Cardiometabolic and Cardiovascular Complications of Obesity in Children

46 In e na ional Jou nal o Pedia ics and Child Heal h, 2020, 8, 46-62 E-ISSN: 2311-8687/20 © 2020 Sa y Science Publishe Ca diome abolic and Ca dio ascula Complica ions o Obesi y in Child en G. Pé ez-Gimeno1,#, P. A gen e-A izón1,#, A.I. Rupé ez1, G. Bueno-Lozano1-3 and L.A. Mo eno1,2,* 1GENUD Resea ch g oup, Uni e sidad de Za agoza, Ins i u o Ag oalimen a io de A agón (IA2), Ins i u o de In es igación Sani a ia (IIS) A agón, Za agoza, Spain 2CIBERObn, Mad id, Spain 3Unidad de Endoc inología Pediá ica, Hospi al Clínico Lozano Blesa, Facul ad de Medicina, Uni e sidad de Za agoza, Za agoza, Spain Abs ac : The ise in obesi y in bo h child en and adul s has made obesi y one o he bigges public heal h p oblems o his cen u y. Obesi y along wi h o he ac o s such as hype ension, insulin esis ance, dyslipidemia and diabe es melli us a e isk ac o s o he de elopmen o ca dio ascula diseases. O e weigh and/o obesi y du ing childhood and i s main enance un il adul li e has been associa ed wi h ea ly s ages o ca dio ascula disease. Fo his eason, he aim o his s udy is o e ise he s a e o he a o ca diome abolic and ca dio ascula complica ions ela ed wi h o e weigh and/o obesi y in child en and adolescen s. The i s consequence o weigh gain is an inc ease in adipose issue, wi h di e en dis ibu ion depending on he sex. The excess o a mass en ails dys unc ion o adipose issue wi h an al e ed sec e ion o adipokines and ins au a ion o a p oin lamma o y en i onmen , which may de i e in me abolic synd ome condi ion. The inc ease o adipose issue along wi h an inc ease in sympa he ic ne ous sys em, igge s an inc eased le en icula mass and wi h a educed dias olic unc ion. The e o e, obesi y should be p e en ed om he ea ly s ages o li e, in o de o a oid obesi y i sel and he me abolic dis u bances ha could unde mine quali y o li e u he on. Keywo ds: Obesi y, Child en, Adolescen s, Ca diome abolic complica ions, Ca dio ascula complica ions . INTRODUCTION Obesi y is cu en ly a wo ldwide pandemic ha has ex emely inc eased in he las decades, being nowadays one o he mos se ious public heal h conce ns, bo h in de eloped and de eloping coun ies. Besides, obesi y is an independen and s ong isk ac o o he de elopmen o ca dio ascula diseases (CDVs) [1]. Due o he mul i ac o ial na u e o obesi y, he e a e many ac o s o ake in o accoun o i s app oach. Socioeconomic ac o s such as ha ing a low income o immig an o igin (black, Hispanic) ha e been ound o in luence he de elopmen o o e weigh o obesi y. Howe e , his se o ac o s seem o ac as a whole and ha e shown a clea e ela ionship wi h he de elopmen o no o obesi y, which can be obse ed as soon as he child is ges a ing [2]. Obesi y de elopmen implies ex a medical cos s ha ange be ween 0.7% and 2.8% o o al heal h spending in a coun y. In addi ion, when BMI is highe han 25 kg/m2 medical cos s inc ease up o 9.1% o o al heal hca e *Add ess co espondence o his au ho a he GENUD Resea ch g oup, Uni e sidad de Za agoza, Ins i u o Ag oalimen a io de A agón (IA2), Ins i u o de In es igación Sani a ia (IIS) A agón, Za agoza, Spain; Tel: +34 876553756; E-mail: lmo eno@uniza .es #Con ibu ed equally o his wo k. expendi u es [3]. In he USA, he es ima ed cos ela i e o obesi y is $149.4 billion [4]. The inc ease in obesi y p e alence has also been obse ed in child en and adolescen s. Indeed, in 2016, 124 million child en and adolescen s had obesi y [5]. Finkels ein e al., obse ed ha hose child en wi h o e weigh o obesi y had an inc ease in medical cos o US$180 and US$220, espec i ely, compa ed o child en wi h no mal weigh [6]. Child en and adolescen s wi h obesi y e y likely will ha e his condi ion in adul hood, also ha ing a high isk o p ema u e dea h [7]. Mo eo e , ha ing o e weigh o obesi y du ing childhood is associa ed wi h me abolic changes, an al e ed adipokine p o ile and a low-g ade in lamma o y s a e, which is mo e exp essed du ing adolescence [8]. Physical exe cise can imp o e he BMI o hose child en wi h obesi y o o e weigh by wo di e en ways: physical educa ion lessons in school and spo s pa icipa ion in hei leisu e- ime [9]. Al hough he e is s ill no ag eemen on how many hou s a e necessa y o exe a p o ec i e e ec on he de elopmen o obesi y [9], a educ ion o o e weigh o obesi y has been obse ed in child en who a ended 90 min o physical educa ion pe week [10]. Howe e , o he in e en ion p og ams ha e inc eased un il 270 min/week wi hou signi ica i e di e ences. Fo his Ca diome abolic and Ca dio ascula Complica ions o Obesi y in Child en In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 47 eason, hose child en who do no pe o m physical ac i i y in hei school hou s a e ecommended o exe cise in hei leisu e- ime. Opposi e o his, in las 20 yea s, child en ha e become mo e seden a y han be o e wi h an inc ease in hei sc een ime. Tha inc ease has been associa ed wi h g ea e consump ion o unheal hy oods. And his has ansla ed in o a posi i e ela ionship be ween sc een ime and obesi y [11, 12]. Recen ly, he e m me abolically heal hy obesi y (MHO) has been p oposed o desc ibe hose indi iduals wi h obesi y bu no ca diome abolic complica ions [13]. Howe e , indi iduals wi h MHO may e en ually de elop CVDs la e in li e [14]. The p opensi y o de elop obesi y and he esponses o me abolic challenges a e di e en be ween he sexes [15, 16]. I is no only he di e ences as o weigh gain and adipose issue accumula ion and dis ibu ion, bu also, he seconda y complica ions associa ed o ha ing o e weigh o obesi y ha also di e be ween he sexes, e en be o e pube y [17]. The mechanisms unde lying hese di e ences s ill need u he esea ch o be comple ely unde s ood, bu sex s e oids, sex ch omosomes and e al/neona al p og amming as well as epigene ic changes seem o be esponsible ac o s [18, 19]. Hence, i is impo an o conside he li elong pe spec i e s a ing om childhood, ying o p e en an ea ly ini ia ion o a he oscle o ic diso de s and he de elopmen o u u e CVDs and hea h ailu e [20, 21]. In his sense, pa en al ole is c ucial o in luence in he p opensi y o become o no obese in he u u e. I is well desc ibed ha he likelihood o become obese begins as soon as in u e o and e en be o e concep ion [22]. The e o e, ma e nal heal h, nu i ion du ing ges a ion o e al exposu e o s ess can be key in he u u e de elopmen o obesi y o me abolic diseases. Besides, nu i ion du ing in ancy, childhood and adolescence a e key pe iods o he u u e de elopmen o no o obesi y. One o he bes me hods o p e en obesi y om he ea ly ages is he ole ha pa en s ha e in hei child en e e yday ou ine. Adop ing a heal hy li es yle om childhood is c ucial o dec ease he p obabili ies o de eloping me abolic diseases in adul hood [23], he e o e pa en s mus clea ly unde s and his message ha migh a oid u u e obesi y de elopmen and i s associa ed como bidi ies. They mus ac i ely p omo e heal hy ea ing habi s, se ing good examples in hei e e yday ou ines and es ablish physical ac i i y as a p io i y om he e y ea ly ages, which will posi i ely a ec bo h, pa en s and child en. Based on he a ailable li e a u e ega ding he complica ions o obesi y in child en, he aim o his Figu e 1: Me abolic complica ions in child en and adolescen s wi h obesi y. The inc ease in he amoun o adipose issue as a consequence o an imbalance be ween ene gy in ake and ene gy expendi u e leads o o e weigh o obesi y and di e se me abolic dis u bances: adipose issue dys unc ion, al e ed adipokine p o ile, me abolic synd ome and ins au a ion o a p oin lamma o y en i onmen . O no e, he e a e me abolic di e ences be ween he sexes esiding on di e en adipose issue localiza ion, me abolism and unc ion. Figu e legend: AT: Adipose issue, IL-6: In e leukin 6, TNF-α: Tumo nec osis ac o alpha, IL-1-β: In e leukin 1 be a, IL-8: In e leukin 8, PAI-1: Plasminogen ac i a o inhibi o -1, VAT: Visce al adipose issue, WC: Wais ci cum e ence, TG: T iglyce ides, HDL: High densi y lipop o eins, IR: Insulin Resis ance. 48 In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 Pé ez-Gimeno e al. e iew is o ga he he e idence ega ding he ca diome abolic and ca dio ascula complica ions ela ed wi h o e weigh and/o obesi y in child en and adolescen s (Figu e 1). As gene al knowledge, we will i s desc ibe how we should assess he excess o adiposi y, wi h an especial ocus in he abdominal egion. BODY COMPOSITION ASSESSMENT IN CHILDREN AND ADOLESCENTS WITH OBESITY Obesi y is de ined as an excess o adiposi y. The mos widely used ool o assessing obesi y is he body mass index (BMI) [5]. In child en, i is used aking in o accoun sex and age speci ic pe cen iles [24]. BMI has impo an limi a ions as i also akes in o accoun lean mass, which may a ise mis aken conclusions. Fa mass may be assessed measu ing skin old hickness, using dual ene gy X- ay abso p iome y (DXA) o ai displacemen ple ismog aphy (BodPod), amongs o he me hods [25]. In child en, adiposi y should be desc ibed as he a mass index (FMI = a mass in kg / heigh 2). The mos me abolically ac i e adipose issue is loca ed in he abdominal egion; he e o e, some au ho s sugges o assess in clinical p ac ice, no only BMI, bu also wais ci cum e ence (WC) o wais o heigh a io (WHR) [1]. In his ega d, abdominal [ isce al) body a has shown a g ea e associa ion wi h he de elopmen o CVDs and mo ali y [26]. Indeed, WC measu emen has shown a good co ela ion wi h isce al a mass [27]. Howe e , he mechanisms h ough which abdominal a con ibu es o he isk o hese diseases a e no comple ely unde s ood [28-30]. Thus, BMI, WC and WHR can be used as p edic o s o ca diome abolic isk in child en and adolescen s [31, 32]. In his sense, he an h opome ic pa ame e s ha e been associa ed wi h some o he abno mali ies included wi hin he me abolic synd ome (Me S), posi i ely co ela ing wi h HOMA-IR and wi h an al e ed adipokine p o ile as i will be desc ibed in he sec ions below. I is impo an o no e he sex di e ences obse ed ega ding adipose issue accumula ion and dis ibu ion. Pube y begins wi h a cha ac e is ic subcu aneous body a mass ha is independen o he age o onse and i is sex speci ic [33]. Du ing pube y, a mass inc eases in emales in o de o ensu e ep oduc ion while a ee mass inc eases in males [33]. This sexual dimo phism is mos ly due o he in luence o sexual ho mones and sex ch omosomes, wi h emales o en showing a mo e bene icial me abolic p o ile. As o adipose issue accumula ion, i is wo h no ing ha i s expansion can occu by hype plasia ( ec ui men o new adipocy es) [34] o hype ophy o he exis ing adipocy es, which is associa ed wi h isce al adipose issue and highe me abolic isk [35, 36]. Es ogens a e sugges ed o a o hype plasia, inc easing adipocy e p ogeni o cells and acili a ing ascula supply o adipose issue [37]. Mo eo e , emales ha e a con inuous inc ease in a mass h oughou de elopmen , while males each hei maximum le els o a accumula ion a pube y [38]. Thus, women exhibi highe le els o adiposi y h ough li espan and accumula e mo e subcu aneous adipose issue (SCAT) in con as o males ha accumula e isce al a (VAT) [39]. I is well known ha accumula ion o a mass in he uppe zone o he body is associa ed wi h ca diome abolic complica ions associa ed wi h obesi y, whe eas a mass accumula ion in he glu eal- emo al egion is no and could e en be p o ec i e [40]. CARDIOMETABOLIC COMPLICATIONS Obesi y and Me abolic Synd ome in Child en Obesi y and o e weigh in child en a e signi ican isk ac o s o de eloping he Me S ea ly in li e o du ing adul hood [21, 41]. Me S can be de ined as he coexis ence o se e al clinical mani es a ions: obesi y, mos ly as cen al (abdominal) a accumula ion, insulin esis ance, glucose in ole ance, high a e ial blood p essu e and dyslipidemia (high iglyce ides and/o low high-densi y lipop o ein choles e ol (HDL-C) concen a ions). All o hem a e he s onges isk ac o s o de eloping CVDs and ype 2 diabe es (T2DM). Along wi h obesi y, he p e alence o Me S in p epube al child en and adolescen s is ala mingly inc easing [20, 42] and young child en and adolescen s can be mani es ed wi h he same biochemical al e a ions as adul s unde going he Me S [43, 44]. Howe e , adul c i e ia should no be simply used in child en o de ine his condi ion. Indeed, o his da e i is con o e sial and he e is no uni ied de ini ion o Me S in child en and adolescen s [45], al hough he in e na ional diabe es ede a ion consensus o he Me S in child en and adolescen s is he mos commonly used de ini ion [46]. Acco ding o he de ini ion [46], WC measu emen is he main Ca diome abolic and Ca dio ascula Complica ions o Obesi y in Child en In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 49 componen as i is an independen p edic o o insulin esis ance, lipid le els and blood p essu e [47]. Besides, in child en and adolescen s wi h obesi y and simila BMI, hose wi h highe amoun o isce al adipose issue ha e lowe insulin sensi i i y [48]. Some au ho s sugges including o he componen s ela ed o insulin esis ance as HOMA-IR o QUICKI o gi e a mo e adjus ed de ini ion o Me S in child en [49]. Mo eo e , he p esence o abdominal a nega i ely a ec s he lipid p o ile, and his has been also obse ed in adolescen s [50]. The a he ogenic index o plasma [AIP), iglyce ides (TG)/HDL-C a io is a no el index used in young pa ien s o p edic ca diome abolic complica ions in child en wi h obesi y [51]. High TG plasma le els hemsel es a e ma ke s o ca diome abolic isk and one o he mos common lipid diso de s obse ed in child en and adolescen s wi h obesi y [52]. Simila ly, apolipop o eins AI and B (ApoAI and ApoB), lipop o ein-associa ed phospholipase A2 (Lp-PLA2) and ApoB/ApoAI a io ha e also been epo ed as use ul ools o p edic insulin esis ance and ca dio ascula diso de s [53]. Inc eased ApoB/ApoA1 a io and i s associa ion wi h ele a ed body weigh , excess adiposi y and an al e ed lipid p o ile has been epo ed in child en [54]. As p e iously men ioned, men and women accumula e adipose issue in a di e en manne and hese dissimila i ies may as well imply di e ences in he ca diome abolic complica ions associa ed wi h obesi y and Me S. Di e en a mass localiza ion implies di e en adipose issue me abolism and unc ion, including a ia ions in adipokine p oduc ion, insulin sensi i i y, mi ochond ial unc ion, a y acid elease and lipolysis, as well as he in lamma o y p o ile [16]. Fu he mo e, i is known ha ene gy balance, glucose and lipid me abolism a e di e en ly egula ed du ing g ow h and in men and women, wi h epidemiological e idence suppo ing ha men a e mo e p one o de elop obesi y and diabe es. The p o ec i e ac ion o es ogens in women which exp ess es ogen ecep o s in di e en issues including he b ain, adipose issue and panc ea ic be a cells seems o be c i ical o explain he sex di e ences [55, 56]. Adolescen s wi h obesi y al eady show ca diome abolic diso de s a ound he onse o pube y [31, 57]. Indeed, accumula ion o adipose issue leading o o e weigh and obesi y a ound 7 yea s o age ha pe sis s un il pube y is a isk ac o o T2DM in midli e [58, 59]. The du a ion o obesi y inc eases he isk o T2DM de elopmen [60]. None heless, i body weigh is educed owa ds no mal BMI alues be o e he onse o pube y, he isk o ca dio ascula and me abolic diseases la e in li e, can be signi ican ly educed [58, 61]. E en so, i obesi y is s a ed in he e y ea ly ages and main ained du ing childhood and adolescence, he isk o de eloping co ona y hea disease is g ea ly inc eased [62]. The no maliza ion o BMI be o e he onse o pube y is key, as i seems o educe o a g ea ex en he isk o Me S and hei associa ed complica ions [58]. Thus, pube y is a key pe iod o no malize body weigh , as insulin sensi i i y dec eases and he e a e majo me abolic and ho monal changes [63]. In heal hy young pa ien s, his nadi in insulin sensi i i y is esol ed when pube y is comple ed. Howe e , i obesi y pe sis s, insulin esis ance can become ch onic, inc easing he ca diome abolic isk in hese pa ien s [63]. Al e ed Sec e ion o Adipokines The e is a wide a ie y o adipokines sec e ed by adipose issue ha in o m he b ain abou ene gy s o es, egula ing ood in ake and sa ie y. Adiponec in and lep in a e he mos widely s udied, al hough esis in, aspin and is a in ha e also been conside ed. Thei sec e ion and unc ion may be a ec ed in indi iduals wi h o e weigh o obesi y, dis up ing he o e all me abolic con ol. In indi iduals wi h obesi y, adipokines a e media o s o he obse ed ca diome abolic isks and o he obesi y associa ed diso de s such as hype iglyce idemia and insulin esis ance. This has been obse ed e en in p epube al child en, al hough s udies in adolescen s a e mo e nume ous [43, 64-66]. Adiponec in is a p o ec i e adipokine, as i s high concen a ions a e associa ed wi h bene icial e ec s such as an an i-in lamma o y ac i i y in he adipose issue [67]. Besides, i has been epo ed o inc ease insulin sensi i i y and, hus, help egula e lipid and glucose me abolism [68, 69]. On he o he hand, low concen a ions o adiponec in ha e been associa ed wi h oxida i e s ess in adipose issue [70]. An in e se associa ion be ween adiponec in concen a ions and Me S and ca diome abolic pa ame e s was shown in adolescen s, indica ing a po en ial ole o adiponec in in he ea ly de elopmen o Me S and o he ca diome abolic complica ions [71, 72]. In addi ion o being a bioma ke o Me S, adiponec in may also be indica i e o in lamma o y p ocesses, as adiponec in concen a ions ha e been in e sely ela ed o C- eac i e p o ein concen a ions (CRP) [73]. 50 In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 Pé ez-Gimeno e al. Plasma lep in concen a ions a e di ec ly associa ed wi h a s o es, as his p o eoho mone is sec e ed om he adipose issue o he bloods eam in p opo ion o he amoun o adipose issue. Lep in ac s as a po en sa ie y signal, inc easing wi h o e eeding and dec easing in s a a ion s a es [74, 75]. Howe e , in addi ion o ood in ake and BMI, lep in concen a ions also a y acco ding o sex, age and ci cadian hy hms [76-78]. Indi iduals wi h obesi y usually ha e high lep in concen a ions, implying lep in esis ance [79, 80]. In addi ion, obesi y has been associa ed wi h a educed lep in anspo ac oss he blood b ain ba ie , which could also con ibu e o he lep in esis ance [81]. Lep in esis ance is equen ly associa ed wi h insulin esis ance and adiposi y, especially wi h isce al a mass, being a isk ac o o he Me S and o he ca dio ascula complica ions in child en and adolescen s [65, 66, 82]. In ac , lep in has been used as an e icien ea men in obese lep in de icien pa ien s o educe he amoun o adipose issue [83, 84]. Rega ding he ela ionship be ween lep in and adiponec in, in spi e o he many s udies which ha e shown dec eased le els o adiponec in and inc eased le els o lep in in child en wi h obesi y, hei co- dependency is no well unde s ood [85]. High lep in o adiponec in a io is also a p edic i e alue o obesi y and an ad e se me abolic p o ile in child en ha seems o be sex-speci ic [86]. Bo h adipokines, lep in and adiponec in, ha e been shown o be good bioma ke s o u u e ca diome abolic isk, and ha e been ound o be associa ed wi h adiposi y bioma ke s such as BMI and WHR, bo h in child en and adolescen s wi h obesi y [85, 86]. High lep in le els along wi h ele a ed ci cula ing iglyce ides in child en wi h obesi y a e associa ed wi h BMI, WC and WHR [87]. O he adipokines such as is a in, aspin and esis in ha e also been conside ed. In child en wi h obesi y, is a in shows a posi i e associa ion wi h insulin esis ance and Me S and aspin plasma concen a ions a e also inc eased in child en wi h obesi y; mo eo e , bo h adipokines a e s ong p edic o s o he in lamma o y bioma ke s umou nec osis ac o alpha (TNF-α) and in e leukin 6 (IL-6) [88, 89]. Along wi h high lep in and low adiponec in plasma le els, highe se um esis in le els ha e been obse ed in me abolically unheal hy p epube al child en [90] and associa ed wi h Me S and ea ly a he oscle osis in child en wi h obesi y [91]. Adipose Tissue Dys unc ion As al eady men ioned, adipose issue is an ac i e endoc ine o gan ha eleases a a ie y o cy okines (adipocy okines) which sec e ion can be al e ed due o di e en ac o s such as o e weigh o obesi y. Dys unc ion o adipose issue in obesi y includes impai men o TG s o age and elease o a y acids o he bloods eam, pe pe ua ing he obesi y s a e and media ing obesi y associa ed complica ions. Besides, he expansion o adipose issue a mass implies changes in he cy okine sec e ion p o ile om AT as well as inc eased u no e o ee a y acids which acili a e insulin esis ance. Fu he mo e, i is no only he amoun o AT, bu also, he dis ibu ion o a mass and i s ec opic accumula ion in o gans o issues which a e key o insulin sensi i i y [92]. Visce al adipose issue (VAT), a he han subcu aneous adipose issue (SCAT) is he esponsible o he ca dio ascula me abolic diseases [28]. Also isce al a accumula ion in adul s and adolescen s has been associa ed wi h a g ea e deg ee o insulin esis ance [93]. Two ypes o VAT ha e shown associa ions wi h CVDs in child en: he epica dial adipose issue (EAT), localized be ween pe ica dium and myoca dium [94] and he pe ica dial adipose issue (PAT), be ween he kidney capsule and he enal ascia [95]. Bo h EAT and PAT a e isk ac o s o CVDs de elopmen . Me abolic al e a ions in AT also include an inc eased insulin sec e ion. Indeed, isce al adipose issue is he one in ol ed in he sec e ion o p o- in lamma o y cy okines, ha ac local and sys emically and i is associa ed wi h he me abolic complica ions o obesi y such as T2DM. As is has been showed, obesi y has also been associa ed wi h an in lamma o y s a us in child en and adolescen s [96-100]. Low-g ade in lamma ion linked o obesi y is due in pa o he abno mal accumula ion o lipids in adipose issue ha leads o he p oduc ion o p o-in lamma o y cy okines including TNF-α, IL-6, IL-1β, IL-8, IL-1 ecep o an agonis . The ela ionship be ween in lamma ion and weigh s a us in child en has also been epo ed h ough CRP [101], as child en wi h high le els o CRP p esen highe indices o cen al adiposi y. In addi ion o TNF-α, IL-6 and CRP, inc eased le els o he bioma ke plasminogen ac i a o inhibi o ype 1 (PAI-1) ha e been obse ed in child en wi h obesi y and a e p oposed as isk ac o s o he de elopmen o CVDs [102]. Ca diome abolic and Ca dio ascula Complica ions o Obesi y in Child en In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 51 Myelope oxidase is also a bioma ke o in lamma ion and ca dio ascula isk in p epube al child en wi h obesi y [102] and i is posi i ely associa ed wi h CRP, HOMA-IR and esis in. Mo eo e , S100 Calcium binding p o ein A4 (S100A4) is also a no el ma ke o insulin esis ance and dys unc ion o adipose issue in p epube al and pube al child en wi h obesi y [103]. As obesi y is cha ac e ised by inc easing le els o lep in and, a he same ime, a d op-in adiponec in le els, he p e iously desc ibed lep in/adiponec in a io is used a as a ma ke o dys unc ion o adipose issue, which leads o in lamma ion and oxida i e s ess. The e o e adiponec in/lep in a io may be also used as an indica o o ca diome abolic isk associa ed o AT dys unc ion [104, 105] I should be men ioned ha ec opic a accumula ion (especially hepa ic a accumula ion, hepa ic s ea osis as a componen o Me S) may also play a ole de e mining he ca diome abolic isk ia insulin esis ance and adipose issue in lamma ion [99]. No el Ma ke s: Ci cula ing miRNAs as P ognos ic Bioma ke s o Ca diome abolic Complica ions Mic oRNAs (miRNAs) a e sho non-coding RNAs, ep esen ing a signi ican p opo ion o he human genome. They a e in ol ed in he ine con ol o gene exp ession. Thousands o di e en miRNAs ha e been desc ibed in humans so a and nowadays i is known ha miRNAs play impo an oles in main aining cellula homeos asis and unc ions [106]. In he pas ecen yea s, hese se o nucleo ides ha e con ibu ed o iden i y epigene ic mechanisms ela ed o obesi y and i s como bidi ies. In his line, miRNAs ela ed wi h p eadipocy e p oli e a ion, insulin sec e ion by panc ea ic β-cell, and glucose up ake by skele al muscle cells ha e been iden i ied in child en wi h obesi y [107]. Thus, non-coding RNAs in child en wi h obesi y a e po en ial bioma ke s o T2DM [108] de elopmen in he u u e, suppo clinicians o iden i y pa ien s a highe ca diome abolic isk and hus, es ablish p e en i e measu es. CARDIOVASCULAR COMPLICATIONS Haemodynamics As p e iously men ioned, obesi y is an anabolic s a e cha ac e ized by an inc ease in adipose issue a mass and i s de i ed me abolic al e a ions. The whole body adap s o he excess adiposi y o main ain homeos asis [109], and he ci cula o y sys em is one o he mos a ec ed by his adap a ion. The inc ease in a mass p edisposes child en wi h o e weigh /obesi y o a high p eload and a e load s a e [110]. In indi iduals wi h obesi y, he e is an inc ease in blood olume, s oke olume, a e ial p essu e and ca diac ou pu [111]. Mo eo e , young people may al eady ha e an inc ease in hea mass depending o hei deg ee o obesi y [112] (Figu e 2). Figu e 2: Ca dio ascula complica ions in child en and adolescen s wi h obesi y. Childhood obesi y implies an inc ease in adipose issue and sympa he ic ne ous sys em, his igge s an inc ease in he le en icle mass. In addi ion, childhood obesi y dec eases dias olic unc ion and gene a es al e a ion in he Sys emic a e ies. Figu e legend: BMI: Body mass index, SCAT: Subcu aneous adipose issue, VAT: isce al adipose issue. 52 In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 Pé ez-Gimeno e al. Ca diac o Vascula S uc u e Le Ven icle Le en icula mass (LVM) inc eases wi h age and he mos commonly used clinical index is he le en icula mass index (LVMI) [113], which is calcula ed om LVM di ided by heigh aised o 2.7 (g/m2.7) [114]. In adul s, BMI has been obse ed o be associa ed wi h LVM and his associa ion seems o s a in ea ly adolescence [115]. Indeed, along wi h he inc ease o obesi y in he las decades, an inc ease in LVM has also been ound [116]. This is also ue o child en wi h obesi y, who show a LVM a ound 4 imes highe han he no mal cu -o poin o hei age, weigh and sex e e ence [117]. O he cha ac e is ics such as u ic acid and bi h weigh we e ound o be good p edic o s o LVMI [118]. Mo eo e , adul s wi h an excess o LVM ha e a educed LV sys olic unc ion and myoca dial pe o mance [117]. Ano he use ul pa ame e o ob ain in o ma ion abou ca diac s uc u e is ela i e wall hickness, which gi es in o ma ion abou LV geome y [119]. Child en wi h o e weigh /obesi y go h ough le en icula emodeling and an inc ease in LV wall s ess [111]. LV emodeling leads o di e en ypes o geome y: eccen ic hype ophy wi h high LVMI and no mal ela i e wall hickness; concen ic hype ophy wi h ele a ed LVMI and ela i e wall hickness; and concen ic emodeling wi h no mal LVMI and inc eased ela i e wall hickness [119]. This changes occu independen ly o he exis ence o no o hype ension and may in luence he de elopmen o CVDs [120]. Howe e , i should be aken in o accoun ha eccen ic hype ophy appea s in 30 % o child en in he US wi h obesi y showing no mal le els o blood p essu e [116]. On he con a y, ano he s udy wi h a high pe cen age o A ican and Ame ican you h ound a highe incidence o LV concen ic hype ophy in child en wi h obesi y and hype ension han in child en wi h obesi y alone. Whe eas hese di e ence did no appea in concen ic emodeling [121], al hough concen ic hype ophy is he ype o emodeling mos ela ed wi h mo ali y in adul s [122]. The bes p edic o o bo h concen ic emodeling and concen ic hype ophy is obesi y. Addi ionally, i should be no ed ha sys olic and dias olic blood p essu e should also be aken in o accoun as concen ic hype ophy media o s [121]. O he s udy showed ha he inc ease in LV mass leads o eccen ic hype ophy in child en wi h obesi y bu wi hou hype ension, concluding ha ela i e wall hickness could be a la e pa ame e in he ca diac changes in child en wi h obesi y [123]. Le en icula hype ophy (LVH) is a ma ke o o gan damage and i s p esence can only be obse ed by echoca diog aphy [124]. As hype ension, i s p esence does no always coincide wi h any symp oms and i is usually unde diagnosed. Bo h hype ension and obesi y a e independen ly associa ed o LVH. Ana omic changes in he le en icle ha e been shown in child en and adolescen s be o e he de elopmen o hype ension [123]. One s udy ound a 35% o p ima y hype ension in pa icipan s wi h obesi y and 41% o he pa icipan s wi h essen ial hype ension showed LVH, concluding ha echoca diog aphy should be a common p ac ice in child en wi h newly-diagnosed hype ension [125]. Ea ly de ec ion o LVH could p e en om u u e ca dio ascula p oblems [123]. Finally, i should be men ioned ha h ee- dimensional (3D) speckle acking echoca diog aphy is a new ool wi h a signi ican ole in he p e en ion o myoca dial al e a ions. Le en icula ejec ion unc ion (LVEF) had been used as a pa ame e o he assessmen o sys olic unc ion. Howe e , is no use ul o an ea ly dys unc ion assessmen [126]. Indeed, child en wi h o e weigh /obesi y ha e shown a p ese ed unc ion o LVEF, whe eas a dec eased LV s ain ha e been obse ed [120]. This sugges s ha 3D s ain a iables could be use ul o he assessmen o ea ly al e a ions in ca diac unc ion and he p e en ion o u u e mo ali y. Righ Ven icle Al hough mos s udies ha e ocused on he s uc u al changes o he LV, a ew au ho s ha e s udied he associa ion be ween obesi y and he igh en icle (RV) [127, 128]. A s udy in child en showed a posi i e co ela ion be ween LV s ain and RV s ain, indica ing an associa ion be ween he abno mali ies in bo h le and igh en icles [128]. Ano he s udy done in child en wi h obesi y and wi hou o he como bidi y showed ha child en wi h obesi y had a signi ican educ ion o sys olic myoca dial de o ma ion, bo h in LV and RV [127]. Howe e , o he s udies did no ind changes in RV unc ion. Ca diac magne ic esonance (CMR) is he gold s anda d o he assessmen o RV unc ion bu , un il now, i has only been used in esea ch s udies [128]. Ca diac Func ion The echoca diog aphy is a nonin asi e me hod widely used in he assessmen o ca dio ascula unc ion. This echnique allows o he iden i ica ion o Ca diome abolic and Ca dio ascula Complica ions o Obesi y in Child en In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 53 wo possible ypes o ca diac dys unc ion: sys olic dys unc ion and dias olic dys unc ion. Sys olic dys unc ion is easily de e mined om he ejec ion ac ion. Howe e , dias olic dys unc ion is mo e di icul o diagnose. Fo his eason, se e al cha ac e is ics a e measu ed o e alua e he dias olic unc ion. The i s cha ac e is ics a e weak E and A, which a e he wo phases o le en icle illing in ea ly and la e dias ole, espec i ely. The o he pa ame e is used o measu e he dis ance om he mi al annulus o he base du ing ea ly dias ole (e`). Mo eo e , he E/A ac ion is ob ained o assess he elaxa ion o he en icle and he E/e´ a io is used o es ima e he le en icula illing p essu e [129]. O he echniques ha e been p oposed o he assessmen o ca diac unc ion. Ca diac magne ic esonance (CMR) is used o he e alua ion o sys olic unc ion, bu wi h inc easing in e es in i s use o assess dias olic unc ion. CMR has ad an ages o e echoca diog aphy due o i s high spa ial esolu ion, which can measu e le a ial size and ans-mi al low [130]. Howe e , i s cos s ou weigh he bene i s. Ano he echnique is echoca diog aphic s ain a e imaging, which is based on he de o mi y o he ca diac muscle du ing he con ac ion and elaxa ion p ocesses [131]. This echnique is no ye used in he classi ica ion o dias olic dys unc ion because i is belie ed ha es o ing o ces and ea ly dias olic load also in luence in en icula elaxa ion [132]. In child en and adolescen s, a posi i e associa ion has been ound be ween obesi y and dias olic dys unc ion. Being he g oup o pa ien s wi h obesi y hose wi h he educed dias olic unc ion. [133]. In addi ion, Po ca -Almela e al. p oposed he E/e´ a io as he mos alid ma ke o dias olic dys unc ion in child en wi h obesi y [134]. Sys emic A e ies Endo helial Func ion An adequa e ascula endo helial unc ion is de e minan o a oid he de elopmen o a he oscle osis [135]. Howe e , al hough clinical mani es a ions o CVDs ake many yea s o appea [136], an accele a ed a he oscle osis has been obse ed in you h wi h obesi y [137]. The mos widely used pa ame e o de e mine endo helial dys unc ion is he b achial a e y low media ed dila ion (FMD) [138, 139]. Se e al s udies ha e shown a lowe FMD in child en wi h obesi y compa ed wi h child en wi h no mal weigh [140-143]. Whe eas o he ha e no obse ed any di e ences [144, 145]. Lo e al., ound a educed FMD wi h he inc ease o age in adolescen s wi h obesi y om 14 yea s [146]. One me a-analysis ound ha FMD is an indica o o special impo ance in child en a low isk o CVD. Because child en wi h ad anced ca dio ascula isk ac o s ha e dys unc ion o NO me abolism and s i ness o he essels [147]. A e ial S i ness Ano he isk ac o associa ed wi h CVDs in adul s is ascula s i ness [148]. A s udy in adul s wi h and wi hou ascula disease showed ha an elas ic ascula sys em was associa ed wi h a dec ease in a he oscle o ic p og ession [149]. I also educes he ca diac demand o he hea h and inc eases co ona y a e y pe usion [150]. The mos widely used a iable o assess a e ial s i ness is cen al pulse wa e eloci y (PWV) [151]. PWV measu es he eloci y o he pulse wa e, c ea ed in sys ole, while i is p opaga ed ac oss he a e ial ee. The e a e di e en me hods o PWV, being ca o id- emo al PWV (c PWV) he gold s anda d [152]. Child en wi h obesi y ha e shown an inc ease in a e ial s i ness a he ca o id a e y [153, 154] and in cen al measu es o PWV. In con as , Lo e al. did no ind an associa ion be ween PWV and adiposi y pe se, bu a highe a e ial s i ness in hype ensi e child en wi h inc eased adiposi y [146]. A sys ema ic e iew which aim was o desc ibe he no mal p og ession o c PWV and i s associa ion wi h o he ca diome abolic isk ac o s showed ha a e ial s i ness inc eased 0,12 m/second pe yea in child en, wi h no di e ences be ween sex [155] . Mo eo e , a posi i e associa ion was ound be ween BP and impai ed glucose me abolism and PWV. Howe e , hey men ioned he need o mo e longi udinal s udies o con i m hei a i ma ions [155]. In addi ion, a posi i e co ela ion be ween hype ension and PWV was also obse ed in ano he s udy in child en [152]. Endo helial Vasodila o y Response NO (ni ic oxide) is a molecule wi h a asodila a ion e ec , and i is p oduced in he endo helium by he NO syn hase du ing he ans o ma ion o L-a ginine in o ci ulline [156, 157]. In addi ion o he p e iously men ioned pa ame e s, he bioa ailabili y o no o NO, he inc ease o asymme ic dime hyla ginine (ADMA) and he L-a ginine/ADMA a io [AAR) ha e been s udied as p edic o s o endo helial unc ion [158]. Child en wi h high BMI showed a educ ion in NO se um le els and an inc ease in ADMA compa ed wi h child en wi h no mal weigh [159]. Lo e al. obse ed highe le els o ADMA and AAR in hype ensi e 54 In e na ional Jou nal o Pedia ics and Child Heal h, 2020 Vol. 8 Pé ez-Gimeno e al. child en wi h obesi y, al hough wi hou s a is ical signi icance [146]. A e ial Thickness Ca o id in ima-media hickness (cIMT) is a non- in asi e echnique ha allows clinicians o diagnose subclinical a he oscle osis [160]. Howe e , al hough he e a e disc epancies among he di e en expe commi ees on he adequacy o he use o his echnique, he Associa ion o Eu opean Paedia ic Ca diology (AEPC) ecommends he measu emen o cIMT [152]. Indeed, cIMT has been associa ed wi h CV isk ac o s and could p edic he possibili y o u u e ca dio-ce eb o ascula disease (35). Based on di e en child en coho s ollowed up un il adul hood, hey obse ed ha ca dio ascula isk ac o s in child en abo e 9 yea s o age a e associa ed wi h IMT and i s consequen impac on adul hood. While he ca dio ascula isks obse ed in child en below 9 yea s did no show such associa ion [161]. A sys ema ic e iew done in showed an inc ease in cIMT in child en and adolescen s wi h o e weigh o obesi y compa ed wi h hei no mal weigh pee s [162]. One s udy in child en showed a posi i e co ela ion be ween EAT and cIMT [28]. Ano he c oss-sec ional s udy in adolescen s ound a posi i e associa ion be ween cIMT and uncal a . The cIMT o a subg oup o hese adolescen s also showed a posi i e associa ion wi h soluble in e cellula adhesion molecule 1 [163]. O he au ho s ha e obse ed ha in p epube al child en EAT and PAT a e be e p edic o s o cIMT han BMI [164]. Simila ly, ano he s udy ound ha HOMA-IR and QUICKI, ma ke s o insulin esis ance, a e independen p edic o s o cIMT in boys wi h o e weigh and obesi y, bu no in gi ls. This di e ences also occu in adul hood, in which ca dio ascula e en s in men occu yea s be o e han in women [165]. High blood p essu e, one o he p e iously men ioned ca dio ascula isk ac o s, has also been obse ed as a good pa ame e o iden i y child en wi h impai ed cIMT [161]. Hype ension has shown a linea ela ionship wi h cIMT in child en and adolescen s independen ly o o he con ounde s [166]. One s udy in heal hy adolescen s showed a posi i e co ela ion be ween he le els o blood p essu e (BP) and IMT [167], while o he s ha e obse ed a s onge ela ionship acco ding o he deg ee o hype ension [168]. Independen ly o obesi y, Lande e al. also ound a s ong posi i e co ela ion be ween sys olic blood p essu e le els du ing day ime, measu ed wi h ambula o y BP moni o ing, and cIMT in child en [169]. Also, ano he s udy using 24-hou ambula o y BP moni o ing in you h wi h ype 1 diabe es melli us obse ed highe IMT in pa ien s wi h a educed noc u nal dipping [170] . Finally, cIMT has also been associa ed wi h o he pa ame e s such as LVH, aking in o accoun age, sex o BMI as con ounde s [171]. Páll e al., showed a highe cIMT in adolescen s wi h whi e-coa hype ension and sus ained hype ension. Howe e , only he g oup o sus ained hype ension showed a signi ican inc ease in LVMI [172]. Au onomic Ne ous Sys em The au onomic ne ous sys em (ANS) modula es ca dio ascula unc ion h ough he sympa he ic ne ous sys em (SNS) and he pa asympa he ic ne ous sys em (PSNS). And he e is a dynamic balance be ween SNS and PSNS called “sympa ho agal balance” [173]. The sum o ANS, SNS and PSNS is he ca diac au onomic modula ion (CAM) [174]. Hea Ra e Va iabili y (HRV) is a non-in asi e me hod o he assessmen o CAM, and he e a e wo ways o ob ain in o ma ion [175]. One is a ime domain, wi h wo indexes: SDNN, he s anda d de ia ion o all RR in e als, which is a ma ke o sympa he ic ac i i y and RMSSD, he squa e oo o he mean o he sum o he squa es o he di e ences be ween adjacen RR in e als, which indica es pa asympa he ic ac i i y [176]. The second is a equency domain, om which 3 pa ame e s a e used: Powe low equency (LF) a ec ed by PSNS and SNS [177], powe high equency (HF), which is a ma ke o pa asympa he ic ac i i y [178] and LF/HF a io, ha is he pa ame e o measu e he sympa ho agal balance [179]. In addi ion, he ba o e lex has also been used as an indica o o CAM [174]. The impai men in a s o age p esen in child en and adul s wi h obesi y implies a high blood low demand [180]. Mo eo e , he inc ease in adipose issue is associa ed wi h an ex a ac i a ion o enin- angio ensin aldos e one sys em, which leads o an inc eased ac i a ion o he SNS wi h a consequen enhancemen o sys emic ascula esis ance ha is aduced in a highe in a ascula olume. 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