CARDIOVASCULAR EFFECTS OF AIR POLLUTANTS
The effects of air pollution on cardiovascular disease is a relative new area of research. Historically, air pollution has not been regarded a significant risk factor for cardiovascular disease, but the World Health Organization estimates that >7 million premature deaths each year can be attributed to urban outdoor and indoor air pollution. Short-term exposure to high levels of particulate matter (PM), especially fine particles of <2.5 µm, has been found to trigger cardiovascular mortality due to myocardial infarction and heart failure. Long-term exposure increases the risk of cardiovascular mortality and reduces life expectancy. Reductions in PM exposure are associated with decreases in mortality. A growing body of evidence has linked PM to increased systemic inflammation, oxidative stress, thrombosis, cardiac ischemia, and heart rate variability. Further investigation of PM and other air pollutants is required to better understand their effects on cardiovascular disease. This will allow development of treatment and optimized prevention strategies in the future.
During the 20th century, three notable extreme air pollution episodes focused the attention of the public and governments on the adverse public health impact of air pollution. These events occurred in the Meuse Valley, Belgium; Donora, Pennsylvania; and London, England, as a consequence of weather conditions that trapped combustion products and other pollutants from coal fires, vehicles, power plants, and industrial emissions in the air. The best known of these events was the Great London smog. In 1952, a cold air inversion trapped combustion products of the entire city of 8.3 million persons and its industry, resulting in an extreme air pollution episode that claimed >10,000 lives. During this event, daily mortality increased nearly fourfold, and the mortality rate remained significantly higher than usual for several weeks after the air pollution event resolved. Surprisingly, the additional deaths that continued to mount were not explained solely by pulmonary disease, but instead most deaths were attributed to cardiovascular etiologies.
These important historical events had a profound impact on local and governmental responses to air pollution and contributed significantly to the passing of the Clean Air Act (CAA) in the United States in 1970, which has been updated and modified several times since. Through the CAA, the U.S. Environmental Protection Agency (EPA) has statutory responsibility to regulate ambient air pollutants, including particulate matter (PM), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), ozone (O3), and lead. The levels of permissible air pollutants are established by the doses at which a measurable health risk is anticipated, allowing for an adequate margin of safety. This risk assessment is based on scientific data updated every 5 years and published as the U.S. National Ambient Air Quality Integrative Science Assessment. Although urban air pollution continues to be a significant challenge, the overall quality of air in the United States has improved continuously since the implementation of the CAA. The improvement in air quality has translated into decreased overall mortality and cardiopulmonary mortality associated with exposure to air pollutants. Yet, despite the remarkable progress made in air quality, health risks of air pollution remain. Intermittent increases in air pollution pose challenges, particularly in vulnerable and sensitive groups, such as older adults, those with low socioeconomic positions, and in individuals with cardiovascular disease, obesity, and diabetes mellitus.
Airborne PM is not a single compound but a mixture of materials that have a carbonaceous core and associated constituents, such as organic compounds, acids, metals, crustal components, and biological materials, including pollen, spores, and endotoxins. Combustion processes, such as those in vehicles and power plants, account for most human-generated PM. Importantly, particles generated by mechanical processes, wind- blown dust, and wildfires also contribute to the mass of PM.
Particles are classified based on their size. Ultrafine particles have an equivalent aerodynamic diameter of <0.1 µm (approximately one one-thousandth the diameter of a human hair). Fine particles (PM2.5) have a diameter of ≤2.5 µm. Coarse particles (PM10) have a diameter between 2.5 and 10 µm. Only particles <10 µm in diameter are respirable (Fig. 18.1). Ultrafine and fine particles are more likely to be produced by combustion, whereas the coarse particles are more likely to contain crustal and biological material. Outdoor PM readily penetrates into homes and buildings, depending on building stock and the use of air conditioning and heating; thus, increases in outdoor PM can result in increased indoor levels of PM. Cooking, smoking, dusting, and vacuuming also contribute to indoor PM, although not much is known about cardiovascular effects induced by exposure to indoor sources of air pollution in the United States. The U.S. national air quality standard for the allowable level of PM2.5 averaged over 24 hours is 35 µg/m3, and the annual average is 12 µg/m3. The standard for PM10 averaged over 24 hours is 150 µg/m3.
|FIG 18.1 Cardiovascular Effects of Air Pollutants. AV, Atrioventricular; CO, carbon monoxide; NO2, nitrogen dioxide; O3, ozone; SA, sinoatrial; SO2, sulfur dioxide.|
Particle size appears to have an impact on the health effects of PM, with PM2.5 having a stronger association with adverse cardiovascular outcomes than that of PM10, presumably due to deeper penetration of fine particles into the lung. PM air pollution, which has the most data for PM2.5, is associated with acute coronary syndrome (unstable angina and myocardial infarction), deep venous thrombosis, rhythm disturbances, stroke, and worsening of heart failure.
The cardiovascular effects associated with PM exposure can be categorized as short-term and long-term. Short-term exposure over a few hours to weeks can trigger cardiovascular disease that can be related to higher mortality and nonfatal events. The strongest evidence is for ischemic heart disease events, especially myocardial infarction and heart failure hospitalizations. Long-term exposure over a few years increases cardiovascular mortality even more than short-term exposure, and decreases life expectancy.
The causal link between inhaled particles depositing on respiratory surfaces and cardiovascular health effects has been a topic of investigation for the past two decades. Exposure to PM can increase heart rate and blood pressure, and can decrease oxygen saturation within hours. PM also affects pulmonary oxygen transport and neural modulation of the sinus node and the vascular system, although the magnitude of these changes is small. An increase in heart rate might be caused by an increase in sympathetic input to the heart or a decrease in parasympathetic input. Exposure to PM decreases cardiac vagal input, as suggested by a decrease in heart rate variability (HRV). Yet, the association between changes in HRV and ambient PM concentrations is inconsistent. Whether the differences relate to the chemical composition of PM, other associated pollutants, age, sex, genetic background, con- current cardiac disease, medications, or the HRV methodology is not known. It is also not known whether change in HRV associated with PM exposure represents an independent measure of risk.
Many epidemiological studies that investigated the associations between air particle pollution and cardiovascular mortality and morbidity in single cities and multiple cities throughout the world showed concordance that ambient air particle pollution is associated with increased cardiovascular mortality and hospitalizations. Two of the most notable studies were the National Morbidity, Mortality and Air Pollution Study and the Air Pollution and Health: A European Approach Project. These studies addressed the effects of air pollution in many U.S. and European cities, and showed that air particle pollution was associated with an increased relative risk of cardiovascular mortality, ranging from 0.4% to 1.5% for each 20 µg/m3 increase in PM10. Likewise, other epidemiological studies linked exposure to PM, particularly traffic-related particles, to the onset of myocardial infarction or hospitalization for acute coronary syndrome, stroke, rhythm disturbances, and heart failure, which were associations that were stronger among individuals with underlying cardiac disease.
Long-term effects of air pollution were established in three important cohort studies: the Harvard Six-Cities Study, the American Cancer Society Study, and the Women’s Health Initiative Observational Study. In contrast to previous studies, these studies investigated the long-term health effects of fine PM for several years in multiple cities, characterized by a large gradient in the concentration and types of air pollution. These studies showed a positive association between PM2.5 and sulfate, and cardiopulmonary mortality and cardiovascular events. Subjects who resided in the most heavily polluted of the Harvard six cities lived on average 2 years less than those who resided in the least polluted city, after potential confounding and effect-modifying factors were taken into consideration.
There are at least three possible mechanisms by which PM induces changes in cardiac physiology: a neural reflex from afferents in the lung that interact with PM directly or indirectly through associated pulmonary inflammation; secondary effects of inflammatory cytokines and acute-phase reactants produced systemically and in the lung, as well as coagulation proteins; and direct effects of particles or adsorbed soluble constituents of PM on cardiac membrane currents responsible for impulse formation and repolarization. The observations that inhalation of fine-particulate air pollution and O3 causes arterial vasoconstriction, and that sympathetic activation reduces endothelium-dependent, flow- mediated vasodilation, provide a mechanistic link between the changes in HRV and the changes in vascular reactivity, which are known risks for cardiac events. Because sudden shifts in neural input to the heart may be arrhythmogenic, changes in HRV imply changes in neural input to the heart as a mechanism of arrhythmia. Such changes would be expected to increase the risk of cardiovascular events secondary to thrombosis and arrhythmias.
The effects of long-term exposure to fine particulate air pollution have been inferred from linking cardiovascular risk factors and estimates of air pollution exposure to the cause of death in epidemiological studies. These observational studies showed that fine particulate air pollution increased the rate of mortality from cardiopulmonary causes. The risk of cardiopulmonary mortality was most strongly associated with fine particles compared with larger particles. Although the mechanisms are unknown, possible explanations of the risks include acceleration of atherosclerosis progression secondary to increased oxidative stress or systemic inflammation, and modulation of factors that enhance coronary plaque instability or electrical instability. Data are emerging that show that PM accelerates atherosclerosis in humans and in animal models of long-term PM exposure, although the effect is probably indirectly mediated through increased inflammation and oxidant stress. For instance, high-sensitivity C-reactive protein (hs-CRP) correlates with cardiac events. The liver produces CRP in response to the cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-α. Measurement of cytokines, and even hs-CRP, may provide a mechanism to assess cardiovascular risk in response to PM exposure. Because of the complexity of the mechanisms that regulate initiation and progression of atherosclerosis, and the complex constituents of PM, proof of a causal effect of PM on the development of atherosclerosis will be a challenge. Yet, the Multi-Ethnic Atherosclerosis Study substudy, MESA Air, did show an association between long-term exposure to PM2.5 and NO2 and coronary artery calcium accumulation.
It is possible that PM has a direct effect on cardiac autonomic function, on cardiac repolarization, or on both, and that PM increases an individual’s susceptibility to myocardial ischemia and to ventricular fibrillation during regional myocardial ischemia. Long-term exposure to air- borne PM might initiate cellular signaling that affects the expression of the cellular proteins that are important to electrical impulse formation and conduction in the heart. Potential protein targets include structural proteins, as well as voltage-gated and ligand-gated channels, and ion exchangers. Thus, cardiac deaths associated with exposure to PM are likely to result from interaction of the direct effects of PM on vascular function, cardiac electrophysiology, autonomic regulation, and/or coronary thrombosis in individuals at high risk for sudden cardiac death.
Exposure to secondhand tobacco smoke is a reasonable model for understanding how exposure to PM mediates changes in the cardio- vascular system and contributes to cardiac events. Acute exposure activates platelets and decreases endothelial function in humans, whereas long-term exposure accelerates the formation of atherosclerosis.
SO2 is a gas produced by coal-burning power plants, smelters, refineries, pulp mills, and food-processing plants. Typical ambient air reactions include formation of sulfuric acid (acid rain) and sulfates. A positive correlation exists between SO2 levels and hospital admissions, the mortality rate in older adults, and the presence of cardiovascular disease. It is often difficult to separate the contributions of individual components of air pollution and to attribute them to health effects. For example, in one study, the total mortality rate was estimated to increase by 5% for each 0.038 parts per million (ppm) increase in SO2; yet, the effects were no longer significant when respirable particles were included in the statistical model. Thus, SO2 is likely to be a surrogate marker of PM because of the common sources of SO2 and PM. The U.S. national air quality standard for the allowable level of SO2 averaged over 1 hour is 75 ppb.
NO2 and nitric oxide (NO) are reactive gases produced by gasoline and diesel fuel combustion, electric power generation, chemical manufacturing, soil emission (including fertilizers), and solid waste disposal. NO2 is also a major indoor air pollutant produced by gas stoves and gas heaters. Both gases are critical components of the photo-oxidation cycle and O3 formation. NO is also produced endogenously at levels that can exceed 1 ppm. It is a mediator and a strong vasodilator and bronchodilator. The ultimate fate of NO2 and NO in ambient air and biological fluids is the formation of nitrite and nitrate.
NO2 is primarily associated with long-term respiratory effects. Children and adults with existing respiratory diseases are at increased respiratory risk from NO2 inhalation. Healthy individuals have shown slightly reduced cardiac output when inhaling NO2 during exercise. Increased levels of NO2 and black carbon are positively associated with arrhythmias. A positive significant association also exists between NO2 and an increased risk of myocardial infarction. Numerous epidemiological studies have linked elevated levels of NO2 to coronary heart disease. Prolonged exposure of coronary heart disease patients to NO2 has been shown to correlate with reduced HRV. Daily exposure to NO2, particularly in older adults, was significantly associated with daily emergency department visits for ischemic heart disease. The U.S. national air quality standard for the allowable level of NO2 averaged over 1 hour is 100 ppb, and averaged over a year is 53 ppb.
CO is produced by combustion. When inhaled, CO binds avidly to hemoglobin, thereby reducing the capacity of blood to deliver oxygen to the tissues. Within tissue, CO may bind to cytochrome P-450, cytochrome oxidase, and myoglobin, which affects intracellular function. Individuals most susceptible to these effects have flow-limiting coronary disease.
A study of the long-term health effects of CO exposure in a comparison of bridge and tunnel workers showed that the relative risk of coronary artery disease was greater in tunnel workers. Prolonged exposure to CO and attendant carboxyhemoglobin (COHb) concentration in excess of 10% increased heart rate, systolic blood pressure, red blood cell mass, and blood volume. CO has been implicated in atherogenesis and in increased risk of myocardial infarction. In general, controlled exposure to CO reduces the time to onset of electrocardiographic evidence of exercise-induced ischemia and angina in individuals with ischemic heart disease, and increases the frequency of ventricular arrhythmias during exercise. These effects occur at COHb levels as low as 2.9%. The baseline COHb in healthy nonsmokers is 0.5% to 1.0%. Prolonged exposure to 9 ppm CO would produce a blood COHb level of approximately 2%. Thus, the U.S. national air quality standards for CO (35 ppm averaged over 1 hour and 9 ppm averaged over 8 hours) should provide protection even for a sensitive population with ischemic heart disease.
O3 is a secondary air pollutant formed in the atmosphere by photo- chemical reactions involving primary pollutants, volatile organic com- pounds, and NOs. The U.S. national ambient air quality standard for ground-level O3 is 0.07 ppm averaged over 8 hours. Exposure to O3 irritates mucous membranes, decreases lung function, increases the reactivity of airways, and causes airway inflammation. Consequently, O3 exposure can cause symptoms of chest pain and decreased exercise capacity. Initial epidemiology studies that showed associations between PM and mortality were not able to reproducibly show similar relationships between O3 and mortality, primarily because there is a close correlation of these two pollutants in many cities. However, several epidemiology studies showed associations between exposure to O3 and increased mortality and morbidity. In one study, an increase in O3 of 21.3 ppb increased the cardiovascular disease mortality rate by 2.5% and the respiratory disease mortality rate by 6.6%; the effect of O3 was independent of that of other pollutants. Whether O3 and PM affect the cardiovascular system by similar or different mechanisms remains unknown.
There are several case-control and retrospective studies that have inves-tigated the association of maternal exposure to air pollution and the risk of congenital heart disease. Each study focused on a different air pollutant. Higher levels of PM2.5 exposure were associated with an increased risk of nonisolated truncus arteriosus, total anomalous pulmonary venous return, coarctation of the aorta, and interrupted aortic arch, as well as any critical isolated and nonisolated congenital heart defect in Florida. The exposure to the 90th percentile of SO2 in Italy was associated with an increased prevalence of congenital heart disease and ventricular septal defects. CO, NO, and black smoke exposure in Northeast England were associated with congenital heart disease. Mechanisms linking air pollution to congenital heart disease remain extremely challenging to study, mainly due to the difficulty in estimating the net effect of environmental pollution in comparison to underlying comorbidities and individual lifestyle factors in pregnant mothers.
WHAT PATIENTS CAN DO TO PROTECT AGAINST CARDIOVASCULAR EFFECTS OF AIR POLLUTION
Patients with heart disease should be made aware of the increased risk associated with exposure to air pollution and educated about strategies to decrease exposure. Patients can reduce their exposure and risk by decreasing their time outdoors when air pollutants are at concentrations believed to impart a health risk and/or by decreasing the intensity of outdoor physical activity. For example, if a patient usually jogs, exercising indoors in an air-conditioned environment can be recommended. If an alternative and acceptable indoor location is not available, one should walk instead of jog. Outdoor PM contributes to indoor PM. When conditions are severe (e.g., wood smoke secondary to a wildfire), activities should be restricted indoors as well, and consideration should be given to using high-efficiency particulate air filter air cleaners to reduce indoor PM levels. PM and NO2 are typically elevated in the morning and afternoon when automotive and truck traffic increases during rush hour commutes. O3 concentration increases in the heat of the day, and therefore, is highest in the midday and in the summer months. In general, patients can reduce exposure by the following: limiting exercise outdoors in the afternoons when air pollutant concentrations are high; exercising indoors or away from roadways; closing doors and windows, and using air conditioning; seeking out air quality reports and forecasts; and using the Air Quality Index (AQI) to guide outdoor activities. The AQI provides a national standard for reporting daily air quality and providing anticipated health effects for the quality reported. The AQI can be reviewed daily in the local media or on the EPA website.