Yoshifumi Maya1,2, Rudolf A Werner1,3,4, Claudia Schütz3,5, Hiroshi Wakabayashi1, Samuel Samnick1,3, Constantin Lapa1, Christina Zechmeister3,5, Roland Jahns3,6, Valérie Jahns3,5, Takahiro Higuchi7,3. 1. Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany. 2. Research Centre, Nihon Medi-Physics Co., Ltd., Chiba, Japan. 3. Comprehensive Heart Failure Center, University of Würzburg, Würzburg, Germany. 4. Else-Kröner-Forschungskolleg, Interdisciplinary Center for Clinical Research, University of Würzburg,Würzburg, Germany. 5. Department of Pharmacology, University of Würzburg, Würzburg, Germany; and. 6. Interdisciplinary Bank of Biomaterials and Data Würzburg (IBDW), University of Würzburg, Würzburg, Germany. 7. Department of Nuclear Medicine, University of Würzburg, Würzburg, Germany thiguchi@me.com.
Abstract
Myocarditis represents a major cause of dilated cardiomyopathy and sudden cardiac death in younger adults. Currently, definitive diagnosis of myocarditis requires endomyocardial biopsy, which is highly invasive and has the drawback of variable sensitivity due to inherent sampling error. Therefore, reliable noninvasive methods to detect and monitor cardiac inflammation are clinically relevant. In this study, we explored the potential of radiolabeled methionine to assess myocardial inflammatory activity in a rat model of experimental autoimmune myocarditis (EAM). METHODS: Autoimmune myocarditis was induced by immunizing Lewis rats twice with porcine cardiac myosin and Freund complete adjuvant. Control animals were treated with adjuvant alone. Dual-tracer autoradiography was performed to assess 14C-methionine uptake and to compare the distributions of 14C-methionine versus 18F-FDG. Hematoxylin and eosin staining and anti-CD68 macrophage staining were performed for histologic analysis. Additionally, cardiac 11C-methionine PET was performed to evaluate the feasibility of in vivo imaging. 18F-FDG PET was also conducted to compare the in vivo uptake of 11C-methionine and 18F-FDG. RESULTS: Multiple focal cardiac inflammatory lesions were histologically identified in myosin-immunized rats, whereas no cardiac lesions were observed in the controls. Autoradiographic images clearly showed a high-density accumulation of 14C-methionine in inflammatory lesions of EAM rats, whereas no significant uptake was observed in the control animals. 14C-methionine uptake was significantly higher in inflammatory lesions than in remote noninflammatory areas and control rat hearts. The distribution of 14C-methionine correlated well with that of 18F-FDG and with macrophage density. The contrast between inflammatory and noninflammatory areas was higher for 18F-FDG than for 14C-methionine (3.45 ± 0.68 vs. 2.07 ± 0.21, respectively; P < 0.05). In the PET imaging study, the regional 11C-methionine uptake (percentage injected dose per cubic centimeter) observed in EAM rats was significantly higher than the values obtained for control animals (0.64 ± 0.09 vs. 0.28 ± 0.02, respectively; P < 0.001). A good positive correlation between 11C-methionine and 18F-FDG uptake was found. CONCLUSION: In a rat model of autoimmune myocarditis, we demonstrated the colocalization of radiolabeled methionine accumulation with 18F-FDG uptake in histologically proven inflammatory lesions. These data suggest that 11C-methionine might represent a promising candidate for the noninvasive detection and monitoring of myocarditis.
Myocarditis represents a major cause of dilated cardiomyopathy and sudden cardiac death in younger adults. Currently, definitive diagnosis of myocarditis requires endomyocardial biopsy, which is highly invasive and has the drawback of variable sensitivity due to inherent sampling error. Therefore, reliable noninvasive methods to detect and monitor cardiac inflammation are clinically relevant. In this study, we explored the potential of radiolabeled methionine to assess myocardial inflammatory activity in a rat model of experimental autoimmune myocarditis (EAM). METHODS:Autoimmune myocarditis was induced by immunizing Lewis rats twice with porcine cardiac myosin and Freund complete adjuvant. Control animals were treated with adjuvant alone. Dual-tracer autoradiography was performed to assess 14C-methionine uptake and to compare the distributions of 14C-methionine versus 18F-FDG. Hematoxylin and eosin staining and anti-CD68 macrophage staining were performed for histologic analysis. Additionally, cardiac 11C-methionine PET was performed to evaluate the feasibility of in vivo imaging. 18F-FDG PET was also conducted to compare the in vivo uptake of 11C-methionine and 18F-FDG. RESULTS: Multiple focal cardiac inflammatory lesions were histologically identified in myosin-immunized rats, whereas no cardiac lesions were observed in the controls. Autoradiographic images clearly showed a high-density accumulation of 14C-methionine in inflammatory lesions of EAM rats, whereas no significant uptake was observed in the control animals. 14C-methionine uptake was significantly higher in inflammatory lesions than in remote noninflammatory areas and control rat hearts. The distribution of 14C-methionine correlated well with that of 18F-FDG and with macrophage density. The contrast between inflammatory and noninflammatory areas was higher for 18F-FDG than for 14C-methionine (3.45 ± 0.68 vs. 2.07 ± 0.21, respectively; P < 0.05). In the PET imaging study, the regional 11C-methionine uptake (percentage injected dose per cubic centimeter) observed in EAM rats was significantly higher than the values obtained for control animals (0.64 ± 0.09 vs. 0.28 ± 0.02, respectively; P < 0.001). A good positive correlation between 11C-methionine and 18F-FDG uptake was found. CONCLUSION: In a rat model of autoimmune myocarditis, we demonstrated the colocalization of radiolabeled methionine accumulation with 18F-FDG uptake in histologically proven inflammatory lesions. These data suggest that 11C-methionine might represent a promising candidate for the noninvasive detection and monitoring of myocarditis.
Authors: Jessica R Salas; Bao Ying Chen; Alicia Wong; Donghui Cheng; John S Van Arnam; Owen N Witte; Peter M Clark Journal: J Nucl Med Date: 2018-04-26 Impact factor: 10.057