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

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 [¹⁸F](4-Fluorophenyl)triphenylphosphonium ([¹⁸F]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, [¹⁸F]FTPP⁺ PET-based ΔΨ_T mapping can measure partial depolarization of myocardial mitochondria following intracoronary DOX infusion in a large animal model.

Figure 1

Timeline of saline and DOX infusions during the PET image acquisition for Group A and B.

Figure 2

Mean normalized TACs for two segments of the LAD (top) and two segments of the RCA (bottom) for the eight animals. The grey shaded area indicates the mean + /-standard error. The blue dotted lines indicate the beginning and end of the control saline infusion (C), whereas the orange dotted lines mark the beginning and end of the DOX infusion (D).

Figure 3

Parametric images of ΔΨ_T before and after the saline (top) as well as the DOX infusion (bottom) for one animal of group A (left) and one animal of group B (right).

Figure 4

Mean (bars) + /- standard error of change in ΔΨ_T for each of the 16 segments and the three types of “interventions” (saline – “SAL”, DOX 1 mg/kg – “DOX1”, and DOX 2 mg/kg – “DOX2”) averaged over the eight studies. The four segments that had a significantly different change in ΔΨ_T compared to the other segments are indicated with asterisks.

Figure 5

Mean (bars) + /- standard error of change in ΔΨ_T for the segments directly exposed to the saline and DOX infusions (a priori defined as segments 7, 8, 13, and 14) as well as the control segments after the saline and DOX infusion (left) and comparison of change in ΔΨ_T for a dose of 1 mg/kg vs 2 mg/kg (right).