Establishment of a Novel Murine Model of Ischemic Cardiomyopathy with Multiple Diffuse Coronary Lesions

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.

An Alternative Technique for Heart Lesion in the Rat: A Step to Fetal Heart Implantation for Cardiac Tissue Repair Running Title: A New Technique of Heart Lesion in Rat

“…The same inconvenient of large involvement of the heart structures and even of the whole organism is obvious when lesions are caused by injection of drugs [17,18,23]. Ferric chloride use is not compatible with MRI imaging investigation, necessary to determine the lesion extent and evolution.…”

“…Heart main artery obstruction was obtained by physical means: cold or heat injury, radiofrequencies [14,15], chemical methods: injections or application of chemicals on the myocardium [16][17][18] or surgical ones as vessel ligation [19]. Presently the most usual experimental model of creating a cardiac lesion remains the temporary or permanent ligation of a coronary artery [9][10][11][12][19][20][21][22] or other type of heart vessels occlusion [23]. The advantage of this model is its proximity with the injury caused by myocardial infarction in clinical practice.…”

“…The advantage of this model is its proximity with the injury caused by myocardial infarction in clinical practice. The disadvantages include the variability of the lesion extent due to the difficulty to obtain a precise location of the coronary artery (or one of its branches) ligation/occlusion and the variability of collateral vessel types [20][21][22][23]. Moreover, the myocardial ischemia around the infarction zone seems to be unfavorable for cells or tissue transplants development that explains the controversial results of such a procedure [7][8][9][10][11]20,23].…”

Relevance of mouse models of cardiac fibrosis and hypertrophy in cardiac research

“…Using SR-BI KO/ApoeR61 h/h mice (mixed C57BL/6 6 129 background) Nakaoka et al [68] established a novel murine model called as “modified HypoE mouse” of ischemic cardiomyopathy with multiple diffuse coronary lesions. They shortened the sustained Paigen diet for the HypoE mice causing mice to survive longer.…”

Widespread Coronary Dysfunction in the Absence of HDL Receptor SR-B1 in an Ischemic Cardiomyopathy Mouse Model

“…In contrast, hypomorphic E mice deficient in SR-B1 with low expression of an allelic variant of mouse apoE (SR-B1 −/− /ApoeR61 h/h ), have a normal life span on a normal chow diet, but die prematurely from repeated spontaneous myocardial infarction as a result of atherothrombosis after 4–8 weeks on a Paigen diet 8 . Recently, some of us showed that by reducing Paigen diet exposure to 1 week extended survival of SR-B1 −/− /ApoER61 h/h mice, and induced a state of progressive ischemic cardiomyopathy 9 .…”