Protective Effects of Ticagrelor on Myocardial Injury After Infarction

BACKGROUND: The P2Y(12) receptor antagonist ticagrelor has been shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We aimed to investigate whether ticagrelor reduces myocardi...

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Autores: Vilahur, G, Gutierrez, M, Casani, L, Varela, L, Capdevila, A, Pons-Llado, G, Carreras, F, Carlsson, L, Hidalgo, A, Badimon, L
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p6896
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6896
Access Level:acceso abierto
Palabra clave:cardiac imaging techniques
cardioprotection
edema
myocardial infarction
purinergic P2Y receptor antagonists
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spelling Protective Effects of Ticagrelor on Myocardial Injury After InfarctionVilahur, GGutierrez, MCasani, LVarela, LCapdevila, APons-Llado, GCarreras, FCarlsson, LHidalgo, ABadimon, Lcardiac imaging techniquescardioprotectionedemamyocardial infarctionpurinergic P2Y receptor antagonistsBACKGROUND: The P2Y(12) receptor antagonist ticagrelor has been shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We aimed to investigate whether ticagrelor reduces myocardial injury to a greater extent than clopidogrel after myocardial infarction (MI) at a similar level of platelet inhibition and to determine the underlying mechanisms. METHODS: Pigs received the following before MI induction: (1) placebo-control; (2) a loading dose of clopidogrel (600 mg); (3) a loading dose of ticagrelor (180 mg); or (4) a loading dose of ticagrelor followed by an adenosine A1/A2-receptor antagonist [8-(p-sulfophenyl)theophylline, 4 mg/kg intravenous] to determine the potential contribution of adenosine in ticagrelor-related cardioprotection. Animals received the corresponding maintenance doses of the antiplatelet agents during the following 24 hours and underwent 3T-cardiac MRI analysis. Platelet inhibition was monitored by ADP-induced platelet aggregation. In the myocardium, we assessed the expression and activation of proteins known to modulate edema formation, including aquaporin-4 and AMP-activated protein kinase and its downstream effectors CD36 and endothelial nitric oxide synthase and cyclooxygenase-2 activity. RESULTS: Clopidogrel and ticagrelor exerted a high and consistent antiplatelet effect (68.2% and 62.2% of platelet inhibition, respectively, on challenge with 20 mu mol/L ADP) that persisted up to 24 hours post-MI (P<0.05). All groups showed comparable myocardial area-at-risk and cardiac worsening after MI induction. 3T-Cardiac MRI analysis revealed that clopidogrel-and ticagrelor-treated animals had a significantly smaller extent of MI than placebo-control animals (15.7 g left ventricle and 12.0 g left ventricle versus 22.8 g left ventricle, respectively). Yet, ticagrelor reduced infarct size to a significantly greater extent than clopidogrel (further 23.5% reduction; P=0.0026), an effect supported by troponin-I assessment and histopathologic analysis (P=0.0021). Furthermore, in comparison with clopidogrel, ticagrelor significantly diminished myocardial edema by 24.5% (P=0.004), which correlated with infarct mass (r=0.73; P<0.001). 8-(p-Sulfophenyl) theophylline administration abolished the cardioprotective effects of ticagrelor over clopidogrel. At a molecular level, aquaporin-4 expression decreased and the expression and activation of AMP-activated protein kinase signaling and cyclooxygenase-2 increased in the ischemic myocardium of ticagrelor-versus clopidogrel-treated animals (P<0.05). These protein changes were not observed in those animals administered the adenosine receptor blocker 8-(p-sulfophenyl) theophylline. CONCLUSIONS: Ticagrelor, beyond its antiplatelet efficacy, exerts cardioprotective effects by reducing necrotic injury and edema formation via adenosine-dependent mechanisms.LIPPINCOTT WILLIAMS & WILKINS2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6896CIRCULATIONISSN: 00097322ISSNe: 15244539reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p68962026-06-14T12:41:47Z
dc.title.none.fl_str_mv Protective Effects of Ticagrelor on Myocardial Injury After Infarction
title Protective Effects of Ticagrelor on Myocardial Injury After Infarction
spellingShingle Protective Effects of Ticagrelor on Myocardial Injury After Infarction
Vilahur, G
cardiac imaging techniques
cardioprotection
edema
myocardial infarction
purinergic P2Y receptor antagonists
title_short Protective Effects of Ticagrelor on Myocardial Injury After Infarction
title_full Protective Effects of Ticagrelor on Myocardial Injury After Infarction
title_fullStr Protective Effects of Ticagrelor on Myocardial Injury After Infarction
title_full_unstemmed Protective Effects of Ticagrelor on Myocardial Injury After Infarction
title_sort Protective Effects of Ticagrelor on Myocardial Injury After Infarction
dc.creator.none.fl_str_mv Vilahur, G
Gutierrez, M
Casani, L
Varela, L
Capdevila, A
Pons-Llado, G
Carreras, F
Carlsson, L
Hidalgo, A
Badimon, L
author Vilahur, G
author_facet Vilahur, G
Gutierrez, M
Casani, L
Varela, L
Capdevila, A
Pons-Llado, G
Carreras, F
Carlsson, L
Hidalgo, A
Badimon, L
author_role author
author2 Gutierrez, M
Casani, L
Varela, L
Capdevila, A
Pons-Llado, G
Carreras, F
Carlsson, L
Hidalgo, A
Badimon, L
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv cardiac imaging techniques
cardioprotection
edema
myocardial infarction
purinergic P2Y receptor antagonists
topic cardiac imaging techniques
cardioprotection
edema
myocardial infarction
purinergic P2Y receptor antagonists
description BACKGROUND: The P2Y(12) receptor antagonist ticagrelor has been shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We aimed to investigate whether ticagrelor reduces myocardial injury to a greater extent than clopidogrel after myocardial infarction (MI) at a similar level of platelet inhibition and to determine the underlying mechanisms. METHODS: Pigs received the following before MI induction: (1) placebo-control; (2) a loading dose of clopidogrel (600 mg); (3) a loading dose of ticagrelor (180 mg); or (4) a loading dose of ticagrelor followed by an adenosine A1/A2-receptor antagonist [8-(p-sulfophenyl)theophylline, 4 mg/kg intravenous] to determine the potential contribution of adenosine in ticagrelor-related cardioprotection. Animals received the corresponding maintenance doses of the antiplatelet agents during the following 24 hours and underwent 3T-cardiac MRI analysis. Platelet inhibition was monitored by ADP-induced platelet aggregation. In the myocardium, we assessed the expression and activation of proteins known to modulate edema formation, including aquaporin-4 and AMP-activated protein kinase and its downstream effectors CD36 and endothelial nitric oxide synthase and cyclooxygenase-2 activity. RESULTS: Clopidogrel and ticagrelor exerted a high and consistent antiplatelet effect (68.2% and 62.2% of platelet inhibition, respectively, on challenge with 20 mu mol/L ADP) that persisted up to 24 hours post-MI (P<0.05). All groups showed comparable myocardial area-at-risk and cardiac worsening after MI induction. 3T-Cardiac MRI analysis revealed that clopidogrel-and ticagrelor-treated animals had a significantly smaller extent of MI than placebo-control animals (15.7 g left ventricle and 12.0 g left ventricle versus 22.8 g left ventricle, respectively). Yet, ticagrelor reduced infarct size to a significantly greater extent than clopidogrel (further 23.5% reduction; P=0.0026), an effect supported by troponin-I assessment and histopathologic analysis (P=0.0021). Furthermore, in comparison with clopidogrel, ticagrelor significantly diminished myocardial edema by 24.5% (P=0.004), which correlated with infarct mass (r=0.73; P<0.001). 8-(p-Sulfophenyl) theophylline administration abolished the cardioprotective effects of ticagrelor over clopidogrel. At a molecular level, aquaporin-4 expression decreased and the expression and activation of AMP-activated protein kinase signaling and cyclooxygenase-2 increased in the ischemic myocardium of ticagrelor-versus clopidogrel-treated animals (P<0.05). These protein changes were not observed in those animals administered the adenosine receptor blocker 8-(p-sulfophenyl) theophylline. CONCLUSIONS: Ticagrelor, beyond its antiplatelet efficacy, exerts cardioprotective effects by reducing necrotic injury and edema formation via adenosine-dependent mechanisms.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6896
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6896
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
dc.source.none.fl_str_mv CIRCULATION
ISSN: 00097322
ISSNe: 15244539
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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