title: Protective Effects of Ticagrelor on Myocardial Injury After Infarction.
abstract: BACKGROUND
  The P2Y12receptor 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 μmol/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.
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Gemma
authors: G
authors: Vilahur
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Manuel
authors: M
authors: Gutiérrez
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Laura
authors: L
authors: Casani
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Lourdes
authors: L
authors: Varela
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Antoni
authors: A
authors: Capdevila
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Guillem
authors: G
authors: Pons-Lladó
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Francesc
authors: F
authors: Carreras
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Leif
authors: L
authors: Carlsson
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.).
authors: Alberto
authors: A
authors: Hidalgo
authors: From Cardiovascular Research Center (CSIC-ICCC), IIB-HSCSP, Barcelona, Spain (G.V., L.C., L.V., L.B.); Radiology Unit, Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (M.G., A.C., A.H.); Cardiology Unit. Hospital de la Santa Creu i Sant Pau (HSCSP), Barcelona, Spain (G.P.-L., F.C.); Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Mölndal, Sweden (L.C.); and Cardiovascular Research Chair UAB (Autonomous University of Barcelona), Spain (L.B.). lbadimon@csic-iccc.org.
authors: Lina
authors: L
authors: Badimon
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077144:Clopidogrel; D051546:Cyclooxygenase 2 / Q000378:metabolism; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011897:Random Allocation; D013552:Swine; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D002316:Cardiotonic Agents; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D051546:Cyclooxygenase 2; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine
keywords: cardiac imaging techniques; cardioprotection; edema; myocardial infarction; purinergic P2Y receptor antagonists