Noninvasive characterization of myocardial molecular interventions by integrated positron emission tomography and computed tomography

J Am Coll Cardiol. 2006 Nov 21;48(10):2107-15. doi: 10.1016/j.jacc.2006.08.029. Epub 2006 Oct 31.

Abstract

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 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Coronary Circulation
  • Feasibility Studies
  • Gene Expression
  • Gene Transfer Techniques*
  • Genes, Reporter
  • Heart / diagnostic imaging*
  • Heart / physiology
  • Herpesvirus 1, Human / enzymology
  • Integrin alphaVbeta3 / metabolism
  • Mutation
  • Myocardial Contraction
  • Myocardium / metabolism*
  • Positron-Emission Tomography*
  • Swine
  • Thymidine Kinase / genetics
  • Tomography, X-Ray Computed*
  • Transgenes
  • Up-Regulation
  • Vascular Endothelial Growth Factor A / genetics*

Substances

  • Integrin alphaVbeta3
  • Vascular Endothelial Growth Factor A
  • Thymidine Kinase