Remote ischaemic preconditioning ameliorates anthracycline-induced cardiotoxicity and preserves mitochondrial integrity.
Animals
Antibiotics, Antineoplastic
Autophagy
Autophagy-Related Proteins
/ metabolism
Cardiotoxicity
Disease Models, Animal
Doxorubicin
Fibrosis
Heart Diseases
/ chemically induced
Hindlimb
/ blood supply
Ischemic Preconditioning
Magnetic Resonance Imaging, Cine
Male
Mitochondria, Heart
/ metabolism
Mitochondrial Dynamics
Myocardium
/ metabolism
Regional Blood Flow
Stroke Volume
Sus scrofa
Time Factors
Ventricular Function, Left
Ventricular Remodeling
Anthracyclines
Cardio-oncology
Cardiotoxicity
Magnetic resonance imaging
Mitochondria
Remote conditioning
Journal
Cardiovascular research
ISSN: 1755-3245
Titre abrégé: Cardiovasc Res
Pays: England
ID NLM: 0077427
Informations de publication
Date de publication:
21 03 2021
21 03 2021
Historique:
received:
15
04
2020
revised:
02
06
2020
accepted:
19
06
2020
pubmed:
1
7
2020
medline:
5
1
2022
entrez:
30
6
2020
Statut:
ppublish
Résumé
Anthracycline-induced cardiotoxicity (AIC) is a serious adverse effect among cancer patients. A central mechanism of AIC is irreversible mitochondrial damage. Despite major efforts, there are currently no effective therapies able to prevent AIC. Forty Large-White pigs were included. In Study 1, 20 pigs were randomized 1:1 to remote ischaemic preconditioning (RIPC, 3 cycles of 5 min leg ischaemia followed by 5 min reperfusion) or no pretreatment. RIPC was performed immediately before each intracoronary doxorubicin injections (0.45 mg/kg) given at Weeks 0, 2, 4, 6, and 8. A group of 10 pigs with no exposure to doxorubicin served as healthy controls. Pigs underwent serial cardiac magnetic resonance (CMR) exams at baseline and at Weeks 6, 8, 12, and 16, being sacrifice after that. In Study 2, 10 new pigs received 3 doxorubicin injections (with/out preceding RIPC) and were sacrificed at week 6. In Study 1, left ventricular ejection fraction (LVEF) depression was blunted animals receiving RIPC before doxorubicin (RIPC-Doxo), which had a significantly higher LVEF at Week 16 than doxorubicin treated pigs that received no pretreatment (Untreated-Doxo) (41.5 ± 9.1% vs. 32.5 ± 8.7%, P = 0.04). It was mainly due to conserved regional contractile function. In Study 2, transmission electron microscopy (TEM) at Week 6 showed fragmented mitochondria with severe morphological abnormalities in Untreated-Doxo pigs, together with upregulation of fission and autophagy proteins. At the end of the 16-week Study 1 protocol, TEM revealed overt mitochondrial fragmentation with structural fragmentation in Untreated-Doxo pigs, whereas interstitial fibrosis was less severe in RIPC+Doxo pigs. In a translatable large-animal model of AIC, RIPC applied immediately before each doxorubicin injection resulted in preserved cardiac contractility with significantly higher long-term LVEF and less cardiac fibrosis. RIPC prevented mitochondrial fragmentation and dysregulated autophagy from AIC early stages. RIPC is a promising intervention for testing in clinical trials in AIC.
Identifiants
pubmed: 32597960
pii: 5864719
doi: 10.1093/cvr/cvaa181
pmc: PMC7983009
doi:
Substances chimiques
Antibiotics, Antineoplastic
0
Autophagy-Related Proteins
0
Doxorubicin
80168379AG
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1132-1143Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
Références
Cardiovasc Res. 2012 May 1;94(2):197-205
pubmed: 22215722
JACC CardioOncol. 2019 Dec;1(2):221-234
pubmed: 32699841
Am J Vet Res. 1979 Nov;40(11):1537-52
pubmed: 525872
Prog Cardiovasc Dis. 2007 Mar-Apr;49(5):330-52
pubmed: 17329180
Nat Med. 2012 Nov;18(11):1639-42
pubmed: 23104132
Eur Heart J. 2020 May 7;41(18):1720-1729
pubmed: 32016393
Circulation. 1993 Mar;87(3):893-9
pubmed: 7680290
J Am Coll Cardiol. 2017 Nov 14;70(20):2552-2565
pubmed: 29145955
J Heart Lung Transplant. 2009 Oct;28(10):1087-93
pubmed: 19782292
Rev Esp Cardiol (Engl Ed). 2017 Jun;70(6):474-486
pubmed: 28330818
Lancet. 2010 Feb 27;375(9716):727-34
pubmed: 20189026
J Am Coll Cardiol. 2019 Jun 11;73(22):2859-2868
pubmed: 31171092
N Engl J Med. 2004 Jul 8;351(2):145-53
pubmed: 15247354
Oxid Med Cell Longev. 2019 Nov 4;2019:3809308
pubmed: 31781334
Circulation. 2015 Jun 2;131(22):1981-8
pubmed: 25948538
Int J Cardiol. 2019 Apr 1;280:163-175
pubmed: 30661849
Basic Res Cardiol. 2018 Mar 7;113(3):14
pubmed: 29516192
Cardiovasc Drugs Ther. 2018 Jun;32(3):245-253
pubmed: 29766336
J Am Coll Cardiol. 2019 Feb 26;73(7):779-791
pubmed: 30784671
Circ Cardiovasc Imaging. 2016 Dec;9(12):
pubmed: 27923796
Int J Cardiol Heart Vasc. 2016 Mar;10:17-24
pubmed: 27213178
Eur Heart J Cardiovasc Imaging. 2018 May 1;19(5):544-552
pubmed: 29106497
Lancet Oncol. 2010 Oct;11(10):950-61
pubmed: 20850381
Eur Heart J. 2016 Sep 21;37(36):2768-2801
pubmed: 27567406
Clin Cardiol. 2016 Feb;39(2):72-82
pubmed: 26807534
J Am Soc Echocardiogr. 2014 Sep;27(9):911-39
pubmed: 25172399
Pflugers Arch. 2017 Feb;469(2):159-181
pubmed: 27928644
JAMA Cardiol. 2016 Dec 1;1(9):1066-1072
pubmed: 27541948
Oncotarget. 2017 Jul 11;8(28):46663-46680
pubmed: 28445146
Pharmacol Toxicol. 1996 Jun;78(6):381-6
pubmed: 8829197
J Am Coll Cardiol. 2015 Jan 20;65(2):177-95
pubmed: 25593060
Lancet. 2019 Oct 19;394(10207):1415-1424
pubmed: 31500849
J Am Coll Cardiol. 2018 May 22;71(20):2281-2290
pubmed: 29540327
Cell Oncol (Dordr). 2011 Aug;34(4):343-54
pubmed: 21538025
Circ Res. 2018 Apr 13;122(8):1102-1108
pubmed: 29467197
J Heart Lung Transplant. 2008 Jan;27(1):86-92
pubmed: 18187092
Circ Res. 2015 Jul 17;117(3):279-88
pubmed: 26058828
ESC Heart Fail. 2019 Dec;6(6):1140-1148
pubmed: 31884717
Cardiovasc Res. 2017 Mar 1;113(3):288-297
pubmed: 28028069
JACC Cardiovasc Imaging. 2018 Aug;11(8):1150-1172
pubmed: 30092971
Eur J Heart Fail. 2017 Jan;19(1):9-42
pubmed: 27565769