maintaining physiological functioning (7). There are two ionic forms of copper found in the body, Cu⁺ (cuprous ion, reduced form) and Cu²⁺ (copper ion, oxidized form) (8), both of which are involved in regulating enzymatic cellular functions (9). Generally, Cu²⁺ is converted to Cu⁺ by reductase enzymes such as duodenal cytochrome b (DCYTB) and six-layer epithelial antigen (Fig. 1) (10). Once taken up by copper transporter 1 (CTR1), Cu²⁺ is transported to different organelles in the cytoplasm and is metabolized by a copper chaperone for cytochrome c oxidase [CCO; COX (cytochrome c oxidase assembly homolog (COX)] 17 (11) and antioxidant-1 (ATOX1) (12).

Copper acts as a catalyst for numerous physiological processes, including energy metabolism, mitochondrial respiration and antioxidant activity (13). Copper is present in the body in its ionic form (14). When the homeostatic balance of copper ion levels is disrupted, such as through excess copper ions, this imbalance can trigger cellular toxicity and induce cell death via various pathways (15). Dysregulation of copper ions can disturb lipid metabolism, resulting in oxidative stress, mitochondrial damage and endothelial cell dysfunction (14), and induce atherosclerosis and other cardiovascular diseases such as arrhythmia and cardiomyopathy (15). While there is a considerable body of literature describing the initial causes of copper dysregulation, there is a dearth of comprehensive exploration into the underlying pathological consequences (16). The primary treatment for dysregulated copper ion levels in cardiovascular diseases involves copper chelating agents; however, alternative methods such as copper ion carriers may also be used but are constrained by technical limitations that necessitate further research and improvement (17).

The present review aims to elucidate the mechanisms by which copper ions are involved in cardiovascular diseases, summarize the impact of copper ion abnormalities on cardiovascular diseases and potential therapeutic approaches, and investigate whether modulating copper ion levels can ameliorate cardiovascular diseases. This review offers innovative perspectives for managing cardiovascular diseases via the regulation of copper levels and paves the way for novel research directions. The inclusion criteria for the present study included: i) Research hypotheses and methods were similar to the research content of the present article to ensure the accuracy of the narrative; ii) the exact date that the research was conducted or published; iii) clear regulations on sample size; iv) clear criteria for patient selection, case diagnosis and staging; v) clear measures for intervention and control; vi) can provide OR (odds ratio) [relative risk (RR), rate difference and hazard ratio (HR)] and its 95% confidence interval, or can be converted into OR (RR, rate difference and HR) and its 95% confidence interval; and vii) if it is measurement data, the mean, standard deviation and sample size should be provided. The literature exclusion criteria were as follows: i) Duplicate reports; ii) research design flaws or poor quality; iii) incomplete data or unclear outcome effects; iv) the statistical method was incorrect and could not be corrected; v) OR was not provided or could not be converted into OR (RR, rate difference, HR) and its 95% confidence interval; vi) the measurement data could not provide mean and standard deviation; and vii) inaccurate animal experiments.

Copper, a trace element essential for life, plays a crucial role in various physiological functions such as respiration, connective tissue formation, wound repair, nutrient energy metabolism and catecholamine synthesis (18). Additionally, copper serves as an important regulator of numerous enzymes involved in physiological processes including neuromodulation and angiogenesis. Dyla et al (19) demonstrated the key role of P-type Wilson ATPase in preventing copper deficiency or toxicity by facilitating the transfer of copper from the liver to the secretory pathway. Maintaining copper homeostasis relies on copper transport proteins; dysregulation and subsequent copper toxicity can occur if this process is disrupted (20). Recent studies have revealed that copper toxicity significantly impacts normal cardiac function (21) and contributes to pathologies including myocardial ischemia/reperfusion (I/R) injury (22), HF (23), atherosclerosis (24) and arrhythmias (25).

The physiological processes of copper metabolism are multifaceted but can be broadly categorized into three main stages: Absorption, transportation and excretion (Fig. 1). The most effective form of copper absorption occurs within the intestinal epithelial cells, where dietary copper is digested and absorbed as Cu²⁺ mediated by divalent metal transport protein 1 (26). While dietary copper typically exists in the form of Cu²⁺, only Cu⁺ can be absorbed and utilized by the body (27). Therefore, in various cell types, Cu²⁺ often requires reduction to Cu⁺ through the action of reductases such as DCYTB, and uptake via a high-affinity mechanism involving CTR1 (28). COX17 facilitates the transport of copper ions to specific proteins such as cytochrome C oxidase (SCO) 1, SCO2 and COX11 to activate enzyme activity within the respiratory chain (29). Chaperone protein copper chaperone for superoxide dismutase (CCS) facilitates the transport of copper ions to superoxide dismutase 1 (SOD1) (28), and ATOX1 plays a crucial role in transporting copper ions to the nucleus for binding with transcription factors to regulate gene expression while also transferring them from the trans-Golgi network (TGN) to ATPase α-peptide (ATP7A) and ATPase β-peptide (ATP7B) (30). ATP7A facilitates the efflux of Cu⁺ from the intestinal epithelium into the circulation whereas ATP7B stores excess Cu⁺ in intracellular vesicles to maintain normal homeostasis (31). Copper bound with ceruloplasmin (CP) or albumin can be transported within specific organelles or secreted from cells and transferred to the liver via the bloodstream (32). In hepatocytes, ATP7B plays a crucial role in facilitating the p62-mediated release of copper from intracellular stores into the cytoplasm, thereby enabling the excretion of surplus copper through its incorporation into bile (33).

Despite high levels of research into the understanding of the role of copper physiologically and pathophysiologically, there remain uncertainties regarding the accurate measurement of copper levels and the long-term effects of copper exposure on cardiovascular health (118). The World Health Organization has recommended a daily intake of 0.9 mg/day for adults weighing 70 kg and has specified a safe upper limit (119). The U.S. Environmental Protection Agency (EPA) has not formally established an oral reference dose for copper or a maximum acceptable dose for inclusion in its Integrated Risk Information System database (120). Toscano et al (121) demonstrated that Wistar rats exposed to copper for 30 days showed a significant increase in blood pressure and myocardial contractility. Another study emphasized the potential adverse effects of copper exposure on myocardial contractility at recommended daily doses, tolerable maximum intake doses, and twice the tolerable maximum intake level, but the validity of these doses requires verification through extensive experimentation (122). Serum copper concentration is influenced not only by food and environmental intake, but also by absorption, excretion and storage, due to human variability. Therefore, it is challenging to estimate the individual benefits or losses from serum copper concentration or determine an optimal level, and researching these issues remains a challenge (123).

Currently, treatments based on copper metabolism in cardiovascular disease can encompass a wide range of options, including copper chelating agents [such as triethylenetetramine (TETA), tetrathiomolybdate (TTM) and disodium ethylene diamine tetraacetic acid (EDTA)], small-molecule inhibitors of copper chaperone proteins (such as DCAL50), copper ion carriers and natural antidote agents (Table II).

Copper chelators are compounds that bind to copper ions to remove toxic copper from cells and prevent its accumulation (124). However, excessive chelation of copper by these compounds can lead to cellular copper deficiency and cell death (9) (Fig. 5). TETA is a chelator that specifically binds to Cu²⁺ ions and has been widely used for the treatment of Wilson's disease (125). It may improve myocardial function in diabetic patients by restoring mitochondrial CCO, CCS and SOD1 activity (67). Additionally, it inhibits the elevation of serum copper levels and effectively mitigates the increase in CP activity following myocardial ischemia (126). TTM is a small hydrophilic compound with high specificity as a copper chelator. It is commonly used to treat Wilson's disease and exhibits a favourable safety profile in this regard (127). Wilson's disease is typically characterized by excessive accumulation of copper in the liver (25). TTM chelates bioavailable copper by forming a TTM-Cu-protein triple complex (128). A study has found that TTM specifically forms a TTM-Cu-ATX1 complex with the intracellular chaperone ATX1 to inhibit copper transport to the TGN and its downstream incorporation into copper proteins (127). Another study revealed that TTM inhibits atherosclerosis in ApoE-deficient mice by reducing bioavailable copper and vascular inflammation (129). In addition to TETA and TTM, EDTA also acts as a metal chelator for various metals including copper (130). A clinical trial demonstrated that EDTA disodium-based infusion reduced recurrent cardiovascular events in type 1 and type 2 diabetic patients with a prior myocardial infarction (131). Trientine diHClide is another common copper chelator used for treating Wilson's disease (132), which can selectively bind Cu²⁺ ions to improve mitochondrial function in patients with hypertrophic cardiomyopathy (73), as well as restore mitochondrial function and normalize myocardial expression and enzymatic activity of proteins involved in energy metabolism among diabetic patients (133).

The disadvantages of the use of metal chelators need to be considered. They have been shown to redistribute heavy metals from other tissues to the brain, increasing brain neurotoxicity and leading to the loss of essential metals, such as zinc, or even hepatotoxicity due to serious side effects due to hepatotoxicity (134). Therefore, when using metal chelators for diseases characterized by excess Cu intake, one must consider carefully their potential risk of neurotoxicity or loss of essential metals.

In addition to broad-spectrum metal ion chelators, drugs that specifically regulate the concentration and distribution of intracellular copper ions have greater potential. DCAL50, an inhibitor of copper chaperones, blocks intracellular copper ion transport and can bind to the copper chaperone proteins ATOX1 and CCS, thereby specifically inhibiting the proliferation of cancer cells without affecting normal cellular function (135). This mechanism may be attributed to the interference with copper ion transport leading to increased ROS levels, mitochondrial dysfunction and reduced ATP production, ultimately inhibiting Cu/Zn SOD1 activity (136). Inhibitors of copper chaperones address the concern of other copper chelators in that they non-selectively bind other metal cations and produce toxic side effects (11). Further research into these inhibitors may offer valuable insights for drug development for the management of cardiovascular diseases.

At present, the methodology for addressing copper deficiency involves the use of copper ion carriers, which are small molecules that form complexes with copper and facilitate its transport across the cell membrane and into the mitochondria (137). The entry of copper ion carriers into the cell leads to copper accumulation, which in-turn, triggers oxidative stress and induces cell death (Fig. 6) (138). Common copper ion carriers include elesclomol and disulfiram. Elesclomol is widely recognized to induce copper overdose and cell death (139), by acting as a copper ion carrier with a hydrophilic pore in its centre, to which Cu²⁺ ions can bind easily, facilitating copper entry into cells, thus increasing the intracellular copper concentration (140), and this, in-turn increases ROS levels, triggering oxidative stress (141) and ultimately cell death. Disulfiram is another known copper ion carrier that helps transport copper into cells; it has shown value in the treatment of alcoholism (138). Both these copper ion carriers have shown value in cancer treatment, but their ability to treat cardiovascular disease requires further study (11). It is important to note that copper ion carriers do not have a well-defined understanding of its specificity for copper ions and exhibit a range of functions, several of which remain incompletely understood (137). Additionally, they are not easy to manipulate during transport and inappropriate copper transport may lead to tissue-specific issues (25), thus, further study is required to improve the function of these carriers. There are natural antidotes, derived from herbs and their derivatives, that target multiple proteins and exhibit fewer side effects and toxicity, while showing higher stability than synthetic chelating agents. For example, turmeric, by itself and its derivatives are highly effective in the treatment of cardiovascular diseases (142). Please refer to Table II for details (143–152).

The effects of Cu/Zn and Fe on cardiovascular diseases are summarized in Table III. Numerous factors can affect cardiovascular disease, including zinc and iron ions. Zinc ions play a critical role in several metabolic reactions and, when combined with copper, form part of the functional group of key enzymes, such as Cu-Zn SOD and endothelial NOS, which functions to prevent atherosclerosis (153). Copper ions have been found to accelerate the oxidation of LDL in vitro, leading to the formation of oxidized LDL and other pro-atherosclerotic by-products; meanwhile, zinc may affect copper bioavailability and metabolism (154) as well as cellular oxidation of LDL (155). Therefore, the ratio of copper to zinc in the diet may be an important determinant of coronary risk (156). Salehifar et al (157) demonstrated in a study that age was negatively correlated with zinc levels and positively correlated with copper levels in healthy volunteers. Patients with idiopathic dilated cardiomyopathy had lower levels of zinc compared with healthy volunteers, and there was a significant difference in the Zn/Cu ratios according to the New York Hospital Authority classification, suggesting that the balance between zinc and copper plays a key role in the development of idiopathic dilated cardiomyopathy (158). Patients with advanced HF, whether in atrial fibrillation or sinus rhythm, exhibit profound hypozincaemia and reduced Zn/Cu ratios due to activation of the adrenergic-angiotensin-aldosterone system and HF drugs (159). In recent years, there has been increasing research on copper and zinc nanoparticles as well as different metals and nanoparticle forms such as metal oxides, all having potential effects on the cardiovascular system (160). Iron death, characterized by oxidative stress due to intracellular Fe²⁺ accumulation, leading to large amounts of ROS production, ultimately results in cell death (161) and contributes to various cardiovascular diseases including atherosclerosis, I/R injury, HF, myocardial infarction and adriamycin cardiomyopathy (162). The underlying mechanism may be related to GSH metabolism (163), abnormal iron metabolism (164), lipid peroxidation (165) and mitochondrial dysfunction (166). Please refer to Table III for details (167–175).

Copper ion levels in cells must be maintained in a state of relative equilibrium, as both excessive and deficient amounts can significantly impact health (176). The present review provides an overview of the fundamental role of copper and its metabolic pathways in physiology. It discusses the mechanisms underlying cardiovascular diseases resulting from copper excess and deficiency, particularly focusing on the pathogenic mechanisms related to oxidative stress and mitochondrial metabolism disorders. Furthermore, it explores potential therapeutic approaches for managing copper-related cardiovascular diseases, such as using copper chelating agents and ion carriers, while also highlighting the limitations of these methods. The balance between normal cellular oxidation and antioxidants must be maintained, as excess copper levels can induce oxidative stress, leading to cell death and cardiovascular disease (14). Therefore, special attention should be paid to this during treatment. For instance, Jomova et al (177) demonstrated that an excess of copper ions led to the aggregation of fatty proteins and abnormal expression of Fe-S cluster proteins, resulting in protein toxic stress and cell death. In addition to oxidative stress and mitochondrial metabolic disorders causing cell death, abnormal copper levels can induce cell death through ROS, ER and inflammatory responses (178). An association has been established between oxidative stress and inflammation, which inevitably plays a crucial role in the pathogenesis of cardiovascular diseases such as atherosclerosis, stroke and HF (41). The presence of copper ions in cells serves a dual function; clinical studies have yielded conflicting results regarding the relationship between copper ion levels and the development of cardiovascular disease (76). Thus, further in-depth research is necessary for future validation. It is worth delving into its pathogenic mechanism and the regulatory mechanisms both physiologically and pathophysiologically (179). While copper chelating agents and carriers may treat diseases effectively, their disadvantages are evident. For example, chelating agents may induce toxicity by binding with other metal ions while off-target effects make copper regulation using copper ion carriers difficult, thus additional studies on how to regulate copper levels are required (180). Furthermore, different organs have distinct copper ion requirements, further complicating the issue of tight copper regulation (181). Investigating the optimal concentration of copper ions in different organs can offer valuable guidance for the optimal treatment of copper ions. Future development of ion regulators should focus on organ/cell specificity and targeting. Recently, Liu et al (182) developed a multifunctional nanocomposite material capable of precisely delivering drugs for treating atherosclerosis. While this method addresses the issue of copper deficiency, further research is required to determine if it can also address excessive copper ion levels. Although various studies on copper-induced cell death have shown promising results, there still remain several challenges, such as how the aggregation of fatty acylated proteins triggers cell death, optimizing the performance of copper regulators and reducing their side effects, determining the mode of death induced by copper overload and deficiency, gaining a comprehensive understanding of the roles of copper in the mitochondria, and whether copper ion carriers can selectively deliver drugs to hypertrophic myocardial tissues through drug delivery systems (183). Further investigation into these questions will improve the understanding of the relationship between copper-induced cell death and heart disease, leading to the development of innovative therapeutic strategies for heart disease.