Cardiovascular Effects of Air Pollutants

History

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 (SO ₂ ) _, nitrogen dioxide (NO ₂ ), carbon monoxide (CO), ozone (O ₃ ), 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.

Particulate Matter

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, windblown 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 (PM _2.5 ) have a diameter of ≤2.5 µm. Coarse particles (PM ₁₀ ) 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 PM _2.5 averaged over 24 hours is 35 µg/m ³ , and the annual average is 12 µg/m ³ . The standard for PM ₁₀ averaged over 24 hours is 150 µg/m ³ .

Particle size appears to have an impact on the health effects of PM, with PM _2.5 having a stronger association with adverse cardiovascular outcomes than that of PM ₁₀ , presumably due to deeper penetration of fine particles into the lung. PM air pollution, which has the most data for PM _2.5 , 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, concurrent 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/m ³ increase in PM ₁₀ . 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 PM _2.5 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 O ₃ 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 PM _2.5 and NO ₂ 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 airborne 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 cardiovascular 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.