Establishment of a novel murine model of ischemic cardiomyopathy with multiple diffuse coronary lesions.
OBJECTIVE
Atherosclerotic lesions of the coronary arteries are the pathological basis for myocardial infarction and ischemic cardiomyopathy. Progression of heart failure after myocardial infarction is associated with cardiac remodeling, which has been studied by means of coronary ligation in mice. However, this ligation model requires excellent techniques. Recently, a new murine model, HypoE mouse was reported to exhibit atherogenic Paigen diet-induced coronary atherosclerosis and myocardial infarction; however, the HypoE mice died too early to make possible investigation of cardiac remodeling. Therefore, we aimed to modify the HypoE mouse model to establish a novel model for ischemic cardiomyopathy caused by atherosclerotic lesions, which the ligation model does not exhibit.


RESULTS
In our study, the sustained Paigen diet for the HypoE mice was shortened to 7 or 10 days, allowing the mice to survive longer. The 7-day Paigen diet intervention starting when the mice were 8 weeks old was adequate to permit the mice to survive myocardial infarction. Our murine model, called the "modified HypoE mouse", was maintained until 8 weeks, with a median survival period of 36 days, after the dietary intervention (male, n = 222). Echocardiography demonstrated that the fractional shortening 2 weeks after the Paigen diet (n = 14) significantly decreased compared with that just before the Paigen diet (n = 6) (31.4±11.9% vs. 54.4±2.6%, respectively, P<0.01). Coronary angiography revealed multiple diffuse lesions. Cardiac remodeling and fibrosis were identified by serial analyses of cardiac morphological features and mRNA expression levels in tissue factors such as MMP-2, MMP-9, TIMP-1, collagen-1, and TGF-β.


CONCLUSIONS
Modified HypoE mice are a suitable model for ischemic cardiomyopathy with multiple diffuse lesions and may be considered as a novel and convenient model for investigations of cardiac remodeling on a highly atherogenic background.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Hajime
H
Nakaoka
Yumiko
Y
Nakagawa-Toyama
Makoto
M
Nishida
Takeshi
T
Okada
Ryota
R
Kawase
Taiji
T
Yamashita
Miyako
M
Yuasa-Kawase
Kazuhiro
K
Nakatani
Daisaku
D
Masuda
Tohru
T
Ohama
Takashi
T
Sonobe
Mikiyasu
M
Shirai
Issei
I
Komuro
Shizuya
S
Yamashita
D000818:Animals; D050197:Atherosclerosis / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000150:complications / Q000175:diagnosis / Q000473:pathology*; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D006333:Heart Failure / Q000209:etiology; D008297:Male; D051379:Mice; D017202:Myocardial Ischemia / Q000209:etiology / Q000401:mortality / Q000473:pathology*; D020257:Ventricular Remodeling / Q000235:genetics
D002784:Cholesterol