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

Source abstract

Abstract 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.