title: 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.
authors.affiliation: Department of Molecular and Comparative Pathobiology, School of Medicine and Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA. kgabriel@jhmi.edu
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Gabrielson
authors.forename: Greta S P
authors.initials: GS
authors.lastname: Mok
authors.forename: Srihdar
authors.initials: S
authors.lastname: Nimmagadda
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.forename: Scott
authors.initials: S
authors.lastname: Pin
authors.forename: Allison
authors.initials: A
authors.lastname: Tsao
authors.forename: Yuchuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Dhrtti
authors.initials: D
authors.lastname: Sooryakumar
authors.forename: S Jianhua
authors.initials: SJ
authors.lastname: Yu
authors.forename: Martin G
authors.initials: MG
authors.lastname: Pomper
authors.forename: Benjamin M W
authors.initials: BM
authors.lastname: Tsui
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003935:Diagnostic Techniques, Cardiovascular; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity*; D004452:Echocardiography; D005260:Female; D006321:Heart / Q000000981:diagnostic imaging* / Q000187:drug effects*; D020287:In Situ Nick-End Labeling; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D015609:Organotechnetium Compounds / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon / Q000379:methods*
chemical_list: D017304:Annexin A5; D015609:Organotechnetium Compounds; C117287:technetium Tc 99m HYNIC annexin V; D004317:Doxorubicin