Protective Effects of Ticagrelor on Myocardial Injury After Infarction
Background—The P2Y12 receptor antagonist ticagrelor has shown to be clinically superior to clopidogrel. Although the underlying mechanisms remain elusive, ticagrelor may exert off-target effects through adenosine-related mechanisms. We sought to investigate whether ticagrelor reduces myocardial injury to a greater extent than clopidogrel after myocardial infarction (MI) at similar level of platelet inhibition and determine the mechanisms behind.
Methods—Pigs received prior to MI-induction: I) placebo-control; II) a loading dose (LD) of clopidogrel (600mg); III) a LD of ticagrelor (180mg); or IV) a LD of ticagrelor followed by an adenosine A1/A2-receptor antagonist (8-p-sulfophenyl-theophylline; 8SPT, 4mg/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 24hours and underwent 3T-cardiac magnetic resonance imaging (CMR) 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 AMPK and its downstream effectors CD36 and eNOS and Cox2 activity.
Results—Clopidogrel and ticagrelor exerted a high and consistent antiplatelet effect (68.2% and 62.2% of platelet inhibition, respectively, upon challenge with 20μM ADP) that persisted up to 24hours post-MI (p<0.05). All groups showed comparable myocardial area-at-risk and cardiac worsening following MI-induction. CMR analysis revealed that clopidogrel- and ticagrelor- treated animals had a significantly smaller extent of MI than placebo-control animals (15.7g/LV and 12.0g/LV vs. 22.8g/LV, 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 histopathological analysis (p=0.0021). Furthermore, as compared to clopidogrel, ticagrelor significantly diminished myocardial edema by 24.5% (p=0.004), which correlated with infarct mass (r=0.73; p<0.001). 8SPT administration abolished the cardioprotective effects of ticagrelor over clopidogrel. At a molecular level, aquaporin-4 expression decreased and the expression and activation of AMPK-signaling and Cox-2 increased in the ischemic myocardium of ticagrelor- vs. clopidogrel- treated animals (p<0.05). These protein changes were not observed in those animals administered the adenosine receptor blocker 8SPT.
Conclusions—Ticagrelor, beyond its antiplatelet efficacy, exerts cardioprotective effects by reducing necrotic injury and edema formation via adenosine-dependent mechanisms.
- antiplatelet agent
- ischemia reperfusion injury
- magnetic resonance imaging
- animal model cardiovascular disease
- Received June 15, 2016.
- Revision received September 22, 2016.
- Accepted October 8, 2016.