Objective: Genetically modified hyperlipidemic mice are increasingly used as an animal model of atherosclerosis, but their coronary artery disease remains poorly characterized. Furthermore, non-invasive tools to detect functional consequences of coronary lesions remain to be tested in mice. Coronary flow velocity reserve (CFVR) by transthoracic Doppler echocardiography provides a hemodynamic measure of coronary artery stenosis severity in humans. Thus, we applied Doppler echocardiography in atherosclerotic mice to study the relationship between CFVR and histologically determined coronary artery narrowing.
Methods: Atherosclerotic LDLR/ApoB48 double knockout mice of 58-72 weeks age (n=12) and age-matched C57BL/6 mice (n=5) were studied. CFVR was measured in anesthetized mice by Doppler echocardiography in the middle left coronary artery (LCA) during adenosine-induced maximal vasodilatation. Histopathology of proximal and middle LCA was studied in serial tissue sections.
Results: All LDLR/ApoB48 double knockout mice had atherosclerotic lesions in the proximal, but not in the middle LCA causing various degrees of luminal narrowing (30-97%). No lesions were found in controls. Compared with controls, CFVR was significantly reduced in the atherosclerotic mice (2.3+/-0.5 vs. 1.7+/-0.5, p=0.02). There was a negative correlation between CFVR and the amount of luminal narrowing (r=-0.91, p=0.001). Average CFVR was consistently lower in mice that had >or=70% than <70% stenosis (1.3+/-0.1, n=7 vs. 2.2+/-0.4, n=5, p=0.0002).
Conclusions: LDLR/ApoB48 double knockout mice are characterized with histologically severe coronary artery narrowings. Reduced CFVR is a consistent feature of these lesions. Doppler echocardiography of coronary artery flow can be used to detect flow-limiting stenosis in living atherosclerotic mice.