TheImpactofNutritionandStatins onCardiovascularDiseases
IoannisZabetakis RonanLordan
AlexandrosTsoupras
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ToMom,Dad,Lorraine,Anthony,Eimear,andSam.
Ronan(RL)
Tomywife,Maria,andmyfamily“Thankyouforeverything.”
Tomyparentsforprovidingtheopportunitiesand toNathaniel,Thiseas,andDebbieforgivingmesmilesandinspirationeveryday.
Contributors
AshwiniD’Souza WesternVascularInstitute,DepartmentofVascularandEndovascularSurgery, UniversityHospitalGalway,NationalUniversityofIreland,Galway,Ireland
NiamhHynes WesternVascularInstitute,DepartmentofVascularandEndovascularSurgery, UniversityHospitalGalway,NationalUniversityofIreland;DepartmentofVascularSurgeryand EndovascularSurgery,GalwayClinic,RoyalCollegeofSurgeonsinIrelandaffiliatedHospital,Galway, Ireland
EdelP.Kavanagh WesternVascularInstitute,DepartmentofVascularandEndovascularSurgery, UniversityHospitalGalway,NationalUniversityofIreland;DepartmentofVascularSurgeryand EndovascularSurgery,GalwayClinic,RoyalCollegeofSurgeonsinIrelandaffiliatedHospital,Galway, Ireland
RonanLordan DepartmentofBiologicalSciences,UniversityofLimerick,Limerick,Ireland
SherifSultan WesternVascularInstitute,DepartmentofVascularandEndovascularSurgery, UniversityHospitalGalway,NationalUniversityofIreland;DepartmentofVascularSurgeryand EndovascularSurgery,GalwayClinic,RoyalCollegeofSurgeonsinIrelandaffiliatedHospital,Galway, Ireland
AudreyTierney SchoolofAlliedHealth,UniversityofLimerick,Limerick,Ireland;Departmentof Rehabilitation,NutritionandSport,SchoolofAlliedHealth,LaTrobeUniversity,Melbourne,VIC, Australia
AlexandrosTsoupras DepartmentofBiologicalSciences,UniversityofLimerick,Limerick,Ireland
IoannisZabetakis DepartmentofBiologicalSciences,UniversityofLimerick,Limerick,Ireland
AuthorBiographies
IoannisZabetakis hasstudiedandworkedinGreece,UnitedKingdomandIreland.Originally achemist,hefellinlovewithfoodscience(sensoryandfunctionalpropertiesoffood). AfteranacademiccareerattheUniversitiesofLeedsandAthensspanning15years,wherehe developedastronginterestinlipidsandcardiovasculardiseases,Ioannisjoinedthe DepartmentofBiologicalSciencesattheUniversityofLimerick(UL)inIreland.InUL, theongoingfocusofhisworkisonthecardioprotectivepropertiesoffoodlipidswitha particularemphasisondairyandmarinefoods.With >75papersandtwopatents,hisquestis towardahealthierdietandlifestylethatwillrenderuslessdependentonmedicines.
http://scieng.ul.ie/departments/life-sciences/people/dr-ioannis-zabetakis
TwitterHandle: @yanzabet
RonanLordan carriedouthisundergraduatestudiesattheUniversityofLimerick,graduating withafirst-classhonorsBachelorofSciencedegreeinBiologicalSciencesandEducation in2015.RonantaughtLeavingCertificateBiologyandChemistryinIrishsecond-levelschools beforereturningtotheUniversityofLimerickin2016tobeginhisPhDscholarshipto studytheroleofdietarypolarlipidsininflammationandcardiovasculardisease.Ronanhas lecturedonvarioustopicsincludinglipidschemistry,genetics,andhealth.Ronanhas publishedseveralpeer-reviewedpapers.Hisresearchinterestsinclude:(a)elucidatingthe structuresofbioactivepolarlipidsinvariousfoods;(b)developingnovelfunctionalfoods andnutraceuticalsagainstcardiovasculardisease;and(c)discerningthemechanismsof platelet-activatingfactor-inducedsystemicinflammation.Ronanistheprocessofcompleting hisPhD.
TwitterHandle: @el_ronan
AlexandrosTsoupras hasstudied(BSc,MSc,PhD)andworkedasachemistandbiochemist since2002inseveralacademicandresearchinstitutionsinGreece,theUnitedStates,and Ireland(i.e.,theUniversityofAthens,theTechnologicalEducationalInstituteofAthens, theDirectorateoftheEnvironmentoftheRegionofAttica,AlbanyMedicalCollege,the UniversityofLimerick,etc.).Hehasparticipatedinresearchregardingtheimplicationof inflammationonseveralchronicdisorders,suchasCVD,cancer,renaldisorders,chronic
infections,etc.Hismaininterestsconcernnotonlythebeneficialpleiotropiceffectsand sideeffectsofseveraldrugs,suchasstatins,antibiotics,antiretrovirals,etc.,butalsothe beneficialeffectsofnutraceuticals,foodsupplements,andbioactivemicroconstituentsof naturalorigin,suchasthosederivedfromhealthyfoods,microorganismsofbiotechnological interest,andseveralmedicinalplants,oninflammatorydisorders.Alexandros’beliefslie onappropriatelyusingandimprovisingtheexistingnaturallyderived“weapons”ofahealthy dietarypatternandlifestyletowardthepreventionofchronicdisorderstoimproveour qualityoflife.Hismottois Aslongaswehavetheopportunity,letusdoourbestforthegood ofallintheshorttimegiventous.
TwitterHandle: @bioflips AuthorBiographies
Preface
Writingabookconstitutesapoliticalpraxis.Anauthorhasthechancetocriticallyevaluate informationandprovidenovelinsightbutalsopromotehis/herviewsonhowwecanimprove ourpractices.Wethinkthatwritingabookisauniqueopportunitytoexposeanovelidea totheworld.Withthisinmind,wearegladtohavewrittenthisbookonthevalueofnutrition andahealthylifestyleinrelationtocardiovasculardiseases(CVD).
Inthisbook,weaddressthenutritionalvalueandbenefitsofahealthydietarypatternfollowing theprinciplesoftheMediterraneandietandreviewthecurrenttrendofoverprescriptionof statinsandtheirsubsequentsideeffects.Bypresentingalltherelevantresearchdataand literatureonthevalueofabalanceddietandtheeffectsandsideeffectsofstatins,weare takingacriticalstanceonhowthemedicalworldviewstheprimarypreventionofCVD.
Thereweretworeasonswhywechosetowritethisbook.
Thefirstoneisthestoryofaclosefriend,Jim.In2011,Jimfeltsomechestpain.Hevisitedhis GPandwasreferredtoacardiologist.Allcheckswereclear,butourfriendwasprescribed statinstolowerhischolesterol.AtthattimeJimwas,andstillis,fitandfollowsahealthydiet, playinggolftwotothreetimesaweek.In2013,afterabout2yearsonstatins,Jimdeveloped typeIIdiabetes.Wewereallshockedwiththisnews.Afewmonthslater,thefirstreports onthesideeffectsofstatinswerepublishedinthe BritishMedicalJournal inMay2013and aclearlinkbetweenstatinsanddiabeteswasdeclaredforthefirsttime.Thepaperthat startedcastingseriousdoubtsontheuseofstatinswastitled“Riskofincidentdiabetes amongpatientstreatedwithstatins:populationbasedstudy.”
Sincethen,alotofevidencehasaccumulatedsuggestingthattacklingCVDisamuchmore complexproblemthanbyjusttacklingtraditionalriskfactorssuchascholesterollevels.
WhenI(IZ)startedteachingthistopictomystudentsattheUniversityofLimerick(UL), Iwastryingtoprovoketheirthinkingbylinkinghealthydiet,lifestyle,andmedicineinthe waythatHippocratesusedtodo,byadvocatingthatthebestmedicineisnutrition.Weoften heldopendiscussionsinthelecturetheatreconcerninghugepharmaceuticalindustries, investedinterests,andourdependenceonstatinsfortheprimarypreventionofCVD.
Mystudentstookthistopicfurtherandtheywerethesecondcatalysttowritethisbook.
OneofmystudentsaskedherGPforadvice.HerGPdescribedhowstatinsareoversubscribed withlimitedfreedomgiventothepatients.Mystudentlearnedthatraisedbloodcholesterol doesnotnecessarilyleadtoatherosclerosisandthattherearemorebeneficialwaystoprevent CVDthansimplytakingpills.Insteadofprescribingstatins,wecouldfollowahealthy dietarypatternsuchastheMediterraneandiet;inthiscase,everyoneonthedietwould benefit—notjustthoseatriskofheartattack.Itwouldhelpreducemetabolicsyndrome, typeIIdiabetes,andobesitywhileloweringthecardiovascularrisk.
Wehavedividedourbookintoninechapters.
In Chapter1,wepresentthecausesofCVDandtheimpactofvariousdietary,genetic,and environmentalfactorsoncardiovascularrisk.
In Chapter2,weintroducetheconceptofinflammationinrelationtohowinflammationis closelylinkednotonlytoCVDbutalsotoanumberofchronicdiseasessuchascancer,obesity, andtypeIIdiabetes.
In Chapter3,wepresentallthecurrentevidencelinkinginflammationtoCVD.Itisclear thatthedevelopmentofCVDoccursduetoelevatedinflammatoryresponsesinthe endothelium.CurrentviewssuggestthatcholesterolistherootcauseofCVD;however, thisdogmaneedstobechallengedasCVDpreventionisstillamajorchallenge.
In Chapter4,wepresenttheevidencefromtheSevenCountriesStudyandsubsequent epidemiologicalstudiesthatleadtotheformationofthe“lipidhypothesis,”whichshaped theviewsofthemedicalworldforseveraldecadesbyfocusingonthereductionofsaturated fatsinthedietandthemedicatedreductionofserumcholesterollevelsfortheprevention ofCVD.
However,althoughserumcholesterollevelsseemedtobeariskfactorforCVD,thereare somenotableexceptions.In Chapter5,wepresenttherelevantresearchsurroundingthe Mediterraneandietandthe“Frenchparadox.”Inparticular,theFrenchparadoxdescribeshow eventhoughthereismoderateintakeofwineandhighlevelsofsaturatedfatconsumption, therearelowlevelsofCVD.Theevidenceandmechanismssurroundingtheseexceptions areexplored.
In Chapter6,weposeanumberofquestionsandpresenttherationaleforprescribingstatinsas aprimarypreventionmethodagainstCVD.Wepresentstatins’modeofactionandtheir relevantsideeffects.
In Chapter7,weevaluatehowcardiovascularriskiscalculated.Currentapproaches, guidelines,andpracticesareratherfocusedonspecifictraditionalriskfactorsasaconsequence ofourfocusonreducingserumcholesterollevels.Wesuggestseveralnovelbiomarkers, includingthoselinkedtoinflammation,inordertoassesscardiovascularrisk.
In Chapter8,wepresentallthedietaryinterventionstudieslinkingthebenefitsofthe MediterraneandiettotheprimarypreventionofCVD.Theevidenceisstrongandclear: ahealthydietisthekeytoreducecardiovascularrisk.
Finally,in Chapter9,werevisitthelipidhypothesisbypresentingaclearlinkbetween inflammationandCVD.Thereisaclearneedtoreevaluateourstanceontheprimary preventionofCVD.AlthoughhighserumcholesterollevelsareassociatedwithCVDrisk,it isclearthatreducingcholesterollevelsaloneisnottheanswertopreventingCVDoccurrence. Webelievethatashiftoffocustowardpreventinginflammatorymanifestationsthrough healthydietandlifestyleiskeyforthepreventionofCVDandrelatedinflammatory manifestations.
RegardlessofyourviewsonstatinsortheimportanceofcholesterolinCVDprevention, wecanallagreeonthis:AhealthydietandlifestyleiskeyforthepreventionofCVD.Globally, themedicalprofessionhasdriftedtowardsolvingallhealth-relatedproblemswithpillsand medication,eventotheextentwhereresearchhasdriftedtowardcreatingmultiplemedications inasinglepill,a“panacea.”CVDisacomplexdiseaseandtherewillbenoonesolutionto itstreatment.
However,webelievepreventioniskeyandweurgegovernmentandhealthcareprofessionals toadvocateforearlydietandlifestyleeducationandpracticetoreducetheoccurrenceof CVDforfuturegenerations.Ourhopeforthereaderisthatthisbookwillgivenewinsights intothecurrentmodesofprimarypreventionandtounderstandthatCVDisaninflammatory manifestationthatcanbeprevented.
WeleaveyouwiththisquotebyThomasEdison:“Thedoctorofthefuturewillgiveno medicine,butwillinteresthispatientsinthecareofthehumanframe,indietandincause andpreventionofdisease.”
Acknowledgments
First,IwouldliketothankmysupervisorandfriendDr.IoannisZabetakisforhiscontinued supportasIprogressinacademia.Togetthisfar,Ihavetoacknowledgethesupportand encouragementofmyformerteachersandcolleaguesatArdscoilPobailBheanntraı ´ and Cola ´ istePobailBheanntraı´.IwouldliketoespeciallymentionMargueriteO’DriscollandDenis O’Sullivan,whofosteredmyinterestinbiochemistryandeducation.Iamindebtedtothe DepartmentofBiologicalSciencesattheUniversityofLimerickforitscontinuedsupport throughoutmyPhD.Inparticular,IwouldliketothankProf.SeanArkins,whoaffordedmethe timeandadvicewhenIneededitmost.Mostimportantly,Iwouldliketothankmyfamily andfriends.Inparticular,IwouldliketothankmybrotherAnthony,mysisterLorraine,their respectivepartners,andmynieceEimearfortheircontinuedsupportandtechnicaladvice. IalsowanttoexpressmysinceregratitudetomypartnerSamanthaandmyparentsJohn andMargaret,forwithoutallyourunwaveringloveandsupportIwouldn’tbethe personIamtoday.
Isfearrcoscna´ leigheas
—RonanLordan
First,Iwouldliketoexpressmyappreciationandgratitudetotheresearchandacademic teamoftheLaboratoryofBiochemistryandFoodChemistry(DepartmentofChemistry, UniversityofAthens,Greece).Iwouldespeciallyliketothankitsformerdirectorandmy previousPI,Prof.ConstantinosA.Demopoulos,forintroducingmetothefantasticworld ofbiochemistryandfoodsciencesandforinspiringmetofollowthepathofresearchtoward counterbalancingthenegativeeffectsofinflammationanditsrelatedchronicdisorderssuch asCVD,mostlythrough“weapons”ofnaturalorigin.
Second,IwouldliketothanktheDepartmentofBiologicalSciences(UniversityofLimerick, Ireland)andespeciallymycolleague,friend,andcurrentPI,Dr.IoannisZabetakis,forgiving metheopportunitytocontinuemyresearchtripbyconnectingourpreviousandcurrent collaboration,andforalwaysbelievinginme.Iwouldalsoliketothankallmyformerand currentstudents,friends,colleagues,andcoauthors(i.e.,Dr.TzortzisNomikos,Dr.Elizabeth Fragopoulou,Dr.ChristosIatrou,Dr.EfstratiosDavakis,Prof.SeanArkins,RonanLordan, andmanyothers),foralwaysinspiring,motivating,andencouragingmetocarryonthistrip.
Mostimportantly,Iwishalsotothankmywife,Maria(Μαρία),myparentsVasiliosand Georgia(Βασίλειος and Γεωργία)andalltheothermembersofmyfamilyfortheirconstant love,support,andencouragement.Especially,IwouldliketothankmybrotherNestor (Νέστωρ),whopassedawaytooearlyinlife,forintroducingmetochess.Whenthinkingof inflammationanditsmultifactorialcausesandeffectsthroughmanypathways,Ialways rememberhimsaying, Allthepiecesontheboardareimportant,eventhelastpawn,ifyouwant toappropriatelyaddressamultichallengingattackofanopponent.
Finally,Iwanttoexpressmyeternalgratitudetothe HolyTrinity (
ρι
—AgiaTriada), andespeciallyto Logos (Λo ´ γ ος—TheWord),foralwayslightingthefirewithinmeforscience andresearch,forthegoodofall:
(ResearchandinvestigatetheScripturesdiligently,becauseyoubelieveand hopethatwithinthemyouwillfindeternallife);StJohn’sGospel5:39. —AlexandrosTsoupras
Ihavealwaysbeenluckyinmyacademiccareer!Iconstantlyhadthechancetosuperviseand collaboratewithtopstudents,frommyfirstPhDstudentinAthenswhoisnowanacademicat theUniversityofAegean(Dr.C.Nasopoulou)throughtodayworkingwithmycoauthors, RonanandAlexandros.Toallmypastandcurrentstudentswhokeepinspiringmeeverydayin thelab,inthelibrary,andinthelecturetheatre,Iwouldliketosayabig“thankyou”fromthe bottomofmyheart!Youarethecatalystsnotonlyforthisbookbutforenrichingmyresearch andteachingpracticeswithnovelideasandapproachesandhelpingmetobecomea bettermentor.
Iwouldalsotothankfourofmymostinfluentialteacherswhohaveplayedandcontinuetoplay amajorroleinmyeducationandmycareer.
Thefirsttwoaremyparents,bothchemists,mymum,EvangeliaKapetanou(forteachingme thefirsteverexperimentwithacetyleneIdidinthefifthclassofprimaryschoolinThebesand forintroducingmetotheworldofchemistry)andmydad,AristotelisZabetakis,forteaching mehowtobeapplicableinmyscientificinquisitionsandtoalwayslookforthe … addedvalue!
ThesecondtwoteachersandcolleaguesIamgratefultoareProfessorsConstantinos DemopoulosandDavidO’HaganattheUniversitiesofAthensandStAndrews,respectively, fortheircontinuoussupportthroughoutmycareer.Ispent2yearswithDavidattheUniversity ofDurhamworkingonthebiosynthesisofalkaloidsformypostdocandsincethen,Davidhas beenaclosefriendandavaluablementor.Constantinosintroducedmetotheworldof biochemistryduringmyBScinChemistryinAthens.Since2000,wehavebeencollaborating onanumberofprojectsexaminingthenutritionalvalueoflipids.Hehasalwaysbeenan inspirationalteacher,friend,andcolleague.
Acknowledgments
SincemovingtoUL,thereareseveralpeoplewhohavemadetheirown,sometimes unknowinglybutalwaysvaluable,contributionstowardtherealizationofthisbook.Many thanksareduetoallmycolleaguesintheDepartmentofBiologicalSciencesinUL.Aspecial thankyouisduetoProfessorsSeanArkinsandPhilJakemaninUL,TomTierneyin Lifes2good,andTimYeomansinShannonABC.
Finally,alltheunknownpatientsandsomefriendswhoareonstatinshaveplayedamajorrole inthedevelopmentofthisbook.Wehopethatthisbookwillcontributetoamoreholistic approachagainstchronicdiseaseswhilealsocontributingtothediscussionsurroundingthe needforimprovedguidelinesforthepreventionofcardiovasculardiseasesthatfocusontherole ofdietandlifestylewithlessrelianceonmedication.
—IoannisZabetakis
UniversityofLimerick,Limerick,Ireland
WetheauthorswouldjustliketothankallinElsevierwhohelpededitthisbook.
TheOriginofChronicDiseases WithRespecttoCardiovascularDisease
RonanLordan,AlexandrosTsoupras,IoannisZabetakis
DepartmentofBiologicalSciences,UniversityofLimerick,Limerick,Ireland
ChapterOutline
1.1Introduction 1
1.2CausesofChronicDiseasesSuchasCVD 3
1.3UnresolvedandEmergingPublicHealthHazardsduetoGenetic,Dietary,Environmental, andLifestyleFactors 6
1.3.1Genetics 7
1.3.2Nutrition,Diet,andLifestyle 9
1.3.3TheEnvironmentandAnthropogenicActivity 13
1.4ConcludingRemarks 15
References 16
FurtherReading 21
1.1Introduction
Onemightwonderwhy,withinagroupofpeoplethatfollowsimilarpatternsofdietand hasanalogousexposuretovariousexternalfactors(suchasenvironmentalfactors),somesuffer illhealthwhileothersdonot.Whataretheunderlyingcausesofdiseases?IsthereanyinformationinourDNA(i.e.,nature)thatprotectsusfromfallingillorisitaneffectofexposureto disease-promotingfactors(i.e.,nurture)?Itwouldbeusefultovisualizeadynamic balancebetweenhealthanddisease(Fig.1.1).Usually,thebalanceshiftstowardthe “health”state;however,undertheinfluenceofvariousriskfactors,thebalancecouldberedirectedtowardthe“disease”state.Inthischapter,wearegoingtoexaminedocumentedtraditionalfactorsbutalsoemergingfactorsthatcaninfluencethisbalancewithreferencetoCVD.
Inourapproach,diseasesarecomplexbiologicalprocessesthataretriggeredbyexternal factorsand/orvariousunderlyingbiochemicalandcellularprocesses.Theseprocessescan
Health Disease
Fig.1.1 Dynamicbalancebetween“Health”and“Disease.”
beinducedeitherendogenouslyorexogenously,andeitheraloneorindifferentcombinations, whichmayresultincellulardysfunction,damage,orcelldeathatacellularlevel.Inthecaseof prolongedcellulardysfunction,tissuesandorgansmaybeaffected,resultinginanarrayof symptomsdependingonthespecifictypeofcellular,tissue,ororgandysfunctionthatoccurs (Ardies,2014).Themajordifferencebetweenthisapproachtodiseaseandotherapproachesas presentedinavarietyofbooksonpreventionmedicine(Faucietal.,2009; LeutholtzandRipoll, 2011)isthatwhenreachingthediseasestate,suchdysfunctionscoexistatboththecellular levelandclinicaldiagnosis.However,whenpatientspresentwithclinicalsymptomsofa chronicdiseasesuchasCVD,underlyingdisordersatthecellularoreventissuelevel (e.g.,endothelialdysfunctionandformationofatheroscleroticplaques)aresometimesnotclinicallyobserveduntilmanyyearsaftertheinitialpathologicalprocesseshavebeentriggeredand theprogressgoneundetected.Physiciansgenerallyviewsymptomsasanendresultfordiagnosticpurposes.However,shouldthesymptomsmaterializeduetoaprocessinitiatedmany yearsbeforeclinicalobservation,thenthediseasedindividualwasunawareoftheirdeveloping conditionandthusunabletopreventitsmanifestation.Insomecases,individualswhoare freeoflifestylesorriskfactorsassociatedwithadiseasecanoftendevelopadiseasedueto geneticand/orenvironmentalfactorsofwhichtheyareunaware.
Globally,thenumberofpeoplediagnosedwithCVDfollowsarisingtrend.TheWorld HealthOrganization(WHO)hasestimatedthatoneinthreeglobaldeathsisbecauseof CVD-relatedeventssuchasmyocardialinfarction(MI)andstroke.In2015,therewere 17.7millionglobaldeathsduetoCVD-relatedevents(WorldHealthOrganization,2017). AccordingtoIreland’sHealthServiceExecutive(HSE), 10,000Irishpeopledieeachyear duetoCVD,includingcoronaryheartdisease(CHD),stroke,andothercirculatorydiseases. CVDaccountfor36%ofalladultdeaths,surpassingcancer,andrespiratorydiseasesas Ireland’sleadingcauseofdeath.OfthosewhodiefromCVD,22%areprematuredeaths(under 65yearsold),withthemajorityofthesedeathsbeingrelatedtoCHD(5000)(HSE,2017).Inthe UnitedKingdom,CVDcausemorethanaquarter(27%)ofalldeaths,oraround155,000deaths eachyear—anaverageof425peopleeachdayoroneeverythreeminutes(Townsendetal., 2015).AccordingtotheAmericanHeartAssociation,asimilarworldwidetrendexists. CVDgloballyaccountfor >17.3milliondeathsperyear,anumberthatisexpectedtorise to >23.6millionby2030.IntheUnitedStates,92.1millionAmericanadultsarelivingwith someformofcardiovasculardisorderortheaftereffectsofastroke,costingmorethan $316 billionforbothdirectandindirectcosts(Benjaminetal.,2017).
AsdevelopingcountriesadoptamoreWesternizedlifestyleandtheincidencesofdiabetes andobesitycontinuetoincreaseworldwide,theestimatednumberofCVD-relateddeathsis
expectedtogloballyriseto23.3millionby2030(WHO,2015).Clearly,thedevelopment ofCVDisamajorglobalconcern,andforseveralreasons,theaforementionedbalancehasbeen tippedtowardthediseasestateforanincreasingnumberofpeople.Takingintoaccountthat CVDareasignificantchallengeforthehealthcaresystemsaroundtheworldandthusamajor economicburden,thereisagreaterneedtodiscovernewtargetsandtodeveloppotentialtherapiesforCVD.Preventioniskeyinreducingglobalmortalityduetochronicdiseasessuchas CVD.Therefore,itisimportanttoseparatetheunderlyingcausesandprocessesofdiseasefrom thesymptomsofdisease.WithafocusonatherosclerosisandthecorrespondingonsetofCVD, itissignificantthattheunderlyingcauseofthediseaseandtheformation,progression,and expansionofplaqueinthewallsofcoronaryarteriesoccuroveraperiodofseveraldecades beforeclinicalsymptomsappear.Peoplewithsubclinicalatherosclerosisarefreeofsymptoms throughoutthemajorityoftheirlife.However,weoftenforgetthattohaveadisease,youdonot necessarilyhavetoexhibitthesymptoms.InWesternizedanddevelopingsocieties,wherethe globalburdenofCVDismostprevalent,peopleseemtobediagnosedwithCVDintheir50s, unawareofthebiochemicaltimebombwithin.
Theunderlyingbiologicaloccurrencesthatcausechronicinflammatoryprocessesatthe endothelium,whichinturnleadstoatherosclerosisandtheeventualonsetofCVDsymptoms, areinitiatedataveryyoungageandcontinueforseveraldecadesbeforeanyclinical symptomsappear.Infact,asymptomaticlesionscanbeformedinearlychildhoodwithoutleadingtotheonsetofCVD(Ross,1999).Giventhatthetransformationofasymptomaticsignalsto symptomsisacontinualprocess,preventingCVDshouldbeconsideredasacontinuousprocess thatinitiateslongbeforetheappearanceofthesymptoms.Itiswidelyquotedthat“thebestform ofdefenceisattack,”hencetacklingtheunderlyingcauseoffattylesionformationisimperative inordertostarttheprocessofdiseaseprevention.Thus,aproactivecollaborativeapproachis requiredtoprotectourcardiovascularhealth,forexamplestartingwiththeeducationofyouths.
Inourview,dietandlifestylearevaluablepreventivetoolsagainstchronicdiseasesandneed tobeconsideredasalifelongtargetandnotjustamiddle-agedresponsetoadebilitatingdisease.Ourcommitmenttofollowingahealthydietandlifestyleincombinationwithmoderate exerciseisintegralinminimizingourriskofdevelopingCVD.Webelievethatnutritionshould beregardedasalifestyleissueandapowerfulandimportantbiochemicaltoolforthepreventionofchronicdiseasessuchasCVD.
1.2CausesofChronicDiseasesSuchasCVD
Diseasescanberegardedasaplethoraofbiologicalprocessesthatcausecellulardysfunctions, usuallyresultingintissueand/ororgandisordersthatinturnmayleadtosymptoms.Thus, weneedtoreadjustourfocusontheunderlyingcausesandmechanismsofthediseasesat themolecularandcellularlevels.Thefocusofpossiblepreventivemeasureswouldneedto addressinhibitingorminimizingthesemechanismsforbeneficialoutcomesinthelongterm.
Additionalfocusshouldalsobegiventotheinterrelationofseveralriskfactors(suchasan unhealthylifestyleanddiet,smoking,stress,lowincomeandeducation,obesity,genetic causes,etc.)withthetriggeringandlong-termprogressionofsuchmolecularandcellularmechanismsunderlyinginflammation-relatedchronicdiseasessuchasCVD.
Itisnowevidentthatoneoftheseunderlyingmechanismsatthemolecularandcellularlevel, whichisrelatedtoacommonmechanisticpathwayoftheinitiationandprogressionofseveral chronicdiseases(suchasCVD,ischemicandrenaldisorders,cancer,diabetes,etc.),isthemanifestationofchronicinflammation,andespeciallythataffectingtheendothelium(Lordanetal., 2018a; Tsouprasetal.,2009).
Inflammationrepresentsaphysiologicalreactionoftheinnateimmunesysteminorderto maintainandprotectaconstantinternalmilieuwhilebeingexposedtocontinuouslychanging environmentalpressures,irrespectiveofwhethertheinitialcausesoriginatefrommicrobial infection,traumaticinjury,ormetabolicdysfunction.Theinflammatoryresponseaimsto reducetheagentthatcausestissueinjury(and/orminimizetheseeffects)toinduceappropriate woundhealingandrepairprogramswhilerestoringtissuehomeostasis.
Inflammatoryresponsesareinitiatedbyinnatesensingmechanismsthatdetectthepresence ofmicrobialinfection,stressedordyingcells,lossofcellularintegrity,barrierbreach,etc. Acascadeofinflammatorypathwaysandmechanisticeffectsissupposedlywellorchestrated bytheimmunesysteminordertoeradicatethecausativeagent.Providedthattheimmune responsesucceedsineliminatingtheinfectiousagentorrepairingtheinitialtissueinjury,the inflammatoryprocesswillbetimelyterminatedandthusonlytransientlyaffecttissuefunction.
However,incaseswheretheinflammationfailstoresolve,forexampleduetothepersistence ofapathogenand/ornotsucceedinginrepairingtheinitiatinginjuryandtissuedysfunction,a sustainedunderlyinginflammatoryprocessdevelops,leadingtotissuedysfunctionsanddetrimentalconsequencesfortheestablishedchronicinflammatoryconditions.
WithreferencetoCVD,chronicandunresolvedinflammatorymanifestationsinthewallsof mediumandlargearteriestriggertheinitiationandprogressionofatherosclerosis,achronic progressivevasculardiseasethatmayleadtoasubsequentmajorcardiovascularevent (Demopoulosetal.,2003;Tsouprasetal.,2018b).Atherosclerosisistheprimarycauseof CVD-relatedeventsleadingtomorbidityandmortality.AsthepathologicalbasisofCVD,atherosclerosisisfeaturedasachronicinflammatorycondition.Inthedevelopmentofatherosclerosis,moleculesthatareproducedbyactivatedinflammatorycellsplayanintegralrole.These moleculescanbecellularsignalingmoleculesorreactivemoleculesandtheyareinvolvedina widevarietyofdiseasessuchascancer,typeIIdiabetesmellitus,osteoporosis,Parkinson’s,and Alzheimer’sdisease(CoussensandWerb,2002; Aggarwaletal.,2006; Tsouprasetal.,2009; DeVirgilioetal.,2016; Ghodsietal.,2016; Bolo ´ setal.,2017; Haarhausetal.,2017;Lordan etal.,2018a).Inaddition,dyslipidaemiaandhypercholesterolemiaareassociatedwithmyeloid
cellexpansion,whichstimulatesinnateandadaptiveimmuneresponses,strengthensinflammation,andacceleratesatherosclerosisprogression(MaandFeng,2016).
Morespecifically,atherosclerosisisinitiatedbyinflammation-inducedendothelialcell(EC) dysfunction/activationthatisoftentriggeredbytheaccumulationoflow-densitylipoprotein (LDL)andotherapolipoprotein(Apo)B-containinglipoproteinsinthewallsoflargeand mediumarteries.Specificallyoxidized(oxLDL)byreactiveoxygenspecies(ROS)and lipidoxidationinduceaninflammatoryresponseintheECsneighboringtheLDLaccumulation andviceversa.Asaresponse,theactivatedECsbegintofurtherreleaseinflammatorymediatorsintothebloodstreamaswellastoexpresscelladhesionmoleculesontheirsurfaceinorder torecruitcirculatingmonocytesandotherimmunecellstothesiteofoxLDLbuild-up.Oncethe monocytesmigrateintothewallsofthearteries,theydifferentiateintomacrophages,whichare abletouptakeoxLDLandformfoamcells.Atheroscleroticplaquesdevelopduetothecontinuousanduncontrollablerecruitmentofmacrophagesandbuild-upoffoamcellsatthesiteof oxLDLaccumulationandthedefectiveclearanceofapoptoticcells/debristhatleadstoa chronicinflammatoryresponse.Astheplaquecontinuestodevelop,itcanbecomeunstable andrupture,leadingtothrombosis,stroke,ormyocardialinfarction(MI)dependingonthelocationoftherupture(MossandRamji,2016).
Thus,inflammationplaysakeyroleinallstagesoftheformationofvascularlesions maintainedandexacerbatedbyriskfactors.Theconsequenceofchronicinflammation isendothelialdysfunction,andwecandefineitasanintegratedmarkerofthedamageto arterialwallsbyclassicriskfactors.Atherosclerosis,whichdevelopsamongthesepatients, isthemaincauseforcardiovascularmortalityanduncontrolledchronicbiologicalinflammation, whichquicklyfavorsendothelialdysfunction(CastellonandBogdanova,2016).Therefore,the developmentofCVDislinkedtoinflammationandhereinidentifiesthefirstpointofattackfor manychronicdiseases.AnactiveareaofresearchisthediscoveryandcharacterizationofinflammatorybiomarkersassociatedwithCVDrisk.Currenttherapiesforatherosclerosismainlymodulatelipidhomeostasis.WhilesuccessfulatreducingtheriskofaCVD-relateddeath,theyare associatedwithconsiderableresidualriskandvarioussideeffects.Thereis,therefore,aneedfor alternativetherapiesaimedatregulatinginflammationinordertoreduceatherogenesis.Inorder toinhibitthedevelopmentofCVDandotherchro nicdiseases,targetinginflammationmaybe thekeytoinhibitingoratleast reducingtheinitialpro cessesthatleadtochronicdiseasedevelopment.Ontheotherhand,inflammationisanomnipresentprocessthatisdirectlyrelatedto dietandlifestylechoices.Eitherpoordietthat isassociatedwiththeconsumptionofinsufficientamountsofspecificessentialnutrients ortheoverconsumptionoffood(especiallyfood withlownutritionalvaluesuchasrefinedcarbohydratesoralcohol)canleadtonutritional imbalances.Whilelinkingnutritionalanddietarychoicestocellfunctionanddiseasedevelopment,weneedtotakeintoconsiderationoneofthefundamentalcausesofobesityand metabolicsyndrome,whichisexcessivecalorieintakecombinedwithalackofphysical activity(MiglaniandBains,2017 ; Tuneetal.,2017 ).
Fig.1.2 LifestylechoicesandCVD ModifiedfromArdies,C.M.,2014.Diet,ExerciseandChronicDisease: TheBiologicalBasisofPrevention,CRCPress,BocaRaton,FL.
Metabolicsyndromeisnotalwaysregardedasadiseaseperse;however,itisaclusterof conditionsincludingabdominalobesity,hypertension,insulinresistance,anddyslipidaemia. Therefore,itislinkedtofactorsassociatedwithatherosclerosis,type2diabetes,andstroke (Fig.1.2).Metabolicsyndromeandobesityarealsoassociatedwithcancer(Belloumetal., 2017),neurologicaldiseases(Luchsingeretal.,2007; Gonzalez-Bulnesetal.,2016),andosteoporosis(DaSilvaetal.,2017).Interestingly,ithasalsobeensuggestedthatalackofphysical activityonitsown(i.e.,whennotstudiedinrelationtootherriskfactors)maybeassociated withthedevelopmentofchronicdiseases(Strongetal.,2005),whereasforsomeresearchers (Boothetal.,2012; Durstineetal.,2013)inactivityisadiseaseonitsown!
Itisofgreatscientificimportancetoclarifytheinterrelationshipbetweeneachoracombinationoftheaforementionedriskfactorsatamolecularlevel.Itisimperativetodiscernthe mechanismsthattriggerandestablishsuchunderlyinginflammatorymanifestationsinsystemicdisorderssuchasthosefoundinCVDinordertoimplementlong-termappropriatepreventivemeasures.
1.3UnresolvedandEmergingPublicHealthHazardsduetoGenetic, Dietary,Environmental,andLifestyleFactors
Whenaddressingthevariousclustersoffactorsthatinfluencethedevelopmentofchronicdiseasesand,inparticular,CVD,itisworthkeepinginmindthatthesefactorscanbeassembled intothreemaingroups:
1.Geneticsandepigeneticsfactors.
2.Nutrition,dietary,andlifestylefactors.
3.Environmentalfactors.
Fig.1.3 Factorsaffectingdiseasesusceptibility.
Inreality,thesegroupsofriskfactorsarenotcompletelyisolatedorunconnected,butseemto beinterrelatedandsometimescoexisting(Fig.1.3).
1.3.1Genetics
Untilrecently,humandiseasesusceptibilitywaslinkedtoinheritableinformationthatwascarriedontheprimarysequenceofourDNA.Weareallendowedwithdifferentgenotypesthat dictateourresponsetoendogenous(e.g.,hormones)andexogenousfactors(e.g.,nutrition, physicalactivity,smoking,stress,pollution,etc.).Epigeneticprocessescontrolcentralgenetic functionsoverthecourseofone’slifetime(WalterandH€ umpel,2017),anditistheseresponses thatformthebasisofanindividual’sgeneticvariabilitytodiseasesusceptibility.Abnormal changesinthesequencesoflinearDNAmayresultintheoccurrenceofgeneanomalies(mutations,deletions,duplications,orgeneamplifications)thatinturncausegeneexpressionto becomedysregulated.Theseprocessescanleadtothedevelopmentofgeneticdiseasesormake anindividualmoresusceptibletootherdiseaseslaterinlife.Epigeneticdisruptionofgene expressioncanalsoplayanequallyimportantroleindiseasedevelopment,aprocessthatis moresusceptiblethantheformertomodulationfromenvironmentalfactors(TangandHo, 2007).Increasingly,itisacceptedthatepigeneticmarksprovideamechanisticlinkbetween theenvironment,nutrition,anddisease(Andersonetal.,2012).
AtherosclerosisandassociatedCVDaremultifaceteddisorders,influencedbyenvironmentalandheritablegeneticriskfactors.Numerousgenevariantsthatareassociatedwithagreater orlesserriskofthedifferenttypesofCVDandofintermediatephenotypes
(i.e.,hypercholesterolemia,hypertension,diabetes)havebeensuccessfullyidentified.Epigeneticmodificationsofthegenome,suchasDNAmethylationandhistonemodifications,have beenreportedtoplayaroleinprocessesunderlyingCVD,includingatherosclerosis,inflammation,hypertension,anddiabetes(Mukaetal.,2016).Becauseofthestrongpredictedgenetic componentsofbothCVDandinflammatorybiomarkers,thereisaninterestinidentifying geneticdeterminantsofinflammatorymarkersandcharacterizingtheirroleinCVD.Recent developmentsinthemethodologicalapproachesofgeneticepidemiology,especially genome-wideassociationstudiesandMendelianrandomizationstudies,havebeeneffective inidentifyingnovelgeneassociationsanddeterminingthecausalityofthesegeneswith CVD(Ramanetal.,2013).Inaddition,theepigeneticregulationoftheinflammatorypathways inrelationtoatherosclerosiswithaspecificattentiontomonocyte-andmacrophage-related processesisanewapproachinthefield(Neeleetal.,2015).
Ofconsiderableimportancearethegene-dietinteractionsasanewfieldofexaminingthe interrelationofthesetworiskfactorsonCVD.Fetalreprogrammingisaprocessthatrefers totheroleofdevelopmentalplasticityinresponsetoenvironmentalandnutritionalsignalsduringgestationandearlylifeanditspotentialadverseconsequencesinlaterlife.Itisbelievedto beresponsibleforthe“fetalorigins”hypothesis,whichlinksthedevelopmentof diseases,includingCVD,tofetalundernutritioninlategestation.Furtherstudiessupportthe evidencethatmaternalundernutritionbeforeandduringpregnancyplaysakeyroleinfetal developmentandreprogramming(Wuetal.,2004; Andersonetal.,2012).
Anincreasingnumberofstudieshaveindicatedthatvariousexogenousandendogenousfactorsthatinfluenceepigeneticprocessesduringdevelopmentalreprogrammingareofcritical importancelaterinlife.TherelationshipbetweenmaternaldietaryfactorsandfetaldevelopmentisanimportantsourceofstudyinordertounderstandtheroleofdifferentfactorsofdiseasedevelopmentandCVD(Gicqueletal.,2008).Otherchronicconditionssuchas animpairedglucosemetabolismleadingtoanincreasedriskofdevelopingtypeII diabetesmellituslaterinlifehavealsobeensuggestedduetomaternalundernutrition (Mietal.,2000; Newsomeetal.,2003).Forinstance,studiesonthematernaldietary ω6/ω3 fattyacidratioduringpregnancyalsoindicateaninverserelationshiptochildneurodevelopmentduringfetallife(Bernardetal.,2013).Otherexogenousfactorssuchassmokingandalcoholcanalsohaveprofoundeffectsonprenataldevelopment,includingabortion,suddeninfant death,andfetalalcoholsyndrome(DiFranzaandLew,1995; Roozenetal.,2017).
Interestingly,studiesarenowexaminingtheroleofpaternalnutritionbeforeconceptionasa riskfactorforcertainconditions(Lambrotetal.,2013).Inthefuture,manydietaryfactors (suchasdietarymethyldonors,cofactors,fat,glucoseintake,catechins,andflavonoids)willplay animportantroleinourunderstandingofgenefunctionandoursusceptibilitytodisease.The connectionbetweengenefunctionanddiseaseisintricatelylinkedtoenvironmentalfactors suchasheavymetals,xenochemicals,andendocrinedisruptors,whicharealsoofmajor
concernfortheprogressiveburdenofglobaldisease(TangandHo,2007).Futureresultsfrom genome-widestudiescoupledwithresultsfromfunctionalstudiesandinvestigationon gene-environmentinteractionswillallowtheimprovementofcardiovascularriskassessment andthediscoveryofnewtargetsfortherapyandprevention(Gianfagnaetal.,2012).
1.3.2Nutrition,Diet,andLifestyle
Themostfamousquotelinkingfoodtodiseaseisthefollowing:“Letfoodbethymedicine andmedicinebethyfood”byHippocratesofKos(460–377BC),whoisuniversallyrecognized asthefatherofmodernmedicine.Hippocrates’workwasbasedonobservationofclinical signsandrationalconclusionsthatdidnotrelyonreligiousormagicalbeliefs(Yapijakis, 2009).Inmodernmedicine,manyepidemiologicalstudiesfocusonthelinksbetweendiet, nutrition,anddisease,withthemostnotableonebeingtheSevenCountriesStudy(see Chapter4).Inthisstudy,itwasfoundthatcertainpopulationsandcultureshavenotablylower incidencesofCVDthanothersdo,duetotheirdiet.Manystudieshavebeencarriedoutsince, includingPREDIMED(PREvencio ´ nconDIetaMEDiterra ´ nea),amulticenter,randomizedprimarypreventiontrialthatwasestablishedtoassessthelong-termeffectsoftheMediterranean dietontheincidencesofclinicalcardiovascularevents(Martı´nez-Gonza ´ lezetal.,2015). AcommonfeatureofthedietamongpopulationsintheMediterraneanisarelativelyhighdietaryintakeofvegetables,fruits,legumes,wholegrains,monounsaturatedfats,andnutsfollowedbymoderateconsumptionoffish,dairyproducts(mainlycheeseandyogurt), alcohol,andlowconsumptionofredandprocessedmeat(Tektonidisetal.,2015).
Furthermore,thereissubstantialevidencetosupportthebenefitsoffishconsumption,particularlyoilyfishsuchassalmon,trout,sardines,mackerel,andherring,toinhibittheonsetof CVD(Megsonetal.,2016).Themajorityofclinicaltrialsandepidemiologicalstudieshave mainlyinvestigatedtheroleofasmallgroupoffish-derivedlipids(suchastheomega-3 andomega-6fattyacidsofmarineorigin)asapreventivenutrientagainstCVD(Bowen etal.,2016; Lands,2016; WatanabeandTatsuno,2017).Nutraceuticalscontainingsuchfish lipidshavealreadybeenonthemarketandcoadministeredinseveralCVDsituations (Bowenetal.,2016).Ontheotherhand,emergingstudieshavereportedthatthemorepolar fishlipids(suchasphospholipidsandglycolipidsofmarineorigin)alsoplayabeneficial preventiveroleagainstatherosclerosisandCVD,bothintheshortandlongterm,mainly bydownregulatingtheinflammatorystatusinthesedisorders(Nasopoulouetal.,2011; Tsouprasetal.,2018a;Lordanetal.,2017).However,furtherresearchisrequiredinorder toinvestigatethepotentialuseofpolarlipidsofmarineoriginasanewclassofmarine-derived nutraceuticals.
Inaddition,sincetheSevenCountriesStudy,fatshavebeendemonizedbyscientists,nutritionalguidelines,andgovernmentpolicies.Recentresearchtrendshaveshownthatdairyproductsmaypossessmanyhealthbenefitsduetotheircontentofanti-inflammatorylipids,contrary
tothenegativeperceptiontheyearnedduetotheirhighlevelsofSFA(LordanandZabetakis, 2017a,b; Lordanetal.,2018b,c; Megalemouetal.,2017).Thus,researchers,themedicalcommunity,andnutritionalguidelineswerefocusedonreducingtheSFAcontentoffoodproducts, includingdairyproducts.ResearchersgenerallyagreethattheeffectsofreducingSFAinfoods aredependentonwhatreplacestheminthediet.ReducedCVDriskhasbeenassociated withthereplacementofSFAwitheither cis-polyunsaturatedfattyacidsor cis-monounsaturatedfattyacids.However,replacementofSFAwithcarbohydratesisassociatedwithnoreductionorevenanincreasedCVDrisk(Givens,2017).Governmentpolicyand nutritionalguidelineshavesupporteddietsbasedonthereductionofSFAforthepreventionof CVD,butitisbecomingincreasinglyapparentthattheseguidelineshavelittle significantbenefitsoncardiovasculardisease,diabetesmellitus,orinsulinresistance (Howardetal.,2006; Tinkeretal.,2008; MichaandMozaffarian,2010; Estruchetal., 2013; Chowdhuryetal.,2014).However,thesefindingsarestillcontentiousandnotalways supportedamongresearchers(Hooperetal.,2011; Dawczynskietal.,2015).Governmentpolicyhasbeeninvolvedinnationalnutritionalguidanceinmanycountrieswithsomenegative andsomepositiveeffects.
Educationandconcurrentgovernmentpolicycanplaycrucialrolesinencouraging appropriatelifestyleandnutritionalchangesinpopulationsaspreventivemeasures.Forexample,countriessuchastheUnitedKingdomandIrelandhavedraftedlegislationtointroducea sugartaxonsugar-sweetenedbeveragesby2018.Thesebeveragescontainsugarssuchas sucroseandhighfructosecornsyrupthathavelongbeenamatterofmuchscientificandpublic concernduetotheiradverseassociationswithobesity,typeIIdiabetesmellitus,andCVD (MalikandHu,2015).In2014,theMexicangovernmentimplementeda10%excisetax(1peso perliter)onsugar-sweetenedbeveragesleviedonmanufacturers(Sa ´ nchez-Romeroetal., 2016).Thiswastogreateffectasmarketresearchhasdemonstratedthattherewasa12% decreaseofsugar-sweetenedbeveragepurchasesbyMexicanhouseholdsbyDecember2014 (Colcheroetal.,2016).Meta-analysisby CabreraEscobaretal.(2013) hasshownthatatax onsugar-sweetenedbeveragesdoes,infact,reducetheirconsumptionandthatthisreduction increaseswithhighertaxrates.Thestudyalsorevealedthatthesereducedconsumption ratesresultedinmodestreductionsofpopulationweight.Therefore,asugartaxmaybeaworthwhilepreventativemeasureforobesityandotherchronicdiseases.Furtherevidencetosupport theroleofnutritionanddietinthedevelopmentandpreventionofcardiovasculardiseasewill beexploredthroughoutthebook.Anindividual’slifestyleisanequallyimportantfactorin determiningsusceptibilitytodisease,andaspreviouslymentioned,peoplewithahealthybalanceddietandregularexercisereducetheirriskofdevelopingchronicdiseasessuchasCVD. However,otherlifestylechoicescanhaveaprofoundimpactonourhealth,regardlessofdietor regularexercise.Onesuchlifestylechoiceissmoking.Mountingresearch(epidemiological, clinical,behavioral,andbiological)hasidentifiedcigarettesmokingasamajorexternalparameterthattriggerscanceraswellascardiovascularandpulmonarydiseases.Ofallthesediseases,
smokingisresponsiblefor90%ofalllungcancers(Peschetal.,2012).In2000,tobaccousewas relatedto >5milliondeathsperyeargloballyandthisfigureisestimatedtoriseto8millionby 2030.Passivesmokingorsecond-handsmokehasalsoemergedasamajorhealthconcernwith evidencethatchildrenandnonsmokershavebeenvictimtoprematuredeathanddisease throughexposuretosmokeinpublicplacesandtheworkplace.
Smokingandpassivesmokingarewell-establishedriskfactorsforCVD.Itishypothesized thattoxicexposuretochemicalconstituentsoftobaccosmokecausespersistentinflammatory changesinendothelialcells(AmbroseandBarua,2004).Cigarettesmokeisamixtureofthousandsofchemicalsgeneratedfromtheburningoftobacco.Thesechemicalshavecytotoxic, mutagenic,andcarcinogeniceffectswhileothersareaddictivecompounds.Someofthecompoundsresponsibleforacutecardiovasculartoxicityhavebeenidentified,includingcarbon monoxide,nicotine(AstrupandKjeldsen,1979),andheavymetalssuchascadmium(Hecht etal.,2013),butmanystillremainelusive.Interestingly,studieshaveshownthatwholesmoke inducesfargreatertoxicityincontrasttocarbonmonoxideornicotinealone(MichaelPittilo, 2000).Therefore,furtherresearchiswarrantedtodiscoverwhatothercompoundsinducecytotoxiceffects.Smokinghasanumberofimmunomodulatoryeffects.Cigarettesmokereduces leukocytechemotaxis,reducestheproductionofimmunoglobulins,modulatesantigenpresentation,promotesautoimmunity,andcausesastrongerinflammatoryreactionbyincreasingthe releaseoftissue-destructivecompounds(e.g.,reactiveoxygenspeciesandproinflammatory cytokines)(Leeetal.,2012a; Johannsenetal.,2014).
Globally,effortshavebeenmadetostemtheimpactofcigarettesmokeonthehealthof oursocietythroughtheimplementationofadvertisingcampaignsandsmokingbans.Smoking banshaveprovedtobesuccessfulinreducingtheincidencesofCVD( Justeretal.,2007; Richiardietal.,2009; Abeetal.,2017)andpulmonarydiseases(Gala ´ netal.,2017)insmokers andpassivesmokers,asevidencedbythe2004successoftheIrishnationalsmokingbanin workplacesandenclosedpublicspaces(Mulcahyetal.,2005; Stallings-Smithetal.,2013). Smokingbanshavebeensupplementedwithadvertisingcampaignsthathavebecomecommonplaceindevelopednationswiththeintentionofreducingtobaccoconsumption.Many countrieshaveintroducedrestrictionsontheadvertisingandpromotionofcigaretteswithwrittenwarningsandimagesplacedoncigarettecartonswarningofthehealthimplications ofsmoking.Economicinterventionshavealsoprovedtobeverybeneficialthroughthe increasedtaxationofcigarettesinmanycountries(Blecher,2008).Otherapproachesinclude nicotinereplacementtherapy,whichtakestheformofabsorbingnicotineviatablets, chewinggum,nasalsprays,patches,lozenges,orelectroniccigarettes(e-cigarettes)inorder toreducewithdrawalsymptomsassociatedwiththecessationofsmokingbyreplacing nicotineinthebloodstream.Althoughthespeedofabsorptionisdifferentbetweenthemethods, thereisnoevidencethatonetreatmentissuperiortoanother.Thechancesofdiscontinuing smokingincreaseby50%–70%throughnicotinereplacementtherapy(Silagyetal.,2004). Areviewby Kaisaretal.(2016) hashighlightedanumberofuncertaintiesinrelationto
e-cigaretteuse,anddispelsthemyththate-cigarettesmerelyemitwatervaporuponuse. Researchisgrowingtosupportthetheorythate-cigarettesemitpotentiallytoxicsubstances duetotheby-productsandconstituentsoftheflavoringadditives,includingtracesofheavy metalsaswellascarcinogenicandteratogenicagents(Goniewiczetal.,2014). Schober etal.(2014) haveshownthate-cigarettesarenotemissionfreeandtheirpollutantscanimpair airquality.Thus,thereisariskof“second-handvaping.”Theuseofe-cigarettesmaybeof majorconcernforfuturepublichealthasthereisnodataavailableinrelationtotheiruse andtheriskofchronicdiseasedevelopment.Asthetrendofe-cigaretteusegrows,itisclear thatthescientificandtoxicologicalevidencetosupporttheirusagelags(Rahmanetal.,2014). Furtherresearchisrequiredinordertoeitherexonerateorrejecte-cigarettesasaviablenicotine replacementmethodandtodevelopinformedmanufacturingregulationstosafeguardour health.
Ofalltheliteratelifestylefactors,inactivityandsedentarylifestylepatternsaredetrimental tohumanhealth.Lowtozerophysicalexerciseandlong-terminactivitywhencombinedwith anunhealthydietaredirectlyassociatedwithobesity,metabolicsyndrome,andtheonsetof manyadversehealthconditions,includingmajornoncommunicablechronicdiseasessuch asCHD,typeIIdiabetesmellitus,andcertaincancers,allofwhichshortenlifeexpectancy. Becausemuchoftheworld’spopulationindevelopedanddevelopingcountriesismainlyinactive(Leeetal.,2012b),obesityiscurrentlycharacterizedasadisease.Anabnormalaccumulationofbodyfat,typically20%abovethenormalidealbodyweight,mayresultinadverse effectsonhealth(AghaandAgha,2017).Thecausesofobesityaremultifactorialandnot entirelyunderstood.However,oneofthemaincausesisanenergyimbalancebetweencalorie intakeandexpenditure.Excesscalorieintakeandassociatedweightgainarecausedbythe interactionbetweentheenvironment,genetics,economics,individualbehaviors,nutrition, andevenourownmicrobiota(LeChatelieretal.,2013; SmithandSmith,2016). Thecommonmetrictocharacterizeanindividual’sweightisbodymassindex(BMI),where aBMIof25–29.9indicatesanoverweightindividual.Anobeseindividualisdefinedasa BMI > 30.ItalsoneedstobetakenintoconsiderationthattheuseofBMIisoftencriticized. Thisisbecause,sincethedevelopmentoftheBMImetric,therearemoreaccuratemeasurementsofbodymassavailablesuchasbioelectricalimpedanceandbody compositionalstudies(Rothman,2008).
Globally, >2.1billionpeopleareeitheroverweightorobese.IntheUnitedStates,almost 35%ofadultsareclassifiedasobeseandone-thirdofchildrenandadolescentsareeither overweightorobese.Obesityisthefifth-leadingcauseofmortalityintheworld,accounting for3.4milliondeathsannually(SmithandSmith,2016).Inactivityhaslongbeenassociated withanincreasedriskofobesityandCVD.Arecentmetaanalysishasshownthatamodestshift frominactivitytoasmallamountofphysicalactivitymayloweryourriskfactorsfordevelopingCVD(Wahidetal.,2016).Theseresultsaresupportedbytherecentprospectivecohort studyinRotterdam,whereitwasfoundthatCVDriskwashigherforthosethatwereinactive
