Detection of dose response in chronic doxorubicin-mediated cell death with cardiac technetium 99m annexin v single-photon emission computed tomography

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 IS 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.