title: Noninvasive molecular imaging of apoptosis in a mouse model of anthracycline-induced cardiotoxicity.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Helen
authors: H
authors: Su
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Natalia
authors: N
authors: Gorodny
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Luis Felipe
authors: LF
authors: Gomez
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Umesh
authors: U
authors: Gangadharmath
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Fanrong
authors: F
authors: Mu
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Gang
authors: G
authors: Chen
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Joseph C
authors: JC
authors: Walsh
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Katrin
authors: K
authors: Szardenings
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.).
authors: Hartmuth C
authors: HC
authors: Kolb
authors: From Siemens Molecular Imaging, Siemens Medical Solutions USA, Inc., Culver City, CA (H.S., N.G., L.F.G., U.G., F.M., G.C., J.C.W., K.S., H.C.K.); and Cleveland Clinic, Cleveland, OH (B.T.). tamarab@ccf.org.
authors: Balaji
authors: B
authors: Tamarappoo
mesh_terms: D000818:Animals; D017209:Apoptosis; D001345:Autoradiography; D015415:Biomarkers / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D004195:Disease Models, Animal; D004317:Doxorubicin; D005462:Fluorine Radioisotopes / Q000008:administration & dosage; D006020:Glycopeptides / Q000008:administration & dosage; D006331:Heart Diseases / Q000139:chemically induced* / Q000175:diagnosis* / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D007275:Injections, Intravenous; D008810:Mice, Inbred C57BL; D057054:Molecular Imaging / Q000379:methods*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D049268:Positron-Emission Tomography / Q000379:methods*; D011237:Predictive Value of Tests; D019275:Radiopharmaceuticals / Q000008:administration & dosage; D016277:Ventricular Function, Left
chemical_list: D015415:Biomarkers; C586095:CP-18 compound; D005462:Fluorine Radioisotopes; D006020:Glycopeptides; D019275:Radiopharmaceuticals; D004317:Doxorubicin; C505409:Casp3 protein, mouse; D053148:Caspase 3
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