Novel Rat Model of Ischemic Cardiomyopathy Induced by Repetitive Myocardial Ischemia/Reperfusion Injury While Conscious

Background A rodent model of ischemic cardiomyopathy (ICM) induced by repetitive brief ischemia/reperfusion (I/R) injury while conscious has not been previously established. Methods and Results A newly developed coronary occluder was implanted in male Wistar rats. A repetitive I/R protocol (20s, 2min, followed by main 30min -ischemia, every 48h, for 4 weeks) was introduced while the animals were conscious. The I/R protocol did not induce transmural scar formation but induced (1) residual myocytes with scattered infiltration of fibrosis (Masson trichrome stain), (2) coronary hypoperfusion (^<201>Tl-Cl autoradiogram), (3) reduced coronary microvascular volume fraction (microCT), and (4) gradually progressive left ventricular (LV) dilation (echocardiography). These parameters of ICM showed interindividual variation; however, the percent increase in LV diastolic area on day 3 was significantly correlated with LV dilation (r=0.91, p<0.0001), fibrosis (r=0.77, p=0.0034), and reduction in microvessels (r=0.67, p=0.040) at week 4. The LV dilatory response on day 3 also correlated with inducible nitric oxide synthase expression (immunohistochemistry, day 3) in the LV (r=0.92, p=0.028). Conclusions A novel rat model of ICM induced by repetitive I/R while conscious showed interindividual variation in the severity of ICM in the advanced stage, but this was predictable non-invasively (by LV dilatory response) during the initial stage of repetitive I/R.