P2Y(12) antagonists and cardiac repair post-myocardial infarction: global and regional heart function analysis and molecular assessments in pigs
Por:
Vilahur, G, Gutierrez, M, Casani, L, Lambert, C, Mendieta, G, Ben-Aicha, S, Capdevila, A, Pons-Llado, G, Carreras, F, Carlsson, L, Hidalgo, A, Badimon, L
Publicada:
1 dic 2018
Resumen:
Aims P2Y(12) antagonists are the standard in antiplatelet therapy but their potential effects on functional myocardial recovery and cardioprotection post-myocardial infarction (MI) are unknown. We investigated in a preclinical model of MI whether ticagrelor and clopidogrel differently affect cardiac repair post-MI.
Methods and results Pigs either received: (i) clopidogrel (600 mg; 75 mg/qd); (ii) ticagrelor (180 mg; 90 mg/bid); and (iii) placebo control. MI was induced by mid-left anterior descending coronary artery balloon occlusion (60 min) and animals received the maintenance doses for the following 42 days. Serial cardiac magnetic resonance was performed at Day 3 and Day 42 for the assessment of global and regional cardiac parameters. We determined cardiac AMP-activated protein kinase (AMPK), Akt/PKB, aquaporin-4, vascular density, and fibrosis. In comparison to controls, both P2Y(12) antagonists limited infarct expansion at Day 3, although ticagrelor induced a further 5% reduction (P < 0.05 vs. clopidogrel) whereas oedema was only reduced by ticagrelor (approximate to 23% P < 0.05). Scar size decreased at Day 42 in ticagrelor-treated pigs vs. controls but not in clopidogrel-treated pigs. Left ventricular ejection fraction was higher 3 days post-MI in ticagrelor-treated pigs and persisted up to Day 42 (P < 0.05 vs. post-MI). Regional analysis revealed that control and clopidogrel-treated pigs had severe and extensive wall motion abnormalities in the jeopardized myocardium and a reduced myocardial viability that was not as evident in ticagrelor-treated pigs (chi(2) P < 0.05 vs. ticagrelor). Only ticagrelor enhanced myocardial AMPK and Akt/PKB activation and reduced aquaporin-4 levels (P < 0.05 vs. control and clopidogrel). No differences were observed in vessel density and fibrosis markers among groups.
Conclusions Ticagrelor is more efficient than clopidogrel in attenuating myocardial structural and functional alterations post-MI and in improving cardiac healing. These benefits are associated with persistent AMPK and Akt/PKB activation.
Filiaciones:
Vilahur, G:
Hosp Santa Creu & Sant Pau, IIB St Pau, Program ICCC, IR, C St Antoni Ma Claret 167, Barcelona 08025, Spain
Inst Salud Carlos III, CIBERCV, Madrid, Spain
Gutierrez, M:
Hosp Santa Creu & Sant Pau, IIB St Pau, Program ICCC, IR, C St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Santa Creu & Sant Pau, Radiol Unit, Barcelona, Spain
Casani, L:
Hosp Santa Creu & Sant Pau, IIB St Pau, Program ICCC, IR, C St Antoni Ma Claret 167, Barcelona 08025, Spain
Inst Salud Carlos III, CIBERCV, Madrid, Spain
Lambert, C:
Hosp Santa Creu & Sant Pau, IIB St Pau, Program ICCC, IR, C St Antoni Ma Claret 167, Barcelona 08025, Spain
Mendieta, G:
Hosp Santa Creu & Sant Pau, IIB St Pau, Program ICCC, IR, C St Antoni Ma Claret 167, Barcelona 08025, Spain
Hosp Clin Barcelona, Dept Cardiol, Barcelona, Spain
Ben-Aicha, S:
Hosp Santa Creu & Sant Pau, IIB St Pau, Program ICCC, IR, C St Antoni Ma Claret 167, Barcelona 08025, Spain
Capdevila, A:
Hosp Santa Creu & Sant Pau, Radiol Unit, Barcelona, Spain
Pons-Llado, G:
Hosp Santa Creu & Sant Pau, Cardiol Unit, Barcelona, Spain
Carreras, F:
Hosp Santa Creu & Sant Pau, Cardiol Unit, Barcelona, Spain
Carlsson, L:
AstraZeneca, Cardiovasc & Metab Dis Innovat Med & Early Dev Bi, Molndal, Sweden
Hidalgo, A:
Hosp Santa Creu & Sant Pau, Radiol Unit, Barcelona, Spain
Badimon, L:
Hosp Santa Creu & Sant Pau, IIB St Pau, Program ICCC, IR, C St Antoni Ma Claret 167, Barcelona 08025, Spain
Inst Salud Carlos III, CIBERCV, Madrid, Spain
UAB, Cardiovasc Res Chair, Barcelona, Spain
Bronze
|