Macro- and microinjury define the heart failure progression after permanent coronary ligation or ischemia-reperfusion in young healthy mice

Abstract

Heart failure (HF) is a major outcome in cardiovascular disease resulting from myocardial infarction (MI). Preclinical studies use MI-induced HF rodent models with either permanent coronary occlusion (PO) or transient ligation to induce ischemia-reperfusion (I/R). Comparisons of inflammation-resolution signaling in these models are understudied. Two-month-old C57BL/6J mice underwent either permanent ligation of the left anterior descending (LAD) coronary artery (PO, n = 26), temporary ligation for 60 min (I/R, n = 30), or served as naïve controls (n = 6). Multidimensional assessments were performed to evaluate structural, functional, cellular, and molecular differences, including echocardiography and targeted quantitation of inflammatory and resolution lipid mediators. Echocardiography with speckle-tracking was acquired and analyzed at baseline, during acute [days; days 1-7 (d1-d7)], and chronic HF [day 56 (d56)]. Speckle-tracking was used to quantitate the infarct area postmyocardial infarction. The PO group showed larger infarcts and impaired systolic function, whereas the I/R group had smaller infarcts with transient left ventricle (LV) dysfunction and recovery by d7 post MI. The PO group showed greater sustained injury with LV wall thinning, intraventricular dilation, and increased fibrotic remodeling by d56. Inflammatory marker analysis revealed limited activation of proinflammatory mediators and specialized proresolving mediators in the I/R at d1 post MI, indicating a less robust inflammatory-resolution response compared with the PO. These findings suggest PO results in irreversible cardiac dysfunction with macroinjury, whereas I/R causes microinjury with functional recovery. Thus, the extent of original injury broadly defines the cardiac remodeling and HF progression, emphasizing the importance of infarct area quantitation, model selection, and injury magnitude in investigating inflammation-resolution signaling in HF pathogenesis.NEW & NOTEWORTHY A major new finding of this study is that permanent LAD ligation (PO) induces more severe and irreversible cardiac dysfunction than ischemia-reperfusion, as evidenced by vector-based speckle-tracking echocardiography, fibrosis, and lipid-mediated inflammatory remodeling. These findings provide mechanistic insight into model-specific differences, a novel method of infarct area quantitation, and inform the selection of preclinical heart failure models for inflammation-resolution signaling.

Keywords: cardiac injury; functional recovery; heart failure; infarct area; inflammation-resolution signaling.