Noninvasive Characterization of Myocardial Molecular Interventions by Integrated Positron Emission Tomography and Computed Tomography

• Published in: Journal of the American College of Cardiology Vol. 48; no. 10; pp. 2107 - 2115
• Main Authors: Wagner, Bettina, Anton, Martina, Nekolla, Stephan G., Reder, Sybille, Henke, Julia, Seidl, Stefan, Hegenloh, Renate, Miyagawa, Masao, Haubner, Roland, Schwaiger, Markus, Bengel, Frank M.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 21.11.2006; Elsevier Science; Elsevier Limited
• Subjects: Adenoviruses; Ammonia; Angiogenesis; Animals; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Coronary Circulation; Feasibility Studies; Gene Expression; Gene Transfer Techniques; Genes, Reporter; Heart; Heart - diagnostic imaging; Heart - physiology; Herpesvirus 1, Human - enzymology; Integrin alphaVbeta3 - metabolism; Intervention; Ischemia; Kinases; Medical sciences; Mutation; Myocardial Contraction; Myocardium - metabolism; Ostomy; Positron-Emission Tomography; Studies; Swine; Thymidine Kinase - genetics; Tissue engineering; Tomography, X-Ray Computed; Transgenes; Up-Regulation; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Ventilation; Germany; MBF; CT; AdVEGF; VEGF; FHBG; Adsr39tk; AdTk-VEGF; PET; Radionuclide study; Characterization; Radiodiagnosis; Non invasive method; Myocardium; Medical imagery; Computerized axial tomography; Circulatory system; Cardiology; Phlebology; Positron emission tomography; Emission tomography
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2006.08.029

Noninvasive Characterization of Myocardial Molecular Interventions by Integrated Positron Emission Tomography and Computed Tomography Bettina Wagner, Martina Anton, Stephan G. Nekolla, Sybille Reder, Julia Henke, Stefan Seidl, Renate Hegenloh, Masao Miyagawa, Roland Haubner, Markus Schwaiger, Frank M. Bengel The goal of this study was to explore the feasibility of integrated positron emission tomography (PET) and computed tomography (CT) for in vivo characterization of cardiac molecular interventions. A model of regional adenoviral transfer of the VEGF121gene to myocardium of healthy pigs was investigated. Successful transgene expression was confirmed by a reporter probe targeting co-expressed HSV1-sr39tk reporter gene. The PET-CT fusion allowed for regional localization of biologic signals, and CT-derived ventricular function and morphology remained unaltered. Increased regional perfusion was identified in areas overexpressing VEGF, corroborating in vivo effects on microvasculature, but noninvasively determined αvβ3integrin adhesion molecule expression was not enhanced. We sought to investigate the usefulness of integrated positron emission tomography (PET) and computed tomography (CT) for in vivo characterization of an angiogenesis-directed molecular intervention. Controversies about the effectiveness of molecular therapies for cardiovascular disease have prompted the need for more powerful noninvasive imaging techniques. In a model of regional adenoviral transfer of the VEGF121gene to myocardium of healthy pigs, PET-CT using multiple molecular-directed radiotracers was employed. Two days after gene transfer, successful transgene expression was noninvasively confirmed by a reporter probe targeting co-expressed HSV1-sr39tk reporter gene. The CT-derived ventricular function and morphology remained unaltered (left ventricular ejection fraction 57 ± 5% in adenovirus-injected animals vs. 53 ± 5% in controls; p = 0.36). Increased regional perfusion was identified in areas overexpressing VEGF (myocardial blood flow during adenosine-induced vasodilation 1.47 ± 0.49 vs. 1.14 ± 0.27 ml/g/min in remote areas; p = 0.01), corroborating in vivo effects on microvascular tone and permeability. Finally, regional angiogenesis-associated αvβ3integrin expression was not enhanced, suggesting little contribution to the perfusion increase. Fusion of CT morphology and tracer-derived molecular signals allowed for accurate regional localization of biologic signals. Findings were validated by control vectors, sham-operated animals, and ex vivo tissue analysis. Integrated PET-CT has the potential to dissect cardiovascular biologic mechanisms from gene expression to physiologic function and morphology. The VEGF overexpression in healthy myocardium increases myocardial perfusion without significant up-regulation of αvβ3integrin adhesion molecules early after the intervention.