REVIEW

CURRENT
OPINION Dyslipidemia and cardiovascular changes
in children
António Pires a, Cristina Sena b, and Raquel Seiça b

Purpose of review
In this review, we firstly highlight the role of dyslipidemia as a trigger in the initiation and progression of
endothelial dysfunction, considered the earliest atherosclerotic lesion and patent in children with risk
factors.
Downloaded from https://journals.lww.com/co-cardiology by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD33O0GyUXvnrsN0YDnHCGBiOgHsG5E72h3IWsVFYMMJoQ= on 03/22/2019

In this context, we also revise methods that reflect the impact of endothelial dysfunction not only on arterial
stiffness but also on cardiovascular morphology, namely, the common carotid intima-media thickness and
the ventricular geometry.
Recent findings
In view of its atherogenic burden, the most widely studied lipoprotein has been low density lipoprotein
cholesterol. However, the smaller, denser, low density lipoprotein cholesterol particles, the nonhigh density
lipoprotein cholesterol fraction, appear to be more atherogenic and a more sensitive cardiovascular risk
marker. Studies have shown that in children, atherogenic lipids have also been linked to cardiovascular
morphological changes, such as the common carotid intima-media thickness and the ventricular geometry,
both independent cardiovascular risk markers.
Summary
In infancy, atherosclerosis is a preclinical disorder in which dyslipidemia plays a crucial role. Due to its
impact on cardiovascular structures, potentially reversible during childhood, dyslipidemia ought to be
managed aggressively to prevent further disease progression that will ultimately culminate in cardiac
disease, a leading cause of mortality in adults.
Keywords
children, common carotid intima-media thickness, dyslipidemia, endothelial dysfunction,
ventricular geometry

INTRODUCTION infarctions. Mendelian randomization studies have

Lipid abnormalities play a vital role in the patho-
physiological mechanisms of atherosclerosis and,
hence, cardiovascular disease. As demonstrated by
classical autopsy studies such as the Bogalusa Heart
Study [1] and the Pathobiological Determinants
of Atherosclerosis in Youth [2] study, the earliest
manifestations of atherosclerosis begin during
childhood in the form of arterial wall fatty streaks,
particularly in high-risk groups such as the obese.
In the Bogalusa Heart study, the prevalence of fatty
streaks was 50% during childhood and 85% during
& Instituto Biomédico de Investigação de Luz e Imagem (IBILI), Faculdade
early adulthood [3 ]. These lesions are character-
ized by the accumulation of lipid-filled macro-
phages within the intima of the artery. Although
clinically silent, they are the precursors of the
&
atheroma plaque [4 ], and thus, represent the
preclinical phase of a progressive disease that ulti-
mately leads to adverse events such as myocardial
shown that for every 1 mmol/l decrease in low
density lipoprotein cholesterol (LDL-C) levels,
the cardiovascular risk decreases by 50% [5]. Thus,
early identification and management of lipid
abnormalities in children are crucial to prevent
the atherosclerotic process and, ultimately, coron-
ary heart disease, a leading cause of death and
morbidity in adults [6].
a
Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra and
b
de Medicina, Laboratório de Fisiologia, Universidade de Coimbra, Coim-
bra, Portugal
Correspondence to António Pires, Hospital Pediátrico, Centro Hospitalar
e Universitário de Coimbra, R. Dr. Afonso Romão, 3030, Coimbra,
Portugal. Tel: +00351 963825877; e-mail: pires1961@gmail.com
Curr Opin Cardiol 2016, 31:95–100
DOI:10.1097/HCO.0000000000000249

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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Pediatrics
KEY POINTS
 In children, atherogenic dyslipidemia contributes
toward endothelial dysfunction, the earliest known
atherosclerotic lesion.
 During early childhood, atherosclerotic changes are
potentially reversible; therefore, early identification
and management of atherogenic dyslipidemia
are paramount.
 In infancy, atherosclerosis is a preclinical disorder;
thus, its impact on the cardiovascular system can only
be accessed through indirect means, such as the
carotid artery IMT and left ventricular geometry.
 Increased carotid artery IMT and LVH are independent
cardiovascular risk factors and, in children, can be
used for risk stratification.
HOW REAL IS THE PROBLEM?
The real prevalence of dyslipidemia among children
has been difficult to assess, as different diagnostic
criteria for its definition have been used. Based on
the results of The National Health and Nutritional
Examination Survey (NHANES), Kit and coworkers
[7] showed that one in five children and adolescents
in the United States have adverse lipid profiles.
However, a recent study by Tomeleri and coworkers
&
[8 ] carried out in Brazilian adolescents, in which
cutoff points proposed by NHANES, the National
Cholesterol Education Program, and the Brazilian
Society of Cardiology for the diagnosis of dyslipide-
mia were compared, showed that the prevalence of
dyslipidemia among adolescents, based on the
respective cutoff points, differed significantly. These
inconsistent results may lead to diagnostic inaccur-
&&
acies, as reported recently by Gooding [9 ], that
ultimately could compromise management. In
2011, the Expert Panel on Integrated Guidelines
for Cardiovascular Health and Risk Reduction in
Children and Adolescents [10] recommended stand-
ard cutoff points that ought to minimize this issue.
However, most of these studies focus mostly a
North American reality and may not be representa-
tive of other populations. Recently, the Expert Dys-
lipidemia Panel of the International Atherosclerosis
&&
Society [11 ] published an international consensus
regarding the management of dyslipidemia whose
recommendations are based on epidemiological and
genetic studies, as well as clinical trials. Although
these recommendations mirror a wider global popu-
lation, they lack a pediatric perspective. Attempts
should also be made to consider cutoff levels based
on age and sex, as the maturation process influences
serum lipids and lipoprotein levels.
96 www.co-cardiology.com
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ADDRESSING THE ISSUE
Among the known cardiovascular risk factors
(obesity, smoking, hypertension, and diabetes mel-
litus), hypercholesterolemia is the most preeminent
and longest-known risk factor related to coronary
heart disease. In children, genetic causes, particu-
larly familial hypercholesterolemia, are the most
&
common causes of atherogenic dyslipidemia [12 ].
During infancy, these cardiovascular risk factors
usually track into adulthood, as exemplified by
the LDL-C levels, which are highly predictive of
adult levels into middle age.
However, the prevalence of secondary dyslipi-
demias is on the rise, mainly because of the escalat-
ing incidence of obesity among youth. In high-risk
groups, it is frequent to find clustering of risk factors,
which hasten the atherosclerotic process. It is
known that risk factors present during adolescence
likely track into young adulthood [6] and are related
to premature adult cardiovascular disease.
As such, efforts to implement risk reduction
strategies through primary prevention should be a
priority, as 80% of adverse cardiovascular events are
preventable through lifestyle modifications, which
should start during infancy when these risk factors
are still reversible.
Therefore, to decrease future adult cardiovascu-
lar disease and its socioeconomic burden on
societies, it is imperative to screen the general
pediatric population during vulnerable maturation
periods and not only at-risk groups. By focusing on
specific groups only, such as the obese or those with
positive family history of dyslipidemia, many cases
would be missed, as a significant number of parents
are ignorant of their own lipid profile status. To
address this issue, population-based studies, such
as NHANES, have provided valuable data on the
age-related lipid concentration serum levels. Gener-
ally, levels reach young adulthood concentrations
by 2 years of age. They then decrease during pubertal
development to again increase thereafter. As such,
screening is aimed at those time intervals, namely,
at the onset of puberty (9–11 years) and young
adulthood (17–21 years), unless other risk factors
coexist where the need for more stringent control
arises [10].
LOOKING BEYOND SERUM LIPOPROTEINS
Screening for dyslipidemia usually includes the
quantification of total cholesterol, LDL-C, high
density lipoprotein cholesterol (HDL-C), and trigly-
cerides fasting serum levels. Classically, the athero-
genic lipid profile comprises high LDL-C, low
HDL-C, and high triglyceride. Although triglyceride
Volume 31  Number 1  January 2016
 Dysli pidemia and cardiovascular changes in children Pires et al.
levels appear to be linked to cardiovascular disease,
as validated in recent epidemiological studies, their
role is still disputed. Nonetheless, raised triglyceride
levels, through the actions of lipoprotein lipase, and
hepatic lipase, contribute to the formation of small
dense lipoprotein particles, which carry a more
aggressive atherogenic phenotype.
Apart from the circulating lipoproteins, their
constituent protein moieties, the apolipoproteins
A-I (Apo A-I) and B (Apo B) also appear to be relevant
in cardiovascular disease risk stratification. In lipid
transport, apolipoproteins function as structural
proteins of HDL-C (Apo A-I) and LDL-C (Apo B).
Apo B levels reflect the spectrum of proatherogenic
particles (very low, intermediate, and LDL-C
particles) and Apo A-I reflect the antiatherogenic
particles. Compared with HDL-C and LDL-C, both
Apo B and Apo A-I appear to be more representative
of the pro- and antiatherogenic particle phenotype
in circulation, respectively [13].
Of particular importance is their ratio (Apo B/
Apo A-I), which reflects the balance between pro-
and antiatherogenic particles, which in adults has
been strongly correlated to myocardial infarction
and stroke. In children, the Apo B/Apo A-I ratio
has also been validated as a predictor of metabolic
syndrome, itself a robust risk factor for cardiovas-
&
cular disease [3 ].
Along the same lines, the non-HDL-C (TC –
HDL-C) fraction is considered a better screening tool
than LDL-C and correlates highly with Apo B, as it
represents the amount of cholesterol carried by the
smaller, more atherogenic molecules and has been
shown to be a powerful predictor of atherosclerosis
compared with other lipoprotein cholesterol
measurements.
THE ROLE OF DYSLIPIDEMIA IN
ENDOTHELIAL DYSFUNCTION
&&
In children [14 ], the first, yet reversible, step
toward atherosclerosis is endothelial dysfunction.
It is considered the earliest atherosclerotic lesion
&
[15 ] and, as such, a preclinical marker of athero-
&
thrombotic disease [16 ]. The endothelium is a met-
abolically active unicellular layer that lines the
vascular system. It is responsible for the expression
of various bioactive mediators that control vascular
function [17]. These, apart from regulating vascular
tone, also have anti-inflammatory and antithrom-
botic properties. Injury to the endothelium because
of various mechanisms, most notably hypercholes-
terolemia, results in the expression of various
mediators that will eventually compromise vascular
homeostasis and, ultimately, cardiovascular integ-
rity.
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Atherogenic lipids, particularly LDL-C particles,
which account for more than 75% of the circulating
&&
atherogenic lipoproteins [11 ], are central to endo-
thelial activation. Impaired endothelium triggers an
inflammatory response that facilitates the entrance
of inflammatory cells and lipids, particularly the
small dense LDL-C particles, to the intimal space.
The production of free oxidative radicals is believed
to induce endothelial dysfunction. Based on the
oxidative stress theory, once LDL-C migrates into
the intima it becomes oxidized (ox-LDL) by reactive
oxygen species, such as superoxide anion radicals,
whose production is stimulated by risk factors, such
&
as hypercholesterolemia [18 ]. Oxidized LDL-C
particles are then taken up by macrophages, which
become lipid-engorged and are then referred to as
foam cells. These cells become then a major source
of oxidative substances in atherosclerotic vessels.
The increased production of reactive oxygen species
has several adverse effects: it decreases nitric oxide
bioavailability and increases the expression of
adhesion molecules, such as vascular cellular and
intracellular adhesion molecules, E-selectin, and
other cytokines. These all help to perpetuate endo-
thelial dysfunction, as exemplified by endothelin-1,
a potent vasoconstrictor that promotes the uptake
of ox-LDL, which, in turn, stimulates the synthesis
of endothelin-1.
Thus, ox-LDL contributes to the proinflamma-
tory cascade that characterizes and propagates endo-
&
thelial activation [19 ].
Expansion of the foam cell population within
the intima forms fatty streaks, the first signs of
atherosclerosis, visible without magnification, and
present in infancy. Over time, continued accumu-
lation of foam cells and proliferation of vascular
smooth cells evolve into atherosclerotic plaques.
This lesion is responsible for adverse clinical out-
comes either by obstructing the arterial lumen or by
rupture, releasing thrombogenic substances. Lipids
are thus the first triggers of cardiovascular athero-
sclerotic disease, initiating and promoting this com-
plex entity. Of all the known cardiovascular risk
factors known, LDL-C is probably the most athero-
genic, and, implicitly, prevention must be focused
on lowering LDL-C serum levels throughout life,
starting in childhood.
ASSESSING ARTERIAL COMPLIANCE:
FUNCTIONAL TESTING
During childhood, clinical manifestations of athe-
rosclerotic disease are rare. Therefore, it is impera-
tive, in those with risk factors, to seek out evidence
of early atherosclerosis through methods that reflect
its atherogenic burden.
www.co-cardiology.com 97
Pediatrics
Endothelial dysfunction compromises nitric
oxide bioavailability, resulting in decreased vascular
tone, which, if sustained, leads to progressive arte-
rial stiffness. Endothelial health may be assessed by
invasive and noninvasive methods, and, in both,
arterial response to an endothelial-dependent
stimulus is quantified.
Coronary angiography is the gold standard
modality to assess the morphological and functional
status of the coronary arterial bed. Apart from out-
lining stenotic lesions, it directly measures the
endothelial-dependent response to vasodilatory
substances. Its applications are, however, of limited
value in children because of the associated costs,
invasiveness, and exposure to radiation and con-
trast. Nonetheless, it may be indicated in very high-
risk situations, such as in children with persistent
coronary artery aneurysms resulting from Kawasa-
ki’s disease.
As endothelial dysfunction is a systemic dis-
order, assessment of peripheral arterial compliance
by noninvasive means can be used as a surrogate for
&
coronary endothelial function [20 ]. Several testing
modalities have been advocated, such as peripheral
& &
arterial tonometry [21 ] and the pulse wave velocity
(PWV). The latter is considered by the European
Society of Cardiology as the most simple, noninva-
sive, and reproducible method for the determi-
nation of arterial stiffness [22], and of particular
interest in children with cardiovascular risk factors
&
[23 ]. Its application has been further refined by the
&
use of MRI-based PWV measurements [24 ]. Another
surrogate of arterial stiffness is the ambulatory arte-
rial stiffness index based on 24-h ambulatory blood
pressure, also validated in children with cardiovas-
& &
cular risk factors [25 ,26 ].
DYSLIPIDEMIA AND CARDIOVASCULAR
CHANGES
Atherogenic lipids induce changes in the cardiovas-
cular system that themselves are independent car-
diovascular risk factors and can be used in routine
clinical practice as surrogates of the atherosclerotic
process.
Ultrasound imaging of the intima-media
thickness of the common carotid artery
The Cardiovascular Risk in Young Finns study
showed that risk factors such as dyslipidemia,
measured during adolescence, were significantly
associated to with adult carotid artery intima-media
thickness (IMT) as measured by ultrasound imaging
[27]. In adults, IMT has gained acceptance as a
noninvasive method to assess the extent of
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Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
structural atherosclerosis, and it has also been
shown to be an independent predictor of future
& &
cardiovascular events [28 ,29 ]. Further evidence
exists that, regardless of abnormal adult LDL-C
levels, exposure to continued elevated serum levels
of LDL-C in adolescence is related to coronary artery
calcium load in adults, a sign of coronary athero-
sclerosis and, implicitly, increased IMT.
This implies that raised LDL-C levels in adoles-
cents may induce permanent changes in the coron-
ary arteries, hence playing an important role in the
pathogenesis of future ischemic heart disease. This
Young Finns study also showed that, apart from
lipoproteins, their transport proteins Apo A-I and
Apo B and the Apo B/Apo A-I ratio also predicted
IMT in adulthood [30]. In children, IMT has, thus,
also emerged as a potential marker of preclinical
atherosclerosis, particularly in high-risk popu-
lations, where it has been correlated to established
&
risk factors such as atherogenic dyslipidemia [3 ]
and, in particular, smaller dense LDL-C particles.
This is, however, not universally accepted. In our
own study of a group of obese children with athero-
genic dyslipidemia, we found no correlations
between the abnormal lipid profile and IMT [31 ],
most likely because of the small sample size in
question. Nevertheless, in view of the existing evi-
dence, IMT ought to be considered for risk stratifi-
cation in children with atherogenic dyslipidemia
and other risk factors.
Obese adolescents with high triglyceride and
low HDL-C levels have been shown to have higher
IMT, higher PWV, and increased carotid artery stiff-
ness. High triglyceride-to-HDL-C ratio correlates
strongly with high non-HDL-C and high PWV in
both lean and obese children, which persist after
adjustment for other risk factors.
&
Recently, de Giorgis and coworkers [32 ]
suggested the triglyceride-to-HDL-C ratio as a novel
marker of endothelial dysfunction in obese chil-
dren, as it correlated, among other markers, to
IMT. However, caution should be exercised when
applying this marker to other risk groups, as the lipid
profile found in the obese, contrary to familial
hypercholesterolemia, is usually high triglyceride,
low HDL-C, and normal LDL-C levels.
Left ventricular structure and function
In adults, cardiac structure and function predict
cardiovascular morbidity and mortality.
Left ventricular hypertrophy (LVH) is an import-
ant independent risk factor in cardiovascular
disease. LVH is classified according to four geo-
metric patterns: concentric hypertrophy, eccentric
hypertrophy, concentric remodeling and normal
Volume 31  Number 1  January 2016
 Dysli pidemia and cardiovascular changes in children Pires et al.
geometry, where concentric LVH carries a higher
prevalence of associated cardiovascular compli-
cations.
Adult studies have linked endothelial dysfunc-
& &
tion not only to LVH [33 ,34 ] but also to impaired
&
cardiac function [35 ]. Activated endothelium
secretes growth factors (platelet-derived growth fac-
tor and transforming growth factor-b) that appear to
promote fibroblast and smooth cell growth, which
eventually leads to myocyte hypertrophy [36].
A recent study by Porcar-Almela and coworkers
&
[37 ] correlated endothelial dysfunction to LVH and
diastolic dysfunction in a group of obese normoten-
sive children. Importantly, an inverse relationship
between Apo A-I and diastolic function was found.
As mentioned previously, the triglyceride-to-
HDL-C ratio may be used as a marker of endothelial
dysfunction in overweight children through its
direct correlation to IMT. Similarly, Di Bonito and
&
coworkers [38 ] also found a direct association with
LVH, particularly the concentric type, in obese chil-
dren.
These findings suggest that, in children, lipid
abnormalities play an important role in cardiac
remodeling and function. Based on these premises,
it is fundamental to diagnose LVH and abnormal
cardiac function early in dyslipidemic children and
implement adequate therapeutic strategies to pre-
vent disease progression, culminating in cardiac
failure.
CONCLUSION
In children, atherosclerosis is a preclinical disorder
related to cardiovascular risk factors and, in particu-
lar, atherogenic dyslipidemia.
During infancy, atherogenic dyslipidemia con-
tributes to endothelial dysfunction and, invariably,
to cardiovascular disease later in life; thus, its timely
management is essential. Furthermore, as athero-
sclerosis is a silent disease during infancy, surrogate
methods to evaluate the impact of dyslipidemia on
the cardiovascular system, such as the carotid artery
IMT and left ventricular geometry, ought to be
implemented in clinical practice, providing a plat-
form for risk stratification and future cardiac
risk reduction.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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34. Oka T, Akazawa H, Naito AT, Komuro I. Angiogenesis and cardiac hyper-
& trophy: maintenance of cardiac function and causative roles in heart failure.
Circ Res 2014; 114:565–571.
The review focuses on the regulatory mechanisms related to myocardial growth
and angiogenesis in cardiac hypertrophy and heart failure.
35. Leucker TM, Jones SP. Endothelial dysfunction as a nexus for endothelial cell-
& cardiomyocyte miscommunication. Front Physiol 2014; 5:328.
The article analyzes the dynamic signalings between the endothelium and cardio-
myocytes and their role within the context of endothelial dysfunction.
36. Leask A. Potential therapeutic targets for cardiac fibrosis: TGFbeta, angio-
tensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ
Res 2010; 106:1675–1680.
37. Porcar-Almela M, Codoner-Franch P, Tuzon M, et al. Left ventricular diastolic
& function and cardiometabolic factors in obese normotensive children. Nutr
Metab Cardiovasc Dis 2015; 25:108–115.
The study relates, among other factors, Apo A-I to left ventricular diastolic function
in obese children.
38. Di Bonito P, Valerio G, Grugni G, et al. Comparison of non-HDL-cholesterol
& versus triglycerides-to-HDL-cholesterol ratio in relation to cardiometabolic
risk factors and preclinical organ damage in overweight/obese children: the
CARITALY study. Nutr Metab Cardiovasc Dis 2015; 25:489–494.
The study highlights the importance of the triglyceride/HDL-C ratio as a marker of
organ damage, namely LVH, in obese children.
Volume 31  Number 1  January 2016