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Kolling Institute of Medical Research, Sydney, NSW, AustraliaFaculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCharles Perkins Centre, University of Sydney, Sydney, NSW, Australia
Faculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCharles Perkins Centre, University of Sydney, Sydney, NSW, AustraliaDepartment of Radiology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tas, AustraliaDepartment of Cardiology, Graduate School of Medicine, Gunma University, Maebashi, Gunma, JapanSydney Medical School Nepean, Faculty of Medicine and Health, Charles Perkins Centre Nepean, The University of Sydney, Sydney, NSW, AustraliaDepartment of Cardiology, Nepean Hospital, Sydney, NSW, Australia
Corresponding author at: Gemma Figtree, Interventional Cardiologist, Royal North Shore Hospital, Research Lead, Cardiovascular Discovery Group, Kolling Institute, University of Sydney, Level 12, Kolling Institute of Medical Research, 10 Westbourne Street, St Leonards, 2065, NSW, Australia.
Affiliations
Kolling Institute of Medical Research, Sydney, NSW, AustraliaFaculty of Medicine and Health, University of Sydney, Sydney, NSW, AustraliaCharles Perkins Centre, University of Sydney, Sydney, NSW, AustraliaDepartment of Cardiology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW, Australia
Ambient air pollution is recognised globally as a significant contributor to the burden of cardiovascular diseases. The evidence from both human and animal studies supporting the cardiovascular impact of exposure to air pollution has grown substantially, implicating numerous pathophysiological pathways and related signalling mediators. In this review, we summarise the list of activated mediators for each pathway that lead to myocardial and vascular injury in response to air pollutants. We performed a systematic search of multiple databases, including articles between 1990 and Jan 2022, summarising the evidence for activated pathways in response to each significant air pollutant. Particulate matter <2.5 μm (PM2.5) was the most studied pollutant, followed by particulate matter between 2.5 μm–10 μm (PM10), nitrogen dioxide (NO2) and ozone (O3). Key pathogenic pathways that emerged included activation of systemic and local inflammation, oxidative stress, endothelial dysfunction, and autonomic dysfunction. We looked at how potential mediators of each of these pathways were linked to both cardiovascular disease and air pollution and included the overlapping mediators. This review illustrates the complex relationship between air pollution and cardiovascular diseases, and discusses challenges in moving beyond associations, towards understanding causal contributions of specific pathways and markers that may inform us regarding an individual’s exposure, response, and likely risk.
]. However, outdoor ambient air pollution remains a leading environmental cause of cardiovascular morbidity and mortality, making it a significant public health consideration for policymakers [
]. Particle matters with an aerodynamic diameter of less than 2.5 μm (PM2.5), and between 2.5 μm–10 μm (PM10), ozone (O3) and nitrogen dioxide (NO2) are amongst the major known hazardous air pollutants (HAP) that can impact cardiovascular health in the acute setting as well as chronic exposure.
In 2015 alone, exposure to PM2.5 was found to be responsible for more than 4 million deaths, up from 3.5 million in 1990, putting it at the fifth highest ranking risk factor for mortality [
Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015.
]. High-income countries comprised only 1% of deaths related to household air pollution but 12% of ambient air pollution-related mortality in that year. Other studies show direct causation on mortality and comorbidities, including a range of cardiovascular diseases [
Studies focussing on the mechanism behind air pollution-related cardiovascular disease (CVD) since the 1980s have implicated the role of systemic and local inflammation, oxidative stress, vascular endothelial damage, plaque vulnerability, hypercoagulable state and autonomic dysfunction as some of the involved pathophysiological pathways. However, the exact mechanisms by which these pathways are activated remain a “hot” topic in environmental health studies. In this context, the role of cardio-respiratory interaction needs further research. The passage of smaller particulate matters from larger airways to alveoli and across the capillary bed to the systemic circulation is thought to cause local inflammation via local endothelial pathways and systemic inflammation by activation of airway receptors. However, little is known about the fate of micro-particulate matters in the bloodstream. Most of the biomarkers that are used for these studies are end-products of these processes, reflecting activity of these signalling pathways. Whilst they have been implicated in both cardiovascular disease processes and seen to be elevated in association with air pollution, the direct causal roles are less clear.
Biological mediators have a new-found home in the systems biology model of diseases. The concepts of exposome (the measure of all the exposures of an individual in a lifetime, and how these exposures relate to health) and pollutome (the totality of all forms of pollution that have the potential to harm human health) aim to complement these models by addressing the interaction between the environment and an individual’s building blocks that results in diseases. It is therefore pertinent to have a summary of the available evidence for all the implicated biomarkers to pave the way for future research in this field.
Aims
For this review, we aimed to collect all the available data from human and animal studies for potential mediators involved in the pathogenesis of myocardial and vascular injuries and to categorise them based on their mechanism of action.
Method
Essential questions in this investigation before identifying potential biomarkers were:
1.
What are primary myocardial and vascular injuries attributed to acute or chronic air pollution exposure?
2.
Which air pollutants are implicated in the pathogenesis of those pathologies?What are the primary mechanisms by which these air pollutants mediate their injury?
3.
What are the mediators released after exposure to air pollutants that activate these pathological pathways that may act as markers of individual susceptibility and higher personal risk of cardiovascular complications?
We examined all systematic reviews since 2015 to have the most recent summary of evidence for each sub-topic of interest and included relevant papers from 1990 on, since most technological advancements in detection and quantification of bio-mediators started in this period. Our choices of search engines were Google Scholar for its superior indexing and search algorithms, and PubMed for its greater number of indexed papers.
Review papers addressing the first question were summarised first to allow a more targeted search for the next steps. Identified mechanisms of injury were atherosclerosis formation and progression leading to coronary artery disease (CAD) and acute coronary syndrome (ACS), congestive cardiac failure (CCF), cardiomyopathy, and pulmonary hypertension (type 1, 2 and 3). To identify relevant HAPs (essential question 2), we used the individual results from the previous step along with the individual pollutant’s name. A HAP was considered relevant if there was at least one review article or human study addressing that HAP—these included PM2.5, PM10, NO2 and O3. Finally, to generate the list of mediators that need to be included, we used the papers that were filtered in question 1 and question 2 and summarised the described pathways linking the identified HAPs to cardiovascular pathologies of interest. Our final list of pathophysiological pathways included systemic inflammation as the leading mechanism, along with local tissue inflammation, such as adipose tissue inflammation, that leads to the production of harmful adipokines, oxidative stress and mitochondrial dysfunction, endothelial dysfunction, impaired lipid metabolism, thrombogenesis, increased plaque vulnerability and autonomic dysfunction.
We then identified individual mediators linked to cardiovascular injury for each pathway by searching for the pathway combined with Boolean keywords + or AND, along with terms cardiovascular disease, ischaemic heart disease, myocardial infarction, coronary artery disease, congestive cardiac failure, congestive heart failure, atherosclerosis, cardiomyopathy, and vascular disease. Using this method allowed us to have a more comprehensive list of mediators to rule out, one by one, by performing inquiries in our elected search engines using individual mediators, with the keywords Air Pollution, Particulate Matter 2.5, Particulate Matter 10, PM2.5, PM10, nitrogen dioxide, carbon dioxide and ozone. To better categorise the final set of mediators, we grouped them into inflammatory and non-inflammatory classes. We then grouped these papers based on individual bio-mediators or, in some instances, the covered pathways. Older papers that had been replaced by newer, more up-to-date evidence, and papers with similar findings were reviewed as a group, and papers that had the best evidence and were most up to date were kept.
This method was chosen to have a maximal screening potential. Potential sources of assessment bias, however, include our reliance on review articles as the initial screening step, which seemed to primarily focus on the effects of PM2.5 and man-made sources of air pollution. Our complete search strategy is outlined in Supplementary material.
Results
Figure 1 outlines the potential biomarkers of myocardial and vascular complications of air pollution and their mechanism of injury.
Figure 1Potential biomarkers of myocardial and vascular complications of air pollution and their mechanisms of injury.
The inflammatory response is triggered in response to tissue injuries as well as internal and external factors that get flagged as potentially harmful. These responses are classed as either acute or chronic, each with a specific set of mediators which result in cellular and vascular events. As shown in Table 1, air pollutants can result in the release of a range of mediators into the systemic circulation that can result in injury to the cardiovascular system.
Table 1Potential air pollution induced systemic inflammatory mediators.
Mediator
Description
Triggers
Effect on CVD
Tumour Necrosis Factor-α (TNF-α)
An important pro-inflammatory cytokine released by monocytes and macrophages. It has been implicated in a range of autoimmune conditions such as rheumatoid arthritis (RA).
C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality: a population-based, prospective study.
Part of the IL-1 family that is released systemically from monocytes, smooth muscle cells and endothelial cells in response to microbial products and endogenous triggers that act on IL-1 receptors.
Ozone exposure initiates a sequential signaling cascade in airways involving interleukin-1beta release, nerve growth factor secretion, and substance P upregulation.
Responsible for eliminating diseased cells by contributing to the inflammatory cascade via activating CD4 and CD8 T-cells. Also has a significant role in the resolution of inflammation.
A pivotal multifunctional cytokine that triggers the release of many other downstream inflammatory cytokines and is the main stimulus for C-reactive protein (CRP) synthesis.
Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells.
A small cytokine that belongs to the CXC subfamily, which is released primarily from monocytes and macrophages, leading to the attraction of other inflammatory cells towards the inflammatory site as well as activation of monocytes and neutrophils. IL-8 has a central role in the inflammatory cascade at the site of coronary artery plaque formation [
Ambient particulate matter induces interleukin-8 expression through an alternative NF-κB (nuclear factor-kappa b) mechanism in human airway epithelial cells.
Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells.
Interleukin-8 levels in human lung epithelial cells are increased in response to coal fly ash and vary with the bioavailability of iron, as a function of particle size and source of coal.
Acceleratory effects of ambient fine particulate matter on the development and progression of atherosclerosis in apolipoprotein E knockout mice by down-regulating CD4+CD25+Foxp3+ regulatory T cells.
There are 13 TLRs recognised that are located on the plasma membrane or endolysosomal compartment, with the primary function of detecting ‘danger signals’ and activating a range of inflammatory mediators.
Cardiomyopathy, atherosclerosis, MI, and myocardial remodelling in CCF [
A superfamily of more than 30 proteins involved in cellular growth and modulating different phases of cellular life, such as differentiation, proliferation, and apoptosis [
A very potent chemokine that belongs to the C-C chemokine family and is released in response to a range of pro-inflammatory stimuli, such as oxidative stress and growth factor, which can result in the attraction of monocytes to sub-endothelium [
NLRP3 belongs to the NOD-like receptor (NLR) family with a pyrin domain, which is involved in inflammasome formation, which in turn can initiate an inflammatory cascade [
Forkhead transcription factors of the O class (FOXOs), consisting of four members, are expressed in most human tissues, and play a role in various cell cycle stages and inflammation, metabolism, and stress resistance [
HAP can induce local tissue inflammation via direct insult as well as indirectly by triggering the systemic inflammatory response. Besides inflammation of the lungs, that is the primary source of systemic cytokine release, the following tissues can also be inflamed following HAP exposure, further releasing harmful mediators:
Adipose tissue inflammation
Long-term exposure to PM2.5 can lead to adipose inflammation [
], leading to the release of adipokines into the circulation. The mechanism behind this effect is not established but may be secondary to systemic inflammation in a similar manner to that proposed to occur in patients with metabolic syndrome. PM2.5 is known to alter mitochondrial activity and gene expression in brown adipose tissue (BAT) and white adipose tissue (WAT) differently, with more exaggerated changes seen in BAT—resulting in a functional mismatch and contributing to a range of metabolic syndrome features including insulin resistance and atherosclerosis [
Air pollution enters the gastrointestinal tract (GIT) via mucociliary clearance of inhaled air, and therefore can directly interact with the GIT epithelium to cause local, and subsequently systemic inflammation by forming reactive oxygen species (ROS) and pro-inflammatory cytokines [
PVAT involves adipocytes surrounding blood vessels and, in normal physiology, has a dominant anticontractile function, but in the pathophysiological state contributes to endothelial dysfunction, atherosclerosis and aortic aneurysm [
Atherosclerosis progression by promoting inflammation and adhesion, vascular remodelling by VEGF modulation, the release of FGF-2 and MMPs and activation of several angiogenic signalling pathways [
Chemical constituents of ambient particulate air pollution and biomarkers of inflammation, coagulation and homocysteine in healthy adults: a prospective panel study.
The most abundant secreted factor by adipocytes, with levels declining following stimulation with insulin, and cytokines such as TNF-α and endothelin-1 increase with IGF-1 stimulation [
]. Adiponectin's level is declined with increased adipose tissue mass, and its function is opposite of that of leptin and resistin, making it an anti-inflammatory and anti-thrombotic agent [
Urban fine particulate air pollution exposure promotes atherosclerosis in apolipoprotein E-deficient mice by activating perivascular adipose tissue inflammation via the Wnt5a/Ror2 signaling pathway.
Oxidative stress refers to the imbalance between the production of reactive oxygen species (ROS) and antioxidants, which play a central role in both local and systemic inflammation. The main active ROS are free radicals (O-) in various forms such as O2-, OH- and H2O2 (superoxide, hydroxyl, and hydrogen peroxide) [
]. ROS serve an essential role in vasodilation in controlled quantities. The different types of ROS differ from each other in terms of their production source and structure. These highly reactive components are controlled using various mechanisms collectively referred to as antioxidants. Failure of this control mechanism or excessive ROS production (endogenous or exogenous) results in an adverse reaction locally and systemically.
In oxidative stress, ROS themselves can be considered mediators that are released in response to exposure to toxins such as PM2.5. Studies have shown that air pollution is a significant source of oxidative stress. PM2.5 comprising metals (iron [Fe], copper [Cu]) and organic species (photochemically aged organics), have the highest oxidative potential (OP) even at moderate concentrations [
]. ROS can also interact with their surrounding lipids in the membrane, resulting in lipid pre-oxidisation. This effect produces a range of compounds, such as hydroxyl fatty acids and oxidised cholesterol, eventually causing destruction and increased membrane permeability, which further promotes local and systemic inflammation [
]. Various mediators are implicated in HAP-induced oxidative stress, as shown in Table 3.
Table 3Potential air pollution induced oxidative stress mediators.
Mediator
Description
Triggers
Effect on CVD
Xanthine oxidoreductase (XOR)
Expressed as either xanthine dehydrogenase (XDH) or xanthine oxide (XO) which are responsible for the oxidation of xanthine to uric acid resulting in the influx of free radicals [
Which consists of three known subtypes neuronal (nNOS), inducible (iNOS) and endothelial (eNOS), stimulates the production of NO both in the physiological state to maintain cardiovascular homeostasis but also in response to pathophysiological stimuli.
NADPH oxidase and mitochondria are relevant sources of superoxide anion in the oxinflammatory response of macrophages exposed to airborne particulate matter.
Primarily responsible for the peroxidation and oxidation of elements such as vitamins, steroids, and certain drugs. Outside its physiological role, CYP contributes to amino acid (AA) metabolism and ROS production.
The role of mitochondrial disorders in acquired cardiovascular pathophysiology has become a subject of great activity owing to correlations seen in hereditary mitochondrial diseases and cardiovascular comorbidities. There are several ways that mitochondrial physiology can be perturbed: altered morphology, disrupted mitochondrial energetics, increased oxidative stress, dysregulation of apoptosis and autophagy, and via increased mitochondrial mutations [
]. More specifically, some of the pathophysiological processes attributed to cardiovascular injury include increased arterial pressure and vascular dysfunction [
Exposure to air pollution, especially PM2.5 and PM10, result in mitochondrial damage resulting in several adverse cardiovascular outcomes such as reduced HRV [
]. This is owing to diverse mitochondrial functions in energy production, regulation of metabolism and homeostasis of elements such as iron and copper and even cellular death mechanisms [
]. Pathways leading to mitochondrial damage are currently poorly understood, and, at present, ROS are the central identified mediators following exposure to toxins such as air pollution, as shown in Table 4.
Table 4Potential air pollution induced mediators of mitochondrial dysfunction.
Mediator
Description
Triggers
Effect on CVD
Mitochondrial reactive oxygen species (m)
Raised ROS due to various internal or exogenous factors are shown to cause mtDNA damage [
Endothelial dysfunction has a critical role in developing atherosclerotic plaques as the initial step in this pathological cascade which is often followed by increased vascular permeability to lipoproteins, enhanced leucocyte adhesion, platelet aggregation, and the production of various inflammatory cytokines. Endothelial dysfunction is a result of various pathophysiological pathways, most notably: oxidative stress, inflammation, leucocyte adhesion and transmigration, apoptosis and cell death, endothelial NO synthase uncoupling, endothelial-to-mesenchymal transition, and endothelial cell senescence [
Effect of vitamin E and omega-3 fatty acids on protecting ambient PM2.5-induced inflammatory response and oxidative stress in vascular endothelial cells.
], direct cytotoxicity and autophagy were proposed as the likely mechanism. Air pollution mediated factors that can lead to endothelial dysfunction are show in Table 5.
Table 5Potential air pollution induced mediators of endothelial dysfunction.
Mediator
Description
Triggers
Effect on CVD
Endothelial microparticles (EMP)
Result from endothelial shedding and are thought to have both beneficial and detrimental effects on the endothelium [
]. As the name implies, it mediates the adhesion of circulating inflammatory molecules to the vascular wall and trans-endothelial migration to vascular intima.
Belongs to the superfamily of immunoglobulins, expressed in the endothelium of blood vessels in most vital organs, including the brain and heart, induced by pro-inflammatory cytokines, and following expression leading to accumulation and transmigration of monocytes and other innate inflammatory cells [
A prominent scavenger receptor that is expressed on ECs, inflammatory cells and cardiomyocytes. LOX-1 receptors located on macrophages can bind to modified LDL (e.g., oxidised carbamylated or acetylated) and non-self or modified self-targets that result in uptake of the modified lipids. Similarly, in endothelial cells, they behave as sensors that can respond to external stimuli and alter their cellular phenotype from anti-inflammatory to pro-inflammatory. In the normal physiological state, these actions eliminate harmful or degraded substances. However, these responses can result in endothelial dysfunction in a pathophysiological state.
Angiotensin-converting enzyme/angiotensin II/angiotensin type 1 receptor axis (ACE/ANGII/AT1R)
Renin-angiotensin system (RAS) with the end-product of angiotensin II has long been identified as an important agent in the pathophysiology of cardiovascular diseases and cardiac remodelling. The development of angiotensin ACE inhibitors and angiotensin receptor blockers (ARBs) have revolutionised the management of hypertension, CCF and IHD [
Usually found in the foregut and oesophagus; however, it is also expressed in VSMCs of the atheroma of large arteries in a pathological state in response to mechanic cyclic stress [
Small proline-rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts.
Small proline-rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts.
Atherosclerotic plaque rupture is considered the leading cause of myocardial infarction and ischaemic stroke. Plaque vulnerability is shown to be increased after exposure to HAPs, likely by upregulation of MMPs and TIMPs. Key mediators are metalloproteases and proteins that modulate these moieties, as shown in Table 6.
Table 6Potential air pollution induced mediators of increased atherosclerotic plaque vulnerability.
Mediator
Description
Triggers
Effect on CVD
Matrix-degrading metalloproteinases (MMPS)
Present in macrophages, endothelial cells, and smooth muscle cells at low levels [
]. Obese patients are shown to be primarily impacted by the pro-thrombogenic effect of PM2.5, which is thought to be modulated by adipose inflammation leading to platelet activation and aggregation [
Table 7Potential air pollution induced thrombogenic mediators.
Mediator
Description
Triggers
Effect on CVD
Soluble CD40 ligand (SCD40L)
A pro-inflammatory and pro-thrombotic protein that belongs to the superfamily of TNF superfamily with receptors on B cells. sCD40L is predominantly sourced from platelets and can enhance platelet activation and aggregation [
Enhanced levels of soluble CD40 ligand exacerbate platelet aggregation and thrombus formation through a CD40-dependent tumor necrosis factor receptor-associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway.
Enhanced levels of soluble CD40 ligand exacerbate platelet aggregation and thrombus formation through a CD40-dependent tumor necrosis factor receptor-associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway.
A cell adhesion protein that belongs to the lectin family, which is stored in platelets and endothelial cells. Once activated, it gets translocated to the cell surface and released as a soluble form to circulation. Once the soluble form is bounded to its receptor PSGL-1, it starts a pro-coagulant cascade [
Autonomic dysregulation, which results from the accentuated sympathetic drive and diminished parasympathetic activity, is considered a major risk factor for adverse cardiovascular outcomes such as cardiac arrest and AMI [
]. This is thought to be due to a shift from sympatho-inhibition to sympatho-excitation as evidenced by studies showing reduced high-frequency heart rate variability (HRV) [
Air pollution and autonomic and vascular dysfunction in patients with cardiovascular disease: interactions of systemic inflammation, overweight, and gender.
]. There is no study directly assessing autonomic nerve activity in response to air pollution, and most of our understanding of the pathophysiology is theoretical.
Inflammatory mediators
Inflammatory mediators can have a direct effect on modulation of autonomic system. These include:
•
Toll-like receptor 2 (TLR2) Methylation: secondary to PM2.5 is shown to result in activation of autonomic system [
Cardiac autonomic dysfunction: particulate air pollution effects are modulated by epigenetic immunoregulation of Toll-like receptor 2 and dietary flavonoid intake.
Airway receptors include sensors located throughout the upper and lower airways (C-nerve fibres, Rapidly adapting pulmonary receptors [RARs] and Slowly adapting pulmonary receptors [SARs]), designed to sense environmental irritants, such as cigarette smoke and air pollutants, leading to a range of reflexes such as coughing and dyspnoea [
Air pollution-induced mediators of C-nerve fibres activation are as follows:
•
Transient receptor potential ankyrin 1 (TRPA1) channel is a small Ca2+-permeant non-selective cation channel activated by cold exposure, environmental irritants, and reactive oxides [
]. Its activation results in inflammatory hyperalgesia and neurogenic inflammation, and, being located on nociceptive neurons, causes the perception of noxious stimuli [
Transient receptor potential vanilloid 1 (TRPV1) channel is present on the nasal mucosa, trachea, bronchi, and alveoli, which senses toxins such as capsaicin, extracellular protons (released during tissue acidosis and ischaemia) as well as excess heat [
]. In the lungs, subtypes of P2X receptors can be found on most microvascular endothelial cells.
Activation of C-nerve fibres result in production of substance P, which is also a potent biological mediator, as shown in Table 8.
Table 8Activated airway receptors following exposure to HAP with the potential to cause cardiovascular damage.
Mediator
Description
Triggers
Effect on CVD
Substance P (SP)
Widely expressed in both central and peripheral nervous systems with functions such as regulating pulmonary and cardiovascular function, emetic reflux, noxious stimuli, and modulating autonomic reflexes [
]. In contrast, over the long term, elevated SP is shown to have a detrimental effect on the heart as it plays a vital role in cardiac mast cell activation [
]. Cardiac mast cell activation does so via three pathways: the release of pro-inflammatory mediators such as TNFα and MMPs; the release of renin; and the production of vascular endothelial growth factor (VEGF) [
Ozone exposure initiates a sequential signaling cascade in airways involving interleukin-1beta release, nerve growth factor secretion, and substance P upregulation.
Baroreceptors are stretch-sensitive sensors located in the carotid sinus and aortic arch to adjust blood pressure in response to alterations in systemic BP by inhibiting the sympathetic or activating the parasympathetic system [
]. Exposure to major air pollutants such as SO2 reduces baroreflex sensitivity (BRS). At the same time, many studies have also shown BP instability following exposure to air pollutants (lowered BP in the acute setting and hypertension in the long term), which can indirectly result in reduced BRS [
]. Thus far, no study has directly examined the effect of air pollution on carotid body chemoreceptors. However, given that there is evidence of hypoxia following exposure to air pollution, it is safe to conclude that these sensors play a role in air pollution-induced autonomic dysregulation [
An important site of lipid metabolism that is also impacted by exposure to air pollution is the intestine. The intestine is a crucial player in lipid metabolism by controlling dietary or biliary cholesterol absorption and synthesising endogenous cholesterol such as apolipoprotein A-1 (apoA-I) and high-density lipoprotein (HDL) via intestine enterocytes [
Another vital source of dysregulation in lipid metabolism is the liver. Air pollutants can result in lipid peroxidation leading to oxidation of a range of lipids, including low-density lipoprotein (LDL) and Apo [
]. The oxidisation of lipids via intestinal and hepatic routes has a range of adverse health impacts, such as diabetes, atherosclerosis, and systemic inflammation [
A member of the scavenger receptor family that is expressed on endothelial cells (ECs), cardiomyocytes, and adipocytes amongst other tissues, which has a crucial role in immune regulation, platelet activation, and regulation of metabolism by regulating fatty acid (FA) uptake in ECs and myocardial tissue and FA metabolism in the liver [
Oxidized LDL attenuates protective autophagy and induces apoptotic cell death of endothelial cells: role of oxidative stress and LOX-1 receptor expression.
Oxidized LDL attenuates protective autophagy and induces apoptotic cell death of endothelial cells: role of oxidative stress and LOX-1 receptor expression.
A critical cardioprotective mediator with a primary anti-atherosclerotic function by reverse cholesterol transport and efflux of cholesterol from macrophages into lipid-free ApoA-I, which results in healthy NO synthesis [
The emergence of new mediators that do not fall under any of the traditional pathogenic pathways is shining a new light in our understanding of the missing links between interaction of HAPs with airway tissues and adverse cardiovascular outcomes (Table 10).
Table 10Novel mediators linking air pollution and cardiovascular injury.
Mediator
Description
Triggers
Effect on CVD
Aryl hydrocarbon receptor (AHR)
Plays a central role in regulating the toxicity of environmental pollutants, and their upregulation results in inflammation, oxidative stress, and lipid infiltration [
By far the largest reservoir of micro-organisms, containing 90% of the human body, which have myriad roles in the body's homeostasis, including their role in the immune system and cell-signalling processes [
Associated with increased CVD comorbidities such as IHD and CAD
Stress hormones
Activation of the Hypothalamus-Pituitary-Adrenal (HPA) axis results in stress hormones, including glucocorticoids and catecholamines. These compounds result in the so-called “fight or flight” by modulating various body functions such as inflammation, metabolism, CNS function and cardiovascular function [
]. In a pathological state caused by excess production either due to continuous stress stimuli, abnormal stress response or malignant tumours, these excess stress hormones can result in metabolic syndrome, excess immune response, EC damage, and atherosclerosis [
]. Through our advancements in household heating methods, we have seen an enormous reduction in mortality attributable to indoor air pollution. Despite this success, industrialisation has resulted in increases in large-scale ambient outdoor air pollution, meaning the impact of air pollution is no longer confined to the place of the pollutant’s origin.
Advancements in molecular biology have enabled our understanding of the complex nature of air pollution—highlighting numerous pathways and mediators of myocardial and vascular injury. In this paper we have demonstrated that local and systemic inflammation get triggered in response to most HAPs via activation of cytokines such as interleukins and TNF-α. Inflammation is usually accompanied by oxidative stress and mitochondrial damage. In most scenarios, pro-atherosclerosis mechanisms, such as endothelial dysfunction, lipid metabolism dysfunction, and increased plaque vulnerability, are also activated. Other biological processes that influence the cardiovascular system, such as autonomic dysfunction and alteration of the gut microbiome, may also be triggered. By providing a big-picture view of the currently accepted HAP-related mediators, we can start to build a physiological framework of HAP activity in vivo beyond the alveoli. We can see that, not only is the widely hypothesised local and systemic inflammatory response indeed being activated, but also alternate non-inflammatory pathways, such as endothelial damage and autonomic dysfunction, are involved, and this may point toward a common, yet-to-be-discovered, ‘pre-inflammatory’ mechanism. The systems biology model put forward in this paper can also be used to improve our understanding of the other environmental triggers leading to CVD. It is noteworthy that the focus of most of the human studies used in this paper was short-term exposure to traffic-related air pollution (TRAP). As such, there is a knowledge gap in our understanding of how these proposed bio-mediators differ in response to other sources of air pollution, such as bush fires or sandstorms. Similarly, although, historically, most of our public health knowledge regarding morbidities and mortality attributable to air pollution comes from cohort studies of the long-term effects of HAPs, a great degree of further research needs to be done on long-term effects on mediators of pathophysiological pathways.
Future directions for researchers should also include examining common pathways for the mediators described in this paper in large-cohort studies. Further, by utilising multiomics (a biological analysis approach in which the data sets are multiple “omes” such as the genome, proteome, transcriptome, epigenome, metabolome, and microbiome) technologies and novel machine-learning techniques, researchers can aim to expand our understanding of pathways leading to activation or deactivation of these mediators. The sub-molecular omic view of diseases, from genomics to metabolomics, equips us to understand ‘pre-inflammatory’ mechanisms that are common between various pathological states. This will be important for our future drug-discovery efforts. Finally, to identify vulnerable or resilient individuals, future studies need to utilise the latest air-quality monitoring technologies and especially high temporal resolution and granular resolution satellite-based data to design long-term assessment of participants’ short-term HAP exposure. This will enable us to risk stratify patients based on their short-term exposomic profile rather than a large-scale long-term estimation of their exposure.
Beyond laying grounds for future directions of HAP-related research, this paper should also be seen as part of the series of ‘wake-up call’ publications in recent years aimed at policymakers and clinicians [
]. Public understanding of the dangers of inhaling HAPs tends to be centred around respiratory implications: the cardiovascular damage may supersede respiratory injuries in susceptible individuals, and this needs to be considered in public health policies, as well as in the day-to-day assessment and education of patients.
Conclusions
Despite many studies showing mediators of inflammation and vascular dysfunction in response to air pollution, we are far from being able to apply this to clinical decision making. Whilst we all see distinct individual differences in lung responses to air pollution, host cardiovascular response to air pollution is less evident. If a marker were shown to be causally involved and could be reliably measured as an integrated marker of exposure and host response, it may have potential as a risk measure that could guide management, both in regard to extra vigilance to avoid exposure, as well as more aggressive primary or secondary prevention strategies. Also, whilst all the above is seen to increase in response to air pollution, many are common mediators of inflammation, and the exact mechanisms are often not known. Is it particulates activating systemic factors in the lungs, or are particles carried in cells or vesicles to organs where damage is then observed (e.g., vasculature, heart)? Improved understanding of the activation points may provide insights to novel drug targets.
Sources of Funding
The authors report the following financial support for the research, authorship and/or publication of this article: GAF reports grants from National Health and Medical Research Council (Australia), Heart Research Australia and the NSW Office of Health and Medical Research; SMG acknowledges the support of the Parker-Hughes Bequest, a NSW Senior Research Fellowship and the Frecker Family.
Disclosures and Acknowledgments
GAF reports personal consulting fees from CSL Ltd, Amgen and Janssen, and grants from Abbott Diagnostic and Sanofi outside the submitted work. The remaining authors have nothing to disclose.
We would like to thank Dr Zara S. Ali for her generous assistance in completing this review.
Estimates and 25-year trends of the global burden of disease attributable to ambient air pollution: an analysis of data from the Global Burden of Diseases Study 2015.
C-reactive protein, interleukin-6 and tumor necrosis factor alpha as predictors of incident coronary and cardiovascular events and total mortality: a population-based, prospective study.
Ozone exposure initiates a sequential signaling cascade in airways involving interleukin-1beta release, nerve growth factor secretion, and substance P upregulation.
Differential expression of pro-inflammatory and oxidative stress mediators induced by nitrogen dioxide and ozone in primary human bronchial epithelial cells.
Ambient particulate matter induces interleukin-8 expression through an alternative NF-κB (nuclear factor-kappa b) mechanism in human airway epithelial cells.
Interleukin-8 levels in human lung epithelial cells are increased in response to coal fly ash and vary with the bioavailability of iron, as a function of particle size and source of coal.
Acceleratory effects of ambient fine particulate matter on the development and progression of atherosclerosis in apolipoprotein E knockout mice by down-regulating CD4+CD25+Foxp3+ regulatory T cells.
Chemical constituents of ambient particulate air pollution and biomarkers of inflammation, coagulation and homocysteine in healthy adults: a prospective panel study.
Urban fine particulate air pollution exposure promotes atherosclerosis in apolipoprotein E-deficient mice by activating perivascular adipose tissue inflammation via the Wnt5a/Ror2 signaling pathway.
NADPH oxidase and mitochondria are relevant sources of superoxide anion in the oxinflammatory response of macrophages exposed to airborne particulate matter.
Effect of vitamin E and omega-3 fatty acids on protecting ambient PM2.5-induced inflammatory response and oxidative stress in vascular endothelial cells.
Small proline-rich repeat 3 is a novel coordinator of PDGFRβ and integrin β1 crosstalk to augment proliferation and matrix synthesis by cardiac fibroblasts.
Enhanced levels of soluble CD40 ligand exacerbate platelet aggregation and thrombus formation through a CD40-dependent tumor necrosis factor receptor-associated factor-2/Rac1/p38 mitogen-activated protein kinase signaling pathway.
Air pollution and autonomic and vascular dysfunction in patients with cardiovascular disease: interactions of systemic inflammation, overweight, and gender.
Cardiac autonomic dysfunction: particulate air pollution effects are modulated by epigenetic immunoregulation of Toll-like receptor 2 and dietary flavonoid intake.
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