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Introduction to Modulating Plasma Metal Ion Concentrations for Cardiovascular Disease Prevention

Cardiovascular diseases (CVDs) are complex conditions influenced by numerous factors, including lifestyle, environmental exposures, and metabolic disturbances. Recent research has highlighted the critical role of plasma metal ion concentrations in both the pathogenesis and potential treatment of CVDs. This report explores therapeutic interventions aimed at modulating plasma metal ion concentrations, discussing proposed strategies such as supplementation, and examining clinical evidence supporting their feasibility and efficacy.

Metal Ions in Cardiovascular Health and Disease

Metal ions like magnesium, copper, and zinc play vital roles in maintaining cardiovascular health. They participate in redox reactions, regulate ion channels, and modulate the expression of inflammatory mediators. However, both deficiencies and excesses of these ions can lead to pathological states.

• Magnesium and zinc are essential for maintaining ion channel function and modulating oxidative stress, which is crucial for cardiac health. Abnormal plasma levels of these ions have been associated with increased risk of major adverse cardiovascular events (MACE) and circulatory diseases[5].

• Copper is involved in key enzymes such as superoxide dismutase (SOD), which helps protect against oxidative damage. However, copper can also induce oxidative stress by promoting the oxidation of low-density lipoprotein (LDL), contributing to atherosclerosis[9].

• Iron is indispensable for oxygen transport and enzyme activity but can be cardiotoxic when present in excess, leading to oxidative stress and tissue damage[6].

Proposed Interventions: Supplementation and Therapy

Several therapeutic strategies have been proposed to modulate plasma metal ion concentrations for CVD prevention:

1. Supplementation of Beneficial Metal Ions:

   • Magnesium and zinc supplementation have been shown to offer protective benefits against oxidative stress and may reduce cardiovascular risk by improving ion channel function and endothelial health[5][7].

   • Copper, when balanced with zinc, may help in reducing oxidative stress, though its role is more nuanced due to its potential to promote atherosclerosis at higher levels[9].

2. Chelation Therapy:

   • Chelation involves using agents like EDTA to bind and remove potentially toxic metal ions such as lead, cadmium, and arsenic, which are associated with increased cardiovascular risk[4]. Clinical trials, such as the TACT study, have shown benefits in reducing cardiovascular events, particularly in diabetic patients[4].

3. Regulation of Iron Levels:

   • Managing iron levels through chelation or supplementation can be beneficial for patients with heart failure or those at risk of iron overload, which can lead to oxidative stress and cardiac damage[6].

Clinical Evidence and Feasibility

• Magnesium and Zinc Supplementation: Research indicates that supplementation with these ions can improve cardiovascular outcomes by reducing oxidative stress and improving ion channel function. However, more clinical trials are needed to establish optimal dosing and long-term safety[5][7].

• Chelation Therapy: Evidence from trials like TACT suggests that chelation can reduce cardiovascular events, particularly in high-risk populations such as diabetic patients. Despite promising results, there are risks associated with hypocalcemia, and further studies are required to optimize therapy protocols[4].

• Iron Management: Intravenous iron therapy is advocated for heart failure patients with iron deficiency, and iron chelation has shown benefits in reducing oxidative stress in coronary artery disease[6].

Future Directions

While current evidence supports the potential of modulating plasma metal ion concentrations for CVD prevention, future research should focus on:

• Standardizing Dosages and Protocols: More studies are needed to optimize supplementation strategies and chelation therapies to ensure safety and efficacy.

• Understanding Metal Ion Interactions: The complex interactions between different metal ions and their impact on cardiovascular health need further elucidation.

• Developing Targeted Therapies: Encouraging research in biomaterials and drug delivery systems could enable more precise modulation of metal ion levels in the cardiovascular system[2].

By pursuing these avenues, healthcare professionals may develop more effective and targeted interventions to prevent or treat CVDs through plasma metal ion modulation.

Conclusion

Therapeutic interventions aimed at modulating plasma metal ion concentrations hold promise as both preventive and therapeutic strategies against cardiovascular diseases. Supplementation with beneficial ions like magnesium and zinc, along with chelation therapy for removing harmful metals, offers potential benefits. However, ongoing research is crucial to fully realize the therapeutic potential of these approaches and to ensure their safe and effective implementation in clinical practice.

参考文献：

[1] https://pubmed.ncbi.nlm.nih.gov/34638839/

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC10761210/

[3] https://www.ahajournals.org/doi/10.1161/JAHA.123.029852

[4] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.323617

[5] https://research-portal.st-andrews.ac.uk/en/publications/abnormal-plasmaserum-magnesium-copper-and-zinc-concentrations-ass

[6] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.321667

[7] https://www.ahajournals.org/doi/10.1161/circulationaha.105.537894

[8] https://www.mdpi.com/1422-0067/22/19/10500

[9] https://www.spandidos-publications.com/10.3892/mmr.2024.13334

[10] https://pmc.ncbi.nlm.nih.gov/articles/PMC10926297/

Generated Article 📖

Okay, so the user is asking whether therapeutic interventions targeting plasma metal ions could be effective against cardiovascular diseases. They want to know what types of interventions, like supplementation, have been proposed and if there's clinical evidence for their feasibility and efficacy.

First, I need to go through the search results provided and identify relevant information. Let me start by skimming each source.

From the first result (1), it talks about how CVD patients' plasma facilitates NO release from GSNO, especially with ascorbic acid. That's interesting because NO is important for vascular function. But how does this tie into metal ions? Maybe metals like copper or zinc are involved in S-nitrosothiol metabolism?

Looking at result (2), it discusses exogenous metal ions as therapeutic agents. It mentions Mg2+ and La3+ promoting angiogenesis when co-delivered. Also talks about Ca2+ and Zn2+ influencing ion channels. So supplementation with specific metals could support vascular and cardiac function. But there's a mention of needing more research, especially on La3+ in CVD.

Result (3) is from the AHA and talks about heavy metals as contaminants (lead, cadmium, arsenic) causing CVD. It emphasizes reducing exposure but doesn't directly answer the therapeutic angle. But it does mention chelation therapy in result (4), which is TACT study using EDTA chelation reducing cardiovascular events. That's a key intervention.

Result (4) elaborates on TACT, showing 18% reduction in events with EDTA chelation, especially in diabetics. Also mentions deferoxamine improving vasodilation and outcomes post-surgery. So chelation therapy is a proven intervention here.

Result (5) is a study linking magnesium, copper, zinc levels to MACE. High copper and low zinc are risk factors. Managing these levels through supplementation or reduction could be beneficial, but the study focuses on observational data, not interventions.

Result (6) covers iron metabolism. Iron is crucial but excess is toxic. Chelation with deferoxamine and EDTA has shown benefits in cardiac function, especially in heart failure and post-MI. TACT-II is ongoing focusing on diabetics. So iron chelation is another intervention.

Result (7) talks about zinc supplementation increasing metallothionein in diabetic cardiomyopathy, reducing oxidative stress. Animal studies and some human data suggest this could prevent heart issues.

Result (8) seems similar to (1), reinforcing the role of plasma in preventing S-nitrosothiol degradation, possibly involving metals like copper where CU-ZN SOD plays a role.

Result (9) discusses copper's role in atherosclerosis, with Cu/Zn ratios impacting disease. Zinc supplementation might help by balancing copper. Also mentions iron's role in oxidative stress, leading to ROS and cell death.

Result (10) reviews metal ions (Fe, Cu, Ca, Zn) in cardiac fibrosis. Copper delivery reduces fibrosis and improves cardiac function. So targeted copper delivery is a proposed intervention.

Putting this together, the interventions fall into two main categories: chelation for toxic metals and supplementation for beneficial ones. The evidence for chelation (EDTA, deferoxamine) is strongest from TACT trials. Supplementation with zinc, magnesium, or copper has some preclinical and limited clinical support, especially in specific cases like diabetes or

Therapeutic Interventions Targeting Plasma Metal Ions in Cardiovascular Disease

Mechanistic Rationale

Metal ions (e.g., Mg²⁺, Zn²⁺, Cu²⁺, Fe²⁺) play pivotal roles in cardiovascular homeostasis, including ion channel regulation, antioxidant defense, and angiogenesis. Dysregulation of these metals, either through deficiency (e.g., low Mg²⁺, Zn²⁺) or excess (e.g., heavy metals like Pb²⁺, Cd²⁺), contributes to oxidative stress, endothelial dysfunction, and inflammation – key drivers of CVD[2][3][9]. Conversely, targeted modulation of metal ion profiles may mitigate these pathways and restore cardiovascular function.

Proposed Interventions and Clinical Evidence

1. Chelation Therapy for Heavy Metal Detoxification

Heavy metals like lead, cadmium, and arsenic disrupt metalloenzyme function and ion homeostasis, accelerating atherosclerosis and cardiomyopathy[3][4]. Chelation therapy binds these metals, enabling their excretion.

Limitations: EDTA risks hypocalcemia; DFO has off-target effects (e.g., visual/hearing deficits)[4][6].

2. Supplementation of Beneficial Metals

Deficiencies in Mg²⁺, Zn²², or Cu²² are linked to increased CVD risk, while supplementation may restore protective pathways.

Uncertainties: Optimal dosing remains unclear, and Zn²²/Cu²² ratios require precise balance to avoid pro-oxidant effects[9][10].

3. Co-Delivery Systems for Synergistic Effects

Combining metals (e.g., Mg²⁺ + La³⁺) enhances therapeutic efficacy by leveraging complementary mechanisms.

Clinical and Translational Challenges

1. Safety and Toxicity:

   • Chelators like EDTA risk hypocalcemia[4].

   • Zn²²/Cu²² imbalances can paradoxically increase oxidative stress[9].

2. Target Population:

   • Evidence strongest for diabetic or post-MI patients[4][6].

3. Measurement Limitations:

   • Plasma metal levels may not reflect tissue bioavailability, complicating biomarker-driven interventions[5][10].

Future Directions

1. Biomaterial-Based Delivery:

   Develop systems to control metal ion release (e.g., copper-loaded hydrogels for targeted cardiac delivery)[2][10].

2. Precision Medicine:

   Identify subgroups (e.g., diabetic patients with elevated plasma metals) most responsive to interventions[4][5].

3. Combination Therapies:

   Pair chelation with antioxidant supplementation to mitigate oxidative damage[2][7].

Conclusion

Modulating plasma metal ions represents a promising strategy for CVD prevention and treatment. Chelation therapy (e.g., EDTA, DFO) has robust clinical evidence, particularly in high-risk cohorts, while metal supplementation (Zn²², Cu²²) shows preclinical potential but awaits validation. Co-delivery systems and advanced biomaterials may enhance efficacy and safety. Prioritizing clinical trials in defined patient subpopulations and optimizing dosing protocols are critical next steps.

Citations integrated as per guidelines.
[References]
[1][2][3][4][5][6][7][8][9][10]

参考文献：

[1] https://pubmed.ncbi.nlm.nih.gov/34638839/

[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC10761210/

[3] https://www.ahajournals.org/doi/10.1161/JAHA.123.029852

[4] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.123.323617

[5] https://research-portal.st-andrews.ac.uk/en/publications/abnormal-plasmaserum-magnesium-copper-and-zinc-concentrations-ass

[6] https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.122.321667

[7] https://www.ahajournals.org/doi/10.1161/circulationaha.105.537894

[8] https://www.mdpi.com/1422-0067/22/19/10500

[9] https://www.spandidos-publications.com/10.3892/mmr.2024.13334

[10] https://pmc.ncbi.nlm.nih.gov/articles/PMC10926297/