Detection of Dose Response in Chronic Doxorubicin-Mediated Cell Death with Cardiac Technetium 99m Annexin V Single-Photon Emission Computed Tomography

Abstract

The aim of this study was to evaluate whether technetium 99m hydrazinonicotinamide (99mTc-HYNIC)-annexin V single-photon emission computed tomography (SPECT) would detect dose-dependent doxorubicin (DOX)-mediated cell death in the heart compared with functional echocardiography. Adult female Sprague-Dawley rats were treated with DOX (cumulative dose of 15 or 7.5 mg/kg) or saline (n = 7) and monitored by echocardiography. Rats were injected with 7 to 8 mCi 99mTc-HYNIC-annexin V and imaged 1 hour postinjection using a small animal dual-head SPECT/computed tomography (CT) system with multipinhole technology. Two regions of interest were drawn in the myocardium and soft tissue regions to calculate the cardiac uptake ratio (CUR) of reconstructed images. Myocardium and blood were harvested for radioactivity measurements or TUNEL assay. Biodistribution of 99mTc-HYNIC-annexin V uptake, CUR from SPECT/CT fused cardiac images, and TUNEL of myocardium demonstrated a dose-dependent toxicity response, with the cumulative 15 mg/kg DOX treatment showing the greatest degree of cell death. In contrast, echocardiography detected functional deficits only at the highest DOX dose. In vivo molecular imaging of DOX-induced cardiac toxicity with 99mTc-HYNIC-annexin V detects dose-dependent cell death before ventricular deficits are observed with echocardiography. 99mTc-HYNIC-annexin V SPECT-based molecular imaging may provide an attractive new technique for assessing early changes in myocardial function in patients undergoing DOX therapy.

Evaluation of a Multi-pinhole Collimator for Imaging Small Animals with Different Sizes

“…The mouse was euthanized 1 h post-injection and then imaged using one-, four-, and five-pinhole configurations under the same acquisition time, i.e., ∼130 min, eliminating the respiratory and cardiac motion artifacts to demonstrate the best achievable resolution for this system. To demonstrate the effectiveness of this system for other more common application, which was mostly available for our study, i.e., cardiac imaging in live animals, we then imaged the anesthetized doxorubicin-induced cardiotoxicity rat model [27] and its corresponding saline control, with body diameters of ∼5 cm under the same acquisition time of ∼64 min. The rats were injected with ∼8 mCi 99m Tc labeled Annexin V to target the apoptotic cells in the heart.…”

Non-invasive imaging and monitoring cardiotoxicity of cancer therapeutic drugs

“…Targeted molecular imaging with SPECT, PET, or MRI may be able to detect cell death due to doxorubicin 25 and to detect subclinical cardiotoxicity.…”

Apoptosis Imaging in Diseased Myocardium

“…Another study with doxorubicin treated rats (cumulative dose: 7.5mg/Kg and 15mg/Kg) demonstrated that dose dependent increase in 99m Tc-annexin V uptake by SPECT/CT and TUNEL positivity. In contrast in this syudy, echocardiography detected ventricular dysfunction only at the highest doxorubicin dose ( Gabrielson, et al, 2008). These data suggest that apoptosis imaging could serve as a more sensitive early marker of doxorubicin cardiotoxixity than left ventricular dysfunction, might providing the opportunity to modify or stop the chemotherapy before clinically overt heart failure.…”