Abstract
ObjectivesAtherosclerotic 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.Methods and ResultsIn 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.ConclusionModified 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.
Highlights
Heart failure is a major cause of death in developed countries
Cardiac remodeling and fibrosis were identified by serial analyses of cardiac morphological features and mRNA expression levels in tissue factors such as matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1, collagen-1, and Transforming growth factor (TGF)-b
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
Summary
Heart failure is a major cause of death in developed countries. It is a common disease; more than 2% of the United States population, or almost 5 million people, are affected, and 30% to 40% of patients die within 1 year of receiving the diagnosis of heart failure. The causes of heart failure are divided into 2 main classes, ischemic and nonischemic. The single largest cause of cardiovascular disease, is the narrowing of arteries over time caused by atherosclerotic plaques or by acute occlusion of the coronary artery by thrombosis, both of which can lead to myocardial infarction (MI) and the eventual development of heart failure [1,2]. Despite the progress in acute-phase treatment, survivors often have critical heart failure. Ischemic cardiomyopathy (ICM), caused by MI and subsequent cardiac remodeling, is an unsolved problem and a significant target for medical treatment
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