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High-Resolution Ultrasound Perfusion Imaging of Therapeutic Angiogenesis

Tuomas T. Rissanen, MD, PhD^_*, Petra Korpisalo, MD^_*, Henna Karvinen, MSc^_*, Timo Liimatainen, PhD, Svetlana Laidinen, MSc^_*, Olli H. Gröhn, PhD,, Seppo Ylä-Herttuala, MD, PhD^_*,_*,,

^_* Department of Biotechnology and Molecular Medicine
Department of Biomedical Nuclear Magnetic Resonance and National Bio Nuclear Magnetic Resonance Facility, A. I. Virtanen Institute, Kuopio, Finland
Department of Medicine
Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

^_* Reprint requests and correspondence: Dr. Seppo Ylä-Herttuala, Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. (Email: Seppo.Ylaherttuala{at}uku.fi).

Objectives: The purpose of this study was to test the feasibility of contrast pulse sequence (CPS) ultrasound imaging for high-resolution perfusion imaging after gene transfer (GT) for therapeutic angiogenesis.

Background: Imaging modalities capable of accurate and feasible perfusion measurement are essential for the preclinical and clinical development of therapeutic angiogenesis. However, current methods suffer from compromises between spatial and temporal resolution and sensitivity. Contrast pulse sequence ultrasound is a recently developed real-time perfusion imaging method that generates high-contrast agent-to-tissue specificity and spatial resolution.

Methods: Contrast pulse sequence ultrasound was used to noninvasively assess parameters of blood flow 6 days after adenoviral vascular endothelial growth factor (AdVEGF) GT in rabbit and mouse hind limbs with bolus intravenous injection of a microbubble contrast medium. Blood volume, mean transit time, perfusion, and time to the arrival of the contrast bolus were calculated with the gamma variate function. Contrast-enhanced power Doppler ultrasound (CEU), dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), and histological capillary measurements were used as reference methods.

Results: Blood volume and perfusion increased over 40- and 20-fold, respectively, 6 days after AdVEGF GT in rabbit skeletal muscles. Perfusion values measured with CPS correlated well with those obtained with CEU (r = 0.975) and DCE-MRI (r = 0.854). However, CPS provided superior spatial and temporal resolution showing blood flow in vessels of only 10 to 20 µm in diameter. Contrast pulse sequence ultrasound was also feasible for imaging of therapeutic angiogenesis in mouse hind limbs both at the arterial and capillary levels. The CPS ultrasound revealed that AdVEGF mainly induces angiogenesis in adipose tissue rather than in the skeletal muscle of mouse hind limbs.

Conclusions: Contrast pulse sequence ultrasound is an efficient and accurate noninvasive real-time perfusion imaging modality in small laboratory animals and also offers a means for the assessment of muscle perfusion in future clinical trials of therapeutic angiogenesis.

Abbreviations and Acronyms   Ad = adenovirus/adenoviral   AdLacZ = adenoviral beta-galactosidase   CEU = contrast-enhanced power Doppler ultrasound   CPS = contrast pulse sequence   CT = computed tomography   DCE-MRI = dynamic contrast-enhanced magnetic resonance imaging   GT = gene transfer   MTT = mean transit time   PET = positron emission tomography   ROI = region of interest   SPECT = single-photon emission computed tomography   VEGF = vascular endothelial growth factor

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