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Evidence accumulated over >50 years of epidemiological and clinical research has established the adverse effects of air pollution on human health.1 2 These studies have formed the basis for legislation to regulate the sources of atmospheric air pollution and to limit the effects of specific air pollutants on both public health and the environment. Efforts to introduce more stringent targets and further improve air quality have been met by legal challenge from industrial groups,3 and therefore understanding the role of individual pollutants is essential to guide effective legislation and public health policy.
Potentially harmful air pollutants include particulate matter, carbon monoxide, nitrogen dioxide, sulfur dioxide, volatile organic compounds and ozone. Acute exposure to fine particulate matter (PM2.5) has been linked to a range of adverse cardiovascular events including acute myocardial infarction and heart failure, with long-term exposure increasing the lifetime risk of death from coronary heart disease.4 While the effects of fine particulate air pollution on morbidity and mortality are incontrovertible, the impact of other potentially harmful pollutants on cardiovascular health is less certain. In this issue of Heart, Henrotin et al (see page 1990) investigate the effect of short-term ozone exposure on cerebral and cardiac ischaemic events.5
Ozone as a secondary atmospheric pollutant
Ozone is a highly reactive colourless gas that is formed in the stratosphere by the action of solar radiation on molecular oxygen. The ozone layer protects the earth's atmosphere from high-energy ultraviolet radiation. Ground level ozone, however, is a ubiquitous and potentially harmful atmospheric pollutant formed when sunlight reacts with nitrogen oxides and hydrocarbons generated from the combustion of fossil fuels.
Controlled studies have demonstrated that exposure to ozone at atmospherically relevant concentrations depletes airways' antioxidants, increases lung inflammation and results in transient bronchial hyper-reactivity and decrements in lung function.6 These observations may explain the association between ambient ozone levels and increased hospital admissions for asthma, or impaired lung development in children. However, it is not immediately apparent how ozone would affect cardiovascular health given that ozone rapidly reacts on contact with the airways' epithelium and cannot directly diffuse into the circulation.
Ozone exposure and cardiovascular disease
Several studies have evaluated the effects of ozone on cardiovascular morbidity and mortality, but the findings from these studies have been inconsistent and a consensus has not been reached.7 Most air pollutants tend to be highly correlated with one another because they have common sources. However, ozone is the exception, and as a secondary pollutant is variably correlated with primary emissions depending on the time of year and prevailing meteorological conditions. Levels are lower in the cool winter months, due to scavenging by nitric oxide from vehicle emissions, and higher in warm sunny weather because of increased photochemistry.
A reanalysis of the American Cancer Society study compared the long-term health effects of exposure to ozone with PM2.5 in almost 500 000 persons.8 This analysis confirmed an independent association between fine particles and cardiovascular mortality, but found that after adjustment for PM2.5, ozone was associated solely with an elevated risk of death due to respiratory causes. A recent systematic review found little evidence that short-term fluctuations in ozone concentrations increased the risk of myocardial infarction.9 In contrast, a small number of studies have reported potentially important associations between ozone and admission to hospital with transient ischaemic attacks or stroke.10–12
Henrotin et al performed a case–control study to assess the effects of ozone on incident and recurrent ischaemic events over a 7-year period within the conurbation of Dijon in the south of France. They report that a 10 μg/m3 increase in ozone concentration was associated with an 11% (95% CI 3% to 21%) increase in recurrent ischaemic cerebrovascular events. The association between ozone and recurrent stroke was strongest when levels increased 3 days prior to admission. Consistent with previous studies, ozone exposure was not associated with acute myocardial infarction over the same period. Surprisingly, ozone was not associated with incident cerebrovascular events despite there being three- to four-fold more incident than recurrent events, raising the possibility that the association with recurrent stroke may have simply been a spurious finding. Alternatively, it may be that the mechanism through which ozone precipitates recurrent stroke is dependent on the existence of a previously ruptured or vulnerable plaque.
One of the challenges for case–control studies of this type is to ensure adequate adjustment for the effects of co-pollutants and other environmental variables. The authors carefully adjusted for temperature and humidity, in addition to a number of other potential confounders, and performed sensitivity analysis suggesting that the association between ozone and recurrent ischaemic events persisted even after adjustment for particular matter and other gaseous pollutants. While it remains possible that this observation is due to residual confounding, a number of factors suggest that the association is real. First, the association with recurrent stroke is consistent whether maximal (hourly) or mean (daily) ozone concentration is used as the exposure variable. Secondly, the authors report a dose response, with the risk of recurrent events being greatest during periods when ozone levels are highest. Thirdly, the association is stronger in high-risk individuals with multiple risk factors for recurrent plaque rupture or thrombosis, suggesting that the hypothesis is biologically plausible.
How might ozone effect the cardiovascular system?
Controlled exposures to air pollutants can help address some of the uncertainty that is inherent to observational studies and provide insight into the mechanisms involved.
As ozone does not readily penetrate the respiratory tract lining fluid, it seems likely that any extrapulmonary effects of exposure are mediated via the generation of lipid peroxidation products and secondary reactive oxygen species. To date, few experimental or clinical studies have assessed the effects of ozone on systemic oxidative stress or the cardiovascular system.
In healthy persons, exposure to ozone with concentrated ambient particles resulted in acute arterial vasoconstriction13 and transient increases in diastolic blood pressure.14 Experimental studies in rodents suggest that recurrent exposure to ozone induces sustained effects on blood pressure through mitochondrial damage, upregulation of vascular F2-isoprostane and nitrotyrosine levels, and perturbation of endothelium-dependent vascular function.15 Given that hypertension is a dominant risk factor for stroke, it is plausible that small changes in blood pressure or vascular tone may conceivably precipitate acute ischaemic events. Interestingly, subsequent human exposure studies suggest that ozone only alters blood pressure in the presence of fine particles.3 16 Ozone is known to potentiate the proinflammatory effects of diesel exhaust particles in the lungs17 and may play a similar role in augmenting the adverse cardiovascular effects of fine particles.
In a recent update to the American Heart Association statement on air pollution and cardiovascular disease, the authors conclude that a causal relationship exists between fine particulate air pollution and cardiovascular morbidity and mortality, and as such particulate air pollution should be considered a modifiable cardiovascular risk factor. While observational studies suggest the same may be true for ozone with respect to cerebrovascular disease, more experimental and clinical data are required to determine the underlying mechanisms and the role of fine particles before we can conclude that reducing ozone concentrations will have similar benefits. The paper by Henrotin and colleagues provides a further valuable addition to this ongoing scientific and public health debate.
Linked articles 200337.
Funding NLM is supported by an Intermediate Clinical Research Fellowship (FS/10/026/28266) from the British Heart Foundation, and is co-applicant on a British Heart Foundation Programme Grant examining the cardiovascular effects of air pollution (RG/10/9/28286).
Competing interests None.
Patient consent Obtained.
Provenance and peer review Commissioned; not externally peer reviewed.
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