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. This
cascade o e en s p oduces an inc ease in en icula
p eload [181] which, as men ioned be o e, implies an
inc ease in LVM wi h an impai men o ca diac
unc ions [180].
Due o he changes in he ca diac s uc u e o
pa ien s wi h obesi y, an impai men o CAM has also
been obse ed [174]. In adul s, CAM impai men has
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Recei ed on 6-10-2020 Accep ed on 11-11-2020 Published on 09-12-2020
DOI: h ps://doi.o g/10.12974/2311-8687.2020.08.8
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