Clinical Review: The Robust Association Between Air Pollutants and Stroke

In 2015, exposure to air pollution contributed to 6.5 million deaths and 167.3 million disability-adjusted life years. In emerging economies, air pollution is ranked in the top 5 of mortality risk factors.¹ However, as research published in the Journal of Stroke¹ pointed out, there is limited awareness regarding the relationship between air pollution and negative effects on the cardiovascular system.

The link between negative respiratory effects and air pollution is intuitive, noted Kuan Ken Lee, MD, of the BHF Centre for Cardiovascular Science at the University of Edinburgh, and colleagues.¹ However, recent research has shown a “robust association” between pollution and myocardial infarction, heart failure, and stroke.¹

Stroke Burden: An Overview

Across the globe, the burden of stroke is significant but highly variable. “Over the past 20 years, high-income countries have experienced a significant decline in age-standardized mortality and [disability-adjusted life year] rates of approximately 20% to 40%,” Dr. Lee and colleagues wrote.¹ “Conversely, the vast majority of strokes (approximately 85%) now occur in [low- and medium-income countries].”

In January 2019, the World Health Organization recognized air pollution as “the greatest environmental risk to health.”² Microscopic pollutants — including airborne particulate matter (PM), ozone, sulphur dioxide, carbon monoxide, nitrogen dioxide, and nitrogen oxide — represent the greatest risk to human health.¹

“Crucially, air pollution differs from other modifiable risk factors [for cardiovascular disease] because exposure to air pollution, for the large majority of people, is unavoidable,” Dr. Lee and colleagues noted. “[E]ven though the individual risk estimates for exposure to air pollution are relatively small compared to other cardiovascular risk factors…the overall population attributable risk and subsequent burden is significant.”¹

Research Challenges

The biological mechanisms driving the association between air pollutants and stroke are complex and require further evaluation.¹ Simplified in vitro studies of neurons, astrocytes, and microglia have shown that exposure to PM resulted in increased susceptibility to oxygen and glucose depravation, synaptic function alteration, and upregulation in inflammatory cytokines.¹ Additional human exposure studies have found that air pollution reduces endothelial function, increases resting cerebrovascular resistance and lowers cerebral blood flow velocity. Furthermore, pollution increases platelet activation and thrombus formation in damaged blood vessels.¹

A study review published in the Journal of Toxicology³ found that air pollution affects the central nervous system “through a variety of cellular, molecular, and inflammatory pathways” that damage brain structures or predispose those who are exposed to neurological diseases. Fine PM and nanoparticles trigger the release of soluble inflammatory mediators within the body, which then rapidly enter the circulatory system and have the potential to directly affect the vascular system.³

“[O]nly preliminary findings are available on the effects of airborne pollutants on the [central nervous system],” noted Sermin Genc, MD, PhD, of the department of Neuroscience, Health and Science Institute at Dokuz Eylul University in Izmir, Turkey, and colleagues. A comparison of study results is difficult due to variations in the types of pollutants measured, different genetic backgrounds of included populations, and variable exposure to environmental conditions.³ However, despite these challenges, investigators have successfully demonstrated a positive correlation between airborne pollution and stroke mortality rates.³

Nanoparticles are of particular concern, due to their size and ability to traverse the alveolar-capillary barrier, enter systemic circulation, and directly affect both vascular and circulating blood cells.¹ However, studying nanoparticle translocation in humans is difficult as it is rife with logistical and technical challenges.¹

Stroke Risk Factors

Harm resulting from air pollution exposure is 2-factor: exposure and toxicity.¹ Smaller particles, Dr. Lee and colleagues noted, can more deeply penetrate the lung and access a larger reactive surface area. Therefore, epidemiological studies have found that the association between PM_2.5 and cardiovascular disease is “more marked and consistent” than PM₁₀.¹

Inflammation, oxidative stress, and lipid modification. Urban PM exposure has been linked to pulmonary inflammation, elevated circulating leucocyte levels, and inflammatory cytokines — including tumor necrosis factor-alpha, interleukin-1, interleukin-6, C-reactive protein, and fibrinogen.¹ Inhaled particles activate local inflammatory responses, resulting in the spillover of inflammatory mediators into systemic circulation and effects on the cardiovascular system.¹

These inflammatory pathways work in tandem with oxidative stress.¹ In particular, diesel exhaust particles impair endothelium-dependent vasodilation, decrease endothelial nitrogen oxide bioavailability and oxidize low-density lipoprotein, leading to the release of highly oxidized phospholipids.¹ These particles increase plasma lipoprotein-associated phospholipase A2, an independent risk factor for stroke.¹

Translocation of nanoparticles. As previously indicated, nanoparticle translocation can affect cardiovascular function. In vitro studies have indicated that combustion-derived nanoparticles, in particular, “activate a proinflammatory response in endothelial cells.”¹ The behavior of these nanoparticles, including upregulation of adhesion molecule expression on endothelial cell surfaces, is “a crucial step during the initiating events of atherosclerosis.”¹

Autonomic dysfunction. Both inhaled particles and the resulting pulmonary inflammation can trigger changes in autonomic functioning, resulting in “altered cardiovascular homeostasis.”¹ According to Dr. Lee and colleagues, “extensive evidence” exists demonstrating reductions in multiple heart rate variability parameters following exposure to PM_2.5.¹ Heart rate variability, a known marker of cardiac autonomic dysfunction, has been credited as a possible mechanism contributing to the relationship between air pollution and cardioembolic stroke.¹

Age and gender. Age and gender may also play a role in the risk for stroke.³ One study, published in the New England Journal of Medicine,⁴ evaluated 65,893 women who were postmenopausal and without previous cardiovascular disease and found a 10 mg increase per cubic meter of PM_2.5 correlated with a 35% increased risk of stroke (95% CI, 8%-68%) and an 83% increase in stroke mortality (95% CI, 11%-200%).

Looking Forward: Possible Interventions

Despite the considerable burden and concerns surrounding air pollution and human health, a “vast majority” of countries do not meet acceptable air quality standards.¹

“Of particular concern are findings that the strength of this association is stronger in low- and middle-income countries where air pollution is projected to rise as a result of rapid industrialization,” investigators noted.¹

One avenue to combat the negative effects of industrialized air pollution, as suggested by Dr. Lee and colleagues, is the using national early warning systems, incorporating real-time PM_2.5 concentrations, and using public health policy to create substantive change.

“Air pollution should be recognized more widely as one of the most important modifiable risk factors for the prevention and management of cardiovascular disease,” Dr. Lee and colleagues concluded. “Healthcare professionals will have an important role in promoting the awareness of this evidence, not just to improve the care of individual patients, but also to place pressure on policy makers for air pollution to be a public health priority.”¹

References

1. Lee KK, Miller MR, Shah ASV. Air pollution and stroke. J Stroke. 2018;20(1):2-11.
2. World Health Organization. Ten threats to global health in 2019.  https://www.who.int/emergencies/ten-threats-to-global-health-in-2019. Accessed June 28, 2019.
3. Genc S, Zadeoglulari Z, Fuss SH, Genc K. The adverse effects of air pollution on the nervous system. J Toxicol. 2012;2012:782462
4. Miller KA, Siscovick DS, Sheppard L, et al. Long-term exposure to air pollution and incidence of cardiovascular events in women. N Engl J Med. 2007;356(5):447-458.