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Heart Failure Reviews

, Volume 22, Issue 3, pp 337–347 | Cite as

The mechanisms of air pollution and particulate matter in cardiovascular diseases

  • Antonella Fiordelisi
  • Prisco Piscitelli
  • Bruno Trimarco
  • Enrico Coscioni
  • Guido Iaccarino
  • Daniela SorrientoEmail author
Article

Abstract

Clinical and epidemiological studies demonstrate that short- and long-term exposure to air pollution increases mortality due to respiratory and cardiovascular diseases. Given the increased industrialization and the increased sources of pollutants (i.e., cars exhaust emissions, cigarette smoke, industry emissions, burning of fossil fuels, incineration of garbage), air pollution has become a key public health issue to solve. Among pollutants, the particulate matter (PM) is a mixture of solid and liquid particles which differently affects human health depending on their size (i.e., PM10 with a diameter <10 μm reach the lung and PM2.5 with a diameter <2.5 μm penetrate deeper into the lung). In particular, the acute exposure to PM10 and PM2.5 increases the rate of cardiovascular deaths. Thus, appropriate interventions to reduce air pollution may promote great benefits to public health by reducing the risk of cardiovascular diseases. Several biological mechanisms have been identified to date which could be responsible for PM-dependent adverse cardiovascular outcomes. Indeed, the exposure to PM10 and PM2.5 induces sustained oxidative stress and inflammation. PM2.5 is also able to increase autonomic nervous system activation. Some potential therapeutic approaches have been tested both in pre-clinical and clinical studies, based on the intake of antioxidants from dietary or by pharmacological administration. Studies are still in progress to increase the knowledge of PM activation of intracellular pathways and propose new strategies of intervention.

Keywords

Air pollution Particulate matter Acute cardiovascular diseases Chronic cardiovascular diseases Oxidative stress 

Introduction

Air pollution is the introduction of harmful substances into the atmosphere and has adverse effects on human health [1]. These substances (i.e., carbon, nitrogen and sulfur oxides, heavy metals, ozone and photochemical oxidants, toxic pollutants) can be solid particles, liquid droplets, or gasses suspended in the air which vary in size, composition, and origin. They can have a natural origin (volcanoes and dust storms) or be man-made (power plants and industrial processes, vehicular traffic, domestic coal burning, industrial and municipal waste incinerators) [2, 3, 4, 5, 6]. Given the variety of sources of air pollution, the concentration of pollutants in the air can change from area to area, also depending on meteorological factors, such as wind speed and direction. The extent of the effects on human health depends on pollutant’s concentration and time of exposure. Indeed, young children and elderly people should be less exposed compared with working adults who often move around different cities. People working in industries are likely the most exposed to chemical toxic compounds or hazardous fumes. Clinical and epidemiological studies have already ascertained that air pollution increases respiratory and cardiovascular mortality [1]. For this reason, it is fundamental to increase the knowledge about the molecular mechanisms by which pollutants affect human health, in order to develop effective therapeutic strategies, and to reduce the emission of pollutants in the air, to limit their effects on health.

The particulate matter

Among the pollutants which can harm human health, here, we focus on the particulate matter (PM) since the increase of its concentration in the air increases the risk of cardiopulmonary and lung cancer mortality [7, 8]. PM is the sum of all solid and liquid particles suspended in the air which came from different sources and are different in chemical composition and size. Depending on its sources, PM can be classified into “primary particles,” which are emitted directly from a source (construction sites, unpaved roads, fields, smokestacks or fires) and “secondary particles,” which can form in complicated reactions of chemicals (sulfur dioxides and nitrogen oxide) that are emitted into the atmosphere from power plants, industries, and automobiles [9, 10].

Primary PM sources are derived from both human (agricultural operations, industrial processes, combustion of wood and fossil fuels, construction and demolition activities, and entrainment of road dust into the air) and natural activities (windblown dust and wildfires). The composition of PM varies in time and space (transition metals, ions, organic compound, quinoid stable radicals of carbonaceous material, minerals, reactive gasses, and materials of biologic origin), and this attributes to PM a different toxicity [11]. Moreover, small particles can absorb and retain toxic substances, which are responsible for lung cell impairment [12]. The deposition of inhaled particles in the respiratory tract depends mainly on breathing pattern and aerodynamic particle size. Particles larger than 10 μm (PM50) are filtered through the nose but they are too large to reach the respiratory tract. Thus, PM50 can be trapped in the mucus lining within the nose and can be easily eliminated through normal breathing activities. Particles smaller than 10 μm can reach the lung (thoracic particles, PM10) and are deposited in the nasal cavities and upper airways with nasal breathing. In this latter group, fine particles (PM2.5), with a diameter <2.5 μm, and ultrafine particles (UFP), with a diameter <0.1 μm, can penetrate deeper into the lungs and deposit in alveolar regions during mouth breathing. PM2.5 can also be absorbed into the bloodstream through alveolar capillaries causing lung and systemic inflammation [9, 10, 12]. Total lung deposition of these particles is about 60% for ultrafine particles and 20% for fine particles [13]. In adults at rest, the nasal deposition of PM2.5 is about 20% and increases to 30–40% during exercise. Lower values (about 10–20%) are reached in children aged 5–15 years [13]. Once deposited in the lung, most particles are removed through several clearance mechanisms. Insoluble particles deposited on ciliated airways are generally removed from the respiratory tract by mucociliary activity within 24–48 h [14]. The clearance from the pulmonary region is usually rapid and may occur through the action of alveolar macrophages, whose removal from the lungs can instead take several weeks [15]. In a polluted environment, in a 24-h period, each lung acinus could receive approximately 30 million particles and each alveolus 1500 particles. Lung airways and alveoli retain 50% of these particles which are mostly composed by PM2.5 [16]. PM2.5 is also the 96% of effectively retained particles in the lung parenchyma [17].

Epidemiological studies and data from animal models indicate that particle pollution exposure affects health and that, in particular, the cardiovascular and the respiratory system are affected primarily [18, 19, 20, 21]. However, the function of several other organs can be also influenced. Moreover, several epidemiological and clinical evidences suggest that PM2.5 and PM10 are associated with increased hospitalization [8, 22, 23] and mortality due to cardiovascular disease [24], especially in persons with congestive heart failure, frequent arrhythmias, or both [25].

Pollution effects on cardiovascular diseases

Cardiovascular diseases (CVD) are actually among the main causes of death in the world [26, 27]. They have a multifactorial etiology and, based on their clinical presentation, can be divided into chronic (i.e., heart failure and hypertension) and acute (i.e., acute myocardial infarction and arrhythmia) conditions.

Several pieces of evidence indicate that air pollutants, and in particular PM, seriously affect the cardiovascular system. Indeed, the inhalation of PM, especially PM2.5 and PM10, promotes cardiovascular events occurring within hours or days after exposure [28]. The heart and the vascular system are highly vulnerable to short-term and long-term exposure to PM2.5, especially in association with aging and existing coronary or structural heart diseases [29]. Accordingly, a cohort study estimates that a short-term exposure to PM2.5 increases the risk of cardiovascular events from 0.4 to 1.0% [14]. A multicity study, including data from Europe, the USA, and Canada, demonstrated that a 10-μg/m3 increase in PM10 is associated with an enhanced rate of mortality with larger effects in Canada [30]. This study suggests higher effects of PM10 on daily mortality in cities with a higher temperature and a larger contribution of traffic emissions to PM. In the Air Pollution and Health: a European Approach (APHEA) project, an increase of sulfur dioxide (SO2) and PM10 was associated with 0.4% increase in the rate of cardiovascular mortality in major European cities [31]. Thus, both PM2.5 and PM10 concentrations are closely associated with cardiovascular diseases, and PM2.5 seems to be a larger determinant of adverse health effects compared with PM10. These effects have been demonstrated in both acute and chronic cardiovascular (CV) diseases in response to short- and long-term exposure to PM as described below.

Several studies demonstrate that short-term exposure to PM can trigger acute cardiovascular events (myocardial infarction, stroke) and long-term exposure increased this risk of heart failure [14].

Acute effects of pollution on CV diseases

The short-term exposure to PM mainly affects acute cardiovascular diseases such as myocardial infarction (MI) and cardiac arrhythmia. An increased risk of MI has been reported in association with short-term exposure to PM2.5 [32]. In particular, it has been found that increased concentrations of PM2.5 are associated with an increased risk of ST-segment elevation myocardial infarction (STEMI). However, no associations have been found with non-ST-segment elevation myocardial infarction (NSTEMI) [43]. This could be the result of the rupture of larger plaque and promotion of thrombus formation in patients with STEMI in response to PM2.5 compared with patients with NSTEMI [43]. Elevated concentrations of fine particles in the air may transiently elevate the risk of MI within a few hours and 1 day after exposure [33]. Also, an increase of PM10 levels is associated with an increased risk of MI in elderly patients [34]. Indeed, a multicity case-crossover study demonstrates that in elderly residents of 21 US cities, a 0.65% increased risk of hospitalization for MI exists per 10-μg/m3 increase in ambient PM10 concentration. The mechanisms for acute, short-term exposure PM-dependent myocardial ischemic injury can be attributed to increased systemic inflammation, altered endothelial function, and enhanced thrombotic tendency, as demonstrated in mouse and dog models of myocardial ischemia [35, 36]. Short PM exposure is also associated with atrial fibrillation (AF). Indeed, in patients with known cardiac disease, PM2.5 is an acute trigger of AF, since it is able within hours to induce a 26% increase of odds of AF for each 6.0-mg/m3 increase in PM2.5 concentration [37]. Sudden cardiac death and cardiac arrhythmias are related to the activity of the autonomic nervous system, that can be measure by changes in the heart rate variability (HRV). It has been shown that the indoor exposure to PM2.5 and household activities cause acute changes in HRV indices among housewives [38].

Chronic effects of pollution on CV diseases

A recent prospective cohort study and meta-analysis in 11 European cohorts from the ESCAPE project shows that long-term exposure to PM is associated with the incidence of coronary events. In particular, a 5-μg/m3 increase in estimated annual mean PM2.5 and a 10-μg/m3 increase in estimated annual mean PM10 are associated with a 13 and 12%, respectively, increased risk of coronary events. This association persists also at low levels of exposure, below the current European limit values (25 μg/m3 for PM2.5, 40 μg/m3 for PM10) [39]. The American Cancer Society (ACS) cohort study demonstrated that prolonged exposure to PM2.5 is associated with heart failure-dependent death and hospitalizations [40]. Accordingly, the reduction of PM2.5 exposure reduced heart failure admissions [41]. However, also, short-term exposure is associated with daily admissions for heart failure [42]. It has been demonstrated that inhalation of air pollutants, such as PM2.5 and black carbon, could favor the development of cardiometabolic disorders, including hypertension [43, 44, 45, 46]. In particular, within a typical Chinese global megacity, 1- to 7-day exposure to PM2.5 is significantly associated with the elevation of systolic blood pressure, ranging from 2.0 to 2.7 mmHg [47]. Increased systemic blood pressure and vasoconstriction due to short-term exposure to PM could lead to increased cardiac afterload and risk of acute decompensated heart failure [48]. Also, long-term exposure to PM2.5 increases the risk of mortality for heart failure [8]. Indeed, fine PM exposure is strongly associated with mortality due to ischemic heart disease, heart failure, and cardiac arrest. For these cardiovascular causes of death, a 10-μg/m3 elevation in fine PM was associated with 8 to 18% increases in mortality risk. A long-term PM2.5 exposure is associated with increased corrected QT duration, a risk factor for arrhythmia [49], in elderly patients. This suggests that the effects of PM on cardiovascular events may be mediated, in part, by changes in cardiac repolarization [50, 51].

In literature, there is poor research referring specifically to the effects of PM in individuals with pre-existing cardiovascular conditions [33, 52, 53]. Furthermore, the few clinical studies that have investigated this matter propose discordant results, probably due to differences in composition and concentration of PM in the cities where the studies were performed, and/or the confounding effect of other pollutant, such as smoking. In patients with myocardial infarction, the inhalation of PM leads to an adverse ventricular remodeling and worsening of myocardial fibrosis [54].

All these findings suggest that an association exists between PM2.5 exposure and acute/chronic CV diseases, and that it is dependent on particles concentration and time of exposure.

Potential biological mechanisms

The link between PM and cardiovascular disease is clearly established but the mechanisms whereby this association exists remain to be fully elucidated. Different potential mechanisms have been hypothesized that can be activated by direct effects of pollutants on the cardiovascular system, blood, and lung receptors or by indirect effects due to pulmonary oxidative stress and inflammatory responses (Fig. 1) [9]. In addition, alterations of the autonomic tone might contribute to the instability of a vascular plaque and initiation of cardiac arrhythmias (Fig. 1). The direct effects of air pollution could be responsible for the acute cardiovascular responses to PM exposure, such as myocardial infarction. The indirect effects, instead, contribute to a systemic inflammatory state, which in turn activates chronic responses impairing vascular function and accelerating atherosclerosis.
Fig. 1

PM target tissues. PM can affect cardiovascular system by different potential mechanisms: direct or indirect lung inflammation, direct blood translocation, and autonomic regulation

Direct translocation into circulation

PM can cross the pulmonary epithelium into the circulation or interact with lung receptors (direct effects) to induce an acute cardiovascular response. The first evidence derives from studies of Nemmar, which demonstrates that ultrafine particles and PM2.5 could translocate into the pulmonary circulation and the systemic circulation [55, 56]. To date, two mechanisms have been described by which PM exposure causes direct cardiovascular dysfunction: reactive oxygen species (ROS) production and regulation of calcium levels.

Indeed, it is known that ROS have a key role in both physiology and pathophysiology of the heart. Moderate ROS production is protective in response to myocardium ischemia [57] but excessive levels induce cell damage which in turn leads to the development of cardiovascular diseases [58]. It is now validated that increased ROS production has also a key role in PM-induced vascular cytotoxicity [59] and cardiac myocyte dysfunction [60, 61]. The oxidative stress induced by a PM-dependent ROS production can also affect vascular function, and PM exposure has been associated with arterial vasoconstriction, by disrupting endothelial vasodilation and endogenous fibrinolysis through ROS [62]. On the other hand, calcium (Ca2+) is vital for cardiomyocyte function, and it is essential for excitation-contraction coupling and regulation of contractile strength [63, 64, 65]. PM-induced peroxide production affects calcium regulation of the Na+-Ca2+ exchange protein [66] and L-type Ca2+ channel protein [67]. These events increase the concentration of cytosolic calcium and reduce sarcoplasmic reticulum stores of the ion. The consequence is the reduced cardiac contractility and the increased Ca2+-activated nuclear signaling which lead to hypertrophy (Fig. 2).
Fig. 2

PM induces cardiovascular dysfunction by ROS production and Ca2+ release. PM causes direct cardiovascular dysfunction by two different mechanisms: ROS production and regulation of calcium levels. Indeed, PM induces an increase of ROS production and an increase in cytosolic calcium. The increase of ROS production affects vascular function, and the increased of Ca2+ levels activates nuclear signaling associated with hypertrophy. Moreover, the combination of oxidative stress and increased Ca2+ levels induced by PM exposure causes mitochondrial dysfunction

The combination of oxidative stress and increased Ca2+ levels induced by PM exposure causes the opening of the mitochondrial permeability transition pore (MTP), leading to reduced mitochondrial membrane polarization and to induced mitochondrial respiration (Fig. 2) [68, 69]. Finally, PM inhibits nitric oxide synthase activity and nitric oxide release into the bloodstream favoring vasoconstriction (Fig. 3) [70].
Fig. 3

Effects of PM in endothelial cells. PM exposure inhibits nitric oxide synthase activity and nitric oxide release into the bloodstream favoring vasoconstriction

Pulmonary oxidative stress and systemic inflammation

It is shown that inhaled pollutants can induce pulmonary oxidative stress/inflammation (indirect effects) that contribute to a systemic inflammatory state which in turn activates hemostatic pathways, impairs vascular function, and accelerates atherosclerosis [71]. This finding has been validated both in vitro [72] and in vivo [42, 73].

One hypothesized mechanism includes pollution-induced lung damage by oxidative stress and inflammation that leads to lung dysfunction, respiratory distress, and cardiovascular disease which are potentially related to hypoxemia [74]. PM is inhaled and enters the lung and deposits on the alveoli, causing an inflammatory response that leads to an increase of circulating proinflammatory biomarkers (C-reactive protein, fibrinogen) and native immune response [43, 45, 46, 74, 75]. A recent in vivo study demonstrated that after PM2.5 exposure for 2 h, a rapid increase of reactive oxygen species generation occurred in the hearts and lungs of rats [44]. Oxidative stress activates specific transcription factors (NF-kappaB and AP-1), which in turn upregulate the expression of genes coding for cytokines, chemokines, and other proinflammatory mediators (Fig. 4). These latter induce the systemic inflammation [76] which leads to the increase of the common carotid artery intima-media thickness and an increase of coronary calcification [77, 78] on one hand but also favors atheromatous plaque destabilization and rupture, and thrombus formation which in turn induce acute events [79]. It has been demonstrated that PM2.5 alone does not alter blood pressure but in response to angiotensin II, the exposure to PM2.5 potentiates hypertension through NAD(P)H oxidase- and eNOS-dependent ROS generation [80]. This, in turn, activates the Rho/ROCK signaling pathway that is a key regulator of vascular smooth muscle tone through its effects on calcium sensitization of the contractile apparatus and is implicated in the pathogenesis of hypertension [80]. Accordingly, it has been suggested that the activation of TLR4 and NADPH oxidase in monocyte/macrophages by oxidized phospholipids may represent one potential mechanism by which PM2.5 mediates systemic inflammation [81].
Fig. 4

PM-dependent systemic inflammation in the lungs. PM exposure induces a rapid increase of reactive oxygen species generation. Oxidative stress activates a specific transcription factor, NF-kappaB, which in turn upregulates the expression of genes coding for proinflammatory mediators. These latter induce a systemic inflammation which favors atheromatous plaque destabilization and rupture and endothelial dysfunction

Disturbance of the autonomic nervous system

The autonomic nervous system has a key role in the control of heart rate (HR) and heart rate variability (HRV), the two predictors of cardiac death in HF [82]. It has been shown that the autonomic nervous system is involved in the pathophysiology of PM-induced cardiopulmonary diseases. Indeed, PM affects HRV, resting HR, and blood pressure, suggesting an activation of the sympathetic drive [79, 83]. HRV decreases rapidly in response to PM exposure [25, 84, 85, 86, 87] due to a decreased parasympathetic input to the heart. This unleashes the activation of the sympathetic drive and increases the incidence of cardiac arrhythmia and the risk of cardiovascular morbidity and mortality [79]. A similar observation also indicates an alternative pathway of SNS activation by showing that fine particulate induces alveolar inflammation, leading to the release of potentially harmful cytokines and the decrease of HRV [88].

It seems that PM exposure alters heart rate control by the autonomic nervous system (ANS) through an increase in systolic blood pressure. Indeed, the chronic exposure to fine PM increases plasma levels of angiotensin II, a potent vasoconstrictor, leading to an increase in blood pressure [89].

Potential therapeutic approaches

It is well established that PM induces oxidative stress by increasing ROS production [90]. Moreover, several diseases are characterized by chronic inflammation and antioxidant deficiency [91] that might increase the susceptibility to the additional oxidative stress caused by air pollution exposure. In this context, antioxidant therapy could be useful to counteract this phenomenon as shown both in vitro and in vivo [92, 93, 94, 95, 96, 97, 98, 99].

Animal studies

Data from animal models suggest that a range of antioxidant compounds can prevent the effects of air pollution, both in vitro and in vivo [92, 93, 94, 95, 96, 97, 98, 99]. It has been shown that fine PM exposure significantly impairs cardiovascular functions by decreasing circulating endothelial progenitor cells (EPCs) [92]. Indeed, PM treatment in mice significantly decreased circulating EPC population, promoted their apoptosis, increased ROS production, and increased serum levels of TNF-α and IL-1β [92]. The treatment with the antioxidant N-acetylcysteine (NAC) or the overexpression of antioxidant enzyme network (AON), that is composed of superoxide dismutase SOD1, SOD3, and glutathione peroxidase (Gpx-1), could effectively reverse this phenomenon [92]. This finding suggests that antioxidants are effective to reduce the adverse effects of PM on EPCs.

Accordingly, NAC had a protective effect on inflammatory response and oxidative stress damage in rats exposed to coal dust [95], and rescued changes in heart rate and the decrease in HRV in rats exposed to urban air particles [96]. Besides pharmacological interventions, antioxidant mechanisms could also be increased by dietary habits since diet is their major source. Indeed, it has been shown that several nutrients (vitamin C, vitamin E, β-carotene, omega-3 fatty acids, vitamin A, and folic acid) in supplementation studies are able to regulate the effects of air pollutants or modulate the immune response [98, 99, 100, 101].

Human studies

Although it is clear that antioxidants are useful for the treatment of PM-induced oxidative stress in animal models, in humans, they seem to be less effective or have long-term side effects. Indeed, several clinical trials have reported no benefit from vitamin E supplementation on coronary heart disease probably due to its effectiveness only at the early stage of the disease [94].

β-Carotene is one of the most widely studied carotenoids for both its pro-vitamin A activity and its abundance in fruits and vegetables [93]. In the last decade, high-dose supplementation with carotenoids or vitamin A has been used successfully in the treatment of oxidative stress in chronic diseases [97]. Moreover, carotenoids reduce the cardiovascular risk by lowering blood pressure, inflammatory cytokines, and markers of inflammation (such as C-reactive protein), and by increasing insulin sensitivity in tissues [93]. However, in a few clinical studies, harmful effects have been observed in response to β-carotene and vitamin A, such as the higher incidence of lung cancer in smokers [102]. Thus, antioxidant vitamins and micronutrients might have the potential to counteract PM effects on human health but further studies are needed with prolonged follow-up or with lower doses of antioxidants to evaluate long-term side effects.

Several studies show that the intake of n-3 PUFA from dietary or a pharmacological supplementation decreases the risk of mortality due to coronary heart disease [103] even if only a few studies have demonstrated the effect of this antioxidant on cardiac function in response to air pollution [104]. In a randomized trial, the supplementation with fish oil significantly decreased the effect of PM2.5 on HRV [104]. In additions to antioxidant-based therapy, it has been shown that statins attenuate PM-dependent reduction of HRV in subjects lacking the GSTM1 allele and that are therefore genetically susceptible to oxidative stress [105].

Conclusions

The short- and long-term exposure to PM contributes to the development and progression of acute and chronic CV diseases. PM can easily enter into the respiratory system and contributes to the development of cardiovascular events by inducing a systemic inflammatory condition or affecting the autonomic nervous system. Given the continuous variability of air pollution, that is associated with the evolution of the technological progress, and individual movements through numerous microenvironments every day, it is not surprising that data from air pollution studies could be very variable. This could limit the ability to significantly link health outcomes with single pollutant and requires, in future studies, the use of new tools to better measure the full air pollution mix and to better quantify the effects of exposure and the toxic combinations of the different pollutants. Appropriate interventions to reduce air pollution may promote great benefits to public health by reducing the risk of CV diseases. Several interventions have been carried out in the last decades which have significantly ameliorated air pollutant exposure in public places. Indeed, the introduction of smoking bans in public places and the new generation of cars with a reduced CO2 emission have been useful to reduce the exposure to air pollutants and consequently the incidence of cardiovascular diseases. Besides these interventions, it is also important to better understand the mechanisms by which air pollution induces damage to the cardiovascular system since this will allow the development of new therapeutic approaches.

Notes

Acknowledgments

This study was supported by grants from “BEYONDSILOS, FP7-ICT-PCP,” “Campania Bioscience, PON03PE_00060_8,” and PRIN 2015EASE8Z_003.

Compliance with ethical standards

Ethical standards

The manuscript does not contain clinical studies or patient data.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.I.O.S, Southern Italy Hospital InstituteMedicina Futura ResearchNaplesItaly
  2. 2.Department of Advanced Biomedical SciencesUniversity Federico II of NaplesNaplesItaly
  3. 3.Division of Cardiac SurgeryAOU San Giovanni di Dio e Ruggi d’AragonaSalernoItaly
  4. 4.Department of Medicine and SurgeryUniversity of SalernoBaronissiItaly

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