Author + information
- Received August 30, 2007
- Revision received October 12, 2007
- Accepted October 18, 2007
- Published online January 1, 2008.
- Tuomas T. Rissanen, MD, PhD⁎,
- Petra Korpisalo, MD⁎,
- Henna Karvinen, MSc⁎,
- Timo Liimatainen, PhD†,
- Svetlana Laidinen, MSc⁎,
- Olli H. Gröhn, PhD,† and
- Seppo Ylä-Herttuala, MD, PhD⁎,⁎,‡,§ ()
- ↵⁎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.
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.
This study was supported by grants from the Academy of Finland, Finnish Foundation for Cardiovascular Research, Sigrid Juselius Foundation, EU Vascular Genomics Network, European Vascular Genomics Network (LSHM-CT-2003-503254), and EU CliniGene network (LSH-CT-2004-018933). Drs. Rissanen and Korpisalo contributed equally to this article.
- Received August 30, 2007.
- Revision received October 12, 2007.
- Accepted October 18, 2007.
- American College of Cardiology Foundation