Original Paper

Ann Nutr Metab 2018;72:96–103 Received: May 4, 2017

Accepted after revision: October 15, 2017
DOI: 10.1159/000484326 Published online: January 18, 2018

Epicardial Fat Thickness in Non-Obese

Neurologically Impaired Children: Association
with Unfavorable Cardiometabolic Risk Profile
Valeria Calcaterra a, b Hellas Cena c Pietro Mariano Casali d Gianluca Iacobellis e
       

Riccardo Albertini f Mara De Amici g Annalisa de Silvestri h

     

Calogero Comparato i Gloria Pelizzo j    

a Department of Internal Medicine University of Pavia, Pavia, Italy; b Department of the Mother and Child Health,
   

Pediatric Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; c Department of Public Health, Experimental
 

and Forensic Medicine, Section of Human Nutrition, University of Pavia, Pavia, Italy; d Istituto Città di Pavia, Pavia,
 

Italy; e Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami, Miller
 

School of Medicine Miami, Miami, FL, USA; f Laboratory of Clinical Chemistry, Fondazione IRCCS Policlinico San
 

Matteo, Pavia, Italy; g Immuno-Allergy Laboratory of Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo,
 

Palermo, Italy; h Biometry and Clinical Epidemiology, Scientific Direction, Fondazione IRCCS Policlinico San Matteo,
 

Pavia, Italy; i Pediatric Cardiology Unit, Children’s Hospital, Istituto Mediterraneo di Eccellenza Pediatrica, Palermo,
 

Italy; j Pediatric Surgery Unit, Children’s Hospital, Istituto Mediterraneo di Eccellenza Pediatrica, Palermo, Italy
 

Keywords density lipoprotein cholesterol <5th percentile, fasting

Epicardial fat · Disability · Children · Cardio-metabolic ·
Non-obese
Abstract
Background: Cardiovascular risk is reported in disabled chil-
dren and epicardial fat (EF) is considered an independent
predictor of cardiovascular disease (CVD). No data on the EF
thickness (EFT) evaluation in disabled children have been
published. Objective: We investigated EFT in neurologically
impaired (NI) children; its relationship with their metabolic
profile was also considered. Methods: Clinical data, body
composition estimation, biochemical profile, and ultra-
sound-measured EFT were performed in 32 disabled pa-
tients (12.4 ± 6.3 years). Pathological parameters were de-
fined using the following criteria: waist circumference >95th
percentile, waist to height ratio (WHtR) >0.5, total choles-
terol and triglycerides (TG) values >95th percentile, high
blood glucose >100 mg/dL, homeostasis model assessment
for insulin resistance (HOMA) >97.5th percentile, and EFT
>3.6 mm. Results: EFT values in NI children were higher com-
pared with control group values (p = 0.02). EFT correlated
with gender (p < 0.001), age (p = 0.02), pubertal stage (p =
0.04), as well as WHtR (p = 0.03). A correlation between EFT
and leptin was also noted (p = 0.04). EFT levels significantly
correlated with pathological TG (p = 0.01) and HOMA-IR (p =
0.04). Conclusions: Higher EFT was observed in NI children
compared with controls. EFT values correlated with clinical,
metabolic, and endocrinological parameters. Ultrasound-
measured EFT could be used to promptly detect subclinical
CVD and to prevent adverse outcomes in disabled children.
© 2018 S. Karger AG, Basel
V.C. and H.C. contributed equally to this work.
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© 2018 S. Karger AG, Basel Prof. Gloria Pelizzo, MD

Pediatric Surgery Unit
Children’ Hospital
E-Mail karger@karger.com
Via dei Benedettini 1, IT–90144 Palermo (Italy)
Nagoya University

www.karger.com/anm
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E-Mail gloriapelizzo @ gmail.com

 Introduction
Subjects with disabilities, especially those with limited
mobility, tend to be at risk for secondary disorders, in-
cluding metabolic syndrome (MS) and allostatic load,
which may contribute to cardiovascular risk [1, 2]. How-
ever, cardiovascular diseases (CVDs), such as myocardial
infarction, are under-diagnosed due to atypical signs or
the absence of patient complaints [3].
Epicardial fat (EF) is a layer of adipose tissue sur-
rounding the heart and coronary vessels. It is externally
limited by the pericardium, with which it shares the
blood supply. EF is considered an independent predic-
tor of coronary atherosclerotic burden, particularly in
non-obese patients, since it produces several pro-ath-
erogenic mediators that may directly influence the de-
velopment and progression of coronary artery disease
through local paracrine effects [4, 5]. Early recognition
of premature atherosclerosis risk factors and/or markers
is an important step since subclinical atherosclerosis
precedes the clinical manifestations of CVD by many
years.
EF may be measured by ultrasound with a simple non-
invasive procedure [6] reported by Iacobellis et al. [7]. EF
thickness (EFT) is a reliable and sensitive marker of car-
diovascular risk and has become an emerging target for
therapeutic and medical interventions [8].
Reports on cardiovascular risk in neurological disabil-
ities in the pediatric age are limited. Even though the cor-
relation of EFT with cardiometabolic biochemical mark-
ers is well known, no data on EFT, as a marker of CVD
risk and adverse metabolic profile development in dis-
abled children, have been described.
The goal of this study was to investigate the presence
of early cardiac modifications through ultrasound-mea-
sured EFT in neurologically impaired (NI) children and
to analyze its relationship with the metabolic profile, in
order to promote adequate interventions and improve
outcomes.
Patients
A total of 32 patients (mean age 12.4 ± 6.3 years, range 1.8–19.2
years) with severe disabilities were included in this single center
cross-sectional study. The subjects’ clinical features, anthropomet-
ric parameters, and body composition assessment are reported in
Table 1.
The subjects were previously scheduled for surgical manage-
ment of nutritional support and cardiac evaluation was performed
during the surgical follow-up.
Epicardial Fat in Disabled Children
Medical diagnoses included cerebral palsy (34.4%), epileptic
encephalopathy (31.2%), and severe psychomotor developmental
delay in dysmorphic syndromes (34.4%). All of the patients living
in a sheltered community were bedridden. Enteral feeding was ad-
opted in all participants (bolus 65.6% and continuous 34.4%). Re-
spiratory physiotherapy was required in all cases, with a <2 h/
week/month session frequency in all patients. All patients received
anticonvulsant therapy with at least 2 of the following drugs: phe-
nobarbital, valproic acid, phenytoin, lamotrigine, topiramate, car-
bamazepine, and clonazepam.
The cross-sectional observational study was performed ac-
cording to the Declaration of Helsinki and with the approval of
the Institutional Review Board. Parents and/or tutors, after re-
ceiving information about the study, were asked for their written
consent.
Methods
In all patients, clinical evaluation, anthropometric measure-
ments, body composition estimation, biochemical profile, and ul-
trasound-measured EFT were performed.
Anamnestic Investigation, Clinical, and Anthropometric
Parameters
Physical examination of the subjects included anthropometric
parameters, blood pressure measurement, as well as pubertal stage
evaluation according to Marshall and Tanner (prepubertal charac-
teristics corresponding to Tanner stage 1).
All the subjects were weighed using a platform-type scale
(Wunder San 200A). To record the weight measurement, the child
was first weighed while being held by his/her parent or legal care-
giver, then the parent or legal caregiver was weighed. The child’s
weight was obtained by calculating the difference between the
weight of the parent or legal caregiver holding the child and their
own weight.
To obtain reliable height and length measurements, anthro-
pometry was performed measuring body segment lengths ac-
cording to Stevenson’s method [9]. Data corresponding to the
average of ulna measurements and tibia lengths were used to
obtain an estimate of stature according to reported equations
[9].
Body mass index (BMI) was calculated by dividing the patient’s
weight in kilograms by height in meters squared. The following
BMI cut-off points were considered: <–2 SDS indicated thinness,
between +1SD and <+2SD indicated overweight, and 2≥ SDS in-
dicated obesity.
Waist circumference (WC) was measured to the nearest centi-
meter with a flexible steel tape, as the minimal circumference mea-
surable on the horizontal plane between the lowest portion of the
rib cage and iliac crest, while the child was in a horizontal position,
without any pressure on the abdominal wall.
WC was considered pathological with values exceeding the
95th percentile for age and sex [10]. Waist to height ratio (WHtR)
was calculated with the standard formula and a cutoff of 0.5 was
used to differentiate low from high WHtR [11].
Mid upper arm circumference was measured midway between
the tip of the acromion and olecranon process, with an accuracy of
0.1 cm using a pediatric steel measuring tape.
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Table 1. Clinical features, anthropometric parameters, and body composition of the subjects

Variable Mean SD p25 p50 p75

Birth weight, g 2,498.5 748.97 2,015 2,800 3,012.5

Age, year 14.60 8.82 6.90 15.93 18.60
Weight, kg 28.47 9.36 18.8 30.25 36.05
BMI, kg/m2 16.87 3.512 14.59 16.94 19.28
BMI-SDS 1.67 2.47 2.62 1.35 0.43
Waist circumference, cm 71.1 15.09 56 76.5 82
Waist-to-height ratio, cm 0.518 0.11 0.48 0.51 0.55
Phase angle (φ), degrees 3.33 27.83 2.7 3.3 3.8
Reactance (R), ohm 52 13.55 41 52 65
Resistance (Xc), ohm 891.78 105.43 814 921 993
Fat mass, n (%) 26.12 11.39 19.6 27.7 34.8
Fat free mass, n (%) 74.73 13.75 65.2 72.3 80.4
Total body water, L 55.70 11.54 48.5 53.5 58.3
Body mass cell, kg 8.16 2.70 6.5 8.6 9.6
Mid upper arm circumference, cm 20.80 4.65 17.5 20.5 23
Daily energy intake, Kcal/die 1,226.90 409.26 285 1,150 1,400

Systolic and diastolic blood pressure (SBP and DBP, respective-
ly) readings were taken twice using a mercury sphygmomanometer,
with an appropriately sized cuff on the right arm, which was slight-
ly flexed at heart level. The second Blood pressure (BP) measure-
ment was used for the analysis. Elevated SBP or DBP were defined
with values exceeding the 95th percentile for age and sex [12].
On the basis of gestational age and birth weight, children were
defined appropriate for gestational age with a birth weight ≥10th
percentile and small for gestational age with a birth weight <10th
percentile [13].
Body Composition
Body composition was estimated by bioelectrical impedance
(BIA-101 model; Akern, Florence, Italy), using an alternating elec-
tric current at low intensity (800 μA) and rate frequency fixed at
50 kHz.
As previously described [6], measurements were assessed on
the left side of the body between the ipsilateral wrist and ankle
bony prominences. The 2 distal current-introducing electrodes
were placed on the dorsal surfaces of the hand and foot, previ-
ously cleansed with alcohol, proximal to the metacarpal phalan-
geal and metatarsal phalangeal joints, respectively. The 2 voltage-
sensing electrodes were applied at the pisiform prominence of the
wrist and between the medial and lateral malleoli of the ankle. The
patient was placed in a supine position for 10 minutes, in order to
allow a homogeneous distribution of body fluids, avoiding any
contact that could short circuit the electrical current pathway;
arms and legs were abducted at a 30–45-degree angle from the
trunk. Measurements were made with the child as relaxed as pos-
sible, taking about 1 minute in total. Resistance, reactance, and
phase angle were registered. Body composition was estimated ac-
cording to Rieken et al. [14].
Biochemical Metabolic Parameters
Metabolic blood assays included fasting blood glucose (FBG),
insulin, total cholesterol, high-density lipoprotein cholesterol
(HDL-C), triglycerides (TG), aspartate aminotransferase, and al-
anine aminotransferase. We calculated non-HDL-C since it is a
better marker of risk than low-density lipoprotein cholesterol, in
both primary and secondary prevention and we also calculated
the TG/HDL-C ratio, which is a reliable predictor of insulin re-
sistance and a powerful independent predictor of developing cor-
onary artery disease. Insulin resistance was calculated with the
homeostasis model assessment for insulin resistance (HOMA-IR)
formula.
Abnormalities in lipid fasting levels were considered for total
cholesterol and TG values exceeding the 95th percentile and HDL-
C values below the 5th percentile for age and sex [15]. Elevated
FBG was defined with values exceeding 100 mg/dL and impaired
insulin sensitivity with HOMA-IR exceeding the 97.5th percentile
for age and sex [16].
Ultrasound-Measured EFT
Ultrasound EFT was measured according to Iacobellis et al. [7],
as already described in a previous study on a pediatric population
[6].Patients were placed in the left lateral decubitus position. EFT
was assessed on the free wall of the right ventricle in 2-dimension-
al long and short heart axis views, at the end of the systole, using a
MyLab 30 Gold Esaote instrument (Esaote S.p.A., Genova, Italy)
with a 3.5–7.5 MHz variable-frequency transducer. The largest
amount of EF is usually seen as an echo free or, if it is massive, as
a hyperechoic space. EFT should not be measured obliquely as it
may result in overestimated measurements. It is recommended to
take the average of 3 measurements, as EF longitudinal thickness
may vary. This method is highly reliable, non-invasive, and inex-
pensive if included in the routine assessment of subjects at risk for
cardiometabolic diseases.
We considered 52 normal weight neurologically healthy sub-
jects (mean age 14.9 ±1.9), formerly enrolled in a previously pub-
lished study [6], as a control group for ultrasound EFT measure-
ment. An EFT cut-off value >3.6 mm was used to predict visceral
obesity (VO) according to the literature [6].
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DOI: 10.1159/000484326
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Table 2. Patients’ epicardial thickness and metabolic parameters. Correlation between EFT and metabolic profile is also reported

Parameter Mean SD p25 p50 p75 Correlation with

EFT, p value

Epicardial fat thickness, mm 2.8 1.6 1.7 2.5 3.2 –

Fasting blood glucose, mg/dL 77.9 55.01 57 67 88 0.46
Fasting insulin, microIU/mL 21.9 21.1 6.3 13.9 30.5 0.56
HOMA-IR, n (%) 4.27 4.71 0.9 2.3 5.9 0.04
Triglycerides, mg/dL 120.6 78.37 67.5 95 148.5 0.01
Total cholesterol, mg/dL 148 38.60 118.5 142 172 0.39
HDL-cholesterol, mg/dL 45.28 14.45 37 43.5 50 0.26
Non-HDL-cholesterol, mg/dL 102.71 39.80 77 100.5 127.5 0.27
Triglyceride/HDL-cholesterol ratio 2.99 2.5 1.50 2.1 3.2 0.0007
Systolic pressure, mm Hg 107.1 16.3 96.5 107.5 120 0.99
Diastolic pressure, mm Hg 67.6 12.6 56.5 66 77 0.16
AST, U/L (range 14–35) 28.2 14.4 18.5 23 33 0.97
ALT, U/L (range 10–35) 22.42 20.21 12 14 27 0.90
Leptin, (range male 2,205–11,149 pg/mL;
female 3,877–77,273 pg/mL) 35,992.6 31,609.4 12,332 27,471 54,266 0.04

ALT, alanine aminotransferase; AST, aspartate aminotransferase; HDL, high-density lipoprotein; HOMA-IR, homeostasis model
assessment for insulin resistance; EFT, epicardial fat thickness.

Statistical Analysis Epicardial Adipose Tissue, Clinical, and Metabolic

All analyses were performed using Stata 14 (StataCorp, College
Station, TX, USA). For our purposes, the data were described as the
mean SD, median, and 25th–75th percentiles if continuous, and as
counts and percent if categorical. Non-parametric correlations be-
tween continuous variables were assessed with the Spearman R test.
The association of categorical variables was assessed with the Fish-
er’s exact test. For the purpose of this analysis, biomarkers were di-
chotomized at the local laboratory cutoff for normality. Associa-
tions between dichotomized biomarkers and EF (mm) were evalu-
ated with regression models; results were expressed as beta coefficient
(mean mm change between non-pathological and pathological val-
ues) and 95% CI. A sample size of 30 should achieve 83% power to
detect a difference of –0.50000 between the null hypothesis correla-
tion of 0.00000 and the alternative hypothesis correlation of 0.50000
using a 2-sided hypothesis test with a significance level of 0.05000.
Results
Clinical Characteristics
A total of 17 male (53.1%) and 15 female (46.8%) chil-
dren were enrolled in the study. Birth weight was either
appropriate or small respectively in 85 and 15% of the
sample. No cases of obesity and only one overweight child
were identified; BMI was <–2 SDS in 13 (40.6%) subjects.
Pathological WC was recorded in 13 (40.6%) subjects.
Pubertal stage was either classified as Tanner 1, Tanner
2–3, and Tanner 4–5 respectively in 9 (28.1%), 4 (12.5%),
and 19 (59.3%) subjects.
Parameters
Patients’ EFT values (2.8 ± 1.6 mm) showed correla-
tion with gender (95% CI 0.86–2.76, p  < 0.001), with
higher values in females than in males (3.73 ± 2.9 vs.
2.0 ± 0.6) and pubertal stage (95% CI 0.50–2.52, p = 0.04)
with higher values in Tanner stage 4–5 than in Tanner 1
and Tanner 2–3 (3.40 ± 1.82 vs. 2.32 ± 1.15 vs. 2.70 ±
1.29). EFT was also correlated with age (p = 0.02, Spear-
man R = 0.40) as well as with WHtR (p = 0.03, Spearman
R  = 0.39). No correlations with BMI-SDS (p  = 0.43,
Spearman R = 0.14), WC (p = 0.19, Spearman R = 0.24),
and body composition (angle phase p = 0.5, Spearman
R = 0.12; fat mass p = 0.31, Spearman R = 0.20; free fat
mass p = 0.33, Spearman R = –0.20) were found. A cor-
relation between EFT and leptin was also noted (p = 0.04,
Spearman R = 0.36).
Mean EFT values in NI children were higher com-
pared to the control group (2.86 ± 1.59 vs. 2.3 ± 0.7, p =
0.02). EFT, predictive of VO, was observed in 7 of 32
(22%) of the subjects.
EFT values and metabolic parameters are reported in
Table 2. EFT significantly correlated with pathological
TG levels (p  = 0.01, 95% CI 0.27–2.45, beta-coefficient
1.36) and HOMA-IR (p = 0.04, 95% CI 0.05–2.22, beta-
coefficient 1.13). A correlation between EFT and the TG/
HDL-C ratio was also noted (r = 0.56, p = 0.0007, 95% CI
0.38–0.75). No correlation between EFT and pathological
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values of FBG (p = 0.46, 95% CI –2.37 to 1.1, beta-coeffi-
cient), total cholesterol (p  = 0.39, 95% CI –1.0 to 2.47,
beta-coefficient –0.63), HDL-C (p = 0.26, 95% CI 0.06–
2.45, beta-coefficient 0.88), non-HDL-C (p = 0.27, 95% CI
0.07–0.38, beta-coefficient 0.20), and diastolic or systolic
pressure (p = 0.41, 95% CI –1.95 to 0.82, beta-coefficient
–0.47) were recorded.
There was a 6 year-old girl (with EFT = 5 mm) who
died of a heart attack 9 months after ultrasound EFT eval-
uation, which was not well defined (the patient was a
community resident and an autopsy was not required).
Discussion
This study investigated ultrasound EFT in non-obese
NI children. In these patients, higher EFT values were ob-
served as well as a high prevalence of EFT predictive of
VO compared with neurologically normal children. EFT
values significantly correlated with clinical, metabolic,
and endocrinological parameters, such as WHtR, TG,
HOMA-IR, and leptin.
EF is an unusual visceral fat depot with anatomical
and functional contiguity with the myocardium and
coronary arteries. It is a white adipose tissue storage fat
that covers 80% of the heart’s surface, representing 20%
of the organ’s total weight, and shares the same embryo-
logic origin with abdominal visceral fat from the splanch-
nopleuric mesoderm. It is also considered the true vis-
ceral fat depot of the heart. Under physiological condi-
tions, EF displays biochemical, mechanical, and
thermogenic cardioprotective properties. Under patho-
logical circumstances, EF is known to locally affect the
heart and coronary arteries through vasocrine or para-
crine secretion of proinflammatory cytokines, even
though influences on this equilibrium remain unclear
[4, 5]. Although EF is needed for heart muscle function,
in recent decades it has been reported that increased
thickness greatly enhances the risk of developing CVD
and MS [4, 5] indicating that ultrasound measured EFT
may be a useful marker for the early detection of sub-
clinical CVD and/or adverse metabolic profile develop-
ment [4, 5].
Ultrasound-measured EFT is a reliable, non-invasive,
and relatively inexpensive marker of visceral adiposity
and ectopic organ-specific fat accumulation. As Iacobellis
et al. [5, 17–20] has reported, EFT was compared with
magnetic resonance imaging measured intra-abdominal
fat and showed excellent correlation and reliability.
Therefore, EFT is thought to measure visceral fat more
100 Ann Nutr Metab 2018;72:96–103
DOI: 10.1159/000484326
precisely and more objectively than WC does. EFT is not
necessarily a marker of obesity, but rather reflects ectopic
fat accumulation.
Unfortunately, visceral fat cannot be estimated with
blood tests; however, measuring visceral fat in NI chil-
dren could help to stratify and predict their cardiometa-
bolic risk, in combination with more traditional risk fac-
tors. As EFT has recently been shown to be a sensitive
target of medications targeting adipose tissue, its use
would also be helpful in tracking visceral fat changes in
pharmacologically treated NI children.
Some conditions associated with intellectual or de-
velopmental disabilities are also highly correlated with
cardiovascular risk factors [1, 2] in the adult age. Most
research has been conducted on subjects with psychiat-
ric problems rather than on young neurologically dis-
abled patients [1, 2, 21, 22]. On the basis of anecdotal
observations, it is suspected that this population is at
greater risk for MS and preclinical cardiovascular events.
Factors such as limited opportunity to exercise, un-
healthy diet, comorbidities, polypharmacy, and hospi-
talization, low healthcare literacy due to limited intel-
lectual ability, all definitely contribute to increased met-
abolic and cardiovascular risks. Indeed, high-risk
conditions and environmental stressors are reported in
subjects with developmental disabilities, particularly in
those with mobility limitations [1, 2]. In general, stress
exerts its effect on most organs and leads to complex,
multi-system homeostatic interactions that may nega-
tively affect health status, increasing morbidity and
mortality [23, 24].
Moreover, in persons with disabilities, cardiovascular
events are under-diagnosed due to the absence of referred
symptoms. Early recognition of premature cardiac patho-
logical signs is important as subclinical symptoms precede
the clinical manifestations of CVD by many years. Body
composition, and in particular fat distribution, may be car-
diovascular and metabolic risk indicators [25]. However in
the pediatric age, contradictory findings on different an-
thropometric measures and cardiometabolic risk associa-
tion have been reported. European Society for Pediatric
Gastroenterolgy Hepatology and Nutrition (ESPGHAN)
Guidelines for the Evaluation and Treatment of Gastroin-
testinal and Nutritional Complications in Children with
Neurological Impairment [26] recommend using skinfold
thickness rather than BMI for nutritional assessment in NI
children, which provides better estimates of body fat. The
guidelines also underscore that their interpretation is very
challenging because children with NI tend to store fat more
centrally (abdomen) than peripherally. Skinfold thickness
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measurements rely on assessing subcutaneous fat and ig-
nore variations in intra-abdominal fat [14].
However, in children with severe disabilities who are
bedridden, the subject position required to measure skin-
fold thickness limits its use for the accurate measurement
of body composition in clinical practice [27]. Thus, some
authors have reported that bioelectrical impedance anal-
ysis, with target-specific equations, is more accurate at
assessing nutritional status in children with severe neuro-
logic impairment than the measurement of skinfold
thickness [14].
We also considered mid upper arm circumference in
addition to BMI, because it is easier to measure (although
non-specific) and WHtR since different studies have in-
dicated stronger associations between measures of ab-
dominal adiposity (i.e., WHtR vs. BMI) with several car-
diovascular risk factors [28, 29], showing that WHtR pro-
vides a better estimate than BMI for risk factors such as
low-density lipoprotein cholesterol (4.1 vs. 6.6%), TG
(10.5 vs. 15.0), and a better estimate of cardiovascular risk
when compared with BMI (WHtR 36% vs. BMI 28%)
[28–30].
In this study, we report a strong correlation between
EFT and WHtR and no correlation with BMI-SDS and
WC; these data indicate that WHtR is a better anthropo-
metric cardiovascular risk predictor and support the evi-
dence that EFT is related to visceral fat, rather than total
adiposity [4, 5].
A significant positive correlation was found between
EFT and age [31] and pubertal stage in our sample,
probably due to early body composition modifications
following decreased mobility such as in aging and hor-
monal perturbation and other metabolic impairment
during puberty. Moreover, even though the death of
our young patient could not be related to other cardio-
vascular risk factors, the presence of such a high EFT
(5 mm) further favors routine monitoring among NI
children.
As far as gender is concerned, our results showed high-
er EFT in females, supporting the results from other au-
thors [32] suggesting that EFT is more strongly associated
with risk factors in women than in men, although a con-
sensus has not yet been reached [7]. This might be ex-
plained by a redistribution of body fat with a greater de-
pot of visceral adipose tissue, which may lead to greater
insulin resistance and increased cardiovascular risk [33].
In the present study, EFT in children was associated
with an unfavorable cardiometabolic risk profile; a posi-
tive correlation between EFT and HOMA-IR and dyslip-
idemia was noted, as already described in the general
Epicardial Fat in Disabled Children
population [4, 5]. Insulin resistance has been largely pos-
tulated as the trigger for metabolic comorbidities in chil-
dren and predictive of type 2 diabetes, which in turn leads
to a higher risk for CVD [34]. While, in patients with type
2 diabetes mellitus, insulin resistance in the adipose tissue
leads to an increase of the intracellular hydrolysis of TGs
and plays a key role in promoting atherosclerosis [35].
Our results showed a significant correlation between in-
sulin resistance and hypertriglyceridemia, suggesting that
EFT could be a more sensitive cardiovascular risk marker
than abdominal adiposity in non-obese compromised
children.
The TG/HDL-C ratio was also significantly correlated
with EFT, while non-HDL-C was not. This may be attrib-
utable to the fact that the TG/HDL-C ratio better discrim-
inated cardiometabolic risk factors than non-HDL-C pa-
rameters [36].
It is well known that insulin resistance is mediated by
adipokines secreted by adipose tissue. Some adipokines
play a major role in insulin resistance and cardiovascular
complications associated with central or VO. Among
these, leptin is considered an independent predictor for
cardiovascular morbidity and mortality and a risk factor
for myocardial infarction [37]. In our cohort of NI chil-
dren, leptin values correlated with EFT independently of
BMI, in agreement with the results reported by Iacobellis
[38] in type 1 diabetes mellitus.
We recognize that this study has some limitations.
The sample size was relatively small (although signifi-
cant) and included a wide age range of patients due to
the difficulties in enrolling and studying NI children.
The time of exposition to neurological impairment was
too short to be responsible for extra EFT accumulation
in the youngest children and it is likely that the poten-
tial effect of a relationship between EFT and the meta-
bolic profile was ‘diluted’ by the youngest subject re-
cruited to the study, leading to a reduced statistical
power. Secondly, ultrasound EFT was measured in the
entire sample, but no other cardiac parameters were
considered.
Finally, we considered a population of subjects with a
severe grade of disability, in which several cardiovascular
factors, such as inadequate nutritional status, low physical
activity level, anticonvulsant multi-therapy, may exert po-
tential additional effects on metabolic abnormalities and
on visceral fat depots, accordingly influencing EFT values.
Data regarding single biomarkers are mandatory to define
the causal role of these results or to support the multi-caus-
al nature of higher EFT found in these patients compared
to the control group matched for age and gender.
133.6.82.173 - 1/20/2018 8:49:21 AM
Ann Nutr Metab 2018;72:96–103 101
DOI: 10.1159/000484326
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 Despite the acknowledged limitations, this study may
be considered a first step for further investigations on NI
children with cardiovascular risk in a wider cohort of sub-
jects, in order to improve their health status and obviate
complications. In the future, a registry for evaluating car-
diovascular patient outcomes in this poorly studied pop-
ulation will also be considered.
Acknowledgments
The authors thank Antonella Tomasi for nursing care, Dr. Sil-
vano Gandini for patient care, Antonio Prisco and Linda Geca for
technical support, Dr. C. Torre and Dr. G. Testa for technical sup-
port in the hormonal evaluation, and Dr. L. Kelly for English revi-
sion of the manuscript.

Disclosure Statement
Conclusion
The authors have no competing interests to declare.
Ultrasound-measured EFT might be a feasible and
reliable method for the evaluation of cardiovascular
Funding Sources
risk in NI children, for early recognition of subclinical
manifestations of CVD and the prevention of adverse The authors did not receive any funding from public, commer-
outcomes. cial, or not-for-profit agencies to conduct this research.

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