title: Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction.
abstract: OBJECTIVE
  In addition to P2Y12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function.
  
  
  RESULTS
  Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks. (1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P<0.001) and 30 mg/kg (21.4%±2.6%; P<0.001) versus control (45.3±1.7%), whereas clopidogrel had no effect (42.4%±2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%±3.5%) versus sham (77.6%±0.9%). All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%±1.6%), chronic (69.2%±1.0%), and acute+chronic (76.3%±1.2%), whereas clopidogrel had no effect (37.4%±3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1β, and interleukin-18, and increased anti-inflammatory 15-epi-lipoxin-A4 levels.
  
  
  CONCLUSIONS
  Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect.
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (Y.Y., J.R.P.-P., M.K.N., Y.B.); Section of Cardiology, Baylor College of Medicine, Houston, TX (G.D.B., Y.B.); and AstraZeneca R&D, Mölndal, Sweden (S.N.).
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (Y.Y., J.R.P.-P., M.K.N., Y.B.); Section of Cardiology, Baylor College of Medicine, Houston, TX (G.D.B., Y.B.); and AstraZeneca R&D, Mölndal, Sweden (S.N.).
authors.forename: Gilad D
authors.initials: GD
authors.lastname: Birnbaum
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (Y.Y., J.R.P.-P., M.K.N., Y.B.); Section of Cardiology, Baylor College of Medicine, Houston, TX (G.D.B., Y.B.); and AstraZeneca R&D, Mölndal, Sweden (S.N.).
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez-Polo
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (Y.Y., J.R.P.-P., M.K.N., Y.B.); Section of Cardiology, Baylor College of Medicine, Houston, TX (G.D.B., Y.B.); and AstraZeneca R&D, Mölndal, Sweden (S.N.).
authors.forename: Manjyot K
authors.initials: MK
authors.lastname: Nanhwan
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (Y.Y., J.R.P.-P., M.K.N., Y.B.); Section of Cardiology, Baylor College of Medicine, Houston, TX (G.D.B., Y.B.); and AstraZeneca R&D, Mölndal, Sweden (S.N.).
authors.forename: Sven
authors.initials: S
authors.lastname: Nylander
authors.affiliation: From the Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston (Y.Y., J.R.P.-P., M.K.N., Y.B.); Section of Cardiology, Baylor College of Medicine, Houston, TX (G.D.B., Y.B.); and AstraZeneca R&D, Mölndal, Sweden (S.N.). ybirnbau@bcm.edu.
authors.forename: Yochai
authors.initials: Y
authors.lastname: Birnbaum
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000077144:Clopidogrel; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005355:Fibrosis; D007274:Injections, Intraperitoneal; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D058921:Purinergic P2Y Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors; D016277:Ventricular Function, Left / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D058921:Purinergic P2Y Receptor Antagonists; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine
keywords: adenosine; aspirin; platelet inhibitors; prostaglandin-endoperoxide synthases; reperfusion injury