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FOCUS ISSUE: CARDIAC IMAGING: CLINICAL RESEARCH

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
Institut für Experimentelle Onkologie und Therapieforschung
Institut für Allgemeine Pathologie und Pathologische Anatomie
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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