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CLINICAL RESEARCH: MOLECULAR AND STEM CELL IMAGING

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

Bettina Wagner, DVM^_*, Martina Anton, PhD, Stephan G. Nekolla, PhD^_*, Sybille Reder, MT^_*, Julia Henke, DVM, Stefan Seidl, MD, Renate Hegenloh, MT, Masao Miyagawa, MD^_*, Roland Haubner, PhD^_*, Markus Schwaiger, MD^_* and Frank M. Bengel, MD^_*,||,_*

^_* Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Germany
Institut für Experimentelle Onkologie und Therapieforschung, Technische Universität München, Germany
Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
Abteilung für Gefäßchirurgie, Technische Universität München, Germany
^|| Division of Nuclear Medicine, Johns Hopkins University, Baltimore, Maryland.

Manuscript received July 31, 2006; accepted August 30, 2006.

^_* Reprint requests and correspondence: Dr. Frank M. Bengel, Division of Nuclear Medicine, Russell H. Morgan Department of Radiology, Johns Hopkins University Medical Institutions, 601 N. Caroline Street, JHOC 3225, Baltimore, Maryland 21287. (Email: fbengel1{at}jhmi.edu).

OBJECTIVES: 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.

BACKGROUND: Controversies about the effectiveness of molecular therapies for cardiovascular disease have prompted the need for more powerful noninvasive imaging techniques.

METHODS: In a model of regional adenoviral transfer of the VEGF₁₂₁ gene to myocardium of healthy pigs, PET-CT using multiple molecular-directed radiotracers was employed.

RESULTS: 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 _vß₃ integrin 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.

CONCLUSIONS: 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 _vß₃ integrin adhesion molecules early after the intervention.

Abbreviations and Acronyms   Adsr39tk = replication defective type 5 adenovirus expressing a mutant herpesviral thymidine kinase reporter gene   AdTk-VEGF = replication defective type 5 adenovirus co-expressing a mutant herpesviral thymidine kinase reporter gene and the human VEGF121 gene   AdVEGF = replication defective type 5 adenovirus expressing the human VEGF121 gene   CT = computed tomography   FHBG = [18F]fluoro-hydroxymethylbutyl-guanine   MBF = myocardial blood flow   PET = positron emission tomography   VEGF = vascular endothelial growth factor

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