Exposomic Determinants of Atherosclerosis: Recent Evidence

Abstract

Purpose of Review

The exposome refers to the total environmental exposures a person encounters throughout life, and its relationship with human health is increasingly studied. This non-systematic review focuses on recent research investigating the effects of environmental factors—such as air pollution, noise, greenspace, neighborhood walkability, and metallic pollutants—on atherosclerosis, a major cause of cardiovascular disease.

Recent Findings

Studies show that long-term exposure to airborne particulate matter can impair endothelial function and elevate adhesion molecule levels, leading to vascular damage. Nighttime traffic noise also negatively impacts endothelial health. On the other hand, living in areas with more greenspace and better neighborhood walkability is linked to reduced arterial stiffness, suggesting protective cardiovascular effects. Mechanisms involved include oxidative stress, inflammation, and sympathetic activation from air pollution and noise. Metallic pollutants, including lead, cadmium, and arsenic, are linked to early signs of atherosclerosis through mechanisms involving oxidative stress. However, the effects of specific pollutants and their interactions remain incompletely understood.

Summary

There is a growing need to mitigate harmful environmental exposures, such as air pollution and noise, while promoting beneficial ones like greenspace, to improve cardiovascular health. Emerging technologies like remote sensing and artificial intelligence can help further our understanding of how the exposome influences cardiovascular outcomes. More research is necessary to clarify the impact of specific pollutants as well as their interactions and how they contribute to atherosclerosis.

Introduction

Environmental exposures are increasingly recognized as important determinants of cardiovascular (CV) health and disease [1]. There is a wealth of data implicating factors such as air pollution, noise pollution, and components of the social environment as determinants of adverse CV outcomes. To date however, these factors are treated as individual factors and their role in CV disease investigated as though they exist in isolation, without interaction with other factors. The reality, however, is that each of exposures co-habitate the same space, have common origins, influence one another and accumulate over long durations. Thus a different approach, where the interdependencies of these exposures is captured is needed [2]. The concept of the exposome was originally proposed to encompass the totality of environmental exposures from conception that may impact human health [3]. Such a definition, however, is nearly impossible to actuate in real life, given the timelines and the need for unbiased analytical measurement approaches that provide certitude that one has accounted for all possible exposures. In recent years, studies have begun to explore a more limited definition of the exposome which comprises a large set of influential exposures, also referred to as the exposome, which are measurable, occur contemporaneously often with common sources and shared epidemiologic reasons [4]. The goal is to gain integrated insights into the impact of a set of meaningful exposures on human health [3, 5]. Given the importance of atherosclerotic CV disease (ASCVD) as the leading cause of global morbidity and mortality and given the fact that a preponderance of its attributable burden may originate from non-genomic, understanding the role of even a more limited set of impactful exposomic determinants could also be quite meaningful.

Ambient fine particulate matter air pollution is now well established as an atherosclerotic CV disease (ASCVD) risk factor [6]. Traffic-related noise pollution has also emerged as a pervasive environmental exposure detrimentally impacting vascular function [7, 8]. The impact of features in the natural environment such as greenspace and the built environment such as roads, land use and neighborhood walkability is now well described [5]. The specific constituents and properties of complex environmental exposures, that mediate their effects remain to be better elucidated. Additionally, the nature of their interactions and their contribution to CV disease warrant further investigation, given their common origins and shared physical spaces. Given that many surrogates in CV disease may provide a glimpse into potential causality, initiation mechanisms and importantly serve as harbingers of major adverse cardiovascular outcomes, evidence that exposomic influences encountered in daily life may contribute to CV surrogates is a very worthwhile and clinically meaningful endeavor. A greater awareness of these exposure-outcome relationships can inform strategies and policies to reduce the environmental burden of ASCVD. This review examines recent human studies on key environmental exposures including air pollution, noise, greenspace, neighborhood walkability, metallic pollutants, and built environment in relation to markers of ASCVD burden.

The Concept of the Environmental Exposome

According to the World Health Organization (WHO), an estimated 12.6 million deaths each year are attributable to unhealthy environments with stroke (2.5 million deaths annually) and ischemic heart disease (2.3 million deaths annually) being the top causes of environmental-related deaths [9]. In some countries in South Asia and Africa, these exposures are responsible for over 40% of the CVD burden [10]These estimates are likely an underestimate, given limited data on various exposures and the relatively few epidemiological studies that assess the role of environmental factors in CV disease. There is a need to examine ASCVD within an exposomic framework, which can help identify distinct downstream pathways and gain valuable mechanistic insights into the combinative effects of environmental exposures. This understanding is crucial for comprehending how daily life, work, and commuting-related environmental exposures influence the development and progression of CV disease. Moreover, understanding the intricate interaction between different components of the environment with each other and with and CV health has the potential to inform large-scale preventive interventions [3].

Human Studies on the Association between Exposomic Factors and Markers of Atherosclerosis Burden

Air Pollution

Prior studies have extensively reviewed the relationship of air pollution with endothelial dysfunction. Panel studies, cross-sectional and prospective longitudinal cohort studies have demonstrated a relationship between long-term exposure to PM_2.5 to endothelial function [11, 12]. A meta-analysis of 25 studies suggested a decrease in flow mediated dilation with long term but not short term increase in PM_2.5 (each 10 μg/m³ increment in short-term PM_2.5 exposure and long term PM_2.5, flow-mediated dilation (FMD) decreased by 0.17% (95% CI: − 0.33%, − 0.00%) and 0.99% (95% CI: − 1.41%, − 0.57%) respectively [13]. Studies of microvascular function using agonist mediated plethysmographic studies in response to diesel exhaust exposures have shown a diminution in response to short-term concentrated exposures. On the other hand, digital microvascular function which is much less dependent on endothelial nitric oxide stimulation has been far more variable with some studies showing an association with pollution exposure [14] and others that have not [15]. Studies in the air pollution literature do not pay heed to the complexity of assessment of endothelial function and tend to lump studies of microvascular function with conduit vessel function leading to interpretative difficulties that is compounded by the variability in levels and compositional differences. Studies have also assessed the relationship between atherosclerosis burden, when assessed by carotid intimal media thickness (CIMT), coronary and abdominal aortic calcium [6, 16, 17]. These once again tend to lump CIMT with other measures of atherosclerosis burden, despite the fact that CIMT may not be the best measures of atherosclerosis burden but a measure that captures some aspects of atherosclerosis such as the vascular remodeling that may occur with risk factor exposure [18]. A systematic study of CIMT along with other measures of atherosclerosis including coronary artery calcification, aortic valve calcification and thoracic aortic calcification concluded that although there are some studies that were neutral for the association, most displayed non-significant trends towards higher atherosclerosis burden with higher PM exposure [19]. Similarly studies of studies of aortic valve and abdominal valvular calcification have not always been consistent when examined in other cohorts and in some studies, near roadway distance as a proxy measure for traffic air pollution exposure has been a stronger predictor than PM_2.5 levels [18, 20–22]. Arterial stiffness as a surrogate, depends on a number of factors including arterial composition, shape, and hemodynamics and do not necessarily always reflect endothelial function. Studies of air pollution and stiffness measures have not always shown consistent findings. A study from the Framingham cohort did not find evidence for a relationship between carotid-femoral pulse-wave velocity, forward pressure wave amplitude, mean arterial pressure, and augmentation index and long- or short-term PM_2.5 exposure, particle number, sulfate, or ozone (O₃), whereas living closer to major roadway was associated with higher carotid-femoral pulse-wave velocity (0.11 m/s higher for living < 50 m vs. 400 ≤ 1000 m) [23]. This finding may suggest a differential PM composition near roads (e.g., for ultrafine particles with a diameter of less than 0.1 micrometers or 100 nanometers). Also, higher co-exposure to traffic noise and socioeconomic differences in people residing near major roadways may be a potential explanation for these results.

Traffic Noise Exposure

Extensive human evidence on the link between noise exposure and vascular (endothelial) dysfunction largely originate from a series of experimental studies in Germany [24]. These studies consistently demonstrated that simulated night-time traffic noise impairs FMD in both healthy individuals and patients at elevated CV risk. In the first study, healthy participants experienced three different aircraft noise scenarios (0, 30, and 60 overflights per night) in a randomized order [25]. Night-time aircraft noise exposure was correlated with reduced FMD (control group: 10.4%; noise 30: 9.7%; noise 60: 9.5%). Additionally, noise exposure decreased pulse transit time (control group: 271.8 ms; noise 30: 270.9 ms; noise 60: 264.9 ms), a parameter linked to increased blood pressure, vascular tone, stiffness, and atherosclerosis. Interestingly, the impairment of FMD was more pronounced when subjects were first exposed to 30 overflights followed by 60, indicating a noise-related sensitization rather than habituation (priming effect). Notably, in a small subgroup (n = 5) exposed to 60 overflights, a single dose of oral vitamin C improved FMD, suggesting that vascular reactive oxygen species may partly contribute to noise-induced endothelial dysfunction and atherosclerosis. In a subsequent study, patients with coronary artery disease or at increased risk (defined as having a high Framingham score of 23%) were exposed to 60 overflights (mean sound pressure level of 46.9 dB) and a control scenario with usual ambient noise (mean sound pressure level of 39.2 dB) [26]. The adverse effects on FMD were more pronounced in these patients (control group: FMD 9.6%; noise 60: FMD 7.9%) compared to the healthy subjects in the previous study. Comparing 60 vs. 120 overflights with the same mean sound pressure level in both scenarios showed FMD of 7.27% and 7.21%, respectively, compared to 10.02% in the control night [27]. Similarly, simulated railway noise exposure with a peak noise level of 65 dB and an average sound pressure level up to 54 dB(A) (30–60 trains per night) significantly deteriorated endothelial function in healthy subjects [28]. As previously shown, endothelial function could be significantly improved by acute oral administration of vitamin C (two grams orally).

A study conducted in Poland demonstrated that long-term aircraft noise exposure (> 60 dB L_den) was associated with higher pulse wave velocity and an increased prevalence of arterial hypertension [29]. Interestingly, it was shown that a short-term noise reduction during the COVID-19 lockdown can reverse the observed negative CV effects [29, 30]. Results from the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA) indicated long-term exposure to railway noise, as well as nighttime noise events mainly related to road traffic noise to be associated with increased brachial-ankle pulse wave velocity [31].

Built Environment, Walkability and Greenspace

Prior American Heart Association statements and a recent document on Urban Environments have compiled the evidence on built environment, transportation, green space and CV/metabolic health [32, 33]. We provide evidence between these aspects of the environment and CV surrogates.

Built Environment

Many aspects of urban design and land use characteristics may not only influence exposures to pollutants but also directly impact CV and metabolic health by indirectly modulating mobility, housing, transport mode and recreational and green space [33, 34]. Previous reviews have extensively reviewed how design features including the 11D and 5-D framework encompassing design, density (of population, housing, and jobs), diversity (of land use), destination (access) and distance (to transit and other non-motorized modes) may all influence exposure to air pollution [34].

Walkability

Active transportation is contingent on availability of walkable neighborhoods and green space suggesting an overlap with such areas and conversely a non-overlap with areas of built environment. Studies have shown that neighborhood walkability is linked with lower risk of atherosclerotic CV disease and risk factors [35–37]. In 2 population-based Canadian cohorts, higher levels of walkability and park accessibility were both associated with significantly lower odds of self-reported hypertension, especially for lower income individuals. Mediation analysis showed that obesity accounted for 50% and 52.9% of the total effect of walkability and park accessibility on hypertension, respectively, meaning that living in walkable areas or near parks is associated with lower odds of hypertension, partially through reductions in obesity [38]. In a randomized crossover study, cardiovascular and pulmonary responses in patients with pre-existing chronic obstructive pulmonary disease or ischemic heart disease who walked in a crowded street in London were compared to those who took a similar walk in Hyde Park. Walking in Hyde Park led to an increase in lung function and decreases in pulse wave velocity and augmentation index, whereas the converse was observed while walking in a crowded street with heavy traffic [39].

Green and Blue Spaces

There is growing evidence supporting an association between green space exposure and cardiometabolic health [40–45]. The distinction between natural green space versus green infrastructure deserves consideration and it is not always clear from studies which is being referred to [46]. A meta-analysis of 23 studies found that increased residential greenery (based on satellite derived indices) was associated with significantly lower systolic and diastolic blood pressure [47]. Several meta-analyses suggest an association between urban greenness and CV and cerebrovascular mortality [48]. At least some studies in urban environments indicate that multiple determinants besides proximity including size, contiguousness (non-fragmented) and spatial distribution may mediate the relationship between greenness and CV health [49]. Relatively few studies have addressed the association of blue spaces and coronary artery calcification (CAC). In an analysis from CARDIA, the association between green and blue spaces (proximity to a river or shoreline) and CAC was investigated. in 1365 Black and 1555 White participants [50]. There was no statistical interaction between the blue and green spaces and race or neighborhood characteristics in association with CAC. Among Black participants, shorter distance to a river and greater green space cover were associated with lower odds of CAC (per interquartile range decrease [1.45 km] to the river: odds ratio [OR], 0.90 [95% CI, 0.84–0.96]; per 10%-point increase of green space cover: OR, 0.85 [95% CI, 0.75–0.95]). Black participants in deprived neighborhoods had lower odds of CAC with shorter distance to a river (per an interquartile range decrease: OR, 0.90 [95% CI, 0.82–0.98]) and greater green space cover (per a 10%-point increase: OR, 0.85 [95% CI, 0.75–0.97]) [50].

A Chinese study investigated the impact of residential green spaces and neighborhood walkability on coronary atherosclerosis in 2,021 adults with suspected coronary heart disease [51]. The research found that increased availability of green spaces within a 1-km radius was associated with reduced atherosclerosis, while higher neighborhood walkability was linked to an increase in coronary artery calcification. The combined exposure to a green space area in a 1-km area and the walkability index were inversely associated with atherosclerosis, albeit with a smaller magnitude than a single-exposure model. Specifically, enhanced physical activity and reduced PM_2.5 partially explained the positive relationship with green spaces, while increased PM_2.5 exposure contributed to the negative impact of walkability. In the large UK Biobank cohort (N = 169,704), the association between the residential walkability index (defined as a function of residential, retail and public transit density, street-level design, and destination accessibility), greenness (measured via normalized difference vegetation, and pulse wave velocity was examined [52]. The authors demonstrated that higher walkability exposure and greenness (lowest vs. highest quartile) were associated with lower pulse wave velocity, which was pronounced in women and older adults. In contrast, in the UK-based Whitehall II Cohort Study (N = 4,349), no consistent associations between residential surrounding greenspace and carotid–femoral pulse wave velocity were observed [53].

Metallic Pollutants

The contribution of trace metals in cardiovascular disease is relatively understudied with the exception of specific metals such as lead, arsenic and cadmium [1, 54–57]. However it is clear that many metals play an important role in ASCVD. Humans are exposed to metals through a multitude of sources and routes including inhalation, ingestion via water and food, dermal contact with soil and dust. In recent years, it has become increasingly evident that exposure to metallic pollutants occurs broadly and often in unsuspected settings, given the ubiquitous presence and exposure due to widespread industrial and public usage.

Metals may induce oxidant stress directly or through broad interference with cellular glutathione levels leading to oxidative stress [54]. Recent evidence also supports a link between epigenetic regulation, via redox sensitive transcription factors that also serve as master epigenetic regulators. There is a growing body of evidence supporting the notion that exposure to nonessential metallic pollutants like lead, cadmium, and arsenic significantly contributes to ASCVD on a global scale [54].

Lead, cadmium, and arsenic exhibit correlations with early indicators of atherosclerosis. A study in Bangladesh with a 7-year follow-up, it was reported that an increase of 11.7 μm and 5.1 μm in CIMT was associated with a 1 standard deviation increase in urinary arsenic (357.9 μg/g creatinine) and well-water arsenic (102 μg/L), respectively [58]. Similarly, a study among the children from Mexico observed that long-term exposure to arsenic led to a 35-μm and 58-μm increase in CIMT for those with total urinary arsenic levels of 35–70 μg/L and > 70 μg/L, respectively, compared to those exposed to < 35 μg/L [59]. In a study in Swedish Malmö Diet and Cancer study CV cohort, it was found that individuals with blood lead levels (BLL) in the highest quartile had an OR of 1.35 (95% CI: 1.09–1.66) for the prevalence of atherosclerotic carotid plaque compared to those in the lowest quartile [60]. Similarly, a Korean study reported a positive association between BLL and the prevalence of moderate-to-severe coronary artery stenosis (CAS) in participants who underwent elective coronary CT angiography for early IHD [61]. Additionally, a recent study in NHANES participants found an independent positive correlation between the risk of subclinical myocardial injury and BLL, when the level was higher than 3.8 μg/dl [62]. A Swedish study found that individuals in the highest quartile of blood cadmium concentration had 2.6-time higher odds of having carotid artery plaques compared to those in the lowest quartile. Additionally, the risk of developing new plaques over a five-year follow-up was 1.8 (95% CI: 0.9–4.0) in the highest quartile. Another large Swedish study reinforced these findings, reporting 1.9-fold increased odds for the presence of any arterial plaque when comparing the highest quartile of blood cadmium to the lowest quartile. Furthermore, a recent Swedish study highlighted a significant positive association between blood cadmium levels and coronary artery calcium scores (CACS). Individuals in the highest quartile had a 60% higher estimated prevalence of high CACS (> 100 Agatston units) compared to those in the lowest quartile [63].

McGraw and colleagues recently show a relationship between urinary metal levels and atherosclerosis progression (measured by coronary artery calcium (CAC)) over 10-year period in > 6000 individuals in the multi-ethnic study of atherosclerosis [33]. The study focused on six metals: three non-essential (cadmium, tungsten, uranium) and three essential metals (cobalt, copper, zinc). Higher urinary levels of these metals were associated with higher CAC at baseline and over the follow-up period. Analysis of the overall metal mixture showed a strong positive association with CAC-SW, suggesting potential synergistic effects of multiple metal exposures [64].

Exposomic Pathophysiological Pathways

Although many of the exact mechanisms related to the association between exposomic factors and atherosclerosis remain unknown, some of the shared pathways have been identified. Major mechanisms shared by air pollution-, noise- and metallic pollution-associated atherosclerosis are oxidative stress, inflammation and the activation of the stress response [11, 65, 66]. These major pathways are presented in Fig. 1. Increase in oxidative stress has been observed in many of the exposure models, including air pollution [67], noise [68], and metallic pollution [69]. Oxidative stress is detrimental for the vascular function, as ROS can interfere with the nitric oxide (·NO) signaling [68]. Activated immune cells can also be sources of ROS, and the state of inflammation is generally associated with different exposomic factors. Air pollution-derived PM and metallic pollutants can interact directly with the surface receptors of immune cells, such as toll-like receptors, and generate pro-inflammatory cytokine release [70, 71]. Noise stress can also lead to increased inflammatory response, but through an indirect pathway, starting with the amygdala and the hypothalamic-pituitary-adrenal (HPA) axis and release of stress hormones [72, 73]. Air pollution and metallic pollution can also directly stimulate the central nervous system through the olfactory bulb tissue [74]. Systemic inflammation can also be initiated through the activation of the sympathetic nervous system and the release of catecholamines into the circulation [75]. The presence of the heightened inflammatory state can further drive activation of prothrombotic pathways [76]. Prothrombotic activation is one of the main mechanisms for atherosclerotic plaque onset and progression. In contrast, green spaces promote physical activity, which plays a key role in reducing obesity, a major risk factor for ASCVD. Physical activity helps decrease body weight, inflammation, and metabolic disturbances, thereby lowering the risk of hypertension and insulin resistance. Furthermore, green spaces contribute to stress reduction by lowering cortisol levels and attenuating sympathetic nervous system activation, offering additional cardiovascular protection [77, 78].

Fig. 1.

Exposomic determinants of atherosclerosis. Exposure to metallic pollutants from diverse sources occurs mostly through inhalation and ingestion. Air pollution, both gaseous and solid (particulate matter), enters the organism through inhalation where it causes pulmonary oxidative stress and inflammation. Pulmonary inflammation can gain systemic character leading to atherosclerotic plaque onset and progression, while oxidative stress has impact on the molecular level, causing lipid, protein and DNA oxidation. Noise acts on the brain’s stress response pathway, activating the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Chronic release of catecholamines and glucocorticoids from the adrenal glands facilitates systemic inflammation and leads to immune cell adhesion and penetration into the endothelial cell layer, causing atherosclerosis. Built environments, mostly through green spaces and walkable neighborhoods can improve atherosclerotic outcomes

New Tools for Integrated Cumulative Exposomic Impact and Impact Assessment

Health impact assessment approaches to date often examine health impact one at a time and with one exposure at a time. Approaches that incorporate the “exposome” - have been proposed by us and others [79–81]. The integration of climate, environmental, social and health data into common platforms and the use of machine learning and artificial intelligence (AI) to explore climate and human health effects provides an unprecedented opportunity for health impact assessment and policy.

In the field of exposure science, new sensor technologies offer the promise of portable—even wearable—monitors that can capture multiple human microenvironments in an integrated assessment for one or multiple chemicals. Such monitors can be combined with cell phone location information and video capability to gather extensive information about neighborhood level and/or personal environmental exposures. Place-based biomonitoring could be done to develop geospatial cumulative exposure profiles. Mapping tools can also highlight areas of concern where targeted biomonitoring might be warranted. Communities living in areas impacted by pesticides or industrial emissions could collaborate in the development of biomonitoring and results communication protocols. Systems science approaches, such as computational modeling and visualization tools, can help address complex issues related to climate change, pollution and health equity in a contextually rich approach that includes spatial relationships. In such approaches, an equally important dimension of the perception of the environment by actors in the system and their responses need are factored into the system. A key requirement for a full-chain equitable and fair HIA process is involvement of citizens and members of different communities whose voices are not usually heard, but provide critical input for equity and fairness. System dynamics involves the use of visual causal maps and formal mathematical computer simulation models to understand the origins of system behavior, analyze models for air pollution mitigation measures, leverage points for multilevel interventions, and indicators for tracking progress [82, 83]. Community engagement and integration of human involvement and engagement together with the role of unexpected factors and sometimes unseen factors in the environment such as neighborhood crime, racism and other unmeasured influences can be captured through community based systems dynamics approaches [84, 85].

High-resolution mass spectrometry (HRMS) allows measurement and identification of vast numbers of exogenous and endogenous compounds in a single analytical run. HRMS methods can detect small molecules such as pharmaceuticals, pesticides, microbial metabolites and other exogenous chemicals that may be present in exposures including air pollution. A variety of resources including, specialized lists compiled by, for example, the U.S. Environmental Protection Agency (EPA) and NORMAN Network often contain additional information to help annotate data. However, identification of chemical species is complicated by the fact that chemicals undergo transformation through reactions. While computational tools can predict transformations, merely predicting first order reactions is prohibitively challenging, let alone second order reactions. Approaches to reduce complexity and dimension reduction such as grouping of chemicals by their sources into groups as well as approaches such as environment wide association studies or EWAS which groups “exposures,” analogous to genotype variants, and links their relationship to a phenotype of interest. These approaches, while a step forward, do not begin to address substantial unresolved complexities in the field which include paucity of systematic data on the various dimensions of exposure, from bioavailability to protein-binding information and the kinetics of hundreds of reactions. Additional complexities in the statistical toolset and assumptions which assume all chemicals are randomly distributed and measured with equal precision, when in fact most chemicals represent communities of exposures. Thus, identifying exposomic relationships from high-dimensional data poses major statistical and computational challenges.

Recently we have demonstrated the value convolutional neural network (CNN)-extracted features from Google Satellite and Street views to explain significant portion of CV and coronary heart disease prevalence at the census tract level respectively [86, 87]. Compared with traditional factors or composite indices for social determinants of health, Google Street View provides unique information that may relate to CHD such as buildings, greenspace, and roads as suggested by the activation maps from Gradient-weighted Class Activation Mapping (Grad-CAM) technique. Our studies have provided proof of concept for machine vision–enabled identification of urban network features associated with risk that in principle may enable rapid identification and targeting interventions in at-risk neighborhoods to reduce CV burden.

Despite the promising potential of these new approaches, they also present significant logistical and financial challenges. High-quality sensor systems capable of measuring multiple exposures simultaneously can be expensive, potentially limiting large-scale deployment. The volume and complexity of data generated by these technologies require sophisticated data management and analysis infrastructure, which can be resource intensive. Ensuring data quality and comparability across different sensor systems and studies remains a challenge, as does the effective integration of exposomic data with clinical and genetic information.

Conclusions and Future Directions

Several knowledge gaps exist in linking the exposome to ASCVD health. Long-term effects of many environmental exposures, including climate change related exposures such as extreme temperatures, droughts, floods, hurricanes, and wildfires, as well as the combined environmental impact on ASCVD health, remain understudied, necessitating more comprehensive research approaches [3]. The interaction between the exposome and genomics is not well-explored, limiting our understanding of how environmental exposure affects specific genetic populations, crucial for tailored interventions. Additionally, interventions addressing the adverse impacts of environmental exposures on ASCVD health, especially in resource-limited areas, lack sufficient understanding and effectiveness evaluation. Related to this important issue, the impact of beneficial parts of the exposome to health and disease, e.g. exercise and greenspace, lacks systematic epidemiological and clinical exploration [88]. While progress has been made in understanding environmental exposure epidemiology, more research is essential to assess region- and population-specific interventions and enhance our understanding of the exposome’s effects on ASCVD health [5]. Lastly, it should be acknowledged that the majority of the findings discussed in this review focus on cardiovascular parameters that are predictive of certain aspects of atherosclerosis, such as endothelial dysfunction, rather than direct assessments of atherosclerosis itself, like CIMT or CAC. Therefore, future studies should focus on direct markers of atherosclerosis in order to provide a clear picture of the atherosclerotic effects of environmental exposures.

Data Availability

No datasets were generated or analysed during the current study.