Review10.1586/14779072.5.2.283 2007 Future Drugs Ltd ISSN 1477-9072 283 www.future-drugs.comPreeclampsia and future cardiovascular riskJ Newstead, P von Dadelszen and Laura A MageeAuthor for correspondenceUniversity of British Columbia, Departments of Obstetrics and Gynaecology and Medicine, and the Centre for Applied Health Research and Evaluation, Child and Family Research Institute of British Columbia, and British Columbias Womens Hospital and Health Centre, 4500 Oak Street, Room 1U59, Vancouver V6H 3N1, BC, CanadaTel.: +1 604 875 2960Fax: +1 604 875 2961lmagee@cw.bc.caKEYWORDS: hypertension, ischemic heart disease, long-term cardiovascular mortality, preeclampsia, pregnancy, strokePregnancy is a metabolic and vascular stress test for women and those who fail are at increased risk of long-term cardiovascular complications. Specifically, women who develop preeclampsia (and/or other manifestations of placental dysfunction) are at increased risk of coronary heart disease, stroke and cardiovascular disease in general. The risk is highest among women who develop both maternal (e.g., hypertension and proteinuria) and fetal (e.g., intrauterine growth restriction) manifestations of abnormal placentation, especially with preterm delivery. Most women who develop a maternal placental syndrome return to a normal clinical state in the weeks following pregnancy and their absolute risk of cardiovascular disease in the short term is very low. However, perhaps having a placentally complicated pregnancy affords women the opportunity to personalize risk and take action. Action is needed. The fact that we, as a population, are getting heavier and more sedentary is an urgent public health issue. The American Heart Association recommends that all women (even those at low cardiovascular risk) pursue dietary and lifestyle changes, in addition to smoking cessation. Engaging women of child-bearing age who may be motivated by a complicated pregnancy would be very valuable, from a public health perspective, given the prevalence and importance of cardiovascular disease in women, and the central role of the woman as caregiver to children, spouses and other family members. Expert Rev. Cardiovasc. Ther. 5(2), 283294 (2007)More than half of the adult population in thedevelopedworldissedentaryorinactive[1].Metabolic syndrome is on the rise and this willonlyleadtofurtherstressonanalreadystrained healthcare system. Public health advo-catesareseekingwaystointerestthepopula-tion in this alarming trend and promote healthbehaviorsthathavebeenproventoimprovelong-term outcomes. Preeclampsiarepresentsjustsuchanoppor-tunityforpersonalizationofrisk.Preeclamp-siaandotherformsofplacentaldysfunctionhavebeenassociatedconsistentlywithexcesslong-term cardiovascular risk. It would appearthat these women have failed the physiologicalstresstestofpregnancy.Thisaffordsthehealthcareprovidertheopportunitytobothinitiateprimarypreventioninwomenatincreasedriskandeducatetheentirefamilyabout healthy lifestyle choices so that society atlarge also benefits.Cardiovascular disease in women: magnitude of the problemCardiovasculardisease(CVD)isthecauseofdeath for just over 50% of women worldwide[2]. The majority of these cardiovascular deathsareduetocoronaryheartdisease(23%)andstroke(18%).Preventioniskey.Nearlytwothirds of women who die suddenly of coronaryheartdiseasehavenopreviouslyrecognizedsymptoms.Also,wenowrecognizetheexist-enceofsubclinicaldiseasethatisamenabletotreatment, rather than viewing CVD as an allor nothing phenomenon.Recognized cardiovascular risk markers in womenTherearemanyglobalrisk-assessmenttoolsthat take a risk marker tally approach to theassessmentofCVDrisk[3].Themostwellknown is the Framingham global risk assess-menttoolthatincorporatesthefollowingCONTENTSCardiovascular disease in women: magnitude of the problemRecognized cardiovascular risk markers in womenIs preeclampsia a new, novel cardiovascular risk factor?What should clinicians do?ConclusionsExpert commentaryKey issuesFive-year viewReferencesAffiliationsFor reprint orders, please contact: reprints@future-drugs.comNewstead, von Dadelszen & Magee284 Expert Rev. Cardiovasc. Ther. 5(2), (2007)traditionalcardiovascularriskmarkers:gender,age,systolicbloodpressure(BP)anditstreatment,totalcholesterolandhigh-densitylipoproteins(HDL)[101].Theseareusedtodetermine the 10-year CVD risk estimate, which is then usedin guidelines to recommend management. These global risk assessment tools must be viewed as imper-fect and still in development for a number of reasons [4]. First,most of the available tools (including the Framingham score)are prone to error, particularly at the extremes of risk. Youngwomen are likely to fall into the low (or optimal) risk categoryand,assuch,theglobalriskassessmenttoolswillonlybemoderately accurate in predicting the 10-year risk of a majorcoronary event. Second, many tools do not take into accountother established risk markers for CVD, such as family historyof premature CVD, diabetes, chronic renal failure and obesity.Third,mosttoolsdonottakeintoaccountnewandnovelcardiovascularriskmarkers.Theseincludemicroalbuminuriaand preclinical atherosclerosis (e.g., measures of vascular func-tionandendothelialhealth).Thesenovelriskmarkersmayalso include a history of hypertensive pregnancy. What is theevidence for this?Is preeclampsia a new, novel cardiovascular risk factor?What is preeclampsia?Hypertensionduringpregnancyisclassifiedas:pre-existing(chronic) hypertension (that was present either prior to pregnancyorbefore20 weeksgestation,orwhichpersistsformorethan6 weekspostpartum)orgestational(preg-nancy-induced)hypertension(appearedafter20 weeksgestation)[5,6].Gestational(pregnancy-induced) hypertension is fur-ther subcategorized according to the pres-enceofproteinuriaand/oradversefea-tures.Proteinuriaisdefinedas0.3 g/dayormorebya24-hurinecollectionor,alternatively,byatleast2+byurinarydipstickoratleast30 mg/mmolurinarycreatininebyspoturinaryprotein:creati-nineratio[7].Adversefeaturesrefertomaternalcomplicationsofpreeclampsia,such as eclampsia (seizure), severe hyper-tension,elevatedliverenzymesorlowplatelets.TheCanadianclassificationsystemdefinespreeclampsiaasgesta-tionalhypertensionwithproteinuriaoradversefeatures.TheAmericanclassifi-cationsystemdefinespreeclampsiaasgestational(pregnancy-induced)hyper-tensionandproteinuria,butgoesontodescribe the potential multiorgan mater-nalandfetalcomplicationsofpre-eclampsia. Women who develop isolatedgestational(pregnancy-induced)hyper-tensionmaydevelopproteinuriaorend-organcomplicationsthatdefinepreeclampsia,orthehypertensionmayremainisolated.Therefore, the classification of a womans hypertensive disorderof pregnancy may change.The hypertensive disorders of pregnancy are common, com-plicating up to 10% of pregnancies worldwide. They representaleadingcauseofmaternalmortalityandmorbidityinpreg-nancy. The most common is gestational hypertension (56%).Usingpopulation-baseddata,approximately1%ofpregnan-ciesarecomplicatedbypre-existinghypertension,56%bygestationalhypertensionwithoutproteinuriaand12%bypreeclampsia [8]. Understanding the pathogenesis of preeclampsia is key to anunderstanding of preeclampsias multisystem and varied clinicalmanifestations.Themostpopulartheoryforthepathogenesisof preeclampsia describes a two-stage process (FIGURE 1) [911]. Thefirststageconsistsofarelativefailureofthematernaluterinespiralarteries(termeduteroplacentalarteriesinpreg-nancy)toundergotheirnormalvascularremodelingade-quatelyforthesubsequentfetoplacentaldemands.Innormalpregnancy, syncytiotrophoblast from the placenta invades thevascular luminal wall of uterine spiral arteries, resulting in lossof the inner elastic lamina and vascular smooth muscle. Theirdiameter increases fourfold to create an intervillous (maternal)blood supply that is high capacitance, low resistance and unre-sponsivetovasoactivestimuli.Thesechangesextendtotheinner third of the myometrium. By contrast, in preeclampsia,particularly early onset, the vascular remodeling of the uterineFigure 1. Pathogenesis of the maternal syndrome of preeclampsia (modified from [9]). ARDS: Acute respiratory distress syndrome; ATN: Acute tubular necrosis; DIC: Disseminated intravascular coagulation; PBL: Peripheral blood leukocyte; PG: Eicosanoid; ROS: Reactive oxygen species.Cytotrophoblast invasionImmunological factorsPoor placentationThrombophiliaMultiple pregnancyFetal macrosomiaAcute atherosis Uteroplacental mismatchIntervilloussoupEndothelial cell activationPBLs Cytokines PGs ROSPlacentaldebrisARDSMaternal syndrome CardiomyopathyEclampsia/strokeEdemaMicroangiopathichemolysis/thrombocytopenia/DICLiver damage/hematoma/ruptureGlomerularendotheliosis/proteinuria/ATNHypertensionPreeclampsia and future cardiovascular riskwww.future-drugs.com 285spiral arteries is more superficial in termsofdepthandthenumbersofuterinearterioles involved. Failureofnormalplacentationcanbecausedbymanyfactors,suchasgenetics(includingapaternalcontribution),maternalthrombophilia,pre-existinghypertension and chronic renal disease, asshown in FIGURE 1. It must also be recog-nizedthat,atterm,amongwomenwithpreeclampsia,thereisanexcessoflarge-for-date fetuses and multiple pregnancies.Underthesecircumstances,itmaybethat the demands of the normally formedfetoplacentalunitoutstripstheabilityoffully remodeled uteroplacental arteries tosupply those demands. Inthesecondstage,whichoccurslaterinpregnancy,fetaldemandsoutstriptheuteroplacentalsupply,resultinginutero-placental mismatch. As a result of this, a soup is released fromtheplacentacontainingsubstancesthatareproinflammatory,prothrombotic,vasoconstrictiveand/orantiangiogenic(e.g., sFlt-1) [12], or result in oxidative stress (i.e., reactive oxy-genspecies).Thissoupcausessystemicmaternalendothelialcelldysfunctionandvasospasm,activationofthecoagulationcascade with the formation of occlusive microthrombi and lossofintravascularfluid.Ultimately,thisleadstotheend-organcomplicationsofpreeclampsia.Itisworthemphasizingthathypertension is but one of these complications and is not partof thepathogenesisof preeclampsia.Also,this placental soupforms part of a forward feedback loop, which causes decreasedplacental perfusion, and so the cycle continues. Itfollowsfromthisdiscussionthatthematernalmanifesta-tions of preeclampsia are varied and can involve any organ sys-tem.Themostcommonmanifestationsare,ofcourse,thosethatmostcommonlydefinepreeclampsia:hypertensionandproteinuria. However, FIGURE 1 highlights that there can be anycombinationorpermutationofcomplications,includinghypertensionwithelevatedliverenzymes.Thereisalsoafetalsyndrome of preeclampsia, resulting from the consequences ofinadequateplacentation,andconsistingof:oligohydramnios(i.e.,lowamnioticfluid),intrauterinefetalgrowthrestriction,abnormalDopplervelocimetryoftheumbilicalarteryorstill-birth.Thisfetalsyndromecanpresentbeforethematernalmanifestationsofpreeclampsia;alternatively,theycanpresentinisolationandrepresentpartofthespectrumofplacentalabnormalities [13]. Why might preeclampsia be a cardiovascular risk marker?PreeclampsiaandCVDshareriskmarkersandhaveasimilarclinical picture and pathology. The hypothesis is that there is anunderlying maternal predisposition to vascular disease. The met-abolicstressofpregnancycausesthis predisposition tovasculardisease to become manifest as preeclampsia. After pregnancy, themetabolic stress is removed and virtually all women return to asubclinicalandnormotensivestate.However,withthepassageof time, they may again be pushed above the threshold for clini-caldisease,manifestedlaterinlifeasCVD.Thishypothesisisillustrated in FIGURE 2 [14]. Similar risk markersRisk markers for preeclampsia and for CVD are similar. Non-modifiable risk markers include: age, family history of the con-dition and ethnicity [15].Ofgreaterinterest arethosethatarepotentiallymodifiableortreatable,including(pre-existing)hypertension, diabetesmellitus,renaldisease, obesity, dyslipi-demia,metabolicsyndrome,microalbuminuria,throm-bophilia (such as antiphospholipid syndrome and hyperhomo-cystenemia) and elevated antibodies to Chlamydia pneumoniaeandcytomegalovirus[1618].Theideathatpreelcampsiaisafailed stress test and pregnancy is a form of the metabolic syn-dromeishelpfulinunderstandingtherelationshipbetweenthe two.Similar pathologyThe pathognomonic placental lesion of preeclampsia is calledacuteatherosisowingtoitshistologicalsimilaritytothelesions of atherosclerosis. Acute atherosis affects the uteropla-cental arteries (termed spiral arteries before pregnancy) of thedecidua(termedendometriumbeforepregnancy)andmyo-metrium. Similar to atherosclerosis, acute atherosis is charac-terizedbyfocalendothelialdisruption,fibrinoidnecrosisofthe arterial wall (containing both immunoglobulin [Ig]M andcomplementthatreflectinflammation),infiltrationofperivascularspacesbymononuclearcells,accumulationoflipid-ladenmacrophagesandlipoprotein(a)deposition[19].Theresultantplaquecontainslipidandcellulardebris.Thevesselscanbecomepartiallyorcompletelyoccludedorcanrupture [20]. Figure 2. Risk markers for vascular disease.Adapted from [14].Population with complicated pregnancy (e.g., preeclampsia)Healthy populationThreshold for vascular or metabolic diseasePregnancies Neonatal life Middle ageAgeVascular risk factorsNewstead, von Dadelszen & Magee286 Expert Rev. Cardiovasc. Ther. 5(2), (2007)Similar clinical picturePreeclampsia is characterized by metabolic changes that closelyresemble those of the metabolic syndrome: Hyperlipidemia (i.e., reduced HDL cholesterol and elevatedtriglycerides,freefattyacidsandlow-densitylipoprotein[LDL] cholesterol) Insulin resistance An increase in coagulation factors [10]These metabolic changes are seen to a lesser extent in normalpregnancy, which can be regarded as a transient metabolic syn-drome or a stress test of sorts. Normal pregnancy is associatedwithhyperlipidemia,relativeinsulinresistance,anincreaseincoagulationfactorsandupregulationoftheinflammatorycas-cade(andneutrophilia)[14].Itisthoughtthatinwomenwithmore abnormal prepregnancy carbohydrate, lipid and/or vascu-lar function, the metabolic stress of pregnancy may push thempastaclinicalthresholdforthemanifestationofvascularormetabolic disease (FIGURE 2). These women manifest, for exam-ple, what we know as gestational hypertension or preeclampsia,gestational diabetes (GDM) or thromboembolism.What is the evidence for an association between preeclampsia & CVD?Inthe1970s,LeonChesley,thefatherofourscientificandclinicalapproachtothehypertensivedisordersofpregnancy,recognizedthatwomenwhosufferfromeclampsiahaveanexcessoflong-termCVD[21].Overthelast10 years,therehave been many publications linking preeclampsia (and othermanifestations of abnormal placentation) with future CVD.Weareawareof12 retrospectivestudies(tencohort[2233]and two casecontrol [22,34]) that have examined an associationbetweengestationalhypertensionorpreeclampsia(withorwithout other adverse placental complications) and subsequentcardiovascularevents(TABLE 1).Thetermadverseplacentalevents refers to stillbirth, placental abruption, preeclampsia ornormotensive intrauterine growth restriction, all of which havecollectivelybeenreferredtoasthematernalplacentalsyn-drome. The outcomes analyzed have included any CVD or themost common specific ones: ischemic heart disease and stroke.ThesestudieshavebeenconductedinCanada[29],Iceland[22,26], Israel [23], Norway [25], Scotland [28,30,33], Sweden [32], theUK [24,34] and the USA [27].Aconsistentassociationhasbeendescribedbetweengesta-tionalhypertensionorpreeclampsiaandanincreasedriskofcardiovascularmortalityormorbidity,comparedwithwomenwhose pregnancies were not complicated by a maternal placentalsyndrome or population norms over a corresponding period oftime [26]. The point estimates for the relative risk (RR) of futurecardiovascular events following a pregnancy complicated by ges-tationalhypertensionorpreeclampsiahaverangedfrom1.3to3.3, with almost all studies finding the association to be signifi-cant, particularly for preeclampsia. The CVD was also reportedtooccurearlierinlife[24].Therealsoseemstobeaconsistentdoseresponserelationship.Moremildmanifestationsofthematernalplacentalsyndrome(i.e.,gestationalhypertensionorisolatedintrauterinefetalgrowthrestriction)havebeenassoci-ated less consistently and less strongly with increased cardiovas-cular risk. More severe manifestations of the maternal placentalsyndrome(i.e.,severepreeclampsiaorpreeclampsiaassociatedwithintrauterinefetalgrowthrestriction,pretermbirthand/orfetal death)haveconsistentlydemonstratedfuturecardiovascu-lar risk to be elevated, with much higher RR values (i.e., pointestimates ranging from 2.78.1). Also, a doseresponse relation-ship was demonstrated for recurrent gestational hypertension orpreeclampsia in subsequent pregnancies. Women with hyperten-sivediseaseinboththeirfirstandsecondpregnancies(vsonlytheir first pregnancy) had an even higher RR of future ischemicheart disease [32]. Over what period of time is this potentially increased cardio-vascularriskmanifested?Theanswerismanyyears,untiltheunderlying maternal predisposition reaches the critical thresholdfor clinical manifestations (FIGURE 3). In summary, preeclampsia specifically (and the maternal pla-centalsyndromeingeneral)hasbeenassociatedwithanincreasedriskoffutureCVDingeneralandstrokeandischemicheartdiseaseinparticular.Therearetwoimportantpoints to make. Firstly, association does not imply causation. Atpresent,themostplausibleexplanationfortheassociationbetween preeclampsia and CVD is that preeclampsia unmasks amaternalpredispositiontovasculardisease.Thissituationisanalogous to GDM, which is a risk marker for, but not a causeof, long-term Type II diabetes. Secondly, the increase in cardio-vascularriskassociatedwithpreeclampsiaorotherplacentalsyndromes is small; the immediate risk is very low (