Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction

Yumei Ye, Gilad D. Birnbaum, Jose R. Perez-Polo, Manjyot K. Nanhwan, Sven Nylander, Yochai Birnbaum

Research output: Contribution to journalArticle

53 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1805-1814
Number of pages10
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Volume35
Issue number8
DOIs
StatePublished - Aug 25 2015

Fingerprint

clopidogrel
Reperfusion Injury
Myocardial Infarction
Reperfusion
Stroke Volume
Adenosine
Ticagrelor
Ischemia
Lipoxins
Interleukin-18
Mitogen-Activated Protein Kinase 3

Keywords

  • adenosine
  • aspirin
  • platelet inhibitors
  • prostaglandin-endoperoxide synthases
  • reperfusion injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. / Ye, Yumei; Birnbaum, Gilad D.; Perez-Polo, Jose R.; Nanhwan, Manjyot K.; Nylander, Sven; Birnbaum, Yochai.

In: Arteriosclerosis, Thrombosis, and Vascular Biology, Vol. 35, No. 8, 25.08.2015, p. 1805-1814.

Research output: Contribution to journalArticle

Ye, Yumei ; Birnbaum, Gilad D. ; Perez-Polo, Jose R. ; Nanhwan, Manjyot K. ; Nylander, Sven ; Birnbaum, Yochai. / Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction. In: Arteriosclerosis, Thrombosis, and Vascular Biology. 2015 ; Vol. 35, No. 8. pp. 1805-1814.
@article{8a529ae9cbaf489987604777305a4c67,
title = "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.",
keywords = "adenosine, aspirin, platelet inhibitors, prostaglandin-endoperoxide synthases, reperfusion injury",
author = "Yumei Ye and Birnbaum, {Gilad D.} and Perez-Polo, {Jose R.} and Nanhwan, {Manjyot K.} and Sven Nylander and Yochai Birnbaum",
year = "2015",
month = "8",
day = "25",
doi = "10.1161/ATVBAHA.115.305655",
language = "English (US)",
volume = "35",
pages = "1805--1814",
journal = "Arteriosclerosis, Thrombosis, and Vascular Biology",
issn = "1079-5642",
publisher = "Lippincott Williams and Wilkins",
number = "8",

}

TY - JOUR

T1 - Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction

AU - Ye, Yumei

AU - Birnbaum, Gilad D.

AU - Perez-Polo, Jose R.

AU - Nanhwan, Manjyot K.

AU - Nylander, Sven

AU - Birnbaum, Yochai

PY - 2015/8/25

Y1 - 2015/8/25

N2 - 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.

AB - 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.

KW - adenosine

KW - aspirin

KW - platelet inhibitors

KW - prostaglandin-endoperoxide synthases

KW - reperfusion injury

UR - http://www.scopus.com/inward/record.url?scp=84938074255&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84938074255&partnerID=8YFLogxK

U2 - 10.1161/ATVBAHA.115.305655

DO - 10.1161/ATVBAHA.115.305655

M3 - Article

C2 - 26044583

AN - SCOPUS:84938074255

VL - 35

SP - 1805

EP - 1814

JO - Arteriosclerosis, Thrombosis, and Vascular Biology

JF - Arteriosclerosis, Thrombosis, and Vascular Biology

SN - 1079-5642

IS - 8

ER -