Ticagrelor Protects the Heart Against Reperfusion Injury and Improves Remodeling After Myocardial Infarction

Abstract

Objective-In addition to P2Y 12 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. Approach and 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-A 4 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. addition to platelet inhibition, ticagrelor, but not clopidogrel, has protective effects against ischemia-reperfusion that may help explain the differences in clinical benefit in the PLATO trial. 7,8 However, a recent multicenter, randomized, double-blind clinical trial did not show a clear clinical benefit in patients with STEMI receiving ticagrelor en route to the hospital versus in the catheterization laboratory. 16 As the study was not powered for benefit on cardiovascular events, it is inconclusive about the hypothesis that administration of ticagrelor after onset of ischemia (in contrast to pretreatment just before reperfusion) can ameliorate reperfusion injury. In addition, as the median time difference between the prehospital and the in-hospital ticagrelor administration groups was only 31 minutes, 16 it is plausible that ticagrelor absorption was insufficient an...

Ticagrelor attenuates myocardial ischaemia–reperfusion injury possibly through downregulating galectin‐3 expression in the infarct area of rats

“…The observed cardioprotective results represented by reduced infarct area and myocardial proinflammatory cytokine levels from our study are in line with previous finding showing that a single acute dose of ticagrelor via intraperitoneal injection (30 mg kg −1 ) 5 min before reperfusion significantly reduced infarct size and reduced the proinflammatory cytokine levels in a rat ischaemia/reperfusion model 15. It is noted that IA/AAR ratio tended to be lower at 24 h as compared to 3 days and 7 days in the placebo‐treated rats ( P  > 0.05).…”

“…Multiple mechanisms have been indicated for the beneficial effects of ticagrelor in attenuating ischaemic insult, including increasing myocardial adenosine levels, augmenting the phosphorylation of the pro‐survival kinases Akt and ERK 1/2 and endothelial NO synthase 15 as well as inhibiting glandular transporter (ENT‐1) on erythrocytes glycoside reuptake, strengthening of the local adenosine response, and vasodilation 14, 27, 33. Previous studies also suggested that the cardioprotective effects of ticagrelor was independent of its role in inhibition of platelet aggregation, as the cardioprotective effects were not observed post clopidogrel application 14, 15.…”

“…Previous studies also suggested that the cardioprotective effects of ticagrelor was independent of its role in inhibition of platelet aggregation, as the cardioprotective effects were not observed post clopidogrel application 14, 15. Beyond the above knowledge on the potential therapeutic mechanisms of ticagrelor in I/R injury models, the present study results suggest that the observed cardioprotective effects of ticagrelor might at least partly be mediated through downregulating the expression of galectin‐3 in the infarct area in this rat model of I/R injury.…”

The Impact of Clinical and Genetic Factors on Ticagrelor and Clopidogrel Antiplatelet Therapy

“…Besides its antiplatelet effect, ticagrelor has a pleiotropic action and it increases plasma adenosine concentration by reducing recapturing of adenosine by red blood cells [32]. Plasma adenosine facilitates arterial vasodilatation and may decrease injury caused by reperfusion [33,34]. It has been reported that ticagrelor prescription before reper fusion, after 4 weeks of antiplatelet treatment, improved animal (a rat) heart function [34].…”

“…Plasma adenosine facilitates arterial vasodilatation and may decrease injury caused by reperfusion [33,34]. It has been reported that ticagrelor prescription before reper fusion, after 4 weeks of antiplatelet treatment, improved animal (a rat) heart function [34]. Compared with clopidogrel, ticagrelor is a more effective drug for decreasing platelet aggregation and the prevention of arterial thrombosis, such as definite stent thrombosis; this is because it has a more beneficial mechanism of action than clopidogrel [29], and it does not require metabolic activation.…”