Transient Rat Cardiac Ischemia from 30–60 Minutes Results in Comparable Left Ventricular Remodeling and Dysfunction
Authors: Chen Quanhai , Wright Fe , Olzinski Alan , Bernard Roberta , Dwyer David , Jucker Beat , Toomey John , Schnackenberg Christine 
Published: November 2023

Ischemic heart disease is a leading cause of heart failure and is commonly treated with revascularization. Cardiomyocyte death, and left ventricular (LV) remodeling are pathophysiological responses to myocardial ischemia. Coronary reperfusion has been shown to both salvage myocardium and contribute to cardiomyocyte death. As a result of necrosis, the infarcted myocardium can extend from the subendocardium through the subepicardium and expand in a time‐dependent process. To characterize the time‐dependent effects of cardiac ischemia, we employed a rat ischemia‐reperfusion (IR) model and evaluated the cardiac remodeling and functional consequences of 30, 45, or 60 minutes (min) ischemia. All studies were conducted in accordance with GSK policy and reviewed by the Institutional Animal Care and Use Committee. Adult male Lewis rats were grouped into sham (n=11), 30 min (n=8), 45 min (n=6) or 60 min (n=5) occlusion of the left anterior descending coronary artery followed by reperfusion for 28 days (I/R). Heart function was measured by echocardiography on day 1 and day 28 after I/R. Left ventricular fibrosis was measured by Masson's trichrome stain on day 29. The results showed that the survival at day 29 was similar in 30 min (100%), 45 min (100%), or 60 min (83%) I/R. On day 1, compared to sham, 30, 45 or 60 min of ischemia significantly increased LV mass to body weight ratio by 34%, 15% and 13%, respectively, with sustained hypertrophy on day 28 (34%, 20%, 24%). Ejection fraction was significantly decreased by 17%, 19% and 20% on day 1 with sustained dysfunction on day 28 (13%, 13%, and 17%). At the level of the infarct, fractional area change was significantly decreased by 24%, 29% and 33% on day 1 with sustained dysfunction on day 28 (31%, 29%, and 36%). Compared to sham, end systolic volume in 30, 45, or 60 min I/R was significantly elevated at day 1 by 38%, 33%, 33% and increased significantly more by day 28 (86%, 57%, 72%), respectively. Interestingly, there was no significant change in end diastolic volume on day 1 post I/R, but it was significantly increased on day 28 by 50%, 29%, and 32% compared to sham. At 4 weeks following 30, 45, or 60 min I/R, LV collagen was significantly increased similarly across I/R groups (13, 14, or 16‐fold). There was a strong, negative correlation between LV fibrosis and systolic function. There were no significant differences in the variances of cardiac structure and function measurements among the I/R groups at any time point. Unlike the permanent cardiac ischemia model where infarcts progress to the subepicardial region, all groups of transient I/R rats had nontransmural infarcts. These data indicate that the maximum systolic dysfunction developed early in transient ischemia‐reperfusion injury, but LV remodeling progressed over time. Furthermore, there was no significant difference in the rat cardiac pathophysiological response to transient ischemia for up to one hour. The reperfused myocardium following 30–60 min ischemia retained the ability to limit cardiomyocyte death and attenuate the progression of necrosis and systolic dysfunction.

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