Modern Concepts of the Role of Fine Particles (PM 2.5) in the Genesis of Atherosclerosis and Myocardial Damage: Clinical and Epidemiological Data, the Main Pathophysiological Mechanisms

Abstract

Due to the fact that atherosclerotic cardiovascular diseases (CVDs) dominate in the structure of morbidity, disability and mortality of the population, the study of the risk factors for the development of atherosclerotic CVDs, as well as the study of the underlying pathogenetic mechanisms thereof, is the most important area of scientific research in modern medicine. Understanding these aspects will allow improving the set of treatment and preventive measures and activities. One of the important risk factors for the development of atherosclerosis, which has been actively studied recently, is air pollution with fine particulate matter (PM 2.5). According to clinical and epidemiological data, the level of air pollution with PM 2.5 exceeds the normative indicators in most regions of the world and is associated with subclinical markers of atherosclerosis and mortality from atherosclerotic CVDs.

The aim of this article is to systematize and discuss in detail the role of PM 2.5 in the development of atherosclerosis and myocardial damage with the consideration of epidemiological and pathogenetic aspects.

Materials and Methods

This narrative review is based on the analysis of publications in the Medline, PubMed, and Embase databases. The terms “fine particles” and “PM 2.5” in combination with “pathophysiological mechanisms,” “cardiovascular diseases”, “atherosclerosis”, “cardiac troponins”, “myocardial damage” and “myocardial injury” were used to search publications.

Conclusion

According to the conducted narrative review, PM 2.5 should be regarded as the significant risk factor for the development of atherosclerotic CVDs. The pro-atherogenic effect of fine particulate matter is based on several fundamental and closely interrelated pathophysiological mechanisms: endothelial dysfunction, impaired lipid metabolism, increased oxidative stress and inflammatory reactions, impaired functioning of the vegetative nervous system and increased activity of the hemostatic system. In addition, PM 2.5 causes subclinical damage to cardiac muscle cells by several mechanisms: apoptosis, oxidative stress, decreased oxygen delivery due to coronary atherosclerosis and ischemic damage of cardiomyocytes. Highly sensitive cardiac troponins are promising markers for detecting subclinical myocardial damage in people living in polluted regions.

1. INTRODUCTION

The air that the population of the entire globe breathes is significantly polluted with numerous substances that can both increase the risk of the development of various diseases in healthy individuals and lead to the aggravation of the existing pathologies [1-3]. Fine (particulate matter (PM 2.5)) constitutes one of the negative air pollutants. At the same time, it is especially alarming that only a small part of the population (about 18%) of our planet breathes the air in which the PM 2.5 content meets the normative indicators of the Guidelines on Air Quality (WHO, 2018) [4]. The recent “Global Burden of Diseases” report notes that exposure to elevated PM 2.5 levels is the fifth leading risk factor for overall mortality in the population. PM 2.5 causes about 4.2 million deaths annually, most of which are deaths from cardiovascular diseases (CVDs) [5]. Atherosclerosis accounts for almost all known CVDs, and it is characterized by many risk factors for development and pathogenetic mechanisms, the study of which is being actively continued at the present time [6]. Determining all risk factors and understanding the pathogenetic mechanisms of atherosclerosis is the essential step toward improvement of preventive and therapeutic measures and activities [6-8].

At present many researchers regard PM 2.5 as the potential risk factor for the development of atherosclerosis and CVDs [8-11]. However, the potential pathogenetic mechanisms underlying the effect of PM 2.5 on the development and progression of atherosclerosis remain unclear.

Besides, several recent studies have found that exposure to PM 2.5 leads to the damage of cardiomyocytes and an increase in the serum levels of cardiac biomarkers (high-sensitivity cardiac troponins, natriuretic peptides), inflammatory biomarkers (C-reactive protein, growth differentiation factor 15, fibrinogen, interleukin 6, interleukin 1 beta) and oxidative stress (8-OH-deoxyguanosine, catalase, malondialdehyde, nitrogen oxide, superoxide dismutase) [12-16]. Mechanisms of myocardial injury can be associated with both direct negative impact of PM 2.5 on myocardial cells and indirect impact (resulting from atherogenesis, which is accompanied by the narrowing of coronary arteries, decrease in the delivery of oxygen and metabolic substrates to cardiomyocytes).

The aim of this article is to systematize and discuss in detail the role of PM 2.5 in the development of atherosclerosis and myocardial damage with consideration of epidemiological and pathogenetic aspects. This narrative review is based on analyzing publications in the Medline, PubMed, and Embase databases. The terms “fine particles” and “PM 2.5” in combination with “pathophysiological mechanisms,” “cardiovascular diseases”, “atherosclerosis”, “cardiac troponins”, “myocardial damage” and “myocardial injury” were used to search publications.

2. DESCRIPTION OF PM 2.5

Fine particulate matter constitutes the complex composition of solid particles and liquid droplets of microscopic size, which differ significantly in their make-up. Conventionally, we may distinguish two groups of sources of PM 2.5 formation: natural and human-driven (anthropogenic). The main natural sources of PM 2.5 air pollutants include volcanic eruptions, sandstorms, and plant sources. The sources of anthropogenic pollution are much more diverse: burning of fossil fuels, emissions from factories, smoke, road dust, vehicle exhaust gases, and some others. The specific make-up of PM 2.5 will differ in different regions of the world since it depends on the sources of pollution and weather conditions, which may also significantly differ in different regions of the planet [17, 18]. This circumstance may also affect the physical and chemical properties of PM 2.5, the size of the particles, concentration and pathogenetic effect on the human body.

Depending on the aerodynamic diameter, they distinguish 4 types of PM: 1) large (PM 10) (diameter ≤ 10 μm), small (PM 2.5) (diameter ≤ 2.5 μm), PM 1.0 (diameter ≤ 1 μm)) and ultrafine (diameter ≤ 0.1 μm). It is believed that the size of the particles that pollute the air determines the nature of their pathogenetic effect on the human body. The size of polluting particles is probably related to the ways and possibilities of penetration thereof into certain organs and tissues of the human body. Thus, larger particles with a diameter in the range of 10-2.5 μm are mainly deposited in the nasal cavity, larynx, trachea, and large and middle bronchi, which most often leads to the development of rhinitis laryngitis, allergic diseases and bronchitis [19]. Smaller particles with an aerodynamic diameter in the range of 2.5-1.0 μm or less can penetrate smaller airways, such as small bronchi and alveoli, which can result in the development of inflammation directly in the lung tissue (pneumonia). The smallest (ultrafine) particles are so small that they can even pass through the alveolar-capillary barrier into the general blood circulation [20]. The concentration of PM 2.5 in the air determines the severity of the inflammatory response reaction and oxidative stress and positively correlates with the morbidity rate/incidence and mortality from CVDs across the population [21]. The characteristics and composition of PM 2.5 are also significantly influenced by the peculiarities of meteorological conditions, which can also be regarded as one of the factors determining the pathogenetic effect of PM 2.5. Thus, for example, organic components of PM 2.5 contribute to the development of atherosclerosis and CVDs, while inorganic components of PM 2.5 mainly affect the bronchopulmonary system [22]. Kim et al. studied the relationship between the chemical components of PM 2.5 (sulfur, silicon, elemental carbon and organic carbon) and one of the main parameters of subclinical atherosclerosis - the carotid intima-media thickness (CIMT) in people living in 6 polluted urban areas of the United States for two years. The most significant increase in CIMT was specific to people who were exposed to organic carbon (0.026 mm (95% confidence interval (CI): 0.019, 0.034) and a lower-value increase in CIMT was specific to people exposed to sulfur (0.022 mm (95% CI: 0.014, 0.031)) and silicon (0.006 mm (95% CI: 0.000, 0.012)) [23]. The results of another large study conducted by Sun et al. confirm the connection of the chemical components of PM 2.5 with the development of subclinical atherosclerosis; however, the closest correlation with an increase in CIMT was specifically attributed to organic carbon [24]. Therefore, these studies are indicative of a different role of PM 2.5 chemical components in the pathogenesis of subclinical atherosclerosis. Moreover, the most significant role in the pathogenesis of atherosclerosis is played by organic chemical components of PM 2.5, in particular, organic carbon.

Despite the clear evidence of the relationship between the increased content of PM 2.5 in the air and the morbidity and mortality of the population from CVDs, the ways and mechanisms of PM 2.5 penetration into vascular cells and their direct toxic effects contribute to the development of atherosclerosis have been unknown for a long time. In light of this fact, several recent fundamental investigations have studied possible ways of PM 2.5 penetration into endothelial cells. Using human umbilical vein endothelial cells (HUVEC) as an object of research, the researchers demonstrated that the chemical components included in PM 2.5 could penetrate the cytoplasm of endothelial cells by four different mechanisms (Fig. 1) [25-28]. The supposed mechanisms of entry are macropinocytosis, clathrin- and caveolin-mediated endocytosis [25]. At the same time, the accumulation of PM 2.5 components in umbilical vein endotheliocytes is not a harmless phenomenon since it is accompanied by damage to mitochondria and lysosomes [26-28]. Thus, this mechanism is likely to be responsible for the development of endothelial dysfunction, which plays an important role in the initiation of atherogenesis.

Fig. (1).

Mechanisms of PM 2.5 penetration into endotheliocytes and adverse intracellular effects.

The degree of contamination and the chemical composition of PM 2.5 are two key factors in the pathogenesis of atherosclerosis [29-32]. It is worth noting that the various components of PM 2.5 do not have the same effect on the inflammatory process and oxidative stress. Thus, according to Y. Huang et al., among the numerous components of PM 2.5, only sulfates, iron and selenium were associated with the degree of inflammatory response (increased percentage of neutrophils in bronchoalveolar lavage) [29]. Transition metal ions (iron, copper, manganese and vanadium) can catalyze the Fenton reaction and similar reactions, which leads to a significant increase in the formation of ROS (superoxide radical, hydrogen peroxide and hydroxyl radical) and a subsequent increase in oxidative stress [30, 31]. Some gaseous compounds, for example, NO2, can also participate in the formation of ROS (peroxynitrite). In addition to this, Mills et al. [32] found that diesel exhaust gas particles (transition metals, polycyclic aromatic hydrocarbons and quinones) significantly enhance oxidative stress. Thus, the accumulation of the above-described PM 2.5 components in vascular cells (endothelial cells, smooth muscle cells and macrophages) will cause oxidative stress, which will further lead to disruption of the functioning of these cells, in particular endothelial dysfunction, inflammatory reaction, the transformation of macrophages and smooth muscle cells into foam cells and their subsequent apoptosis, which will enhance the growth of the necrotic nucleus of an atherosclerotic plaque. Obviously, higher levels of these PM 2.5 components will increase oxidative stress and its adverse manifestations.

The influence of many individual components on the development of atherosclerosis and CVD is contradictory, according to various studies, and the specific mechanisms are not definitively known [29-33]. It is due to the multicomponent composition of PM 2.5 in the natural air environment and the presence of other factors in the population (lifestyle, the presence of chronic subclinical diseases, etc.), which can also affect the pathogenesis of atherosclerosis and CVD, so it is difficult to understand what effect is characteristic of each specific component. To uncover specific mechanisms, strictly controlled experimental studies are necessary with the exclusion of all potentially influencing factors.

2.1. Epidemiological and Clinical Research Data Providing Evidence of PM 2.5 Relationship with Atherosclerosis

To date, considerable amount of epidemiological and clinical research has been accumulated, confirming the adverse effects of PM 2.5 on human health, and in particular on the development and progression of atherosclerosis and CVDs. In many of these studies, subclinical parameters (markers) of atherosclerosis, such as carotid intimal thickness (CIMT), coronary artery calcification (CAC), thoracic aortic calcification (TAC) and ankle-brachialis index (ABI), have been assessed in healthy people living in disadvantaged regions. That said, almost all epidemiological research carried out confirms the presence of a correlation between exposure to PM 2.5 and these subclinical markers of atherosclerosis (Table 1).

Table 1.

Epidemiological studies on the relation of PM 2.5 with atherosclerosis.

Study Date and Country and/or Locality	Number of Individuals Examined	Average Concentration of PM 2.5 in the Air, μg/m3	Assessed Biomarker of Subclinical Atherosclerosis	Key Study Findings Evidencing the Relation between Pollution of Air with PM 2.5 and Subclinical Markers of Atherosclerosis	Source
1998-2003, Los-Angeles (USA)	n = 798	20,3	CIMT	A strong correlation between increased PM 2.5 levels and CIMT value. For every 10 μg / m3 increase in PM 2.5, the average increase in CIMT was 5.9% (CI = 1-11%). The largest increase in CIMT (by 15.7% (95% CI = 5.7-26.6%)) was characteristic of women aged 60 years	Künzli et al. [34]
2007-2009, University of Southern California (USA)	n = 861	15,7	CIMT	The increase in the degree of air pollution with PM 2.5 with the increase in CIMT by 7.8 μm (95% CI = 0.3-15.9) and 10.1 μm (95% CI = 1.8-18.5) in children aged 0-5 years and children aged 6-12 years, respectively.	Breton et al. [35]
2000-2003, Germany	n = 3380	16,8	CIMT	The increase in the content of PM 2.5 was associated with the 4.3% increase in CIMT (95% CI = 1.9-6.7%)	Bauer et al. [36]
2000-2005, USA	n = 5560	16,6	CIMT	The increase in PM 2.5 levels by 2.5 μg/m3 was associated with the annual increase in TIMSA of 5 μm (95% CI = 2.6-7.4 μm/yr)	Adar et al. [37]
2000-2002, USA	n = 5172	16,7	CIMT	CIMT positively correlated with the effect of PM 2.5 (1-4% increase for every 21 μg/m3) even after adjusting for age-sex characteristics and other risk factors for atherosclerosis	Diez Roux et al. [38]
2000-2002, USA	n = 6256	13,66	CIMT	The increase in PM 2.5 consisting of a number of components (sulfur, elemental carbon, organic carbon) with the exception of silicon, was closely correlated with CIMT.	Sun et al. [24]
2000-2003, Germany	n = 4494	22,8	CAC	People living closer to the source of air pollution with PM 2.5 (highway) had a higher CCA value. Halving the distance between the house and the road was associated with a 7.0% increase in CAC (95% CI = 1.1-14.4%).	Hoffmann et al. [40]
2002-2012, USA	n = 6795	20,6	CAC	For each increase in PM 2.5 by 5 μg/m3, CAC increased by 4.1 Agatston units per year.	Kaufman et al. [41]
2000-2003, Ruhr Area (Germany)	n = 4348	22,8	ABI	Living near highways was associated with a decrease in ABI, which is characteristic of the presence of atherosclerotic diseases in peripheral arteries. In addition, people living in the immediate vicinity of a road (within the radius of 50 m) had a 1.77 (95% CI = 1.21-2.1) times higher risk of developing atherosclerotic diseases compared with those living in a distance of more than 200 meters.	Hoffmann et al. [42]
2000-2003, Germany	n = 4248	16,62	TAC	The 2.4 μg m3 increase in PM 2.5 in the air is associated with the 18.1% increase in TAC (95% CI = 6.6-30.9%)	Kälsch et al. [43]

Abbreviations: CIMT - carotid intimal thickness, CAC - coronary artery calcification, TAC - thoracic aortic calcification, ABI - ankle-brachialis index.

In one of the earliest epidemiological studies by Künzli et al. [34], researchers reported that a 10 µg/m³ increase in PM 2.5 was associated with the 5.9% increase in CIMT (95% CI = 1-11%). Notably, individuals of different gender and age were differently susceptible to the effects of PM 2.5. Thus, the highest degree of increase in CIMT (by 15.6%, 95% CI = 5.7-26.6%) was typical for women over 60 years old [34]. Subsequently, many studies have confirmed the existence of the relation between exposure to PM 2.5 and the increase in the marker of subclinical atherosclerosis - CIMT [35-39]. One of the significant sources of atmospheric air pollution (increased concentration of PM 2.5) is road transport, especially in conditions of heavy traffic. Hoffmann et al. studied the relationship of prolonged stay of people in conditions of heavy traffic with one of the key markers of subclinical atherosclerosis (CAC), which was evaluated using electron beam tomography. According to the researchers, the most significant increase in CAC was typical for people living at a distance of less than 50 meters from the road (1.63 (95% CI, 1.14 to 2.33). As we moved away from the highway, the risk of subclinical atherosclerosis development gradually decreased: 51-100 meters - 1.34 (95% CI, 1.00 to 1.79), 101-200 meters - 1 1.08 (95% CI, 0.85 to 1.39). According to the results of statistical analysis, when the distance between a residential building and a highway was reduced, there was a 7% increase in CAC (95% CI, 0.1 to 14.4) [40]. Another large prospective cohort study examined the relationship between prolonged exposure to polluted atmospheric air and the progression of coronary calcification and CIMT over ten years of follow-up. Annually, the Cardiac Calcium Score (Agatston score) increased by 4.1 units (95% CI 1.4-6.8) for each increase in the level of PM 2.5 by 5 mg/m³ in atmospheric air. However, in this study, exposure to PM 2.5 was not associated with the progression of CIMT [41], which contrasts with the results of other academic specialists. The population-based cohort study conducted in the Ruhr region of Germany has shown that exposure to PM 2.5 is associated with the decrease in ABI, and it is in women that the stronger associations were observed [42]. Kälsch et al. investigated the relationship between PM 2.5 exposure and thoracic aortic calcification (TAC), evaluated by electron beam tomography and considered a reliable marker of subclinical atherosclerosis. Prolonged exposure to fine particulate matter has been strongly associated with increased TAC [43]. Table 1 contains the main major clinical and epidemiological studies demonstrating a close relationship between elevated levels of PM 2.5 in ambient air (above the WHO recommended threshold of 10 mg/m³) and parameters of subclinical atherosclerosis (CIMT, CAC, ABI, TAC).

A number of studies show a strong positive relationship between the elevated PM 2.5 levels and mortality from CVDs [44]. Crouse et al. in their largest cohort study involving 2.1 non-immigrant Canadian adults, investigated the association between elevated PM 2.5 levels and cardiovascular mortality. Based on statistical analysis, the authors found that elevated concentrations of PM 2.5 (> 10 mg/m³) are associated with a higher risk of death from coronary heart disease (CHD) (1.31 (95% CI: 1.27, 1.35) [45]. Additionally, the data obtained in the course of several studies indicate that even optimal PM 2.5 levels (<10 μg/m³) in the ambient air may also increase the risk of adverse cardiovascular events. Thus, the studies conducted by Pinault et al. [46] and Christidis et al. [47] showed the increased risk of mortality from cardiovascular diseases at relatively low average PM 2.5 levels in the ambient air (at 6.3 μg/m³ and 5.9 μg/m³) [46, 47] Huynh et al. in their recent study found that low PM 2.5 concentrations (6.9 μg/m³) correlate with CAC grade in asymptomatic adult patients with low cardiovascular risk, regardless of other risk factors [48]. Thus, even an acceptable (by WHO standards) level of ambient air pollution is a risk factor for the development of atherosclerosis and coronary heart disease (CHD). The results of these several studies indicate the need to adjust the safe values for PM 2.5 (<10 µg/m³) recommended by the WHO Air Quality Guidelines. Further research is needed in this area to confirm the findings.

Several studies have reported that targeted measures to prevent pollution and reduce PM 2.5 air concentration can effectively reduce the risk of atherosclerosis and CVDs in a healthy population. Thus, the researchers found that alongside the decrease in the level of air pollution in Beijing, the serum concentrations of biomarkers of inflammation and oxidative stress in the surveyed population decreased [49, 50].

Thus, a number of clinical and epidemiological studies have clearly confirmed the existence of a close relationship between the concentration of PM 2.5 in the ambient air and subclinical markers of atherosclerosis, which allows PM 2.5 to be regarded as the significant and independent risk factor for the development and progression of atherosclerosis.

2.2. Pathogenetic Mechanisms Underlying the Proatherogenic Effect of PM 2.5

The main but not the only mechanisms for the development and progression of atherosclerosis are oxidative stress, inflammation, endothelial dysfunction, lipid metabolism disorders, hemostasis disorders and impaired functioning of the vegetative nervous system. Since the formation of atherosclerotic plaques is an extremely complex and multistage process involving the interaction of a number of cell populations (endothelial cells, monocytes, macrophages, smooth muscle cells, T-lymphocytes, etc.) and mechanisms [51-53], for a more holistic and accurate understanding of the role, played by PM 2.5 in the development of atherosclerosis, one should consider separately the specific effect of PM 2.5 on each of the above-mentioned components and mechanisms. Therefore, in the next sections, we will sequentially consider the effect of PM 2.5 on the above-mentioned mechanisms underlying the proatherogenic effect of PM 2.5.

2.2.1. PM 2.5 and Endothelial Dysfunction

Endothelial dysfunction is one of the generally recognized initiating mechanisms underlying the development and progression of atherosclerosis [51]. Under normal conditions, vascular endothelial cells produce a number of regulatory biologically active compounds that cause narrowing and dilation of blood vessels, depending on the existing needs of the human body. Various physicochemical factors, including PM 2.5, increased blood pressure (BP), reactive oxygen species (ROS)/reactive nitrogen species (RNS), low-density lipoproteins (LDLs), oxidized LDLs (ox-LDLs), can cause damage to the endothelial cells or changes in the endothelial permeability [52]. In addition, many chemical components included in PM 2.5 can directly penetrate endotheliocytes and cause damage to intracellular organelles (lysosomes, mitochondria), causing endothelial dysfunction [26-28]. As a result of endotheliocyte damage, the barrier function of the endothelium weakens, which leads to increased transportation of many components of blood plasma, including LDLs, through the endothelial barrier into the subendothelial space, where these atherogenic particles are accumulated/oxidized, subsequently initiating the formation of an arterial sclerotic disease [53-55]. LDL particles accumulated in the vascular walls undergo oxidation by RNS produced by endothelial cells and macrophages, which leads to the formation of ox-LDLs, the accumulation of which impairs the function of endothelial cells, completing the vicious pathogenetic circle [51, 55].

In order to assess the state of the vascular endothelium, the following main non-invasive methods are used: the test with reactive vascular hyperemia, measurements of the initial diameter of the arteries, and flow-mediated dilation (FMD) [56, 57]. An extensive study has shown that long-term exposure of a human body to PM 2.5 disrupts the function of endothelial cells by decreasing FMD and also causes vasoconstriction (reduction in the original diameter of the arteries) [58]. Academic specialists suggest that PM 2.5-induced dysfunction of endothelial cells is mainly mediated by the indirect cytotoxic effects caused by the inflammatory cytokines and oxidative stress [59]. Fine PM 2.5 particles induce the generation of ROS and RNS in the endothelial cells of the human lung vessels, which leads to the disruption of the endothelial barrier and to the secretion of a large amount of pro-inflammatory cytokines [60]. Several recent studies have shown that PM 2.5 can directly damage the endothelial cells of the human umbilical vein, which can be regarded as the trigger for the development of atherosclerosis [61, 62]. After the damage to the endothelium, LDLs penetrate the vascular wall through the damaged area of the endothelial cells and are oxidized by ROS to ox-LDLs. Besides, PM 2.5 causes overexpression of cell adhesion molecules such as intercellular adhesion molecules-1 (ICAM-1) and vascular adhesion molecules 1 (VCAM-1) on the surface of the endothelial cells. These adhesion molecules recruit leukocytes, such as T cells and monocytes, and promote their migration through the endothelial layer into the subendothelial space, where they multiply and differentiate into macrophages [63]. Besides, PM 2.5 enhances the secretion by the endothelial cells of monocytic chemotactic protein-1 (MCP-1), platelet-derived growth factor (PDGF) and macrophage colony-stimulating factor (M-CSF), which enhance the migration of monocytes to the focus of atherosclerotic lesion and activate their differentiation into macrophages. At the same time, PDGF stimulates the migration and proliferation of smooth muscle cells that migrate from the middle layer of the vascular wall to the intima, where they multiply and capture atherogenic lipid particles. Both macrophages and smooth muscle cells take up atherogenic lipoproteins to form foam cells. A large number of foam cells are deposited in the subendothelial layer of the inner lining of the artery, forming yellow lipid stripes (spots), which, as a rule, do not rise or slightly rise above the surface of the endothelium, which is the earliest sign of the development of atherosclerosis. Over time, the foam cells die, releasing their contents and thereby replenishing the contents of the necrotic nucleus of the atherosclerotic lesion focus, filled with lipids and cellular debris [51, 55].

Scavenger receptors are expressed more often on the surface of macrophages in response to the endothelial dysfunction that causes an accumulation of LDLs and ox-LDLs in the vascular wall. This accelerates the phagocytosis of LDLs and ox-LDLs, which results in the development of foam cells [64]. Geng et al. in their experimental study, found that the effect of PM 2.5 on the bodies of experimental mice suffering from atherosclerosis stimulates the transformation of macrophages and smooth muscle cells into foam cells through the intracellular molecular pathway (TLR4/MyD88/ NF-kB) (Fig. 2) [65]. This mechanism increases the risk of rupture of atherosclerotic plaques, which can contribute to its further growth inside the coronary artery lumen and increase the risk of myocardial infarction.

Fig. (2).

Transformation of macrophages into foam cells via intracellular molecular pathway (TLR4/MyD88/NF-kB).

Besides, excess ox-LDLs content, conditioned by the effect of PM 2.5, stimulated the expression of the ox-LDL (LOX-1) receptor, enhancing the dysfunction of the endothelial cells and accelerating atherogenesis [66]. Thus, PM 2.5 can trigger and enhance atherogenesis due to the damage to and dysfunction of endothelial cells and participation in a number of further links in the pathogenesis of atherosclerosis (Fig. 3).

Fig. (3).

PM2.5-induced atherosclerosis: pathophysiological mechanisms.

2.2.2. PM 2.5 and Lipid Metabolism Disorders

More than 100 years ago, Russian academic specialists Anichkov and Ignatovskii were the first to show that lipid metabolism disorders are one of the key risk factors for the development of atherosclerosis and CVDs [67]. Although the dietary habits of people make the greatest contribution to the disturbance of lipid metabolism [67], some academic specialists have also traced the relationship between the effect of PM 2.5 fine particles and lipid metabolism disorders [68-70]. Thus, the randomized, double-blind study has shown that exposure to PM 2.5 causes significant changes in the concentrations of a number of metabolic parameters of blood serum, in particular, the lipid spectrum, amino acids, glucose and several hormonal parameters [70]. The experimental study by L. Guan and colleagues has shown that the exposure of adult rats to PM 2.5 for 12 weeks leads to apparent changes in lipid profile (increase in the level of triglycerides, LDLs, and cholesterol). Adverse changes in lipid profile have been accompanied by atherosclerotic cerebrovascular disease [71].

A number of other studies have also clearly shown that exposure to PM 2.5 in the human body can cause dyslipidemia due to the increase in the concentration of total cholesterol, LDs, triglycerides, and also lowering of antiatherogenic lipid (high-density lipoproteins, or HDL) levels, which, in turn, will increase the risk of formation of atherosclerotic plaques (Fig. 3) [72, 73]. The Multi-Ethnic Study of Atherosclerosis Air Pollution (MESA) has shown that HDL concentration in the blood serum decreases by 0.64 μmol/L (95% CI -0.82 to 0.71 μmol/L) for each increase in the concentration of air pollutants PM 2.5 of 5 μg/m³ [74]. Thus, the adverse effect of PM 2.5 negatively correlates with the level of antiatherogenic (protective) HDLs in the human blood serum.

Several recent studies have reported that the functional properties of HDLs are no less important than their serum levels. Chemical substances contained in PM 2.5 enter into oxidation-reduction reactions with protein and lipid components of HDLs, causing the dysfunction of the latter [75]. Another study has also found that short-term exposure to high PM 2.5 levels reduced the antioxidant and anti-inflammatory properties of HDLs [76]. Specific antiatherogenic effects of HDLs that are impaired by the effect of PM 2.5 include restricting the transport of excess cholesterol to the subendothelial space and macrophages, increasing the breakdown of oxidized phospholipids and ox-LDLs, and inhibiting LDLs oxidation [77, 78]. In the pilot study, long-term exposure to elevated PM 2.5 levels was associated with increased cholesterol and macrophage levels in the atherosclerotic plaques in the case of laboratory mice [79]. Compared with the mice exposed to the air cleaned of PM 2.5, the mice exposed to PM 2.5 had decreased HDLs levels and increased levels of LDLs and ox-LDLs [80]. It has also been shown that PM 2.5 can enhance the development of atherosclerosis by increasing the expression of scavenger receptors and the accumulation of the oxidatively modified form of cholesterol (7-ketocholesterol) in the vascular wall [81]. Besides, PM 2.5 can also lead to the disorder of lipid metabolism due to the changes in the composition of the intestinal microflora, which is associated with the progression of atherosclerosis [82]. Thus, these data provide compelling evidence that PM 2.5 can accelerate the accumulation of lipids in the vascular wall, the formation of atherosclerotic plaque and its growth by altering the lipid metabolism: increasing the level of atherogenic and decreasing the level of antiatherogenic particles, stimulating the oxidation of LDLs and phospholipids, changing the expression and functioning of scavenger receptors, LDLs receptors and ox-LDLs receptors.

2.2.3. PM 2.5, Oxidative Stress and Inflammation

PM 2.5 contained in the air, during inhalation, enter the bronchial tree and alveoli and are deposited on their walls. These foreign particles first trigger local and then systemic immune-inflammatory reactions, which is accompanied by cell damage, generation of ROS and increased oxidative stress. Oxidative stress and immune-inflammatory reactions are one of the key links in the pathophysiology of atherosclerosis, both at the initial stage of its development and at subsequent stages of the pathogenesis of atherosclerosis [51-55].

Chemical constituents of fine particles (PM 2.5) depend on many factors and are very diverse. The most frequent components of PM 2.5 are organic substances (aldehydes, polycyclic aromatic hydrocarbons, organic carbon, etc.) and inorganic compounds (transition and heavy metal ions, silicon, sulfur, elemental carbon, etc.), forming a complex mixture. When these substances make it into the body, they can alter redox homeostasis and redox processes due to the intensification of the ROS/RNS formation [83]. The accumulation of the latter leads to oxidative stress and damage to the structural components of cells, which, in turn, induces the inflammatory response reaction. Oxidative stress and inflammatory processes are closely interrelated and potentiate each other's action, leading to the damage of the structural components of cells. Thus, oxidative stress is accompanied by increased formation of ROS/RNS, which causes direct damage to the structure of DNA, lipids and protein molecules that make up intracellular organelles and cell membranes. Damage to organelles and cell membranes can lead to impaired cell function, cell death and the release of cytoplasmic contents into the extracellular space, which can enhance local immune-inflammatory responses [51]. In addition, ROS and RNS stimulate the secretion of various inflammatory cytokines and mediators by immune and non-immune cells and promote the oxidation of LDLs in the blood to ox-LDLs, as well as stimulate the secretion of chemokines and pro-inflammatory factors by endothelial cells, which will further worsen the redox homeostasis in the body and form the vicious pathogenetic circle [51, 55, 84]. Heavy metal ions loaded on the surface of PM 2.5 can catalyze the Fenton reaction to produce ROS. Elevated levels of ROS enhance the activity of the nicotinamide adenine dinucleotide phosphate oxidase enzyme (NADPH oxidase), which causes mitochondrial damage and cell dysfunction [85]. A recent study has shown that PM 2.5 can cause mitochondrial damage in macrophages, activate the mitochondrial apoptosis pathway, increase lipid accumulation therein, and induce apoptosis of foam cells and macrophages, which further aggravates the pathogenesis of atherosclerosis [86].

The bronchopulmonary system is directly exposed to various air pollutants, including PM 2.5. PM 2.5 adsorbed on the surface of the airways can damage the epithelial cells of the airways and initiate local inflammation of the bronchi and alveoli (bronchitis, alveolitis), which leads to the production of a large number of inflammatory mediators and ROS (Fig. 3). Given the high degree of blood supply to the bronchopulmonary system, inflammatory mediators and ROS in large quantities will penetrate the systemic inflammatory blood flow, contributing to the development of the systemic inflammatory response [87]. In addition, a recent study has shown that in addition to mechanical damage to cells, PM 2.5 can directly activate the MyD88/NF-kB signaling pathway through Toll-like receptors (TLRs) on the surface of alveolar macrophages in the lungs. Effects of PM 2.5 on several types of TLRs, in particular TLR2 and/or TLR4, enhance the release of inflammatory cytokines by macrophages [88]. The systemic inflammatory response results in a significant increase in the concentration of pro-inflammatory factors, leading to the increased migration and proliferation of monocytes, migration of smooth muscle cells, transformation of monocytes, macrophages and smooth muscle cells into foam cells, which promotes the formation and growth of the atherosclerotic plaque.

Several studies indicate the possible role of PM 2.5 components in inflammatory processes taking place in certain organs and tissues, among which the adipose tissue is of great importance [89-92]. Thus, in case of prolonged exposure, the toxic components of PM 2.5 by means of the bloodstream penetrate the adipose tissue, where they accumulate in large quantities and cause chronic inflammation and the release of adipokines into the bloodstream. Many of these adipokines, including visfatin, resistin and adiponectin, are directly involved in the pathogenesis of atherosclerosis by way of regulating the functioning of endothelial, smooth muscle cells and macrophages [93-97]. In general, the inflammatory response and oxidative stress are mutually supportive and interacting to induce a number of atherogenesis processes from formation to rupture of atherosclerotic plaques [7, 50, 55]. Thus, PM 2.5 contributes to the onset and development of atherosclerosis by inducing the oxidative stress and the inflammatory response reaction.

It is worth noting that the composition of PM2.5 can play an important role in the development of oxidative stress and inflammation. For some PM2.5 components, specific mechanisms by which ROS are formed, have been disclosed. Thus, ions of transition metals (iron, copper, manganese and vanadium) catalyze the Fenton reaction, which contributes to the formation of a hydroxyl radical. NO2 is a source of peroxynitrite formation, which is one of the most active ROSs [29-32].

2.2.4. PM 2.5 and the Vegetative Nervous System

Although the vegetative nervous system (VNS) plays a vital role in the regulation of the cardiovascular system (CVS), its excessive activation under certain physiological and pathological conditions adversely affects the functioning of the CVS and can contribute to the development and progression of many CVDs [98, 99]. The main markers for assessing the state of the VNS are heart rate (HR), heart rate variability (HRV), and blood pressure (BP) [100, 101]. Interestingly, the impact of PM 2.5 can lead to dysfunction of the VNS and change the above-mentioned parameters, which is fraught with the formation of CVDs. Thus, several epidemiological studies have shown that exposure to PM 2.5 can disrupt the functioning of the VNS, in particular, leading to changes in the HR and HRV [100, 101]. Several clinical and experimental studies have shown that excessive oxidative stress and systemic inflammation induced by PM 2.5 are accompanied by changes in the functioning of the VNS, which is expressed by the increase in BP and HR, and by the decrease in HRV [102-104]. Exposure to PM 2.5 can also result in dysfunction of the sympathetic nervous system, causing rapid changes in blood pressure regulation. Thus, Fuks et al. in their population-based cohort study (n=4539), showed that prolonged exposure to elevated concentrations of PM 2.5 in residential premises is associated with increased blood pressure and a higher risk of arterial hypertension (AH) over the next five years of follow-up [105]. Animal experiments have shown that exposure to PM 2.5 can lead to direct damage and inflammation of the hypothalamus, which, in turn, may be associated with over-activation of the sympathetic nervous system [106]. Another study reports that PM 2.5 impairs the functioning of the parasympathetic nervous system by way of increasing the methylation of the genes encoding the production of the pro-inflammatory cytokines [107]. Thus, PM 2.5 can directly disrupt the functioning of the vegetative nervous system and increase the risk of AH. AH, in turn, is the independent risk factor for the formation and aggravation of atherosclerosis and CVDs by way of a number of known mechanisms [108-113]. The increased level of BP in itself can damage the endothelium as a result of the hemodynamic shock and activation of the oxidative stress, which leads to the increase in the synthesis of collagen and fibronectin by the endothelial cells. AH can also result in the activation of the enzymes that cause the oxidation of LDLs and in the increase in the formation of ox-LDLs [112]. In the case of AH, there is a higher expression of PDGF, which additionally induces the migration and proliferation of smooth muscle cells in the intima of the vessels, making atherosclerosis worse (Fig. 3) [105]. Besides, high BP is the risk factor for the rupture of atherosclerotic plaques and further adverse consequences in the form of acute cardiovascular accidents (acute myocardial infarction, sudden cardiac death, stroke, etc.) [114-117]. This is due to the fact that after the rupture of the atherosclerotic plaque, its contents are released into the bloodstream, in particular inflammatory and prothrombotic factors (collagen, tissue factor, thromboxane, etc.) that trigger the process of thrombus formation, as well as the fragments of the atherosclerotic plaque that cause rapid mechanical obstruction of the blood vessels (coronary or intracerebral), into which they get.

2.2.5. Impact of PM 2.5 on the Hemostatic System

The exposure of humans and experimental animals to PM 2.5 increases thrombogenicity and thrombosis, which is indicative of quite a significant impact of PM 2.5 on the hemostatic system [1, 118-123]. Thus, the experimental study by A. Nemmar et al. has found that exposure to exhaust particles increases platelet activation and causes peripheral thrombosis [118]. Some inflammatory mediators released into the blood stream on exposure to pollutants can accelerate processes of blood coagulation. G. Mutlu and colleagues reported that the exposure of laboratory mice to PM 2.5 enhances the production of interleukin 6 by alveolar macrophages. This inflammatory mediator, in turn, increases the level of fibrinogen, and the activity of coagulation factors II, VIII, and X of the hemostatic system, which leads to reduced coagulation time and accelerated formation of arterial thrombus [119]. Experimental studies are consistent with the results of clinical studies. Under the exposure of a healthy human body to PM 2.5, there can be observed a reduction of prothrombin time, activated partial thromboplastin time and an increase in plasma levels of fibrinogen and D-dimers which indicates a hypercoagulable state [120-122]. Some researchers report the effect of individual components of PM 2.5 on the hemostasis system parameters [29]. Thus, according to Huang et al. elevated levels of copper, zinc and vanadium in the composition of PM2.5 lead to an increase in the level of fibrinogen in the bloodstream [29]. In another study, it was reported that ions of some transition metals (iron, titanium, cobalt, cadmium) in PM 2.5 are associated with increased levels of fibrinogen, tissue plasminogen inhibitor (tPA) and plasminogen activator-1 inhibitor (PAI-1) [123], however, the mechanism of increasing these markers of the hemostasis system has not been established.

2.2.6. PM 2.5 and Subclinical Myocardial Injury

A number of recent studies have shown evidence that PM 2.5 causes subclinical damage to cardiac muscle tissue [12-16]. Thus, even short-term exposure to environmental pollutants, including PM 2.5, leads to a significant increase in serum levels of high-sensitivity cardiac troponin I (on average, by 22.9-154.7% compared with initial concentrations) in people living in contaminated areas [12]. In addition to changes in the concentration of troponins, the examined people showed increased levels of growth differentiation factor 15 and 8-OH-deoxyguanosine, which indicated the enhancement of inflammatory processes and oxidative stress [12]. The results of this clinical study are consistent with the results of the experimental study. Laboratory animals exposed to atmospheric air pollutants had significantly higher serum concentrations of the cardiac marker (cardiac troponin I), the inflammatory marker (C-reactive protein) and oxidative stress markers (malondialdehyde, catalase, nitrogen oxide, superoxide dismutase) compared with the control group (p < 0.05) [16].

In general, high-sensitivity cardiac troponins are not only valuable biomarkers of acute myocardial infarction but they also allow detection of myocardial injury in other pathological and physiological conditions that have a negative effect on cardiomyocytes [98, 111, 124-128]. The mechanisms of the increase of cardiac troponins in blood serum under the exposure of a human body to PM 2.5 are not definitely known. Based on the analysis of the results of a number of clinical and experimental studies [12-16], there can be distinguished several mechanisms underlying the PM 2.5-induced myocardial injury and the increase of cardiac troponins in blood serum: 1) initiation of cardiomyocyte apoptosis; 2) enhancement of oxidative stress accompanied by increased production of reactive oxygen species that damage cell membranes of cells, including cardiomyocytes. Damage to the cell membrane of myocardial cells may be accompanied by an increase in the release of cardiac troponin molecules localized in the cytoplasm (cytosolic fraction of cardiac troponin). This fraction of troponins contains relatively few (approximately 5%) molecules of their total amount in the cardiomyocyte; hence, the degree of increase in serum levels of cardiac troponins under exposure to PM 2.5 is also relatively small; 3) subclinical ischemic injury caused by narrowing of the lumen of coronary vessels due to the development and progression of atherosclerosis. Thus, high-sensitivity cardiac troponins can be considered as laboratory biomarkers for assessing myocardial injury and the state of the cardiovascular system in people living in highly contaminated regions, which needs further research and clarification.

CONCLUSION

According to the conducted narrative review, PM 2.5 should be regarded as a significant risk factor for the development of atherosclerosis and CVDs. This is confirmed by the number of clinical and epidemiological studies that have revealed the existence of a close relationship between the increase in the concentration of PM 2.5 in the ambient air and markers of subclinical atherosclerosis (carotid intima-media thickness (CIMT), coronary artery calcification (CAC), thoracic aorta calcification (TAC), and ankle-brachial index (ABI). The pro-atherogenic effect of fine particulate matter is based on several basic and closely interrelated pathophysiological mechanisms: endothelial dysfunction, impaired lipid metabolism, increased oxidative stress and inflammatory reactions, impaired functioning of the vegetative nervous system and increased activity of the hemostatic system. In addition, PM 2.5 causes subclinical injury of cardiac muscle cells by several mechanisms: apoptosis, oxidative stress, decreased oxygen delivery due to coronary atherosclerosis and ischemic damage of cardiomyocytes. Highly sensitive cardiac troponins are promising markers for detecting subclinical myocardial damage in people living in polluted regions.

CONSENT FOR PUBLICATION

Not applicable.

FUNDING

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CONFLICT OF INTEREST

The authors declare no conflict of interest, financial or otherwise.