Abstract
Cardiovascular disease remains the leading cause of mortality accounting up to 40% of all deaths, but, currently, cancer is prominent cause of death globally. Anthracyclines are the cornerstone of chemotherapy in women with breast cancer. However, its clinical use is limited by their cardiotoxic effects that can trigger heart failure development. Vascular toxicity of chemotherapy may be linked with endothelial dysfunction because anthracycline damage of endothelial cells can lead to the development and progression of cardiomyopathy by decreasing the release and activity of endothelial factors and, ultimately, endothelial cell death. These processes suppress anti-inflammatory and vascular reparative functions and initiate the development of future cardiovascular events. Recent studies have shown that chemotherapy may induce toxicity in the vascular endothelium and is accompanied by systemic endothelial dysfunction in patients with diagnosed cardiovascular diseases. Because the initial endothelial cell insult is likely asymptomatic, there is often a long delay between the termination of doxorubicin therapy and the onset of vascular disorders. In this case, genetic susceptibility factor will help to identify susceptible patients in the future. The objectives of this study were to evaluate prognostic role of molecular (endothelin-1) and genetic factors (gene polymorphisms of endothelial nitric oxide (NO) synthase (NOS3, rs1799983), endothelin-1 receptor type A (EDNRA, C+70G, rs5335) and NADPH oxidase (C242T, rs4673) in development of endothelial dysfunction and anthracycline-induced cardiotoxicity in women without cardiovascular diseases.
References
1.
Thorn
CF
, Oshiro
C
, Marsh
S
, Hernandez-Boussard
T
, McLeod
H
, Klein
TE
, et al. Doxorubicin pathways: pharmacodynamics and adverse effects
. Pharmacogenet Genomics
. 2011
;21
(7
):440
–6
. .2.
Mitry
MA
, Edwards
JG
. Doxorubicin induced heart failure: phenotype and molecular mechanisms
. Int J Cardiol Heart Vasc
. 2016
;10
:17
–24
. .3.
Octavia
Y
, Tocchetti
CG
, Gabrielson
KL
, Janssens
S
, Crijns
HJ
, Moens
AL
. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies
. J Mol Cell Cardiol
. 2012
;52
(6
):1213
–25
. .4.
Jang
WJ
, Choi
DY
, Jeon
IS
. Vascular endothelial dysfunction after anthracyclines treatment in children with acute lymphoblastic leukemia
. Korean J Pediatr
. 2013
;56
(3
):130
–4
. .5.
dos Santos
DS
, dos Santos Goldenberg
RC
. Doxorubicin-induced cardiotoxicity: from mechanisms to development of efficient therapy
. 2018
. 6.
Simůnek
T
, Stérba
M
, Popelová
O
, Adamcová
M
, Hrdina
R
, Gersl
V
. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron
. Pharmacol Rep
. 2009 Jan–Feb
;61
(1
):154
–71
. .7.
Raj
S
, Franco
VI
, Lipshultz
SE
. Anthracycline-induced cardiotoxicity: a review of pathophysiology, diagnosis, and treatment
. Curr Treat Options Cardiovasc Med
. 2014
;16
(6
):315
. .8.
Salazar-Mendiguchía
J
, González-Costello
J
, Roca
J
, Ariza-Solé
A
, Manito
N
, Cequier
A
. Anthracycline-mediated cardiomyopathy: basic molecular knowledge for the cardiologist
. Arch Cardiol Mex
. 2014
;84
(3
):218
–23
. .9.
Ghigo
A
, Li
M
, Hirsch
E
. New signal transduction paradigms in anthracycline-induced cardiotoxicity
. Biochim Biophys Acta
. 2016
;1863
(7
):1916
–25
. .10.
Plana
JC
, Galderisi
M
, Barac
A
, Ewer
MS
, Ky
B
, Scherrer-Crosbie
M
, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging
. J Am Soc Echocardiogr
. 2014 Sep
;27
(9
):911
–39
. .11.
Minotti
G
, Menna
P
, Salvatorelli
E
, Cairo
G
, Gianni
L
. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity
. Pharmacol Rev
. 2004
;56
(2
):185
–229
. .12.
Senchenkov
A
, Litvak
DA
, Cabot
MC
. Targeting ceramide metabolism: a strategy for overcoming drug resistance
. J Natl Cancer Inst
. 2001
;93
(5
):347
–57
. .13.
Zhang
S
, Liu
X
, Bawa-Khalfe
T
, Lu
LS
, Lyu
YL
, Liu
LF
, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity
. Nat Med
. 2012
;18
(11
):1639
–42
. .14.
Niu
J
, Azfer
A
, Wang
K
, Wang
X
, Kolattukudy
PE
. Cardiac-targeted expression of soluble Fas attenuates doxorubicin-induced cardiotoxicity in mice
. J Pharmacol Exp Ther
. 2009
;328
(3
):740
–8
. .15.
Teplyakov
AT
, Shilov
SN
, Popova
AA
, Berezikova
EN
, Neupokoeva
MN
, Grakova
EV
, et al. The prognostic value of the NT-proBNP biomarkers and Fas ligand in assessing the risk of cardiotoxicity of anthracycline chemotherapy
. Cardiovasc Ther Prev
. 2019
;18
(1
):127
–33
. .16.
Economou
E
, Farmakis
D
, Stefanadis
C
. Elevated circulating levels of the soluble from Fas/APO-1, an important cofactor to the activation of apoptosis, in chronic heart failure
. Eur Heart J
. 1998
;19
:A468
..17.
Luu
AZ
, Chowdhury
B
, Al-Omran
M
, Teoh
H
, Hess
DA
, Verma
S
. Role of endothelium in doxorubicin-induced cardiomyopathy
. JACC Basic Transl Sci
. 2018 Dec
;3
(6
):861
–70
. .18.
Kahler
J
, Ewert
A
, Weckmuller
J
, Stobbe
S
, Mittmann
C
, Koster
R
, et al. Oxidative stress increases endothelin-1 synthesis in human coronary artery smooth muscle cells
. J Cardiovasc Pharmacol
. 2001
;38
:49
–57
.19.
Thijssen
DH
, Black
MA
, Pyke
KE
, Padilla
J
, Atkinson
G
, Harris
RA
, et al. Assessment of flow-mediated dilation in humans: a methodological and physiological guideline
. Am J Physiol Heart Circ Physiol
. 2011
;300
(1
):H2
–12
. .20.
Yeboah
J
, Folsom
AR
, Burke
GL
, Johnson
C
, Polak
JF
, Post
W
, et al. Predictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosis
. Circulation
. 2009
;120
(6
):502
–9
. .21.
Jang
WJ
, Choi
DY
, Jeon
IS
. Vascular endothelial dysfunction after anthracyclines treatment in children with acute lymphoblastic leukemia
. Korean J Pediatr
. 2013
;56
(3
):130
–4
. .22.
Gaо
L
, Wang
W
, Li
YL
, et al. Sympathoexcitation by central ANG II: roles for AT-1 receptor upregulation and NAD(P)H oxidase in RVLM
. Am J Physiol Heart Circ Physiol
. 2005
;288
(5
):H2271
–9
..23.
Wyche
KE
, Wang
SS
, Griendling
KK
, Dikalov
SI
, Austin
H
, Rao
S
, et al. C242T CYBA polymorphism of the NADPH oxidase is associated with reduced respiratory burst in human neutrophils
. Hypertension
. 2004
;43
(6
):1246
–51
. .24.
Moreno
MU
, San José
G
, Fortuño
A
, Beloqui
O
, Díez
J
, Zalba
G
. The C242T CYBA polymorphism of NADPH oxidase is associated with essential hypertension
. J Hypertens
. 2006
;24
(7
):1299
–306
. .25.
Wojnowski
L
, Kulle
B
, Schirmer
M
, Schlüter
G
, Schmidt
A
, Rosenberger
A
, et al. NAD(P)H oxidase and multidrug resistance protein genetic polymorphisms are associated with doxorubicin-induced cardiotoxicity
. Circulation
. 2005
;112
(24
):3754
–62
. .26.
Böhm
F
, Pernow
J
. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease
. Cardiovasc Res
. 2007
;76
(1
):8
–18
. .27.
Rubanyi
GM
, Polokoff
MA
. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology
. Pharmacol Rev
. 1994
;46
(3
):325
–415
. PMID: 7831383
..28.
Rahman
T
, Baker
M
, Hall
DH
, Avery
PJ
, Keavney
B
. Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study
. J Hum Hypertens
. 2008
;22
(4
):282
–8
. .29.
Okan
G
, Yıldız
Z
, Gökdemir
G
, Yorulmaz
E
, Vural
P
, Doğru-Abbasoğlu
S
, et al. G-231A and G+70C polymorphisms of endothelin receptor type-A gene could affect the psoriasis area and severity index score and endothelin 1 levels
. Indian J Dermatol
. 2015
;60
(2
):211
. .30.
Bühler
K
, Ufer
M
, Müller-Marbach
A
, Brinkmann
U
, Laule
M
, Stangl
V
, et al. Risk of coronary artery disease as influenced by variants of the human endothelin and endothelin-converting enzyme genes
. Pharmacogenet Genomics
. 2007
;17
(1
):77
–83
. .31.
Aydin
AF
, Vural
P
, Oruç
ÇU
, Doğru-Abbasoğlu
S
, Özderya
A
, Karadağ
B
, et al. The evaluation of endothelin 1 (EDN1) and endothelin receptor type A (EDNRA) gene polymorphisms in Hashimoto’s thyroiditis
. Int Immunopharmacol
. 2014
;21
(1
):181
–5
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