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Protective Effects of Ticagrelor on Myocardial Injury After Infarction

Circulation (New York, N.Y.), 2016-11, Vol.134 (22), p.1708-1719 [Peer Reviewed Journal]

2016 by the American College of Cardiology Foundation and the American Heart Association, Inc. ;2016 American Heart Association, Inc. ;ISSN: 0009-7322 ;EISSN: 1524-4539 ;DOI: 10.1161/CIRCULATIONAHA.116.024014 ;PMID: 27789556

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  • Title:
    Protective Effects of Ticagrelor on Myocardial Injury After Infarction
  • Author: Vilahur, Gemma ; Gutiérrez, Manuel ; Casani, Laura ; Varela, Lourdes ; Capdevila, Antoni ; Pons-Lladó, Guillem ; Carreras, Francesc ; Carlsson, Leif ; Hidalgo, Alberto ; Badimon, Lina
  • Subjects: Adenosine - analogs & derivatives ; Adenosine - pharmacology ; Animals ; Blood Platelets - drug effects ; Cardiotonic Agents - pharmacology ; Clopidogrel ; Cyclooxygenase 2 - metabolism ; Myocardial Infarction - drug therapy ; Myocardial Infarction - enzymology ; Myocardial Infarction - pathology ; Platelet Aggregation Inhibitors - pharmacology ; Random Allocation ; Swine ; Ticagrelor ; Ticlopidine - analogs & derivatives ; Ticlopidine - pharmacology
  • Is Part Of: Circulation (New York, N.Y.), 2016-11, Vol.134 (22), p.1708-1719
  • Description: BACKGROUND:The P2Y12 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 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.
  • Publisher: United States: by the American College of Cardiology Foundation and the American Heart Association, Inc
  • Language: English
  • Identifier: ISSN: 0009-7322
    EISSN: 1524-4539
    DOI: 10.1161/CIRCULATIONAHA.116.024014
    PMID: 27789556
  • Source: Geneva Foundation Free Medical Journals at publisher websites
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