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1、Novel evidence for a greater burden of ambient air pollution on cardiovascular diseaseby Pier Mannuccio Mannucci,Sergio Harari,and Massimo FranchiniHaematologica 2019 Epub ahead of printCitation:Pier Mannuccio Mannucci,Sergio Harari,and Massimo Franchini.Novel evidence for a greater burden of ambien
2、t air pollution on cardiovascular disease.Haematologica.2019;104:xxxdoi:10.3324/haematol.2019.225086Publishers Disclaimer.E-publishing ahead of print is increasingly important for the rapid dissemination of science.Haematologica is,therefore,E-publishing PDF files of an early version of manuscripts
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4、rs final approval;the final version of the manuscript will thenappear in print on a regular issue of the journal.All legal disclaimers that apply to thejournal also pertain to this production process.Copyright 2019 Ferrata Storti Foundation.Published Ahead of Print on October 31,2019,as doi:10.3324/
5、haematol.2019.225086.haematologica|2019;104(12)12019 Ferrata Storti FoundationMaterial published in Haematologica is covered by copyright.All rights are reserved to the Ferrata Storti Foundation.Use ofpublished material is allowed under the following terms andconditions:https:/creativecommons.org/li
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7、or com-mercial purposes is not allowed without permission in writingfrom the publisher.Correspondence:PIER MANNUCCIO MANNUCCIpiermannuccio.mannuccipoliclinico.mi.itHaematologica 2019Volume 104(12):1-9doi:10.3324/haematol.2019.225086Check the online version for the most updatedinformation on this art
8、icle,online supplements,and information on authorship&disclosures:www.haematologica.org/content/104/12/1Ambient and household air pollution is a major health problem world-wide,contributing annually to approximately seven million of all-cause avoidable deaths,shorter life expectancy,and significant
9、directand indirect costs for the community.Air pollution is a complex mixture ofgaseous and particulate materials that vary depending on their source andphysicochemical features.Each material has detrimental effects on humanhealth,but a number of experimental and clinical studies have shown astrong
10、impact for fine particulate matter(PM2.5).In particular,there is moreand more evidence that PM2.5exerts adverse effects particularly on the car-diovascular system,contributing substantially(mainly through mecha-nisms of atherosclerosis,thrombosis and inflammation)to coronary arteryand cerebrovascula
11、r disease,but also to heart failure,hypertension,diabetesand cardiac arrhythmias.In this review,we summarize knowledge on themechanisms and magnitude of the cardiovascular adverse effects of short-and long-term exposure to ambient air pollution,particularly for the PM2.5size fraction.We also emphasi
12、ze that very recent data indicate that theglobal mortality and morbidity burden of cardiovascular disease associatedwith this air pollutant is dramatically greater than what has been thoughtup to now.Novel evidence for a greater burden of ambient air pollution on cardiovascular diseasePier Mannuccio
13、 Mannucci,1Sergio Harari,2and Massimo Franchini31Scientific Direction,IRCCS Ca Granda Maggiore Policlinico Hospital Foundation,Milan;2Department of Pneumology and Semi-Intensive Care Unit,Department of RespiratoryPhysiopathology and Pulmonary Hemodynamics,Ospedale San Giuseppe MultiMedica,Milan and
14、3Department of Haematology and Transfusion Medicine,Carlo Poma Hospital,Mantua,ItalyABSTRACTFerrata Storti FoundationReceived:April 18,2019.Accepted:June 19,2019.Pre-published:October 31,2019.IntroductionPollution of the ambient(outdoor)and household(indoor)air is recognized asone of the main risk f
15、actors for premature death,morbidity and disability-adjustedlife-years,leading to significant direct and indirect costs for the community.1-3TheWorld Health Organization(WHO)warns us that globally ambient and householdair is dangerously polluted for nine out of ten people,leading every year to at le
16、astseven million avoidable deaths,3,4mainly from such atherothrombotic cardiovascu-lar diseases(CVD)as coronary artery and cerebrovascular disease,but also to othernon-communicable diseases such as cancer and chronic obstructive pulmonary dis-ease.5,6Diseases associated with air pollution are respon
17、sible for three times morepremature deaths than AIDS,tuberculosis and malaria combined,and 15 timesmore than all wars and other violent causes.The air pollutome is a complex mixture of gases(nitrogen oxides,ozone,sulfurdioxide,ammonia and carbon monoxide),volatile droplets(quinones and poly-cyclic a
18、romatic hydrocarbons),and primary and secondary particulate matter(PM).Secondary PM forms in the air from primary precursors such as nitrogen dioxide,sulphur dioxide,ammonia,and volatile organic components.The physicochemicalcomposition of air pollution varies,depending on environmental factors such
19、 asgeographical and meteorological conditions and the prevailing sources,i.e.indus-trial activity,agriculture,and road,sea and air traffic.7Fossil fuel combustion is amajor source of ambient air pollution,whereas burning of biomass used for cook-ing and heating is the most important source of househ
20、old air pollution,particu-larly in low-and middle-income countries.There is robust epidemiological evi-dence that PM is an extremely dangerous component for human health so that itREVIEW ARTICLEmay be considered a reliable proxy of the burden of ambi-ent air pollution on morbidity and mortality.7PM
21、is a com-plex and heterogeneous mixture commonly classified onthe basis of size as coarse(aerodynamic diameter 10 m;PM10),fine(diameter 2.5 m;PM2.5),or ultrafine(0.1m;PM0.1)fractions.8Even though there is much evidence on the deleteriousimpact of air pollution on multiple body organs and sys-tems,6a
22、 recent joint statement from the EuropeanRespiratory Society(ERS)and the American ThoracicSociety(ATS)identified the cardiovascular system as themain target of air pollution,due,in particular,to PM2.5.9,10PM2.5penetrates deep into the lower respiratory tract,escapes host defense and alveolar clearin
23、g mechanisms,and may reach the blood stream and organs(including theplacenta and the brain)through translocation across bio-logical membranes.Moreover,the large surface of PM2.5facilitates the adsorption of organic material,heavy metalsand other toxic substances,and offers room for oxygenradical gen
24、eration in the lungs and blood.The joint ERS/ATS statement is supported by a numberof studies that in the last 20-30 years have unequivocallylinked air pollution to CVD as the leading cause of globalmortality,morbidity and disability.11,12The most recentreport by the Global Burden of Disease(GBD),wh
25、ich pro-vides a source of annually updated,age-and sex-specificglobal data on all-cause mortality and related risk factors,indicates that at least 19 of the 56 million annual deathsworldwide are attributed to CVD;this is many more thanto cancer(9.5 millions)and chronic obstructive pulmonarydisease(3
26、.9 millions).1The same report also estimated thatambient air pollution ranks eighth in a list of 79 mortalityrisk factors.12The magnitude of this risk is explained bythe pervasive,persistent and unavoidable exposure to airpollution,resulting in a high population-attributable riskfraction.With this b
27、ackground,we aim to update knowledge onthe 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 thatthe global burden of PM2.5pollution on mortality and mor-bidity from CVD and other non-commun
28、icable diseases ismuch greater than that previously established by the twomajor sources of information,i.e.the WHO and the GBD.Biomechanisms of atherothrombosis associated withair pollution The biological mechanisms through which air pollution,and particularly the PM2.5size fraction,influence theocc
29、urrence of cardiovascular events are complex,multiple,and interdependent.13,14Following inhalation,PM2.5leads tothe production of pro-oxidative(i.e.reactive oxygenspecies)and pro-inflammatory biological mediators(i.e.such cytokines as interleukin-6 and tumor necrosis factor),acute-phase reactants su
30、ch as C-reactive protein,andvasoactive hormones such as the endothelins.These areproduced in the lungs and released into the blood streamand onto the vessel wall.15-17The secretion of adhesionmolecules by the inflamed pulmonary endothelial cellsresults in binding and activation of leukocytes andplat
31、elets,with the generation of tissue factor-bearingmicroparticles that are hemostatically active and that leadto systemic activation of blood coagulation.18-20Accordingly,high PM2.5concentrations are accompaniedby such hypercoagulability biomarkers as high plasmalevels of fibrinogen and D-dimer and e
32、nhanced thrombinformation.21Besides the thromboinflammatory activitiesof PM2.5,another biomechanism of the CVD elicited byPM is the stimulation of the airway sensory nerves,result-ing in the imbalance of the autonomic control of the heartand reduced heart rate variability,a risk factor for suddendea
33、th and severe arrythmias.22,23Experimental data are par-alleled by studies in humans that have shown an inverserelationship between PM exposure and heart rate variabil-ity.24-26A similar underlying mechanism(i.e.autonomicimbalance affecting vascular tone and reactivity)has beenadvocated to explain t
34、he association between exposure toair pollutants and increased blood pressure.27,28PM inhibitsthe production of the endogenous vasodilator nitric oxide,whose reduced bioavailability may contribute toincreased blood pressure.29,30Furthermore,experimentalstudies have shown that chronic PM exposure lea
35、ds to theprogression of atherosclerotic vascular lesions throughpro-inflammatory mechanisms.31For instance,the intra-tracheal acute administration to hyperlipidemic rabbits ofambient PM1031and the long-term exposure to PM2.5ofgenetically susceptible,apolipoprotein E-deficient miceenhance the growth
36、of atherosclerotic plaques.32The clin-ical relevance of the atherogenic effects of air pollutionwas confirmed by studies in humans,showing a positivecorrelation between the exposure to higher PM levels inthe air and the degree of carotid intima-medial thicknessand coronary artery calcification.33,34
37、Figure 1 summarizesthe main mechanisms of PM-induced cardiovasculareffects 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 hypothalamicpituit
38、ary adrenal axis,epigenomic dysregulation,and per-turbation of the gut microbiome.35Air pollution and cardiovascular diseasesIn the last few years,the assessment of exposure toambient air pollution has become more and more accuratethrough the acquisition of satellite data and their integra-tion with
39、 ground station measurements.With this back-ground,Rajagopalan et al.11summarized the degree of evi-dence linking air pollution to different CVD.Most of thewell-established evidence concerns all-cause and cardio-vascular mortality,followed by emerging evidence(although this still awaits confirmation
40、)for hypertension,diabetes,non-fatal myocardial infarction,unstable angina,non-fatal stroke,and heart failure,whereas there is stillinsufficient evidence for venous thromboembolism andatrial fibrillation.Short-term effects of air pollution relatedto daily or multi-day exposure were methodologicallye
41、valuated by means of time-series or case-crossover stud-ies.Evaluation of long-term effects was based upon cohortand crossover studies that captured the population impactof exposure over several years.36Mechanistically,whileshort-term exposure mainly causes endothelium-mediat-ed processes(such as im
42、paired vasodilation and coronaryvasoconstriction),oxidative stress and thromboinflamma-tion are likely to be the predominant mechanisms for thelong-term effects.14,36,37Short-term effectsThe association between the daily and multi-day vari-ability of air pollution and adverse health outcomes wasesta
43、blished in the first half of the last century.The smogP.M.Mannucci et al.2haematologica|2019;104(12)accidents in the Meuse Valley(Belgium,1930),Donora(Pennsylvania,1948),and London(UK,1952)causedpeaks of increased hospitalization and deaths and it wasthese that first established a link between acute
44、 exposureto air pollution and adverse cardiopulmonary events.38,39Since then,a large number of additional studies have eval-uated the effects of PM on daily and multi-day changes incardiovascular morbidity and mortality.Data from 50 million people living in the 20 largesturban areas of the USA(the N
45、ational Morbidity,Mortalityand Air Pollution Study;NMMAPS)showed that,for each10 g/m3rise in PM10recorded on the day before death,there was a 0.68%increase in cardiopulmonary mortali-ty.40In Europe,the Air Pollution and Health EuropeanApproach(APHEA-2)study of 43 million people living in29 large cit
46、ies estimated a 0.76%increase in cardiovascu-lar deaths for each 10 g/m3rise in PM10.41These data areconsistent with those of the Meta-analysis of ItalianStudies on the Short-term Effects of Air Pollution(MISA).42In addition,the multi-city Air Pollution and HealthEuropean and North American Approach
47、(APHENA)showed that a 10 g/m3acute rise in PM10was associatedwith 0.2-0.6%higher total mortality,with similar effectson cardiovascular mortality.43Other studies chose to analyze the short-term cardio-vascular effects of air pollution in terms of morbidity(i.e.ischemic heart disease,arrhythmias and h
48、eart failure).Forinstance,in a US population over 65 years of age hospitaladmissions due to heart failure showed a 1.28%increasein risk for each 10 g/m3PM2.5rise registered on the sameday.44Wellenius et al.,45who from 1986 to 1999 analyzedthe association between PM air pollution and hospitaladmissio
49、ns for heart failure in seven US cities,found thata 10 g/m3rise in PM10was accompanied by a 0.7%increase on the same day in the rate of admissions.In theframework of the Intermountain Heart CollaborativeStudy(IHCS),a 10 g/m3increase in short-term exposureto fine PM was associated with a 4.5%increase
50、 in the riskof acute coronary events.46The association between traf-fic-related air pollution and acute myocardial infarction isalso supported by the European Health Effects of AirPollution among Susceptible Subpopulations(HEAPSS)study.47Two more recent multicenter studies conducted incities in the