Review Article 评论文章

Originally Published 25 April 2024 最初发布于 2024 年 4 月 25 日

Heavy Metal Exposure and Cardiovascular Disease
重金属暴露与心血管疾病

Ziwei Pan, Tingyu Gong 11918392@zju.edu.cn, and Ping Liang https://orcid.org/0000-0001-6806-3735 pingliang@zju.edu.cnAuthor Info & Affiliations
潘紫薇、龚婷玉11918392@zju.edu.cn 、梁平https://orcid.org/0000-0001-6806-3735 pingliang@zju.edu.cn 作者信息及单位

Circulation Research 流通研究

Volume 134, Number 9
第134卷第9号

https://doi.org/10.1161/CIRCRESAHA.123.323617IF: 16.5 Q1 B1
https://doi.org/10.1161/CIRCRESAHA.123.323617如果：16.5 Q1 B1

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Abstract 抽象的

Heavy metals are harmful environmental pollutants that have attracted widespread attention due to their health hazards to human cardiovascular disease. Heavy metals, including lead, cadmium, mercury, arsenic, and chromium, are found in various sources such as air, water, soil, food, and industrial products. Recent research strongly suggests a connection between cardiovascular disease and exposure to toxic heavy metals. Epidemiological, basic, and clinical studies have revealed that heavy metals can promote the production of reactive oxygen species, which can then exacerbate reactive oxygen species generation and induce inflammation, resulting in endothelial dysfunction, lipid metabolism distribution, disruption of ion homeostasis, and epigenetic changes. Over time, heavy metal exposure eventually results in an increased risk of hypertension, arrhythmia, and atherosclerosis. Strengthening public health prevention and the application of chelation or antioxidants, such as vitamins and beta-carotene, along with minerals, such as selenium and zinc, can diminish the burden of cardiovascular disease attributable to metal exposure.
重金属是有害的环境污染物，因其对人类心血管疾病的健康危害而受到广泛关注。重金属，包括铅、镉、汞、砷和铬，存在于空气、水、土壤、食品和工业产品等多种来源中。最近的研究强烈表明心血管疾病与接触有毒重金属之间存在联系。流行病学、基础和临床研究表明，重金属可以促进活性氧的产生，从而加剧活性氧的产生并诱发炎症，导致内皮功能障碍、脂质代谢分布、离子稳态破坏和表观遗传变化。随着时间的推移，重金属暴露最终会导致高血压、心律失常和动脉粥样硬化的风险增加。加强公共卫生预防和应用螯合剂或抗氧化剂，如维生素和β-胡萝卜素，以及矿物质，如硒和锌，可以减轻因金属接触而导致的心血管疾病的负担。

Cardiovascular disease (CVD) is the leading cause of global death. It is estimated that ≈523 million people suffer from CVD and 18.6 million people die from CVD-related causes per year worldwide.¹ Over the past few decades, through epidemiological, basic, and clinical studies, scientists have recognized that increasing age, genetics, tobacco, high blood cholesterol, high blood pressure, physical inactivity, obesity, diabetes, stress, excessive alcohol use, and diet/nutrition promote the development of CVD.² Despite advancements in prevention techniques and therapies, there is still a substantial unknown risk and traditional risk factors fail to account for all potential risks.
心血管疾病（CVD）是全球死亡的主要原因。据估计，全球每年约有 5.23 亿人患有 CVD，1860 万人死于与 CVD 相关的原因。 ¹过去几十年来，通过流行病学、基础和临床研究，科学家们认识到年龄增长、遗传、烟草、高胆固醇、高血压、缺乏运动、肥胖、糖尿病、压力、过量饮酒和饮食/营养促进CVD的发展。 ²尽管预防技术和治疗方法取得了进步，但仍然存在大量未知风险，传统风险因素无法解释所有潜在风险。

Heavy metal pollution has been a known issue for centuries. Heavy metals include toxic metals, such as arsenic (As), cadmium (Cd), lead (Pb), and mercury (Hg), and some of the essential trace metals, such as chromium (Cr), cobalt (Co), copper (Cu), magnesium (Mg), manganese (Mn), molybdenum (Mo), nickel (Ni), selenium (Se), tungsten (W), vanadium (V), iron (Fe), and zinc (Zn). Exposure is common due to increased industrialization and anthropogenic activities. These sources of contamination can originate from industrial emissions, agricultural activities, fossil fuel combustion, waste disposal, and many other sources. Factors such as social and personal activities, like tobacco use, and exposure to metals in commonly used commercial products, including paint, gasoline, electronics, water pipes, and certain foods, significantly contribute to overall risk. These aspects should be carefully considered when assessing potential health hazards.^3,4
几个世纪以来，重金属污染一直是一个众所周知的问题。重金属包括砷 (As)、镉 (Cd)、铅 (Pb) 和汞 (Hg) 等有毒金属，以及一些必需的微量金属，例如铬 (Cr)、钴 (Co)、铜(Cu)、镁(Mg)、锰(Mn)、钼(Mo)、镍(Ni)、硒(Se)、钨(W)、钒(V)、铁(Fe)和锌(Zn)。由于工业化和人类活动的增加，暴露现象很常见。这些污染源可能来自工业排放、农业活动、化石燃料燃烧、废物处理和许多其他来源。社会和个人活动（如吸烟）以及接触常用商业产品（包括油漆、汽油、电子产品、水管和某些食品）中的金属等因素，都会显着增加总体风险。在评估潜在的健康危害时，应仔细考虑这些方面。 ^{3 , 4}

Exposure to environmental factors, such as heavy metals, is a crucial and modifiable element in CVD risk named environmental cardiology.⁵ Evidence of the role of environmental exposure to heavy metals in CVD risk has rapidly increased over the past 2 decades.⁶ Several heavy metals, such as arsenic, mercury, cadmium, and lead, are notable for their widespread contamination, long-lasting effects on the body, and renal and cardiovascular toxicity.^6,7 Exposure to environmental toxicants, such as lead, cadmium, arsenic, and mercury, is known to have lasting side effects on the cardiovascular system, such as hypertension, arrhythmia, and atherosclerosis^8–11 (Figure 1). In addition, while some essential trace metals are essential and beneficial for human health, studies have also reported significant associations between imbalances in essential metals and CVD risk.¹² For example, high serum copper or low serum magnesium with low serum zinc is particularly associated with increased cardiovascular mortality,¹³ and the accumulation of intracellular copper can induce oxidative stress and result in cuproptosis, which disturbs cellular homeostasis.¹⁴ In addition, ferroptosis, an iron-dependent form of regulated cell death caused by accumulation of intracellular iron, also mediates the pathogenesis and progression of numerous cardiovascular diseases, including atherosclerosis, drug-induced heart failure, myocardial ischemia-reperfusion injury, sepsis-induced cardiomyopathy, arrhythmia, and diabetic cardiomyopathy.^15,16
接触重金属等环境因素是 CVD 风险的一个关键且可改变的因素，称为环境心脏病学。 ⁵过去 20 年来，有关重金属环境暴露对 CVD 风险的影响的证据迅速增加。 ⁶砷、汞、镉和铅等多种重金属因其广泛的污染、对身体的长期影响以及肾脏和心血管毒性而引人注目。 ^{6 , 7}众所周知，接触铅、镉、砷和汞等环境毒物会对心血管系统产生持久的副作用，例如高血压、心律失常和动脉粥样硬化^8-11 （图 1 ）。此外，虽然一些必需微量金属对人类健康至关重要且有益，但研究也报告了必需金属失衡与心血管疾病风险之间的显着关联。 ¹²例如，高血清铜或低血清镁和低血清锌尤其与心血管死亡率增加相关， ¹³细胞内铜的积累可诱导氧化应激并导致铜凋亡，从而扰乱细胞稳态。 ¹⁴此外，铁死亡是一种由细胞内铁积累引起的铁依赖性调节性细胞死亡形式，也介导许多心血管疾病的发病机制和进展，包括动脉粥样硬化、药物诱发的心力衰竭、心肌缺血再灌注损伤、败血症-诱发心肌病、心律失常和糖尿病性心肌病。^{15 , 16}

Figure 1. **Distribution of heavy metals and their effects on the human cardiovascular system.** The diagram depicts the distribution of arsenic (As), cadmium (Cd), lead (Pb), mercury (Hg), and chromium (Cr) in the environment (rivers, oceans, air, and soil) and the exposure source (food, drinking water, and industrial products). When exposure to heavy metals, they enter the body through inhalation, ingestion and dermal contact, eventually lead to cardiovascular abnormalities such as arrhythmia, hypertension and atherosclerosis.
图 1 .重金属的分布及其对人体心血管系统的影响。该图描绘了环境（河流、海洋、空气和土壤）中砷 (As)、镉 (Cd)、铅 (Pb)、汞 (Hg) 和铬 (Cr) 的分布以及暴露源（食物）、饮用水和工业产品）。当接触重金属时，它们通过吸入、食入和皮肤接触进入体内，最终导致心律失常、高血压和动脉粥样硬化等心血管异常。

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Here, we will discuss the toxic metals but also give considerable attention to chromium which, as an essential metal, exhibits different characteristics. We will illustrate the mechanisms underlying the association between heavy metal toxicity and CVD, highlight the importance of preventing heavy metal pollution and promoting effective treatment after heavy metal exposure.
在这里，我们将讨论有毒金属，但也会对铬给予相当大的关注，铬作为一种重要金属，表现出不同的特性。我们将阐明重金属毒性与CVD之间的关联机制，强调预防重金属污染和促进重金属暴露后有效治疗的重要性。

CLASSIFICATION OF HEAVY METALS AND CARDIOVASCULAR HAZARDS
重金属和心血管危害的分类

Here, we sequentially introduce the distribution, cardiovascular effect, and possible toxicity mechanism of toxic metals of As, Cd, Pb, Hg, and Cr.
在此，我们依次介绍有毒金属As、Cd、Pb、Hg、Cr的分布、心血管效应以及可能的毒性机制。

Arsenic (As) 砷（As）

Arsenic is a naturally occurring substance derived from minerals and is highly toxic to human health.¹⁷ Both in the environment and within the human body, this toxic element can be found in both organic and inorganic forms. Arsenic exposure is typically modeled as the sum of inorganic (pentavalent and tetravalent) and methylated (monomethylarsenic acid and dimethylarsenic acid) arsenic species in urine.¹⁸ The inorganic and most toxic forms of arsenic (arsenate and arsenite) are found in soils, crops, and water.¹⁹ These usually occur as byproducts of human-industrialized agriculture or other industries. Arsenic trioxide, for example, may be found in pesticides and is also used in wood preservatives whereas gallium arsenide and arsine gas are widely present in the electronics industry, particularly related to the production of semiconductor devices. Overall, the consumption of contaminated water and daily diet are the main reasons for human exposure to arsenic.^20–22 Foods with high inorganic arsenic levels include rice, cereals, other grains, vegetables, fruit, tobacco smoke, beers, and wines.^18,19 Seafoods may also contain high levels of largely nontoxic organic arsenicals, such as arsenobetaine and arsenocholine.^19,23
砷是一种从矿物质中提取的天然物质，对人体健康具有剧毒。 ¹⁷在环境和人体内，这种有毒元素都以有机和无机形式存在。砷暴露通常被建模为尿液中无机砷（五价和四价）和甲基化砷（一甲基砷酸和二甲基砷酸）的总和。 ¹⁸砷的无机形式和毒性最强的形式（砷酸盐和亚砷酸盐）存在于土壤、农作物和水中。 ¹⁹这些通常是人类工业化农业或其他工业的副产品。例如，三氧化二砷可能存在于杀虫剂中，也用于木材防腐剂，而砷化镓和砷化氢气体广泛存在于电子工业中，特别是与半导体器件的生产相关。总体而言，饮用受污染的水和日常饮食是人类接触砷的主要原因。 ^20–22无机砷含量高的食物包括大米、谷物、其他谷物、蔬菜、水果、烟草烟雾、啤酒和葡萄酒。 ^{18 , 19}海鲜还可能含有高含量的无毒有机砷，例如砷甜菜碱和砷胆碱。 ^{19 , 23}

Arsenic has been prospectively associated with changes in blood pressure levels^24–27 and carotid atherosclerosis,^24,28,29 and these epidemiological findings are consistent with data from animal models.^30,31
砷已被前瞻性地与血压水平的变化^24-27和颈动脉粥样硬化^{24 , 28 , 29}相关，并且这些流行病学发现与动物模型的数据一致。 ^{30 , 31}

The underlying reason for arsenic-induced CVD is mainly due to the oxidative damage induced by reactive oxygen species (ROS) such as superoxide anion radicals, singlet oxygen, peroxyl radicals, or hydrogen peroxide. Arsenic is reduced to a trivalent state during metabolism. Trivalent arsenic can then limit the synthesis of glutathione by binding with sulfhydryl groups and disrupting sulfhydryl-containing enzymes, hence inducing oxidative stress.³² Such stress can then affect gene expression, inflammatory responses, and nitric oxide (NO) homeostasis.³³ The impaired production of endothelial NO homeostasis also induces vascular endothelial dysfunction, which is reflected by an imbalance between vascular relaxation and contraction.
砷诱发CVD的根本原因主要是超氧阴离子自由基、单线态氧、过氧自由基或过氧化氢等活性氧(ROS)引起的氧化损伤。砷在新陈代谢过程中被还原为三价状态。然后，三价砷可以通过与巯基结合并破坏含巯基的酶来限制谷胱甘肽的合成，从而诱导氧化应激。 ³²这种压力会影响基因表达、炎症反应和一氧化氮 (NO) 稳态。 ³³内皮 NO 稳态产生受损也会诱发血管内皮功能障碍，这表现为血管舒张和收缩之间的不平衡。

Additionally, in pentavalent arsenic, the substitution of the less stable pentavalent arsenic anion for the stable phosphorus anion in phosphate can occur. This causes high-energy bonds in molecules like ATP to hydrolyze quickly and lose their high-energy phosphate bonds, thereby uncoupling mitochondrial respiration.³⁴
另外，在五价砷中，可能会发生稳定性较差的五价砷阴离子取代磷酸盐中稳定的磷阴离子的情况。这会导致 ATP 等分子中的高能键快速水解并失去高能磷酸键，从而使线粒体呼吸解偶联。 ³⁴

There are further potential mechanisms for arsenic-induced CVD. For example, poor ventricular contraction and relaxation, impaired heart structure and development, and thrombotic activation are all caused by the arsenic-induced dysregulated proteins via lipid peroxidation.³⁵ In addition, arsenic is also linked to epigenetic changes. During the Strong Heart Study, the methylation of blood-derived DNA from 2321 participants (mean age, 56.2; 58.6% women) was measured, and a total of 20 and 13 differentially methylated positions were identified as potential mediators for CVD incidence and mortality, respectively. These findings provide part of the biological link between arsenic and CVD.³⁶
砷诱发的 CVD 还有进一步的潜在机制。例如，心室收缩和舒张不良、心脏结构和发育受损以及血栓激活都是由砷通过脂质过氧化诱导的失调蛋白引起的。 ³⁵此外，砷还与表观遗传变化有关。在“强心脏研究”期间，测量了 2321 名参与者（平均年龄 56.2 岁；58.6% 女性）的血液 DNA 甲基化，总共有 20 个和 13 个差异甲基化位置被确定为 CVD 发病率和死亡率的潜在介质。分别。这些发现提供了砷与CVD之间的部分生物学联系。 ³⁶

Lead (Pb) 铅（Pb）

Human activity results in the production of lead, a heavy metal that is not necessary for life. Volcanic activity and geochemical weathering are the greatest natural sources. Anthropogenic sources of lead, such as lead-based paints, gasoline additives, food-can soldering, batteries, water pipes, and munitions, are commonly found. Humans are mainly exposed to lead through tobacco products, drinking water, food, electronics, and fuel.^37–40
人类活动会产生铅，这是一种生命所不需要的重金属。火山活动和地球化学风化是最大的自然资源。铅的人为来源很常见，例如含铅油漆、汽油添加剂、食品罐头焊接、电池、水管和弹药。人类主要通过烟草制品、饮用水、食品、电子产品和燃料接触铅。 ^37–40

Exposure to lead increases the risk of developing CVDs, including hypertension, atherosclerosis, and cardiac and vascular complications.³ The health effects of lead result from its ability to form strong bonds with proteins and its interference with zinc- and calcium (both divalent cations)-dependent functions, particularly antioxidant functions by inhibiting glutathione synthesis and reducing superoxide dismutase activity.^7,41,42 Excessive production of free radicals leads to oxidative stress, increased lipid peroxidation, and disruption of NO levels. These effects eventually cause endothelial dysfunction, which induces atherosclerosis.^43–46
接触铅会增加患心血管疾病的风险，包括高血压、动脉粥样硬化以及心脏和血管并发症。 ³铅对健康的影响源于它能够与蛋白质形成牢固的键，并干扰锌和钙（均为二价阳离子）依赖性功能，特别是通过抑制谷胱甘肽合成和降低超氧化物歧化酶活性来干扰抗氧化功能。 ^{7 , 41 , 42}自由基的过量产生会导致氧化应激、脂质过氧化增加和一氧化氮水平破坏。这些影响最终导致内皮功能障碍，从而诱发动脉粥样硬化。 ^43–46

In addition, lead competes with calcium for binding to a calcium-dependent protein, named calmodulin, which is involved in cell contraction and critical for cardiovascular processes, thus triggering inflammation and cell death. By replacing calcium, lead inhibits the effect of calmodulin on the synthesis of NO, possibly resulting in hypertension.⁴⁷ In rats, lead exposure activates NF-κB (nuclear factor κB) signaling pathway, leading to systemic inflammation, which is characterized by the excessive production of ROS and has been associated with CVD.^48,49
此外，铅与钙竞争与钙依赖性蛋白质（称为钙调蛋白）的结合，该蛋白质参与细胞收缩并对心血管过程至关重要，从而引发炎症和细胞死亡。通过替代钙，铅会抑制钙调蛋白对 NO 合成的作用，可能导致高血压。 ⁴⁷在大鼠中，铅暴露会激活 NF-κB（核因子 κB）信号通路，导致全身炎症，其特点是 ROS 过量产生，并与 CVD 相关。 ^{48 , 49}

Lead exposure can result in epigenetic modifications, including alterations in both histone structure and DNA methylation.⁵⁰ In addition, chronic lead exposure (< 10 mg/dL) has been associated with inhibitions of protein binding to methyl-CpG and alterations of DNA methyltransferases.⁵¹
铅暴露会导致表观遗传修饰，包括组蛋白结构和 DNA 甲基化的改变。 ⁵⁰此外，慢性铅暴露 (< 10 mg/dL) 与蛋白质与甲基 CpG 结合的抑制和 DNA 甲基转移酶的改变有关。 ⁵¹

Both epidemiological and experimental evidence strongly supports the involvement of DNA methylation in CVD.⁵² Further investigation is needed to explore the potential relationship between lead-induced epigenetic changes and their impact on CVD.⁵³
流行病学和实验证据都强烈支持 DNA 甲基化参与 CVD。 ⁵²需要进一步研究来探索铅引起的表观遗传变化及其对 CVD 的影响之间的潜在关系。 ⁵³

Mercury (Hg) 汞 (Hg)

Mercury has been ranked as the third most toxic environmental hazard after arsenic and lead. Mercury exists in 3 forms, each with distinct toxicological properties: elemental Hg (Hg0), inorganic Hg (Hg salts), and organic Hg (methyl mercury [MeHg]). The toxic effects of mercury imposed on humans and other organisms are dependent on many factors including the chemical form, amount, exposure pathway, and differences in vulnerability between exposed subjects.^54,55 Among these, methylmercury is the most harmful form of Hg due to its high bioavailability and neurotoxicity.^56,57
汞被列为继砷和铅之后的第三大有毒环境危害。汞以 3 种形式存在，每种形式都具有不同的毒理学特性：元素汞 (Hg0)、无机汞（汞盐）和有机汞（甲基汞 [MeHg]）。汞对人类和其他生物体的毒性作用取决于许多因素，包括化学形式、含量、暴露途径以及暴露对象之间脆弱性的差异。 ^{54 , 55}其中，甲基汞因其高生物利用度和神经毒性而成为最有害的汞形式。 ^{56 , 57}

Human activity is the main cause of mercury releases, particularly residential coal burning for heating and cooking, industrial processes, recycling facilities, medical or municipal incinerators, mercury-containing latex paint, and mining activities for gold and other metals.⁵⁸ Mercury also occurs naturally and is found in air, water, and soil. It is released into the environment from various natural sources, such as volcanic activity, weathering of rocks, geologic deposits of mercury, and volatilization from the ocean.^59,60 Most of the mercury found in the environment is in the form of metallic mercury and inorganic mercury compounds. However, microorganisms (bacteria, phytoplankton in the ocean, and fungi) convert inorganic mercury to methylmercury. Human exposure to mercury may occur via a variety of pathways, including consumption of foodstuffs (eg, freshwater fish or seafood, rice), occupational uses, dental amalgams, beauty products, laxatives, infant products, and mercury-containing vaccines.^58,60 Methylmercury can accumulate in the food chain with increasing concentrations at higher trophic levels. In this way, in contaminated waters, it is fish at the top of the food chain that builds up the highest amounts of methylmercury in their bodies, placing risk at people who consume them.⁵⁶ Conversely, plants tend to have very low levels of mercury, even if grown in soils containing mercury at significantly higher than background levels.
人类活动是汞释放的主要原因，特别是用于取暖和烹饪的住宅燃煤、工业加工、回收设施、医疗或市政焚烧炉、含汞乳胶漆以及黄金和其他金属的采矿活动。 ⁵⁸汞也自然存在，存在于空气、水和土壤中。它通过各种自然来源释放到环境中，例如火山活动、岩石风化、汞的地质沉积和海洋挥发。 ^{59 , 60}环境中发现的大部分汞以金属汞和无机汞化合物的形式存在。然而，微生物（细菌、海洋中的浮游植物和真菌）将无机汞转化为甲基汞。人类可能通过多种途径接触汞，包括食用食品（例如淡水鱼或海鲜、大米）、职业用途、牙科汞合金、美容产品、泻药、婴儿产品和含汞疫苗。 ^{58 , 60}甲基汞可以在食物链中积累，并且在较高营养级别浓度不断增加。这样，在受污染的水域中，处于食物链顶端的鱼类体内甲基汞含量最高，从而给食用它们的人带来风险。 ⁵⁶相反，植物的汞含量往往非常低，即使生长在汞含量显着高于背景水平的土壤中也是如此。

Numerous epidemiological studies suggest that mercury can negatively affect cardiovascular function,^61–63 increasing the risk of hypertension, coronary heart disease, atherosclerosis, and myocardial infarction.¹¹ One report published by the National Research Council Committee in 2000 suggested an association between MeHg, the most common and toxic form of organic mercury, and cardiovascular dysfunction.⁶⁴ The overall cardiovascular effects of mercury include oxidative stress–decreased oxidative defense, inflammation, thrombosis, vascular smooth muscle proliferation and migration, reduced NO bioavailability, dyslipidemia, and dysfunctions of the immune system, endothelia, and mitochondria.⁶⁵
大量流行病学研究表明，汞会对心血管功能产生负面影响， ^61-63会增加患高血压、冠心病、动脉粥样硬化和心肌梗塞的风险。 ¹¹国家研究委员会委员会 2000 年发表的一份报告表明，甲基汞（最常见且有毒的有机汞形式）与心血管功能障碍之间存在关联。 ⁶⁴汞对心血管的总体影响包括氧化应激——氧化防御能力下降、炎症、血栓形成、血管平滑肌增殖和迁移、一氧化氮生物利用度降低、血脂异常以及免疫系统、内皮细胞和线粒体功能障碍。 ⁶⁵

The toxic effects of mercury in all its forms have been demonstrated in vitro, in animals, and in humans. Mercury can form selenium-mercury complexes by bonding to selenium and thiol (-SH)-containing molecules. Thus, it can reduce the efficiency of different antioxidant enzymes, such as glutathione peroxidase, catalase, and superoxide dismutase, due to the deficiency of selenium-binding proteins.^66–68 Thus, exposure to mercury increases the production of free radicals and ROS and increases the risk of developing CVD. Moreover, Hg has the potential to affect phospholipases and increase the oxidation of LDL (low-density lipoprotein).⁶⁹ Another mechanism responsible for the toxic effects of mercury is the inactivation of paraoxonase, an extracellular antioxidative enzyme related to HDL (high-density lipoprotein), which causes dysfunctional HDL to reduce reverse cholesterol transport and reduce the antioxidant activity of LDL.^70,71 This process is directly involved in the development of atherosclerosis and the risk of acute myocardial infarction, coronary heart disease, and carotid artery stenosis.⁷² In addition, mercury induces the formation of arachidonic acid metabolites, such as prostaglandins, thromboxanes, leukotrienes, and related compounds, which are all considered mediators of inflammatory responses that may relate to cardiovascular problems.⁷³
各种形式的汞的毒性作用已在体外、动物和人体中得到证实。汞可以通过与含硒和硫醇 (-SH) 的分子结合形成硒-汞络合物。因此，由于硒结合蛋白的缺乏，它会降低不同抗氧化酶的效率，例如谷胱甘肽过氧化物酶、过氧化氢酶和超氧化物歧化酶。 ^66–68因此，接触汞会增加自由基和活性氧的产生，并增加患 CVD 的风险。此外，汞有可能影响磷脂酶并增加 LDL（低密度脂蛋白）的氧化。 ⁶⁹造成汞毒性作用的另一个机制是对氧磷酶的失活，对氧磷酶是一种与 HDL（高密度脂蛋白）相关的细胞外抗氧化酶，它会导致 HDL 功能失调，从而减少胆固醇反向转运并降低 LDL 的抗氧化活性。 ^{70 , 71}这一过程直接涉及动脉粥样硬化的发展以及急性心肌梗塞、冠心病和颈动脉狭窄的风险。 ⁷²此外，汞还会诱导花生四烯酸代谢物的形成，例如前列腺素、血栓素、白三烯和相关化合物，这些物质都被认为是可能与心血管问题相关的炎症反应的介质。 ⁷³

Cadmium (Cd) 镉 (Cd)

Cadmium is a poisonous metal found worldwide, with a long biological half-life of 17 to 30 years, and is hard to excrete from the body. This metal has many industrial uses in batteries, pigments, plastic stabilizers, and solar panels. Individuals are exposed to cadmium through daily diet and tobacco smoke. Contaminated water, industrial exposure, agricultural fertilizer, and ambient air may also cause cadmium exposure.^74,75
镉是一种世界范围内发现的有毒金属，其生物半衰期长达17至30年，并且很难从体内排出。这种金属在电池、颜料、塑料稳定剂和太阳能电池板等领域有许多工业用途。个人通过日常饮食和吸烟接触镉。受污染的水、工业接触、农业肥料和环境空气也可能导致镉暴露。 ^{74 , 75}

There is robust experimental and epidemiological evidence on the association of cadmium with CVD.^10,76–78 In rodent models, cadmium can induce hypertension^79,80 and increase atherosclerotic plaque development.⁸¹ Free cadmium and protein-bound cadmium are released into the circulation or delivered to target tissues, resulting in various side effects, including oxidative stress, lipid peroxidation, ion homeostasis, inflammation, cell death, and fibrosis.⁷⁵
有强有力的实验和流行病学证据证明镉与 CVD 之间存在关联。 ^{10 , 76–78}在啮齿动物模型中，镉可诱发高血压^{79 , 80}并增加动脉粥样硬化斑块的形成。 ⁸¹游离镉和蛋白质结合镉被释放到循环系统中或输送到靶组织，导致各种副作用，包括氧化应激、脂质过氧化、离子稳态、炎症、细胞死亡和纤维化。 ⁷⁵

Cadmium increases oxidative stress by being a catalyst in the formation of ROS, increasing lipid peroxidation, and depleting glutathione and protein-bound sulfhydryl groups.⁸² Cadmium and zinc share numerous chemical similarities. As a result, cadmium can substitute zinc in various antioxidant enzymes, including paraoxonase, catalase, superoxide dismutase, and glutathione peroxidase. This substitution leads to an imbalance in free radicals.^83,84 Cadmium has been found to affect the functioning and signaling of NO by impairing the phosphorylation of endothelial NO synthase⁸⁵ and disrupting endothelial vasodilation.⁸⁶ In addition, cadmium modulates calcium concentrations, resulting in the inhibition of the plasma membrane Ca²⁺ pump. Chronic exposure to cadmium leads to a diminished response to induced calcium signaling.^87,88 Cadmium-induced endoplasmic reticulum stress can trigger caspase-12- and caspase-9-involved cell apoptosis.⁸⁷ The cadmium-induced endothelial cell death is considered to be an important factor in the development of cadmium-induced atherosclerosis.⁸⁹
镉可作为 ROS 形成的催化剂，增加脂质过氧化作用，并消耗谷胱甘肽和蛋白质结合的巯基，从而增加氧化应激。 ⁸²镉和锌有许多化学相似之处。因此，镉可以替代各种抗氧化酶中的锌，包括对氧磷酶、过氧化氢酶、超氧化物歧化酶和谷胱甘肽过氧化物酶。这种替代导致自由基失衡。 ^{83 , 84}已发现镉通过损害内皮 NO 合酶⁸⁵的磷酸化并破坏内皮血管舒张来影响 NO 的功能和信号传导。 ⁸⁶此外，镉可调节钙浓度，从而抑制质膜 Ca ²⁺泵。长期接触镉会导致对诱导钙信号传导的反应减弱。 ^{87 , 88}镉诱导的内质网应激可触发 caspase-12 和 caspase-9 相关的细胞凋亡。 ⁸⁷镉诱导的内皮细胞死亡被认为是镉诱导的动脉粥样硬化发展的重要因素。 ⁸⁹

Similar to lead, cadmium contamination may cause genetic and epigenetic changes. An epigenome-wide association study explored epigenetic changes in DNA methylation and different methylated positions have been identified in current and former smokers exposed to cadmium. High-concentrate cadmium exposure in cigarette smoke may potentially lead to adverse health outcomes through epigenetic mechanisms.^90,91
与铅类似，镉污染可能会导致遗传和表观遗传变化。一项全表观基因组关联研究探讨了 DNA 甲基化的表观遗传变化，并在当前和以前接触镉的吸烟者中发现了不同的甲基化位置。香烟烟雾中的高浓度镉暴露可能通过表观遗传机制导致不良健康结果。 ^{90 , 91}

Chromium (Cr) 铬 (Cr)

Chromium is usually found in 2 forms, trivalent (Cr [III]) and hexavalent (Cr [VI]). The trivalent form of chromium is the dominant species in the environment and is required for health, having essential positive effects on glucose, lipid, and protein metabolism. The lack of Cr (III) causes diabetes, CVD, and high blood pressure. Conversely, Cr (VI) is considered hazardous where exposure can cause CVD, renal illness, liver disease, and cancer in humans.^92,93
铬通常有两种形式：三价 (Cr [III]) 和六价 (Cr [VI])。三价铬是环境中的主要物种，是健康所必需的，对葡萄糖、脂质和蛋白质代谢具有重要的积极影响。缺乏 Cr (III) 会导致糖尿病、CVD 和高血压。相反，Cr (VI) 被认为是危险的，接触它会导致人类心血管疾病、肾病、肝病和癌症。 ^{92 , 93}

According to several studies, Cr (III) plays an important role in the prevention and treatment of CVD. Individuals suffering from CVD have shown lower plasma Cr (III) levels compared with healthy subjects.⁹⁴ Cr (III) has also been reported to regulate blood pressure,⁹⁵ improve the blood lipid profile,⁹⁶ and act as an anti-inflammatory and antioxidative agent, which inhibits both NF-κB activation and proinflammatory and cytokine inflammatory mediator generation and enhances antioxidant enzyme activity.^94,95
多项研究表明，Cr(III)在CVD的预防和治疗中发挥着重要作用。与健康受试者相比，患有 CVD 的个体血浆 Cr (III) 水平较低。据报道， ⁹⁴ Cr (III) 还可以调节血压， ⁹⁵改善血脂状况， ⁹⁶并可作为抗炎和抗氧化剂，抑制 NF-κB 激活以及促炎和细胞因子炎症介质的生成，并增强抗氧化作用酶活性。 ^{94 , 95}

Naturally occurring chromium is usually present as trivalent Cr (III) whereas hexavalent Cr (VI) in the environment is almost totally derived from human activities. While the general population is mainly exposed to trivalent chromium Cr (III) through food and dietary supplements⁹⁷ those at risk from Cr (VI) are primarily those involved in industrial processes such as galvanizing, painting, leather manufacture, steel production, and corrosion prevention. Interestingly, tobacco smoke also contains Cr (VI); thus, co-exposure of this to other metals, such as cadmium, lead, and nickel, is possible for smokers.⁹⁸
天然存在的铬通常以三价 Cr(III) 形式存在，而环境中的六价 Cr(VI) 几乎完全来自人类活动。虽然一般人群主要通过食品和膳食补充剂接触三价铬 Cr (III) ^97，但面临 Cr (VI) 风险的人群主要是参与镀锌、喷漆、皮革制造、钢铁生产和防腐等工业过程的人员。有趣的是，烟草烟雾中还含有Cr(VI)；因此，吸烟者可能同时接触其他金属，例如镉、铅和镍。 ⁹⁸

Several epidemiological findings have confirmed that Cr (III) supplementation helps to improve CVD.^94,99–101 Overall, the results of several studies have shown the positive role of Cr (III) supplementation in carbohydrate and lipid metabolism,¹⁰² blood pressure changes,¹⁰³ the levels of oxidative stress markers,¹⁰⁴ and inflammatory indices.¹⁰¹
多项流行病学研究结果证实，补充 Cr (III) 有助于改善 CVD。 ^{94 , 99–101}总体而言，多项研究结果表明补充 Cr (III) 对碳水化合物和脂质代谢、 ¹⁰²血压变化、 ¹⁰³氧化应激标志物水平、 ¹⁰⁴和炎症指标具有积极作用。 ¹⁰¹

However, Cr (VI) exerts opposing effects to those of Cr (III) and can induce oxidative stress, chronic inflammation, endothelial dysfunction, cell death, genetic development, and instability.^105–108 Following bloodstream absorption, Cr (VI) is quickly taken up by erythrocytes and converted to Cr (III) inside red blood cells. In contrast, Cr (III) attaches directly to transferrin, an iron-transporting protein in the plasma, and does not easily traverse red blood cell membranes.¹⁰⁹ Ascorbic acid, glutathione reductase, hydrogen peroxide, and glutathione can all reduce Cr (VI) to form reactive intermediates such as Cr (V), Cr (IV), thiyl radicals, hydroxyl radicals, and finally Cr (III). Any of these species could damage proteins, membrane lipids, DNA, and cause other disruptions to the integrity and functionality of cells.¹¹⁰
然而，Cr (VI) 与 Cr (III) 具有相反的作用，可诱发氧化应激、慢性炎症、内皮功能障碍、细胞死亡、遗传发育和不稳定。 ^105–108血液吸收后，Cr (VI) 很快被红细胞吸收并在红细胞内转化为 Cr (III)。相比之下，Cr (III) 直接附着在转铁蛋白（血浆中的铁转运蛋白）上，并且不易穿过红细胞膜。 ¹⁰⁹抗坏血酸、谷胱甘肽还原酶、过氧化氢和谷胱甘肽均可还原 Cr(VI)，形成反应中间体，如 Cr(V)、Cr(IV)、硫基自由基、羟基自由基，最后形成 Cr(III)。这些物种中的任何一种都可能损害蛋白质、膜脂、DNA，并对细胞的完整性和功能造成其他破坏。 ¹¹⁰

Studies based on human umbilical vein endothelial cells and Wistar rats have revealed that exposure to Cr (VI) can activate the NF-κB signaling pathway, induce the mRNA expression of inflammatory factors (NLRP3 [NOD-like receptor thermal protein domain associated protein 3], ICAM-1 [intercellular cell adhesion molecule-1], VCAM-1 [vascular cell adhesion molecule-1], TNF-α [tumor necrosis factor α] and IL [interleukin]-1β), and increase intracellular ROS.^106,107 Ultimately, such factors may contribute to endothelial dysfunction, cell apoptosis, tissue damage, and the development of CVD. In addition, numerous recent studies have implicated epigenetic mechanisms in the cause of Cr (VI)-induced cytotoxicity.¹¹¹ For example, it has been reported that Cr (VI) can easily inhibit cellular processes and promote DNA damage either via oxidative or nonoxidative methods. This can trigger various toxic effects inside the cellular system and might activate or silence the expression of critical genes.¹¹² This alters DNA methylation levels and global and gene-specific histone posttranslational modifications, emphasizing epigenetics as a possible underlying mechanism of the toxicity and cell-transforming ability of Cr (VI).¹¹³
基于人脐静脉内皮细胞和Wistar大鼠的研究表明，Cr（VI）暴露可以激活NF-κB信号通路，诱导炎症因子（NLRP3 [NOD样受体热蛋白域相关蛋白3]的mRNA表达）、ICAM-1[细胞间细胞粘附分子-1]、VCAM-1[血管细胞粘附分子-1]、TNF-α[肿瘤坏死因子α]和IL[白细胞介素]-1β），并增加细胞内ROS。 ^{106 , 107}最终，这些因素可能导致内皮功能障碍、细胞凋亡、组织损伤和 CVD 的发展。此外，最近的许多研究表明表观遗传机制与 Cr (VI) 诱导的细胞毒性有关。 ¹¹¹例如，据报道，Cr (VI) 可以通过氧化或非氧化方法轻松抑制细胞过程并促进 DNA 损伤。这可能会在细胞系统内引发各种毒性作用，并可能激活或沉默关键基因的表达。 ¹¹²这会改变 DNA 甲基化水平以及全局和基因特异性组蛋白翻译后修饰，强调表观遗传学作为 Cr (VI) 毒性和细胞转化能力的可能潜在机制。 ¹¹³

MECHANISMS OF HEAVY METAL–INDUCED CARDIOTOXICITY
重金属引起的心脏毒性机制

Heavy metals can induce cardiotoxicity through various mechanisms. Studies suggest that exposure to heavy metals can disrupt essential pathways of cardiovascular functions, including oxidative stress, chronic inflammation, lipid metabolism, impaired vascular endothelial function, disruption of ion homeostasis, and epigenetic effects. Among these, there are some general mechanisms that apply to all toxic metals and other specific mechanisms that are idiosyncratic to the individual metal in question (Figure 2).
重金属可通过多种机制诱发心脏毒性。研究表明，接触重金属会破坏心血管功能的重要途径，包括氧化应激、慢性炎症、脂质代谢、血管内皮功能受损、离子稳态破坏和表观遗传效应。其中，有一些适用于所有有毒金属的通用机制，以及其他特定金属所特有的机制（图 2 ）。

Figure 2. **Mechanisms of heavy metal–induced cardiovascular toxicity.** The diagram illustrates the mechanism of heavy metal–induced cardiovascular toxicity in different manners: oxidative stress and reactive oxygen species (ROS) generation, lipid metabolism distribution, inflammatory reactions, endothelial dysfunction, disruption of ion homeostasis, direct cellular damage, and apoptosis. For detail, As, Cd, Hg, and Pd are able to bind to the—SH containing molecules, leading to enzyme inactivation and oxidative stress. Cr (VI) in the process of being converted to Cr (III) may also form hydroxyl radicals. The production of reactive oxygen and inactivation of enzymes can further disturb lipid metabolism, lower the HDL level, elevate the OX-LDL level, and promote foam cell formation, which may develop into atherosclerosis. In addition, heavy metals can directly or indirectly (via the activation of MAPK, p38, JNK and ERK) change the DNA modification, causing epigenetic changes that may induce inflammatory responses (via inducing the mRNA expression of inflammatory factors) or apoptosis (caspase-involved). Meanwhile, heavy metals can interfere with ion channels and transporters, thus altering cellular ion homeostasis. Its effect on nitric oxide (NO) synthase can further lead to NO disruption, resulting in endothelial dysfunction. Bcl-2 indicates B-cell lymphoma-2; ERK, extracellular signal-regulated kinase; HDL, high-density lipoprotein; hERG, human ether-à-go-go–related gene; IL-6, interleukin-6; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; mtROS, mitochondria reactive oxygen species; NLRP3, NOD-like receptor thermal protein domain associated protein 3; OX-LDL, oxidized low-density lipoprotein; PARP, poly ADP-ribose polymerase; and SR, sarcoplasmic reticulum.
图2 .重金属诱发心血管毒性的机制。该图以不同方式说明了重金属诱导心血管毒性的机制：氧化应激和活性氧（ROS）的产生、脂质代谢分布、炎症反应、内皮功能障碍、离子稳态破坏、直接细胞损伤和细胞凋亡。具体而言，As、Cd、Hg 和 Pd 能够与含有 SH 的分子结合，导致酶失活和氧化应激。 Cr(VI)在转化为Cr(III)的过程中也可能形成羟基自由基。活性氧的产生和酶的失活会进一步扰乱脂质代谢，降低HDL水平，升高OX-LDL水平，并促进泡沫细胞形成，从而可能发展为动脉粥样硬化。此外，重金属可以直接或间接（通过激活MAPK、p38、JNK和ERK）改变DNA修饰，引起表观遗传变化，从而可能诱导炎症反应（通过诱导炎症因子的mRNA表达）或细胞凋亡（caspase-涉及）。同时，重金属会干扰离子通道和转运蛋白，从而改变细胞离子稳态。它对一氧化氮 (NO) 合酶的影响可进一步导致 NO 破坏，导致内皮功能障碍。 Bcl-2表示B细胞淋巴瘤-2； ERK，细胞外信号调节激酶； HDL，高密度脂蛋白； hERG，人类ether-à-go-go相关基因； IL-6、白介素-6； JNK，c-Jun N 末端激酶； MAPK，丝裂原激活蛋白激酶； mtROS，线粒体活性氧； NLRP3，NOD 样受体热蛋白结构域相关蛋白 3； OX-LDL，氧化低密度脂蛋白； PARP，聚ADP-核糖聚合酶；和 SR，肌浆网。

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Oxidative Stress and ROS Generation
氧化应激和 ROS 生成

Oxidative stress results from an imbalance between the production and detoxification of ROS. The toxicity of ROS is based on their ability to oxidize intra- and extracellular structures, such as proteins, lipids, and nucleic acids. Several enzyme systems are known to protect the body against ROS. These enzymes include superoxide dismutase, catalase, glutathione peroxidase, paraoxonase, thioredoxin, heme oxygenase, and others.⁷
氧化应激是由于 ROS 的产生和解毒之间的不平衡造成的。 ROS 的毒性基于其氧化细胞内和细胞外结构（例如蛋白质、脂质和核酸）的能力。已知有几种酶系统可以保护身体免受活性氧的侵害。这些酶包括超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化物酶、对氧磷酶、硫氧还蛋白、血红素加氧酶等。 ⁷

Increased oxidative stress plays an important role in heavy metal–induced adverse health effects.¹¹⁴ The generation of ROS can occur in many ways. Many metals have electron-sharing properties and are therefore capable of forming covalent bonds with sulfhydryl groups of proteins (eg, glutathione, cysteine, homocysteine, metallothionein, and albumin). Divalent toxic metals, such as lead, cadmium, and mercury, bind to sulfhydryl groups affecting the efficiency of different antioxidant enzymes. This can cause antioxidant enzymes such as glutathione peroxidase, catalase, metallothionein, and superoxide dismutase, to be reduced as the intracellular concentrations of ROS are correspondingly increased.^42,66–68
氧化应激增加在重金属引起的不良健康影响中起着重要作用。 ¹¹⁴ ROS 的产生可以通过多种方式发生。许多金属具有电子共享特性，因此能够与蛋白质（例如谷胱甘肽、半胱氨酸、高半胱氨酸、金属硫蛋白和白蛋白）的巯基形成共价键。二价有毒金属，如铅、镉和汞，与巯基结合，影响不同抗氧化酶的效率。这会导致谷胱甘肽过氧化物酶、过氧化氢酶、金属硫蛋白和超氧化物歧化酶等抗氧化酶减少，而细胞内ROS浓度相应增加。 ^{42 , 66–68}

There are also other more idiosyncratic mechanisms of ROS-related toxicity. Lead, for example, competes with zinc to bind to sulfhydryl groups of delta-ALAD (aminolevulinic acid dehydratase, the enzyme involved in heme metabolism), preventing the binding of ALAD to aminolevulinic acid and generating ROS.^115,116 Cadmium may also substitute for iron and copper in proteins that contain these biologically necessary metals. As a result, iron and copper, after being released from their usual binding proteins, may produce ROS, as both elements can be more easily involved in reduction-oxidation reactions.^84,117
还有其他更特殊的 ROS 相关毒性机制。例如，铅与锌竞争与 δ-ALAD（氨基乙酰丙酸脱水酶，参与血红素代谢的酶）的巯基结合，阻止 ALAD 与氨基乙酰丙酸结合并产生 ROS。 ^{115 , 116}镉还可以替代含有这些生物必需金属的蛋白质中的铁和铜。因此，铁和铜从其通常的结合蛋白中释放出来后，可能会产生ROS，因为这两种元素更容易参与氧化还原反应。 ^{84 , 117}

Inflammatory Reactions 炎症反应

The activation of the inflammatory pathway occurs mainly through proinflammatory and cytokine inflammatory mediators. Both in vitro and in vivo studies have shown a correlation between heavy metal exposure and the increased release of proinflammatory cytokines and inflammatory mediators through various mechanisms.^118–120 For example, mercury has been reported to activate inflammatory responses by binding to SH groups of NF-κB and changing its effects on gene expression.¹²¹ Mercury can also induce the formation of arachidonic acid metabolites such as prostaglandins, thromboxanes, leukotrienes, and related compounds, which are all considered mediators of the inflammatory response, even in cardiovascular problems.⁷³ Lead exposure induces inflammatory reaction mainly through activating MAP kinases, which then play a major role in the generation of proinflammatory cytokines (TNF-α, IL-1β, and TGF-β [transforming growth factor-beta]).⁴³ Recent studies have revealed that many cytokines (such as NLRP3, IL-1β, IL-6, IL-8, and IL-12) are altered in individuals exposed to arsenic and chromium, thus indicating that arsenic and chromium exposure could trigger a cell-mediated inflammatory response.^108,122
炎症途径的激活主要通过促炎和细胞因子炎症介质发生。体外和体内研究都表明，重金属暴露与通过各种机制增加促炎细胞因子和炎症介质的释放之间存在相关性。 ^118–120例如，据报道，汞可通过与 NF-κB 的 SH 基团结合并改变其对基因表达的影响来激活炎症反应。 ¹²¹汞还可以诱导花生四烯酸代谢物的形成，例如前列腺素、血栓素、白三烯和相关化合物，这些物质都被认为是炎症反应的介质，甚至在心血管问题中也是如此。 ⁷³铅暴露主要通过激活 MAP 激酶诱发炎症反应，而 MAP 激酶随后在促炎细胞因子（TNF-α、IL-1β 和 TGF-β [转化生长因子-β]）的生成中发挥重要作用。 ⁴³最近的研究表明，暴露于砷和铬的个体中许多细胞因子（例如 NLRP3、IL-1β、IL-6、IL-8 和 IL-12）会发生改变，因此表明砷和铬暴露可能会引发细胞介导的炎症反应。 ^{108 , 122}

Endothelial Dysfunction and Vascular Impairment
内皮功能障碍和血管损伤

It has been shown that exposure to some heavy metals is associated with hypertension and atherosclerosis, both of which could be attributable to dysfunctional endothelial and smooth muscle cells.^123,124 Metal-containing fine particles in the air, specifically those with a size of ≤2.5 microns, can induce endothelial injury. This occurs through 2 main mechanisms: by impacting the mobilization of endothelial progenitor cells from the bone marrow to the peripheral blood and by inhibiting the signaling events that are initiated by the stimulation of vascular endothelial growth factor receptors.¹²⁵
研究表明，接触某些重金属与高血压和动脉粥样硬化有关，这两者都可能归因于内皮细胞和平滑肌细胞功能失调。 ^{123 , 124}空气中含金属的细颗粒物，特别是尺寸≤2.5微米的细颗粒物，可诱发内皮损伤。这是通过两种主要机制发生的：影响内皮祖细胞从骨髓到外周血的动员，以及抑制由血管内皮生长因子受体刺激引发的信号事件。 ¹²⁵

Some heavy metals have been linked to endothelial dysfunction. Lead, cadmium, arsenic, and chromium exposure can inhibit eNOS (endothelial NO synthase) and decrease NO production, eventually causing increased endothelial dysfunction, vasoconstrictor activity, and vascular injury.^33,45,85,126 Low-mercury exposure increases eNOS activity/expression, thus increasing NO, while in response to high-mercury exposure, a decrease in eNOS activity/expression and NO has been observed.¹²⁷
一些重金属与内皮功能障碍有关。铅、镉、砷和铬暴露会抑制 eNOS（内皮一氧化氮合酶）并减少一氧化氮的产生，最终导致内皮功能障碍、血管收缩活性和血管损伤加剧。 ^{33 , 45 , 85 , 126}低汞暴露会增加 eNOS 活性/表达，从而增加 NO，而响应于高汞暴露，已观察到 eNOS 活性/表达和 NO 减少。 ¹²⁷

In addition, cadmium, lead, mercury, and arsenic can enhance the expression of endothelial cell adhesion molecules. This alters signaling, increases permeability, and induces oxidative stress and inflammation, all of which are proatherosclerotic stimuli.^{120,128–130} These changes can alter vascular function including contractility, localized blood flow, resultant arterial stiffness, and resultant hypertension.
此外，镉、铅、汞、砷可增强内皮细胞粘附分子的表达。这会改变信号传导，增加通透性，并诱发氧化应激和炎症，所有这些都是促动脉粥样硬化的刺激物。 ^{120 , 128–130}这些变化可以改变血管功能，包括收缩性、局部血流、由此产生的动脉僵硬度和由此产生的高血压。

Lipid Metabolism Distribution
脂质代谢分布

Chronic exposure to environmental metals can systemically affect lipid metabolism at the cellular level. Studies have demonstrated that exposure to heavy metals such as lead, cadmium, mercury, and arsenic can lead to dyslipidemia by interfering with the activity of enzymes involved in lipid metabolism (eg, lipoprotein lipase, hepatic lipase, and acyl-CoA cholesterol acyltransferase).^69,131–133 Chronic exposure to arsenic, lead and cadmium can be characterized by elevated levels of LDL cholesterol and triglycerides and reduced HDL cholesterol levels.^{131,132,134,135}
长期接触环境金属会系统性地影响细胞水平的脂质代谢。研究表明，接触铅、镉、汞和砷等重金属会干扰参与脂质代谢的酶（例如脂蛋白脂肪酶、肝脂肪酶和酰基辅酶A胆固醇酰基转移酶）的活性，从而导致血脂异常。 ^{69 , 131–133}长期接触砷、铅和镉的特点是 LDL 胆固醇和甘油三酯水平升高，HDL 胆固醇水平降低。 ^{131 , 132 , 134 , 135}

Furthermore, arsenic inhibits the expression of peroxisome proliferator-activated receptor gamma, causing hyperglycemia and dyslipidemia.¹³⁶
此外，砷会抑制过氧化物酶体增殖物激活受体γ的表达，导致高血糖和血脂异常。 ¹³⁶

Disruption of Ion Homeostasis and Arrhythmia
离子稳态的破坏和心律失常

Heavy metals interfere with ion channels and transporters that are crucial for maintaining cellular ionic balance. This disruption can affect electrical signaling within the heart, leading to arrhythmias and altered cardiac contractility. For instance, lead and cadmium are known to interfere with calcium (Ca²⁺) signaling. They compete with calcium for transport via channels and pumps in the endoplasmic reticulum. They may also compete with calcium in calcium-dependent processes and interact with calmodulin, thus disturbing calcium homeostasis and resulting in arrhythmia.^87,88 Chronic arsenic exposure is associated with cardiovascular toxicity by reducing the surface expression of the human ether-à-go-go–related gene (KCNH2), which results in an increased risk of prolonged QT and torsade de pointes.¹³⁷ While the potential for arsenic-induced prolonged QT is well established as a side effect of treating acute promyelocytic leukemia, there is also evidence suggesting an association between low-chronic exposure to arsenic and QT prolongation.^138,139
重金属会干扰对维持细胞离子平衡至关重要的离子通道和转运蛋白。这种干扰会影响心脏内的电信号传导，导致心律失常和心肌收缩力改变。例如，已知铅和镉会干扰钙 (Ca ²⁺ ) 信号传导。它们与钙竞争通过内质网中的通道和泵的运输。它们还可能在钙依赖性过程中与钙竞争并与钙调蛋白相互作用，从而扰乱钙稳态并导致心律失常。 ^{87 , 88}慢性砷暴露通过降低人 ether-à-go-go 相关基因 (KCNH2) 的表面表达而与心血管毒性相关，从而导致 QT 延长和尖端扭转型室性心动过速的风险增加。 ¹³⁷虽然砷引起 QT 间期延长的可能性已被证实是治疗急性早幼粒细胞白血病的副作用，但也有证据表明，低度长期接触砷与 QT 间期延长之间存在关联。 ^{138 , 139}

Epigenomic Effects 表观基因组效应

Toxic heavy metals have epigenomic effects that include effects on DNA methylation and histone modification that can influence gene expression and downstream transcription.^36,140 Epigenetic modifications caused by heavy metals like lead and cadmium may be attributed to their ability to replace zinc, an essential element of various enzymes involved in epigenetic regulation.¹⁴¹ It has also been reported that Cr (VI) can induce DNA damage and might activate or silence the expression of critical genes,¹¹² thus altering DNA methylation levels as well as global and gene-specific histone posttranslational modifications.
有毒重金属具有表观基因组效应，包括对 DNA 甲基化和组蛋白修饰的影响，从而影响基因表达和下游转录。 ^{36 , 140}铅和镉等重金属引起的表观遗传修饰可能归因于它们替代锌的能力，锌是参与表观遗传调节的各种酶的必需元素。 ¹⁴¹据报道，Cr (VI) 可以诱导 DNA 损伤，并可能激活或沉默关键基因的表达， ¹¹²从而改变 DNA 甲基化水平以及全局和基因特异性组蛋白翻译后修饰。

Heavy metal–induced epigenomic changes such as DNA methylation can be developed into new biomarkers for heavy metal exposure assessment. For example, arsenic-associated blood biomarkers based on DNA methylation can also explain part of the association between arsenic and CVD.³⁶ These epigenomic results of metals can further explain the overlap between environmental factors and precision cardiology, thus informing clinical decisions.
重金属诱导的表观基因组变化（例如 DNA 甲基化）可以开发成用于重金属暴露评估的新生物标志物。例如，基于 DNA 甲基化的砷相关血液生物标志物也可以部分解释砷与 CVD 之间的关联。 ³⁶金属的这些表观基因组结果可以进一步解释环境因素与精准心脏病学之间的重叠，从而为临床决策提供信息。

Direct Cellular Damage and Apoptosis
直接细胞损伤和凋亡

Heavy metals such as cadmium,¹⁴² lead,¹³¹ mercury,¹⁴³ and arsenic¹⁴⁴ can induce direct damage to cardiac cells, leading to apoptosis (programmed cell death). Many related upstream mechanisms can also induce cellular apoptosis, such as ROS, inflammatory reactions, activation of caspases, disrupted calcium homeostasis, and DNA damage. For example, long-term exposure to Cd²⁺ upregulates the expression of p53. p53 binds with Bax (Bcl2-associated X protein), Bcl-2 (B-cell lymphoma-2) and Bcl-xL (B-cell lymphoma-extra large) to inhibit protein but enhances pore formation in the mitochondrial transmembrane and disturbs membrane potential. This results in the activation of procaspase-3 (inactive form) to caspase-3 (active form) and cell apoptosis.¹⁴² These effects of cellular damage and apoptosis can result in structural alterations and functional impairments in the heart muscle.
镉、 ¹⁴²铅、 ¹³¹汞、 ¹⁴³和砷¹⁴⁴等重金属可对心肌细胞造成直接损伤，导致细胞凋亡（程序性细胞死亡）。许多相关的上游机制也可以诱导细胞凋亡，例如ROS、炎症反应、半胱天冬酶激活、钙稳态破坏和DNA损伤。例如，长期暴露于 Cd ²⁺会上调 p53 的表达。 p53 与 Bax（Bcl2 相关 X 蛋白）、Bcl-2（B 细胞淋巴瘤-2）和 Bcl-xL（B 细胞淋巴瘤-超大）结合以抑制蛋白质，但增强线粒体跨膜中的孔形成并干扰膜潜在的。这导致 procaspase-3（非活性形式）激活为 caspase-3（活性形式）并导致细胞凋亡。 ¹⁴²细胞损伤和细胞凋亡的这些影响可能导致心肌结构改变和功能损伤。

HEAVY METAL EXPOSURE PREVENTION AND TREATMENT
重金属暴露预防和治疗

Public Health Prevention 公共卫生预防

Individuals affected by environmental heavy metal pollution often remain unaware of their predicament. Implementing public health measures through legislation and taking steps to mitigate and control sources of exposure are imperative in minimizing metal contamination in air, water, and food, thereby safeguarding the general population.
受环境重金属污染影响的个人往往意识不到自己的困境。通过立法实施公共卫生措施，并采取措施减轻和控制暴露源，对于最大限度地减少空气、水和食品中的金属污染，从而保护广大民众至关重要。

Fine particles are the most hazardous components of air pollution. These can readily enter the bloodstream and may contain high metal concentrations and thus pose a particularly grave threat to the cardiovascular system. Regulating emissions from industrial sites and implementing air purification methods can prevent heavy metal exposure caused by air pollution.
细颗粒物是空气污染中最危险的成分。它们很容易进入血液，并且可能含有高浓度的金属，因此对心血管系统构成特别严重的威胁。规范工业场所排放并实施空气净化方法可以防止空气污染引起的重金属暴露。

Heavy metals can also enter water bodies through industrial processes, agricultural runoff, and improper waste disposal. These then accumulate in sediments, posing risks to aquatic ecosystems and human health. To combat this, industries should adopt cleaner production techniques and invest in pollution prevention technologies.
重金属还可以通过工业过程、农业径流和不当的废物处理进入水体。这些物质随后在沉积物中积累，对水生生态系统和人类健康构成风险。为了解决这个问题，工业界应该采用清洁生产技术并投资于污染防治技术。

Furthermore, ensuring food staples’ quality and implementing effective tobacco control measures can reduce public exposure to lead and cadmium-heavy metals. The US Food and Drug Administration could also establish product standards to minimize metal exposure induced by tobacco products. These and other additional strategies are clearly needed to curtail heavy metal exposures.¹⁴⁵
此外，确保主食质量并实施有效的烟草控制措施可以减少公众对铅和镉重金属的接触。美国食品和药物管理局还可以制定产品标准，以尽量减少烟草产品引起的金属暴露。显然需要这些和其他附加策略来减少重金属暴露。 ¹⁴⁵

Medical Interventions After Exposure
暴露后的医疗干预

Heavy metal–induced cardiotoxicity poses significant health risks, necessitating effective treatment strategies to mitigate its adverse effects on the cardiovascular system.
重金属引起的心脏毒性会带来严重的健康风险，因此需要采取有效的治疗策略来减轻其对心血管系统的不利影响。

Chelation Therapy 螯合疗法

When a molecule, either organic or inorganic, has the potential to form 2 or more stable bonds with a single metal atom, it is called a chelator, chelating agent, or chelating ligand.¹⁴⁶ Chelation is a process in which organic chelator molecules are introduced into the blood. There, they bind target metal ions with high affinity, forming stable complexes that can be excreted from the body. Commonly used chelating agents include dimercaprol, ethylenediaminetetraacetic acid (EDTA), and dimercaptosuccinic acid (DMSA).^147,148
当一个分子，无论是有机分子还是无机分子，有可能与单个金属原子形成 2 个或更多个稳定键时，它被称为螯合剂、螯合剂或螯合配体。 ¹⁴⁶螯合是将有机螯合剂分子引入血液的过程。在那里，它们以高亲和力结合目标金属离子，形成稳定的复合物，可以从体内排出。常用的螯合剂包括二巯基丙醇、乙二胺四乙酸（EDTA）和二巯基丁二酸（DMSA）。 ^{147 , 148}

Chelation therapy with EDTA has been used to treat atherosclerotic disease since 1956¹⁴⁹ but without a solid scientific basis. In 2002, the Cochrane Collaboration reported that there was insufficient evidence for or against chelation therapy to make a recommendation.¹⁵⁰ It was in this context of uncertainty, largely to respond to the public health question posed by EDTA chelation therapy, that the TACT (Trial to Assess Chelation Therapy) was developed.¹⁵¹ A factorial design was selected for TACT to mimic the clinical chelation practice where the eligible patients were randomly assigned to 1 of 4 groups.¹⁵¹
自 1956 年起，EDTA 螯合疗法就被用于治疗动脉粥样硬化性疾病¹⁴⁹ ，但缺乏坚实的科学依据。 2002 年，Cochrane 协作组织报告称，没有足够的证据支持或反对螯合疗法来提出建议。 ¹⁵⁰正是在这种不确定性的背景下，主要是为了回应 EDTA 螯合疗法提出的公共卫生问题，开发了 TACT（评估螯合疗法的试验）。 ¹⁵¹ TACT 选择析因设计来模拟临床螯合实践，其中符合条件的患者被随机分配到 4 组中的一组。 ¹⁵¹

Active intravenous (IV) chelation infusions+active oral multivitamins and minerals.
活性静脉（IV）螯合输注+活性口服多种维生素和矿物质。

Active IV chelation infusions+placebo oral multivitamins and minerals.
活性静脉螯合输液+安慰剂口服多种维生素和矿物质。

Placebo IV chelation infusions+active oral multivitamins and minerals.
安慰剂 IV 螯合输注+活性口服多种维生素和矿物质。

Placebo IV chelation infusions+placebo oral multivitamins and minerals.
安慰剂 IV 螯合输液+安慰剂口服多种维生素和矿物质。

TACT enrolled 1708 patients experiencing myocardial infarction and each participant was randomly assigned to receive either 40 infusions of EDTA-based chelation therapy or a placebo. Overall, there was a stepwise reduction with the addition of a double placebo of oral multivitamins and minerals, chelation, or both. At a median 5-year follow-up, the study found an 18% (P=0.035) decrease in the relative risk of combined cardiovascular events among participants. Additionally, a subgroup analysis involving 633 participants with diabetes revealed a greater event reduction of 41% (P=0.0002).¹⁵²
TACT 招募了 1708 名患有心肌梗塞的患者，每位参与者被随机分配接受 40 次基于 EDTA 的螯合疗法或安慰剂的输注。总体而言，通过添加口服多种维生素和矿物质、螯合剂或两者的双重安慰剂，剂量逐步减少。在中位 5 年随访中，研究发现参与者复合心血管事件的相对风险降低了 18%（ P = 0.035）。此外，一项涉及 633 名糖尿病患者的亚组分析显示，事件减少了 41%（ P = 0.0002）。 ¹⁵²

Specific adverse effects of heavy metals in patients with diabetes have been discussed for over 20 years. Metals bind to glycation end-products of diabetes and promote the formation of ROS in an autocatalytic reaction. These processes may provide an explanation for the amplified benefit seen with edetate chelation in the diabetic subgroup of TACT.¹⁴⁶
重金属对糖尿病患者的具体不良影响已经被讨论了 20 多年。金属与糖尿病的糖基化终产物结合，并在自催化反应中促进ROS的形成。这些过程可能为 TACT 糖尿病亚组中乙二胺四乙酸螯合所带来的放大益处提供了解释。 ¹⁴⁶

However, it is noticeable that like any chelating agent, EDTA binds to both essential and toxic metals. It has been reported that urine excretion of lead, cadmium, zinc, and calcium increased after EDTA treatment.¹⁵³ However, the Food and Drug Administration reviewed their database encompassing over 30 years and reported only 4 cases of hypocalcemia-induced mortality following definite edetate disodium infusion over perhaps millions of infusions that had been administered in the United States. Nevertheless, the risk of chelation therapy still cannot be ignored.¹⁵⁴
然而，值得注意的是，与任何螯合剂一样，EDTA 会与必需金属和有毒金属结合。据报道，EDTA治疗后尿液中铅、镉、锌和钙的排泄量增加。 ¹⁵³然而，美国食品和药物管理局审查了其涵盖 30 多年的数据库，并报告了在美国进行的数百万次输注中，只有 4 例因注射确定的依地酸二钠而导致低钙血症导致死亡的病例。尽管如此，螯合疗法的风险仍然不容忽视。 ¹⁵⁴

The National Institutes of Health is currently conducting a follow-up trial, TACT2 (REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02733185), to replicate or refute the results of TACT in post-MI diabetes patients. To prospectively reproduce the findings of TACT, the investigative team for TACT2 preserved the same factorial design used in TACT. The primary objective in TACT2 is to determine if the edetate disodium-based chelation strategy prolongs the time to the first occurrence of the composite TACT2 primary end point compared with the placebo chelation strategy. The secondary purposes included confirming the unexpectedly beneficial results in TACT; further explaining the potential benefits of edetate disodium-based chelation through mechanistic studies; and collecting and storing blood and urine samples from patients, to support future mechanistic research.¹⁵⁵ TACT3a (NCT03982693) is further planned to involve the study of patients with diabetes and critical limb ischemia that will expand and define the role of chelation and examine novel agents. This is currently at the level of enrollment.
美国国立卫生研究院目前正在进行一项后续试验 TACT2（注册：URL： https://www.clinicaltrials.gov ；唯一标识符：NCT02733185），以复制或反驳 TACT 在 MI 后糖尿病患者中的结果。为了前瞻性地重现 TACT 的研究结果，TACT2 的研究团队保留了 TACT 中使用的相同析因设计。 TACT2 的主要目标是确定与安慰剂螯合策略相比，基于乙二胺四乙酸二钠的螯合策略是否延长复合 TACT2 主要终点首次出现的时间。次要目的包括确认 TACT 中意想不到的有益结果；通过机理研究进一步解释乙二胺四乙酸二钠螯合的潜在益处；收集和储存患者的血液和尿液样本，以支持未来的机制研究。 ¹⁵⁵ TACT3a (NCT03982693) 进一步计划涉及糖尿病和严重肢体缺血患者的研究，这将扩大和定义螯合的作用并检查新药物。目前处于招生水平。

Antioxidant Supplementation
补充抗氧化剂

Antioxidants are compounds that neutralize harmful ROS and reduce oxidative damage in cells. They play a crucial role in maintaining cellular health and preventing oxidative stress-related diseases. In the context of heavy metal exposure, antioxidants can help restore the balance between oxidative stress and the body’s defense mechanisms.
抗氧化剂是中和有害活性氧并减少细胞氧化损伤的化合物。它们在维持细胞健康和预防氧化应激相关疾病方面发挥着至关重要的作用。在重金属暴露的情况下，抗氧化剂可以帮助恢复氧化应激和身体防御机制之间的平衡。

Studies have shown promising results regarding the effectiveness of antioxidant supplementation in alleviating heavy metal–induced toxicity. Vitamins such as vitamin C, vitamin E, and beta-carotene, and minerals, such as selenium and zinc, have demonstrated potent antioxidant properties.^156,157 These nutrients scavenge free radicals, enhance the body’s natural detoxification processes, and protect cellular structures from oxidative damage caused by heavy metals.
研究表明，补充抗氧化剂在减轻重金属引起的毒性方面的有效性具有良好的前景。维生素 C、维生素 E 和 β-胡萝卜素等维生素以及硒和锌等矿物质已被证明具有强大的抗氧化特性。 ^{156 , 157}这些营养素可清除自由基，增强人体的自然解毒过程，并保护细胞结构免受重金属引起的氧化损伤。

Antioxidant supplementation may reduce heavy metal exposure effects, but this should not be a standalone treatment. A holistic approach involving minimizing exposure, implementing safety measures, providing nutritional support, and seeking medical advice is also crucial. Since the efficacy of chelation therapy is still under consideration, there is an urgent need for more strategies to alleviate heavy metal toxicity. Molecular studies have now uncovered many mechanisms of cardiotoxicity induced by heavy metals. As they have done so, this has made it possible to use milder, more specific chelating agents in combination with symptomatic treatment such as using antioxidants, liver support, and supplementation of nutrients. In addition, low-dose exposure remains a subtle and hidden threat, which may remain difficult to diagnose. Therefore, it is important to raise people’s awareness of heavy metal toxicity and reduce their exposure to environmental heavy metal pollution.
补充抗氧化剂可以减少重金属暴露的影响，但这不应该是一种独立的治疗方法。包括尽量减少接触、实施安全措施、提供营养支持和寻求医疗建议的整体方法也至关重要。由于螯合疗法的疗效仍在考虑中，因此迫切需要更多的策略来减轻重金属毒性。分子研究现已揭示重金属引起心脏毒性的许多机制。正如他们所做的那样，这使得使用更温和、更特异性的螯合剂与对症治疗（例如使用抗氧化剂、肝脏支持和补充营养物质）相结合成为可能。此外，低剂量暴露仍然是一种微妙且隐藏的威胁，可能仍然难以诊断。因此，提高人们对重金属毒性的认识，减少环境重金属污染的暴露具有重要意义。

HEAVY METAL EXPOSURE AND RESEARCH METHODS
重金属暴露和研究方法

Besides clinical trials, epidemiological studies and toxicological experiments are of great value in evaluating the cardiovascular adverse effects of heavy metals and the impact of metal chelation.
除临床试验外，流行病学研究和毒理学实验对于评估重金属对心血管的不良反应以及金属螯合的影响也具有重要价值。

Epidemiological Studies 流行病学研究

Epidemiological studies play a crucial role in understanding the prevalence, risk factors, and potential treatments associated with heavy metal toxicity. Many mechanisms uncovered by studies based on rodents and cell lines are difficult to reproduce in human exposure situations.
流行病学研究在了解重金属毒性的患病率、危险因素和潜在治疗方法方面发挥着至关重要的作用。基于啮齿动物和细胞系的研究发现的许多机制在人类暴露情况下很难重现。

Heavy metal exposure has been linked to a range of health effects including neurological disorders, CVD, renal dysfunction, and carcinogenesis. Studies have demonstrated associations between specific heavy metals (eg, arsenic, lead, mercury, cadmium, chromium) and CVD.^27,57,158 The NHANES (National Health and Nutrition Examination Survey) studies of the United States have contributed much to the body of evidence linking heavy metals to CVD risk.¹⁰ One recent review of the environmental factors of CVD called for high-quality prospective cohort studies to investigate the effects of metal exposure.¹⁵⁹ The evaluation of criteria and methods after heavy metal exposure is important and still awaiting further clarification (Table 1).
重金属暴露与一系列健康影响有关，包括神经系统疾病、心血管疾病、肾功能障碍和致癌。研究已证明特定重金属（例如砷、铅、汞、镉、铬）与 CVD 之间存在关联。 ^{27 , 57 , 158}美国的 NHANES（国家健康和营养检查调查）研究为将重金属与 CVD 风险联系起来的证据做出了很大贡献。 ¹⁰最近一项关于 CVD 环境因素的综述呼吁开展高质量的前瞻性队列研究来调查金属暴露的影响。 ¹⁵⁹重金属暴露后的标准和方法评估很重要，仍有待进一步明确（表1 ）。

Table 1. Heavy Metals Exposure Source, Half-Life, Excretion, and Regulatory Guidelines
表 1 .重金属暴露源、半衰期、排泄和监管指南

Metal 金属	Source 来源	Half-life 半衰期	Excretion 排泄	Measure 措施	Guideline 指南
Arsenic 砷	Water consumption, soils, food (rice, cereals, other grains, vegetables, fruit, especially seafood), drinks (beers, wines), tobacco smoke, air, and dust 耗水量、土壤、食物（大米、谷物、其他谷物、蔬菜、水果，尤其是海鲜）、饮料（啤酒、葡萄酒）、烟草烟雾、空气和灰尘	Inorganic: 无机： Blood: 4–6 h 血液：4–6 小时 Urine: 1–30 d 尿液：1-30 天 Methylated: 甲基化： Blood: 20–30 h 血液：20–30 小时	Urine 尿 Nails 指甲 Hair 头发 Skin 皮肤 Sweat 汗	Urine level 尿液水平 Hair level 头发水平 Nail level 指甲级别	Both inorganic and methylated: 无机和甲基化： 35 μg/g creatinine of urine (based on CDC) 尿液肌酐 35 μg/g（根据 CDC）
Lead	Water consumption, foods, drinks, soil, tobacco smoke, electronics, lead-based paints, gasoline additives, food-can soldering, automobile batteries, water pipes, munitions, and combustion sources	Blood: 28–36 d Bones: 20–30 y	Urine Biliary	Blood level Bone level (X-ray fluorescence)	5 μg/dL of blood (based on CDC) 30 µg/dL of blood (based on ACGIH) 40 µg/dL of blood (based on OSHA)
Mercury	Food (freshwater fish or seafood, rice), occupational uses, dental amalgams, beauty products, laxatives, infant products, and mercury-containing vaccines	Elemental: Blood: 1–3 d Whole body: 1–3 wk Inorganic: Blood: 1–3 wk Organic: Blood: 50 d Whole body: 50 d	Urine Breath Hair	Blood level (methylmercury) Urine level (Elemental and inorganic mercury) Hair level (methylmercury)	5 μg/L of blood (based on WHO)
Cadmium	Food (green vegetables, grains, shellfish, organ meats), tobacco smoke, water consumption, industrial process (batteries, pigments, plastic stabilizer), agricultural fertilizer, and ambient air	Liver: 4–19 y Kidneys: 6–38 y	Urine	Blood level Urine level	3 μg/g creatinine of urine (Based on OSHA) 5 μg/L of blood (Based on OSHA)
Chromium	Water consumption, ambient air, tobacco smoke, food, and industrial processes (galvanizing, painting, leather manufacture, steel production, corrosion prevention)	Cr (III) and Cr (IV) Blood: within hours Urine: 8 h	Urine Biliary Hair Nails Sweat	Blood level Urine level	3 μg/dL Cr of blood (based on CDC) 10 μg/L Cr of urine (based on CDC)

ACGIH indicates American Conference of Governmental Industrial Hygienist; CDC, Centers for Disease Control and Prevention; EPA, Environmental Protection Agency; OSHA, Occupational and Safety Health Administration; and WHO, World Health Organization.
ACGIH表示美国政府工业卫生学家会议； CDC，疾病控制与预防中心； EPA，环境保护局； OSHA，职业与安全健康管理局；和世界卫生组织。

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Meta-analysis of ≈350 000 individuals from 37 countries showed that exposure to arsenic, lead, and cadmium was directly associated with an increased risk of CVD incidence and mortality, with a linear-shaped dose-response curve.¹⁵⁸ NHANES 1999 to 2004, conducted by the US National Center for Health Statistics, studied participants ≥20 years of age with determinations of cadmium in blood (n=10 991) and urine (n=3496). Cadmium levels in blood, but not in urine, were then associated with a modest elevation in blood pressure levels.⁷⁷ By using a sample comprising 16 028 adults aged ≥ 40 years who were enrolled in the NHANES 1999 to 2012, another study highlighted the potential utility of blood markers for CVD risk assessment, prevention, and precision health.¹⁶⁰
对来自 37 个国家约 35 万人的荟萃分析表明，砷、铅和镉的暴露与 CVD 发病率和死亡率的风险增加直接相关，且剂量反应曲线呈线性。 ¹⁵⁸ NHANES 1999 年至 2004 年由美国国家卫生统计中心开展，对 20 岁以上的参与者进行了研究，测定了血液 (n=10 991) 和尿液 (n=3496) 中的镉含量。血液中的镉含量（而非尿液中的镉含量）与血压水平适度升高相关。 ⁷⁷另一项研究通过使用 16 028 名 40 岁以上成年人（1999 年至 2012 年参加 NHANES）的样本，强调了血液标记物在 CVD 风险评估、预防和精准健康方面的潜在效用。 ¹⁶⁰

Many epidemiological studies have linked single metals to their cardiovascular toxicity. Tellez Plaza et al reported a study of 3348 patients with measurement of urinary cadmium. Elevated levels of urinary cadmium were found to increase the incidence of all-cause, cardiovascular, and coronary heart disease mortality and to be stronger in patients with known diabetes.⁷⁶ A systematic review of 12 studies of cadmium exposure and clinical CVD reported a positive association between cadmium levels and coronary heart disease, stroke, and peripheral artery disease. These associations were significant after adjusting for smoking status.⁷⁸
许多流行病学研究已将单一金属与其心血管毒性联系起来。 Tellez Plaza等人报道了一项对3348名患者进行尿镉测量的研究。研究发现，尿镉水平升高会增加全因死亡率、心血管病死亡率和冠心病死亡率，并且在已知糖尿病患者中这种情况更为严重。 ⁷⁶对 12 项关于镉暴露和临床 CVD 的研究进行的系统回顾表明，镉水平与冠心病、中风和外周动脉疾病之间存在正相关。在调整吸烟状况后，这些关联非常显着。 ⁷⁸

Though experimental studies suggest heavy metal exposure increases CVD risk, few human studies have investigated multiple metal exposures and their potential antagonistic effects on CVD. One related study from the NHANES found that exposure to heavy metal mixtures does indeed increase the risk of CVD. This highlights the need for more comprehensive research on the effects of multiple metal exposures and the antagonistic effect between essential and toxic metals on CVD risk.¹⁶¹
尽管实验研究表明重金属暴露会增加 CVD 风险，但很少有人类研究调查多种金属暴露及其对 CVD 的潜在拮抗作用。 NHANES 的一项相关研究发现，接触重金属混合物确实会增加患 CVD 的风险。这凸显了需要对多种金属暴露的影响以及必需金属和有毒金属之间对 CVD 风险的拮抗作用进行更全面的研究。 ¹⁶¹

As for the chelation treatment, in the 1950s, Clarke et al¹⁴⁹ tested the effect of EDTA in a group of patients with severe angina and found remarkable symptomatic and electrocardiographic improvement after repeated EDTA infusions in 17 out of 20 patients. Following these observations, and despite the lack of well-powered clinical trials to evaluate its efficacy, the use of EDTA to treat angina and other forms of atherosclerotic disease continued 50 years after Clarke’s initial report until in 2002, TACT was initiated. TACT was a double-blind, placebo-controlled clinical trial conducted to investigate the efficacy of chelation therapy in treating coronary artery disease. The primary end point was a composite of adverse cardiovascular events, including death, reinfarction, stroke, and hospitalization for angina. Surprisingly, the trial demonstrated a modest but statistically significant reduction in the risk of the primary end point among patients receiving chelation therapy. This unexpected outcome prompted considerable discussion and further research.¹⁶²
至于螯合治疗，20世纪50年代，Clarke等¹⁴⁹在一组严重心绞痛患者中测试了EDTA的效果，发现20名患者中的17人在重复输注EDTA后症状和心电图有显着改善。根据这些观察结果，尽管缺乏强有力的临床试验来评估其疗效，但在 Clarke 首次报告 50 年后，人们仍然继续使用 EDTA 治疗心绞痛和其他形式的动脉粥样硬化疾病，直到 2002 年 TACT 启动。 TACT 是一项双盲、安慰剂对照临床试验，旨在研究螯合疗法治疗冠状动脉疾病的疗效。主要终点是不良心血管事件的复合终点，包括死亡、再梗死、中风和心绞痛住院治疗。令人惊讶的是，该试验表明，接受螯合治疗的患者主要终点风险略有降低，但具有统计学显着性。这一意想不到的结果引发了广泛的讨论和进一步的研究。 ¹⁶²

Epidemiological investigations have also explored the role of antioxidants and dietary modifications in reducing the impact of heavy metal exposure. These studies emphasize the potential of antioxidants and certain antioxidant-rich foods as adjunctive treatments.¹⁶³
流行病学调查还探讨了抗氧化剂和饮食调整在减少重金属暴露影响方面的作用。这些研究强调了抗氧化剂和某些富含抗氧化剂的食物作为辅助治疗的潜力。 ¹⁶³

Basic Experimental Models
基本实验模型

Cellular Models 蜂窝模型

As exposure to heavy metals can lead to serious cardiovascular complications, cell models have emerged as indispensable tools for investigating the related underlying mechanisms. Various cell types have been used to study heavy metal–induced cardiotoxicity, including cardiomyocytes,¹⁶⁴ endothelial cells (eg, EA.hy926),^165,166 fibroblasts, and vascular smooth muscle cells.¹⁶⁷
由于接触重金属可能导致严重的心血管并发症，细胞模型已成为研究相关潜在机制不可或缺的工具。多种细胞类型已被用于研究重金属诱导的心脏毒性，包括心肌细胞、 ¹⁶⁴内皮细胞（例如EA.hy926）、 ^165、166成纤维细胞和血管平滑肌细胞。 ¹⁶⁷

Pluripotent stem cell–derived cardiomyocytes offer a useful alternative to human primary cardiac myocytes for evaluating function and understanding heavy metal–induced cardiovascular toxicity, particularly as primary cardiac myocytes are difficult to obtain and maintain in vitro.^168–170 Moreover, pluripotent stem cell–derived cells can be utilized to assemble 3-dimensional model structures. The generation of 3-dimensional tissues has enabled the speeding up of the maturation of pluripotent stem cell–derived cardiomyocytes and made it possible to capture the complex organ-level interactions of the adult human heart more accurately in vitro.¹⁶⁸
多能干细胞衍生的心肌细胞为人类原代心肌细胞提供了一种有用的替代品，用于评估功能和了解重金属诱导的心血管毒性，特别是因为原代心肌细胞难以在体外获得和维持。 ^168–170此外，多能干细胞衍生的细胞可用于组装 3 维模型结构。 3维组织的产生加速了多能干细胞衍生的心肌细胞的成熟，并使得在体外更准确地捕捉成人心脏复杂的器官水平相互作用成为可能。 ¹⁶⁸

Overall, cell-based studies have revealed a number of heavy metal–induced cardiotoxicity mechanisms, including oxidative stress, inflammation, mitochondrial dysfunction, and cell death pathways. Compounds with antioxidant, anti-inflammatory, and chelating properties have also shown promise in protecting such cardiac cells against metal-induced damage (Table 2).
总体而言，基于细胞的研究揭示了许多重金属诱导的心脏毒性机制，包括氧化应激、炎症、线粒体功能障碍和细胞死亡途径。具有抗氧化、抗炎和螯合特性的化合物也显示出在保护此类心肌细胞免受金属诱导的损伤方面的前景（表 2 ）。

Table 2. Representative Studies of Heavy Metal Cardiovascular Toxicity Using Animal Models and Cellular Models
表 2 .利用动物模型和细胞模型进行重金属心血管毒性的代表性研究

Heavy metals 重金属	Model		Exposure duration 曝光时间	Concentration 专注	Toxic effect 毒性作用	Ref
Arsenic (As) 砷（As）	Animal models 动物模型	Apolipoprotein E knock-out (apoE^−/−) mice (C57BL/6 background) 载脂蛋白 E 敲除 (apoE ^−/− ) 小鼠（C57BL/6 背景）	13 wk 13周	10–200 ppb 10–200ppb	Increased atherosclerotic plaque size 动脉粥样硬化斑块尺寸增加	³⁰
		Apolipoprotein E knock-out (apoE^−/−) mice; ApoE^−/− and As3mt^−/− double knockout mice (C57BL/6 background) 载脂蛋白 E 敲除 (apoE ^−/− ) 小鼠； ApoE ^−/−和 As3mt ^−/−双敲除小鼠（C57BL/6 背景）	13 wk 13周	200 ppb 200ppb	As3MT is required for arsenic to induce reactive oxygen species and promote atherosclerosis 砷需要As3MT来诱导活性氧并促进动脉粥样硬化	³¹
		Wistar rats 维斯塔鼠	200 d 200天	50 ppm	Elevated blood pressure and oxidative stress 血压升高和氧化应激	¹⁷¹
		Wistar rats 维斯塔鼠	4 wk 4周	5 mg/kg body weight 5毫克/公斤体重	Increased cardiac markers in serum and oxidative stress markers in heart; decreased level of serum high-density lipoprotein cholesterol 血清中的心脏标志物和心脏中的氧化应激标志物增加；血清高密度脂蛋白胆固醇水平降低	¹³³
		Rabbit 兔子	18 wk 18周	5 mg/L 5毫克/升	Endothelial dysfunction and impaired nitric oxide formation 内皮功能障碍和一氧化氮形成受损	¹⁷²
	Cellular models 蜂窝模型	PAECs PAEC	24 h 24小时	1, 2.5, 5, 10, 25, 30, 40 μM	Downregulated endothelial nitric oxide synthase 下调内皮一氧化氮合酶	¹⁷³
		HUVECs 人脐静脉内皮细胞	3 h 3小时	0.5 μM 0.5μM	Endothelial cells and polymorphonuclear neutrophils activation; inflammation 内皮细胞和多形核中性粒细胞活化；炎	¹⁷⁴
		Human microvessel-derived endothelial cell 人微血管源性内皮细胞	24 h 24小时	0.5, 1, 5, 10 μM 0.5、1、5、10μM	Apoptosis; endothelial dysfunction; downregulated thrombin responses; disturbed Ca²⁺ homeostasis 细胞凋亡；内皮功能障碍；下调凝血酶反应； Ca ²⁺稳态紊乱	¹⁷⁵
Lead (Pb) 铅（Pb）	Animal models 动物模型	Wistar rats 维斯塔鼠	30 d 30天	First dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g 首剂：10μg/100g；后续剂量：0.125 μg/100 g	Vascular dysfunction; oxidative stress; inflammatory; activation of the MAPK 血管功能障碍；氧化应激；炎症； MAPK的激活	⁴³
		Wistar rats 维斯塔鼠	3 d 3天	25, 50, 100 mg/kg 25、50、100毫克/公斤	Increase cardiac enzymes, lactate dehydrogenase, and creatine kinase; changes in histopathology 增加心肌酶、乳酸脱氢酶、肌酸激酶；组织病理学变化	¹⁷⁶
		Sprague-Dawley control rats Sprague-Dawley对照大鼠	3 mo 3个月	0.01% lead acetate 0.01%醋酸铅	Elevation of blood pressure 血压升高	⁴⁵
		Pregnant ICR mice 怀孕的ICR小鼠	From gestation day 1.5 until offspring weaning 从妊娠第1.5天到后代断奶	50 mg/kg per day 每天 50 毫克/公斤	Offspring mice exhibit heart dysfunction; cardiomyocyte sarcomere dysplasia; mitochondrial dysfunction 后代小鼠表现出心脏功能障碍；心肌细胞肌节发育不良；线粒体功能障碍	¹⁷⁷
		Swiss albino mice 瑞士白化小鼠	24 h 24小时	50 mg/kg body weight 50毫克/公斤体重	DNA damage; ROS generation; inflammation DNA损伤； ROS生成；炎	¹⁷⁸
		Wistar rats 维斯塔鼠	7 d 7天	First dose: 8 μg/100 g of Pb acetate; subsequent dose: 0.1 μg/100 g once a day 第一剂：8μg/100g醋酸铅；后续剂量：0.1μg/100g，每天一次	Oxidative stress; increased systolic blood pressure 氧化应激；收缩压升高	¹⁷⁹
	Cellular models 蜂窝模型	HUVECs 人脐静脉内皮细胞	24 h 24小时	Plasma from upper lead acetate treated rats 来自上层醋酸铅治疗大鼠的血浆	Reduction of circulating NO 减少循环NO	¹⁷⁹
		Rat aortic endothelial cells 大鼠主动脉内皮细胞	1, 24, 48 h 1、24、48小时	0, 0.01, 0.1, 0.5, 1.0 ppm 0、0.01、0.1、0.5、1.0 ppm	Oxidative stress; inactivation of endothelium-derived nitric oxide; lipid peroxidation 氧化应激；内皮源性一氧化氮的失活；脂质过氧化	⁴⁴
		Human myocardial cells (AC16) 人心肌细胞（AC16）	24 h 24小时	0, 0.5, 1, 2, 4, 8, 16, 32 μg/mL 0、0.5、1、2、4、8、16、32 微克/毫升	Oxidative stress; inflammation; apoptosis 氧化应激；炎;细胞凋亡	¹⁶⁴
		Rat cardiomyocyte H9c2 cell lines 大鼠心肌细胞H9c2细胞系	12, 24 h 12、24小时	25, 50, 100, 200 μM 25、50、100、200μM	Increased expression of CYP1A1 CYP1A1 表达增加	¹⁷⁶
Mercury (Hg) 汞 (Hg)	Animal models 动物模型	Wistar rats 维斯塔鼠	30 d 30天	First dose, 4.6 μg/kg; subsequent dose, 0.07 μg/kg per day 首剂，4.6 μg/kg；后续剂量，每天 0.07 μg/kg	Oxidative stress; decreased NO bioavailability; endothelial dysfunction 氧化应激； NO生物利用度降低；内皮功能障碍	¹⁸⁰
		Wistar rats 维斯塔鼠	28 d 28天	40 mg/kg 40毫克/公斤	Increased oxidative stress and decreased levels of glutathione along other antioxidant enzymes 氧化应激增加，谷胱甘肽及其他抗氧化酶水平降低	¹⁸¹
		ICR mice ICR小鼠	2 or 4 wk 2或4周	50 or 500 μg/kg per day HgCl₂ or 20 μg/kg per day MeHg 每天 50 或 500 μg/kg HgCl 每天₂或 20 μg/kg MeHg	Elevated blood glucose and plasma lipid peroxidation 血糖升高和血浆脂质过氧化	¹⁸²
	Cellular models 蜂窝模型	β-cell–derived HIT-T15 cells; isolated mouse islets β细胞衍生的HIT-T15细胞；分离的小鼠胰岛	5 min, 1 h, 4 h 5分钟、1小时、4小时	0.5, 1 μmol/L 0.5、1μmol/L	Elevated of oxidative stress and Pik3 activity 氧化应激和 Pik3 活性升高	¹⁸²
	Cellular models 蜂窝模型	BPAECs 双酚AEC	0–120 min 0–120 分钟	0, 1, 5, 10, 15, 25, 50 μM	Activation of phospholipase A2; release of arachidonic acid 磷脂酶A2的激活；花生四烯酸的释放	⁶⁹
Cadmium (Cd) 镉 (Cd)	Animal models 动物模型	ICR mice ICR小鼠	8 wk 8周	100 mg/L CdCl₂ via drinking water 100 mg/L CdCl ₂通过饮用水	Oxidative damage, hypertension, and vascular dysfunction. 氧化损伤、高血压和血管功能障碍。	⁷⁹
		Apolipoprotein E knockout (ApoE^−/−) mice 载脂蛋白 E 敲除 (ApoE ^−/− ) 小鼠	28 d 28天	100 mg/L CdCl₂ via drinking water 100 mg/L CdCl ₂通过饮用水	Endothelial dysfunction; increased total cholesterol levels 内皮功能障碍；总胆固醇水平升高	⁸¹
		C57BL/6 mice C57BL/6小鼠	4 wk 4周	20 nmol/kg 20纳摩尔/千克	Heart dysfunction; increased DNA methylation 心脏功能障碍； DNA甲基化增加	¹⁸³
		Sprague-Dawley rats 斯普拉格-道利大鼠	10 wk 10周	15 ppm CdCl₂ via drinking water 饮用水中含有 15 ppm CdCl ₂	Imbalance in the MMP-TIMP system; cardiac inflammation MMP-TIMP系统失衡；心脏炎症	¹⁸⁴
		Wistar rats 维斯塔鼠	30 d 30天	5 mg/kg body weight 5毫克/公斤体重	Distorted myofibrils arrangement; vacuolization and congestion in the vessels; oxidant-antioxidant imbalance; inflammation; apoptosis; DNA damage 肌原纤维排列扭曲；血管内空泡化和充血；氧化剂-抗氧化剂失衡；炎;细胞凋亡； DNA损伤	¹⁸⁵
	Cellular models 蜂窝模型	Endothelial hybrid cell line (EA. hy926) 内皮杂交细胞系（EA.hy926）	2–24 h 2-24小时	10–1000 nmol/L 10–1000 纳摩尔/升	Inhibition of NO production by blocking eNOS phosphorylation 通过阻断 eNOS 磷酸化来抑制 NO 产生	⁸⁵
		NIH 3T3 cells 美国国立卫生研究院 3T3 细胞	12 h 12小时	15 μM 15μM	Cell death triggered by ER stress and involving caspase-12 内质网应激引发的细胞死亡并涉及 caspase-12	⁸⁷
		Human bronchial epithelial cells 人支气管上皮细胞	24 h 24小时	5, 10, 20, 30, 40, 50, 60, 70, 80 μM	Decreased cell viability; declined mitochondrial membrane potential; oxidative stress; apoptosis; activate JNK, ERK, and p38 MAPK 细胞活力下降；线粒体膜电位下降；氧化应激；细胞凋亡；激活 JNK、ERK 和 p38 MAPK	¹⁸⁶
		H9 embryonic stem cell-derived cardiomyocytes H9胚胎干细胞来源的心肌细胞	0–23 h 0–23小时	0–100 μM 0–100μM	Reduced cell viability; apoptosis; cardiac sarcomeric disorganization; elevated reactive oxygen; cardiac arrhythmias 细胞活力降低；细胞凋亡；心脏肌节紊乱;活性氧升高；心律失常	¹⁶⁹
		H9 embryonic stem cell–derived endothelial cells H9胚胎干细胞来源的内皮细胞	24 h 24小时	0–100 μM 0–100μM	Apoptosis; endothelial dysfunction 细胞凋亡；内皮功能障碍	¹⁷⁰
Hexavalent chromium (Cr (VI)) 六价铬 (Cr(VI))	Animal models 动物模型	Wistar rats 维斯塔鼠	35 d 35天	4 mg/kg body weight 4毫克/公斤体重	Hematologic variations; oxidative stress; heart dysfunction; structure disorder; cardiomyocyte apoptosis 血液学变异；氧化应激；心脏功能障碍;结构紊乱；心肌细胞凋亡	¹⁰⁶
		Swiss mice 瑞士老鼠	6 wk 6周	1.5 mg/kg 1.5毫克/公斤	Changes in the lymphatic space, blood vessels, and SOD activity 淋巴空间、血管和 SOD 活性的变化	¹⁸⁷
		Kunming mice 昆明小鼠	30 d 30天	0.25 mg/kg, 0.50 mg/kg 1.25 mg/kg 0.25毫克/公斤、0.50毫克/公斤、1.25毫克/公斤	Oxidative stress; lipid accumulation; impaired glucose tolerance 氧化应激；脂质堆积；糖耐量受损	¹⁸⁸
	Cellular models 蜂窝模型	HUVECs;THP-1 cells HUVEC；THP-1 细胞	24 h 24小时	20 μM, 3 μM separately 分别为 20 μM、3 μM	Endothelial dysfunction; monocyte inflammation; cell adhesion 内皮功能障碍；单核细胞炎症；细胞粘附	¹⁰⁷
	Cellular models 蜂窝模型	HUVECs 人脐静脉内皮细胞	24 h 24小时	10, 20, 40, 60, 80, 100, 150, 200 μM	Oxidative stress; inflammation; apoptosis by activating mitochondrial apoptosis pathways 氧化应激；炎;通过激活线粒体凋亡途径来促进细胞凋亡	¹⁰⁸

BPAEC indicates bovine pulmonary artery endothelial cell; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; HUVEC, human umbilical vein endothelial cell; ICR mice, Institute of Cancer Research mice; JNK, c-Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NIH 3T3 cells, National Institutes of Health 3T3 cells; PAEC, porcine aortic endothelial cell; ROS, reactive oxygen species; THP-1, Tohoku Hospital Pediatrics-1; and TIMP, tissue Inhibitor of metalloproteinase.
BPAEC表示牛肺动脉内皮细胞； eNOS，内皮一氧化氮合酶； ER，内质网； ERK，细胞外信号调节激酶； HUVEC，人脐静脉内皮细胞； ICR小鼠，癌症研究所小鼠； JNK，c-Jun N 末端激酶； MAPK，丝裂原激活蛋白激酶； MMP，基质金属蛋白酶； NIH 3T3细胞，美国国立卫生研究院3T3细胞； PAEC，猪主动脉内皮细胞； ROS，活性氧； THP-1，东北医院儿科-1；和 TIMP，金属蛋白酶组织抑制剂。

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Animal Models 动物模型

Animal models are essential in studying heavy metal toxicity, as they allow controlled exposure conditions, repeated measurements, and the ability to dissect molecular and cellular mechanisms. Additionally, ethical considerations often restrict direct human experimentation, making animal models crucial for advancing our understanding of how such metals operate in vivo.
动物模型对于研究重金属毒性至关重要，因为它们可以控制暴露条件、重复测量以及剖析分子和细胞机制的能力。此外，伦理方面的考虑常常限制直接的人体实验，因此动物模型对于增进我们对此类金属在体内如何运作的理解至关重要。

Various species have been used to study heavy metal toxicity, including rodents, fish,¹⁸⁹ and nonhuman primates.¹⁹⁰ Rodents are the most common choice due to their relative genetic similarity to humans and ease of handling in laboratory settings.
多种物种已被用于研究重金属毒性，包括啮齿动物、鱼类、 ¹⁸⁹和非人类灵长类动物。 ¹⁹⁰啮齿动物是最常见的选择，因为它们与人类的遗传相似性并且易于在实验室环境中处理。

Animal studies have helped reveal heavy metal toxicity mechanisms such as oxidative stress, inflammation, DNA damage, and interference with essential minerals, thus aiding in therapeutic interventions and preventive strategies (Table 2).
动物研究有助于揭示重金属毒性机制，如氧化应激、炎症、DNA 损伤和必需矿物质的干扰，从而有助于治疗干预和预防策略（表 2 ）。

Based on these animal-derived in vivo/vitro models, along with studies of human samples, many cutting-edge techniques can be used for mechanistic studies. These include RNA sequencing (RNA-seq) and epigenotyping by sequencing (epiGBS) to assess gene expression and DNA methylation changes; and single-cell RNA sequencing to analyze gene expression profiles of specific cells.^191–193 Such high-throughput technologies can provide a more detailed and fuller insight into the heavy metal toxic mechanisms and aid in the development of therapeutic strategies.
基于这些动物体内/体外模型，以及对人体样本的研究，许多尖端技术可用于机理研究。其中包括 RNA 测序 (RNA-seq) 和通过测序进行表观基因分型 (epiGBS)，以评估基因表达和 DNA 甲基化变化；以及单细胞 RNA 测序来分析特定细胞的基因表达谱。 ^191–193这种高通量技术可以提供对重金属毒性机制更详细、更全面的了解，并有助于制定治疗策略。

In Silico and Computational Models
计算机模型和计算模型

Computational models also can play pivotal roles in the understanding and prediction of heavy metal toxicity.
计算模型在理解和预测重金属毒性方面也可以发挥关键作用。

Quantitative structure-activity relationship models are computational tools used to predict the biological or pharmacological activity of molecules based on their chemical structure. One Quantitative structure-activity relationship model was used to predict heavy metal mixture toxicity. This revealed additive, synergistic, and antagonistic effects based on ionization potential, the first hydrolysis constant, and formation constant value.¹⁹⁴ In another study, such a model also characterized binding constants between p53 and metal ions, revealing strong binding affinity between Cd²⁺/Hg²⁺/Pb²⁺ and p53.¹⁹⁵
定量结构-活性关系模型是用于根据分子的化学结构预测分子的生物或药理活性的计算工具。一种定量构效关系模型用于预测重金属混合物的毒性。这揭示了基于电离势、第一水解常数和形成常数值的加和、协同和拮抗效应。 ¹⁹⁴在另一项研究中，此类模型还表征了 p53 和金属离子之间的结合常数，揭示了 Cd ²⁺ /Hg ²⁺ /Pb ²⁺和 p53 之间的强结合亲和力。 ¹⁹⁵

Physiologically based pharmacokinetic models simulate heavy metal absorption, distribution, metabolism, and excretion within the body by considering physiological parameters and chemical properties. These have been used to assess cadmium toxicological reference values for the US population,¹⁹⁶ describe the toxicokinetics of Cr (III) and Cr (VI) in humans,¹⁹⁷ evaluate oral exposure to relatively low levels of arsenic in water or food in human health risk,¹⁹⁸ and predict distributions of blood MeHg as a function of MeHg intake.¹⁹⁹
基于生理学的药代动力学模型通过考虑生理参数和化学性质来模拟重金属在体内的吸收、分布、代谢和排泄。这些已用于评估美国人口的镉毒理学参考值， ¹⁹⁶描述了人体中 Cr (III) 和 Cr (VI) 的毒代动力学， ¹⁹⁷评估口服暴露于水或食物中相对较低水平的砷对人类健康的风险， ¹⁹⁸并预测血液 MeHg 的分布作为 MeHg 摄入量的函数。 ¹⁹⁹

Advanced computational techniques such as machine learning and artificial intelligence have also been incorporated to analyze large datasets related to heavy metal toxicity. Five machine learning models were established to identify the links between heavy metal exposure and coronary heart disease based on datasets from the NHANES (2003–2018).²⁰⁰ Using this data from the NHANES (2003–2016), another machine learning model achieved an accuracy rate of 77.40%, identifying Pb and Cd as primary determinants of hypertension.²⁰¹
机器学习和人工智能等先进计算技术也被用来分析与重金属毒性相关的大型数据集。基于 NHANES（2003-2018）的数据集，建立了五个机器学习模型来识别重金属暴露与冠心病之间的联系。 ²⁰⁰利用 NHANES（2003-2016 年）的数据，另一个机器学习模型的准确率达到 77.40%，将 Pb 和 Cd 确定为高血压的主要决定因素。 ²⁰¹

The comprehensive understanding of heavy metal–induced cardiotoxicity relies on a multimodel approach encompassing in vitro cell cultures, animal models, and computational tools. Each model offers unique advantages and addresses specific research questions, contributing to a holistic assessment of heavy metal-related cardiovascular health risks.
对重金属引起的心脏毒性的全面理解依赖于包括体外细胞培养、动物模型和计算工具的多模型方法。每种模型都具有独特的优势并解决特定的研究问题，有助于对与重金属相关的心血管健康风险进行全面评估。

CONCLUSIONS 结论

Over the past few decades, human activities have led to severe heavy metal pollution and resulted in increased heavy metal exposure. An expanding body of epidemiological and experimental evidence suggests a relationship between heavy metal exposure and CVD. Heavy metals may lead to different cardiac phenotypes through various mechanisms including increased oxidative activity, inflammatory responses, DNA damage, and interference with ion homeostasis. These ultimately result in endothelial dysfunction, vascular impairment, disruption of ion homeostasis, effects upon DNA methylation, and corresponding CVDs, such as hypertension, arrhythmias, and atherosclerosis.
过去几十年来，人类活动造成了严重的重金属污染，导致重金属暴露量增加。越来越多的流行病学和实验证据表明重金属暴露与心血管疾病之间存在关系。重金属可能通过多种机制导致不同的心脏表型，包括增加氧化活性、炎症反应、DNA损伤和干扰离子稳态。这些最终导致内皮功能障碍、血管损伤、离子稳态破坏、DNA甲基化影响以及相应的CVD，例如高血压、心律失常和动脉粥样硬化。

Chelation therapy is the most common treatment after heavy metal exposure. This acts by binding target metal ions and forming stable complexes to then excrete them from the body. Clinically, chelation therapy involves multiple administrations of an edetate disodium-based infusion that contains vitamins, heparin, electrolytes, and procaine. Despite Food and Drug Administration approval, chelation therapy still poses a slight risk, as presented by 4 cases of hypocalcemia-induced mortality recorded among millions of such infusions. Overall, further research is needed to improve our understanding of cardiovascular toxicity from heavy metal exposure.¹⁵⁴
螯合疗法是重金属暴露后最常见的治疗方法。它通过结合目标金属离子并形成稳定的复合物，然后将其从体内排出来发挥作用。临床上，螯合疗法涉及多次施用含有维生素、肝素、电解质和普鲁卡因的乙二胺四乙酸二钠输液。尽管获得了食品和药物管理局的批准，螯合疗法仍然存在轻微风险，数百万次此类输注中记录了 4 例低钙血症导致的死亡病例。总的来说，需要进一步的研究来提高我们对重金属暴露引起的心血管毒性的理解。 ¹⁵⁴

Epidemiological and basic studies are 2 effective methods to study heavy metal exposure. These studies have not only confirmed the relationship between heavy metal exposure and CVD but also confirmed the effectiveness of chelation therapy for heavy metal exposure through TACT investigation.¹⁵¹ Further molecular mechanisms underlying heavy metal–induced cardiovascular diseases have been thoroughly studied through in vitro and in vivo experiments using cell and animal models.
流行病学和基础研究是研究重金属暴露的两种有效方法。这些研究不仅证实了重金属暴露与CVD之间的关系，而且通过TACT研究证实了螯合疗法对重金属暴露的有效性。 ¹⁵¹通过使用细胞和动物模型进行的体外和体内实验，已对重金属诱发的心血管疾病的进一步分子机制进行了深入研究。

This review summarizes toxic heavy metals and their distribution, relationship with CVDs, molecular mechanisms, and treatment options after exposure. It also summarizes common research approaches and models for heavy metal toxicity studies, laying the foundation for future research on heavy metals and cardiovascular health issues.
本综述总结了有毒重金属及其分布、与 CVD 的关系、分子机制以及暴露后的治疗选择。总结了重金属毒性研究的常用研究方法和模型，为未来重金属与心血管健康问题的研究奠定了基础。

Currently, the impact of heavy metal exposure on cardiovascular health is still underestimated, and the assessment of multiple exposures to heavy metal risks in the environment poses a significant challenge. Therefore, it is imperative for future efforts to prevent and control environmental heavy metal pollution through the improvement of relevant public health policies and other effective measures. In addition, the development of analytical techniques for environmental heavy metal detection and multiexposure risk assessment remain crucial research directions for this field. The use of larger sample sizes, scientifically designed studies, strict controls, and confounding factors in high-quality prospective cohort studies will continue to help accurately assess the health risks posed by multiple exposures to heavy metals and their interactions with cardiovascular health, providing a scientific basis for the formulation of relevant public health policies.
目前，重金属暴露对心血管健康的影响仍然被低估，环境中多种重金属暴露风险的评估提出了重大挑战。因此，未来亟待通过完善相关公共卫生政策和其他有效措施来防治环境重金属污染。此外，环境重金属检测和多重暴露风险评估分析技术的发展仍然是该领域的重要研究方向。在高质量的前瞻性队列研究中使用更大的样本量、科学设计的研究、严格的控制和混杂因素将继续有助于准确评估多次接触重金属及其与心血管健康的相互作用所带来的健康风险，提供科学依据。制定相关公共卫生政策的依据。

Acknowledgments 致谢

Due to space limitations, the authors are unable to include all of the important articles on health; they also apologize to those investigators whom we omitted in this review.
由于篇幅限制，作者无法收录所有有关健康的重要文章；他们还向我们在本次审查中遗漏的调查人员致歉。

Footnote 脚注

Nonstandard Abbreviations and Acronyms
非标准缩写词和首字母缩略词

ALAD 阿拉德: aminolevulinic acid dehydratase
氨基乙酰丙酸脱水酶
DMSA 二甲基丙烯酸甲酯: dimercaptosuccinic acid 二巯基丁二酸
CVD: cardiovascular disease 心血管疾病
EDTA 乙二胺四乙酸: ethylenediaminetetraacetic acid
乙二胺四乙酸
eNOS 内皮型一氧化氮合酶: endothelial NO synthase 内皮NO合酶
HDL 高密度脂蛋白: high-density lipoprotein 高密度脂蛋白
ICAM-1: intercellular cell adhesion molecule-1
细胞间细胞粘附分子-1
IL 伊尔: interleukin 白细胞介素
LDL 低密度脂蛋白: low-density lipoprotein 低密度脂蛋白
MAPK: mitogen-activated protein kinases
有丝分裂原激活蛋白激酶
NF-κB 核因子κB: nuclear factor κ-light-chain-enhancer of activated B cells
活化 B 细胞的核因子 κ-轻链增强子
NHANES 国家卫生科学研究院: National Health and Nutrition Examination Survey
全国健康与营养检查调查
NLRP3: NOD-like receptor thermal protein domain associated protein 3
NOD样受体热蛋白结构域相关蛋白3
NO 不: nitric oxide 一氧化氮
ROS 活性氧: reactive oxygen species 活性氧
TACT 塔克特: Trial to Assess Chelation Therapy
评估螯合疗法的试验
TGF-β 转化生长因子-β: transforming growth factor-beta
转化生长因子-β
TNF-α 肿瘤坏死因子-α: tumor necrosis factor α 肿瘤坏死因子α
VCAM-1: vascular cell adhesion molecule-1
血管细胞粘附分子-1

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Abstract 抽象的

CLASSIFICATION OF HEAVY METALS AND CARDIOVASCULAR HAZARDS重金属和心血管危害的分类

Arsenic (As) 砷（As）

Lead (Pb) 铅（Pb）

Mercury (Hg) 汞 (Hg)

Cadmium (Cd) 镉 (Cd)

Chromium (Cr) 铬 (Cr)

MECHANISMS OF HEAVY METAL–INDUCED CARDIOTOXICITY重金属引起的心脏毒性机制

Oxidative Stress and ROS Generation氧化应激和 ROS 生成

Inflammatory Reactions 炎症反应

Endothelial Dysfunction and Vascular Impairment内皮功能障碍和血管损伤

Lipid Metabolism Distribution脂质代谢分布

Disruption of Ion Homeostasis and Arrhythmia离子稳态的破坏和心律失常

Epigenomic Effects 表观基因组效应

Direct Cellular Damage and Apoptosis直接细胞损伤和凋亡

HEAVY METAL EXPOSURE PREVENTION AND TREATMENT重金属暴露预防和治疗

Public Health Prevention 公共卫生预防

Medical Interventions After Exposure暴露后的医疗干预

Chelation Therapy 螯合疗法

Antioxidant Supplementation补充抗氧化剂

HEAVY METAL EXPOSURE AND RESEARCH METHODS重金属暴露和研究方法

Epidemiological Studies 流行病学研究

Basic Experimental Models基本实验模型

Cellular Models 蜂窝模型

Animal Models 动物模型

In Silico and Computational Models计算机模型和计算模型

CONCLUSIONS 结论

Acknowledgments 致谢

Footnote 脚注

Nonstandard Abbreviations and Acronyms非标准缩写词和首字母缩略词

REFERENCES 参考

eLetters 电子信件

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Ziwei Pan

Tingyu Gong 11918392@zju.edu.cn

Ping Liang https://orcid.org/0000-0001-6806-3735 pingliang@zju.edu.cn

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CLASSIFICATION OF HEAVY METALS AND CARDIOVASCULAR HAZARDS
重金属和心血管危害的分类

MECHANISMS OF HEAVY METAL–INDUCED CARDIOTOXICITY
重金属引起的心脏毒性机制

Oxidative Stress and ROS Generation
氧化应激和 ROS 生成

Endothelial Dysfunction and Vascular Impairment
内皮功能障碍和血管损伤

Lipid Metabolism Distribution
脂质代谢分布

Disruption of Ion Homeostasis and Arrhythmia
离子稳态的破坏和心律失常

Direct Cellular Damage and Apoptosis
直接细胞损伤和凋亡

HEAVY METAL EXPOSURE PREVENTION AND TREATMENT
重金属暴露预防和治疗

Medical Interventions After Exposure
暴露后的医疗干预

Antioxidant Supplementation
补充抗氧化剂

HEAVY METAL EXPOSURE AND RESEARCH METHODS
重金属暴露和研究方法

Basic Experimental Models
基本实验模型

In Silico and Computational Models
计算机模型和计算模型

Nonstandard Abbreviations and Acronyms
非标准缩写词和首字母缩略词

Affiliations