Detection of anthracycline-induced cardiotoxicity using perfusion-corrected 99mTc sestamibi SPECT

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.

Imaging of Chemotherapy-Induced Acute Cardiotoxicity with 18F-Labeled Lipophilic Cations

“…Intra-animal variability data of 18 F-Mitophos (Supplement Figure 4) showed good cardiac uptake repeatability with average divergence of image derived cardiac SUV of 8.0  4.3% from baseline scans. 18 F-FBnTP showed similar biodistribution to 18 F-Mitophos, with higher uptake in the heart (SUV 7.42  0.43 at 5 min via ex vivo biodistribution), and rapid clearance from the bloodstream ( Table 1) High liver uptake and retention was observed, with consistent heart to liver ratios around 2 throughout the 60 min protocol.…”

“…Cardiac time-activity profiles were measured from the cardiac orientated -detector, for both 18 F-Mitophos and 99m Tc-Sestamibi (Figure 2 A, B). In control hearts, 18 F-Mitophos exhibited an average single pass extraction and retention of 66 ± 5% (n = 5) of injected spike at 20 min post injection in comparison to 99m Tc-Sestamibi which showed 31 ± 4% (n = 5) retention. In control hearts the kinetic washout rate, K, from 2 min post injection for 18 F-Mitophos and 99m Tc-Sestamibi was 1.1x10 -3 ± 3x10 -4 %ID/min and 4.5x10 -3 ± 1.0x10 -3 %ID/min respectively (Supplement Figure 1).…”

“…Sprague Dawley rats (n = 4, 408 ± 95 g) underwent 60 min dynamic PET-CT scans with injection of 18 F-Mitophos (6.2 ± 2.0 MBq). After 48 h, animals were scanned a second time with 18 F-Mitophos (7.2 ± 1.2 MBq). Cardiac SUV30-60 was determined from dynamic scan TAC of the left ventricle and was used to calculate variability.…”

“…3,9 Measuring evolving cardiac damage at a sub-cellular level using a molecular imaging approach could provide earlier and more sensitive assessment of cardiotoxicity, however most approaches explored to date are limited in capacity or in a relatively early stage . 10,11 'Metabolism' tracers such as 18 F-FDG and 11 C-acetate have been investigated, however, cardiac retention is heavily influenced by other parameters, such as dietary substrate availability, which complicate their use. 12 Tracers more closely related to the mechanisms of cardiotoxicity such as 123 I-MIBG, which is sensitive to sympathetic nervous system alterations, show greater promise and have shown response to DOX treatment preclinically, and in patients.…”

“…17 Our collaborators have recently demonstrated the potential for using radiolabelled lipophilic cations to report on doxorubicin-induced mitochondrial dysfunction with 99m Tc-sestamibi for SPECT imaging. 18 While proof of concept with SPECT imaging has been demonstrated, PET has significant advantages for this approach in terms of sensitivity and the capacity for 3dimensional pharmacokinetic analysis.…”