Abstract
Introduction: Hypercholesterolemia is a risk factor for premature arteriosclerosis. Inflammation and oxidative stress are thought to contribute to endothelial dysfunction preceding vasculopathy. We investigated the association between inflammation, glycocalyx biomarkers, endothelial function, and vascular parameters in children with hypercholesterolemia. Methods: In 22 patients (LDL-cholesterol >130 mg/dL; median age [IQR]: 13 [2.3] years) and 22 controls (13 [2.5] years), tumor necrosis factor-alpha (TNF-α), oxidized cholesterol (oxLDL), and glycocalyx biomarkers (Syndecan-1, Hyaluronan) were measured using immunoassays. Endothelial function was assessed by peripheral arterial tonometry, sublingual glycocalyx and microcirculation by videomicroscopy and carotid intima-media thickness by ultrasound. Results: OxLDL was significantly higher in patients (78.9 [38.2] vs. 50.3 [16.6] U/L, p = 0.002), whereas all other experimental parameters were comparable between groups. Multivariate analysis revealed a significant association of Syndecan-1 with TNF-α (β = 0.75, p < 0.001) and with hypercholesterolemia (β = 0.31, p = 0.030). The interaction term combining TNF-α and hypercholesterolemia showed a significant effect (p = 0.034). Sex was an independent predictor of endothelial function. Conclusion: The combined effect of hypercholesterolemia and inflammation on glycocalyx perturbation and the impact of sex in the premature development of arteriosclerosis deserve further evaluation. Therapeutic approaches tackling low-grade systemic inflammation may offer potential to prevent or delay progression of cardiovascular disease and cardiovascular complications.
Journal Section:
Basic/Transitional Science: Research Article
References
1.
Xu
J
, Murphy
SL
, Kochanek
KD
, Arias
E
. Mortality in the United States, 2021
. NCHS Data Brief
. 2022
;2022
(456
):1
–8
.2.
Berenson
GS
, Srinivasan
SR
, Bao
W
, Newman
WP
3rd, Tracy
RE
, Wattigney
WA
. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study
. N Engl J Med
. 1998
;338
(23
):1650
–6
. .3.
Prell
C
, Koletzko
B
. Hyperlipidemias in childhood and adolescence
. Monatsschrift Kinderheilkunde
. 2016
:1
–15
.4.
Harada-Shiba
M
, Ohtake
A
, Sugiyama
D
, Tada
H
, Dobashi
K
, Matsuki
K
, et al. Guidelines for the diagnosis and treatment of pediatric familial hypercholesterolemia 2022
. J Atheroscler Thromb
. 2023
;30
(5
):531
–57
. .5.
de Ferranti
SD
, Steinberger
J
, Ameduri
R
, Baker
A
, Gooding
H
, Kelly
AS
, et al. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American heart association
. Circulation
. 2019
;139
(13
):e603
–34
. .6.
Jarvisalo
MJ
, Raitakari
M
, Toikka
JO
, Putto-Laurila
A
, Rontu
R
, Laine
S
, et al. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes
. Circulation
. 2004
;109
(14
):1750
–5
. .7.
Lee
H
, Dichtl
S
, Mormanova
Z
, Dalla Pozza
R
, Genzel-Boroviczeny
O
. In adolescence, extreme prematurity is associated with significant changes in the microvasculature, elevated blood pressure and increased carotid intima-media thickness
. Arch Dis Child
. 2014
;99
(10
):907
–11
. .8.
de Jongh
S
, Lilien
MR
, Bakker
HD
, Hutten
BA
, Kastelein
JJ
, Stroes
ES
. Family history of cardiovascular events and endothelial dysfunction in children with familial hypercholesterolemia
. Atherosclerosis
. 2002
;163
(1
):193
–7
. .9.
Weinbaum
S
, Cancel
LM
, Fu
BM
, Tarbell
JM
. The glycocalyx and its role in vascular physiology and vascular related diseases
. Cardiovasc Eng Technol
. 2021
;12
(1
):37
–71
. .10.
Bonetti
PO
, Pumper
GM
, Higano
ST
, Holmes
DR
Jr, Kuvin
JT
, Lerman
A
. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia
. J Am Coll Cardiol
. 2004
;44
(11
):2137
–41
. .11.
Wagner
M
, Anzinger
E
, Hey
F
, Reiter
K
, Wermelt
JZ
, Pastor-Villaescusa
B
, et al. Monitoring of the microcirculation in children undergoing major abdominal and thoracic surgery: a pilot study
. Clin Hemorheol Microcirc
. 2023
;83
(3
):217
–29
. .12.
Puchwein-Schwepcke
A
, Artmann
S
, Rajwich
L
, Genzel-Boroviczeny
O
, Nussbaum
C
. Effect of gestational age and postnatal age on the endothelial glycocalyx in neonates
. Sci Rep
. 2021
;11
(1
):3133
. .13.
Narverud
I
, Retterstøl
K
, Iversen
PO
, Halvorsen
B
, Ueland
T
, Ulven
SM
, et al. Markers of atherosclerotic development in children with familial hypercholesterolemia: a literature review
. Atherosclerosis
. 2014
;235
(2
):299
–309
. .14.
Vlahos
AP
, Naka
KK
, Bechlioulis
A
, Theoharis
P
, Vakalis
K
, Moutzouri
E
, et al. Endothelial dysfunction, but not structural atherosclerosis, is evident early in children with heterozygous familial hypercholesterolemia
. Pediatr Cardiol
. 2014
;35
(1
):63
–70
. .15.
Jehlicka
P
, Stožický
F
, Mayer
O
Jr, Varvařovská
J
, Racek
J
, Trefil
L
, et al. Asymmetric dimethylarginine and the effect of folate substitution in children with familial hypercholesterolemia and diabetes mellitus type 1
. Physiol Res
. 2009
;58
(2
):179
–84
. .16.
Bruzzi
P
, Predieri
B
, Madeo
S
, Lami
F
, Iughetti
L
. Longitudinal evaluation of endothelial markers in children and adolescents with familial hypercholesterolemia
. Acta Biomed
. 2021
;92
(5
):e2021343
. .17.
Hudgins
LC
, Annavajjhala
V
, Kovanlikaya
A
, Frank
MD
, Solomon
A
, Parker
TS
, et al. Non-invasive assessment of endothelial function in children with obesity and lipid disorders
. Cardiol Young
. 2016
;26
(3
):532
–8
. .18.
Dalla Pozza
R
, Ehringer-Schetitska
D
, Fritsch
P
, Jokinen
E
, Petropoulos
A
, Oberhoffer
R
, et al. Intima media thickness measurement in children: a statement from the association for European paediatric cardiology (AEPC) working group on cardiovascular prevention endorsed by the association for European paediatric cardiology
. Atherosclerosis
. 2015
;238
(2
):380
–7
. .19.
van Bergen En Henegouwen
K
, Hutten
BA
, Luirink
IK
, Wiegman
A
, de Groot
E
, Kusters
DM
. Intima-media thickness in treated and untreated patients with and without familial hypercholesterolemia: a systematic review and meta-analysis
. J Clin Lipidol
. 2022
;16
(2
):128
–42
. .20.
Braamskamp
M
, Langslet
G
, McCrindle
BW
, Cassiman
D
, Francis
GA
, Gagne
C
, et al. Effect of rosuvastatin on carotid intima-media thickness in children with heterozygous familial hypercholesterolemia: the CHARON study (hypercholesterolemia in children and adolescents taking rosuvastatin open label)
. Circulation
. 2017
;136
(4
):359
–66
. .21.
Riggio
S
, Mandraffino
G
, Sardo
MA
, Iudicello
R
, Camarda
N
, Imbalzano
E
, et al. Pulse wave velocity and augmentation index, but not intima-media thickness, are early indicators of vascular damage in hypercholesterolemic children
. Eur J Clin Invest
. 2010
;40
(3
):250
–7
. .22.
Stefanutti
C
, Mesce
D
, Pacella
F
, Di Giacomo
S
, Turchetti
P
, Forastiere
M
, et al. Optical coherence tomography of retinal and choroidal layers in patients with familial hypercholesterolaemia treated with lipoprotein apheresis
. Atheroscler Suppl
. 2019
;40
:49
–54
. .23.
Pajkowski
M
, Dudziak
M
, Chlebus
K
, Hellmann
M
. Assessment of microvascular function and pharmacological regulation in genetically confirmed familial hypercholesterolemia
. Microvasc Res
. 2021
;138
:104216
. .24.
Lona
G
, Endes
K
, Kochli
S
, Infanger
D
, Zahner
L
, Hanssen
H
. Retinal vessel diameters and blood pressure progression in children
. Hypertension
. 2020
;76
(2
):450
–7
. .25.
Nussbaum
C
, Cavalcanti Fernandes Heringa
A
, Mormanova
Z
, Puchwein-Schwepcke
AF
, Bechtold-Dalla Pozza
S
, Genzel-Boroviczeny
O
. Early microvascular changes with loss of the glycocalyx in children with type 1 diabetes
. J Pediatr
. 2014
;164
(3
):584
–9 e1
. .26.
Narverud
I
, Ueland
T
, Nenseter
MS
, Retterstøl
K
, Telle-Hansen
VH
, Halvorsen
B
, et al. Children with familial hypercholesterolemia are characterized by an inflammatory imbalance between the tumor necrosis factor α system and interleukin-10
. Atherosclerosis
. 2011
;214
(1
):163
–8
. .27.
Martino
F
, Loffredo
L
, Carnevale
R
, Sanguigni
V
, Martino
E
, Catasca
E
, et al. Oxidative stress is associated with arterial dysfunction and enhanced intima-media thickness in children with hypercholesterolemia: the potential role of nicotinamide-adenine dinucleotide phosphate oxidase
. Pediatrics
. 2008
;122
(3
):e648
–55
. .28.
Puchwein-Schwepcke
A
, Genzel-Boroviczeny
O
, Nussbaum
C
. The endothelial glycocalyx: physiology and pathology in neonates, infants and children
. Front Cell Dev Biol
. 2021
;9
:733557
. .29.
Stanhewicz
AE
, Wenner
MM
, Stachenfeld
NS
. Sex differences in endothelial function important to vascular health and overall cardiovascular disease risk across the lifespan
. Am J Physiol Heart Circ Physiol
. 2018
;315
(6
):H1569
–88
. .30.
Hayward
CS
, Kelly
RP
. Gender-related differences in the central arterial pressure waveform
. J Am Coll Cardiol
. 1997
;30
(7
):1863
–71
. .31.
van den Berg
BM
, Spaan
JA
, Vink
H
. Impaired glycocalyx barrier properties contribute to enhanced intimal low-density lipoprotein accumulation at the carotid artery bifurcation in mice
. Pflugers Arch
. 2009
;457
(6
):1199
–206
. .32.
Stefanutti
C
, Julius
U
, Watts
GF
, Harada-Shiba
M
, Cossu
M
, Schettler
VJ
, et al. Toward an international consensus-Integrating lipoprotein apheresis and new lipid-lowering drugs
. J Clin Lipidol
. 2017
;11
(4
):858
–71.e3
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