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...
| Authors: | ; ; ; ; ; ; ; ; ; |
|---|---|
| Format: | Article |
| Status: | Published version |
| Publication date: | 2016 |
| Country: | España |
| Institution: | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| Repository: | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| OAI Identifier: | oai:iibsantpau.fundanetsuite.com:p6896 |
| Online Access: | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6896 |
| Access Level: | Open access |
| Keyword: | cardiac imaging techniques cardioprotection edema myocardial infarction purinergic P2Y receptor antagonists |
| _version_ | 1878729109648965632 |
|---|---|
| author | Vilahur, G |
| 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 |
| author_browse | Badimon, L Capdevila, A Carlsson, L Carreras, F Casani, L Gutierrez, M Hidalgo, A Pons-Llado, G Varela, L 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 |
| collection | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_01a61069e1a42eac3c485013b2eefbbd |
| institution | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| instname_str | Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau) |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:iibsantpau.fundanetsuite.com:p6896 |
| publishDate | 2016 |
| publishDateSort | 2016 |
| publisher | LIPPINCOTT WILLIAMS & WILKINS |
| publisherStr | LIPPINCOTT WILLIAMS & WILKINS |
| reponame_str | r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau |
| spelling | Protective Effects of Ticagrelor on Myocardial Injury After Infarction Vilahur, G Gutierrez, M Casani, L Varela, L Capdevila, A Pons-Llado, G Carreras, F Carlsson, L Hidalgo, A Badimon, L cardiac imaging techniques cardioprotection edema myocardial infarction purinergic P2Y receptor antagonists 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. LIPPINCOTT WILLIAMS & WILKINS https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6896 |
| spellingShingle | Protective Effects of Ticagrelor on Myocardial Injury After Infarction Vilahur, G cardiac imaging techniques cardioprotection edema myocardial infarction purinergic P2Y receptor antagonists |
| status_str | publishedVersion |
| title | 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_short | Protective Effects of Ticagrelor on Myocardial Injury After Infarction |
| title_sort | Protective Effects of Ticagrelor on Myocardial Injury After Infarction |
| topic | cardiac imaging techniques cardioprotection edema myocardial infarction purinergic P2Y receptor antagonists |
| topic_facet | cardiac imaging techniques cardioprotection edema myocardial infarction purinergic P2Y receptor antagonists |
| url | https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=6896 |