Noninvasive Molecular Imaging of Apoptosis in a Mouse Model of Anthracycline-Induced Cardiotoxicity

• Published in: Circulation. Cardiovascular imaging Vol. 8; no. 2; p. e001952
• Main Authors: Su, Helen, Gorodny, Natalia, Gomez, Luis Felipe, Gangadharmath, Umesh, Mu, Fanrong, Chen, Gang, Walsh, Joseph C., Szardenings, Katrin, Kolb, Hartmuth C., Tamarappoo, Balaji
• Format: Journal Article
• Language: English
• Published: United States 01.02.2015
• Subjects: Animals; Apoptosis; Autoradiography; Biomarkers - metabolism; Caspase 3 - metabolism; Disease Models, Animal; Doxorubicin; Fluorine Radioisotopes - administration & dosage; Glycopeptides - administration & dosage; Heart Diseases - chemically induced; Heart Diseases - diagnosis; Heart Diseases - diagnostic imaging; Heart Diseases - metabolism; Heart Diseases - pathology; Heart Diseases - physiopathology; In Situ Nick-End Labeling; Injections, Intravenous; Mice, Inbred C57BL; Molecular Imaging - methods; Myocardium - metabolism; Myocardium - pathology; Positron-Emission Tomography - methods; Predictive Value of Tests; Radiopharmaceuticals - administration & dosage; Ventricular Function, Left
• ISSN: 1941-9651; 1942-0080; 1942-0080
• DOI: 10.1161/CIRCIMAGING.114.001952

Anthracycline-induced cardiotoxicity and myocardial dysfunction may be associated with apoptosis. Caspase 3 catalyzes a terminal step in apoptosis, and its expression may serve as a marker of cardiomyocyte apoptosis. We synthesized 18F-CP18, a caspase-3 substrate and evaluated cardiac 18F-CP18 uptake in a mouse model of anthracycline cardiotoxicity. For 12 weeks, mice were injected with doxorubicin, 3 mg/kg/week, or vehicle (control). Left ventricular fractional shortening was quantified by echocardiography. CP18 uptake after intravenous injection of 250 μCi of 18F-CP18, 24 hours post-doxorubicin treatment was quantified by microPET, autoradiography, and gamma counting. Apoptosis was assessed by enzymatic assay of myocardial caspase 3 and TUNEL staining of tissue sections. Compared with controls, at 6 and 12 weeks of doxorubicin treatment, fractional shortening was reduced (20.7%±2.5% versus 31%±3.5%, P=0.010; and 20.3%±3.1% versus 32.4%±2.1%, P=0.011). Doxorubicin treatment was associated with increased 18F-CP18 uptake in %ID/g by gamma counting from 0.36±0.01 (week 1) to 0.78±0.01 (week 12), P=0.003. A similar increase in 18F-CP18 uptake was observed by microPET (0.41±0.04 versus 0.73±0.1, P=0.014) and autoradiography (1.1±0.3 versus 2.8±0.2 P=0.001). Caspase 3 enzymatic activity and apoptosis by TUNEL staining were also increased after 12 weeks of doxorubicin compared with weeks 1 and 3. CP18 uptake in controls was relatively unchanged at weeks 1, 3, and 12. In a mouse model of cardiotoxicity, doxorubicin treatment is associated with increased myocardial caspase 3 expression and an increase in CP18 uptake. 18F-CP18 may be useful for detection of anthracycline-induced myocardial apoptosis.