Running head: SMOG LAKE CITY 1. Smog Lake City: Exploring Air Pollution and Atherosclerosis. Mary Carolyn Fleck. Joselyn Londer.

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1 Running head: SMOG LAKE CITY 1 Smog Lake City: Exploring Air Pollution and Atherosclerosis By Mary Carolyn Fleck Joselyn Londer Jessica Mitchell Matthew Thomas Westminster College MSN 610 December 2014

2 SMOG LAKE CITY 2 Copyright 2014 Mary Carolyn Fleck Joselyn Londer Jessica Mitchell Matthew Thomas

3 SMOG LAKE CITY 3 WESTMINSTER COLLEGE School of Nursing and Health Sciences Scholarly Paper Approval Form Authors: Mary Carolyn Fleck Joselyn Londer Jessica Mitchell Matthew Thomas School or Department: Westminster College School of Nursing and Health Sciences Title of Scholarly Paper: Smog Lake City: Exploring Air Pollution and Atherosclerosis The above named master s Scholarly Paper has been read by the MSN 610 faculty and has been found to be satisfactory regarding content, English usage, format, citations, bibliographic style, and consistency, and is ready for submission to the Westminster College Library. Date Chair Date MSN Program Director

4 SMOG LAKE CITY 4 STATEMENT OF PERMISSION TO DUPLICATE SCHOLARLY PAPER Authors: Mary Carolyn Fleck Joselyn Londer Jessica Mitchell Matthew Thomas School or Department: Westminster College School of Nursing and Health Sciences Title of Scholarly Paper: Smog Lake City: Exploring Air Pollution and Atherosclerosis On the basis of an occasional and individual request, the Westminster College Giovale Library staff is given the right to make a copy of the above-named master's Scholarly Paper. The Westminster College Giovale Library is also given the right to mail or otherwise disseminate the copy to the requesting party and to be reimbursed by the requesting party for the cost of duplicating and mailing the Scholarly Paper. The above rights may be withdrawn by the author at any time when the Director of the Westminster College Giovale Library will be notified in writing that these rights are terminated by the above-named author. We hereby give my permission to the Westminster College Giovale Library staff to duplicate the above-named master's Scholarly Paper: Signature Date Signature Date Signature Date Signature Date

5 SMOG LAKE CITY 5 STATEMENT OF PERMISSION TO DIGITIZE SCHOLARLY PAPER Authors: Mary Carolyn Fleck Joselyn Londer Jessica Mitchell Matthew Thomas School or Department: Westminster College School of Nursing and Health Sciences Title of Scholarly Paper: Smog Lake City: Exploring Air Pollution and Atherosclerosis The Giovale Library of Westminster College is planning to develop an online electronic repository for Westminster theses, projects, and scholarly papers. In order to include your research in this college repository when it is implemented, we need your permission. This permission, as delineated below, may be withdrawn by the author at any time by notifying the Director of the Giovale Library in writing that permission is withdrawn. We hereby give my permission to the Westminster College Giovale Library staff to include an electronic copy of my project in its online electronic repository for educational purposes only. We retain ownership rights to our work, including the right to use it in future works such as articles or books. Signature Date Signature Date Signature Date Signature Date

6 SMOG LAKE CITY 6 Abstract Epidemiological studies have shown an association between air pollution exposure and cardiovascular disease (CVD). However, the underlying mechanisms and pathways involved in pollution-induced CVD are not fully understood. Atherosclerosis, the process of arterial plaque formation, is a key factor in the development of many cardiovascular events. Our assumption is that exposure to air pollution is associated with the development and progression of atherosclerosis. We performed a systematic review of literature to determine if a relationship exists between exposure to air pollutants and atherosclerosis, and found evidence that supports a positive correlation. The key pollutants under investigation are particulate matter (PM), diesel exhaust (DE), mixed emissions (ME), nitric oxide (NO), ozone (O 3 ), and carbon monoxide (CO). We performed our search in several databases, and all subsequent literary findings were reviewed by our four group members. Significance of each article to our topic was then examined and articles were excluded that were not found to be relevant based on our exclusion criteria. The research was then determined to either support or invalidate our theory. We were able to discuss recommendations and formulate methods of teaching to be implemented in our local patient population. In conclusion, we discovered a clear association between exposure to air pollution and the development and progression of atherosclerosis, and have developed specific recommendations for nurse practitioners to educate their patients based on their level of risk. Search terms included: atherosclerosis, pollution, air pollution, seasonal air pollution, progression, development, and exacerbation.

7 SMOG LAKE CITY 7 Table of Contents Introduction...8 Background...9 Atherosclerosis...9 Air Pollution...11 Epidemiology...14 Methods...17 Results...18 Discussion...21 Particulate Matter (PM) Micrometer Particles Micrometer Particles...24 Ultra-Fine/Nano...26 Diesel Exhaust...26 Others: NO 2, CO, O Areas for Future Study...30 Recommendations...32 Limitations...37 Conclusion...38 References...40 Appendices...60

8 SMOG LAKE CITY 8 Introduction Seasonal air pollution in the Salt Lake Valley has been an ongoing and worsening problem for many years. During the cold winter months, a weather phenomenon called inversion traps cold, polluted air in the Salt Lake Valley beneath a cap of high-pressure warm air. The high pressure system may sit over Utah for weeks, thus causing pollution to build up and trap contaminants like ozone, particulate matter, carbon monoxide, sulfur dioxide and nitrogen dioxide. In January of 2014, the Environmental Protection Agency (EPA) recognized Utah as having some of the poorest air quality in the nation. The level of air contaminants in Salt Lake City even surpassed that of Beijing, a city notorious for having the worst air pollution in the world (Donoghue, 2014, para. 17). As Salt Lake City residents and nurse practitioners, it is important we understand the risks of air pollution exposure and how it systemically impacts the body. It is known that air pollution negatively affects the respiratory system, and may even cause cancer (EPA, 2013). In recent years, there has been a significant amount of data linking exposure to air pollution with cardiovascular disease. Our group is interested in reviewing literature regarding the detrimental effects that air pollution may have on the cardiovascular system. Cardiovascular disease (CVD) is the leading cause of death worldwide (WHO, 2014, para. 1) and is strongly associated with atherosclerosis. Numerous epidemiological and observational studies recognize increases in cardiovascular mortality and hospitalizations from exposure to air contaminants especially particulate matter (PM). In fact, the absolute number of deaths attributable to PM is much higher for cardiovascular than for pulmonary causes (Yamawaki, 2006, p.

9 SMOG LAKE CITY 9 129). There are numerous mechanisms that may be involved in PM-related cardiovascular disease progression including endothelial dysfunction and atherosclerosis. As nurse practitioners (NPs), it is important that we are aware of all of the risk factors for CVD, including air pollution, a potentially modifiable risk factor, so that we are better prepared to treat and educate our patients. We pose the question: is air pollution a risk factor to the general public for the development and progression of atherosclerosis? Considering the detrimental effects that air pollution has been shown to have on the cardiovascular system, we have assumed that a positive correlation can also be made between exposure to air pollution and the development and progression of atherosclerosis. If found to be supported by current research, we are interested in exploring what methods of prevention and management are indicated. Air pollution is a major public concern that necessitates changes in legislation and individual personal practice in our community. Background Atherosclerosis Atherosclerosis is a disease caused by plaque build-up inside the cerebral, coronary, and peripheral arteries (Zhao, 2014). The National Heart, Lung, and Blood Institute defines the components of plaque as made up of fat, cholesterol, calcium, and other substances found in the blood (2011, para. 2). Initially, the intima within the vessels thickens with the growth of smooth muscle cells and a fatty streak is formed primarily from lipids. Macrophages, highly associated with inflammation, and lipoproteins such as apolipoprotein E (ApoE), very-low-density lipoprotein

10 SMOG LAKE CITY 10 (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) also become trapped along the wall of the vessel and become foam cells, which are the hallmark of the early atheroma (Zhao, 2014, para. 3). Over time, the fatty streak calcifies and hardens forming a fibrous plaque, decreasing the elasticity of the blood vessel, and narrowing the lumen walls. This limits the flow of oxygenated blood throughout the body and can lead to serious cardiac dysfunction such as coronary artery disease, heart attack, stroke, and sometimes death. Most people who have atherosclerosis do not have any symptoms until the plaque severely narrows or totally blocks an artery (NHLBI, 2011, para. 1) causing a medical emergency such as a heart attack or stroke. The symptoms are usually the result of a particular artery being blocked. For instance, if one of the coronary arteries has limited blood flow, the patient may experience chest pain. Moreover, if a carotid artery is blocked, the patient would likely experience changes in cognition. The diagnosis of atherosclerosis is based on several factors including physical exam, symptoms, personal and family history, and a variety of medical tests. One of the main diagnostic tests performed is called the ankle/brachial index (ABI), which compares the blood pressure in the ankle with the blood pressure in the arm. Kunzli et al. explain that a hemodynamically relevant stenosis of the arterial lumen proximal to the distal measurement leads to a decrease in the ABI that correlates well with the severity of the stenosis (2011, p. 339). Ultrasonography is also a form of measurement that has been shown to detect hemodynamic changes in the central vessels of the carotid circulation (Kunzli et al., 2011, p. 339). Other measures of atherosclerosis and arterial wall changes include CIMT, coronary artery

11 SMOG LAKE CITY 11 calcification (CAC), aortic artery calcification (AOC), and retinal vessel diameter. Kunzli et al. (2011) describe measuring the CIMT as the most validated technique for measurement of progression of atherosclerosis (p. 338) in clinical trials. Certain factors that contribute to the progression of atherosclerosis include endothelial dysfunction and inflammation, which are often associated with smoking, hypertension, diabetes, and dyslipidemia. According to Zhao, endothelial vasodilator dysfunction is an initial step in atherosclerosis and is felt to be caused principally by loss of endothelium-derived nitric oxide. Evidence of inflammation in atherosclerotic lesions has been noted from the earliest histologic observations and inflammation is central to understanding the pathogenesis of atherosclerosis. Macrophages that have been modified by oxidized LDL release a variety of inflammatory substances, cytokines, and growth factors (2014, p. 12). Cytokines and C-reactive protein (CRP) are markers of inflammation that are highly associated with atherosclerosis. Brucker et al. (2014) studied cytokines and carotid intima-media thickness (CIMT) with regard to the association between atherosclerosis and taxi drivers who were exposed to air pollution both with and without co-morbidities. This research found that taxi drivers had higher cytokine levels likely causing an increase in CIMT, giving breadth to their hypothesis that chronic exposure to air pollution increases risk of cardiovascular disease. Air Pollution Air pollution is a product of man-made and natural sources that together consist of liquids, gases, and solids in the environment. Harris (2013) explained

12 SMOG LAKE CITY 12 natural sources include pollen from plants, gases and particulate matter from volcanoes and decomposing organic matter, and windblown dust (para. 1). Manmade pollutants come from automobile and industrial emissions, and particles released into the air from erosion and human impact on the environment as well. They are also produced from the burning of fossil fuels most often hydrocarbons, sulfur oxides, nitrogen, carbon monoxide/dioxide and particulate matter. The gases that tend to have higher content in urban regions are methane, carbon monoxide, sulfur dioxide, nitrogen dioxide, ozone, ammonia and hydrogen sulfide (Harris, 2013). Brook and Rajagopalan cite that although both gaseous (e.g., ozone) and particulate pollutants may be linked to problems, the evidence is strongest that the PM fraction poses the greatest risks to the cardiovascular system (2010, p. 291). Each component of air pollution can be further broken down in order to understand its effect on atherogenesis. PM, for example, is defined by its size and composition. The particles can range in size from ultrafine particles (UFPs) only a few nanometers in diameter to coarser particles, which measure up to 10 micrometers in diameter (PM 10 ). PM 10 was the first to be studied by the U.S. government. In early studies on animals, it was found that PM 10 instilled into the lungs for 4 weeks led to greater atherosclerotic burden and a more advanced plaque phenotype (Brook & Rajagopalan, 2010, p. 295). It has been found to be capable of coating and penetrating the tracheobronchial area (Shrey, 2010), whereas fine particulate matter, PM 2.5, is capable of reaching the smaller airways and migrating down into the alveoli. PM 2.5 was the next to be studied in 1997, and was determined to cause cardiovascular (CV) events such as decreased heart rate variability and

13 SMOG LAKE CITY 13 increased blood pressure (Uzoigwe, 2013). Ultra-fine particulate matter, less than PM 0.1, is being researched most currently and seems to have the greatest effect on the cardiovascular system as it is the most easily penetrated into the bloodstream from the terminal alveoli of the airway (Brook & Rajagopalan, 2010). Ozone (O 3 ), which occurs in both natural and man-made forms, is most often formed in the summer from man-made products when radiation from the sun reacts with chemical emissions from traffic, thermal, and industrial plants. O 3, along with PM, has also been shown to correlate with CV events. O 3 reacts in the body to form an inflammatory response resulting in increased oxidative stress, a process associated with CVD. Other mechanisms of CVD correlated with O 3 exposure, noted by Uzoigwe (2013) include altered endothelial function, vascular tone, variations in autonomic control and initiation of systemic inflammatory response. Another major component of air pollution, nitrogen dioxide (NO 2 ), results from vehicular, electric utility and industry emissions, and is also associated with CV mortality. Based on a 2004 study in rats by Takano et al, NO 2 is an atherogenic risk primarily in obese subjects (Uzoigwe, 2013, p. 448). Sulfur dioxide (SO 2 ), another compound, accumulates in outdoor air pollution from the burning of fossil fuels, sulfur fuels, diesel engines and mineral smelting. Uzoigwe et al. found that high levels of SO 2 and ambient total suspended particles have been linked to increased blood viscosity and CVD (2013). Besides NO 2 and SO 2, carbon monoxide (CO), which primarily comes from automobiles in an urban setting, is also correlated with the atherosclerotic process and primarily causes hypoxia secondary to carboxyhemoglobin formation.

14 SMOG LAKE CITY 14 Lastly, carbon disulfide (CS 2 ) is found in ambient air in close proximity to industrial plants manufacturing such products as rayon and cellophane. Uzoigwe et al. noted that studies performed on animals showed the progression of atherosclerosis, enhanced by CS 2 as evidenced by elevated serum cholesterol, phospholipids, and triglycerides (2013, p. 451). With a few contradicting studies showing no actual correlation between the two, it is assumed that there are coronary effects when those that are predisposed to coronary heart disease (CHD) are exposed to CS 2. In addition to the pollutants mentioned above, a few other components of air pollution should be noted, including lead and cigarette smoke. No articles investigating lead and cigarette smoke met our search criteria, so they are not included in our review. Although there are many constituents of air pollution, Brook and Rajagopalan point out that exposure to isolated pollutants rarely occurs in nature. They cite, for example, that the presence of ozone and other gaseous co-pollutants may modulate responses to PM 2.5 and/or UFP inhalation (2010, p. 296). Studying the effect that individual pollutants have on the cardiovascular system is important as well as looking at ambient air pollution as a whole. Epidemiology Epidemiological and observational studies have shown a strong relationship between air pollution and increased cardiovascular morbidity and mortality (Peters & Pope, 2002; Pope et al., 2004; Van Eeden, Leipsic, Man, & Sin, 2012). Quan et al. report that exposure to air pollution and road traffic may increase the risk of acute myocardial infarction and cardiopulmonary mortality, and the associations between air pollution and cardiovascular effects may be particularly strong for vehicle-related

15 SMOG LAKE CITY 15 pollutants (2010, p. 739). Plasma oxidized LDL, a strong clinical indicator of atherosclerosis, was found to be positively correlated with the carbon load of airway macrophages, a marker of chronic exposure to carbon particles derived from burning fossil fuels (p. 4), in a study done by Jacobs et al. (2011). A 2011 study performed by Gerke et al. concluded that although socioeconomic and lifestyle choices cannot be ruled out, individuals living in the center of a city have almost double the risk of having coronary artery calcification compared with those living further away. Dockery et al. recognized an increase in hospitalizations and increased cardiopulmonary disease in the early nineties (1993). They calculated an increased cardiovascular mortality of 1.4% with an increase of fine particulate pollution by every increase in 10 µg/m 3 above minimally accepted values (Dockery, 1993), also showing a correlation between coronary artery disease (CAD) and living proximity to high levels of air pollution. More recently, in a very large cohort study performed in the Netherlands, researchers concluded that long-term exposure to traffic related air pollution may shorten life expectancy (Hoek et al., 2002). Clancy et al. (2002) found a 10.3% decrease in cardiovascular death in Dublin as a result of the coal ban that reduced black smoke concentrations by 70%. Breton et al. (2012) recently reported childhood exposure to O 3 to be associated with increased CIMT in young adulthood, recognizing air pollution to influence the atherogenic process early in life. Although a significant amount of data linking ambient air pollution with increased cardiovascular morbidity, mortality, and hospitalizations exists, the pathophysiological pathways involved are not fully understood. One possible pathway of CVD development secondary to PM exposure is through

16 SMOG LAKE CITY 16 atherogenesis. The first study to find an association of PM exposure with atherosclerosis in human subjects was published in 2005 by Kunzli et al. This crosssectional study included 798 individuals, and showed a 5.9% increase in carotid intima-medial thickness for every 10 µg/m 3 rise in PM 2.5 levels. A cohort study released shortly thereafter in 2007 by Hoffmann et al. reported that long-term residential exposure to high traffic is associated with coronary artery atherosclerosis (p. 495). Hoffmann et al. released another study in 2009 reporting increased systemic inflammatory markers in men associated with long-term residential exposure to high levels of PM 2.5, which might provide a link between air pollution and coronary atherosclerosis (p. 1302). A cross-sectional analysis of the Registre Gironi del Cor: the Gerona Heart Register study (REGICOR Study) was performed to examine whether or not there was an association between long-term exposure to traffic-related air pollution and subclinical atherosclerosis (Rivera et al., 2013). Exposure to trafficrelated air pollution was estimated based on the participant s home average outdoor concentrations of nitrogen dioxide (NO 2 ) and proximity to traffic. Atherogenesis markers were then calculated using ABI and CIMT. Researchers found a positive correlation between long-term, traffic-related air pollution and subclinical atherosclerosis (Rivera et al., 2013). Bauer et al. (2010) studied PM and its relation to subclinical atherosclerosis by assessing long-term exposure to PM and gauging distance to traffic and CIMT using data from the Heinz Nixdorf Recall. The researchers found that the variables mentioned above did in fact increase CIMT, suggesting that exposure to air pollution may lead to subclinical atherosclerosis. As part of the German AIRGENE study, Bruske et al. (2011) reported that the

17 SMOG LAKE CITY 17 accumulation of acute and subacute effects or the chronic exposure to ambient particulate and gaseous air pollution may result in the promotion of atherosclerosis, mediated in part by increased levels of lipoprotein-associated phospholipase A2 and subsequently increased levels of their major pro-atherogenic and pro-inflammatory downstream products (p. 925). Methods In performing our integrative systematic review, we first conducted a search for related literature in GriffinSearch, Westminster College s library search engine that is comprised of common databases including EBSCOhost, MEDLINE, PubMed, CINAHL, Cochrane Library, Health Source, Science Direct, SpringerLink, Biological Sciences Abstracts, BioOne, ACS, and Alt-HealthWatch. Additionally, we searched all relevant and important library-archived materials. Search terms included: atherosclerosis, pollution, air pollution, seasonal air pollution, progression, development, and exacerbation. These key terms were searched in all combinations using Boolean phrases. To include the most current and up-to-date information, the search was limited to articles published in 2009 or later while those published prior to 2009 were included only if they were considered to be a gold standard in the field. All articles found were recorded in a findings table (see Appendix A) and relevant sources were recorded on an evidence table (see Appendix B). Duplicate entries were omitted. After all relevant findings from the database searches had been recorded, the articles were evenly divided between group members for reading and further determination of significance. Exclusion criteria, as determined by the group,

18 SMOG LAKE CITY 18 included any article older than five years unless deemed a gold standard in the field and those studies with p-values of greater than 0.05 for research including p- values. We also excluded research that described subjects who had unrelated comorbidities, like asthma, which might be considered confounding variables in determining air pollution s effect on the cardiovascular system specifically. The evidence was graded based on Brown s evidence grading guidelines, with A1 evidence being from [a] well-designed meta-analysis or well-done systematic review with results that consistently support a specific action (2014, p. 256). Evidence from randomized controlled trials (RCTs) was graded as A2 while findings from evidence-based practice guidelines and quasi-experimental studies were graded B1 and B2 respectively. Evidence from observational studies, including cohort and cross sectional studies, was graded either C1 if the results were consistent, or C2 if the results were inconsistent. Finally, evidence graded D came from expert opinion (Brown, 2014). The included articles cited references were also checked for relevance to our literature review and were incorporated into our evidence table based on inclusion and exclusion criteria and evidence-grading considerations previously defined. Government resources such as the U.S. Department of Health and Human Services, Centers for Disease Control and Prevention (CDC), and Environmental Protection Agency (EPA) were also used in our search. Results Resulting from our literature review, we found that 73 articles met our search criteria, which are explained above in the Methods section of this paper. With

19 SMOG LAKE CITY 19 further investigation we excluded 20 of these articles (see Appendix A) based on poor evidence (inadequate p-value or low-grade evidence), extraneous variables, and/or year published. We will discuss the results of the articles that met the inclusion criteria. Sixteen of the articles were systematic reviews, which are the highest graded level of evidence (A1). Of the 16 systematic reviews that we examined, the majority of them attempted to explain the relationship between air pollution and CVD by exploring the commonly studied pathways of disease development. For example, one systematic review by Shrey et al. (2011) explained the possible effects of ambient particulate matter on the CV system and the possible mechanisms and pathways that can lead to CV damage, such as thrombosis, vascular dysfunction, atherosclerosis, myocardial infarction, and arrhythmia. The authors explain that nanoparticles could possibly have direct effects on vascular endothelium causing local oxidative stress and inflammation, or that PM may indirectly cause CV events through pulmonary oxidative stress and inflammation leading to release of cytokines, CRP, and plasma fibrinogen factor. While some evidence exists to support these pathways as the link between CVD and air pollution, the authors recognize that the exact mechanisms involved are largely unknown and that more research is needed to fully understand the process. Despite a lack of definitive evidence linking air pollution and CVD by a particular pathway, all of the literature reviews recognize a definite relationship between ambient air pollution and the development and progression of CVD, as well as atherogenesis as a possible causative factor. None of the literature reviews we analyzed focused solely on the relationship of atherosclerosis and air pollution.

20 SMOG LAKE CITY 20 The RCTs provided the most consistently strong evidence indicating a link between air pollution exposure and the development of atherosclerosis. We reviewed sixteen RCTs, all of which were studies performed on animals, to examine the effects of various air pollutants on the cardiovascular system. Of the sixteen RCTs we reviewed, all but one supported our assumption that exposure to air pollution is associated with atherosclerosis development and progression. Fifteen of the studies linked exposure of one or more air pollutants to atherosclerosis or factors known to be associated with its development or progression. The single study that did not support our assumption was a study investigating the lipid-lowering medications known as statins in relation to their control of inflammation caused by air pollution. While the study did not directly state that there is a correlation between air pollution and atherosclerosis, the researchers did report decreased inflammatory markers associated with atherosclerosis from the use of statins. Four articles described cross sectional studies, which are graded as evidence level B2. Two of the articles found a positive relationship between increased CIMT and exposure to PM. Both of the other cross sectional studies found increased markers of inflammation and sub-clinical atherosclerosis associated with exposure to air pollution. Twelve of the articles reported the results of cohort studies. Most of the cohort studies found a positive association between air pollution exposure and an increase in inflammatory markers, CIMT, or CAC, which are all associated with atherosclerosis development and progression. Two of the articles reported no significant association between PM exposure and atherosclerosis. One of those

21 SMOG LAKE CITY 21 cohort studies was performed in an area with low levels of ambient air pollution, which does not contradict other research supporting the link between air pollution exposure and CVD development, but only indicates that it is not a major concern in areas with lower levels of air pollution. The literature we have evaluated overwhelmingly indicates that exposure to air pollutants is associated with atherosclerosis. We will now discuss in detail the research regarding individual pollutants and their relationship to CVD and atherosclerosis. Discussion Particulate Matter As discussed above, one of the major components of air pollution that contributes to atherogenesis is PM, also called particle pollution. According to Franchini and Mannucci (2011), PM has the most serious adverse effects due to its wide range of toxic materials such as nitric oxides. PM may have detrimental CV effects via three general pathways: instigation of systemic inflammation and/or oxidative stress, alterations in autonomic balance, and potentially by direct actions upon the vasculature of particle constituents capable of reaching the systemic circulation (Brook, 2008, p. 175). Araujo (2011) also noted these systemic prooxidant and pro-inflammatory effects identified by the detection of biomarkers of oxidative alteration of proteins, lipids and/or DNA in the circulating blood or in products excreted in the urine and increased circulating leukocytes, adipokines and macrophages and increased blood levels of GM-CSF, IL-6, IL-1, stnf-rii, CRP, and scd40l (p. 84). Brook and Rajagopalan report that recent studies have suggested

22 SMOG LAKE CITY 22 that another pathway may also affect atherosclerosis due to PM exposure by stimulating a robust innate immune response. This is typified by the generous presence of macrophages and high levels of inos [inducible nitric oxide synthase] in atherosclerotic plaques in response to PM 2.5 exposure. Chronic ambient exposure to PM 2.5 has also been shown to increase tissue factor expression in macrophages and smooth muscles cells in atherosclerosis (2010, p. 295). Although the pathways that cause PM to have an effect on atherosclerosis is still under review, we are aware that PM of greatest concern are those ten micrometers in diameter or smaller, as they are capable of passing into the body through the respiratory system. PM is typically grouped by size into three categories: the largest, 10 micrometers (µm or microns) in diameter; 2.5 µm particles; and ultrafine or nanoparticles (less than 2.5 µm). Bauer et al. (2010) studied PM and its relation to subclinical atherosclerosis by assessing long-term exposure to PM and gauging distance to traffic and CIMT using data from the Heinz Nixdorf Recall. The researchers found that the variables mentioned above did in fact increase CIMT, suggesting that exposure to air pollution may lead to subclinical atherosclerosis.

23 SMOG LAKE CITY 23 (EPA, 2013) 10 micrometer particles. Components of air pollution that are less than 10 µm, but greater than 2.5 are referred to as inhalable coarse particles (EPA, 2013, para. 3). Some examples of these manmade coarse particles are coal dust, fly ash, wood smoke, diesel soot, asbestos fibers, and roadside particles from tire and brake wear (American Lung Association, 2011, para. 2). One of the first RCTs linking atherosclerosis to PM 10 was published in 2002 by Suwa et al. The authors reported that exposing rabbits to PM 10 caused a systemic inflammatory response, and was associated with progression of atherogenesis in the aorta and coronary arteries. Their analysis of the atherosclerotic process showed more advanced atherosclerotic lesions associated with PM 10 ; such lesions are more vulnerable to rupture, leading to the development of acute coronary events (Suwa et al., 2002). Chen et al. (2013) conducted an RCT that exposed one group of ApoE knockout mice to ambient air (PM 10 and PM 2.5 ) and another to ambient air filtered by a HEPA filter for two

24 SMOG LAKE CITY 24 months. They found that the PM group had substantially higher serum total cholesterol, LDL, tumor necrosis factor-alpha, and CRP, demonstrating that PM exposure could cause systemic inflammation and oxidative stress leading to atherosclerosis. Another study by Tranfield et al. (2010) instilled ambient air pollution (PM < 10 µm in diameter) into the airways of Watanabe heritable hyperlipidemic rabbits and examined their abdominal aortic plaques. They found an increased accumulation of foam cells just below the plaque surfaces and essentially a plaque remodeling, indicating greater plaque endothelial instability, modeling unstable atherosclerotic plaques in humans. A 2011 study by Poursafa et al. found that even in children aged ten to eighteen years old, markers of endothelial dysfunction and a pro-coagulant state (defined by the authors as the presence of increased serum thrombomodulin and tissue factor levels) were present when participants lived in areas with abnormally high ambient PM 10 levels. 2.5 micrometer particles. Particles that are less than 2.5 microns, also called fine particles, are found in nearly all types of combustion including motor vehicles, power plants, residential wood burning, forest fires, agricultural burning, and some industrial processes (AirNow, 2014, para. 2) and are 1/30th the width of a human hair (CDC, 2013a, para. 2). One of the largest human multifaceted studies completed on air pollution and its relation to atherosclerosis are the cohort studies: MESA (Multi-Ethnic Study of Atherosclerosis) and MESA Air (Multi-Ethnic Study of Atherosclerosis and Air Pollution). One subset of the MESA study led by Adar et al. (2013) examined long-term concentrations of PM 2.5 and progression of CIMT as a

25 SMOG LAKE CITY 25 marker of atherosclerosis and found that increased CIMT progression was positively associated with high long-term PM 2.5 concentrations. A MESA Air study investigated vascular responses to short and long-term exposure to fine particulate matter (PM 2.5 ) using ultrasound to measure arterial diameter and flow-mediated dilation of the brachial arteries, as a measurement of vascular endothelial function. This research revealed that long-term exposure to PM 2.5 was significantly linked to compromised endothelial function (Krishnan et al., 2012). This evidence is supported by a 2008 Sun et al. report that exposure of ApoE mice to ambient air PM 2.5 exaggerates atherosclerosis and is associated with increases in tissue factor expression in atherosclerotic plaques (p. 136). A study by Floyd et al. (2009) exposed ApoE mice to concentrated ambient air particles (CAPS) made up of PM 2.5. This study was the first to address molecular alterations induced within atherosclerotic plaques following CAPS exposure. Researchers found 611 altered genes in mice exposed to CAPS versus the control group; many of these alterations are associated with CVD, plaque progression, and plaque rupture. They reported a 57% increase in plaque area with exposure to CAPS. This study provides comprehensive evidence relating CAPS exposure directly to molecular alterations indicative of disease progression within atherosclerotic plaques of ApoE mice (Floyd et al., 2009, p. 402). Many studies have been conducted regarding PM 2.5 and its negative effects on the cardiovascular system. The American Heart Association states that the overall evidence is consistent with a causal relationship between PM 2.5 exposure and cardiovascular morbidity and mortality (Franchini & Mannucci, 2011, p. 2409).

26 SMOG LAKE CITY 26 Ultra-fine or nanoparticles. UFP are less than 0.1 µm in diameter and are especially concerning as they are small enough to pass through the lung tissue into the bloodstream, circulating like the oxygen molecules themselves (American Lung Association, 2013, para. 5). According to Araujo and Nel (2009), ultra-fine particles enhance early atherosclerosis, partly due to their high content in redox cycling chemicals and their ability to synergize with known pro-atherogenic mediators in the promotion of tissue oxidative stress (para. 1). A literature review evaluating the contribution of individual mediators and mechanisms associated with cardiopulmonary toxicity following inhalation of nanoparticles and UFP, reported significant evidence of translocation of UFP and nanoparticles into systemic circulation resulting in increased endothelial dysfunction, oxidative stress, inflammation, coagulation, vasoconstriction, and atherogenic lesion development. The authors report that both the activation of mast cells by nanoparticles and UFP, as well as the inhibition of nitric oxide, are likely mechanisms of inflammation and oxidative stress. They conclude that toxicological studies in rodents support the notion that UFP has greater effect on the CV system, but that it is not likely that one mediator or mechanism is solely responsible for these systemic cardiovascular effects, rather, that these effects are due to multiple contributing factors which are dependent on the physicochemical characteristics of inhaled UFP and NP [nanoparticles] (Shannahan et al., 2012, p. 334). Diesel Exhaust Diesel engine exhaust is made up of a mixture of hundreds of fine particles and gases. Some of the gas constituents include carbon monoxide, oxygen, carbon

27 SMOG LAKE CITY 27 dioxide, nitrogen, sulfur compounds, and low-molecular-weight hydrocarbons like formaldehyde and benzene, which are known carcinogens. Diesel exhaust (DE) particles are both fine and ultrafine particles, and include carbon, organic compounds, sulfates, nitrates, and metals. These particles have large enough surface areas to easily absorb organic compounds, but are small enough to be easily respired into the deep lungs (EPA, 2002). As ambient air pollution is composed of many gases and particles from many sources, DE is a useful model of traffic-related air pollutants, which accounts for up to 90% of the fine particulate mass in ambient air of many major cities (Bai, 2011, p. 185). Epidemiological studies have shown exposure to traffic-related air pollutants as a serious CV risk factor, which makes research of DE particularly helpful in understanding how gases and particulates interact together in the body pathologically. Numerous studies have found that DE has negative effects on both pulmonary and cardiovascular systems. The EPA (2002) recognizes DE as a carcinogen with long-term exposure. Hirano et al. (2003) reported that DE exposure accelerates the progression of atherosclerosis in ApoE mice. A follow-up study that focused on the pathways involved in the development of DE-induced atherosclerosis reported that DE exposure up-regulates inos activity and expression which contributes to the progression of atherosclerosis induced by DE inhalation (Bai et al., 2011, p. 190). A more recent study focused on the particulate portion of DE and its involvement in atherogenesis in ApoE mice. Miller et al. fed ApoE mice a high-fat, western diet for eight weeks in an attempt to induce complex atherosclerotic plaques, with parallel experiments in normal chow fed wild-type mice. Researchers found that

28 SMOG LAKE CITY 28 exposure of the particulate constituents of diesel exhaust increases both the size and complexity of atherosclerotic plaques in vivo, and may therefore increase the susceptibility of plaques to rupture (2013, p. 8). Similarly, Campen et al. studied the effect of inhaled DE on the aortas of ApoE mice and found increasing trends in macrophage accumulation and collagen content, suggesting that plaques were advanced to a more fragile, potentially more vulnerable state (2010, p. 310). In their 2013 study, Yin et al. found that DE emissions induced systemic pro-oxidant effects that led to the development of dysfunctional HDL, and went on to cite that this may be one of the mechanisms by which air pollution contributes to enhanced atherosclerosis (p. 1153). Other Pollutants In addition to PM and DE, there has been substantial research on CV risk associated with CO, oxides of nitrogen (NO 2, NO), SO 2, O 3, sulfates (SO 4 ), nitrates (NO 3 ), and carbon black. Carbon black (CB) is a mimetic of soot-like PM derived from the incomplete combustion of diesel engines (Yamawaki, 2006, p.129). In fact, Wilker et al. (2013) described it as a more specific marker for traffic particles than PM 2.5 (p. 1065). Yamawaki and Iwai treated human umbilical vein endothelial cells with nano-sized particles of CB and found that CB directly affects the endothelium, causing cytotoxic injury, inflammatory responses, and inhibition of cell growth. As EC injury/inflammation and membrane disintegration are related to the initiation of atherosclerosis, the direct effects of nanoparticles on ECs may represent one mechanism behind environmental air pollution-mediated atherosclerosis and ischemic

29 SMOG LAKE CITY 29 heart disease (2006, p. 129). As previously discussed nano-sized particles are able to translocate from the lungs into the blood. It has been hypothesized that nano-sized particles are typically missed by phagocytosing cells in the body, permitting them to be taken up by epithelial and endothelial cells (EC) directly inducing inflammation and cell injury. This may promote thrombosis and atherosclerotic plaque destabilization. Additionally, Wilker et al. found a positive association between [CB] exposure...and subsequent subclinical atherosclerosis measured by CIMT (2013, p. 1065). Lund et al. studied the effects of gasoline engine exhaust on ApoE null mice and found that such exposure to vehicular source air pollutants results in upregulation of circulating and vascular factors associated with progression of atherosclerosis (2009, p. 511), including matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9), and endothelin-1 (ET-1). Recent research seems to indicate that no single pollutant is responsible for inducing atherosclerosis development and progression, but that an interaction of gases and particulates may be responsible. In order to elucidate which signaling pathways are involved in air pollution induced atherosclerosis, Lund et al. performed a follow-up study exposing ApoE mice to DE, gasoline engine emissions (GEE), and mixed emissions (a mixture of GEE and DE), and evaluated them for oxidative stress and lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) expression, which are markers of atherosclerosis and CVD. They found that acute exposure to GEE, DE, and ME all resulted in increased vascular lipid peroxidation and LOX-1 expression, but that ME resulted in more oxidative stress and expression of LOX-1 than GEE or DE

30 SMOG LAKE CITY 30 alone. These results suggest that ME exposure is associated with the expression of factors associated with exacerbation of atherosclerosis (Lund, 2011, p. 86). A similar study exposed ApoE mice to whole combustion emissions (gasoline, diesel, coal, hardwood), biogenically derived secondary organic aerosols (SOAs), or prominent combustion-source gases (NO, NO 2, CO), and then analyzed the aortas. Researchers found that NO and CO alone induced some aspects of vascular response (increased MMP-9 and ET-1 levels), but only vehicular emissions (gasoline and diesel) induced a complex systemic vascular response, including vascular lipid peroxidation, which is a marker for oxidative stress and possibly a promoter of vascular disease (Campen, 2010). Areas for Future Study As research on the relationship between atherosclerosis and air pollution is relatively new, there is a significant need for further research. In regard to scientific research, one of the most respected forms of study is the RCT. There remains, however, a lack of RCTs intentionally exposing humans to air pollutants, which makes a definitive statement of positive correlation difficult. As it would be unethical to perform RCTs of this nature on humans, further epidemiological studies, especially studies that control confounding variables, would greatly benefit researchers, care providers, and the public alike. The EPA has recently funded an analysis of data collected from the MESA cohort, which has focused on the development and progression of atherosclerosis in individuals living in six American cities. Brook and Rajagopalan cite that this study will be capable of providing the most definitive answers to this important issue within the next few years. Other remaining questions,

31 SMOG LAKE CITY 31 such as susceptibility factors, gene-environment interactions, and the responsible air pollutant compounds and sources will also be evaluated (2010, p. 295). Such a study may help further evaluate and explain if other factors such as socioeconomic status and lifestyle factors play into the development of atherosclerosis and its correlation with air pollution. Some research indicates that members of the population most affected by high amounts of particulate matter in the air are those who may be predisposed to respiratory or cardiovascular illness due to conditions like asthma or hyperlipidemia. Exploring the roles of predisposing conditions on the development of atherosclerosis may be helpful in understanding this disease process, especially in relation to the degree of air pollution to which the population is exposed. Another variable of unknown significance is that of population subgroups. For instance, some of the research shows that middle-aged women seem to be at higher risk for developing atherosclerosis after exposure to air pollution than other subgroups. It is known that genetics play a role in the development of atherosclerosis, but it is not clear whether individuals with certain genetic polymorphisms are at greater risk. A literature review by Zanobetti et al. analyzed the available research on geneenvironment interaction and cardiovascular disease. The review remarks that unfortunately, the studies differed substantially in both the cardiovascular outcomes examined and the polymorphisms examined, so there is little confirmation of results across cohorts (2011, p. 349). The most significant finding of their review is that the response to air pollution essentially is only seen in people with unfavorable

32 SMOG LAKE CITY 32 polymorphisms (p. 350). More research is needed to determine the role of genetic susceptibility in CVD development related to air pollution. Another area of research that could be strengthened is that of determining specifically which air pollutants are the most harmful and cause the greatest amount of disease. Additionally, identifying areas with high levels of air pollution, as well as, seasonal variance in air quality could help us more effectively educate patients. Air pollution may be found to be non-specific with a generalized negative impact, but differentiating the consequences of different types of air pollution may play a role in providing better opportunities for CVD prevention. Finally, one area that significantly lacks research is a potential treatment for atherosclerosis derived from air pollution. There has been some promising research suggesting that treatment with statins may reduce plaque formation in blood vessels. As NPs, we would like to see future studies performed identifying specific recommendations for preventing atherosclerosis caused by air pollution based on individual risk factors. Recommendations Although the purpose of this systematic review was to explore whether a connection exists between air pollution and the development of atherosclerosis, our group also reviewed current recommendations to reduce exposure to air pollution published by U.S. government agencies. NPs and other care providers play an essential role in relaying this information and providing specific recommendations to patients, especially to high risk patients who live in heavily polluted areas.

33 SMOG LAKE CITY 33 In Healthy People 2020, a document published by the Office of Disease Prevention and Health Promotion, a division of the U.S. Department of Health and Human Services (USDHHS), the authors establish the nation s promotion and disease prevention aspirations for a ier nation (Fielding et al., 2012, p. 30). This includes addressing environmental quality as a leading indicator (LHI). USDHHS cites that poor air quality is linked to premature death, cancer, and long-term damage to respiratory and cardiovascular systems...globally, nearly 25% of all deaths and the total disease burden can be attributed to environmental factors (2014a, para. 1). According to USDHHS, approximately 127 million people in the United States live in counties that exceed national air quality standards (2014a, para. 2). The USDHHS has officially listed three goals in terms of environmental and outdoor air quality that they hope to achieve by the year 2020 (2014b, p. 1): 1. Reduce the number of days the Air Quality Index (AQI) exceeds 100, weighted by population and AQI 2. Increase use of alternative modes of transportation for work 3. Reduce air toxic emissions to decrease the risk of adverse effects caused by mobile, area, and major sources of airborne toxins According to an LHI progress update published by the USDHHS, preliminary data has shown that the AQI has decreased from a baseline value of in 2008 to in 2011, exceeding the Healthy People 2020 target value of (USDHHS, 2014b, p. 1).

34 SMOG LAKE CITY 34 USDHHS cites recommendations from the Centers for Disease Control and Prevention (CDC), specifically the CDC Recommendations for Improving Health through Transportation Policy. To help improve air quality, the CDC recommendations include (2014, p. 3): Reduce human exposure to transportation-related air pollution and the adverse impacts associated with air pollutants by: o Retrofitting existing diesel vehicles with current pollution control measures to reduce emissions o Requiring effective inspection and maintenance programs for medium- and heavy-duty vehicles o Providing incentives for motor vehicle drivers to purchase vehicles with technologies designed to control pollution and reduce emissions o Strengthening congestion mitigation and air quality programs o Seeking solutions to reduce pollution generated by ports, highvolume roadways and railroads Improve the respiratory and cardiovascular of the U.S. population by improving air quality. Possible strategies include: o Promoting transportation choices and innovative transportation measures that reduce emissions o Shifting to active transportation and public transportation modes o Reducing vehicle miles traveled per capita Support policies that reduce environmental pollution (including greenhouse gas

35 SMOG LAKE CITY 35 emissions) by changing to renewable energy sources, strengthening fuel efficiency policies, and expanding programs that reduce the number of vehicles in the fleet with poor fuel economy. In adhering to these guidelines and in order to provide the best recommendations about air pollution and its connection to atherosclerosis, education should focus on identifying populations at higher risk. The EPA explains that the AQI and air quality forecasts are tools used to determine levels of particulates, O 3, CO, SO 2, and NO 2. The EPA gives advisory recommendations based on the AQI and level of risk. (EPA, 2014) The American Heart Association states that there is no safe threshold of effect [of air pollution] and it has been recommended that patients with cardiovascular diseases, or individuals at risk of developing cardiovascular diseases, such as the elderly or subjects with diabetes or metabolic syndrome, should be educated about the risk of air pollution (Moller et al., 2010, p. 363). The general population should be educated about decreasing their exposure to air pollution by implementing simple interventions such as having air filters in the home, limiting