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Abstract

Ambient particulate matter (PM) pollution is estimated to be responsible for 3.2 million deaths annually worldwide. Although many studies have demonstrated PM as a serious risk factor for cardiovascular diseases, less is known on its association with cerebrovascular events. Over the last decade, however, an increasing number of studies have provided data showing a relationship between PM exposure and ischemic stroke (IS). In this article, we will report on existing epidemiologic findings for an association between PM exposure and IS based on a systemic literature search. Thus, despite inconsistencies in the results, currently available data suggest that PM exposure is a risk factor for IS, especially in patients with preexisting illnesses. With regards to the mechanisms leading to PM-dependent vascular damage, in particular proinflammatory, prooxidative, as well as proatherogenic pathways have been suggested to be involved. Notably, to date there is only one study published, which demonstrates the influence of PM exposure on cerebrovascular function. We will discuss reasonable approaches for future neurovascular research in this field.

Keywords

air pollution atherosclerosis ischemic stroke particulate matter systemic inflammation

INTRODUCTION

Air pollution is a heterogeneous mixture of gases, liquids, and solid particles, which all may be hazardous to health. Its main constituents, along with particulate matter (PM), are nitric oxides (NO_x), sulfur oxides (SO₂), carbon monoxide (CO), and ozone (O₃). However, many epidemiologic studies have shown that in particular, PM exposure is a risk factor for cardiorespiratory diseases and lung cancer.¹ The Global Burden of Disease Study estimates ambient PM to be responsible for 3.2 million deaths per year and 76 million years of healthy life lost.² Inhalable PM is classified according to the aerodynamic diameter of its particles: coarse (<10 μm), fine (<2.5 μm), and ultrafine (<0.1 μm) PM can be distinguished (Table 1). It is assumed that coarse particles are cleared in the upper airways, while fine PM reaches the lungs. Ultrafine PM however, may even infiltrate the alveoli.³ Mechanistically, PM exposure is thought to induce systemic inflammation, atherosclerosis, enhanced thrombogenicity, and vasoconstriction.³ These potentially harmful processes are closely linked with the pathogenesis of ischemic stroke (IS), one of the leading causes for death worldwide.

Table 1.

Particulate matter (PM) is divided in three fractions according to the median diameter of the particles

	Particle size (median diameter)	Penetration into the body (average)
Coarse PM	10 μm	Upper airways
Fine PM	2.5 μm	Bronchi
Ultrafine PM	0.1 μm	Alveoli, eventually blood circulation

PM, particulate matter.

This size-related classification reflects the ability of PM to penetrate the human airways.

PARTICULATE MATTER AND HUMAN HEALTH

Particulate Matter is a Risk Factor for Cardiovascular and Respiratory Diseases

Particulate matter exposure is thought to induce harmful biologic pathways, both acutely within days and chronically when exposure persists for years or a lifetime. Large time series analyses have been conducted in North America and Europe to estimate the acute health risk of PM exposure.^{4, 5} It was found that coarse PM levels measured on a daily basis were significantly associated with short-term increases in mortality on individual days, particularly with cardiopulmonary mortality (Table 2). However, risk increases were relatively small and did not exceed beyond 1%. In contrast, cohort studies focusing on chronic PM exposure and longer term cardiovascular endpoints showed a clear relationship (Table 3).^{6, 7, 8} The Harvard Six Cities study for example found that cardiopulmonary mortality in Steubenville, a US city with high ambient air pollution concentrations over a study period of 14 to 16 years, was increased by 37%.⁶ This corresponds to around one fourth of the mortality risk elevation estimated for chronic smokers.⁶ Brook et al.⁹ reviewed a substantial number of similar cohort studies and suggested a minimum of 10% higher cardiovascular mortality with each 10 μg/m³ increase in fine PM concentration. Conversely, it was estimated that each 10 μg/m³ decrease in fine PM was associated with an increase of 0.61 years in mean life expectancy in the United States.¹⁰ With regards to morbidity, the Womeńs Health Initiative identified chronic fine PM exposure as being associated with a 24% increase in the incidence of cardiovascular events.⁷

Table 2.

Synopsis of studies investigating PM exposure and acute cardiovascular risk

Study	Endpoints	Pollutant		(0.95 CI)
National morbidity, mortality, and air pollution study³	All-cause mortality	PM 10	Relative rate	1.005 (1.001–1.009)
National morbidity, mortality, and air pollution study³	Cardiovascular mortality	PM 10	Relative rate	1.007 (1.002–1.012)
Air Pollution and Health:a European Approach⁵	Cardiovascular mortality	PM 10	Relative risk	1.008 (1.005–1.011)

0.95 CI, 95% confidence interval.

Risk elevations per 10 μg/m³ increase in coarse PM (PM 10) exposition.

Table 3.

Synopsis of studies investigating PM exposure and long-term cardiopulmonary risk

Study	Endpoints	Pollutant		(0.95 CI)
Harvard Six Cities Study⁵	Cardiopulmonary mortality	Diverse pollutants	Rate ratio	1.37 (1.11–1.68)
Women's Health Initiative⁶	Cardiovascular events	PM2.5	Hazard ratio	1.24 (1.09–1.41)
American Cancer Society Study⁷	Lung cancer mortality	PM2.5	Relative risk	1.14 (1.04–1.23)

0.95 CI, 95% confidence interval.

Risk elevations per 10 μg/m³ increase in fine PM (PM 2.5).

Given the accumulating evidence for a clear association of PM exposure with increased cardiovascular morbidity and mortality, safety limits for coarse and fine PM have been introduced in the US and in Europe. Notably however, no study was able to define a threshold below which PM exposure would be harmless.⁹

PARTICULATE MATTER AND ISCHEMIC STROKE RISK

The associations between PM and all-type strokes are less clear. Studies from 15 cities in Europe, New Zealand, and Australia failed to find an association between PM exposure and risk of all-type stroke.^{11, 12} In this section, we will focus on a possible link between PM exposure and IS. We identified all epidemiologic studies, which provided data for the correlation between PM exposure and IS risk, comprising mortality, hospitalization, or stroke survey data. For this, we performed a World Wide Web-based internet search using Medline and PubMed. Our key search terms were any combinations of ‘air pollution’, ‘PM’, ‘stroke’, and ‘Is'. We included all studies, which provided data for an association of PM and IS and which were published in English before 30 July 2013. We have identified 18 studies, which fulfilled these criteria (Table 4).^{13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31}

Table 4.

Synopsis of studies investigating PM exposure and risk of ischemic stroke

Location	Year	N	Design	Increase in PM		Results (0.95 CI)
Japan¹³	2013	23,002	Time series	10 μg/ m³ PM 8	Rate ratio	Lag 0:1.016 (1.003–1.030)Lag 1:1.002 (0.989–1.016)Lag 2:1.003 (0.991–1.014)
Boston¹⁴ (USA)	2012	1,705 onsets	Case crossover	15→15–40 μg/m³ in PM 2.5	OR	Lag 1:1.34 (1.13–1.58)∗
Kaohsiung¹⁵ (Taiwan)	2003	11,528 hospital admissions	Case crossover	IQR in PM 10	OR	Lag 0:1.46 (1.32–1.61)∗
Como¹⁶ (Italy)	2010	759 hospital admissions	Case crossover	—	RR	Lag 4:1.078 (1.05–1.10)∗
London¹⁷ (Great Britain)	2012	1,832 hospital admissions	Ecological study (1995–2004)	10 μg/m³ PM 10	Rate ratio	1.86 (1.1–3.13)
Edmonton¹⁸ (Canada)	2012	5,927 hospital admissions	Case crossover	IQR in PM 2.5	OR	Lag 1:1.14 (1.03–1.26) Lag 1–3:1.16 (1.02–1.31)
Tokyo¹⁹ (Japan)	2011	24,628 deaths	Time series	10 μg/m³ PM 2.5	Rate ratio	Lag 0:1.014 (0.999–1.028)
Scania²⁰ (Sweden)	2010	11,267 hospital admissions	Time series analysis and case crossover	<15→>30 μg/m³ PM 10	RR	Lag 1:1.13 (1.04–1.22)
Copenhagen²¹ (Denmark)	2010	4,092 hospital admissions	Case crossover	IQR in UFP	OR	Lag 0:1.06 (0.99–1.13)
Taipei²² (Taiwan)	2006	1,494 hospital admissions	Time series	IQR in PM 2.5	OR	Lag 3:1.059 (0.984–1.134)
Nueces County²⁴ (USA)	2008	2,350 onsets	Ecological study	IQR in PM 2.5	Risk ratio	Lag 0:1.03 (0.99–1.07)Lag 1:1.03 (1.00–1.07)
Seoul²⁵ (Korea)	2002	7,137 deaths	Time series	IQR in total PM	RR	Lag 0:1.03 (1.00–1.06)
9 cities²⁶ (USA)	2005	155, 503 hospital admissions	Case crossover	IQR in PM 10	RR	Lag 0:1.0103 (1.0004–1.0204)
Takashima²⁷ (Japan)	2012	2,038onsets	Case crossover	IQR in PM 7	OR	No positive results
Lyon²⁸ (France)	2012	376 onsets	Case crossover	PM 2.5 and PM 10 (diverse)	OR	No positive results
Ontario²⁹ (Canada)	2011	9,202 onsets	Case crossover	10 μg/m³PM 10	RR	No positive results (except diabetes patients)
Dijon²⁹ (France)	2007	1,487 onsets	Case crossover	10 μg/m³ in PM 10	OR	No positive results
13 major urban regions³⁰ (Japan)	2007	46,370 deaths	Case crossover	30 μg/m³ in PM 7	OR	No positive results

CI, confidence interval; IQR, interquartile range, lagx, days before onset or hospital admission; N, study population, 0.95 CI, 95%; OR, odds ratio; PMx, particulate matter with median aerodynamic diameter, RR, relative risk, ∗, result is statistically significant (P-value<0.05).

Search in Medline (PubMed search engine) 30, July 2013, search terms: all combinations of ‘air pollution’, ‘particulate matter’, and ‘stroke’, ‘ischemic stroke’. Inclusion criteria: data for PM and ischemic stroke. Out of four studies analyzing data from Edmonton, three were excluded. All other studies were included.

ACUTE EFFECTS OF PARTICULATE MATTER EXPOSURE

Although most studies on PM and cardiovascular diseases have been conducted in developed western countries, first impulses for epidemiologic research on IS came from South Korea and Taiwan.^{15, 22, 25} An increase in PM by an interquartile range in Seoul was associated with a 3% higher IS mortality.²⁵ Furthermore, the same increase in PM exposure resulted in a statistically significant increase in the hospitalization rate due to IS in Kaohsiung (Taiwan) of 46%.^{15, 25} Subsequent studies on a link between IS and PM were conducted in the United States, Japan, and Europe. These are countries in which PM levels are 3 to 5 times lower than in the megacities of emerging nations. The largest of these studies investigated 150,000 IS hospital admissions of people aged 65 or older in nine US cities.²⁶ An interquartile range increase in coarse PM led to a 1% increase in hospitalizations.²⁶ Findings of higher IS risks even in areas with absolutely low PM burden, such as in southern Sweden, have further substantiated PM exposure as worldwide risk factor for IS.²⁰

However, a considerable number of studies did not find a correlation between PM levels and cerebrovascular diseases.^{20, 27, 28} Only three results reached the level of significance.^{14, 16, 25} This reveals limitations of comparing air pollution and its influence on health outcomes globally. The composition of PM varies dramatically dependent on pollution sources like car traffic or industry. A recent study from Japan showed that also geographically specific sources of PM, in this case Asian desert dust, are related to IS risk.³² In addition, most of the risk factors for cerebrovascular diseases on the individual level (especially, coexisting heart disease, hypertension, and also ethnical differences) are not specified in most of the studies.

Although this ecological bias cannot be denied, the design of individual studies has notably been improved during the last years. First post hoc analyses of medical records in Taiwan and in the United States were limited to the endpoint ‘hospital admission date due to Is'.^{15, 26} However, this approach addressed the temporal relationship between PM exposure and onset of ischemia inaccurately. Lokken et al.³³ showed that analysis of symptom-onset time instead (reconstructed from medical records) reveals a significantly more impressive risk of PM by abolishing a bias toward the null of 66%. Subsequently, in a study performed in Boston, measurements of ‘moderate’ PM levels (as defined by official US PM standards) were associated with a 34% higher IS risk.¹⁴ At the same time, the interaction between PM exposure and well-known risk factors for IS has been revealed. Analysis of ∼10,000 IS hospital admissions in Ontario (Canada) found an association between PM exposure and IS only in the subgroup of patients with coexisting diabetes mellitus.²⁹ Another recent study also demonstrated that patients with coexisting heart failure and diabetes mellitus were at higher risk of hospitalization.¹⁸ Furthermore, patients with a history of stroke were more susceptible to the effects of PM exposure. In contrast, there was no increase in IS risk for people with first-ever stroke.²⁷

Taken together, there is accumulating evidence for a considerable relationship between PM exposure and IS risk even in moderately polluted regions, in particular for people with preexisting illnesses. However, post hoc analyses limited to the acute risk over a few days cannot reveal the entire relevance of air pollution. As shown for the cardiovascular system above, chronic PM exposure for years leads to more severe risk elevations. Therefore, cohort studies, which prospectively observe IS risk for years are warranted to demonstrate the actual hazard of PM exposure.

BIOLOGIC EFFECTS OF PARTICULATE MATTER ON THE VASCULATURE

Biologic mechanisms leading to harmful PM-dependent effects on health have been examined in several experimental in vivo and in vitro studies. For the cerebral vasculature, it has been shown that a moderate elevation in fine PM concentration leads to an increased cerebral vascular resistance combined with a lower blood flow velocity.³⁴ However, the underlying pathways that explain the specific risk of PM exposure for the brain vessels are widely unknown. Thus, this chapter explores key steps of PM-dependent pathomechanisms, from its incorporation into the body up to vascular dysfunction, and highlights some promising experimental approaches for neurovascular research.

Exposure to ambient PM initiates typical pathophysiological alterations in men within hours or days.^{35, 36, 37, 38, 39} Systemic markers of inflammation such as interleukin 6, C-reactive protein, and white blood cell count are increased.^{35, 36, 37, 38, 39} Furthermore, prothrombotic activity is enhanced and arterial blood pressure is elevated.^{35, 36, 37, 38, 39} These general findings suggest that exposure to PM triggers a complex systemic signaling cascade. It involves activation of proinflammatory and immune pathways as well as activation of the autonomic nervous system.⁹

PARTICULATE MATTER CAUSES SYSTEMIC INFLAMMATION

The most likely gateway for PM into the body is through the alveoli.^{40, 41} Despite a functioning airway defense such as mucociliary clearance, large fractions of fine and ultrafine PMs are capable of reaching the respiratory zone of the lungs.^{40, 41}In vitro and in vivo studies showed that PM exposure increases reactive oxygen species (ROS) formation and the number of proinflammatory markers in bronchoalveolar lavage.^{40, 41} This suggests that local proinflammatory processes and oxidative stress within the lungs are of relevance in the complex cascade that subsequently has deleterious systemic effects.

In a recent study, it was demonstrated that PM-induced oxidative stress and inflammation are mediated through activation of the local intrapulmonary innate immune system, i.e. via toll-like receptors and scavenger receptors.⁴¹ Alveolar macrophages and dendritic cells recognize pathogenic patterns via toll-like receptor-4 and scavenger receptor-A.⁴¹ Subsequently, ROS-releasing enzymes such as nicotinamide adenine dinucleotide phosphate-oxidase oxidase are activated, and proinflammatory cytokines such as interleukin 6 are released.^{41, 42, 43} Large fractions of PM, e.g. transition metals, oxidize phospholipids (surfactants) in the lungs.^{41, 42, 43} Oxidized surfactants in turn are ligands for toll-like receptor and scavenger receptor.^{41, 42, 43} This activation of the local pulmonary innate immune system leads to a powerful burst of ROS and proinflammatory markers within the lung parenchyma. In addition, up to 80% of PM, predominantly the coarse fraction, is able to enter pulmonary parenchyma by transcytosis through macrophages and alveolar epithelium cells.⁴⁴ These particles can access the pulmonary circulatory system and are subsequently adducted by plasma proteins.⁴⁴ As a consequence, the occurrence of these PM–protein complexes in pulmonary and systemic circulations can induce systemic immune responses, particularly in adipose tissue.^{43, 44}

In summary, PM exposure is capable of triggering a complex immune response, which is initiated locally in the lung parenchyma and which subsequently activates systemic proinflammatory cascades (Figure 1). Both mechanisms, the proinflammatory reaction of the lungs and the translocation of particles to other organs, are thought to be responsible for the endothelial dysfunction after PM exposure.⁴⁵

Figure 1.

Proinflammatory pathways activated by particulate matter (PM). (Electron microscopy images with kind permission of Dr Kristin Ladell and Dr Gerhard Kolde: http://www.edoc.hu-berlin.de/dissertationen/ladell-kristin-2001-05-25/HTML/). Particulate matter oxidizes surface active agents (surfactants) in the alveoli of the lung. Oxidized surfactants activate toll-like receptor 4 (TLR-4), which stimulates the release of proinflammatory cytokines from alveolar macrophages. This activates the production of reactive oxygen species by local neutrophil granulocytes. In addition, large fractions of PM reach pulmonary circulation via transcytosis through alveolar epithelium cells. These proinflammatory mediators enter pulmonary capillaries and arrive in the circulatory system where they cause systemic inflammation. H₂O₂, hydrogen peroxide; IL, interleukin, O₂⁻, superoxide radical; TNF, tumor necrosis factor.

PARTICULATE MATTER POTENTIATES RISK FACTORS—ATHEROSCLEROSIS AND THE CRUCIAL ROLE OF PREEXISTING ILLNESS

Systemic inflammatory processes are closely linked to the pathogenesis of atherosclerosis.⁴⁶ Even the first stages of vascular dysfunction are characterized by invasion of circulating macrophages into the arterial wall.⁴⁶ Later on, during manifest atherosclerosis, both cellularity inside the plaques as well as systemic inflammatory status determine the risk of a plaque rupture.⁴⁶ In this context, PM may accelerate systemic and local proinflammatory processes and thereby critically contribute to the progression of the atherogenic cascade.^{42, 47}

Several animal studies investigated the influence of PM exposure on the development of cardiovascular diseases, particularly atherosclerosis and related cardiovascular events. Most of them failed to find significant changes in young and healthy animals.⁴⁸ In contrast, atherosclerosis and vascular inflammation significantly exacerbated when transgenic animals with comorbidities were assessed, for example mice with metabolic disorders (apolipoprotein E-knockout mice on a high-fat diet) or rabbits with preexisting atherosclerotic lesions.^{48, 49} These findings underline the proinflammatory and prooxidative theory of PM-induced vascular damage. It can be hypothesized that PM-derived systemic and vascular proinflammatory processes have a critical additional impact on plaque vulnerability, which, in general, depends on the plaque burden and the systemic inflammatory status (Figure 2).⁴⁶ Correspondingly, in clinical studies, individuals with diabetes, obesity, and hypertension have shown greater physiologic responses to PM exposure (including significantly increased blood pressure and white blood cell count).^{38, 39}

Figure 2.

Putative particulate matter (PM)-dependent pathomechanisms leading to potentiation of atherosclerosis. Particulate matter itself and PM-related inflammation oxidize low-density lipoproteins (LDLs). Oxidized LDLs (oxLDLs) are more susceptible to uptake by macrophages in the vessel wall. In addition, inflammation leads to egress of monocytes from the bone marrow, which invade into the atherosclerotic lesions and differentiate to macrophages. Taken together, PM causes plaque growth and increases plaque vulnerability. Particulate matter-related reactive oxygen species also impair nitrogen monoxide (NO) production in the endothelium cells of the vessels. This causes vasoconstriction and breaks down antioxidative protection.

In addition, mechanisms of plaque growth could be linked to PM exposure via lipoprotein metabolism. Particularly, low-density lipoproteins (LDLs), which transfer cholesterol to peripheral tissues, contribute to the number and volume of atherosclerotic lesions.⁴⁶ It has been demonstrated that enhanced ROS production results in increasing oxidation of LDLs.⁴⁶ These oxidized LDLs have a high affinity to phagocyting macrophages located in subendothelial connective tissue.⁴⁶ Consequently, PM exposure could actively accelerate the plaque burden resulting from ROS formation and circulating PM–protein adducts.⁴⁷

PERSPECTIVES ON NEUROVASCULAR RESEARCH

The acute impact of PM exposure on ROS formation and the systemic inflammatory status may explain the increased acute IS risk within days as shown in the epidemiologic studies. Wellenius et al.³⁴ showed with transcranial Doppler ultrasound in patients that slightly increased PM levels indeed lead to higher cerebral vascular resistance and lower blood flow velocity at rest. However, the epidemiologic evidence for cardiovascular outcomes demonstrated that these short-term processes contribute to less than 5% of the full risk of PM exposure.^{4, 6} Thus, there is a clear rationale to conduct experimental studies to demonstrate the impact of chronic PM exposure on IS outcome and to investigate the mechanisms involved. First evidence already suggests that long-term PM exposition accelerates common carotid artery intima-media thickness facilitating carotid artery disease, a major risk factor for IS.^{50, 51}

Importantly, there are two known characteristics, which distinguish the cardiovascular from the presumed cerebrovascular responses to PM exposure. First, a few studies suggested that PM can be translocated directly into the rhinal cortex via olfactory tract and bulb through the cribriform plate.⁵² This alternative lung-independent gateway for PM could result in direct damage to the brain parenchyma and vasculature. It has been shown that chronic exposure to urban air pollution can lead to disruption of the blood–brain barrier, endothelial activation, and enhanced inflammatory status of the brain.⁵³ Second, high LDL levels have not been shown as an independent risk factor for IS in contrast to their high impact on cardiovascular outcomes.⁵⁴ However, the PM-driven acceleration of arterial plaque burden is maintained by LDL.⁴⁷ Therefore, the proinflammatory and oxidative effects of PM could involve blood levels of LDL in the interaction of risk factors leading to atherosclerosis of the cerebral vessels. Both of these mechanisms provide PM exposure with a particular link to cerebral ischemia.

Taken together, experimental short- and long-term studies in vivo are warranted. They should include radioactively marked PM to elucidate the particle's way into the brain. Furthermore, there is a rationale to investigate the role of PM on IS outcome in transgenic animal models of obesity or diabetes.

CONCLUSION

There is accumulating evidence for an association of ambient PM exposure and IS risk. Further epidemiologic and experimental studies are necessary to clarify the impact of chronic PM exposure on ischemic brain injury. One crucial aspect in this connection is to decipher the influence of preexisting illnesses and the hazard potential of specific PM sources. Finally, experimental research is warranted to elucidate the deleterious mechanisms of PM exposure on cerebral vasculature.

Footnotes

The authors declare no conflict of interest.

ACKNOWLEDGMENTS

We would like to thank Dr Kristin Ladell (Cardiff University) and Dr Gerhard Kolde (Charité) for permission to use their EM images for . We would like to thank Mrs. Catherine Aubel for her writing assistance.

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Impact of Particulate Matter Exposition on the Risk of Ischemic Stroke: Epidemiologic Evidence and Putative Mechanisms

Abstract

Keywords

INTRODUCTION

PARTICULATE MATTER AND HUMAN HEALTH

Particulate Matter is a Risk Factor for Cardiovascular and Respiratory Diseases

PARTICULATE MATTER AND ISCHEMIC STROKE RISK

ACUTE EFFECTS OF PARTICULATE MATTER EXPOSURE

BIOLOGIC EFFECTS OF PARTICULATE MATTER ON THE VASCULATURE

PARTICULATE MATTER CAUSES SYSTEMIC INFLAMMATION

PARTICULATE MATTER POTENTIATES RISK FACTORS—ATHEROSCLEROSIS AND THE CRUCIAL ROLE OF PREEXISTING ILLNESS

PERSPECTIVES ON NEUROVASCULAR RESEARCH

CONCLUSION

Footnotes

ACKNOWLEDGMENTS

References