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P.M. Mannucci et al.
carried out in China documented that there, in the highly polluted urban areas, there was a positive association between PM exposure and coronary artery disease mor- bidity and mortality.50,51 However, the observed effects on health were surprisingly smaller in magnitude per amount of pollution exposure than the corresponding effects in less polluted areas of the Western countries, even though the population-attributable risk fraction is greater in China due to its large population density.52
With regards to air pollution and cerebrovascular dis- eases, a study from South Korea demonstrated an associ- ation with stroke mortality.53 In nine US cities, Wallenius et al.54 observed that, in people aged 65 years or over, an acute PM10 increase of 22 μg/m3 was associated with a 1.03% higher rate of hospital admissions for ischemic stroke. Across 204 US counties, Dominici et al.44 reported a 0.81% increase in hospital admissions due to ischemic cerebrovascular disease per 10 μg/m3 increment of PM2.5 on the same day. Other studies in North America and Europe confirmed the association between increased hos- pital admissions for stroke and elevations of coarse, fine and ultra-fine PM.5,44,56 Finally, a time-series analysis con- ducted from 2000 to 2006 in 75 US cities estimated a 1.03% increase in deaths for CVD, a 1.22% increase for myocardial infarction, and a 1.76% increase for stroke.57
Considering the huge amount of published clinical data on the cardiovascular adverse effects of PM ambient air pollution, several systematic reviews have attempted to summarize these data by performing quantitative analy- ses of pooled data.58-76 We report their main results in Table 1. These confirm that there is a strong association between exposure to periods of high air pollution and car- diovascular morbidity and mortality.58-60,62-68,70-74
Long-term effects
In addition to the short-term effects of relatively short- lasting peaks of exposure to air pollution, there is also robust evidence that annual exposure or exposure over several years increases the risk of cardiovascular morbidi- ty and mortality.6 The large Harvard Six Cities Study (HSCS) was the first to document an association between air pollution and increased general and cardiopulmonary mortality, by means of a 14- to 16-year survival analysis of a population of approximately 8,000 US citizens.77 The extended follow up of the HSCS showed that the relative risk ratio of cardiovascular mortality increased by 1.28 for a 10 μg/m3 rise in PM2.5.78 Positive associations between long-term exposure to air pollutants and all-cause and car- diovascular mortality were confirmed in other prospective studies in the framework of large cohorts from the general population.6 For example, the American Cancer Society (ACS) conducted a study between 1982 and 1989. They linked local ambient air quality to the individual risks of more than 500,000 residents from approximately 150 US cities. They found a 1.17 risk ratio for all-cause mortality in association with increased levels of PM2.5.79 The extend- ed 16-year follow up of the ACS study demonstrated that for each 10 μg/m3 rise in the mean annual PM2.5 concentra- tion there was a 6% increased risk of cardiopulmonary deaths.80 In addition, the multicenter European Study of Cohorts for Air Pollution Effects (ESCAPE) found an increased hazard ratio (HR) of 1.07 for all-cause mortality for a 5 μg/m3 rise in PM2.5.81 Sub-analyses from the ESCAPE cohort showed an association between long-term PM2.5 exposure and the risk of acute coronary events and stroke
(HR: 1.13 and 1.40 for a 5 μg/m3 rise in PM2.5).82,83 More recently, a prospective cohort study from the Netherlands demonstrated that the long-term exposure to ultrafine par- ticles was associated with an increased risk for all incident CVD (HR: 1.18, 95%CI: 1.03-1.34), myocardial infarction (HR: 1.34, 95%CI: 1.00-1.79) and heart failure (HR: 1.76, 95%CI: 1.17-2.66).84 The impact on the cardiovascular sys- tem of long-term exposure to air was also observed in a study from Hong Kong, which demonstrated that, for 10- μg/m3 PM2.5 the increase in the mortality HR of residents was 1.22 (95%CI: 1.08-1.39) for cardiovascular causes, 1.42 (95%CI: 1.16-1.73) for ischemic heart disease, and 1.24 (95%CI: 1.00-1.53) for cerebrovascular disease.85 Taken together, these studies provide unequivocal evi- dence of the positive association between prolonged exposure to particulate air pollution and adverse cardio- vascular events.61,72,75,76
Air pollution and venous thromboembolism
Less is known about the association between air pollu- tion exposure and venous thromboembolism (VTE), the third most frequent CVD.86 Dales et al.87 reported a short- term increase in hospital admissions for venous thrombo- sis and pulmonary embolism in Santiago, Chile, that was proportional to the concentration of particulate and gaseous air pollutants. In Italy, the elevation of coarse (but not finer) PM was associated with more admission rates to the emergency room for venous thromboembolism.88 While some studies documented the long-term associa- tion of airborne pollution and deep vein thrombosis,89 oth- ers found no link,90 making the relationship between VTE and PM exposure still to be determined. Some indirect evi- dence corroborating a positive association comes from a systematic review and meta-analysis by Dentali et al.91 who observed that VTE had a significantly higher inci- dence in winter; a finding that matched the parallel sea- sonal increase in PM. Thus, more studies are needed to clarify whether or not there is a short- and long-term asso- ciation between air pollution and VTE, a concept that is biologically plausible given the systemic hypercoagulable state in both conditions.
Recent striking findings
Until recently, the WHO and the GBD (i.e. the two main sources of data on global mortality, morbidity and disability) were in close agreement on a figure of approxi- mately four million deaths attributed to ambient PM2.5; deaths that could be avoided. Both sources also agreed that CVD is the main cause of death attributed to PM2.5. However, in 2018 and 2019, two studies did estimate a much greater mortality and morbidity burden, both glob- ally and in Europe. These studies used a new and more accurate hazard ratio function of PM2.5 concentration- response. The Global Exposure Mortality Model (GEMM) has a number of advantages over the Integrated Exposure Response (IER) function employed by both the WHO and the GBD. It is based on individual concentration-response data stemming exclusively from exposure to ambient air PM2.5, thereby avoiding sources other than the ambient air that were additional components of the IER (household air, active and passive cigarette smoking). Furthermore, the GEMM was developed by Burnett and 50 other authors8 from the analysis of much larger and more geo- graphically extended individual data, obtained from the PM2.5 concentration–response in 41 cohorts from 16 coun-
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haematologica | 2019; 104(12)