Severe coronary artery stenoses and reduced coronary flow velocity reserve in atherosclerotic mouse model: Doppler echocardiography validation study.
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.
Saraste
Antti
A
Department of Medicine, Turku University Hospital, Turku, Finland. antti.saraste@utu.fi
Kytö
Ville
V
Laitinen
Iina
I
Saraste
Markku
M
Leppänen
Pia
P
Ylä-Herttuala
Seppo
S
Saukko
Pekka
P
Hartiala
Jaakko
J
Knuuti
Juhani
J
D000818:Animals; D050197:Atherosclerosis / Q000150:complications* / Q000000981:diagnostic imaging; D023921:Coronary Stenosis / Q000150:complications* / Q000000981:diagnostic imaging*; D015150:Echocardiography, Doppler; D053805:Fractional Flow Reserve, Myocardial; D008297:Male; D051379:Mice; D018345:Mice, Knockout