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PET imaging of mitochondrial function in acute doxorubicin-induced cardiotoxicity: a proof-of-principle study

Mitochondrial dysfunction plays a key role in doxorubicin-induced cardiotoxicity (DIC). In this proof-of-principle study, we investigated whether PET mapping of cardiac membrane potential, an indicator of mitochondrial function, could detect an acute cardiotoxic effect of doxorubicin (DOX) in a larg...

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Detalles Bibliográficos
Autores principales: Detmer, Felicitas J., Alpert, Nathaniel M., Moon, Sung-Hyun, Dhaynaut, Maeva, Guerrero, J. Luis, Guehl, Nicolas J., Xing, Fangxu, Brugarolas, Pedro, Shoup, Timothy M., Normandin, Marc D., Pelletier-Galarneau, Matthieu, El Fakhri, Georges, Petibon, Yoann
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9005533/
https://www.ncbi.nlm.nih.gov/pubmed/35414642
http://dx.doi.org/10.1038/s41598-022-10004-6
Descripción
Sumario:Mitochondrial dysfunction plays a key role in doxorubicin-induced cardiotoxicity (DIC). In this proof-of-principle study, we investigated whether PET mapping of cardiac membrane potential, an indicator of mitochondrial function, could detect an acute cardiotoxic effect of doxorubicin (DOX) in a large animal model. Eight Yucatan pigs were imaged dynamically with [(18)F](4-Fluorophenyl)triphenylphosphonium ([(18)F]FTPP(+)) PET/CT. Our experimental protocol included a control saline infusion into the left anterior descending coronary artery (LAD) followed by a DOX test infusion of either 1 mg/kg or 2 mg/kg during PET. We measured the change in total cardiac membrane potential (ΔΨ(T)), a proxy for the mitochondrial membrane potential, ΔΨ(m), after the saline and DOX infusions. We observed a partial depolarization of the mitochondria following the DOX infusions, which occurred only in myocardial areas distal to the intracoronary catheter, thereby demonstrating a direct association between the exposure of the mitochondria to DOX and a change in ΔΨ(T). Furthermore, doubling the DOX dose caused a more severe depolarization of myocardium in the LAD territory distal to the infusion catheter. In conclusion, [(18)F]FTPP(+) PET-based ΔΨ(T) mapping can measure partial depolarization of myocardial mitochondria following intracoronary DOX infusion in a large animal model.