Childhood age and associations between childhood metabolic syndrome and adult risk for metabolic syndrome, type 2 diabetes mellitus and carotid intima media thickness : The international childhood cardiovascular cohort consortium

Childhood Age and Associa ions Be ween Childhood Me abolic Synd ome and Adul Risk o Me abolic Synd ome, Type 2 Diabe es Melli us and Ca o id In ima Media Thickness: The In e na ional Childhood Ca dio ascula Coho Conso ium Juha Koskinen, MD, PhD; Cos an G. Magnussen, PhD; Alan Sinaiko, MD; Jessica Woo, MHSA, PhD; Elaine U bina, MD, MS; Da id R. Jacobs, J , PhD; Julia S einbe ge , MD, MS; Ronald P ineas, MB, BS, PhD; Ma hew A. Sabin, MD, PhD; T udy Bu ns, MPH, PhD; Ge ald Be enson, MD; Lydia Bazzano, MD, PhD; Alison Venn, PhD; Jo ma S.A. Viika i, MD, PhD; Nina Hu i-K€ ah€ onen, MD, PhD; Olli Rai aka i, MD, PhD; Te ence Dwye , MD, MPH; Ma kus Juonala, MD, PhD Backg ound-—The e is pauci y o knowledge conce ning he specific age in you h when he associa ions o me abolic synd ome (Me S) begin o be ope a i e. Thus, we in es iga ed he ela ion o age o he associa ions o childhood Me S wi h adul Me S, ype 2 diabe es melli us and high ca o id in ima-media hickness. Me hods and Resul s-—Fi e housand eigh -hund ed h ee pa icipan s we e analyzed in 4 coho s udies (Ca dio ascula Risk in Young Finns, Bogalusa Hea S udy, P ince on Lipid Resea ch S udy, Insulin S udy). In e na ional cu o s and p e iously used 75 h pe cen ile cu o s we e used o child en o define Me S and i s componen s. Mean ollow-up pe iod was 22.3 yea s. Logis ic eg ession was used o calcula e isk a ios and 95% confidence in e als. Childhood Me S and o e weigh we e associa ed wi h o e 2.4- old isk o adul Me S om he age o 5 yea s onwa d. Risk o ype 2 diabe es melli us was inc eased om he age o 8 ( isk a io, 2.6–4.1; 95% confidence in e al, 1.35–6.76 and 1.12–7.24, espec i ely) onwa d o he 2 childhood Me S c i e ia based on in e na ional cu -o alues and o childhood o e weigh . Risk o high ca o id in ima-media hickness was significan a ages 11 o 18 yea s in ela ion o childhood Me S o o e weigh ( isk a io, 2.44–4.22; 95% confidence in e al, 1.55–3.55 and 2.55–5.66, espec i ely). Con inuous childhood Me S sco e was associa ed wi h adul Me S om he age o 5, wi h ype 2 diabe es melli us om he age o 14 and wi h high ca o id in ima-media hickness om he age o 11 yea s onwa d. Conclusions-—Adul Me S was p edic ed by Me S in childhood beginning a age 5. Howe e , adul ype 2 diabe es melli us and subclinical a he oscle osis we e no p edic ed by childhood da a un il a e age 8. Body mass index measu emen alone a he same age poin s p o ided simila findings. (J Am Hea Assoc. 2017;6:e005632. DOI: 10.1161/JAHA.117.005632.) Key Wo ds: ca o id in ima-media hickness •me abolic synd ome •obesi y • ype 2 diabe es melli us F om he Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine (J.K., C.G.M.) and Depa men o Medicine (J.S.A.V., M.J.), Uni e si y o Tu ku, Finland; Hea Cen e (J.K.) and Di ision o Medicine (J.S.A.V., M.J.), Tu ku Uni e si y Hospi al, Tu ku, Finland; Menzies Ins i u e o Medical Resea ch, Uni e si y o Tasmania, Hoba , Aus alia (C.G.M., A.V.); Depa men o Pedia ics (A.S.) and Di ision o Epidemiology and Communi y Heal h, School o Public Heal h (D.R.J.), Uni e si y o Minneso a, Minneapolis, MN; Di ision o Bios a is ics and Epidemiology, Depa men o Pedia ics, Cincinna i Child en’s Hospi al Medical Cen e and Uni e si y o Cincinna i College o Medicine, Cincinna i, OH (J.W.); Di ision o Ca diology, Depa men o Pedia ics, Cincinna i Child en’s Hospi al Medical Cen e and Uni e si y o Cincinna i, Cincinna i, OH (E.U.); Depa men o Pedia ics, Uni e si y o Minneso a Masonic Child en’s Hospi al, Minneapolis, MN (J.S.); Di ision o Public Heal h Sciences, Wake Fo es Uni e si y School o Medicine, Wins on-Salem, NC (R.P.); Mu doch Child en’s Resea ch Ins i u e, Royal Child en’s Hospi al, Pa k ille, Aus alia (M.A.S., T.D.); Depa men o Pedia ics, Uni e si y o Melbou ne, Pa k ille, Aus alia (M.A.S., T.D.); Depa men o Epidemiology, College o Public Heal h, Uni e si y o Iowa, Iowa Ci y, IA (T.B.); Depa men o Epidemiology, Tulane Cen e o Ca dio ascula Heal h, Tulane Uni e si y School o Public Heal h and T opical Medicine, New O leans, LA (G.B.); Depa men s o Epidemiology and Bios a is ics and Bioin o ma ics, Tulane Uni e si y Heal h Sciences Cen e , Tulane Uni e si y, New O leans, LA (L.B.); Depa men o Pedia ics, Uni e si y o Tampe e School o Medicine and Tampe e Uni e si y Hospi al, Tampe e, Finland (N.H.-K.); Depa men o Clinical Physiology and Nuclea Medicine, Uni e si y o Tu ku and Tu ku Uni e si y Hospi al, Tu ku, Finland (O.R.). Co espondence o: Juha Koskinen, MD, PhD, Resea ch Cen e o Applied and P e en i e Ca dio ascula Medicine, Uni e si y o Tu ku, Kiinamyllynka u 10, FIN-20520, Tu ku, Finland. E-mail: jkkosk@u u.fi Recei ed Janua y 19, 2017; accep ed June 14, 2017. ª2017 The Au ho s. Published on behal o he Ame ican Hea Associa ion, Inc., by Wiley. This is an open access a icle unde he e ms o he C ea i e Commons A ibu ion-NonComme cial License, which pe mi s use, dis ibu ion and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed and is no used o comme cial pu poses. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 1 ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om Me abolic synd ome (Me S) is a cons ella ion o me abolically in e ela ed a iables, including obesi y, hype ension, dyslipidemia, hype glycemia, and, in some analyses, also including hype insulinemia. 1 I is well known ha adul s wi h Me S a e a inc eased isk o ype 2 diabe es melli us (T2DM) and ca dio ascula disease (CVD). 2 The po en ial impo ance o childhood Me S has been ou lined in a consensus s a emen om he Ame ican Hea Associ- a ion 3 ha no ed he need o addi ional esea ch in child en and adolescen s in o de o cla i y i s ela ion o he de elopmen o adul ca dio ascula isk and disease. 3 Defining he age when childhood me abolic isk exposu e begins o be associa ed wi h adul ca dio-me abolic isk and a he oscle osis would help ocus pedia ic ca egi e s on p e en i e s a egies, including e alua ion and in e en ion. Using longi udinal da a om a collabo a i e s udy, we ha e p e iously shown a ela ion be ween pedia ic Me S and adul Me S, T2DM, and high ca o id a e y in ima-media hickness (cIMT), a subclinical ma ke o a he oscle osis. 4 Howe e , he s udy did no conside he specific age o ages in you h when he associa ion begins o be ope a i e o whe he o e weigh alone in childhood p edic s adul ou comes di e en ially acco ding o age o measu emen . In he p esen s udy, we used da a om 5803 indi iduals in 4 la ge, p ospec i e coho s udies pa icipa ing in he In e na ional Childhood Ca dio ascula Coho (i3C) Conso - ium 5 ha ha e ollowed pa icipan s om childhood in o adul hood. The objec i e o he s udy is o examine he age in childhood when he ela ionship o childhood Me S and o e weigh (acco ding o childhood Me S c i e ia) is fi s associa ed wi h adul Me S, T2DM, and cIMT. Because he e is no s anda d defini ion o pedia ic Me S, we compa ed 3 p e iously published defini ions. 4,6 Me hods De ailed s udy cha ac e is ics and me hods o he 4 coho s a e desc ibed elsewhe e. These p e ious epo s also include analyses o loss o ollow-up o show ha he ep esen a- i eness o he coho s was main ained. 5,7–12 Da a we e analyzed in 5803 pa icipan s om 4 longi u- dinal coho s udies (YFS [Ca dio ascula Risk in Young Finns S udy], BHS [Bogalusa Hea S udy], PLRS [P ince on Lipid Resea ch S udy], and IS [Minneso a Insulin S udy]) ha measu ed isk ac o s o Me S in childhood and adul hood. Each s udy was app o ed by he app op ia e ins i u ional e iew boa ds, and w i en in o med consen o assen was ob ained om all he s udy pa icipan s aged >18 o assen and consen om hei pa en s o pa icipan s aged <18. Da a om mo e han 1 age (maximum, 1 isi pe pa icipan pe age g oup) we e en e ed in o he childhood analyses om he 5803 pa icipan s (eg, in YFS, a pa icipan examined a age 6, 9, and 12 yea s had da a en e ed in o he analyses om all 3 ages). Fo subjec s wi h mul iple ollow-up isi s in adul hood, da a om he mos ecen isi we e used o maximize he leng h o ollow-up. De ails o he me hods used o he measu emen o weigh , heigh , blood p essu e (BP), lipid le els, glucose and insulin le els, cIMT, and o he co a ia es in each coho s udy a e p o ided elsewhe e. 5,7–12 Heigh and weigh we e mea- su ed a all ime poin s. Body mass index (BMI) was calcula ed om he o mula: weigh (kg)/heigh (m) 2 . A andom ze o sphygmomanome e was used o measu e BP. Venous blood samples we e aken a e a 12-hou as om he an ecubi al ein. In YFS a baseline, se um choles e ol and iglyce ides we e measu ed using ully enzyma ic Boeh inge CHOD-PAP ki s wi h an OLLI 3000 analyze . Subsequen ly, Olympus Sys em eagen analyze in a clinical chemis y analyze (AU400; Olympus, Tokyo, Japan) was used o de e mine lipid le els. Se um high-densi y lipop o ein (HDL) choles e ol was measu ed by he dex an sulpha e 500 000 me hod. Low- densi y lipop o ein choles e ol was calcula ed using he F iedewald o mula. 13 In BHS, HDL-choles e ol and iglyc- e ides we e measu ed using chemical p ocedu es wi h a Technicon Au o Analyze II (Technicon Ins umen Co p, Ta y own, NY), acco ding o he labo a o y manual o he Lipid Resea ch Clinics p og am. Since his ime, hese a iables we e de e mined by enzyma ic p ocedu es 14 using he Abbo VP ins umen (Abbo Labo a o ies, No h Chicago, IL). In PLRS da a, all se um lipid measu emen s we e pe o med wi h s anda d me hods in Cen e s o Disease Con ol and P e en ion–s anda dized labo a o ies. 15 Child- hood glucose le els we e measu ed wi h an ABA-100 sys em by using he hexokinase me hod. In adul hood, glucose le els we e measu ed wi h a Dade Dimension Xpand sys em by using he hexokinase/glucose-6-phospha e dehyd ogenase me hod. 15,16 In IS, se um lipids we e analyzed in he Uni e si y o Minneso a labo a o y wi h a Cobas FARA. HDL- choles e ol was de e mined a e p ecipi a ion o non-HDL lipop o eins wi h a magnesium/dex an p ecipi a ing eagen . Clinical Pe spec i e Wha Is New? •The da a om his s udy p o ide help o in o m he iming o ini ia ing clinical sc eening o ca dio ascula isk ac o s. Wha A e he Clinical Implica ions? •E alua ion o me abolic isk ac o le els p o ide meaning ul p edic ion o adul ou comes a ound he ime o pube y onse . •Using body mass index alone p o ides essen ially simila esul s compa ed o he con en ional me abolic synd ome model. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 2 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om T iglyce ides we e de e mined wi h a s anda d glyce ol blanked enzyma ic iglyce ide me hod. Blood samples we e analyzed o glucose wi h a Beckman Glucose Analyze II (Beckman Ins umen s Inc, Fulle on, CA). Insulin samples we e de e mined wi h a adioimmunoassay ki (Equa e RIA; Binax Co p, Po land, ME). B-mode ul asound s udies o he le ca o id a e y we e pe o med a ollow-ups using s anda dized p o ocols in each s udy. In YFS, o assess in aindi idual ep oducibili y o ul asound measu emen s, 57 subjec s we e e-examined 3 mon hs a e he ini ial isi . The a e age absolu e di e ence and SD be ween measu emen s was 0.050.04 mm. In BHS, 75 pa icipan s unde wen epea ul asound examina ions 10 o 12 days a e hei ini ial isi o de e mine in aindi idual ep oducibili y. The a e age absolu e di e ence and SD be ween measu emen s o all cIMT segmen s was 0.050.03 mm. In IS, ep o- ducibili y o he cIMT showed a mean di e ence (SD) o 0.020.03 o analysis sepa a ed by 1 week. Defini ion o Me S and I s Componen s in Childhood Table 1 lis s he componen s and alues o he 3 Me S defini ions used in his s udy. BMI was used as he measu e o adiposi y because wais ci cum e ence was no a ailable a baseline in all coho s. Fas ing insulin was used when glucose was no a ailable o he YFS, BHS, o IS coho s a baseline. We gene a ed age-, sex-, ace-, coho -, and s udy-yea – specific pe cen iles o BMI, sys olic and dias olic BPs, HDL- choles e ol, iglyce ides, insulin, and glucose. Fo he modified Na ional Choles e ol Educa ion P og am (Me SNCEP75) defini ion, a pa icipan was ca ego ized as ha ing Me S i he o she had any 3 o he ollowing 5 componen s: BMI o wais ci cum e ence ≥75 h pe cen ile; sys olic o dias olic BP ≥75 h pe cen ile; HDL-choles e ol ≤25 h pe cen ile; iglyce ides ≥75 h pe cen ile; o insulin/ glucose ≥75 h pe cen ile. The second childhood Me S defini ion used age- and sex- s anda dized pedia ic cu poin s a ailable in he li e a u e o deno e each componen isk ac o (Me SPed). 4 A pa icipan was ca ego ized as ha ing Me S i he o she ulfilled o e weigh plus any 2 o 4 emaining isk componen c i e ia. O e weigh o obesi y we e defined acco ding o he Cole classifica ion. 17 P ehype ension o hype ension was defined acco ding o he Fou h Repo on High Blood P essu e in Child en and Adolescen s om he Na ional High Blood P essu e Educa ion P og am. 18 Low HDL-choles e ol and high iglyce ides we e defined using cu poin s p oposed om g ow h-cu e da a ha we e linked o adul defini ions. 19 Hype glycemia was defined as plasma glucose ≥5.60 mmol/L (100 mg/dL). 20 Hype insulinemia was defined when glucose was una ailable as ha ing insulin le els abo e age-, sex-, ace-, s udy-coho –, and s udy-yea – specific 75 h pe cen ile. The hi d Me S defini ion (Me SCook) was desc ibed by Cook e al 21 using he Na ional Choles e ol Educa ion P og am (Adul T ea men Panel III) defini ion modified o age. O e weigh o obesi y and ele a ed BP was defined as BMI o sys olic o dias olic BP ≥90 h pe cen ile. Ele a ed alues o iglyce ides we e defined a le els a o abo e 1.695 mmol/L (150 mg/dL) and o glucose le els a o abo e 5.6 mmol/L (100 mg/dL); dec eased le els o HDL- choles e ol we e defined as le els a o below 1.036 mmol/L (40 mg/dL). When glucose was no a ailable, we used hype insulinemia (≥90 h pe cen ile). Finally, a con inuous Me S sco e o child en was cons uc ed based on a sex- and ace-specific algo i hm de i ed om confi ma o y ac o analysis o da a om he Na ional Heal h and Nu i ion Examina ion Su ey. 22 Pa icipan s wi h missing glucose da a we e excluded om he con inuous Me S analyses. Table 1. Me S Defini ions and Thei Componen s Used in This S udy Me S Defini ion O e weigh Ele a ed BP High T iglyce ide Le el Low-HDL Choles e ol Glucose/Insulin Abno mali y Me SNCEP75 (any 3 componen s) BMI ≥75 h pe cen ile Sys olic and/o dias olic BP ≥75 h pe cen ile T iglyce ides ≥75 h pe cen ile HDL-choles e ol ≤25 h pe cen ile Glucose o insulin le el ≥75 h pe cen ile Me SCook (any 3 componen s) BMI ≥90 h pe cen ile Sys olic and/o dias olic BP ≥90 h pe cen ile o >130/85 mm Hg ≥150 mg/dL ≤40 mg/dL Glucose ≥100 mg/ dL o insulin ≥90 h pe cen ile Me SPed (o e weigh +any 2 componen s) Cole classi ica ion NHBPEP-classi ica ion G ow h cu e dependen * G ow h cu e dependen * Glucose ≥100 mg/ dL o insulin ≥90 h pe cen ile BP indica es blood p essu e; Me S, me abolic synd ome; NCEP, Na ional Choles e ol Educa ion P og am; NHBPEP, he Na ional High Blood P essu e Educa ion P og am. *A ailable only om age o 6 yea s onwa d. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 3 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om Defini ion o Me S in Adul hood Me S in adul hood was defined by he diagnos ic c i e ia p o ided by a join s a emen om he In e na ional Diabe es Fede a ion Task Fo ce on Epidemiology and P e en ion, Na ional Hea , Lung and Blood Ins i u e, he Ame ican Hea Associa ion, he Wo ld Hea Fede a ion, he In e na ional A he oscle osis Socie y, and he In e na ional Associa ion o he S udy o Obesi y. 23 Me S was diagnosed when 3 o mo e o he ollowing 5 c i e ia we e p esen : wais ci cum e ence cu poin s o ≥102 cm o men and ≥88 cm o women o define abdominal obesi y; iglyce ides ≥1.695 mmol/L (150 mg/dL); HDL-choles e ol <1.036 mmol/L (40 mg/dL) in men o <1.295 mmol/L (50 mg/dL) in women; BP ≥130/ ≥85 mm Hg o BP-lowe ing medica ion; o as ing glucose ≥5.6 mmol/L (100 mg/dL). Defini ion o T2DM in Adul hood Pa icipan s we e classified as ha ing T2DM i hey: (1) had a as ing plasma glucose ≥7.0 mmol/L (≥126 mg/dL); (2) had a glycohemoglobin (A1C) le el o ≥6.5% (48 mmol/mol); (3) epo ed ecei ing o al hypoglycemic agen s and/o insulin injec ions and did no ha e ype 1 diabe es melli us; o (4) epo ed a his o y o physician-diagnosed T2DM. Women who epo ed ha ing physician-diagnosed diabe es melli us only du ing he e m o hei p egnancy we e conside ed o ha e had ges a ional diabe es melli us. Defini ion o High cIMT in Adul hood Consis en wi h p e ious epo s, 24 high cIMT in adul hood was defined as a maximum cIMT ≥90 h pe cen ile o age-, sex-, ace-, s udy-yea –, and s udy-coho –specific alues (YFS, BHS). Fo IS, high cIMT in adul hood was defined as a mean alue ≥90 h pe cen ile (age, sex, ace, and s udy yea ) because maximum alues we e no a ailable. Da a on cIMT we e no a ailable o he PLRS coho and we e excluded om he analyses examining high cIMT. S a is ical Analysis The YFS coho examined child en om specific bi h coho s wi h 3-yea in e als (ages 3, 6, 9, 12, 15, and 18 yea s a baseline su ey), whe eas he o he s udies had pa icipan s a ying ac oss all ages om 3 o 18 yea s. The e o e, dic a ed by YFS being he la ges coho , indi iduals om BHS, PLRS, and IS a age g oups o 3 o 4, 5 o 7, 8 o 10, 11 o 13, 14 o 16, and 17 o 18 yea s we e included in he espec i e age g oups wi h he 3-, 6-, 9-, 12-, 15-, and 18-yea -olds om YFS. To ake in o accoun possible di e ences a ibu ed o age, sex, ace, and secula ends in isk ac o s, s udy coho , and di e en me hodology age-, sex-, ace-, s udy-yea –, and s udy-coho – specific isk ac o pe cen iles we e gene a ed o childhood isk ac o s. Age- and sex-adjus ed ANOVA o con inuous a iables and logis ic eg ession o ca ego ical a iables was used o compa e cha ac e is ics among he s udy g oups. Fo main analyses, di e en mul i a ia e echniques (Poisson eg ession wi h ime o se , mul inomial eg ession, Cox p opo ional haza ds a ios, and logis ic eg ession) we e used o calcula e isk a ios (RR) and 95% confidence in e als (95% CI). Conclusions d awn om he esul s we e essen ially simila independen o he me hod used. In he Resul s sec ion, he alues om he logis ic eg ession a e shown, which had he lowes Akaike and Bayesian c i e ion in o ma ion alues. All eg ession analyses using da a om bo h sexes we e adjus ed wi h sex and all eg ession models combining da a om se e al coho s we e addi ionally adjus ed o s udy coho , and yea o minimize he e ec o he e ogenei y o he pa icipan s a ibu ed o geog aphy and physiology. Because o almos no T2DM e en s we e obse ed in he 2 younges age g oups, we collapsed hese 2 g oups (3–4 and 5–7 yea olds) in o 1 age g oup (3–7 yea olds) when analyzing u u e isk o T2DM. S a is ical analyses we e pe o med wi h SAS so wa e ( e sion 9.4; SAS Ins i u e, Ca y, NC). S a is ical significance was in e ed as P<0.05. Resul s Clinical Cha ac e is ics Table 2 shows he numbe o childhood isi s in each s udy coho and he clinical cha ac e is ics o he s udy subjec s. MeanSD ollow-up ime was 22.39.5 yea s. PLRS had he oldes and IS had he younges pa icipan s a adul ollow-up. Subjec s we e p edominan ly whi es (76%) and blacks (24%). Childhood insulin le els, Me SNCEP75, and adul hood Me S did no ha e significan di e ences among he g oups (P>0.16). O he wise s a is ically significan di e ences in clinical cha - ac e is ics we e obse ed among he s udy g oups (Palways <0.05). The no mali y assump ions o he esiduals we e assessed by examining his og ams o he esiduals and no mal p obabili y plo s. The esiduals we e no mally dis ibu ed. Childhood Me S and O e weigh P edic ing he Risk o Adul Me S Tables 3 and 4 show RRs and 95% CIs (sexes combined and sepa a ely, espec i ely) acco ding o child age (ages 3–18, di ided in o 3-yea in e als) o childhood Me S p edic ion o adul Me S. Childhood Me S was a significan p edic o o adul Me S om ages 5 (RR, 2.43–3.39 wi h 95% CI 1.74– 3.40 and 1.68–6.83, espec i ely) o 18 yea s (RR, 3.64– DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 4 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om 5.13; 95% CI, 2.90–4.56 and 3.23–8.15, espec i ely) o he 3defini ions, excep ha he associa ion in males using he Me SCook defini ion did no become significan un il 8 yea s (RR, 4.62; 95% CI, 2.41–8.83). Nex , we emo ed BMI om he Me SNCEP75 c i e ia; he esul s based on any 2 o he emaining componen s emained essen ially simila o Me SNCEP75. Finally, a mul i a iable model including all indi idual Me SNCEP75 isk ac o s was cons uc ed. All Me SNCEP75 componen s we e significan p edic o s be ween ages 5 o 18 yea s (Table 5). When s udy coho s we e analyzed sepa a ely, he RRs o childhood Me S in p edic ing adul hood Me S we e consis en wi h Table 3 ( esul s shown in Table 6). Childhood Me S P edic ing he Risk o Adul T2DM Because o low numbe o T2DM e en s, we collapsed 2 younges age g oups (3–4 and 5–7 yea olds) in o 1 age g oup (3–7 yea olds). Childhood Me S became a significan Table 2. Cha ac e is ics o S udy Subjec s a Thei Fi s Obse a ion in Childhood and Thei Mos Recen Obse a ion in Adul hood BHS IS PLRS YFS PValue* All Coho s N 1983 322 562 2936 5803 Childhood da a Age, y 11.23.5 14.31.6 12.63.1 10.93.9 <0.0001 11.84.0 Age ange, y 3 o 18 11 o 18 6 o 18 3 o 18 3 o 18 E hinici y (whi e/black %) 62/38 78/22 71/29 100/0 <0.0001 76/24 BMI, kg/m 2 19.34.5 22.85.2 19.94.4 17.93.0 <0.0001 19.24.3 Sys olic BP, mm Hg 10211 1089 10413 11111 <0.0001 10612 Dias olic BP, mm Hg 5013 5613 6311 6510 <0.0001 5614 Glucose, mmol/L 4.60.5 4.90.4 4.80.44 4.70.7 <0.0001 4.60.5 Insulin, mU/L 10.48.2 11.58.8  10.06.8 0.16 10.47.6 T iglyce ides, mmol/L 0.780.40 1.010.58 0.850.42 0.770.35 <0.0001 0.790.40 HDL-choles e ol, mmol/L 1.500.44 1.130.25 1.390.32 1.600.32 <0.0001 1.510.40 Childhood Me S, % Me SNCEP75 20 20 20 19 0.16 19 Me SPed 9 14 4 3 <0.0001 6 Me SCook 5 9 14 3 <0.0001 5 Con inuous Me S sco e (mean) 0.950.78 0.100.69 0.710.78 0.670.63 <0.0001 0.830.80 Adul hood da a Age, y 31.38.0 23.32.5 42.16.8 34.48.1 <0.0001 33.28.5 Age ange, y 19 o 51 19 o 35 19 o 57 21 o 50 19 o 57 BMI, kg/m 2 27.57.1 26.46.5 28.76.9 25.34.7 <0.0001 26.56.2 Sys olic BP, mm Hg 11413 11010 12015 11914 <0.0001 11614 Dias olic BP, mm Hg 6911 6510 7911 7311 <0.0001 7111 Glucose, mmol/L 4.70.9 4.80.8 5.01.5 5.20.9 <0.0001 4.91.0 T iglyce ides, mmol/L 1.320.95 1.090.63 1.521.47 1.300.94 <0.0001 1.310.97 HDL-choles e ol, mmol/L 1.280.40 1.190.28 1.180.38 1.350.34 <0.0001 1.300.37 Me S, % 20 9 32 25 0.009 23 T2DM, % 1 0 5 2.5 0.17 2 cIMT mean, mm  0.4430.057  0.6030.097 <0.0001 0.5910.104 cIMT maximum, mm 0.7190.192  0.6430.101 <0.0001 0.6720.148 Values a e mean (SD), unless o he wise men ioned. BHS indica es he Bogalusa Hea S udy; BMI, body mass index; BP, blood p essu e; cIMT, ca o id in ima-media hickness; HDL, high- densi y lipop o ein; IS, he Insulin S udy; Me S, me abolic synd ome; PLRS, he P ince on Lipid Resea ch S udy; YFS, he Ca dio ascula Risk in Young Finns S udy. *Age- and sex-adjus ed P alues om g oup compa isons. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 5 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om p edic o o adul T2DM a age 8 yea s (RR, 2.85–4.14; 95% CI, 1.12–7.24 and 1.37–12.4, espec i ely) and con inued h ough age 18 (RR, 7.63; 95% CI, 3.85–15.1 and 1.98–10.2, espec i ely) wi h he Me SCook, and Me SPed me hods. De ailed esul s a e shown in Table 7. Significan associa ions be ween childhood Me S and adul hood T2DM we e obse ed om 14 yea s onwa d by he Me SNCEP75 me hod (RR, 3.59; 95% CI, 2.09–6.16). When sexes we e analyzed sepa a ely (Table 8), he associa ion in emales be ween childhood Me S and adul T2DM was inconsis en and spo adic, wi h Me SCook significan a age 11 o 13, Me SPed and Me SNCEP75 significan a age 14 o 16, and Me SPed and Me SCook significan a age 17 o 18. Simila esul s wi h childhood Me S ela ion o adul T2DM we e ob ained by using o e weigh alone (Table 9). O he Me SNCEP75 isk ac o s did no show consis en associa ion wi h adul T2DM. When s udy coho s we e analyzed sepa a ely, he ou come was un eliable, because o almos no ou come e en s (Table 10). Childhood Me S P edic ing he Risk o Adul High cIMT Childhood Me S measu ed by all me hods p edic ed adul - hood high cIMT 2- o 4- old in he 11 o 18 age g oups. De ailed RR and 95% CI a e p esen ed in Table 11. The esul s we e he same when sexes we e analyzed sepa a ely (Table 12). When BMI was emo ed om he Me SNCEP75 c i e ia, he associa ion was no longe s a is ically significan in he 11 o 16 emale age g oups (P>0.13). F om he Me SNCEP75 isk ac o s, only high BMI showed consis en associa ion wi h adul cIMT om he age o 11 onwa d (Table 13). High BP was associa ed wi h la e in ima-media hickness a ages 5 o 7, high insulin a ages 11 o 16, and high iglyce ides and low HDL choles e ol a ages 14 o 18. When indi idual coho s we e analyzed (Table 14), high adul cIMT was p edic ed only in YFS and BHS o 11- o 18-yea - olds. Childhood Con inuous Me S Sco e P edic ing he Risk o Adul Me S, T2DM, and High cIMT The associa ion be ween childhood con inuous Me S and adul hood ou comes is shown in Table 15, wi h he analyses limi ed o hose wi h childhood glucose da a. The esul s we e simila o he 3 Me S me hods (ie, significan o adul Me S a all ages and significan o T2DM and cIMT a adolescen ages). When sexes we e analyzed sepa a ely, p edic ion o he adul Me S was significan om age 5 onwa d (RR, 2.14; 95% CI, 1.19–3.85 o males and RR, 3.79; 95% CI, 1.89–7.77 o emales) and high cIMT om age 11 onwa d (RR, 2.02; 95% CI, 1.20–3.37 o males and RR, 1.82; 95% CI, 1.11–2.98 o Table 3. RRs and Thei 95% CIs o Childhood Me S P edic ing he Risk o Adul hood Me S Age a Childhood Measu emen in Yea s (No. o Me S E en s in Adul hood/No. o Subjec s) 3 o4(N=74/422) 5 o 7 (N=144/859) 8 o 10 (N=238/1054) 11 o 13 (N=351/1410) 14 o 16 (N=316/1334) 17 o 18 (N=275/949) RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue Me SNCEP75 (yes/no) 1.77 (0.98–3.20) 0.060 2.43 (1.74–3.40) <0.0001 3.21 (2.51–4.11) <0.0001 2.91 (2.37–3.58) <0.0001 3.26 (2.66–3.99) <0.0001 3.64 (2.90–4.56) <0.0001 Me SPed (yes/no)*   3.17 (1.92–5.22) <0.0001 2.76 (2.01–3.80) <0.0001 3.18 (2.46–4.11) <0.0001 3.68 (2.84–4.76) <0.0001 3.20 (2.28–4.51) <0.0001 Me SCook (yes/no) 1.50 (0.57–3.92) 0.40 3.39 (1.68–6.83) 0.0006 4.08 (2.62–6.35) <0.0001 3.79 (2.57–5.58) <0.0001 4.10 (2.84–5.93) <0.0001 5.13 (3.23–8.15) <0.0001 All models a e adjus ed o sex, s udy coho , and yea . CI indica es 95% confidence in e al; Me S, me abolic synd ome, RR, isk a io. *Me SPed was defined only o subjec s aged 6 o 18 yea s. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 6 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om Table 4. Sex-Specific RRs and Thei 95% CIs o Childhood Me S P edic ing he Risk o Adul hood Me S Males Age in Yea s (No. o Subjec s) 3 o4(N=44/203) 5 o 7 (N=85/376) 8 o 10 (N=119/461) 11 o 13 (N=180/655) 14 o 16 (N=171/620) 17 o 18 (N=132/438) RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue Me S a ian s Me SNCEP75 (yes/no) 1.91 (0.88–4.15) 0.10 1.85 (1.16–2.97) 0.010 3.28 (2.29–4.69) <0.0001 3.13 (2.33–4.22) <0.0001 3.62 (2.72–4.82) <0.0001 3.96 (2.83–5.53) <0.0001 Me SPed (yes/no)*   3.36 (1.54–7.30) 0.0022 3.68 (2.32–5.84) <0.0001 4.03 (2.73–5.95) <0.0001 4.30 (2.97–6.23) <0.0001 3.33 (2.02–5.49) <0.0001 Me SCook (yes/no) 0.79 (0.17–3.86) 0.77 2.19 (0.77–6.19) 0.14 4.62 (2.41–8.83) <0.0001 4.75 (2.55–8.85) <0.0001 3.60 (2.14–6.03) <0.0001 4.13 (2.24–7.61) <0.0001 Me SNCEP75 † (yes/no, omi ing BMI om he Me S de ini ion) 1.48 (0.75–2.94) 0.26 1.72 (1.14–2.60) 0.009 2.21 (1.61–3.02) <0.0001 2.59 (1.98–3.38) <0.0001 2.52 (1.95–3.25) <0.0001 2.88 (2.16–3.84) <0.0001 Females 3 o4(N=30/219) 5 o 7 (N=59/483) 8 o 10 (N=119/593) 11 o 13 (N=171/755) 14 o 16 (N=145/714) 17 o 18 (N=143/511) RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue Me S a ian s Me SNCEP75 (yes/no) 1.61 (0.63–4.09) 0.31 3.22 (1.99–5.21) <0.0001 3.17 (2.24–4.46) <0.0001 2.78 (2.07–3.72) <0.0001 2.94 (2.20–3.91) <0.0001 3.46 (2.54–4.72) <0.0001 Me SPed (yes/no)   2.93 (1.52–5.65) 0.0013 2.11 (1.35–3.32) 0.0011 2.64 (1.86–3.74) <0.0001 3.20 (2.22–4.61) <0.0001 3.13 (1.96–5.00) <0.0001 Me SCook (yes/no) 2.48 (0.73–8.41) 0.15 4.65 (1.81–11.9) 0.0014 3.68 (2.00–6.77) <0.0001 3.45 (2.07–5.73) <0.0001 4.72 (2.80–7.97) <0.0001 6.99 (3.41–14.3) <0.0001 Me SNCEP75 † (yes/no, omi ing BMI om he Me S de ini ion) 1.13 (0.50–2.52) 0.76 2.94 (1.85–4.67) <0.0001 2.65 (1.93–3.65) <0.0001 2.63 (2.01–3.43) <0.0001 2.34 (1.82–3.01) <0.0001 2.12 (1.62–2.77) <0.0001 All models a e adjus ed o sex, s udy coho , and yea . BMI indica es body mass index; CI, 95% confidence in e al; Me S, me abolic synd ome; RR, isk a io. *Me SPed was defined only o subjec s aged 6 o 18 yea s. † Me S s a us was ulfilled i he o she ulfilled any 2 o he emaining Me S componen s (blood p essu e, iglyce ides, o glucose/insulin abo e 75 h pe cen ile and high-densi y lipop o ein choles e ol below 25 h pe cen ile). DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 7 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om Table 5. Mul i a iable RRs and Thei 95% CIs o Childhood Me S Risk Fac o s P edic ing he Risk o Adul hood Me S Risk Fac o (Yes/ No)* Age a Childhood Measu emen in Yea s (No. o Me S E en s in Adul hood/No. o Subjec s) 3 o4 5 o7 8 o10 11 o13 14 o16 17 o18 RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue High BMI 75 1.20 (0.67–2.13) 0.53 2.39 (1.73–3.29) <0.0001 2.49 (1.97–3.13) <0.0001 2.89 (2.38–3.51) <0.0001 3.21 (2.66–3.87) <0.0001 3.51 (2.84–4.33) <0.0001 High BP 75 1.15 (0.69–1.92) 0.59 1.62 (1.20–2.20) 0.002 2.11 (1.70–2.64) <0.0001 1.61 (1.34–1.93) <0.0001 1.22 (1.02–1.45) 0.03 1.57 (1.30–1.91) <0.0001 High insulin 75 1.14 (0.67–1.94) 0.63 2.01 (1.46–2.77) <0.0001 1.77 (1.39–2.25) <0.0001 2.28 (1.86–2.79) <0.0001 2.14 (1.77–2.59) <0.0001 1.86 (1.50–2.29) <0.0001 High iglyce ides 75 1.37 (0.78–2.41) 0.26 1.70 (1.23–2.36) 0.001 1.83 (1.44–2.33) <0.0001 2.14 (1.75–2.61) <0.0001 2.28 (1.89–2.75) <0.0001 2.00 (1.62–2.46) <0.0001 Low HDL 75 2.09 (1.23–3.55) 0.006 2.13 (1.54–2.94) <0.0001 1.91 (1.51–2.42) <0.0001 2.27 (1.87–2.77) <0.0001 1.88 (1.56–2.28) <0.0001 1.98 (1.61–2.44) <0.0001 All models a e adjus ed o sex, s udy coho , and yea . BMI indica es body mass index; BP, blood p essu e; CI, 95% confidence in e al; HDL, high-densi y lipop o ein; Me S, me abolic synd ome; RR, isk a io. *High BMI, BP, insulin, iglyce ides ≥age, sex, ace, s udy coho , and yea -specific 75 h pe cen ile and low HDL ≤25 h pe cen ile. Table 6. RRs and Thei 95% CIs o Childhood Me S P edic ing Risk o Me S in Adul hood S a ified by S udy Coho Age (y) 3 o4 5 o7 8 o10 11 o13 14 o16 17 o18 RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue YFS Me SNCEP75 (yes/no) 1.76 (0.96–3.22) 0.063 2.25 (1.52–3.35) <0.0001 2.89 (2.13–3.93) <0.0001 2.61 (1.98–3.44) <0.0001 3.06 (2.34–4.02) <0.0001 3.27 (2.45–4.36) <0.0001 BHS Me SNCEP75 (yes/no) 2.53 (0.12–93.3) 0.61 2.98 (1.52–5.85) 0.001 3.59 (2.26–5.71) <0.0001 3.38 (2.33–4.89) <0.0001 3.13 (2.22–4.40) <0.0001 4.16 (2.77–6.26) <0.0001 IS Me SNCEP75 (yes/no)       2.86 (0.91–9.00) 0.07 9.05 (3.51–23.4) <0.0001 6.78 (1.88–24.0) 0.0033 PLRS Me SNCEP75 (yes/no)   2.17 (0.29–15.9) 0.44 6.44 (2.15–19.2) 0.0009 4.01 (1.95–8.25) 0.0002 3.37 (1.38–8.18) 0.0072 5.55 (1.76–17.5) 0.0035 Models adjus ed o sex. BHS indica es he Bogalusa Hea S udy; CI, 95% confidence in e al; IS, he Insulin S udy; Me S, me abolic synd ome; PLRS, he P ince on Lipid Resea ch S udy; RR, isk a io; YFS, he Ca dio ascula Risk in Young Finns S udy. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 8 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om emales) o bo h males and emales. Because o he small numbe o diabe es melli us cases, esul s we e inconsis en in significance bu consis en in di ec ion. The isk o T2DM was significan o 8 o 10- and 14 o 16-yea -old males (RR, 4.19; 95% CI, 1.16–15.1 and RR, 3.40; 95% CI, 1.72–6.71, espec i ely) and o 8 o 10- and o 17 o 18-yea -old emales (RR, 3.43; 95% CI, 1.32–8.86 and RR, 2.99; 95% CI, 1.34–6.68, espec i ely). Discussion The esul s om his s udy demons a e ha childhood Me S and o e weigh in bo h males and emales seems o p edic inc eased isk o adul Me S om age 5 yea s onwa d. In addi ion, childhood Me S iden ifies child en om ages 8 o 14 yea s onwa d who a e a inc eased isk o adul T2DM and ea ly subclinical a he oscle osis measu ed by cIMT. Simila esul s we e ound when an Me S sco e, using Me S componen s as con inuous a iables, was subs i u ed o he Me S, which uses dicho omized componen s o define isk. We and o he s ha e assessed pedia ic Me S as a isk ac o o adul Me S, T2DM, and high cIMT in coho s consis ing o bo h child en and adolescen s. A p ospec i e s udy o o me s uden s om he P ince on lipid esea ch s udy epo ed ha child en aged 5 o 19 yea s wi h Me S we e mo e likely o ha e Me S, T2DM, and clinical CVD 25 o 30 yea s la e as adul s. 10,25 Simila associa ions we e obse ed in he YFS and BHS s udies conce ning Me S, T2DM, and cIMT. 4,6 Howe e , he numbe o pa icipan s in hose s udies was oo small o be able o conside age- s a ified analyses, and li le is cu en ly known abou he age when childhood Me S exposu e begins o ela e o adul isk. The p esen s udy, wi h a coho o 5803 indi iduals, shows ha a significan ela ion be ween childhood Me S and adul Me S begins as ea ly as age 5 (ou da a a ea lie ages a e spa se and we he e o e do no conside hem defini i e), and he ela ion o T2DM and subclinical a he oscle osis begins in ea ly adolescence. In con as o he p esen s udy, a 10-yea longi udinal s udy o 1604 Pima Indians aged 5 o 19 yea s wi h da a ob ained a age 26 yea s showed ha clus e ing o CVD isk ac o s in 3 childhood age g oups (5–9, 10–14, and 15–19 yea s) inc eased he isk o ea ly T2DM. 26 The sligh ly younge age a which a ela ion o adul T2DM was ecognized may be ela ed o he known inc eased isk o de elopmen o diabe es melli us in he Pima popula ion. A s anda d uni e sal me hod o defining pedia ic Me S is no a ailable, and he c i e ia cu en ly used ha e been a iably adop ed om adul s anda ds. 3 In he p esen epo , we show ha he esul s be ween 3 di e en pedia ic Me S defini ions we e essen ially simila in p edic ing adul Me S, T2DM, and cIMT. In addi ion, he cMe S sco e, using isk ac o s as con inuous a iables, esul ed in findings simila Table 7. RRs and Thei 95% CIs o Childhood Me S P edic ing he Risk o Adul hood T2DM Age a Childhood Measu emen in Yea s (No. o T2DM E en s in Adul hood/No. o Subjec s) 3 o7*(N=12/1281) 8 o 10 (N=19/1054) 11 o 13 (N=26/1410) 14 o 16 (N=34/1334) 17 o 18 (N=34/949) RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue RR (95% CI) PValue Me SNCEP75 (yes/no) 1.54 (0.58–2.50) 0.33 1.46 (0.64–3.48) 0.38 1.67 (0.86–3.23) 0.13 3.59 (2.09–6.16) <0.0001 2.61 (1.50–4.56) 0.0007 Me SPed (yes/no) † 1.64 (0.20–13.0) 0.63 2.85 (1.12–7.24) 0.027 3.21 (1.59–6.46) 0.0011 5.15 (2.74–9.68) <0.0001 7.63 (3.85–15.1) <0.0001 Me SCook (yes/no) 3.73 (0.73–16.9) 0.09 4.14 (1.37–12.4) 0.011 5.57 (2.52–12.3) <0.0001 5.54 (2.61–11.7) <0.0001 4.50 (1.98–10.2) 0.0003 All models a e adjus ed o sex, s udy coho , and yea . CI indica es 95% confidence in e al; Me S, me abolic synd ome; RR, isk a io; T2DM, ype 2 diabe es melli us. *Because o low numbe o ou comes, 2 younges age g oups we e collapsed in o 1 age g oup. † Me SPed was defined only o subjec s aged 6 o 18 yea s. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 9 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om Re e ences 1. Rea en GM. Ban ing lec u e 1988. Role o insulin esis ance in human disease. Diabe es. 1988;37:1595–1607. 2. Wilson PW, D’Agos ino RB, Pa ise H, Sulli an L, Meigs JB. Me abolic synd ome as a p ecu so o ca dio ascula disease and ype 2 diabe es melli us. Ci cula ion. 2005;112:3066–3072. 3. S einbe ge J, Daniels SR, Eckel RH, Hayman L, Lus ig RH, McC indle B, Mie us-Snyde ML; Ame ican Hea Associa ion A he oscle osis, Hype ension, Council on Ca dio ascula Nu sing, and Council on Nu i ion, Physical Ac i i y. 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Koskinen J, Kahonen M, Viika i JS, Tai onen L, Lai inen T, Ronnemaa T, Leh imaki T, Hu i-Kahonen N, Pie ikainen M, Jokinen E, Helenius H, Ma sson N, Rai aka i OT, Juonala M. Con en ional ca dio ascula isk ac o s and me abolic synd ome in p edic ing ca o id in ima-media hickness p og ession in young adul s: he Ca dio ascula Risk in Young Finns S udy. Ci cula ion. 2009;120:229–236. DOI: 10.1161/JAHA.117.005632 Jou nal o he Ame ican Hea Associa ion 16 Childhood Me abolic Synd ome P edic ing Adul Risk Koskinen e al ORIGINAL RESEARCH by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om Ma kus Juonala Bazzano, Alison Venn, Jo ma S.A. Viika i, Nina Hu i-Kähönen, Olli Rai aka i, Te ence Dwye and J , Julia S einbe ge , Ronald P ineas, Ma hew A. Sabin, T udy Bu ns, Ge ald Be enson, Lydia Juha Koskinen, Cos an G. Magnussen, Alan Sinaiko, Jessica Woo, Elaine U bina, Da id R. Jacobs, In e na ional Childhood Ca dio ascula Coho Conso ium Me abolic Synd ome, Type 2 Diabe es Melli us and Ca o id In ima Media Thickness: The Childhood Age and Associa ions Be ween Childhood Me abolic Synd ome and Adul Risk o Online ISSN: 2047-9980 Dallas, TX 75231 is published by he Ame ican Hea Associa ion, 7272 G een ille A enue,Jou nal o he Ame ican Hea Associa ionThe doi: 10.1161/JAHA.117.005632 2017;6:e005632; o iginally published Augus 16, 2017;J Am Hea Assoc. h p://jaha.ahajou nals.o g/con en /6/8/e005632 Wo ld Wide Web a : The online e sion o his a icle, along wi h upda ed in o ma ion and se ices, is loca ed on he o mo e in o ma ion. h p://jaha.ahajou nals.o gAccess publica ion. Visi he Jou nal a is an online only OpenJou nal o he Ame ican Hea Associa ionSubsc ip ions, Pe missions, and Rep in s: The by gues on Janua y 4, 2018h p://jaha.ahajou nals.o g/Downloaded om