Air pollution and cardiovascular diseases

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RevistaPortuguesadeCardiologia41(2022)709---717

www.revportcardiol.org

Revista Portuguesa de

Cardiologia

Portuguese Journal of Cardiology

GUIDELINES

Air pollution and cardiovascular diseases: A position paper

Daniel Caldeira

^a^,^b^,^c^,^d^,∗

, Fátima Franco

^a^,^e

, Sérgio Bravo Baptista

^a^,^f^,^g

, Soﬁa Cabral

^a^,^h^,ⁱ^,^j

, Maria do Carmo Cachulo

^a^,^k

, Hélder Dores

^a^,^l^,^m

, António Peixeiro

^a^,ⁿ

,

Rui Rodrigues

^a^,^h^,ⁱ^,^j

, Mário Santos

^a^,^h^,ⁱ^,^j

, Ana Teresa Timóteo

^a^,^m^,^o

, João Vasconcelos

^p^,^q

, Lino Gonc ¸alves

^a^,^k

aSociedadePortuguesadeCardiologia,Lisboa,Portugal

bServic¸odeCardiologia,HospitalUniversitáriodeSantaMaria---CHULN,Portugal

cCardiovascularPharmacologyandTherapeuticsUnit,CentroCardiovasculardaUniversidadedeLisboa(CCUL@RISE),CAML, FaculdadedeMedicina,UniversidadedeLisboa,Portugal

dLaboratoryofClinicalPharmacologyandTherapeutics,FaculdadedeMedicinadaUniversidadedeLisboa,Portugal

eUnidadeTratamentoICAvanc¸ada(UTICA),Servic¸odeCardiologia,CentroHospitalarUniversitáriodeCoimbra,Coimbra, Portugal

fHospitalProf.DoutorFernandodaFonseca,EPE,CardiologyDepartment,Amadora,Portugal

gCentroCardiovasculardaUniversidadedeLisboa(CCUL@RISE),CAML,FaculdadedeMedicina,UniversidadedeLisboa,Portugal

hDepartmentofCardiology,CentroHospitalarUniversitáriodoPorto,Porto,Portugal

iUMIB-UnidadeMultidisciplinardeInvestigac¸ãoBiomédica,ICBAS-InstitutodeCiênciasBiomédicasAbelSalazar,Universidade doPorto,Porto,Portugal

jITR-LaboratoryforIntegrativeandTranslationalResearchinPopulationHealth,Porto,Portugal

kCentroHospitalareUniversitáriodeCoimbra,ICBR-FacultyofMedicine,UniversityofCoimbra,Coimbra,Portugal

lHospitaldaLuz,Lisbon,Portugal

mNOVAMedicalSchool,Lisbon,Portugal

nServic¸odeCardiologia,CentroHospitalareUniversitáriodaCovadaBeira(CHUCB)Covilhã,Portugal

oServic¸odeCardiologia,HospitalSantaMarta,CentroHospitalarUniversitárioLisboaCentral,Lisboa,Portugal

pUniversidadedeLisboa,InstitutodeGeograﬁaeOrdenamentodoTerritório(CentrodeEstudosGeográﬁcos),Portugal

qInstitutoPolitécnicodeLeiria,Portugal Received10May2022;accepted17May2022

KEYWORDS Airpollution;

Cardiovascular disease;

Ischemicheart disease;

Abstract Airpollutionisoneofthemainenvironmentalriskfactorsforhealthandislinked tocardiovasculardiseases,whicharetheleadingcauseofmortalityworldwide.

In thisposition paper,we discuss themain airpollutants andhow they canpromote the developmentofcardiovasculardiseaseorcardiovascularevents.Wealsosummarisethemain evidencesupporting the association between air pollution andcardiovascular events, such ascoronaryevents (acutecoronarysyndromes/myocardialinfarction; chroniccoronary syndromes),stroke,heartfailureandmortality.Somerecommendationsaremadebasedonthese dataandtheEuropeanSocietyofCardiologyguidelinesoncardiovasculardiseaseprevention,

∗Correspondingauthor.

E-mailaddress:dgcaldeira@hotmail.com(D.Caldeira).

https://doi.org/10.1016/j.repc.2022.05.006

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D.Caldeira,F.Franco,S.BravoBaptistaetal.

Cerebrovascular disease;

Burdenofdisease

acknowledgingthatitisimportanttoincreaseawarenessandliteracyonthistopicinPortugal.

PALAVRAS-CHAVE Poluic¸ãodoar;

Doenc¸a cardiovascular;

Doenc¸acardíaca isquémica;

Doenc¸a

cerebrovascular;

Cargadadoenc¸a

Poluiçãodoaredoençascardiovasculares:documentodeposição

Resumo Apoluic¸ãodoaréumdosprincipaisfatoresderiscoambientalparaasaúdeeestá associadaàprincipalcausademorteemtodoomundoquesãoasdoenc¸ascardiovasculares.

Nestepositionpaperdiscutimosaformacomoosprincipaispoluentesatmosféricospodempro- moverodesenvolvimentodedoençasoueventoscardiovasculares.Tambémagregámosamelhor evidência quesuporta aassociação entrepoluição do are eventos cardiovasculares,como eventoscoronários(síndromescoronáriasagudas/enfartedomiocárdio;síndromescoronárias crónicas),acidentevascularcerebral,insuficiênciacardíacaeoriscodemorte.Foramfeitas recomendaçõesdeacordocomaevidência,osdadosnacionaiseasorientaçõesdaSociedade Europeia deCardiologia sobreprevençãode doenças cardiovasculares,reconhecendoque é importanteaumentarasensibilizaçãoeliteraciasobreestetemaemPortugal.

Introduction

Cardiovascular diseases (CVDs) are the leading cause of mortality worldwide according to World Health Organiza- tion(WHO)data.¹In2019,approximately19millionpeople diedduetocardiovascular(CV)causes,themajoritydueto myocardialinfarctionandstroke.CVDsaccountforapproxi- matelyonethirdofallprematuredeaths,beforetheageof 70,duetononcommunicablediseases.Expectedly,ischemic heartdiseaseandstrokeweretheno-communicableleading causesofdiseaseburdenin2019.²

The risk for CVdisease derivesfrom genetics,lifestyle andenvironmentalfactors.CVDssharesomemodiﬁablerisk factors that can be addressed individually such as smoking, sedentarism, unhealthy dietary habits, hypertension, dyslipidemia,diabetes,andobesity.Oneenvironmentalrisk factorthatisunavoidableformostpeopleispollution.

Pollutionexistsinmanyformssuchasairpollution,soil pollution, water pollution, noise pollution, among other types. Air pollution is the single biggest environmental health risk factor, including cardiovascular risk and its importanceneedstobehighlightedastheriskofdeathisat leastsimilartothatofexposuretosmoking.^3---5

Air pollution

Airpollutionisthecontaminationoftheindoororoutdoor environmentbyany chemical,physicalor biologicalagent that modiﬁes the natural characteristics of the air.¹ Usu- allytheconceptofairpollutionreferstoacombinationof heterogeneousand complex ﬂuids, gases,and particulate matter(PM).⁶

Themainsourceofindoorairpollutionvariesgeograph- icallybutcomesessentiallyfromcookingandheatingusing

inefficientfuels and/or the use of traditional stoves, but alsofrom the use of consumerproducts suchas cleaning surface pesticides and solvents, among other sources.^7,8 Outdoor air pollutionderives fromroad traffic, emissions fromindustries,agricultural,trashorwildfireandreleased indoorpollution.

Thecomponentsofairpollutionthoughttobeinvolved in cardiovascular risk are nitrogen dioxide (NO2), carbon monoxide(CO),andsulfurdioxide(SO2),aswellasPM,and otherssuchasozone(O3)orvolatileorganiccompounds.⁹

Particulate matter (PM) is classiﬁed in three groups according to the particles size: Coarse particles (PM10, diameter<10and≥2.5␮m),ﬁneparticles(PM2.5,diameter

<2.5␮m),andultraﬁneparticles(<0.1␮m).

Themain sourceofPMisroadtrafﬁc;theemittedpar- ticlescan reachthe respiratoryairways.The likelihoodof reaching the distal airways increases the smaller the PM is. Airborne PM can result fromdirect emissions into the atmosphereor can be theresultof a reaction withother substances in the atmosphere. Combustion processes are themainsourceofprimaryparticleemissionintotheatmo- sphere,whileroadtrafﬁcistheprimarycauseofemissions inurbanareas.¹⁰

Sulfurdioxide(SO2)isgenerallyproducedfromtheburn- ingoffossilfuelssuchascoalandoiland thesmeltingof mineralores,includingaluminum, copper, zinc,lead,and iron,whichcontainsulfur.Industrialfacilitiesandmaritime transportarethemainsourcesofSO2emissions.Roadtrafﬁc (mainlyfromdieselvehicles)isthemainsourceofNO2.^11,12 Ozone is formed through a photochemical reaction involving sunlight and gaseous precursors such as NO2 or volatileorganic compounds,which canexplainwhy ozone pollutiontypicallyoccursonwarmandsunnydays.^12,13

In Portugal, road trafﬁc and industries are the main sourceofpollutants,butseasonallytheforestwildﬁresare

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RevistaPortuguesadeCardiologia41(2022)709---717 other relevant sources of air pollution. The main pollu-

tantsresultingfrombiomassburningareCO,NO2,SO2and PM. According to the WHO, exposure to smoke fromfor- estﬁres,particularlytosuspendedPM,hasbeenassociated withrespiratoryandcardiovasculardiseases,andevenwith increasedmortality.¹⁴

Regardingindoorenvironment,second-handsmokeisthe majorsourceofairpollution,globally.InEurope,outdoorPM 2.5insidepenetrationviaairexchangeisalsoamajorfactor responsibleforindoorpollution.¹⁵

Pathophysiology of the cardiovascular effects of air pollution

Therearethreepossiblemechanismsthatexplainthecar- diovasculareffectsofairpollutionwhicharenotmutually exclusive:1)Lunginﬂammationwithsystemicinﬂammatory andoxidativemediators;2)Translocationofparticleswith vasculardeposition;3)Autonomicnervoussystemdysregu- lation.

Regarding the inflammatory/oxidative hypothesis, it is knownthatcommonairpollutants,suchasNO2,O3andPM arepro-oxidant. Exposuretothese inhaled pollutants can lead to oxidative stress, through different cellularmech- anisms, suchasthe uncouplingof nitricoxidesynthetase, mitochondrial dysfunction and formation of reactive oxy- gen species.¹⁶ Prolonged exposure to this pollutants can leadtoachroniclow-levelinflammationinthelungs¹⁷ and theprocesscanextendsystemically.¹⁸ Systemicinflamma- tory mediators can influence the atherosclerotic process, which, in theworst-case scenario,can leadto rupture of plaquesandsubsequentacutecoronaryorcerebrovascular syndromes.^19---22

Some small pollutant particles can cross the alveolar- capillarymembrane andcirculate intheblood influencing thecardiovascularsystemdirectly.²³ PMexposureislinked toabnormalactivationofthehemostaticsystem,leadingto apro-coagulantandantifibrinolyticstate.^19,24,25Exposureto airpollutantsalsoinducessomeendothelialinjuries,lead- ingtoanincreaseofendothelialcellapoptosis,adecreased circulating level of endothelial progenitor cells and tight junctionproteindegradation.^6,26,27AfterPMinhalation,we observeariseininterleukin-6,whichleadstoincreasedfib- rinogen,factorVIIIandtissuefactorrelease.^19,21Adisrupted endothelialcellbarrier,anincreaseincoagulationfactors, areductioninfibrinolyticcapacityandplateletactivation, all represent plausible pathophysiological mechanisms to promotethrombusformation.^28,29Recentstudiesalsoshow thatinhalednanoparticlescangointosystemiccirculation andaccumulateincommonsitesofatherosclerosis;adirect toxicinteractionisplausible.³⁰

Inhaled pollutants activate alveolar receptors that may also inﬂuence autonomic nervous system, impair- ing autonomic balance and favoring sympathetic over parasympathetictone.Autonomicbalanceimpairmentmay contribute to increased cardiovascular risk through the inductionofpro-hypertensivevasoconstrictionandthepre- dispositiontoarrhythmias.^31,32

Review of the evidence for the association between air pollution and cardiovascular events

In order to review the association between air pollution and cardiovascular events, a search was performed in MEDLINEtoretrievethemainreviewsandconsensusdocu- mentstoidentifyaggregatedevidenceinsystematicreviews usingthe keywords ‘‘air pollution’’,‘‘coronary disease’’,

‘‘myocardialinfarction’’, ‘‘stroke’’,‘‘heart failure’’.The authors selected publications based on when they were updatedandtheirrepresentativeness.

The six systematic reviews included were published between 2013 and 2020 and focused on long- and short- term effects of air pollutants on cardiovascular diseases (CVD).12,16,33---36 Their main characteristics are shown in Table1.Allreviewsevaluatedlong-termexposure,except forShahetal.thatassessedtheeffectofshort-termexpo- suretoambientair pollutiononCVD.³⁶ One review(Hoek etal.) focusedontheeffectofPM,fourreviewsassessed PMandnitrogenoxides,^12,33---35 andShahetal.studiedthe effectofPM,NO2andotherairpollutants(SO2,CO,O3)in cardiovascularoutcomes.

Hoek etal.showedthat witha10 mcg/m³increase in PM2.5,overallmortalityincreasedby6%andcardiovascular mortalityby11%.¹⁶All-causemortalitywasalsoraisedwith anincreasedexposuretoelementalcarbonandNO2.¹⁶

Cesaroni et al. focused on the association between long-term exposure to PM and NO2 and the incidence of acute coronary events in 11 cohorts participating in the European Study of Cohorts for Air Pollution Effects (ESCAPE project).The authors observeda positive associ- ationbetweenlong-termexposuretoPMandtheincidence ofcoronaryevents.³³

Stafoggia etal.assessed theeffectof long-term exposure to PM withinthe 11 cohorts included in the ESCAPE project.Theauthorsfound apositiveassociationbetween long-termexposuretoPM2.5andstrokeincidenceespecially amongparticipants≥60yearsofageandamongthosewho hadneverbeensmokers.³⁴

Cesaronietal.andStafoggiaetal.highlightedtheharm- ful effects of PM even at low concentrations, since they observed a positive association between long-term expo- suretoPMandtheincidenceofcoronaryeventsandstroke, respectively,forexposurelevelsbelowthecurrentEuropean limits.^33,34

Regardingotherairpollutants,Shahetal.reportedthat increases in CO and SO2 were associated with heart failure (HF) hospitalization or death (3.52% per 1 part per million (95%conﬁdence interval[CI]2.52-4.54) and2.36%

per10partsperbillion[95%CI1.35-3.38],respectively).³⁶ IncreasesinO3concentrationwerenotassociatedwithHF hospitalizationordeath(0.5%per10partsperbillion,95%

CI-0.10to1.02).³⁶

Pranata et al. analyzed other CVD outcomes including ischemicheart disease(IHD),hypertension,andatrial ﬁb- rillation (AF), reporting a positive statistical association betweenlong-termexposuretoPMandNO2andincreased incidenceofIHD,hypertension,andAF.³⁵

Overall,allreviewsreportedthatexposuretoincreased levels of air pollution was consistently associated with 711

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Table1 Maincharacteristicsofselectedsystematicreviewsassessingtheimpactofairpollutantsincardiovascularevents.

Study Publication year

Location Exposure

temporality

No.Studies included

Studydesign Airpollution exposure variables

Subjects(n) Population Mainﬁndings

Pranata etal.

2020 China,Taiwan, SouthKorea, Japan,US, Canada,Europe, UK,Sweden,Italy, Netherlands, Denmark,Greece, Switzerland

Long-term exposure

49 Cohort

studies

PM2.5;P10;

NO2

28215394 Adults,both sexes

Airpollutants(PM 2.5,PM10,NO2) areassociated withanincreased incidenceofCVD, all-cause

mortality,andCVD mortality

Hoeketal. 2013 US,Canada, China,Japan, Germany,Sweden, Italy,Netherlands, Switzerland, France,Scotland, Denmark,New Zealand

Long-term exposure

39(30 relatedto cardiovascular

disease)

Cohort studies

PM2.5 NR Adults,both

sexes

Long-term exposuretoPM2.5 isassociatedwith mortalityfrom CVD

Faustini etal.

2014 US,Canada,

Sweden,Germany, Italy,Norway, France, Netherlands, China,Japan,New Zealand

Long-term exposure

23 Cohortand

case-control studies

PM2.5;NO2 NR Adults,both sexes

Theauthors reporteda13%

and20%increase incardiovascular mortalityaftera 10␮g/m³increase inNO2andPM2.5 concentrations, respectively Theauthors observedasimilar riskestimatefor all-causemortality instudies

investigatingthe long-termeffects ofbothNO2and PM2.5(4%versus 5%increase, respectively)using anexposure metricof10

␮mg/m³

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RevistaPortuguesadeCardiologia41(2022)709---717 Table1(Continued)

Study Publication year

Location Exposure

temporality

No.Studies included

Studydesign Airpollution exposure variables

Subjects(n) Population Mainﬁndings

Shahetal. 2013 USA,Canada, Italy,Asia,Taiwan, Japan,HongKong, Australia,New Zealand,Brazil, SouthKorea,UK, Netherlands

Short-term exposure

35 Time-series,

Case- crossover

CO;NO2; SO2;O3; PM2.5;PM10

NR Adults,both

sexes

Airpollutionhasa closetemporal associationwith heartfailure hospitalization andheartfailure mortality Stafoggia

etal.

(ESCAPE Project)

2014 Europe(Finland, Sweden,Denmark, Germany,andItaly

Long-term exposure

11 Cohort

studies

PM2.5;

PM10;

nitrogen oxides

Authorsreporteda positive

association betweenPM2.5 and

cerebrovascular eventsevenfor exposurelevels belowthecurrent Europeanlimits Cesaroni

etal.

(ESCAPE Project)

2015 Europe(Finland, Sweden,Denmark, Germany,and Italy)

Long-term exposure

11 Cohort

studies

PM2.5;

PM10;

nitrogen oxides

Authorsreported anincreased incidenceof coronaryeventsin adultsexposedto particulatematter (PM2.5andPM10), evenforexposure levelsbelowthe currentEuropean limits.

NR:Notreported;PM:Particulatematter;US:UnitedSates;UK:UnitedKingdom.

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Figure1 Summaryestimatesoftheimpactofairpollutantsoncardiovasculareventrisk.

severalimportant adversecardiovascularhealth outcomes (Figure1).

Air pollution indexes in Portugal

The indexesofair pollutioninPortugal havebeen declin- ing. The PM indexesare currently lower than the annual threshold recommended by the European Union Ambient Air Quality Directives (Figure2). Even though, asseen in Figure2, the qualityof the airregarding both PM2.5 and PM10inlargercitiessuchasLisbonandPortoislowerthan average,itsuggeststhattherearegeographicdiscrepancies asregardsairpollution.In line withthesedata,the 2020 QualityofAirReportstatesthatinPortugal,itisestimated thatyearlyPM2.5mightberesponsiblefor4900premature deathsand53000yearsoflifelost(YLL),using2018esti- mates.PrematuredeathsattributabletoNO2andO3exceed altogether1000andtheYLLalsoexceed10000years.³⁷This

meansthatthisshareofairpollutantscontributestoamajor diseaseburden in Portugal,anda signiﬁcant share ofthis burdenislikelytobecardiovascular.

Position statement/conclusion

Airpollution is arealthreat tocardiovascularhealth and shouldnotbeunderestimatedbypeople,organizationsand decision/policymakersinvolvedinthepreventionandtreat- ment of CVDs. This topic was recently endorsed by the guidelinesofEuropeanSocietyofCardiologyonCVDpreven- tion,whichrecommendencouragingavoidanceoflong-term exposuretoregionswithhighairpollutioninpatientswithat leasthighcardiovascularrisk(classofrecommendationIIb andlevelofevidenceC).Thiscallsfortheneedforbetter monitoringandwarningsystems,toatleastinformpatients aboutthesitesandperiodsofthishigh-riskexposure.

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RevistaPortuguesadeCardiologia41(2022)709---717

Figure2 DataofPM2.5andPM10inPortugal.ThedashedlinesrepresentthethresholdsofEuropeanUnionAmbientAirQuality Directives.DatafromPM2.5wereretrievedfromBraueretal.,WorldBankdata,andBritoetal.^38---40ThePM10dataanddatafrom LisbonandPortostations(averageyearlydatacalculatedfromtheavailablereportedvalues)wereretrievedfromthePortuguese EnvironmentAgency’swebsite.⁴¹

Cardiovascular disease opportunistic screening may be alsoconsideredinhighairpollutionregions(classofrecom- mendationIIbandlevelofevidenceC),⁴²particularlywhere highvolumeroadtrafﬁcexistssuchasinLisbonandPorto, aswellasinregionswithhighindexesofairpollutiondue toindustrialpollutants.⁴³

Avoiding smoking andsecond-hand smoke (aneglected type ofair pollution),reducing the use ofmotor vehicles wheneverpossible and exercising preferably at sites with lowerairpollution,aretherecommendationsatindividual- levelrelatedtoairpollution.Othertypesofindividual-level interventionsstillrequirefurtherdatabeforerecommenda- tionscanbemade.

The PortugueseSocietyofCardiologyadvocatesgreater interdisciplinaryinvolvement toimproveknowledge of air qualityexposureandcardiovasculardiseases, includingby strengtheningenvironmentalmonitoring;it alsoadvocates foraconcertedefforttoraiseawarenessandliteracyonthis issue inPortugalamongallstakeholders,includinghealth- careprovidersandclinicians.

Funding

None.

Conﬂict of interest

Noneoftheauthorshaveconﬂictofinterestsregardingthe topicofthisarticle.

Appendix A. Supplementary material

Supplementary material associated with this article can be found in the online version at doi:10.1016/j.

repc.2022.05.006.

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