Noninvasive characterization of myocardial molecular interventions by integrated positron emission tomography and computed tomography.
OBJECTIVE
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 VEGF(121) 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 alpha(v)beta3 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 alpha(v)beta3 integrin adhesion molecules early after the intervention.
Wagner
Bettina
B
Nuklearmedizinische Klinik und Poliklinik, Technische Universität München, Germany.
Anton
Martina
M
Nekolla
Stephan G
SG
Reder
Sybille
S
Henke
Julia
J
Seidl
Stefan
S
Hegenloh
Renate
R
Miyagawa
Masao
M
Haubner
Roland
R
Schwaiger
Markus
M
Bengel
Frank M
FM
D000818:Animals; D003326:Coronary Circulation; D005240:Feasibility Studies; D015870:Gene Expression; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006321:Heart / Q000000981:diagnostic imaging* / Q000502:physiology; D018259:Herpesvirus 1, Human / Q000201:enzymology; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D049268:Positron-Emission Tomography; D013552:Swine; D013937:Thymidine Kinase / Q000235:genetics; D014057:Tomography, X-Ray Computed; D019076:Transgenes; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D039302:Integrin alphaVbeta3; D042461:Vascular Endothelial Growth Factor A; D013937:Thymidine Kinase