Characterizing preclinical models of ischemic heart failure: differences between LAD and LCx infarctions

Abstract

Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n = 15) or the proximal left circumflex artery (LCx; n = 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 ± 3.2% vs. 10.6 ± 1.9%, P = 0.03), depressed systolic function (LV ejection fraction; 39.8 ± 7.5% vs. 54.1 ± 4.6%, P < 0.001), and more LV remodeling (end-systolic volume index; 82 ± 25 ml/m(2) vs. 51 ± 18 ml/m(2), P = 0.02, LAD vs. LCx, respectively) compared with the LCx MI approach without compromising the survival rate. At the papillary muscle level, echocardiographic strain analysis revealed no differences in radial and circumferential strain between LAD and LCx MIs. However, in contrast with the LCx MI, the LAD MI resulted in significantly decreased longitudinal strain. The proximal LAD MI model induces more LV remodeling and depressed LV function relative to the LCx MI model. Location of MI significantly impacts the severity of HF, thus careful consideration is required when choosing an MI model for preclinical HF studies.

Keywords: anterior; posterior; remodeling; sphericity; torsion.

Fig. 1.

Representative images of balloon occlusion site. Balloon is inflated at the proximal left anterior descending artery (LAD). Images at top show before the occlusion, and images at bottom show during the occlusion. Arrows indicate the position of the balloon. LCx, left circumflex artery.

Fig. 2.

Temporal changes of systolic parameters and volume indexes. LAD myocardial infarction (MI) had significantly lower ejection fraction and larger end-systolic volume index (ESVI) than both LCx MI and Sham at 1 and 3 mo after the MI. LAD MI showed decreased peak LV pressure rate of rise (dP/dt_max) after MI; however, LCx MI took similar course to the Sham without significant decrement. Ejection fraction and volume indexes were assessed by 3-dimensional echocardiography. *P < 0.05 against Sham; †P < 0.01 against Sham; ¶P < 0.05 against LCx MI; ‡P < 0.01 against LCx MI. EDVI, end-diastolic volume index.

Fig. 3.

Representative images of the infarct in LAD and LCx MI. Although the scar in LAD MI involves apex, the scar of LCx MI was shifted toward base with less apical involvement to the left anterior.

Fig. 4.

Scar size and the ventricular weight adjusted by the body weight (BW). Size of the scar was significantly larger in LAD MI than in LCx MI. In LAD MI, despite the initial infarct area of 35–40% assessed by MRI, infarct size becomes to around 15% at 3 mo because of scar thinning and hypertrophy of nonischemic remote area. Ventricular weight increased in MI pigs without statistical difference between the MI groups. NS, not significant.

Fig. 5.

Survival curves of each group. Similar survival rate up to 1 mo was seen in LAD (n = 96) and LCx MI (n = 9). Note that there are a few deaths after 48 h due to heart failure in LAD group.

Fig. 6.

Left ventricular (LV) strain, torsion, and sphericity by 2-dimensional echocardiography 3 mo after MI. The LV short axis was divided into 6 segments and categorized into 3 zones: ischemic, border, and remote areas. Radial strain (RS) and circumferential strain (CS) were analyzed at the papillary muscle level. Both MI groups presented impaired RS and CS at the remote area, as well as global RS and CS compared with Sham. Sham values are average of all the segments. LAD MI presented significantly lower longitudinal strain (LS) than LCx MI. LV torsion was significantly less in MI groups than in Sham; however, no difference was found between LAD and LCx MI. LV sphericity index was higher in MI pigs than in Sham.