Review Article
Air Pollution Exposure as a Risk Factor for Cardiovascular Disease Morbidity and Mortality Anna Koulova, MD,* and William H. Frishman, MD†
Abstract: There is growing evidence of an association between increasing exposure to air pollutants (both short-term and long-term exposures) and elevated risk of mortality and incidence of cardiovascular diseases in certain high-risk populations and throughout different geographic regions. The pathophysiologic mechanisms of air pollutant–induced cardiovascular morbidity and mortality are actively being studied, with autonomic system dysregulation and inflammatory pathway activation believed to be among the key culprits. Policy changes at the local and global levels are addressing the need for more stringent air pollution standards. These initiatives are projected to lower costs and improve health outcomes. In this review, we examine some major studies of the cardiovascular health impacts of air pollution. Key Words: air pollution, cardiovascular disease, inflammation, health impact (Cardiology in Review 2014;22: 30–36)
elderly, women, and patients with cardiopulmonary comorbidities, to air pollutants.5,17,18 The difficulty in consistently assessing the role of air pollutants in disease may be due to the myriad forms of air pollution found in the environment, ranging from gaseous to inhalable PM. The gaseous offenders are carbon monoxide (CO),18a nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone.19 PM are just as common and are classified according to their aerodynamic diameter into 3 groups (Fig. 1).20,21 This review focuses on the link between air pollutants and cardiovascular diseases (CVDs). We examine epidemiologic studies and discuss the potential role of various pathophysiologic mechanisms in the association of air pollution and CVD. In addition, we summarize the health outcomes of reduced air pollution levels due to action at the national and local levels.
EPIDEMIOLOGICAL STUDIES
T
he health effects of air pollution have been of increasing concern over the past 50 years as methods to measure pollutant concentrations have become more sophisticated, and medical knowledge regarding their potential deleterious effects has grown.1–8b The World Health Organization identifies urban air pollution as an important cause of global mortality, being responsible for an estimated 700,000 premature deaths.9 In the United States alone, data from the Environmental Protection Agency indicate that as many as 60,000 deaths annually are related to particulate air pollution. Longitudinal studies from 1979 through 2000 looking at the mortality data of 500,000 individuals throughout the United States indicate that for every 10-µg/m3 increase in fine particles (particulate matter [PM] 2.5), all-cause mortality increased by 6% annually and cardiopulmonary mortality by 9%.10,11 Other large studies such as the Air Pollution and Health: A Combined European and North American Approach and the US National Morbidity, Mortality and Air Pollution Study examined the concentration-dependent effects of pollution on risk of mortality across all age groups. Stronger associations were observed for the elderly and unemployed than for the general population.12–15 However, despite the reported deleterious effects of air pollution on human health, some large, longitudinal studies, such as the Multiethnic Study of Atherosclerosis, find no significant association between exposure and greater arterial stiffness, a risk factor for atherosclerosis.16 These controversial findings raise questions about the potentially greater susceptibility of specific populations, such as the
From the *Department of Medicine, Mt. Sinai Health System/St. Lukes-Roosevelt Hospital Center, New York, NY; and †Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, NY. The authors have no conflict of interest to report. Correspondence: William H. Frishman, MD, Department of Medicine, New York Medical College, Valhalla, NY 10595. E-mail: [email protected]. © 2013 Lippincott Williams & Wilkins ISSN: 1061-5377/13/2201-0030 DOI: 10.1097/CRD.0000000000000000
30 | www.cardiologyinreview.com
Short-Term Exposure Studies Mustafic et al19 conducted a meta-analysis of studies examining the acute cardiac health effects of many different air pollutants. They found an increased risk of near-term myocardial infarction (MI) with short-term (up to 7 days) exposure to CO, NO2, SO2, PM2.5, and PM10 across all studies. Ozone gas was the only pollutant not significantly linked with an acute cardiac event. Similar trends for cardiovascular-related hospital admissions were shown in large US-based studies.22,23 There is also an association between out-of-hospital cardiac arrest and fine PM, where ozone was a contributing factor.24 The relatively rapid onset of deleterious cardiac effects is reinforced in the single pollutant multivariate analysis by Peters et al.4 In this case cross-over study, the authors found that the risk of MI was associated with elevated concentrations of PM2.5. Specifically, raising PM2.5 levels by 25 µg/m3 in the preceding 2 hours and raising PM2.5 levels by 20 µg/m3 in the 24 hours before the onset of an MI had a significant association with increased risk of an acute cardiac event (odds ratio [OR] 1.48 and OR 1.69 for the 2 time periods, respectively). Further support for the short-term effect of air pollutants is provided by the study of increases in gaseous air pollutants and the risk of MI.3 A 10-µg/m3 concentration of NO2 and CO measured over 0 to 2 days before the occurrence of MI carried an OR of 1.028 [95% confidence interval (CI), 1.005–1.052]. A surrogate for direct measurement of pollutant concentrations is exposure to traffic. Peters et al25 found an association of proximity to traffic and nearterm onset of MI (OR, 2.92; 95% CI, 2.22–3.83; P < 0.001). Indeed, a significant portion of the deleterious effects of air pollutants on cardiovascular function seem to occur within a short time frame of several months. Schwartz time series model suggests that using a time scale of months increases the estimated effects of PM air pollution and accounts for approximately half of the difference between short-term and long-term studies.26
Long-Term Exposure Studies Although short-term studies provide an understanding of acute endpoints, long-term studies may elucidate the cumulative effects of air pollutants on CVD development and progression.26a,26b
Cardiology in Review • Volume 22, Number 1, January/February 2014
Cardiology in Review • Volume 22, Number 1, January/February 2014
Air Pollution & CVD
to 95th percentile difference in the average exposure over 30 years was 1.51 (95% CI, 0.96–2.16) for NO2, 1.22 (0.98–1.52) for CO, 1.39 (0.94–2.07) for PM10, and 1.24 (0.77–2.02) for SO2. NO2 exposure was most highly correlated with out-of-hospital deaths with an OR of 2.17 (1.05–4.51).8 Looking at trends in hospital admissions for residents in New England who were over 65 years of age, Kloog et al30 found that for every 10-µg/m3 increase in PM2.5 exposure over 7 years there is a 4.22% increase in hospitalization (1.06–4.75). However, this study failed to show statistical significance between admitting diagnosis and PM2.5 exposure.
Bipollutant Models
FIGURE 1. Types of particulate air pollutants. Particulate air pollutants are classified according to their aerodynamic diameter. PM100 represent the largest particles. PM10 have a diameter of ≤10 µm and are the result of mechanical crushing and grinding of surfaces. PM2.5 have diameters of ≤2.5 µm and are mainly derived from the combustion of fossil fuels. Fine PM0.1 have diameters of ≤0.1 µm and principally come from soot, acid condensates, and sulfate and nitrate particles from Environment Canada.21 Large, prospective mortality studies such as the Cancer Prevention II Study linked the risk factor data for 1.2 million adults in US metropolitan areas with air pollution levels. Mortality due to coronary artery disease, congestive heart failure, and arrhythmias was most significantly associated with long-term air pollutant exposure. With each subsequent 10-µg/m3 elevation in fine PM, cardiovascular mortality increased between 8% and 18%.27 In a study of long-term exposure (6 years) to PM2.5 in 65,893 postmenopausal women residing in 38 metropolitan areas in the United States,6 the outcomes are even more striking. Each increase in PM2.5 by increments of 10 µg/m3 was associated with a 24% increase in the risk of a cardiovascular event [hazard ratio (HR), 1.24; 95% CI, 1.09–1.41] and 76% increase in the risk of death from CVD (HR, 1.76; 95% CI, 1.25–2.47). HRs were adjusted for age, race, smoking status, educational level, household income, body mass index, and comorbid conditions, such as diabetes, hypertension, and hyperlipidemia.6 Another large cohort of 120,000 subjects was followed up for 20 years in the Netherlands Cohort Study-AIR (NLCS-AIR) study conducted in The Netherlands.2 This was the subset of a larger study on risk factors for lung cancer, but also examined cardiovascular causes of mortality. For a 10-µg/m3 increase in the black smoke concentration, the relative risk (RR) was 1.05 (95% CI, 1.00–1.11) for natural-cause mortality and RR was 1.04 (0.95–1.13) for cardiovascular mortality. For cardiovascular mortality related to increasing traffic density, the RR was 1.05 (0.99–1.12).2 Jerrett et al28 lend further support to the link between traffic exposure and cardiac mortality. Exposure of over 22,000 subjects to the heavily polluted Los Angeles expressways resulted in an RR of 1.2 (1.04–1.39) for cardiopulmonary mortality.28 A subpopulation enrolled in the German Heinz Nixdorf Recall Study also demonstrated a tight association between proximity to a major roadway and the risk of developing coronary artery calcification.29 Similar to studies on traffic pollutant exposure and CVD, a case control study of 45- to 70-year-old subjects living in a Stockholm county in Sweden examined the effects of a variety of gaseous and PM pollutants. The OR for a fatal MI associated with the 5th © 2013 Lippincott Williams & Wilkins
Very few studies have examined possible synergistic effects of air pollutants on cardiovascular health outcomes. The Results of Cardiovascular Risk and Air Pollution in Tuscany Study analyzed the effects of 2 pollutants simultaneously on the risk of acute MI hospitalization. The largest effect was found when examining CO and NO2 (combined OR = 1.004).17
High-Risk Groups Certain populations seem to be more vulnerable to the deleterious effects of air pollution. Nuvolone et al17 found that elderly persons (age ≥75 years), females, and older patients with hypertension and chronic obstructive pulmonary disease were at greater risk for acute MI associated with short-term exposure to air pollutants. In particular, females were found to be at an increased risk (OR, 1.025; 95% CI, 1.003–1.047). Data from the Nurses Health Study demonstrated similarly increased health risks for women.5 Each 10-μg/m3 elevation of PM2.5 exposure in the previous 12 months was associated with an increased risk of all-cause mortality (HR, 1.26; 95% CI, 1.02‒1.54) and fatal CHD (HR, 2.02; 95% CI, 1.07‒3.78) after controlling for known risk factors.5 Patients with preexisting CAD were also found to be at increased risk for acute ischemic events (unstable angina or MI) when compared with healthy subjects, with increases in PM2.5 concentration.18 In addition, elderly patients who were exposed to ambient levels of black carbon (a measure of traffic-related particulate air pollution) were at greater risk for developing postexercise –0.1 mm ST-segment depression (P = 0.02 for 12-hour mean black carbon; P = 0.001 for 5-hour black carbon).31 In another study, patients who had experienced ventricular arrhythmia episodes were at increased risk for recurring arrhythmias within 3 days of exposure to rising air pollutant levels of PM2.5, black carbon, SO2, CO, and NO2, suggesting that people with preexisting cardiovascular conditions are more vulnerable to the deleterious health effects of air pollution.32 A study of patients who had been previously hospitalized for coronary artery disease points to the same conclusion. Patients who after discharge from the hospital had spent more time in or near traffic and with higher exposures to black carbon demonstrated increased T-wave alternans, indicating greater cardiac electrical instability and a higher risk for complications.33
THE AFTERMATH OF DISASTERS Human destruction or natural disasters result in the release of large amounts of chemicals into the air, which have acute or chronic effects on the local community. The aftermath of the 9/11 World Trade Center attacks provides such an example. Chemical analysis of the debris reveals that very coarse PM (
Air Pollution Exposure as a Risk Factor for Cardiovascular Disease Morbidity and Mortality Anna Koulova, MD,* and William H. Frishman, MD†
Abstract: There is growing evidence of an association between increasing exposure to air pollutants (both short-term and long-term exposures) and elevated risk of mortality and incidence of cardiovascular diseases in certain high-risk populations and throughout different geographic regions. The pathophysiologic mechanisms of air pollutant–induced cardiovascular morbidity and mortality are actively being studied, with autonomic system dysregulation and inflammatory pathway activation believed to be among the key culprits. Policy changes at the local and global levels are addressing the need for more stringent air pollution standards. These initiatives are projected to lower costs and improve health outcomes. In this review, we examine some major studies of the cardiovascular health impacts of air pollution. Key Words: air pollution, cardiovascular disease, inflammation, health impact (Cardiology in Review 2014;22: 30–36)
elderly, women, and patients with cardiopulmonary comorbidities, to air pollutants.5,17,18 The difficulty in consistently assessing the role of air pollutants in disease may be due to the myriad forms of air pollution found in the environment, ranging from gaseous to inhalable PM. The gaseous offenders are carbon monoxide (CO),18a nitrogen dioxide (NO2), sulfur dioxide (SO2), and ozone.19 PM are just as common and are classified according to their aerodynamic diameter into 3 groups (Fig. 1).20,21 This review focuses on the link between air pollutants and cardiovascular diseases (CVDs). We examine epidemiologic studies and discuss the potential role of various pathophysiologic mechanisms in the association of air pollution and CVD. In addition, we summarize the health outcomes of reduced air pollution levels due to action at the national and local levels.
EPIDEMIOLOGICAL STUDIES
T
he health effects of air pollution have been of increasing concern over the past 50 years as methods to measure pollutant concentrations have become more sophisticated, and medical knowledge regarding their potential deleterious effects has grown.1–8b The World Health Organization identifies urban air pollution as an important cause of global mortality, being responsible for an estimated 700,000 premature deaths.9 In the United States alone, data from the Environmental Protection Agency indicate that as many as 60,000 deaths annually are related to particulate air pollution. Longitudinal studies from 1979 through 2000 looking at the mortality data of 500,000 individuals throughout the United States indicate that for every 10-µg/m3 increase in fine particles (particulate matter [PM] 2.5), all-cause mortality increased by 6% annually and cardiopulmonary mortality by 9%.10,11 Other large studies such as the Air Pollution and Health: A Combined European and North American Approach and the US National Morbidity, Mortality and Air Pollution Study examined the concentration-dependent effects of pollution on risk of mortality across all age groups. Stronger associations were observed for the elderly and unemployed than for the general population.12–15 However, despite the reported deleterious effects of air pollution on human health, some large, longitudinal studies, such as the Multiethnic Study of Atherosclerosis, find no significant association between exposure and greater arterial stiffness, a risk factor for atherosclerosis.16 These controversial findings raise questions about the potentially greater susceptibility of specific populations, such as the
From the *Department of Medicine, Mt. Sinai Health System/St. Lukes-Roosevelt Hospital Center, New York, NY; and †Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, NY. The authors have no conflict of interest to report. Correspondence: William H. Frishman, MD, Department of Medicine, New York Medical College, Valhalla, NY 10595. E-mail: [email protected]. © 2013 Lippincott Williams & Wilkins ISSN: 1061-5377/13/2201-0030 DOI: 10.1097/CRD.0000000000000000
30 | www.cardiologyinreview.com
Short-Term Exposure Studies Mustafic et al19 conducted a meta-analysis of studies examining the acute cardiac health effects of many different air pollutants. They found an increased risk of near-term myocardial infarction (MI) with short-term (up to 7 days) exposure to CO, NO2, SO2, PM2.5, and PM10 across all studies. Ozone gas was the only pollutant not significantly linked with an acute cardiac event. Similar trends for cardiovascular-related hospital admissions were shown in large US-based studies.22,23 There is also an association between out-of-hospital cardiac arrest and fine PM, where ozone was a contributing factor.24 The relatively rapid onset of deleterious cardiac effects is reinforced in the single pollutant multivariate analysis by Peters et al.4 In this case cross-over study, the authors found that the risk of MI was associated with elevated concentrations of PM2.5. Specifically, raising PM2.5 levels by 25 µg/m3 in the preceding 2 hours and raising PM2.5 levels by 20 µg/m3 in the 24 hours before the onset of an MI had a significant association with increased risk of an acute cardiac event (odds ratio [OR] 1.48 and OR 1.69 for the 2 time periods, respectively). Further support for the short-term effect of air pollutants is provided by the study of increases in gaseous air pollutants and the risk of MI.3 A 10-µg/m3 concentration of NO2 and CO measured over 0 to 2 days before the occurrence of MI carried an OR of 1.028 [95% confidence interval (CI), 1.005–1.052]. A surrogate for direct measurement of pollutant concentrations is exposure to traffic. Peters et al25 found an association of proximity to traffic and nearterm onset of MI (OR, 2.92; 95% CI, 2.22–3.83; P < 0.001). Indeed, a significant portion of the deleterious effects of air pollutants on cardiovascular function seem to occur within a short time frame of several months. Schwartz time series model suggests that using a time scale of months increases the estimated effects of PM air pollution and accounts for approximately half of the difference between short-term and long-term studies.26
Long-Term Exposure Studies Although short-term studies provide an understanding of acute endpoints, long-term studies may elucidate the cumulative effects of air pollutants on CVD development and progression.26a,26b
Cardiology in Review • Volume 22, Number 1, January/February 2014
Cardiology in Review • Volume 22, Number 1, January/February 2014
Air Pollution & CVD
to 95th percentile difference in the average exposure over 30 years was 1.51 (95% CI, 0.96–2.16) for NO2, 1.22 (0.98–1.52) for CO, 1.39 (0.94–2.07) for PM10, and 1.24 (0.77–2.02) for SO2. NO2 exposure was most highly correlated with out-of-hospital deaths with an OR of 2.17 (1.05–4.51).8 Looking at trends in hospital admissions for residents in New England who were over 65 years of age, Kloog et al30 found that for every 10-µg/m3 increase in PM2.5 exposure over 7 years there is a 4.22% increase in hospitalization (1.06–4.75). However, this study failed to show statistical significance between admitting diagnosis and PM2.5 exposure.
Bipollutant Models
FIGURE 1. Types of particulate air pollutants. Particulate air pollutants are classified according to their aerodynamic diameter. PM100 represent the largest particles. PM10 have a diameter of ≤10 µm and are the result of mechanical crushing and grinding of surfaces. PM2.5 have diameters of ≤2.5 µm and are mainly derived from the combustion of fossil fuels. Fine PM0.1 have diameters of ≤0.1 µm and principally come from soot, acid condensates, and sulfate and nitrate particles from Environment Canada.21 Large, prospective mortality studies such as the Cancer Prevention II Study linked the risk factor data for 1.2 million adults in US metropolitan areas with air pollution levels. Mortality due to coronary artery disease, congestive heart failure, and arrhythmias was most significantly associated with long-term air pollutant exposure. With each subsequent 10-µg/m3 elevation in fine PM, cardiovascular mortality increased between 8% and 18%.27 In a study of long-term exposure (6 years) to PM2.5 in 65,893 postmenopausal women residing in 38 metropolitan areas in the United States,6 the outcomes are even more striking. Each increase in PM2.5 by increments of 10 µg/m3 was associated with a 24% increase in the risk of a cardiovascular event [hazard ratio (HR), 1.24; 95% CI, 1.09–1.41] and 76% increase in the risk of death from CVD (HR, 1.76; 95% CI, 1.25–2.47). HRs were adjusted for age, race, smoking status, educational level, household income, body mass index, and comorbid conditions, such as diabetes, hypertension, and hyperlipidemia.6 Another large cohort of 120,000 subjects was followed up for 20 years in the Netherlands Cohort Study-AIR (NLCS-AIR) study conducted in The Netherlands.2 This was the subset of a larger study on risk factors for lung cancer, but also examined cardiovascular causes of mortality. For a 10-µg/m3 increase in the black smoke concentration, the relative risk (RR) was 1.05 (95% CI, 1.00–1.11) for natural-cause mortality and RR was 1.04 (0.95–1.13) for cardiovascular mortality. For cardiovascular mortality related to increasing traffic density, the RR was 1.05 (0.99–1.12).2 Jerrett et al28 lend further support to the link between traffic exposure and cardiac mortality. Exposure of over 22,000 subjects to the heavily polluted Los Angeles expressways resulted in an RR of 1.2 (1.04–1.39) for cardiopulmonary mortality.28 A subpopulation enrolled in the German Heinz Nixdorf Recall Study also demonstrated a tight association between proximity to a major roadway and the risk of developing coronary artery calcification.29 Similar to studies on traffic pollutant exposure and CVD, a case control study of 45- to 70-year-old subjects living in a Stockholm county in Sweden examined the effects of a variety of gaseous and PM pollutants. The OR for a fatal MI associated with the 5th © 2013 Lippincott Williams & Wilkins
Very few studies have examined possible synergistic effects of air pollutants on cardiovascular health outcomes. The Results of Cardiovascular Risk and Air Pollution in Tuscany Study analyzed the effects of 2 pollutants simultaneously on the risk of acute MI hospitalization. The largest effect was found when examining CO and NO2 (combined OR = 1.004).17
High-Risk Groups Certain populations seem to be more vulnerable to the deleterious effects of air pollution. Nuvolone et al17 found that elderly persons (age ≥75 years), females, and older patients with hypertension and chronic obstructive pulmonary disease were at greater risk for acute MI associated with short-term exposure to air pollutants. In particular, females were found to be at an increased risk (OR, 1.025; 95% CI, 1.003–1.047). Data from the Nurses Health Study demonstrated similarly increased health risks for women.5 Each 10-μg/m3 elevation of PM2.5 exposure in the previous 12 months was associated with an increased risk of all-cause mortality (HR, 1.26; 95% CI, 1.02‒1.54) and fatal CHD (HR, 2.02; 95% CI, 1.07‒3.78) after controlling for known risk factors.5 Patients with preexisting CAD were also found to be at increased risk for acute ischemic events (unstable angina or MI) when compared with healthy subjects, with increases in PM2.5 concentration.18 In addition, elderly patients who were exposed to ambient levels of black carbon (a measure of traffic-related particulate air pollution) were at greater risk for developing postexercise –0.1 mm ST-segment depression (P = 0.02 for 12-hour mean black carbon; P = 0.001 for 5-hour black carbon).31 In another study, patients who had experienced ventricular arrhythmia episodes were at increased risk for recurring arrhythmias within 3 days of exposure to rising air pollutant levels of PM2.5, black carbon, SO2, CO, and NO2, suggesting that people with preexisting cardiovascular conditions are more vulnerable to the deleterious health effects of air pollution.32 A study of patients who had been previously hospitalized for coronary artery disease points to the same conclusion. Patients who after discharge from the hospital had spent more time in or near traffic and with higher exposures to black carbon demonstrated increased T-wave alternans, indicating greater cardiac electrical instability and a higher risk for complications.33
THE AFTERMATH OF DISASTERS Human destruction or natural disasters result in the release of large amounts of chemicals into the air, which have acute or chronic effects on the local community. The aftermath of the 9/11 World Trade Center attacks provides such an example. Chemical analysis of the debris reveals that very coarse PM (
