Abstract
By the time cardiotoxicity-associated cardiac dysfunction is detectable by echocardiography it is often beyond meaningful intervention. 99mTc-sestamibi is used clinically to image cardiac perfusion by single photon emission computed tomography (SPECT) imaging, but as a lipophilic cation its distribution is also governed by mitochondrial membrane potential (ΔΨm). Correcting scans for variations in perfusion (using a ΔΨm-independent perfusion tracer such as (bis(N-ethoxy-N-ethyldithiocarbamato)nitrido 99mTc(V)) (99mTc-NOET) could allow 99mTc-sestamibi to be repurposed to specifically report on ΔΨm as a readout of evolving cardiotoxicity. Isolated rat hearts were perfused within a γ-detection apparatus to characterize the pharmacokinetics of 99mTc-sestamibi and 99mTc-NOET in response to mitochondrial perturbation by hypoxia, ionophore (CCCP) or doxorubicin. All interventions induced 99mTc-sestamibi washout; hypoxia from 24.9 ± 2.6% ID to 0.4 ± 6.2%, CCCP from 22.8 ± 2.5% ID to −3.5 ± 3.1%, and doxorubicin from 23.0 ± 2.2% ID to 17.8 ± 0.7, p < 0.05. Cardiac 99mTc-NOET retention (34.0 ± 8.0% ID) was unaffected in all cases. Translating to an in vivo rat model, 2 weeks after bolus doxorubicin injection, there was a dose-dependent loss of cardiac 99mTc-sestamibi retention (from 2.3 ± 0.3 to 0.9 ± 0.2 ID/g with 10 mg/kg (p < 0.05)), while 99mTc-NOET retention (0.93 ± 0.16 ID/g) was unaffected. 99mTc-NOET therefore traps in myocardium independently of the mitochondrial perturbations that induce 99mTc-sestamibi washout, demonstrating proof-of-concept for an imaging approach to detect evolving cardiotoxicity.
Highlights
By the time cardiotoxicity-associated cardiac dysfunction is detectable by echocardiography it is often beyond meaningful intervention. 99mTc-sestamibi is used clinically to image cardiac perfusion by single photon emission computed tomography (SPECT) imaging, but as a lipophilic cation its distribution is governed by mitochondrial membrane potential (ΔΨm)
If cardiac retention of 99mTc-MIBI or other SPECT and PET lipophilic cations could be corrected for perfusion, either by pharmacokinetic modelling or using a parallel “true” perfusion imaging agent which is independent of mitochondrial function or other metabolic parameters, it may be possible to develop tracers that report on cardiac ΔΨm as a non-invasive clinical readout of mitochondrial cardiotoxicity
Hypoxic buffer perfusion caused this trapping to fall to 11.3 ± 5.2% (p < 0.05) after 5 minutes and 0.4 ± 6.2% after 45 minutes (p < 0.05). 99mTc-NOET was stably retained within the myocardium during aerobic perfusion (34 ± 8% of injected dose), and its retention was unaffected by hypoxic buffer perfusion. 99mTc-MIBI time activity curves were best fitted by a tri-exponential equation
Summary
By the time cardiotoxicity-associated cardiac dysfunction is detectable by echocardiography it is often beyond meaningful intervention. 99mTc-sestamibi is used clinically to image cardiac perfusion by single photon emission computed tomography (SPECT) imaging, but as a lipophilic cation its distribution is governed by mitochondrial membrane potential (ΔΨm). If cardiac retention of 99mTc-MIBI or other SPECT and PET lipophilic cations could be corrected for perfusion, either by pharmacokinetic modelling or using a parallel “true” perfusion imaging agent which is independent of mitochondrial function or other metabolic parameters, it may be possible to develop tracers that report on cardiac ΔΨm as a non-invasive clinical readout of mitochondrial cardiotoxicity. Such an approach would provide more responsive, accurate, personalized treatment regimes, or could be employed as an imaging biomarker of novel cardioprotective regimes or therapies. We investigated the possibility of pairing 99mTc-MIBI with 99mTc-NOET (bis (N-ethoxy-N-ethyldithiocarbamato)nitrido 99mTc(V)), which is a lipophilic uncharged (and ΔΨm independent) “true” perfusion imaging agent[21] to report on cardiotoxicity by SPECT
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