title: Severe coronary artery stenoses and reduced coronary flow velocity reserve in atherosclerotic mouse model: Doppler echocardiography validation study.
abstract: 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.
authors.affiliation: Department of Medicine, Turku University Hospital, Turku, Finland. antti.saraste@utu.fi
authors.forename: Antti
authors.initials: A
authors.lastname: Saraste
authors.forename: Ville
authors.initials: V
authors.lastname: Kytö
authors.forename: Iina
authors.initials: I
authors.lastname: Laitinen
authors.forename: Markku
authors.initials: M
authors.lastname: Saraste
authors.forename: Pia
authors.initials: P
authors.lastname: Leppänen
authors.forename: Seppo
authors.initials: S
authors.lastname: Ylä-Herttuala
authors.forename: Pekka
authors.initials: P
authors.lastname: Saukko
authors.forename: Jaakko
authors.initials: J
authors.lastname: Hartiala
authors.forename: Juhani
authors.initials: J
authors.lastname: Knuuti
mesh_terms: 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