Critical infarct size to induce ventricular remodeling, cardiac dysfunction and heart failure in rats

Abstract

Ventricular remodeling, decreased left ventricular systolic function, and heart failure have been associated with poor long-term outcomes after myocardial infarction [1,2]. Thus, it is critical to know the pathophysiological alterations involved in these processes for myocardial infarction management. A rat coronary artery ligation leads to a wide range of infarct size, cardiac remodeling and left ventricular dysfunction. In addition, it is accepted that the coronary occlusion consequences are closely related to infarction size, which is a powerful determinant of survival [3], ventricular remodeling [4], and cardiac systolic function [5]. In order to determine the association between infarct size and outcomes after coronary occlusion, the animals were divided into three groups (small, moderate or large infarct size), but this division was not homogeneous among the studies because the animals were randomly placed in the groups. Consequently, the infarct size that is necessary to determine morphological, functional, and clinical alterations after the coronary occlusion, still needs to be determined. The present study was carried out to determine the critical infarct size to induce ventricular remodeling, cardiac dysfunction, and heart failure in a rat model. Myocardial infarction was induced following the method described previously [6]. Six months after surgery, Sham (n=67) and infarcted animals (n=166) were subjected to transthoracic echocardiography, and euthanized the next day. The echocardiographic exams and morphometric analysis were performed as described previously [6,7]. The left ventricular remodeling was defined as the infarcted values of the left ventricular end-diastolic cavity areas with a difference of N2 and standard deviations above Sham group mean. The systolic dysfunction was defined as the infarcted values of posterior wall shortening velocity (PWSV) with a difference of b2 and standard deviations under Sham group mean. The diastolic dysfunction was defined as the infarcted values of E/A ratio with a difference of N2 and standard deviations above Sham group mean. The variables utilized to determine heart failure included pleuropericardial effusion, left atrial thrombi, ascites, or right ventricular hypertrophy (right ventricle weight-to-body weight ratio N0.8 mg/g) [8]. An infarct size cut-off valuewas derived from the receiver-operating characteristic (ROC) curve according to the infarct size value to maximize sensitivity, specificity, and predictivity values in order to anticipate remodeling, cardiac dysfunctions, and heart failure. The bias between histology and echocardiogram in the infarct size assessment was evaluated by Bland & Altman. After a six-month follow-up, the infarct size in the infarcted animals ranged from 18.5% to 57%, with an average of 40±9% assessed by histology, and 42±9% assessed by echocardiogram, and bias between the methods at −1.15%. The infarct size cut-off values were 36% (area under ROC curves (AUC): 0.70; 95% CI: 0.61-0.78; p=0.017) for ventricular remodeling; 38% (AUC: 0.72; 95% CI: 0.64-0.80; p=0.001) for PWSV; 44% (AUC: 0.72; 95% CI: 0.64–0.79; pb0.001) for E/A ratio and 40% (AUC: 0.65; 95% CI: 0.56-0.73; p=0.004) for heart failure. Among the infarcted rats, 93% presented ventricular remodeling; 86% showed systolic dysfunction; 47% presented diastolic dysfunction; and 66% had heart failure. The knowledge of the critical infarct size necessary to induce remodeling, cardiac dysfunction, and heart failure in this model can be extremely useful, since infarct size can be early estimated after the coronary occlusion by non invasive methods, such as echocardiogram. In the present study, the infarct size was determined by histology, even though this measurement had low bias when compared to infarct size measured by echocardiography. In conclusion, the identification of the critical infarct size to induce ventricular remodeling, cardiac dysfunction, and heart failure might be particularly useful in longitudinal studies about therapeutic and pathophysiological aspects following coronary occlusion. Our data indicate that the minimum infarct size to cause these morphological, functional and clinical abnormalities is 36%, 38%, and 40%, respectively. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology (Shewan and Coats 2010;144:1–2).