Cardiovascular diseases (CVD) are the leading cause of mortality and a significant contributor to disability worldwide. According to the 2019 update of the global burden of disease (GBD) study, the total global mortality attributed to CVD continued to increase from 12.1 million in 1990 to 18.6 million in 2019 (1). Although often overlooked, environmental exposure is a crucial risk factor for CVD (2). Lead, primarily from industrial sources but still present in paints and fuels in some countries (3), contributes to nearly one million deaths and 21.7 million disability-adjusted life-years (DALY) globally (4). Unlike blood lead with a 30-day half-life, bone lead, lasting years to decades, more accurately indicates long-term exposure and accumulation.

Lead exposure is recognized as a risk factor for the incidence and mortality of CVD (4–6). Studies have reported that even at low levels, lead exposure can increase the incidence of hypertension, stroke, and other CVD. Emerging evidence has demonstrated an association between bone lead and resistant hypertension (7). A meta-analysis revealed that a 10 µg/g increase in bone lead was associated with a 0.26 mmHg increase in systolic blood pressure (SBP) (95% CI: 0.02–0.50) (8). In addition, Nitin B. Jain et al. reported that the group with increased bone lead levels were at higher risk for future ischemic heart disease (IHD), for the reason that lead exposure can damage the inner lining of blood vessels, leading to inflammation and the formation of plaque, which can cause the narrowing of blood vessels (9). Yang et al., in their 2017 prospective study on a population cohort, revealed a notable decrease in the left ventricle's systolic function due to environmental lead exposure (10).

Understanding the burden of CVD caused by chronic lead exposure is key for implementing prevention strategies, a comprehensive study is needed to provide a clear picture of the situation. Fortunately, the GBD Study 2019 has identified lead exposure as a risk factor for CVD. Therefore, we estimated spatial and temporal trends in the burden of lead-related CVD and identified heavily affected regions based on the latest data from GBD 2019 and improved methods. This information is vital for government and health system decision-making regarding the implementation of effective prevention and mitigation strategies.

This study aimed to estimate the worldwide impact of chronic lead exposure on CVD and analyze its 30-year patterns. The study found that the age-standardized death and DALY rates of CVD resulting from chronic lead exposure decreased over time. We visualized the temporal trends of all CVD, IHD, Stroke and HHD from 1990 to 2019 using Joinpoint analysis. Additionally, we found the inverse association between SDI and the lead-related age-standardized DALY and death rates of CVD. In 2019, the highest burden of CVD attributable to lead exposure was observed in the regions with low and low-middle SDI regions, including South Asia, North Africa and Middle East.

Over the past 30-years, there has been a significant decrease in the burden of chronic lead exposure-related CVD at the global level. However, this trend varies by region and country. Our findings indicate that, except for Central Asia, the ASR of deaths and DALYs related to CVD have decreased in most countries and regions, with the highest reduction observed in the high-SDI region, high-income Asia Pacific. Previous studies have highlighted the significant impact of environmental factors and lifestyle on the development of CVD (16). Therefore, the decline may be primarily attributed to the implementation of lead exposure reduction strategies and the increased health consciousness among the population (17, 18). Lead was classified as the second major toxic substances by the United States of America Agency for Toxic Substances and Disease Registry (ATSDR) in 2007, and was designated as a priority heavy metal by the Ministry of Food and Drug Safety. The policy of eliminating lead from gasoline, fuels and paints in high-SDI countries has significantly reduced the amount of lead in the environment, which has led to a substantial decrease in lead levels in the population (17, 19, 20). Similarly, many developing countries, including China and Indian, have implemented laws or policies aimed at reducing lead exposure (21, 22). The widespread use of statins and low-dose aspirin for primary and secondary prevention of CVD is another contributing factor (23, 24). Furthermore, significant advancements in medical technology and increased health awareness over the past 30 years have gradually lowered the burden of CVD associated with lead exposure.

Lead exposure continues to pose a significant health challenge for low- and middle-income countries (25). Our study also found the inverse association between the SDI and burden of lead exposure-related CVD. Several factors may explain the higher age-standardized death and DALY rates of lead exposure-related CVD in low SDI regions. Apart from potential shortcomings in law enforcement, low SDI regions might have worse medical, nutritional, educational or mental healthcare conditions, which increases the burden of CVD attributed to lead exposure. Also, the aging population in these regions makes them more susceptible to CVD (26). Environmental pollution and lead exposure control measures may not receive adequate attention or implementation is another reason. A recent study in the low- and middle-income countries indicated that informal lead acid battery recycling and manufacture, metal mining and processing, electronic waste, and the use of lead as a food adulterant, primarily in spices, were major sources of lead exposure (27). Therefore, to reduce the burden of CVD associated with lead exposure in the low and middle-income regions and countries, such as Central Asia (especially in Afghanistana and Uzbekistan), North Africa and Middle East (especially in Yemen and Sudan) and South Asia, it is crucial to improve the regulation of heavy metal and electronic industries, protect specially exposed individuals, and restrict the use of lead as food adulterants. On the other hand, increasing investments in the CVD prevention and treatment are essential. Improving cardiovascular health care and increasing awareness of the risks of stroke and lead exposure may also contribute to the global decline in lead exposure-related CVD burden (28). These measures also assist in reducing the burden of other diseases associated with lead exposure, such as idiopathic developmental intellectual disability (IDII) and chronic kidney disease (20, 29).

Our results indicated that the burden of CVD attributed to lead exposure were higher among males than females. There were several possible explanations for this gender difference. First, the distribution of risk factors for CVD, such as hypertension, diabetes, obesity, alcohol drinking and smoking, are different between males and females (30). Many studies have shown that smoking and alcohol consumption increased blood lead concentrations (31, 32), and males tend to have higher blood lead levels due to their higher prevalence of smoking and alcohol consumption. Second, estrogen plays a protective role in the cardiovascular system and contributes to the sex differences observed (33). Third, a higher proportion of males work in occupations with potential lead exposure, such as construction and mechanical work, which increases their exposure to lead (34). Notably, for the elderly population, the high lead-related burden of CVD related to lead exposure may be attributed to their greater susceptibility to lead exposure and the cumulative effects of lead exposure over time (35).

Lead exposure is associated with a significant burden of specific types of CVD, with IHD and stroke being the two leading causes, followed by HHD. Several studies have found that chronic lead exposure can cause lipid disturbance by altering lipid metabolism, leading to the increased prevalence of IHD and stroke (36). Furthermore, hypertension is a known risk factor for IHD and stroke (37, 38), and previous studies have shown a positive correlation between blood lead levels and elevated systolic and diastolic blood pressure (39, 40). The IHD related to lead exposure can be explained through multiple mechanisms, including its role in elevating blood pressure by increasing vascular tension and peripheral vascular resistance (41). Lead can impair kidney function and heighten the risk of chronic kidney disease (CKD) (42). Vaziri ND et al. have shown that long-term exposure to low levels of lead can intensify the deactivation of nitric oxide by reactive oxygen species. This leads to a functional deficiency of nitric oxide and a compensatory upregulation of nitric oxide synthase, resulting in increased blood pressure due to oxidative stress and endothelial dysfunction (43). Minkyeong Kim et al. discovered that lead exposure can induce inflammation by activating the nuclear transcription factor-κB, leading to cerebral vascular damage (35). Bruce P. Lanphear et al. found that lead contributes to the risk of stroke by elevating levels of oxidative stress (4, 44). Additionally, research by Marzie Boskabady et al. has identified that lead exposure increases pro-inflammatory cytokines, which in turn heightens the risk of stroke (31). Zheutlin et al. also reported that long-term lead exposure was associated with resistant hypertension (7). Therefore, chronic lead exposure significantly increases the risk of CVD, especially IHD and stroke (9).

The main advantage of our study is that it offers the first comprehensive assessment of the global burden of CVD attributable to chronic lead exposure using the latest estimated data of the GBD 2019. Although our study could raise awareness of the impact of lead exposure, there are some limitations to the GBD study. Firstly, the availability and quality of data vary in different countries, with lower SDI countries and regions potentially providing insufficient and inaccurate data, which could lead to biased results. Secondly, over the past 30 years, the GBD studies may have undergone changes in population proportions and CVD information, which is an inherent limitation of the series of GBD studies. Thirdly, in the GBD study, bone lead levels were calculated from blood lead rather than measured directly. Fourthly, GBD database did not collect data on the prevalence, awareness and treatment of lead-related CVDs. Finally, the coexistence of multiple chronic diseases is common in the older population, but the GBD study only identified one specific cause.

In conclusion, our study found that the elderly, males, and the low SDI regions, especially in South Asia, are at greater risk of CVD attributable to lead exposure. Furthermore, the global age-standardized deaths and DALYs rates of lead-related CVD have decreased gradually from 1999 to 2019. Based on our study results, we recommend that governments in low-SDI regions should strengthen the implementation of lead exposure prevention strategies and gradually raise awareness of self-protection among lead-exposed individuals to reduce the cardiovascular burden due to chronic lead exposure.