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P.M. Mannucci et al.
dence that PM is an extremely dangerous component for human health so that it may be considered a reliable proxy of the burden of ambient air pollution on morbidity and mortality.7 PM is a complex and heterogeneous mix- ture commonly classified on the basis of size as coarse (aerodynamic diameter <10 μm; PM10), fine (diameter <2.5 μm; PM2.5), or ultrafine (<0.1 μm; PM0.1) fractions.8
Even though there is much evidence on the deleterious impact of air pollution on multiple body organs and sys- tems,6 a recent joint statement from the European Respiratory Society (ERS) and the American Thoracic Society (ATS) identified the cardiovascular system as the main target of air pollution, due, in particular, to PM2.5.9,10 PM2.5 penetrates deep into the lower respiratory tract, escapes host defense and alveolar clearing mechanisms, and may reach the blood stream and organs (including the placenta and the brain) through translocation across bio- logical membranes. Moreover, the large surface of PM2.5 facilitates the adsorption of organic material, heavy metals and other toxic substances, and offers room for oxygen radical generation in the lungs and blood.
The joint ERS/ATS statement is supported by a number of studies that in the last 20-30 years have unequivocally linked air pollution to CVD as the leading cause of global mortality, morbidity and disability.11,12 The most recent report by the Global Burden of Disease (GBD), which pro- vides a source of annually updated, age- and sex-specific global data on all-cause mortality and related risk factors, indicates that at least 19 of the 56 million annual deaths worldwide are attributed to CVD; this is many more than to cancer (9.5 millions) and chronic obstructive pulmonary disease (3.9 millions).1 The same report also estimated that ambient air pollution ranks eighth in a list of 79 mortality risk factors.12 The magnitude of this risk is explained by the pervasive, persistent and unavoidable exposure to air pollution, resulting in a high population-attributable risk fraction.
With this background, we aim to update knowledge on the effects on the cardiovascular system of acute (short- term) and chronic (long-term) exposure to ambient air pol- lution. We also draw attention to new data indicating that the global burden of PM2.5 pollution on mortality and mor- bidity from CVD and other non-communicable diseases is much greater than that previously established by the two major sources of information, i.e. the WHO and the GBD.
Biomechanisms of atherothrombosis associated with air pollution
The biological mechanisms through which air pollution, and particularly the PM2.5 size fraction, influence the occurrence of cardiovascular events are complex, multiple, and interdependent.13,14 Following inhalation, PM2.5 leads to the production of pro-oxidative (i.e. reactive oxygen species) and pro-inflammatory biological mediators (i.e. such cytokines as interleukin-6 and tumor necrosis factor), acute-phase reactants such as C-reactive protein, and vasoactive hormones such as the endothelins. These are produced in the lungs and released into the blood stream and onto the vessel wall.15-17 The secretion of adhesion molecules by the inflamed pulmonary endothelial cells results in binding and activation of leukocytes and platelets, with the generation of tissue factor-bearing microparticles that are hemostatically active and that lead to systemic activation of blood coagulation.18-20 Accordingly, high PM2.5 concentrations are accompanied
by such hypercoagulability biomarkers as high plasma levels of fibrinogen and D-dimer and enhanced thrombin formation.21 Besides the thromboinflammatory activities of PM2.5, another biomechanism of the CVD elicited by PM is the stimulation of the airway sensory nerves, result- ing in the imbalance of the autonomic control of the heart and reduced heart rate variability, a risk factor for sudden death and severe arrythmias.22,23 Experimental data are par- alleled by studies in humans that have shown an inverse relationship between PM exposure and heart rate variabil- ity.24-26 A similar underlying mechanism (i.e. autonomic imbalance affecting vascular tone and reactivity) has been advocated to explain the association between exposure to air pollutants and increased blood pressure.27,28 PM inhibits the production of the endogenous vasodilator nitric oxide, whose reduced bioavailability may contribute to increased blood pressure.29,30 Furthermore, experimental studies have shown that chronic PM exposure leads to the progression of atherosclerotic vascular lesions through pro-inflammatory mechanisms.31 For instance, the intra- tracheal acute administration to hyperlipidemic rabbits of ambient PM1031 and the long-term exposure to PM2.5 of genetically susceptible, apolipoprotein E-deficient mice enhance the growth of atherosclerotic plaques.32 The clin- ical relevance of the atherogenic effects of air pollution was confirmed by studies in humans, showing a positive correlation between the exposure to higher PM levels in the air and the degree of carotid intima-medial thickness and coronary artery calcification.33,34 Figure 1 summarizes the main mechanisms of PM-induced cardiovascular effects that act synergistically in the frame of a multifacto- rial impact on cardiovascular events. Additional mecha- nisms have been advocated although with less robust evi- dence, such as PM-induced activation of the hypothalamic pituitary adrenal axis, epigenomic dysregulation, and per- turbation of the gut microbiome.35
Air pollution and cardiovascular diseases
In the last few years, the assessment of exposure to ambient air pollution has become more and more accurate through the acquisition of satellite data and their integra- tion with ground station measurements. With this back- ground, Rajagopalan et al.11 summarized the degree of evi- dence linking air pollution to different CVD. Most of the well-established evidence concerns all-cause and cardio- vascular mortality, followed by emerging evidence (although this still awaits confirmation) for hypertension, diabetes, non-fatal myocardial infarction, unstable angina, non-fatal stroke, and heart failure, whereas there is still insufficient evidence for venous thromboembolism and atrial fibrillation. Short-term effects of air pollution related to daily or multi-day exposure were methodologically evaluated by means of time-series or case-crossover stud- ies. Evaluation of long-term effects was based upon cohort and crossover studies that captured the population impact of exposure over several years.36 Mechanistically, while short-term exposure mainly causes endothelium-mediat- ed processes (such as impaired vasodilation and coronary vasoconstriction), oxidative stress and thromboinflamma- tion are likely to be the predominant mechanisms for the long-term effects.14,36,37
Short-term effects
The association between the daily and multi-day vari- ability of air pollution and adverse health outcomes was
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haematologica | 2019; 104(12)