In vivo dynamic nuclear polarization magnetic resonance imaging reveals cardiac mitochondrial redox imbalance as an early indicator of heart failure

Heart failure is a major cause of mortality worldwide. Accumulating evidence indicates that mitochondrial dysfunction, particularly excessive generation of reactive oxygen species (ROS) from the mitochondrial electron transport chain (ETC), plays a vital role in the onset and progression of heart failure. Importantly, mitochondrial dysfunction is believed to emerge at an early stage of heart failure development. However, due to the lack of noninvasive techniques to directly evaluate cardiac mitochondrial function in vivo, the timing and dynamics of mitochondrial functional alterations during the early phase of heart failure development remain unclear. Carbamoyl-PROXYL (CmP) is a membrane-permeable nitroxyl probe that mediates redox reactions within the mitochondrial ETC in the presence of reduced nicotinamide adenine dinucleotide, thereby sensitively indicating mitochondrial electron transfer dynamics. We applied in vivo dynamic nuclear polarization magnetic resonance imaging (DNP-MRI) to a mouse model of doxorubicin (DOX)-induced heart failure to validate its utility. In DOX-treated mice, the CmP reduction rate was significantly accelerated as early as 30 min after drug administration. However, no significant change was detected in epirubicin-treated mice compared with control animals. Considering that DOX induces ROS production through redox cycling at mitochondrial ETC complex I, these results demonstrate that in vivo DNP-MRI enables noninvasive visualization of ETC-associated mitochondrial redox imbalance in the living heart immediately after the onset of cardiotoxic stress, even when ROS generation has just begun and conventional functional changes are unapparent. Therefore, in vivo DNP-MRI represents a powerful noninvasive modality for the early diagnosis of heart failure.