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Recombinant human soluble domain of CD39L3 and ticagrelor: cardioprotective effects in experimental myocardial infarction.
Vilahur, Gemma; Radike, Monika; Sutelman, Pablo; Ben-Aicha, Soumaya; Gutiérrez, Manuel; Casaní, Laura; Hovdal, Daniel; Ongstad, Emily L; Gabrielsen, Anders; Hidalgo, Alberto; Fjellström, Ola; Carlsson, Leif; Badimon, Lina.
Afiliación
  • Vilahur G; Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
  • Radike M; Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain.
  • Sutelman P; Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
  • Ben-Aicha S; Radiology Department, Liverpool Heart and Chest Hospital NHS Foundation Trust, Liverpool, UK.
  • Gutiérrez M; Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
  • Casaní L; Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
  • Hovdal D; Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
  • Ongstad EL; Research Institute, Hospital de la Santa Creu i Sant Pau, IIB-Sant Pau, C/Sant Antoni Mª Claret 167, Barcelona 08025, Spain.
  • Gabrielsen A; DMPK, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Hidalgo A; Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • Fjellström O; Early Clinical Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Carlsson L; Radiology Department, Hospital Josep Trueta, Girona, Spain.
  • Badimon L; Projects, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
Eur Heart J ; 45(17): 1553-1567, 2024 May 07.
Article en En | MEDLINE | ID: mdl-38486376
ABSTRACT
BACKGROUND AND

AIMS:

The ecto-nucleoside triphosphate diphosphohydrolases of the CD39 family degrade ATP and ADP into AMP, which is converted into adenosine by the extracellular CD73/ecto-5-nucleotidase. This pathway has been explored in antithrombotic treatments but little in myocardial protection. We have investigated whether the administration of solCD39L3 (AZD3366) confers additional cardioprotection to that of ticagrelor alone in a pre-clinical model of myocardial infarction (MI).

METHODS:

Ticagrelor-treated pigs underwent balloon-induced MI (90 min) and, before reperfusion, received intravenously either vehicle, 1 mg/kg AZD3366 or 3 mg/kg AZD3366. All animals received ticagrelor twice daily for 42 days. A non-treated MI group was run as a control. Serial cardiac magnetic resonance (baseline, Day 3 and Day 42 post-MI), light transmittance aggregometry, bleeding time, and histological and molecular analyses were performed.

RESULTS:

Ticagrelor reduced oedema formation and infarct size at Day 3 post-MI vs. controls. A 3 mg/kg AZD3366 provided an additional 45% reduction in oedema and infarct size compared with ticagrelor and a 70% reduction vs. controls (P < .05). At Day 42, infarct size declined in all ticagrelor-administered pigs, particularly in 3 mg/kg AZD3366-treated pigs (P < .05). Left ventricular ejection fraction was diminished at Day 3 in placebo pigs and worsened at Day 42, whereas it remained unaltered in ticagrelor ± AZD3366-administered animals. Pigs administered with 3 mg/kg AZD3366 displayed higher left ventricular ejection fraction upon dobutamine stress at Day 3 and minimal dysfunctional segmental contraction at Day 42 (χ2P < .05 vs. all). Cardiac and systemic molecular readouts supported these benefits. Interestingly, AZD3366 abolished ADP-induced light transmittance aggregometry without affecting bleeding time.

CONCLUSIONS:

Infusion of AZD3366 on top of ticagrelor leads to enhanced cardioprotection compared with ticagrelor alone.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apirasa / Adenosina Trifosfatasas / Ticagrelor / Infarto del Miocardio Límite: Animals / Humans / Male Idioma: En Revista: Eur Heart J Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Apirasa / Adenosina Trifosfatasas / Ticagrelor / Infarto del Miocardio Límite: Animals / Humans / Male Idioma: En Revista: Eur Heart J Año: 2024 Tipo del documento: Article País de afiliación: España Pais de publicación: Reino Unido