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Corresponding author. Department of Cardiovascular Sciences Fondazione Policlinico Universitario A. Gemelli IRCCS L.go A. Gemelli, 1, 00168, Rome, Italy.
Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, ItalyDepartment of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart Rome, Italy
1 These authors equally contributed as last authors to this work.
Filippo Crea
Footnotes
1 These authors equally contributed as last authors to this work.
Affiliations
Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, ItalyDepartment of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart Rome, Italy
1 These authors equally contributed as last authors to this work.
Giovanna Liuzzo
Footnotes
1 These authors equally contributed as last authors to this work.
Affiliations
Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, ItalyDepartment of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart Rome, Italy
Ambient air pollution has emerged as an important yet often overlooked risk factor for atherosclerosis and ischemic heart disease.
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Air pollution and in particular PM2.5 can promote the formation, the progression and the destabilization of the atherosclerotic plaques.
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Mechanisms underlying the association between air pollution are multiple and not completely understood.
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There is a strong need for randomized, controlled clinical trials to demonstrate the efficacy of specific interventions targeting air pollution.
Abstract
Ambient air pollution, and especially particulate matter (PM) air pollution <2.5 μm in diameter (PM2.5), has clearly emerged as an important yet often overlooked risk factor for atherosclerosis and ischemic heart disease (IHD). In this review, we examine the available evidence demonstrating how acute and chronic PM2.5 exposure clinically translates into a heightened coronary atherosclerotic burden and an increased risk of acute ischemic coronary events. Moreover, we provide insights into the pathophysiologic mechanisms underlying PM2.5-mediated atherosclerosis, focusing on the specific biological mechanism through which PM2.5 exerts its detrimental effects. Further, we discuss about the possible mechanisms that explain the recent findings reporting a strong association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, increased PM2.5 exposure, and morbidity and mortality from IHD. We also address the possible mitigation strategies that should be implemented to reduce the impact of PM2.5 on cardiovascular morbidity and mortality, and underscoring the strong need of clinical trials demonstrating the efficacy of specific interventions (including both PM2.5 reduction and/or specific drugs) in reducing the incidence of IHD. Finally, we introduce the emerging concept of the exposome, highlighting the close relationship between PM2.5 and other environmental exposures (i.e.: traffic noise and climate change) in terms of common underlying pathophysiologic mechanisms and possible mitigation strategies.
Coronary atherosclerosis represents the principal aetiology underlying ischemic heart disease (IHD), and considerable efforts have been made towards the early identification and treatment of traditional cardiovascular (CV) risk factors for atherosclerosis, such as hypertension, smoking, dyslipidaemia and type 2 diabetes mellitus. Indeed, the recognition of these risk factors and their consequent treatment and prevention portended more than a 50% decline in IHD-related mortality in the past 50 years [
]. However, IHD still remains one of the leading causes of disability and mortality worldwide and, therefore, the focus is shifting towards the identification of novel pathways to reduce residual atherosclerotic risk.
Air pollution is a complex mixture of unwanted particulate and gaseous material released into the environment by human activities. Air pollution includes ambient (outdoor) and household (indoor) pollution [
]. Ambient air pollution originates principally from fossil-fuel combustion, while household air pollution is caused mainly by the combustion of biomass fuels, smoking and gas stoves [
]. Ambient air pollution represents the world's fourth leading cause of disease and death and, notably, more than 50% of these deaths can be attributed to atherosclerotic CV diseases, including IHD and stroke, with accumulating evidence supporting a consistent relationship between increased air pollution exposure and progression of atherosclerosis [
Taking a stand against air pollution-the impact on cardiovascular disease: a joint opinion from the world heart federation, American college of cardiology, American heart association, and the European society of cardiology.
]. Moreover, air pollution is nearly ubiquitous as the World Health Organization (WHO) estimates that >90% of the world's population lives in areas with annual mean levels of air pollutants exceeding the WHO global air quality guidelines limits [
World Health Organization WHO global air quality guidelines: particulate matter (PM2.5 and PM10), ozone, nitrogen dioxide, sulfur dioxide and carbon monoxide.
]. Among the different components of air pollution, particulate matter with aerodynamic diameter ≤2.5 μm (PM2.5) demonstrated the strongest association with CV diseases. Indeed, multiple evidence links PM2.5 exposure to increased susceptibility to coronary atherosclerosis development and progression to high-risk plaques prone to rupture [
Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study.
Moreover, the recent coronavirus disease 2019 (COVID-19) pandemic showed a consistent relationship between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, increased PM2.5 exposure and mortality due to ischaemic cardiac events, suggesting an interaction between infective agents and air pollution in the pathogenesis of IHD [
The purpose of this review is to provide updated evidence of the pathophysiological mechanisms underlying air pollution-mediated atherosclerosis, focusing on the specific mechanisms through which PM2.5 can promote formation, progression and destabilization (i.e.: rupture) of atherosclerotic plaques. Moreover, we aim to examine the concept of exposome, highlighting the close relationship between PM2.5 and other environmental exposures (i.e.: traffic noise and climate change) and underscoring the common pathophysiologic mechanisms, as well as the possible mitigation strategies. Indeed, gaining a deep insight into the pathophysiological mechanisms of PM2.5-mediated atherosclerosis could pave the way for the development of novel specific therapeutic strategies aiming to reduce the impact of air pollution on CV mortality worldwide.
2. Current evidence linking air pollution and atherosclerosis
The impact of urban ambient air pollution, especially combustion-derived PM, has being increasingly studied in recent years due to the high density of urban populations and the increasing levels of traffic-derived emissions worldwide. PM includes both organic and inorganic particles and is categorized according to the aerodynamic diameter into coarse particles (2.5–10 μm in diameter; PM10), fine particles (PM2.5), and ultrafine particles (<0.1 μm in diameter; PM0.1) [
]. The aerodynamic diameter is critical for the toxic effects of PM, as small particles, such as PM2.5 and PM0.1, might contribute disproportionately due to their large reactive surface area and their ability to penetrate deeply into the alveoli and directly into the bloodstream, causing damages and dysfunction of tissues and cells far from the lungs [
Additionally, a key determinant of the harmful effect of PM2.5 on the CV system is the different time frames of exposure. Indeed, short-term PM2.5 exposure (hours) has been strongly associated with the risk of acute coronary syndrome (ACS), as the immediate responses following PM2.5 exposure are all potential initiators and promoters of atherothrombotic events (i.e., sympathoadrenal activation, release of circulating inflammatory biomarkers, endothelial dysfunction, release of pro-coagulant proteins and platelets activation) [
]. Moreover, short-term PM2.5 exposure is associated with acute vascular modifications, such as arterial vasoconstriction and impaired vascular reactivity, that could be additional triggers for plaque destabilization in susceptible individuals [
]. However, acute exposure to PM2.5 might even more likely trigger an ACS in the context of chronic long-term (years) exposure, promoting the progression of the atherosclerotic burden and leading to the development of vulnerable plaque features (i.e., plaque inflammation, weakening of fibrous cap and increased lipid content) and potentiating the deleterious effects of other traditional CV risk factors (i.e., hypertension, dyslipidaemia, type 2 diabetes mellitus) [
]. Chronic PM2.5 exposure, by promoting the development of a vulnerable systemic state with underlying vulnerable plaques, can exponentially increase the risk of acute ischemic events that are likely to be precipitated by acute variations in PM2.5 exposure (Fig. 1).
Fig. 1Hypothetical model that illustrates the relationship between particulate matter ≤2.5 μm (PM2.5) exposure and atherosclerosis.
Chronic long-term exposure (decades) may promote the progression of atherosclerosis and the development of vulnerable plaque features, whereas acute short-term rise in PM2.5 levels (months/weeks) may precipitate the development of acute cardiovascular events.
The dose of PM2.5 exposure is also important to consider. Many epidemiologic studies demonstrated that increasing levels of PM2.5 are strongly associated with clinical markers of atherosclerosis, increased risk of myocardial infarction (MI) and CV mortality [
]. The PM2.5 dose-response curve demonstrates a non-linear relationship, with a steep increase at low concentrations and some flattening at higher levels, although there is no lower concentration threshold below which exposures can be considered safe [
World Health Organization WHO global air quality guidelines: particulate matter (PM2.5 and PM10), ozone, nitrogen dioxide, sulfur dioxide and carbon monoxide.
]. Several studies demonstrated a significant association between increased PM2.5 exposure and the progression of atherosclerosis using different imaging techniques, including computed tomography (CT), coronary computed tomography angiography (CCTA), magnetic resonance and intravascular imaging, to quantify clinical surrogates of atherosclerosis, such as carotid intima-media thickness (CIMT), coronary artery calcium (CAC), thoracic and abdominal aortic calcification, and arterial brachial index (ABI) (Supplementary Table 1). Among these, CAC assessed by CT is probably the best direct surrogate for atherosclerosis and it has been demonstrated to be a strong predictor for future CV events, as plaques with high calcium tend to progress faster and thus may be identified by the burden of atherosclerosis or its progression. In this regard, the Multi-Ethnic Study of Atherosclerosis (MESA) Air Pollution is the largest study evaluating the association between PM2.5 and CAC. A cross-sectional analysis of 5172 patients from the MESA Air Pollution study assessed the effects of PM2.5 exposures of the previous 20 years and reported a significant association of CIMT with PM2.5 (RR 1.01; 95% Confidence Interval [CI]: 1.00 to 1.02 per 12.5 μg/m3), whereas no significant association was reported for CAC and ABI [
]. Conversely, a 10-year longitudinal analysis including 6795 patients of the MESA Air Pollution study cohort assessed the relationship between CAC progression at repeated CT and reported no significant association between PM2.5 and CIMT change, whereas PM2.5 was significantly associated with progression of CAC (for each 5 μg PM2.5/m3 increase, CAC progressed by 4.1 Agatston units per year, 95% CI: 1.4 to 6.8) [
Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study.
]. Thus, results are somewhat inconsistent and CAC progression remains a surrogate for the atherosclerotic burden rather than plaque vulnerability. Accordingly, it may not accurately reflect the mechanism by which PM2.5 mediates the risk of ACS being rather a hallmark for other mechanisms. To overcome these limitations, the same imaging techniques along with intracoronary imaging modalities (especially optical coherence tomography [OCT] thank to its high resolution) have been used to investigate in-vivo atherosclerotic plaque features and to detect signs of plaque vulnerability (i.e.: thin fibrous cap, lipid necrotic core, plaque inflammation, presence of healed disruptions, and plaque angiogenesis) following PM2.5 exposure. A recent study using serial CCTA showed that an increase of 1 μg/m3 in PM2.5 concentration was associated with an increased risk of developing high-risk coronary plaques at follow-up (defined as plaques with low attenuation, spotty calcium, positive remodelling, fibrofatty or necrotic core components and greater plaque volume) [
]. Recently, our group assessed the relationship between long-term exposure to air pollutants and mechanisms of coronary instability evaluated by OCT in patients with ACS, and we demonstrated that patients with plaque rupture (PR) as the mechanism of plaque instability were chronically exposed to significantly higher PM2.5 levels than those with intact fibrous cap. PM2.5 was independently associated with PR as well as with the presence of thin cap fibroatheroma and macrophages at the culprit site and with higher levels of serum C-reactive protein (CRP) [
A significant association has been reported between increased PM2.5 exposure and the risk of non-fatal MI, especially for ST-segment elevation MI compared with non-ST-segment elevation MI and in patient with angiographic evidence of coronary artery disease [
] (Supplementary Table 2). In particular, the European Study of Cohorts for Air Pollution Effects (ESCAPE) study showed that a 5 μg/m3 increase in estimated annual mean PM2.5 was associated with a 13% increased risk of acute coronary events (hazard ratio [HR] 1.13; 95% CI: 0.98 to 1.30) [
Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE Project.
]. In addition, a time-stratified case-crossover study recently conducted in China showed that each 10 μg/m3 increase in PM2.5 exposure (mean exposure on the same day of death and 1 day prior) was significantly associated with a 4.14% (95% CI: 1.25–7.12%) increase in odds of MI mortality [
]. Similarly, a meta-analysis of 34 studies of short-term air pollution exposure showed that each increase of 10 μg/m3 in PM2.5 exposure significantly increased the risk of MI by 2.5% (relative risk: 1.025; 95% CI: 1.015–1.036) [
However, it should be noted that some studies investigating the association between PM2.5 and progression of atherosclerosis or non-fatal MI provided null or inconclusive results, possibly because the different study designs and evaluated endpoints (Supplementary Table 1 and Supplementary Table 2).
3. PM2.5 and atherosclerosis: Pathogenetic mechanisms
3.1 Oxidative stress
PM2.5 can promote the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) by interfering with many cellular mechanisms, including NADPH oxidases (NOXs), endothelial nitric oxide synthase (eNOS) uncoupling and mitochondrial respiratory chain dysfunction [
]. In particular, the activation of NOXs with the consequent overproduction of superoxide radicals can determine mitochondrial damage in macrophages, with the activation of the mitochondrial-mediated apoptosis of foam cells and lipid accumulation and growth of the necrotic core in the atherosclerotic plaques [
]. Likewise, eNOS uncoupling leads to the production of superoxide radicals, instead of nitric oxide (NO), that combine with NO leading to the formation of the highly reactive intermediate peroxynitrite (ONOO-). Progressively, the accumulation of ONOO- radicals can directly oxidize the circulating low-density lipoproteins (LDL) to oxidized LDL (ox-LDL) which further stimulates NOXs to produce free radicals and, by activating the scavenger receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), downregulate eNOS expression and stimulate vascular smooth muscle cells (VSMCs) proliferation and extracellular matrix deposition, finally contributing to intimal hyperplasia and vascular remodelling [
]. Similarly, the polycyclic aromatic hydrocarbons on the surface of PM2.5 are agonists for the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated transcriptional factor that migrates to the nucleus, binds to the AhR nuclear transporter, and activates the transcription of several proatherogenic and pro-inflammatory pathways fostering oxidative stress, vascular damage and inflammation. AhR activation can stimulate the uptake of cholesterol by macrophages and the proliferation and migration of VSMCs, promoting the formation of foam cells and of the fibrous cap around the necrotic core [
Air particulate matter induced oxidative stress and inflammation in cardiovascular disease and atherosclerosis: the role of Nrf2 and AhR-mediated pathways.
PM2.5 exposure has been associated with increased levels of systemic inflammation markers, including CRP, plasma fibrinogen and several pro-inflammatory cytokines, and PM2.5 can directly activate circulating leukocytes and the vascular endothelium and promote cell adhesion and migration [
]. These pro-inflammatory effects of PM2.5 could exacerbate the development of ACS by increasing the likelihood of plaque destabilization and/or arterial thrombosis as part of the inflammatory process [
Mechanistically, PM2.5 can trigger the activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome leading to caspase-1 activation and the secretion of pro-inflammatory and proatherogenic cytokines [
]. The NLRP3 promotes macrophage polarization towards the pro-inflammatory M1 phenotype, thus developing a persistent pro-inflammatory and proatherogenic vascular milieu characterized by macrophage proliferation and vascular infiltration, production of several pro-inflammatory mediators, VSMCs migration, increased foam cell formation and degradation of extracellular matrix components [
The smallest particles of PM2.5 can directly cross the alveolar-capillary barrier gaining access to the blood circulation and reaching the sites of vascular lesions where they are phagocytosed by macrophages as an attempt to defend against the invading xenobiotics. The progressive accumulation of these biologically persistent particles can further promote the activation and amplification of pro-inflammatory pathways leading to the release of several pro-inflammatory cytokines and free radicals (a mechanism known as “frustrated phagocytosis”) [
PM2.5 can directly cause inflammation in other vascular sites, including the adipose tissue and the brain. The adipose tissue releases several hormones, cytokines, extracellular matrix proteins, growth factors and vasoactive molecules collectively called adipokines. PM2.5 is demonstrated to induce chronic inflammation in the adipose tissue fostering the release of adipokines, including adiponectin, resistin, visfatin, and chemerin, that promote atherosclerosis by influencing the function of endothelial cells, VSMCs, and macrophages in vessel walls leading to the activation of nuclear factor kappa light-chain-enhancer of activated B cells (NF-kB), release of cytokines, activation of matrix metalloproteinases (MMPs) and expression of vascular adhesion molecules [
]. The activation of MMPs, in particular, promotes the degradation of extracellular matrix components such as collagen and elastin in the fibrous cap, thus reducing the stability of the atherosclerotic plaques [
Oxidative stress acts synergistically with inflammation by upregulating the secretion of inflammatory cytokines by immune and non-immune (e.g.: endothelial) cells and promotes the oxidation of circulating lipoproteins, in particular LDL to the highly atherogenic ox-LDL, that are preferentially up taken by macrophages through the CD36 scavenger receptor leading to the formation of foam cells and the growth of lipid-rich atherosclerotic plaques [
Finally, PM2.5 can promote systemic inflammation by fostering leucopoietic activity in leucopoietic tissues (i.e., bone marrow and spleen) as well as arterial inflammation [
]. A recent study using F-fluorodeoxyglucose positron emission tomography/computed tomography in 503 subjects demonstrated that a higher PM2.5 exposure was associated with increased leucopoietic activity and arterial inflammation. PM2.5 exposure associated with MACE and mediation analysis demonstrated that increased leucopoietic activity and arterial inflammation mediate the link between PM2.5 and MACE [
PM2.5 exposure can reduce heart rate variability (HRV) by inducing systemic inflammation and oxidative stress, as functional variations in genes involved in oxidative stress, such as glutathione S-transferase M1 (GSTM1) and haemoxygenase-1 (HMOX-1), demonstrated to modulate these effects [
PM2.5 can establish an imbalance in the autonomic nervous system with increased sympathetic activity. Indeed, the exposure of pulmonary C-nerve fibres to PM2.5 can determine the activation of specific mechanoreceptors in the lungs, such as transient receptor potential ankyrin 1 (TRPA1), transient receptor potential vanilloid 1 (TRPV1), and purinergic P2X channels [
Pulmonary diesel particulate increases susceptibility to myocardial ischemia/reperfusion injury via activation of sensory TRPV1 and β1 adrenoreceptors.
], with the activation of neural reflex arcs that lead to central sympathetic activation and release of vasoconstrictive mediators including catecholamines [
]. PM2.5 exposure can regulate central hypothalamic sympathetic activation likely by inducing neuroinflammation and may also directly, through the smallest particles entering the bloodstream, or indirectly, through circulating factors and oxidative stress, damage the blood-brain barrier leading to altered permeability and influencing neuronal functions [
Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation.
Finally, PM2.5 upregulates the production of endothelin-1 (ET-1) and the expression of both its receptors type A and type B in coronary arteries, thus shifting the balance of the vasomotor tone towards vasoconstriction [
]. Likewise, PM2.5 can lead to increased circulating levels of angiotensin II and the activation of the angiotensin II type 1 receptor axis in vascular endothelial cells (VECs), which promote oxidative stress and vascular inflammation, stimulate the biosynthesis of ET-1 and upregulate the expression of type A endothelin receptors in VSMCs [
PM2.5 exposure has been associated with decreased levels of high-density lipoprotein (HDL) cholesterol and apolipoprotein A1, increased levels of LDL cholesterol, ox-LDL, total cholesterol, triglycerides, lipoprotein(a) and the ratio of apolipoprotein B/A1 as well with the presence of lipid-rich and inflamed atherosclerotic plaques [
]. Indeed, PM2.5 promotes a unique form of dyslipidaemia characterized by high levels of circulating fatty acids such as palmitate, myristate, and palmitoleate, and decreased phospholipid species, likely through the activation of lipolysis, the dysregulation of lipid metabolism in the liver, and the induction of mitochondrial dysfunction. The exposure of vascular endothelial cells to heightened levels of fatty acid can foster vascular inflammation, activating the NF-κB pathway and NLRP3 inflammasome, and impair growth factor signalling such as insulin and vascular endothelial growth factor [
In addition, PM2.5 can promote HDL cholesterol dysfunction leading to reduced antioxidant and anti-inflammatory capacities, decreased paraoxonase activity, and alterations in the reverse cholesterol transport from cells and extracellular tissues to the liver, resulting in increased circulating LDL and ox-LDL levels and LDL-induced monocyte migration to atherosclerotic plaques [
]. Similarly, PM2.5 can promote the modification of cholesterol into 7-ketocholesterol in the circulating LDL fractions further stimulating the CD36-mediated phagocytosis by macrophages. 7-ketocholesterol is the most abundant modified sterol in atherosclerotic lesions, where it promotes endothelial dysfunction and oxidative stress activating NOXs [
PM2.5 exposure has been associated with changes in different biomarkers of systemic coagulation and fibrinolysis, including fibrinogen, endogenous thrombin, von Willebrand factor, tissue-plasminogen activator (tPA) and plasminogen activator inhibitor (PAI)-1, as well as with increased platelet activation and reduced activated partial thromboplastin time and prothrombin time [
Long-term exposure to air pollution and markers of inflammation, coagulation, and endothelial activation: a repeat-measures analysis in the Multi-Ethnic Study of Atherosclerosis (MESA).
]. Acute PM2.5 exposure results in impaired endogenous fibrinolysis and increased thrombus formation, thus suggesting that PM2.5 could heighten the risk of atherothrombotic events [
]. PAI-1 is a serine protease that inhibits tPA and urokinase plasminogen activator and activates plasminogen into plasmin inducing fibrinolysis. IL-6 is produced by alveolar macrophages following PM2.5 exposure and is associated with increased generation of intravascular thrombin and acceleration of arterial thrombosis by increasing the expression of fibrinogen, factor VIII, von Willebrand factor, and the activity of factor II and X. Moreover, IL-6 reduces the transcription of thrombosis inhibitors, including antithrombin and protein S, and promotes the activation of Signal Transducer And Activator Of Transcription 3 (STAT3) in bone marrow progenitor cells resulting in neutrophilia and thrombocytosis [
]. Finally, PM2.5 exposure can promote vascular thrombosis by inducing IL-6 dependent activation of platelets, increasing platelet-monocyte aggregates and reducing the release of the fibrinolytic tPA from the vascular endothelium [
Epigenetic reprogramming includes all the alterations in gene expression (activation or repression) and function, without any changes in the underlying DNA sequence. Of note, epigenetic reprogramming can be influenced by several environmental stimuli including PM2.5 [
DNA methylation typically involves the promoter regions leading to chromatin condensation and inhibition of gene expression. PM2.5 exposure has been associated with reduced DNA methylation (and consequent overexpression) of genes involved in several pathways relevant for the induction of atherosclerosis including oxidative stress, cytokine signalling and vascular expression of adhesion molecules [
]. In particular, PM2.5 demonstrated to increase the levels of pro-inflammatory and prothrombotic molecules by reducing DNA methylation in related genes [
Similarly, histone modifications can influence gene expression by changing chromatin configuration. Histone acetylation, by diminishing the histone–DNA interactions, leads to transcriptionally active chromatin whereas deacetylation, conversely, leads to transcriptionally inactive chromatin. Instead, the result of the histone methylation or demethylation depends on the specific methylation site and may result in either gene activation (e.g.: methylation on lysine 4 or 36 on histone H3) or repression (e.g.: H3 methylation on lysine 9 or 27). PM2.5 exposure has been associated with several histone modifications in blood leukocytes (e.g.: H3 lysine 9 acetylation, H3 lysine 9 tri-methylation, H3 lysine 27 tri-methylation) and these modifications have been clinically correlated with increase in blood pressure, vascular inflammation and atherosclerosis progression [
Micro-RNA (miRNAs) are a class of highly conserved, small non-coding post-transcriptional regulators of many cellular pathways with an emerging role in the pathogenesis of atherosclerosis [
]. The overexpression of miR-21 in macrophages results in decreased secretion of pro-inflammatory cytokines and lipid accumulation together with increased production of anti-inflammatory cytokines, whereas its deficiency promoted endothelial dysfunction, vascular inflammation and plaque necrosis leading to accelerated atherosclerosis [
]. PM2.5 exposure has been associated with reduced expression of miR-21 in leukocytes suggesting a role of PM2.5-induced alterations in miRNA expression in the amplification of vascular inflammation, endothelial dysfunction and atherosclerosis [
]. PM2.5 can influence the expression of miRNAs that regulate the production of pro-inflammatory cytokines (i.e.: miR-21-5p, miR-187-3p, miR-146a-5p, miR-1-3p, and miR-199a-5p) [
Mitochondrial DNA (mtDNA) is particularly sensitive to PM2.5-induced oxidative stress damage given the absence of histone protection and DNA repair activity in mitochondria. Alterations in mtDNA can alter the RNA and proteins produced by the mitochondria, with alterations of mitochondrial homeostasis and impairment of mitochondrial energetical function and related mechanisms, such as beta-oxidation and electron transport chain, resulting in mitochondrial dysfunction. The presence of mitochondrial dysfunction can potentiate several mechanisms strictly related to atherosclerosis such as oxidative stress and vascular inflammation [
Finally, another point to consider is the interplay between air pollution and pre-existing genetic factors. Recent studies investigated the interaction between PM2.5 and genetic predisposition to IHD such as polygenic risk score and specific genes involved in oxidative stress and inflammatory pathways [
]. Gene-air pollution interaction studies aimed to assess the contribution of genetic variation to inter-individual heterogeneity in susceptibility to PM2.5, reporting interactions to cluster in a few genes related to detoxification (GSTM1 and GSTT1), inflammation (IL-6), iron processing (HFE), and microRNA processing (GEMIN4 and DGCR8) [
3.7 Synergistic effects of air pollution and other environmental exposures: The concept of exposome
Based on the increasing awareness of the major impact of environmental risk factors, the exposome concept was recently introduced to identify a new emerging field of research investigating the effects of all environmental exposures on human health such as air pollution, traffic noise and climate change [
]. Traffic noise can activate a stress reaction chain with stress responses involving the hypothalamus, the limbic system, and the autonomic nervous system leading to the activation of the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medulla axis and, finally, an increase in heart rate and in levels of stress hormones (cortisol, adrenalin, and noradrenaline), enhanced platelet reactivity, vascular inflammation, and oxidative stress [
]. A recent study reported that a combined exposure to air and transportation noise pollution is significantly associated with an increased risk of CV events compared to the exposure to one or none of them mainly mediated by arterial inflammation [
]. The adverse effects of traffic noise are much more significant during night-time, likely through disruption of sleep–wake cycle, sleep deprivation and/or fragmentation and perturbation of time periods critical for physiological and mental restoration [
]. Accordingly, a recent study demonstrated that exposure to aircraft noise during night-time increased vascular and cerebral oxidative stress through NOXs activation as well as triggered vascular dysfunction leading to an increased risk of CV events [
The use of fossil fuels with the significant emission of greenhouse gases caused a significant global warming of ∼1.5 °C above the preindustrial level and that will likely increase in the next years, raising concerns about the risk of climate change for human health [
Climate Change 2022 Impacts, Adaptation and Vulnerability Working Group II Contribution to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change.
]. High temperatures have been associated with an increased risk of ACS and CV events through several mechanisms including higher cardiac strain and blood viscosity, increased IL-6 levels and sleep disturbance [
]. Furthermore, global warming is associated with an increased incidence of natural disasters, such as wildfires, desert storms, and volcano eruptions, that further release PM2.5 and greenhouse gases, leading to the amplification of the deleterious health effects as well as global warming in a positive feedback fashion [
Many epidemiological studies addressing the recent COVID-19 pandemic reported a strong association between SARS-CoV-2 infection, increased PM2.5 exposure, and morbidity and mortality from IHD [
]. Several key mechanisms involved in the pathogenesis of SARS-CoV-2 infection can cross-react and have synergistic effects with those induced by PM2.5, thus exponentially increasing the risk of ischemic events.
The SARS-CoV-2 host cell receptor, the angiotensin-converting enzyme 2 (ACE-2), is widely expressed in several organs, including heart pericytes and endothelial cells [
]. ACE-2 is a transmembrane protein that actively regulates systemic blood pressure by catalysing the hydrolysis of the vasoconstrictive angiotensin II into the vasodilative angiotensin 1-7 [
]. The activation of ACE2 leads to the inhibition of the NF-kB along with the enhancement of the nuclear factor erythroid 2-related factor 2 (NRF2) anti-inflammatory pathway, thus decreasing inflammation and oxidative stress in the vasculature [
]. The binding of SARS-CoV-2 to ACE2 reduces its bioavailability leading to increased angiotensin II levels and, therefore, increased vasoconstriction, vascular inflammation and oxidative stress, in an additive manner to PM2.5 [
]. The binding of SARS-CoV-2 to heart pericytes and endothelial cells can directly damage the endothelium and cause endothelial dysfunction and microvascular impairment, thus potentiating the PM2.5-induced endothelial damage, promoting atherosclerosis and impairing coronary blood flow reserve with increased susceptibility to myocardial ischaemia. PM2.5 exposure has been demonstrated to increase the expression of ACE2 in endothelial cells, thus promoting their infection by SARS-CoV-2 and leading to increased viral load and enhanced systemic response with a pro-inflammatory and prothrombotic milieu that may further predispose to the development of ACS [
The ACE-2 receptor plays a central role in the pathogenesis of both SARS-CoV-2) infection and PM2.5-mediated atherosclerotic cardiovascular disease. Indeed, PM2.5exposure can increase the expression of ACE2, thus promoting the binding of SARS-CoV-2 to endothelial cells. SARS-CoV-2 fusion requires the cleavage of the S1 by the TMPRSS2 in order to bind the ACE2 receptor and be internalized for replication. The consequently reduced bioavailability of ACE2 leads to increased circulating levels of angiotensin II level, which promotes vasoconstriction, vascular inflammation, and oxidative stress. Finally, the binding of SARS-CoV-2 to the endothelial cells can directly cause endothelial dysfunction and microvascular impairment, thus potentiating PM2.5-induced endothelial damage and increasing the susceptibility to myocardial ischaemia. ACE-2: Angiotensin-Converting Enzyme 2; SARS-CoV-2: Severe Acute Respiratory Syndrome Coronavirus 2; PM2.5: Particulate Matter ≤2.5 μm; S1: Spike Protein; TMPRSS2: Transmembrane Serine Protease 2; RBD: Receptor-Binding Domain.
The formation of PM2.5-SARS-CoV-2 aggregates could facilitate the penetration of the virus into the alveoli and the crossing of the alveolar-capillary barrier, thus further increasing the viral load and potentiating systemic inflammation [
]. Indeed, the involvement of the CV system in COVID-19 infection might be the consequence of an exaggerated systemic inflammatory response due to host immune system dysregulation consequent to a viral infection that could be enhanced by increased PM2.5 exposure, thus leading to an exaggerated cytokine release (i.e.: cytokine storm), inflammasome activation, and a pro-inflammatory vascular milieu with diffuse intravascular coagulation and increased propensity to ischemic coronary events (plaque instability and coronary artery thrombotic occlusion) [
]. Despite PM2.5 is likely to synergize with SARS-CoV-2 and potentiate different mechanisms of COVID-19 relevant for the pathogenesis of atherosclerosis and ACS, including endothelial dysfunction, systemic inflammatory response and systemic prothrombotic state, the precise relationship between PM2.5, SARS-CoV-2 and ACS are not fully understood yet. Further research is warranted to potentially develop targeted therapies aiming to reduce the impact of COVID-19 on CV morbidity and mortality.
Finally, it should be noted that the recent COVID-19 pandemic has only further highlighted the well-known association between PM2.5 exposure and increased susceptibility and mortality from several respiratory tract infections (viral and bacterial) [
]. In this regard, PM2.5 can promote the expression of ICAM-1, the host cell receptor for human rhinoviruses, in epithelial lung cells. Similarly, PM2.5 can foster oxidative stress and the production of the receptor for platelet-activating factor (PAFR), thus increasing the adhesion of Streptococcus pneumoniae (the most common aetiological agent of bacterial pneumonia) to human airway epithelial cells [
To date, no specific interventions aiming at reducing PM2.5 exposure have demonstrated to reduce the incidence of IHD in randomized clinical trials. However, the significant association between increased levels of PM2.5 and ischemic events as well as the improvement in surrogate markers of atherosclerosis with reduced PM2.5 exposure are highly suggestive that pollution prevention and control measures might be extremely effective. Indeed, the unprecedented pollution control actions with restricted air pollution emissions during the 2008 Beijing Olympics provided a quasi-experimental opportunity to examine biologic responses to drastic changes in air pollution levels. The decreased average concentrations of PM2.5 observed during the Olympic period (reduced by 27% from the pre-Olympic period) was associated with a significant reduction in circulating levels of biomarkers related to oxidative stress, thrombosis and systemic/vascular inflammation (i.e., CRP, white blood cell count, fibrinogen, von Willebrand factor, sCD40L) as well as with the improvement of HRV and blood pressure levels in young healthy subjects [
]. Likewise, a recent analysis of the CV disease burden from ambient air pollution estimated that a complete phase-out of fossil fuel-related emissions (especially PM2.5) could lead to a reduction in the excess mortality rate of 3.61 million per year worldwide and an increase in mean life expectancy in Europe of 1.2 years [
5.1 Governmental and public policy mitigation strategies
Primary prevention with the implementation of societal and governmental interventions represents the primary goal that should be pursued. These interventions include the shift to clean low-polluting renewable energy sources (such as wind, tidal, geothermal, and solar), transportation reforms promoting the use of low- and zero-emission vehicles as well as the restriction of traffic (especially trucks) in city centres, and the reduction of traffic emissions through the use of diesel particle traps, catalytic converters, or alternative fuels (e.g., natural gas, electric cars). Similarly, urban landscape reforms are urgently needed, including the reduction of minimum distances between sources and people, the relocation of traffic sources (e.g., major trafficked roads), and the avoidance of mixed-use areas (industrial-residential) [
]. The socioeconomic status seems to be particularly relevant in determining an increased susceptibility to the harmful effects of PM2.5 on the CV system. In this regard, a recent study reported that the association between PM2.5 and CV mortality was stronger in patients with higher Social Deprivation Index (SDI) (a validated estimate of socioeconomic status, with higher SDI suggesting greater deprivation and lower socioeconomic status). These results suggests that governmental interventions to reduce PM2.5 might be most effective and impactful in communities of low socioeconomic status [
However, the completion of these measures may inevitably take longer and, therefore, the implementation of personal measures might be crucial, especially for more susceptible individuals such as patients with a prior history of coronary artery disease, pregnant women, children and elderly people.
5.2 Personal exposure mitigation strategies
Current approaches include active personal exposure mitigation with home air cleaning and personal equipment such as face masks and air purifiers, behavioural modifications to reduce passive exposures and pharmacologic approaches (Fig. 3). Despite these strategies are easily available, relatively cheap and highly effective, they are yet commonly overlooked. The use of FFP2 respirators at both high and low levels of PM2.5 exposures demonstrated to improve blood pressure and HRV [
]. Portable or installed air purifiers such as high-efficiency particulate air (HEPA) filtration are a promising and affordable method that can significantly lower indoor PM2.5 levels leading to the improvement of several surrogate markers of atherosclerosis, including blood pressure, insulin sensitivity, inflammatory markers, stress hormones, and metabolomic profiles [
]. Behavioural strategies include closing car and home windows, the use of cabin air filters for air-conditioning, changing travel routes, staying indoors and lifestyle changes including physical exercise in green areas away from major roadways. These measures can be particularly relevant in those who are susceptible, nevertheless also healthy subjects who have a sedentary lifestyle can benefit from it. Indeed, several studies demonstrated that the benefits of aerobic exercise nearly always exceed the risk of PM2.5 exposure across a wide range of concentrations [
]. Finally, growing attention has been given to pharmacological interventions that could potentially protect against the PM2.5-mediated adverse effects on atherosclerosis, although any can be recommended at this time. If clinically indicated, the use of medications for primary and secondary prevention of IHD (i.e., statins) as well as dietary supplements (i.e., vitamins, fish or olive oil) should be strongly encouraged, as they could reduce the impact of PM2.5 on surrogate measures of atherosclerosis [
]. A parallel, placebo control, randomized, clinical trial is currently ongoing (NCT04762472) and will randomize 200 patients to either Montelukast (10mg/daily) or image-matched placebo. The study aims to test the hypothesis of pulmonary inflammation and oxidative stress-related vascular dysfunction in PM2.5 and PM10 air pollution and to evaluate the impact of Montelukast treatment as compared with placebo on predictive atherosclerosis surrogates (brachial vascular reactivity evaluated by flow-mediated dilation and CIMT). Given the prominent role of oxidative stress, pharmacological approaches to prevent or reverse the effects of PM2.5 have been mainly focusing on compounds with antioxidant properties with contrasting results. The effects of targeted interventions able to disrupt the oxidative stress pathways and/or enhance antioxidant defences could be important areas of interest, and further research is needed to identify additional key pathways and develop a personalized and targeted medicine approach [
As previously discussed, other environmental exposures (i.e., noise and climate change) significantly contribute and synergize with air pollution in determining an increased risk of IHD. Hence, along with air pollution control, interventions aiming to reduce the impact of the exposome on human health are urgently needed.
Vehicle traffic (e.g., cars, trains and aircrafts) is the main source of noise pollution and an increasing public health problem. Given that vehicle traffic is strongly related to both noise and air pollution, the implementation of the same governmental strategies aiming at reducing air pollution could be effective also for noise pollution, in particular transportation reforms and urban landscape reforms. In addition, specific interventions to reduce noise pollution might include noise barriers in densely populated areas, building insulation against noise, lower speed limits and the application of quiet road surfaces. For aircraft noise, specific measures might include the ban of nocturnal air traffic (as noise during night-time is associated with the most pronounced health effects), new engine technologies (fleet evolution) and air traffic management [
Similarly, one of the main sources of greenhouse gases is vehicle traffic emissions due to the combustion of fossil fuels. Aggressive policies directed toward the reduction of greenhouse gases emission are urgently needed, and these interventions should include a switch to clean fuels, the implementation of transportation reforms and the reduction of traffic emissions.
6. Conclusions and future directions
It is now widely recognised that PM2.5 is associated with enhanced atherosclerosis development and progression. The comprehension of PM2.5-induced molecular mechanisms underlying this association would be extremely helpful in order to identify potential therapeutic targets and to prevent the occurrence and/or the progression of atherosclerosis. From a clinical perspective, there is a strong need for randomized, controlled clinical trials to demonstrate the efficacy of specific interventions targeting air pollution including both personal equipment and/or specific drugs to reduce the incidence of IHD before their use can be recommended in clinical practice. Finally, societal and governmental interventions aiming to decrease the emission of air pollutants, traffic noise and greenhouse gases are urgently needed in order to reduce the significant impact of these environmental exposures on CV morbidity and mortality worldwide.
CRediT authorship contribution statement
Rocco A. Montone: Data curation, Formal analysis, Writing – original draft, extraction and analysis of data, drafting of the manuscript, design and revision of the manuscript, All authors have read and agreed to the published version of the manuscript. Riccardo Rinaldi: Data curation, Formal analysis, Writing – original draft, extraction and analysis of data, drafting of the manuscript, design and revision of the manuscript, All authors have read and agreed to the published version of the manuscript. Alice Bonanni: Data curation, Formal analysis, Writing – original draft, extraction and analysis of data, drafting of the manuscript, design and revision of the manuscript, All authors have read and agreed to the published version of the manuscript. Anna Severino: revision of the manuscript, All authors have read and agreed to the published version of the manuscript. Daniela Pedicino: revision of the manuscript, All authors have read and agreed to the published version of the manuscript. Filippo Crea: design and revision of the manuscript, All authors have read and agreed to the published version of the manuscript. Giovanna Liuzzo: design and revision of the manuscript, All authors have read and agreed to the published version of the manuscript.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Figures created with BioRender.co.
Appendix A. Supplementary data
The following is the Supplementary data to this article.
Taking a stand against air pollution-the impact on cardiovascular disease: a joint opinion from the world heart federation, American college of cardiology, American heart association, and the European society of cardiology.
Association between air pollution and coronary artery calcification within six metropolitan areas in the USA (the Multi-Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study.
Long term exposure to ambient air pollution and incidence of acute coronary events: prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE Project.
Air particulate matter induced oxidative stress and inflammation in cardiovascular disease and atherosclerosis: the role of Nrf2 and AhR-mediated pathways.
Pulmonary diesel particulate increases susceptibility to myocardial ischemia/reperfusion injury via activation of sensory TRPV1 and β1 adrenoreceptors.
Long-term exposure to concentrated ambient PM2.5 increases mouse blood pressure through abnormal activation of the sympathetic nervous system: a role for hypothalamic inflammation.
Long-term exposure to air pollution and markers of inflammation, coagulation, and endothelial activation: a repeat-measures analysis in the Multi-Ethnic Study of Atherosclerosis (MESA).
Climate Change 2022 Impacts, Adaptation and Vulnerability Working Group II Contribution to the Sixth Assessment Report of the Intergovernmental Panel on Climate Change.
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