Atherosclerosis 366 (2023) 22–31

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Review article

Impact of air pollution on ischemic heart disease: Evidence, mechanisms,

clinical perspectives
Rocco A. Montone a, *, Riccardo Rinaldi b, Alice Bonanni a, Anna Severino a, b, Daniela Pedicino a,
Filippo Crea a, b, 1, Giovanna Liuzzo a, b, 1
a
Department of Cardiovascular Sciences, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
b
Department of Cardiovascular and Pulmonary Sciences, Catholic University of the Sacred Heart Rome, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Ambient air pollution, and especially particulate matter (PM) air pollution <2.5 μm in diameter (PM2.5), has
Atherosclerosis clearly emerged as an important yet often overlooked risk factor for atherosclerosis and ischemic heart disease
Ischemic heart disease (IHD). In this review, we examine the available evidence demonstrating how acute and chronic PM2.5 exposure
Air pollution
clinically translates into a heightened coronary atherosclerotic burden and an increased risk of acute ischemic
Particulate matter
Pathophysiology
coronary events. Moreover, we provide insights into the pathophysiologic mechanisms underlying PM2.5-
Exposome mediated atherosclerosis, focusing on the specific biological mechanism through which PM2.5 exerts its detri­
mental 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 under­
scoring 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.

1. Introduction [2]. Ambient air pollution originates principally from fossil-fuel com­
bustion, while household air pollution is caused mainly by the com­
Coronary atherosclerosis represents the principal aetiology under­ bustion of biomass fuels, smoking and gas stoves [3]. Ambient air
lying ischemic heart disease (IHD), and considerable efforts have been pollution represents the world’s fourth leading cause of disease and
made towards the early identification and treatment of traditional car­ death and, notably, more than 50% of these deaths can be attributed to
diovascular (CV) risk factors for atherosclerosis, such as hypertension, atherosclerotic CV diseases, including IHD and stroke, with accumu­
smoking, dyslipidaemia and type 2 diabetes mellitus. Indeed, the lating evidence supporting a consistent relationship between increased
recognition of these risk factors and their consequent treatment and air pollution exposure and progression of atherosclerosis [4–6]. More­
prevention portended more than a 50% decline in IHD-related mortality over, air pollution is nearly ubiquitous as the World Health Organization
in the past 50 years [1]. However, IHD still remains one of the leading (WHO) estimates that >90% of the world’s population lives in areas
causes of disability and mortality worldwide and, therefore, the focus is with annual mean levels of air pollutants exceeding the WHO global air
shifting towards the identification of novel pathways to reduce residual quality guidelines limits [7]. Among the different components of air
atherosclerotic risk. pollution, particulate matter with aerodynamic diameter ≤2.5 μm
Air pollution is a complex mixture of unwanted particulate and (PM2.5) demonstrated the strongest association with CV diseases.
gaseous material released into the environment by human activities. Air Indeed, multiple evidence links PM2.5 exposure to increased suscepti­
pollution includes ambient (outdoor) and household (indoor) pollution bility to coronary atherosclerosis development and progression to

* Corresponding author. Department of Cardiovascular Sciences Fondazione Policlinico Universitario A. Gemelli IRCCS L.go A. Gemelli, 1, 00168, Rome, Italy.
E-mail address: roccoantonio.montone@unicatt.it (R.A. Montone).
1
These authors equally contributed as last authors to this work.

https://doi.org/10.1016/j.atherosclerosis.2023.01.013
Received 28 July 2022; Received in revised form 23 December 2022; Accepted 17 January 2023
Available online 20 January 2023
0021-9150/© 2023 Elsevier B.V. All rights reserved.
R.A. Montone et al. Atherosclerosis 366 (2023) 22–31

high-risk plaques prone to rupture [8–10]. Therefore, PM2.5 is emerging therapeutic strategies aiming to reduce the impact of air pollution on CV
as a major determinant of the residual atherosclerotic CV risk worldwide mortality worldwide.
[11].
Moreover, the recent coronavirus disease 2019 (COVID-19) 2. Current evidence linking air pollution and atherosclerosis
pandemic showed a consistent relationship between severe acute res­
piratory syndrome coronavirus 2 (SARS-CoV-2) infection, increased The impact of urban ambient air pollution, especially combustion-
PM2.5 exposure and mortality due to ischaemic cardiac events, sug­ derived PM, has being increasingly studied in recent years due to the
gesting an interaction between infective agents and air pollution in the high density of urban populations and the increasing levels of traffic-
pathogenesis of IHD [12]. derived emissions worldwide. PM includes both organic and inorganic
The purpose of this review is to provide updated evidence of the particles and is categorized according to the aerodynamic diameter into
pathophysiological mechanisms underlying air pollution-mediated coarse particles (2.5–10 μm in diameter; PM10), fine particles (PM2.5),
atherosclerosis, focusing on the specific mechanisms through which and ultrafine particles (<0.1 μm in diameter; PM0.1) [3]. The aero­
PM2.5 can promote formation, progression and destabilization (i.e.: dynamic diameter is critical for the toxic effects of PM, as small particles,
rupture) of atherosclerotic plaques. Moreover, we aim to examine the such as PM2.5 and PM0.1, might contribute disproportionately due to
concept of exposome, highlighting the close relationship between PM2.5 their large reactive surface area and their ability to penetrate deeply into
and other environmental exposures (i.e.: traffic noise and climate the alveoli and directly into the bloodstream, causing damages and
change) and underscoring the common pathophysiologic mechanisms, dysfunction of tissues and cells far from the lungs [13].
as well as the possible mitigation strategies. Indeed, gaining a deep Additionally, a key determinant of the harmful effect of PM2.5 on the
insight into the pathophysiological mechanisms of PM2.5-mediated CV system is the different time frames of exposure. Indeed, short-term
atherosclerosis could pave the way for the development of novel specific PM2.5 exposure (hours) has been strongly associated with the risk of

Fig. 1. Hypothetical 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.

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acute coronary syndrome (ACS), as the immediate responses following increased risk of developing high-risk coronary plaques at follow-up
PM2.5 exposure are all potential initiators and promoters of athero­ (defined as plaques with low attenuation, spotty calcium, positive
thrombotic events (i.e., sympathoadrenal activation, release of circu­ remodelling, fibrofatty or necrotic core components and greater plaque
lating inflammatory biomarkers, endothelial dysfunction, release of pro- volume) [8]. Recently, our group assessed the relationship between
coagulant proteins and platelets activation) [14,15]. Moreover, long-term exposure to air pollutants and mechanisms of coronary
short-term PM2.5 exposure is associated with acute vascular modifica­ instability evaluated by OCT in patients with ACS, and we demonstrated
tions, such as arterial vasoconstriction and impaired vascular reactivity, that patients with plaque rupture (PR) as the mechanism of plaque
that could be additional triggers for plaque destabilization in susceptible instability were chronically exposed to significantly higher PM2.5 levels
individuals [16]. However, acute exposure to PM2.5 might even more than those with intact fibrous cap. PM2.5 was independently associated
likely trigger an ACS in the context of chronic long-term (years) expo­ with PR as well as with the presence of thin cap fibroatheroma and
sure, promoting the progression of the atherosclerotic burden and macrophages at the culprit site and with higher levels of serum
leading to the development of vulnerable plaque features (i.e., plaque C-reactive protein (CRP) [17].
inflammation, weakening of fibrous cap and increased lipid content) and A significant association has been reported between increased PM2.5
potentiating the deleterious effects of other traditional CV risk factors (i. exposure and the risk of non-fatal MI, especially for ST-segment eleva­
e., hypertension, dyslipidaemia, type 2 diabetes mellitus) [8,17,18]. tion MI compared with non-ST-segment elevation MI and in patient with
Chronic PM2.5 exposure, by promoting the development of a vulnerable angiographic evidence of coronary artery disease [14][21] (Supple­
systemic state with underlying vulnerable plaques, can exponentially mentary Table 2). In particular, the European Study of Cohorts for Air
increase the risk of acute ischemic events that are likely to be precipi­ Pollution Effects (ESCAPE) study showed that a 5 μg/m3 increase in
tated by acute variations in PM2.5 exposure (Fig. 1). estimated annual mean PM2.5 was associated with a 13% increased risk
The dose of PM2.5 exposure is also important to consider. Many of acute coronary events (hazard ratio [HR] 1.13; 95% CI: 0.98 to 1.30)
epidemiologic studies demonstrated that increasing levels of PM2.5 are [22]. In addition, a time-stratified case-crossover study recently con­
strongly associated with clinical markers of atherosclerosis, increased ducted in China showed that each 10 μg/m3 increase in PM2.5 exposure
risk of myocardial infarction (MI) and CV mortality [15]. The PM2.5 (mean exposure on the same day of death and 1 day prior) was signifi­
dose-response curve demonstrates a non-linear relationship, with a steep cantly associated with a 4.14% (95% CI: 1.25–7.12%) increase in odds of
increase at low concentrations and some flattening at higher levels, MI mortality [14]. Similarly, a meta-analysis of 34 studies of short-term
although there is no lower concentration threshold below which expo­ air pollution exposure showed that each increase of 10 μg/m3 in PM2.5
sures can be considered safe [3,19]. Indeed, the adverse effects of PM2.5 exposure significantly increased the risk of MI by 2.5% (relative risk:
can manifest even with levels of exposure below the WHO recommended 1.025; 95% CI: 1.015–1.036) [23].
standards of 5 μg/m3 annually [7]. Several studies demonstrated a sig­ However, it should be noted that some studies investigating the as­
nificant association between increased PM2.5 exposure and the pro­ sociation between PM2.5 and progression of atherosclerosis or non-fatal
gression of atherosclerosis using different imaging techniques, including MI provided null or inconclusive results, possibly because the different
computed tomography (CT), coronary computed tomography angiog­ study designs and evaluated endpoints (Supplementary Table 1 and
raphy (CCTA), magnetic resonance and intravascular imaging, to Supplementary Table 2).
quantify clinical surrogates of atherosclerosis, such as carotid
intima-media thickness (CIMT), coronary artery calcium (CAC), thoracic 3. PM2.5 and atherosclerosis: Pathogenetic mechanisms
and abdominal aortic calcification, and arterial brachial index (ABI)
(Supplementary Table 1). Among these, CAC assessed by CT is probably 3.1. Oxidative stress
the best direct surrogate for atherosclerosis and it has been demon­
strated to be a strong predictor for future CV events, as plaques with high PM2.5 can promote the generation of reactive oxygen species (ROS)
calcium tend to progress faster and thus may be identified by the burden and reactive nitrogen species (RNS) by interfering with many cellular
of atherosclerosis or its progression. In this regard, the Multi-Ethnic mechanisms, including NADPH oxidases (NOXs), endothelial nitric
Study of Atherosclerosis (MESA) Air Pollution is the largest study oxide synthase (eNOS) uncoupling and mitochondrial respiratory chain
evaluating the association between PM2.5 and CAC. A cross-sectional dysfunction [24]. In particular, the activation of NOXs with the conse­
analysis of 5172 patients from the MESA Air Pollution study assessed quent overproduction of superoxide radicals can determine mitochon­
the effects of PM2.5 exposures of the previous 20 years and reported a drial damage in macrophages, with the activation of the
significant association of CIMT with PM2.5 (RR 1.01; 95% Confidence mitochondrial-mediated apoptosis of foam cells and lipid accumula­
Interval [CI]: 1.00 to 1.02 per 12.5 μg/m3), whereas no significant as­ tion and growth of the necrotic core in the atherosclerotic plaques [25,
sociation was reported for CAC and ABI [20]. Conversely, a 10-year 26]. Likewise, eNOS uncoupling leads to the production of superoxide
longitudinal analysis including 6795 patients of the MESA Air Pollu­ radicals, instead of nitric oxide (NO), that combine with NO leading to
tion study cohort assessed the relationship between CAC progression at the formation of the highly reactive intermediate peroxynitrite
repeated CT and reported no significant association between PM2.5 and (ONOO-). Progressively, the accumulation of ONOO- radicals can
CIMT change, whereas PM2.5 was significantly associated with pro­ directly oxidize the circulating low-density lipoproteins (LDL) to
gression of CAC (for each 5 μg PM2.5/m3 increase, CAC progressed by oxidized LDL (ox-LDL) which further stimulates NOXs to produce free
4.1 Agatston units per year, 95% CI: 1.4 to 6.8) [9]. Thus, results are radicals and, by activating the scavenger receptor lectin-like oxidized
somewhat inconsistent and CAC progression remains a surrogate for the low-density lipoprotein receptor-1 (LOX-1), downregulate eNOS
atherosclerotic burden rather than plaque vulnerability. Accordingly, it expression and stimulate vascular smooth muscle cells (VSMCs) prolif­
may not accurately reflect the mechanism by which PM2.5 mediates the eration and extracellular matrix deposition, finally contributing to
risk of ACS being rather a hallmark for other mechanisms. To overcome intimal hyperplasia and vascular remodelling [27].
these limitations, the same imaging techniques along with intracoronary Heavy metals on the surface of PM2.5 can catalyse Fenton and
imaging modalities (especially optical coherence tomography [OCT] Fenton-like reactions fostering the generation of ROS [28]. Similarly,
thank to its high resolution) have been used to investigate in-vivo the polycyclic aromatic hydrocarbons on the surface of PM2.5 are ago­
atherosclerotic plaque features and to detect signs of plaque vulnera­ nists for the aryl hydrocarbon receptor (AhR). AhR is a ligand-activated
bility (i.e.: thin fibrous cap, lipid necrotic core, plaque inflammation, transcriptional factor that migrates to the nucleus, binds to the AhR
presence of healed disruptions, and plaque angiogenesis) following nuclear transporter, and activates the transcription of several proa­
PM2.5 exposure. A recent study using serial CCTA showed that an in­ therogenic and pro-inflammatory pathways fostering oxidative stress,
crease of 1 μg/m3 in PM2.5 concentration was associated with an vascular damage and inflammation. AhR activation can stimulate the

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uptake of cholesterol by macrophages and the proliferation and migra­ 3.3. Autonomic and neuroendocrine dysfunction
tion of VSMCs, promoting the formation of foam cells and of the fibrous
cap around the necrotic core [29,30]. PM2.5 exposure can reduce heart rate variability (HRV) by inducing
systemic inflammation and oxidative stress, as functional variations in
3.2. Inflammation genes involved in oxidative stress, such as glutathione S-transferase M1
(GSTM1) and haemoxygenase-1 (HMOX-1), demonstrated to modulate
PM2.5 exposure has been associated with increased levels of systemic these effects [41–43].
inflammation markers, including CRP, plasma fibrinogen and several PM2.5 can establish an imbalance in the autonomic nervous system
pro-inflammatory cytokines, and PM2.5 can directly activate circulating with increased sympathetic activity. Indeed, the exposure of pulmonary
leukocytes and the vascular endothelium and promote cell adhesion and C-nerve fibres to PM2.5 can determine the activation of specific mech­
migration [31]. These pro-inflammatory effects of PM2.5 could exacer­ anoreceptors in the lungs, such as transient receptor potential ankyrin 1
bate the development of ACS by increasing the likelihood of plaque (TRPA1), transient receptor potential vanilloid 1 (TRPV1), and puri­
destabilization and/or arterial thrombosis as part of the inflammatory nergic P2X channels [44,45], with the activation of neural reflex arcs
process [32]. that lead to central sympathetic activation and release of vasoconstric­
Mechanistically, PM2.5 can trigger the activation of the nucleotide- tive mediators including catecholamines [46,47]. Moreover, PM2.5 can
binding oligomerization domain-like receptor protein 3 (NLRP3) determine endothelial injury and chronic vascular inflammation pro­
inflammasome leading to caspase-1 activation and the secretion of pro- moting acute autonomic nerve disorders and changes in blood pressure
inflammatory and proatherogenic cytokines [33]. The NLRP3 promotes [48]. PM2.5 exposure can regulate central hypothalamic sympathetic
macrophage polarization towards the pro-inflammatory M1 phenotype, activation likely by inducing neuroinflammation and may also directly,
thus developing a persistent pro-inflammatory and proatherogenic through the smallest particles entering the bloodstream, or indirectly,
vascular milieu characterized by macrophage proliferation and vascular through circulating factors and oxidative stress, damage the blood-brain
infiltration, production of several pro-inflammatory mediators, VSMCs barrier leading to altered permeability and influencing neuronal func­
migration, increased foam cell formation and degradation of extracel­ tions [49,50]. Additionally, PM2.5 has been demonstrated to directly
lular matrix components [32]. affect the parasympathetic system and trigger parasympathetic dysau­
The smallest particles of PM2.5 can directly cross the alveolar- tonomia [51].
capillary barrier gaining access to the blood circulation and reaching Finally, PM2.5 upregulates the production of endothelin-1 (ET-1) and
the sites of vascular lesions where they are phagocytosed by macro­ the expression of both its receptors type A and type B in coronary ar­
phages as an attempt to defend against the invading xenobiotics. The teries, thus shifting the balance of the vasomotor tone towards vaso­
progressive accumulation of these biologically persistent particles can constriction [52,53]. Likewise, PM2.5 can lead to increased circulating
further promote the activation and amplification of pro-inflammatory levels of angiotensin II and the activation of the angiotensin II type 1
pathways leading to the release of several pro-inflammatory cytokines receptor axis in vascular endothelial cells (VECs), which promote
and free radicals (a mechanism known as “frustrated phagocytosis”) [34, oxidative stress and vascular inflammation, stimulate the biosynthesis of
35]. ET-1 and upregulate the expression of type A endothelin receptors in
PM2.5 can directly cause inflammation in other vascular sites, VSMCs [54].
including the adipose tissue and the brain. The adipose tissue releases
several hormones, cytokines, extracellular matrix proteins, growth fac­ 3.4. Metabolic alterations
tors and vasoactive molecules collectively called adipokines. PM2.5 is
demonstrated to induce chronic inflammation in the adipose tissue PM2.5 exposure has been associated with decreased levels of high-
fostering the release of adipokines, including adiponectin, resistin, vis­ density lipoprotein (HDL) cholesterol and apolipoprotein A1,
fatin, and chemerin, that promote atherosclerosis by influencing the increased levels of LDL cholesterol, ox-LDL, total cholesterol, tri­
function of endothelial cells, VSMCs, and macrophages in vessel walls glycerides, lipoprotein(a) and the ratio of apolipoprotein B/A1 as well
leading to the activation of nuclear factor kappa light-chain-enhancer of with the presence of lipid-rich and inflamed atherosclerotic plaques [55,
activated B cells (NF-kB), release of cytokines, activation of matrix 56]. Indeed, PM2.5 promotes a unique form of dyslipidaemia charac­
metalloproteinases (MMPs) and expression of vascular adhesion mole­ terized by high levels of circulating fatty acids such as palmitate, myr­
cules [36]. The activation of MMPs, in particular, promotes the degra­ istate, and palmitoleate, and decreased phospholipid species, likely
dation of extracellular matrix components such as collagen and elastin through the activation of lipolysis, the dysregulation of lipid metabolism
in the fibrous cap, thus reducing the stability of the atherosclerotic in the liver, and the induction of mitochondrial dysfunction. The expo­
plaques [37]. sure of vascular endothelial cells to heightened levels of fatty acid can
Oxidative stress acts synergistically with inflammation by upregu­ foster vascular inflammation, activating the NF-κB pathway and NLRP3
lating the secretion of inflammatory cytokines by immune and non- inflammasome, and impair growth factor signalling such as insulin and
immune (e.g.: endothelial) cells and promotes the oxidation of circu­ vascular endothelial growth factor [57].
lating lipoproteins, in particular LDL to the highly atherogenic ox-LDL, In addition, PM2.5 can promote HDL cholesterol dysfunction leading
that are preferentially up taken by macrophages through the CD36 to reduced antioxidant and anti-inflammatory capacities, decreased
scavenger receptor leading to the formation of foam cells and the growth paraoxonase activity, and alterations in the reverse cholesterol transport
of lipid-rich atherosclerotic plaques [38]. from cells and extracellular tissues to the liver, resulting in increased
Finally, PM2.5 can promote systemic inflammation by fostering circulating LDL and ox-LDL levels and LDL-induced monocyte migration
leucopoietic activity in leucopoietic tissues (i.e., bone marrow and to atherosclerotic plaques [38,58]. Similarly, PM2.5 can promote the
spleen) as well as arterial inflammation [39]. A recent study using modification of cholesterol into 7-ketocholesterol in the circulating LDL
F-fluorodeoxyglucose positron emission tomography/computed fractions further stimulating the CD36-mediated phagocytosis by mac­
tomography in 503 subjects demonstrated that a higher PM2.5 exposure rophages. 7-ketocholesterol is the most abundant modified sterol in
was associated with increased leucopoietic activity and arterial atherosclerotic lesions, where it promotes endothelial dysfunction and
inflammation. PM2.5 exposure associated with MACE and mediation oxidative stress activating NOXs [59].
analysis demonstrated that increased leucopoietic activity and arterial
inflammation mediate the link between PM2.5 and MACE [40]. 3.5. Enhanced thrombosis and hypercoagulability

PM2.5 exposure has been associated with changes in different

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biomarkers of systemic coagulation and fibrinolysis, including fibrin­ dysfunction and atherosclerosis [76]. PM2.5 can influence the expression
ogen, endogenous thrombin, von Willebrand factor, tissue-plasminogen of miRNAs that regulate the production of pro-inflammatory cytokines
activator (tPA) and plasminogen activator inhibitor (PAI)-1, as well as (i.e.: miR-21-5p, miR-187-3p, miR-146a-5p, miR-1-3p, and
with increased platelet activation and reduced activated partial throm­ miR-199a-5p) [77].
boplastin time and prothrombin time [60,61]. Acute PM2.5 exposure Mitochondrial DNA (mtDNA) is particularly sensitive to PM2.5-
results in impaired endogenous fibrinolysis and increased thrombus induced oxidative stress damage given the absence of histone protection
formation, thus suggesting that PM2.5 could heighten the risk of athe­ and DNA repair activity in mitochondria. Alterations in mtDNA can alter
rothrombotic events [62,63]. the RNA and proteins produced by the mitochondria, with alterations of
Experimental studies demonstrated that PM2.5 exposure leads to a mitochondrial homeostasis and impairment of mitochondrial ener­
TNF-α-dependent increase in PAI-1 and an IL-6-dependent activation of getical function and related mechanisms, such as beta-oxidation and
coagulation [64]. PAI-1 is a serine protease that inhibits tPA and uro­ electron transport chain, resulting in mitochondrial dysfunction. The
kinase plasminogen activator and activates plasminogen into plasmin presence of mitochondrial dysfunction can potentiate several mecha­
inducing fibrinolysis. IL-6 is produced by alveolar macrophages nisms strictly related to atherosclerosis such as oxidative stress and
following PM2.5 exposure and is associated with increased generation of vascular inflammation [78].
intravascular thrombin and acceleration of arterial thrombosis by Finally, another point to consider is the interplay between air
increasing the expression of fibrinogen, factor VIII, von Willebrand pollution and pre-existing genetic factors. Recent studies investigated
factor, and the activity of factor II and X. Moreover, IL-6 reduces the the interaction between PM2.5 and genetic predisposition to IHD such as
transcription of thrombosis inhibitors, including antithrombin and polygenic risk score and specific genes involved in oxidative stress and
protein S, and promotes the activation of Signal Transducer And Acti­ inflammatory pathways [79]. Gene-air pollution interaction studies
vator Of Transcription 3 (STAT3) in bone marrow progenitor cells aimed to assess the contribution of genetic variation to inter-individual
resulting in neutrophilia and thrombocytosis [65]. Finally, PM2.5 heterogeneity in susceptibility to PM2.5, reporting interactions to cluster
exposure can promote vascular thrombosis by inducing IL-6 dependent in a few genes related to detoxification (GSTM1 and GSTT1), inflam­
activation of platelets, increasing platelet-monocyte aggregates and mation (IL-6), iron processing (HFE), and microRNA processing
reducing the release of the fibrinolytic tPA from the vascular endothe­ (GEMIN4 and DGCR8) [80].
lium [62,63,66,67].
3.7. Synergistic effects of air pollution and other environmental
3.6. Epigenetic reprogramming and genetic factors exposures: The concept of exposome

Epigenetic reprogramming includes all the alterations in gene Based on the increasing awareness of the major impact of environ­
expression (activation or repression) and function, without any changes mental risk factors, the exposome concept was recently introduced to
in the underlying DNA sequence. Of note, epigenetic reprogramming identify a new emerging field of research investigating the effects of all
can be influenced by several environmental stimuli including PM2.5 environmental exposures on human health such as air pollution, traffic
[68]. noise and climate change [81].
DNA methylation typically involves the promoter regions leading to Traffic noise is an omnipresent exposure that is likely to synergize with
chromatin condensation and inhibition of gene expression. PM2.5 PM2.5 in mediating an increased risk of atherosclerosis and IHD [82]. Traffic
exposure has been associated with reduced DNA methylation (and noise can activate a stress reaction chain with stress responses involving the
consequent overexpression) of genes involved in several pathways hypothalamus, the limbic system, and the autonomic nervous system
relevant for the induction of atherosclerosis including oxidative stress, leading to the activation of the hypothalamic-pituitary-adrenal axis and the
cytokine signalling and vascular expression of adhesion molecules [69]. sympathetic-adrenal-medulla axis and, finally, an increase in heart rate and
In particular, PM2.5 demonstrated to increase the levels of in levels of stress hormones (cortisol, adrenalin, and noradrenaline),
pro-inflammatory and prothrombotic molecules by reducing DNA enhanced platelet reactivity, vascular inflammation, and oxidative stress
methylation in related genes [70]. [83]. A recent study reported that a combined exposure to air and trans­
Similarly, histone modifications can influence gene expression by portation noise pollution is significantly associated with an increased risk of
changing chromatin configuration. Histone acetylation, by diminishing CV events compared to the exposure to one or none of them mainly medi­
the histone–DNA interactions, leads to transcriptionally active chro­ ated by arterial inflammation [84]. The adverse effects of traffic noise are
matin whereas deacetylation, conversely, leads to transcriptionally much more significant during night-time, likely through disruption of
inactive chromatin. Instead, the result of the histone methylation or sleep–wake cycle, sleep deprivation and/or fragmentation and perturba­
demethylation depends on the specific methylation site and may result tion of time periods critical for physiological and mental restoration [85].
in either gene activation (e.g.: methylation on lysine 4 or 36 on histone Accordingly, a recent study demonstrated that exposure to aircraft noise
H3) or repression (e.g.: H3 methylation on lysine 9 or 27). PM2.5 during night-time increased vascular and cerebral oxidative stress through
exposure has been associated with several histone modifications in NOXs activation as well as triggered vascular dysfunction leading to an
blood leukocytes (e.g.: H3 lysine 9 acetylation, H3 lysine 9 tri- increased risk of CV events [86,87].
methylation, H3 lysine 27 tri-methylation) and these modifications The use of fossil fuels with the significant emission of greenhouse
have been clinically correlated with increase in blood pressure, vascular gases caused a significant global warming of ~1.5 ◦ C above the prein­
inflammation and atherosclerosis progression [71,72]. dustrial level and that will likely increase in the next years, raising
Micro-RNA (miRNAs) are a class of highly conserved, small non- concerns about the risk of climate change for human health [88]. High
coding post-transcriptional regulators of many cellular pathways with temperatures have been associated with an increased risk of ACS and CV
an emerging role in the pathogenesis of atherosclerosis [73]. The events through several mechanisms including higher cardiac strain and
overexpression of miR-21 in macrophages results in decreased secretion blood viscosity, increased IL-6 levels and sleep disturbance [89,90].
of pro-inflammatory cytokines and lipid accumulation together with Thus, global warming can increase the individual susceptibility to IHD
increased production of anti-inflammatory cytokines, whereas its defi­ which may be further exacerbated by PM2.5 or other environmental
ciency promoted endothelial dysfunction, vascular inflammation and exposures [91]. Furthermore, global warming is associated with an
plaque necrosis leading to accelerated atherosclerosis [74,75]. PM2.5 increased incidence of natural disasters, such as wildfires, desert storms,
exposure has been associated with reduced expression of miR-21 in and volcano eruptions, that further release PM2.5 and greenhouse gases,
leukocytes suggesting a role of PM2.5-induced alterations in miRNA leading to the amplification of the deleterious health effects as well as
expression in the amplification of vascular inflammation, endothelial global warming in a positive feedback fashion [92].

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4. COVID-19 and air pollution 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-
Many epidemiological studies addressing the recent COVID-19 capillary barrier, thus further increasing the viral load and potentiating
pandemic reported a strong association between SARS-CoV-2 infec­ systemic inflammation [98,99]. Indeed, the involvement of the CV
tion, increased PM2.5 exposure, and morbidity and mortality from IHD system in COVID-19 infection might be the consequence of an exag­
[12]. Several key mechanisms involved in the pathogenesis of gerated systemic inflammatory response due to host immune system
SARS-CoV-2 infection can cross-react and have synergistic effects with dysregulation consequent to a viral infection that could be enhanced by
those induced by PM2.5, thus exponentially increasing the risk of increased PM2.5 exposure, thus leading to an exaggerated cytokine
ischemic events. release (i.e.: cytokine storm), inflammasome activation, and a
The SARS-CoV-2 host cell receptor, the angiotensin-converting pro-inflammatory vascular milieu with diffuse intravascular coagulation
enzyme 2 (ACE-2), is widely expressed in several organs, including and increased propensity to ischemic coronary events (plaque instability
heart pericytes and endothelial cells [93]. ACE-2 is a transmembrane and coronary artery thrombotic occlusion) [100,101]. Despite PM2.5 is
protein that actively regulates systemic blood pressure by catalysing the likely to synergize with SARS-CoV-2 and potentiate different mecha­
hydrolysis of the vasoconstrictive angiotensin II into the vasodilative nisms of COVID-19 relevant for the pathogenesis of atherosclerosis and
angiotensin 1-7 [94]. The activation of ACE2 leads to the inhibition of ACS, including endothelial dysfunction, systemic inflammatory
the NF-kB along with the enhancement of the nuclear factor erythroid response and systemic prothrombotic state, the precise relationship
2-related factor 2 (NRF2) anti-inflammatory pathway, thus decreasing between PM2.5, SARS-CoV-2 and ACS are not fully understood yet.
inflammation and oxidative stress in the vasculature [95]. The binding Further research is warranted to potentially develop targeted therapies
of SARS-CoV-2 to ACE2 reduces its bioavailability leading to increased aiming to reduce the impact of COVID-19 on CV morbidity and
angiotensin II levels and, therefore, increased vasoconstriction, vascular mortality.
inflammation and oxidative stress, in an additive manner to PM2.5 [96]. Finally, it should be noted that the recent COVID-19 pandemic has
The binding of SARS-CoV-2 to heart pericytes and endothelial cells can only further highlighted the well-known association between PM2.5
directly damage the endothelium and cause endothelial dysfunction and exposure and increased susceptibility and mortality from several respi­
microvascular impairment, thus potentiating the PM2.5-induced endo­ ratory tract infections (viral and bacterial) [102]. In this regard, PM2.5
thelial damage, promoting atherosclerosis and impairing coronary blood can promote the expression of ICAM-1, the host cell receptor for human
flow reserve with increased susceptibility to myocardial ischaemia. rhinoviruses, in epithelial lung cells. Similarly, PM2.5 can foster oxida­
PM2.5 exposure has been demonstrated to increase the expression of tive stress and the production of the receptor for platelet-activating
ACE2 in endothelial cells, thus promoting their infection by SARS-CoV-2 factor (PAFR), thus increasing the adhesion of Streptococcus pneumo­
and leading to increased viral load and enhanced systemic response with niae (the most common aetiological agent of bacterial pneumonia) to
a pro-inflammatory and prothrombotic milieu that may further predis­ human airway epithelial cells [103].
pose to the development of ACS [97] (Fig. 2).

Fig. 2. Mechanisms of SARS-CoV-2 and PM2.5 leading to cardiovascular disease.

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.

27
R.A. Montone et al. Atherosclerosis 366 (2023) 22–31

5. Mitigation strategies CV system. In this regard, a recent study reported that the association
between PM2.5 and CV mortality was stronger in patients with higher
To date, no specific interventions aiming at reducing PM2.5 exposure Social Deprivation Index (SDI) (a validated estimate of socioeconomic
have demonstrated to reduce the incidence of IHD in randomized clin­ status, with higher SDI suggesting greater deprivation and lower so­
ical trials. However, the significant association between increased levels cioeconomic status). These results suggests that governmental in­
of PM2.5 and ischemic events as well as the improvement in surrogate terventions to reduce PM2.5 might be most effective and impactful in
markers of atherosclerosis with reduced PM2.5 exposure are highly communities of low socioeconomic status [108].
suggestive that pollution prevention and control measures might be However, the completion of these measures may inevitably take
extremely effective. Indeed, the unprecedented pollution control actions longer and, therefore, the implementation of personal measures might
with restricted air pollution emissions during the 2008 Beijing Olympics be crucial, especially for more susceptible individuals such as patients
provided a quasi-experimental opportunity to examine biologic re­ with a prior history of coronary artery disease, pregnant women, chil­
sponses to drastic changes in air pollution levels. The decreased average dren and elderly people.
concentrations of PM2.5 observed during the Olympic period (reduced
by 27% from the pre-Olympic period) was associated with a significant 5.2. Personal exposure mitigation strategies
reduction in circulating levels of biomarkers related to oxidative stress,
thrombosis and systemic/vascular inflammation (i.e., CRP, white blood Current approaches include active personal exposure mitigation with
cell count, fibrinogen, von Willebrand factor, sCD40L) as well as with home air cleaning and personal equipment such as face masks and air
the improvement of HRV and blood pressure levels in young healthy purifiers, behavioural modifications to reduce passive exposures and
subjects [104,105]. Likewise, a recent analysis of the CV disease burden pharmacologic approaches (Fig. 3). Despite these strategies are easily
from ambient air pollution estimated that a complete phase-out of fossil available, relatively cheap and highly effective, they are yet commonly
fuel-related emissions (especially PM2.5) could lead to a reduction in the overlooked. The use of FFP2 respirators at both high and low levels of
excess mortality rate of 3.61 million per year worldwide and an increase PM2.5 exposures demonstrated to improve blood pressure and HRV [16,
in mean life expectancy in Europe of 1.2 years [106]. 109], whereas surgical masks are not very effective in filtering PM2.5
[110]. Portable or installed air purifiers such as high-efficiency partic­
5.1. Governmental and public policy mitigation strategies ulate air (HEPA) filtration are a promising and affordable method that
can significantly lower indoor PM2.5 levels leading to the improvement
Primary prevention with the implementation of societal and of several surrogate markers of atherosclerosis, including blood pres­
governmental interventions represents the primary goal that should be sure, insulin sensitivity, inflammatory markers, stress hormones, and
pursued. These interventions include the shift to clean low-polluting metabolomic profiles [111,112]. Behavioural strategies include closing
renewable energy sources (such as wind, tidal, geothermal, and solar), car and home windows, the use of cabin air filters for air-conditioning,
transportation reforms promoting the use of low- and zero-emission changing travel routes, staying indoors and lifestyle changes including
vehicles as well as the restriction of traffic (especially trucks) in city physical exercise in green areas away from major roadways. These
centres, and the reduction of traffic emissions through the use of diesel measures can be particularly relevant in those who are susceptible,
particle traps, catalytic converters, or alternative fuels (e.g., natural gas, nevertheless also healthy subjects who have a sedentary lifestyle can
electric cars). Similarly, urban landscape reforms are urgently needed, benefit from it. Indeed, several studies demonstrated that the benefits of
including the reduction of minimum distances between sources and aerobic exercise nearly always exceed the risk of PM2.5 exposure across a
people, the relocation of traffic sources (e.g., major trafficked roads), wide range of concentrations [113]. Finally, growing attention has been
and the avoidance of mixed-use areas (industrial-residential) [5,107]. given to pharmacological interventions that could potentially protect
The socioeconomic status seems to be particularly relevant in deter­ against the PM2.5-mediated adverse effects on atherosclerosis, although
mining an increased susceptibility to the harmful effects of PM2.5 on the any can be recommended at this time. If clinically indicated, the use of

Fig. 3. Mitigation strategies to lower exposure to air pollution.

The figure schematizes personal and governmental interventions to reduce air pollution and the consequent exposure.

28
R.A. Montone et al. Atherosclerosis 366 (2023) 22–31

medications for primary and secondary prevention of IHD (i.e., statins) CRediT authorship contribution statement
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 sur­ Rocco A. Montone: Data curation, Formal analysis, Writing –
rogate measures of atherosclerosis [114]. A parallel, placebo control, original draft, extraction and analysis of data, drafting of the manu­
randomized, clinical trial is currently ongoing (NCT04762472) and will script, design and revision of the manuscript, All authors have read and
randomize 200 patients to either Montelukast (10mg/daily) or agreed to the published version of the manuscript. Riccardo Rinaldi:
image-matched placebo. The study aims to test the hypothesis of pul­ Data curation, Formal analysis, Writing – original draft, extraction and
monary inflammation and oxidative stress-related vascular dysfunction analysis of data, drafting of the manuscript, design and revision of the
in PM2.5 and PM10 air pollution and to evaluate the impact of Mon­ manuscript, All authors have read and agreed to the published version of
telukast treatment as compared with placebo on predictive atheroscle­ the manuscript. Alice Bonanni: Data curation, Formal analysis, Writing
rosis surrogates (brachial vascular reactivity evaluated by – original draft, extraction and analysis of data, drafting of the manu­
flow-mediated dilation and CIMT). Given the prominent role of oxida­ script, design and revision of the manuscript, All authors have read and
tive stress, pharmacological approaches to prevent or reverse the effects agreed to the published version of the manuscript. Anna Severino:
of PM2.5 have been mainly focusing on compounds with antioxidant revision of the manuscript, All authors have read and agreed to the
properties with contrasting results. The effects of targeted interventions published version of the manuscript. Daniela Pedicino: revision of the
able to disrupt the oxidative stress pathways and/or enhance antioxi­ manuscript, All authors have read and agreed to the published version of
dant defences could be important areas of interest, and further research the manuscript. Filippo Crea: design and revision of the manuscript, All
is needed to identify additional key pathways and develop a personal­ authors have read and agreed to the published version of the manu­
ized and targeted medicine approach [115]. script. Giovanna Liuzzo: design and revision of the manuscript, All
authors have read and agreed to the published version of the
5.3. Reducing the impact of the exposome manuscript.

As previously discussed, other environmental exposures (i.e., noise Declaration of competing interest
and climate change) significantly contribute and synergize with air
pollution in determining an increased risk of IHD. Hence, along with air The authors declare that they have no known competing financial
pollution control, interventions aiming to reduce the impact of the interests or personal relationships that could have appeared to influence
exposome on human health are urgently needed. the work reported in this paper.
Vehicle traffic (e.g., cars, trains and aircrafts) is the main source of
noise pollution and an increasing public health problem. Given that Acknowledgements
vehicle traffic is strongly related to both noise and air pollution, the
implementation of the same governmental strategies aiming at reducing Figures created with BioRender.co.
air pollution could be effective also for noise pollution, in particular
transportation reforms and urban landscape reforms. In addition, spe­ Appendix A. Supplementary data
cific interventions to reduce noise pollution might include noise barriers
in densely populated areas, building insulation against noise, lower Supplementary data to this article can be found online at https://doi.
speed limits and the application of quiet road surfaces. For aircraft noise, org/10.1016/j.atherosclerosis.2023.01.013.
specific measures might include the ban of nocturnal air traffic (as noise
during night-time is associated with the most pronounced health ef­
References
fects), new engine technologies (fleet evolution) and air traffic man­
agement [87]. [1] G.H. Gibbons, C.E. Seidman, E.J. Topol, Conquering atherosclerotic
Similarly, one of the main sources of greenhouse gases is vehicle cardiovascular disease — 50 Years of progress, N. Engl. J. Med. 384 (9) (2021
Mar 4) 785–788.
traffic emissions due to the combustion of fossil fuels. Aggressive pol­
[2] D.E. Newby, P.M. Mannucci, G.S. Tell, et al., Expert position paper on air
icies directed toward the reduction of greenhouse gases emission are pollution and cardiovascular disease, Eur. Heart J. 36 (2015) 83–93b.
urgently needed, and these interventions should include a switch to [3] S. Rajagopalan, P.J. Landrigan, Pollution and the heart, N. Engl. J. Med. 385
clean fuels, the implementation of transportation reforms and the (2021) 1881–1892.
[4] G.A. Roth, G.A. Mensah, C.O. Johnson, et al., Global burden of cardiovascular
reduction of traffic emissions. diseases and risk factors, 1990-2019: update from the GBD 2019 study, J. Am.
Coll. Cardiol. 76 (25) (2020 Dec 22) 2982–3021.
6. Conclusions and future directions [5] P.J. Landrigan, R. Fuller, N.J.R. Acosta, et al., The Lancet Commission on
pollution and health, Lancet (London, England) 391 (10119) (2018 Feb 3)
462–512.
It is now widely recognised that PM2.5 is associated with enhanced [6] M. Brauer, B. Casadei, R.A. Harrington, et al., Taking a stand against air
atherosclerosis development and progression. The comprehension of pollution-the impact on cardiovascular disease: a joint opinion from the world
heart federation, American college of cardiology, American heart association, and
PM2.5-induced molecular mechanisms underlying this association would the European society of cardiology, J. Am. Coll. Cardiol. 77 (13) (2021 Apr 6)
be extremely helpful in order to identify potential therapeutic targets 1684–1688.
and to prevent the occurrence and/or the progression of atherosclerosis. [7] World Health Organization, WHO global air quality guidelines: particulate matter
(PM2.5 and PM10), ozone, nitrogen dioxide, sulfur dioxide and carbon monoxide,
From a clinical perspective, there is a strong need for randomized,
World Heal. Organ. (9544) (2021) 1302. https://apps.who.int/iris/handle/1066
controlled clinical trials to demonstrate the efficacy of specific in­ 5/345329.
terventions targeting air pollution including both personal equipment [8] S. Yang, S.P. Lee, J.B. Park, et al., PM2.5 concentration in the ambient air is a risk
factor for the development of high-risk coronary plaques, Eur Hear J. Cardiovasc
and/or specific drugs to reduce the incidence of IHD before their use can
Imaging 20 (12) (2019 Dec 1) 1355–1364.
be recommended in clinical practice. Finally, societal and governmental [9] J.D. Kaufman, S.D. Adar, R.G. Barr, et al., Association between air pollution and
interventions aiming to decrease the emission of air pollutants, traffic coronary artery calcification within six metropolitan areas in the USA (the Multi-
noise and greenhouse gases are urgently needed in order to reduce the Ethnic Study of Atherosclerosis and Air Pollution): a longitudinal cohort study,
Lancet 388 (10045) (2016 Aug 13) 696–704.
significant impact of these environmental exposures on CV morbidity [10] F. Liang, F. Liu, K. Huang, et al., Long-term exposure to fine particulate matter
and mortality worldwide. and cardiovascular disease in China, J. Am. Coll. Cardiol. 75 (7) (2020 Feb 25)
707–717.
[11] F.L.J. Visseren, F. MacH, Y.M. Smulders, et al., ESC Guidelines on cardiovascular
disease prevention in clinical practice, Eur. Heart J. 42 (34) (2021) 3227–3337,
2021 Sep. 7.

29
R.A. Montone et al. Atherosclerosis 366 (2023) 22–31

[12] A. Pozzer, F. Dominici, A. Haines, et al., Regional and global contributions of air [41] S.K. Park, A.H. Auchincloss, M.S. O’Neill, et al., Particulate air pollution,
pollution to risk of death from COVID-19, Cardiovasc. Res. 116 (14) (2020 Dec 1) metabolic syndrome, and heart rate variability: the multi-ethnic study of
2247–2253. atherosclerosis (MESA), Environ. Health Perspect. 118 (10) (2010 Oct)
[13] U. Franck, S. Odeh, A. Wiedensohler, B. Wehner, O. Herbarth, The effect of 1406–1411.
particle size on cardiovascular disorders–the smaller the worse, Sci. Total [42] N. Pieters, M. Plusquin, B. Cox, et al., An epidemiological appraisal of the
Environ. 409 (20) (2011 Sep 15) 4217–4221. association between heart rate variability and particulate air pollution: a meta-
[14] C.A. Pope, J.B. Muhlestein, J.L. Anderson, et al., Short-term exposure to fine analysis, Heart 98 (15) (2012 Aug) 1127–1135.
particulate matter air pollution is preferentially associated with the risk of ST- [43] M.S. Lee, K Do Eum, S.C. Fang, et al., Oxidative stress and systemic inflammation
segment elevation acute coronary events, J. Am. Heart Assoc. 4 (12) (2015 Dec as modifiers of cardiac autonomic responses to particulate air pollution, Int. J.
1), e002506. Cardiol. 176 (1) (2014) 166–170.
[15] Y. Liu, J. Pan, C. Fan, et al., Short-term exposure to ambient air pollution and [44] S. Robertson, A.L. Thomson, R. Carter, et al., Pulmonary diesel particulate
mortality from myocardial infarction, J. Am. Coll. Cardiol. 77 (3) (2021 Jan 26) increases susceptibility to myocardial ischemia/reperfusion injury via activation
271–281. of sensory TRPV1 and β1 adrenoreceptors, Part. Fibre Toxicol. 11 (1) (2014)
[16] S.G. Al-Kindi, R.D. Brook, S. Biswal, S. Rajagopalan, Environmental determinants 1–10.
of cardiovascular disease: lessons learned from air pollution, Nat. Rev. Cardiol. 17 [45] M.S. Hazari, N. Haykal-Coates, D.W. Winsett, et al., TRPA1 and sympathetic
(10) (2020 Oct 1) 656–672. activation contribute to increased risk of triggered cardiac arrhythmias in
[17] R.A. Montone, M. Camilli, M. Russo, et al., Air pollution and coronary plaque hypertensive rats exposed to diesel exhaust, Environ. Health Perspect. 119 (7)
vulnerability and instability: an optical coherence tomography study, JACC (2011 Jul) 951–957.
Cardiovasc. Imaging 15 (2) (2022 Feb) 325–342. [46] C.M. Perez, M.S. Hazari, A.K. Farraj, Role of autonomic reflex arcs in
[18] R.B. Hamanaka, G.M. Mutlu, Particulate matter air pollution: effects on the cardiovascular responses to air pollution exposure, Cardiovasc. Toxicol. 15 (1)
cardiovascular system, Front. Endocrinol. 9 (2018) 680. (2015 Jan 1) 69–78.
[19] R. Burnett, H. Chen, M. Szyszkowicz, et al., Global estimates of mortality [47] A. Hajat, A.V. Diezroux, C. Castro-Diehl, et al., The association between long-term
associated with long-term exposure to outdoor fine particulate matter, Proc. Natl. air pollution and urinary catecholamines: evidence from the multi-ethnic study of
Acad. Sci. U. S. A. 115 (38) (2018 Sep 18) 9592–9597. atherosclerosis, Environ. Health Perspect. 127 (5) (2019 May 1), 57007.
[20] A.V. Diez Roux, A.H. Auchincloss, T.G. Franklin, et al., Long-term exposure to [48] R.D. Brook, B. Urch, J.T. Dvonch, et al., Insights into the mechanisms and
ambient particulate matter and prevalence of subclinical atherosclerosis in the mediators of the effects of air pollution exposure on blood pressure and vascular
Multi-Ethnic Study of Atherosclerosis, Am. J. Epidemiol. 167 (2008) 667–675. function in healthy humans, Hypertension (New York) 54 (3) (2009 Sep 1)
[21] C.A. Pope, J.B. Muhlestein, H.T. May, et al., Ischemic heart disease events 659–667.
triggered by short-term exposure to fine particulate air pollution, Circulation 114 [49] Z. Ying, X. Xu, Y. Bai, et al., Long-term exposure to concentrated ambient PM2.5
(23) (2006 Dec) 2443–2448. increases mouse blood pressure through abnormal activation of the sympathetic
[22] G. Cesaroni, F. Forastiere, M. Stafoggia, et al., Long term exposure to ambient air nervous system: a role for hypothalamic inflammation, Environ. Health Perspect.
pollution and incidence of acute coronary events: prospective cohort study and 122 (1) (2014) 79–86.
meta-analysis in 11 European cohorts from the ESCAPE Project, BMJ (2014 Jan [50] S. Heidari Nejad, R. Takechi, B.J. Mullins, et al., The effect of diesel exhaust
21) 348. exposure on blood-brain barrier integrity and function in a murine model,
[23] H. Mustafić, P. Jabre, C. Caussin, et al., Main air pollutants and myocardial J. Appl. Toxicol. 35 (1) (2015 Jan 1) 41–47.
infarction: a systematic review and meta-analysis, JAMA 307 (7) (2012 Feb 15) [51] E. Tobaldini, V. Bollati, M. Prado, et al., Acute particulate matter affects
713–721. cardiovascular autonomic modulation and IFN-γ methylation in healthy
[24] L. Risom, P. Møller, S. Loft, Oxidative stress-induced DNA damage by particulate volunteers, Environ. Res. 161 (2018 Feb 1) 97–103.
air pollution, Mutat. Res. 592 (1–2) (2005 Dec 30) 119–137. [52] X. Xiao, L. Cao, R. Wang, Z xing Shen, Y xiao Cao, Airborne fine particulate
[25] J. Liu, S. Liang, Z. Du, et al., PM 2.5 aggravates the lipid accumulation, matter alters the expression of endothelin receptors in rat coronary arteries,
mitochondrial damage and apoptosis in macrophage foam cells, Environ. Pollut. Environ. Pollut. 218 (2016 Nov 1) 487–496.
249 (2019 Jun 1) 482–490. [53] M. Camilli, M. Russo, R. Rinaldi, et al., Air pollution and coronary vasomotor
[26] Y. Bai, Q. Sun, Fine particulate matter air pollution and atherosclerosis: disorders in patients with myocardial ischemia and unobstructed coronary
mechanistic insights, Biochim. Biophys. Acta 1860 (2016) 2863–2868. arteries, J. Am. Coll. Cardiol. 80 (2022) 1818–1828.
[27] R.S. Gangwar, G.H. Bevan, R. Palanivel, L. Das, S. Rajagopalan, Oxidative stress [54] X. Xu, H. Xu, A. Qimuge, et al., MAPK/AP-1 pathway activation mediates AT1R
pathways of air pollution mediated toxicity: recent insights, Redox Biol. 34 (2020 upregulation and vascular endothelial cells dysfunction under PM2.5 exposure,
Jul 1), 101545. Ecotoxicol. Environ. Saf. 170 (2019 Apr 15) 188–194.
[28] E. Distefano, A. Eiguren-Fernandez, R.J. Delfino, et al., Determination of metal- [55] G. Bell, S. Mora, P. Greenland, et al., Association of air pollution exposures with
based hydroxyl radical generating capacity of ambient and diesel exhaust high-density lipoprotein cholesterol and particle number: the multi-ethnic study
particles, Inhal. Toxicol. 21 (9) (2009) 731–738. of atherosclerosis, Arterioscler. Thromb. Vasc. Biol. 37 (5) (2017 May 1)
[29] A.O. Lawal, Air particulate matter induced oxidative stress and inflammation in 976–982.
cardiovascular disease and atherosclerosis: the role of Nrf2 and AhR-mediated [56] L.A. McGuinn, A. Schneider, R.W. McGarrah, et al., Association of long-term PM
pathways, Toxicol. Lett. 270 (2017 Mar 15) 88–95. 2.5 exposure with traditional and novel lipid measures related to cardiovascular
[30] D. Wu, N. Nishimura, V. Kuo, et al., Activation of aryl hydrocarbon receptor disease risk, Environ. Int. 122 (2019 Jan 1) 193–200.
induces vascular inflammation and promotes atherosclerosis in apolipoprotein [57] B.G. Hill, B. Rood, A. Ribble, P. Haberzettl, Fine particulate matter (PM 2.5)
E-/- mice, Arterioscler. Thromb. Vasc. Biol. 31 (6) (2011 Jun) 1260–1267. inhalation-induced alterations in the plasma lipidome as promoters of vascular
[31] D.W. Riggs, N. Zafar, S. Krishnasamy, et al., Exposure to airborne fine particulate inflammation and insulin resistance, Am. J. Physiol. Heart Circ. Physiol. 320 (5)
matter is associated with impaired endothelial function and biomarkers of (2021 May 1) H1836–H1850.
oxidative stress and inflammation, Environ. Res. 180 (2020 Jan 1), 108890. [58] J. Li, C. Zhou, H. Xu, et al., Ambient air pollution is associated with HDL (High-
[32] C.A. Pope, A. Bhatnagar, J.P. McCracken, et al., Exposure to fine particulate air Density lipoprotein) dysfunction in healthy adults, Arterioscler. Thromb. Vasc.
pollution is associated with endothelial injury and systemic inflammation, Circ. Biol. 39 (3) (2019 Mar 1) 513–522.
Res. 119 (11) (2016 Nov 11) 1204–1214. [59] X. Rao, J. Zhong, A. Maiseyeu, et al., CD36-dependent 7-ketocholesterol
[33] R.D. Arias-Pérez, N.A. Taborda, D.M. Gómez, et al., Inflammatory effects of accumulation in macrophages mediates progression of atherosclerosis in response
particulate matter air pollution, Environ. Sci. Pollut. Res. Int. 27 (34) (2020 Dec to chronic air pollution exposure, Circ. Res. 115 (9) (2014) 770–780.
1) 42390–42404. [60] A. Hajat, M. Allison, A.V. Diez-Roux, et al., Long-term exposure to air pollution
[34] M.R. Miller, J.B. Raftis, J.P. Langrish, et al., Inhaled nanoparticles accumulate at and markers of inflammation, coagulation, and endothelial activation: a repeat-
sites of vascular disease, ACS Nano 11 (5) (2017 May 23) 4542–4552. measures analysis in the Multi-Ethnic Study of Atherosclerosis (MESA),
[35] D.M. Brown, I.A. Kinloch, U. Bangert, et al., An in vitro study of the potential of Epidemiology 26 (3) (2015 May 1) 310–320.
carbon nanotubes and nanofibres to induce inflammatory mediators and [61] C.M. Tabor, C.A. Shaw, S. Robertson, et al., Platelet activation independent of
frustrated phagocytosis, Carbon N. Y. 45 (9) (2007 Aug 1) 1743–1756. pulmonary inflammation contributes to diesel exhaust particulate-induced
[36] Q. Wan, X. Cui, J. Shao, et al., Beijing ambient particle exposure accelerates promotion of arterial thrombosis, Part. Fibre Toxicol. 13 (2016 Feb 9) 6.
atherosclerosis in ApoE knockout mice by upregulating visfatin expression, Cell [62] A.J. Lucking, M. Lundback, N.L. Mills, et al., Diesel exhaust inhalation increases
Stress Chaperones 19 (5) (2014 Sep 1) 715. thrombus formation in man, Eur. Heart J. 29 (24) (2008 Dec) 3043–3051.
[37] H. Nagase, R. Visse, G. Murphy, Structure and function of matrix [63] N.L. Mills, H. Törnqvist, M.C. Gonzalez, et al., Ischemic and thrombotic effects of
metalloproteinases and TIMPs, Cardiovasc. Res. 69 (3) (2006 Feb 15) 562–573. dilute diesel-exhaust inhalation in men with coronary heart disease, N. Engl. J.
[38] F. Yin, A. Lawal, J. Ricks, et al., Diesel exhaust induces systemic lipid Med. 357 (11) (2007 Sep 13) 1075–1082.
peroxidation and development of dysfunctional pro-oxidant and pro- [64] G.M. Mutlu, D. Green, A. Bellmeyer, et al., Ambient particulate matter accelerates
inflammatory high-density lipoprotein, Arterioscler. Thromb. Vasc. Biol. 33 (6) coagulation via an IL-6–dependent pathway, J. Clin. Invest. 117 (10) (2007 Oct 1)
(2013 Jun) 1153–1161. 2952–2961.
[39] Y. Goto, H. Ishii, J.C. Hogg, et al., Particulate matter air pollution stimulates [65] G.R.S. Budinger, J.L. McKell, D. Urich, et al., Particulate matter-induced lung
monocyte release from the bone marrow, Am. J. Respir. Crit. Care Med. 170 inflammation increases systemic levels of PAI-1 and activates coagulation
(2004) 891–897. through distinct mechanisms, PLoS One 6 (4) (2011), e18525.
[40] S. Abohashem, M.T. Osborne, T. Dar, et al., A leucopoietic-arterial axis [66] N.L. Mills, H. Törnqvist, S.D. Robinson, et al., Diesel exhaust inhalation causes
underlying the link between ambient air pollution and cardiovascular disease in vascular dysfunction and impaired endogenous fibrinolysis, Circulation 112 (25)
humans, Eur. Heart J. 42 (2021) 761–772. (2005 Dec) 3930–3936.

30
R.A. Montone et al. Atherosclerosis 366 (2023) 22–31

[67] A. Nemmar, P.H.M. Hoet, D. Dinsdale, et al., Diesel exhaust particles in lung [92] M. Shiraiwa, K. Ueda, A. Pozzer, et al., Aerosol health effects from molecular to
acutely enhance experimental peripheral thrombosis, Circulation 107 (8) (2003 global scales, Environ. Sci. Technol. 51 (2017) 13545–13567.
Mar 4) 1202–1208. [93] C.I. Lin, C.H. Tsai, Y.L. Sun, et al., Instillation of particulate matter 2.5 induced
[68] A. Shukla, N. Bunkar, R. Kumar, et al., Air pollution associated epigenetic acute lung injury and attenuated the injury recovery in ACE2 knockout mice, Int.
modifications: transgenerational inheritance and underlying molecular J. Biol. Sci. 14 (3) (2018 Feb 12) 253–265.
mechanisms, Sci. Total Environ. 656 (2019 Mar 15) 760–777. [94] N. Hayashi, K. Yamamoto, M. Ohishi, et al., The counterregulating role of ACE2
[69] A. Baccarelli, R.O. Wright, V. Bollati, et al., Rapid DNA methylation changes after and ACE2-mediated angiotensin 1-7 signaling against angiotensin II stimulation
exposure to traffic particles, Am. J. Respir. Crit. Care Med. 179 (7) (2009 Apr 1) in vascular cells, Hypertens. Res. 33 (11) (2010 Nov) 1182–1185.
572–578. [95] Y. Fang, F. Gao, Z. Liu, Angiotensin-converting enzyme 2 attenuates
[70] C. Wang, R. Chen, M. Shi, et al., Possible mediation by methylation in acute inflammatory response and oxidative stress in hyperoxic lung injury by regulating
inflammation following personal exposure to fine particulate air pollution, Am. J. NF-κB and Nrf2 pathways, QJM 112 (12) (2019 Dec 1) 914–924.
Epidemiol. 187 (3) (2018 Mar 1) 484–493. [96] L. Chen, X. Li, M. Chen, Y. Feng, C. Xiong, The ACE2 expression in human heart
[71] J.K. Kresovich, Z. Zhang, F. Fang, et al., Histone 3 modifications and blood indicates new potential mechanism of heart injury among patients infected with
pressure in the beijing truck driver air pollution study, Biomarkers 22 (6) (2017 SARS-CoV-2, Cardiovasc. Res. 116 (6) (2020) 1097–1100.
Aug 18) 584–593. [97] R.A. Montone, G. Iannaccone, M.C. Meucci, F. Gurgoglione, G. Niccoli,
[72] Y. Zheng, M. Sanchez-Guerra, Z. Zhang, et al., Traffic-derived particulate matter Myocardial and microvascular injury due to coronavirus disease 2019, Eur.
exposure and histone H3 modification: a repeated measures study, Environ. Res. Cardiol. 15 (2020) e52.
153 (2017 Feb 1) 112–119. [98] V. Tanwar, J.M. Adelstein, L.E. Wold, Double trouble: combined cardiovascular
[73] L.J.F. Peters, E.A.L. Biessen, M. Hohl, et al., Small things matter: relevance of effects of particulate matter exposure and coronavirus disease 2019, Cardiovasc.
MicroRNAs in cardiovascular disease, Front. Physiol. 11 (2020 Jul 7) 793. Res. 117 (1) (2021 Jan 1) 85–95.
[74] J. Feng, A. Li, J. Deng, et al., miR-21 attenuates lipopolysaccharide-induced lipid [99] T. Borisova, S. Komisarenko, Air pollution particulate matter as a potential carrier
accumulation and inflammatory response: potential role in cerebrovascular of SARS-CoV-2 to the nervous system and/or neurological symptom enhancer:
disease, Lipids Health Dis. 13 (2014 Feb 7) 27. arguments in favor, Environ. Sci. Pollut. Res. Int. 28 (30) (2021) 40371–40377.
[75] A. Canfrán-Duque, N. Rotllan, X. Zhang, et al., Macrophage deficiency of miR-21 [100] B. Bikdeli, M.V. Madhavan, D. Jimenez, et al., COVID-19 and thrombotic or
promotes apoptosis, plaque necrosis, and vascular inflammation during thromboembolic disease: implications for prevention, antithrombotic therapy,
atherogenesis, EMBO Mol. Med. 9 (9) (2017 Sep) 1244–1262. and follow-up: JACC state-of-the-art review, J. Am. Coll. Cardiol. 75 (23) (2020
[76] S. Fossati, A. Baccarelli, A. Zanobetti, et al., Ambient particulate air pollution and Jun 16) 2950–2973.
microRNAs in elderly men, Epidemiology 25 (1) (2014 Jan) 68–78. [101] G.G. Stefanini, M. Montorfano, D. Trabattoni, et al., ST-elevation myocardial
[77] R. Chen, H. Li, J. Cai, et al., Fine particulate air pollution and the expression of infarction in patients with COVID-19: clinical and angiographic outcomes,
microRNAs and circulating cytokines relevant to inflammation, coagulation, and Circulation 141 (25) (2020) 2113–2116.
vasoconstriction, Environ. Health Perspect. 126 (1) (2018 Jan 1), 017007. [102] J. Grigg, Air pollution and respiratory infection: an emerging and troubling
[78] C.V. Breton, A.Y. Song, J. Xiao, et al., Effects of air pollution on mitochondrial association, Am. J. Respir. Crit. Care Med. 198 (6) (2018) 700–701.
function, mitochondrial DNA methylation, and mitochondrial peptide expression, [103] E.W. Spannhake, S.P. Reddy, D.B. Jacoby, X.Y. Yu, B. Saatian, J. Tian, Synergism
Mitochondrion 46 (2019 May 1) 22–29. between rhinovirus infection and oxidant pollutant exposure enhances airway
[79] I. Romieu, H. Moreno-Macias, S.J. London, Gene by environment interaction and epithelial cell cytokine production, Environ. Health Perspect. 110 (7) (2002)
ambient air pollution, Proc. Am. Thorac. Soc. 7 (2010) 116–122. 665–670.
[80] C.K. Ward-Caviness, A review of gene-by-air pollution interactions for [104] W. Huang, G. Wang, S.E. Lu, et al., Inflammatory and oxidative stress responses of
cardiovascular disease, risk factors, and biomarkers, Hum. Genet. 138 (2019) healthy young adults to changes in air quality during the Beijing Olympics, Am. J.
547–561. Respir. Crit. Care Med. 186 (11) (2012 Dec 1) 1150–1159.
[81] T. Münzel, O. Hahad, M. Sørensen, et al., Environmental risk factors and [105] D.Q. Rich, H.M. Kipen, W. Huang, et al., Association between changes in air
cardiovascular diseases: a comprehensive expert review, Cardiovasc. Res. 118 pollution levels during the Beijing Olympics and biomarkers of inflammation and
(2022) 2880–2902. thrombosis in healthy young adults, JAMA 307 (19) (2012 May 16) 2068–2078.
[82] H. Kälsch, F. Hennig, S. Moebus, et al., Are air pollution and traffic noise [106] J. Lelieveld, K. Klingmüller, A. Pozzer, et al., Cardiovascular disease burden from
independently associated with atherosclerosis: the Heinz Nixdorf Recall Study, ambient air pollution in Europe reassessed using novel hazard ratio functions,
Eur. Heart J. 35 (2014) 853–860. Eur. Heart J. 40 (20) (2019 May 1) 1590–1596.
[83] T. Münzel, M. Sørensen, T. Gori, et al., Environmental stressors and cardio- [107] S. Rajagopalan, S.G. Al-Kindi, R.D. Brook, Air pollution and cardiovascular
metabolic disease: part II-mechanistic insights, Eur. Heart J. 38 (8) (2017 Feb 1) disease: JACC state-of-the-art review, J. Am. Coll. Cardiol. 72 (17) (2018)
557–564. 2054–2070.
[84] M.T. Osborne, S. Abohashem, N. Naddaf, et al., The combined effect of air and [108] G.H. Bevan, D.A. Freedman, E.K. Lee, S. Rajagopalan, S.G. Al-Kindi, Association
transportation noise pollution on atherosclerotic inflammation and risk of between ambient air pollution and county-level cardiovascular mortality in the
cardiovascular disease events, J. Nucl. Cardiol. (2022), https://doi.org/10.1007/ United States by social deprivation index, Am. Heart J. 235 (2021) 125–131.
s12350-022-03003-7. [109] J.P. Langrish, X. Li, S. Wang, et al., Reducing personal exposure to particulate air
[85] M.T. Osborne, A. Radfar, M.Z.O. Hassan, et al., A neurobiological mechanism pollution improves cardiovascular health in patients with coronary heart disease,
linking transportation noise to cardiovascular disease in humans, Eur. Heart J. 41 Environ. Health Perspect. 120 (3) (2012 Mar) 367–372.
(2020) 772–782. [110] J. Wcherrie, A. Apsley, H. Cowie, et al., Effectiveness of face masks used to protect
[86] S. Kröller-Schön, A. Daiber, S. Steven, et al., Crucial role for Nox2 and sleep Beijing residents against particulate air pollution, Occup. Environ. Med. 75 (6)
deprivation in aircraft noise-induced vascular and cerebral oxidative stress, (2018) 446–452.
inflammation, and gene regulation, Eur. Heart J. 39 (2018) 3528–3539. [111] H. Li, J. Cai, R. Chen, et al., Particulate matter exposure and stress hormone
[87] T. Münzel, M.R. Miller, M. Sørensen, et al., Reduction of environmental pollutants levels: a randomized, double-blind, crossover trial of air purification, Circulation
for prevention of cardiovascular disease: it’s time to act, Eur. Heart J. 41 (2020) 136 (7) (2017 Aug 1) 618–627.
3989–3997. [112] R. Chen, A. Zhao, H. Chen, et al., Cardiopulmonary benefits of reducing indoor
[88] S. Langsdorf, S. Löschke, V. Möller, A. Okem, Climate Change 2022 Impacts, particles of outdoor origin: a randomized, double-blind crossover trial of air
Adaptation and Vulnerability Working Group II Contribution to the Sixth purifiers, J. Am. Coll. Cardiol. 65 (21) (2015 Jun 2) 2279–2287.
Assessment Report of the Intergovernmental Panel on Climate Change, 2022. [113] M. Tainio, A.J. de Nazelle, T. Götschi, et al., Can air pollution negate the health
www.ipcc.ch. benefits of cycling and walking? Prev. Med. 87 (2016 Jun 1) 233–236.
[89] K. Bhaskaran, B. Armstrong, S. Hajat, A. Haines, P. Wilkinson, L. Smeeth, Heat [114] H. Tong, Dietary and pharmacological intervention to mitigate the
and risk of myocardial infarction: hourly level case-crossover analysis of MINAP cardiopulmonary effects of air pollution toxicity, Biochim. Biophys. Acta 1860
database, BMJ 345 (2012), e8050. (12) (2016 Dec 1) 2891–2898.
[90] K. Chen, S. Breitner, K. Wolf, et al., Temporal variations in the triggering of [115] J. Barthelemy, K. Sanchez, M.R. Miller, H. Khreis, New opportunities to mitigate
myocardial infarction by air temperature in Augsburg, Germany, 1987-2014, Eur. the burden of disease caused by traffic related air pollution: antioxidant-rich diets
Heart J. 40 (2019) 1600–1608. and supplements, Int. J. Environ. Res. Publ. Health 17 (2) (2020 Jan 2) 630.
[91] A. Peters, A. Schneider, Cardiovascular risks of climate change, Nat. Rev. Cardiol.
18 (2021) 1–2.

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