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PRECLINICAL STUDIES

Functional and Morphologic Imaging of Coronary Atherosclerosis in Living Mice Using High-Resolution Color Doppler Echocardiography and Ultrasound Biomicroscopy

Johannes Wikström, MSc^_*, Julia Grönros, MSc^_*, Göran Bergström, MD, PhD and Li-ming Gan, MD, PhD^_*,,_*

^_* Department of Physiology, Institute of Physiology and Pharmacology
Department of Clinical Physiology, Cardiovascular Institute, The Sahlgrenska Academy, Göteborg University, Göteborg, Sweden

Manuscript received December 20, 2004; revised manuscript received April 14, 2005, accepted April 25, 2005.

^_* Reprint requests and correspondence: Dr. Li-ming Gan, Göteborg University, Institute of Physiology and Pharmacology, Department of Physiology, Box 432, 405 30 Göteborg, Sweden (Email: li-ming.gan{at}hjl.gu.se).

OBJECTIVES: This study aimed to establish non-invasive methods of assessing coronary artery morphology in normal and atherosclerotic mice in vivo.

BACKGROUND: Coronary flow velocity reserve (CFVR) has been shown to correlate with coronary minimal lumen diameter (MLD) in patients with coronary artery stenosis. In mice, there are no existing non-invasive imaging techniques allowing quantitative measurement of the coronary artery morphology and function.

METHODS: Systemic hemodynamic effects of adenosine were studied in seven C57BL/6 mice. In 17 C57BL/6 mice, CFVR was measured in the mid left coronary artery (LCA) using either hypoxia- or adenosine-induced coronary hyperemia. Further, in another 10 atherosclerotic low-density lipoprotein receptor (LDLR)^–/– mice, the hypoxia-induced CFVR was performed and proximal LCA MLD was measured using ultrasound biomicroscopy (UBM). Histologic sections of the LCA were collected.

RESULTS: The adenosine dose of 160 µg/kg/min induced maximal coronary hyperemia without any systemic hemodynamic effects. Adenosine and hypoxia-induced CFVR values averaged at 2.0 ± 0.1 and 1.9 ± 0.3, respectively, in C57BL/6 mice (p = NS). In LDLR^–/– mice, CFVR and MLD ranged between 1.4 to 2.9 µm and 190 to 370 µm, respectively. Histology revealed proximal lumen-narrowing plaques in the LCA. Significant correlation was found between hypoxia-induced CFVR and the MLD (p < 0.005, R² = 0.8707).

CONCLUSIONS: The CDE and UBM technique can be used to measure atherosclerosis-related lumen narrowing of the LCA in living mice. These non-invasive techniques may provide us with novel tools for following up disease status in mouse coronary arteries in a quantitative manner.

Abbreviations and Acronyms   BP = blood pressure   CDE = color Doppler echocardiography   CFR = coronary flow reserve   CFVR = coronary flow velocity reserve   HR = heart rate   LCA = left coronary artery   LDLR = low-density lipoprotein receptor   MLD = minimal lumen diameter   UBM = ultrasound biomicroscope

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