Non-invasive imaging of mitochondrial dysfunction and anthracycline cardiotoxicity by repurposing 99mTc Sestamibi SPECT imaging: SI:Abstracts ISHR-ES Amsterdam

Background: Anthracyclines are a common therapy for numerous malignancies including leukemia, lymphoma, and myeloma. However, they are highly toxic to the heart, inducing coronary heart disease, cardiomyopathy and heart failure. Cardiotoxicity critically limits chemotherapeutic dose, and can develop years post-therapy. During this period, cardiotoxicity is monitored clinically by changes in cardiac structure and contractility using echocardiography or MUGA scanning. However, anthracycline cardiotoxicity is initiated at the subcellular level, associated with mitochondrial dysfunction and elevated oxidative stress, meaning these techniques are insensitive and diagnose too late to allow meaningful intervention.

Methods and results: Mitochondrial dysfunction is fundamental to anthracycline cardiotoxicity, mediated by severe iron overload and oxidative stress. We are developing nuclear imaging approaches to probe mitochondrial function and oxidative stress as predictors of evolving cardiotoxicity. The SPECT tracer 99mTc sestamibi (MIBI) is used clinically to visualize cardiac perfusion, but being a lipophilic cation, its cardiac retention is more accurately a function of both perfusion and mitochondrial membrane potential (ΔΨm).

We are investigating repurposing MIBI to report on ΔΨm as a non-invasive readout of cardiotoxicity. In an in vivo rat model of chronic cardiotoxicity (using doxorubicin loaded osmotic minipumps), we demonstrate dose-dependent loss of cardiac MIBI retention before any detectable changes in cardiac function, measured via echocardiography. We have also shown that co-infusion of doxorubicin with the iron chelator deferiprone limits anthracycline cardiotoxicity and mitochondrial iron overload, and restores cardiac MIBI retention.

Conclusion: This demonstrates the potential of MIBI imaging as an early readout of evolving cardiotoxicity and as a means of evaluating novel cardioprotectant strategies.