Regional cardiac dysfunction and dyssynchrony in a murine model of afterload stress

Abstract

Small animal models of afterload stress have contributed much to our present understanding of the progression from hypertension to heart failure. High-sensitivity methods for phenotyping cardiac function in vivo, particular in the setting of compensated cardiac hypertrophy, may add new information regarding alterations in cardiac performance that can occur even during the earliest stages of exposure to pressure overload. We have developed an echocardiographic analytical method, based on speckle-tracking-based strain analyses, and used this tool to rapidly phenotype cardiac changes resulting from afterload stress in a small animal model. Adult mice were subjected to ascending aortic constriction, with and without subsequent reversal of the pressure gradient. In this model of compensated hypertrophic cardiac remodeling, conventional echocardiographic measurements did not detect changes in left ventricular (LV) function at the early time points examined. Strain analyses, however, revealed a decrement in basal longitudinal myofiber shortening that was induced by aortic constriction and improved following relief of the pressure gradient. Furthermore, we observed that pressure overload resulted in LV segmental dyssynchrony that was attenuated with return of the afterload to baseline levels. Herein, we describe the use of echocardiographic strain analyses for cardiac phenotyping in a mouse model of pressure overload. This method provides evidence of dyssynchrony and regional myocardial dysfunction that occurs early with compensatory hypertrophy, and improves following relief of aortic constriction. Importantly, these findings illustrate the utility of a rapid, non-invasive method for characterizing early cardiac dysfunction, not detectable by conventional echocardiography, following afterload stress.

Figure 1. Changes in global and regional contractile function in an experimental model of pressure overload.

The schematic of the experimental design is shown (A). Global peak longitudinal strain (endocardial) in the sham and aortic constricted animals at 1 week before randomization (B) and in the AAC and de-AAC animals at 7 weeks (C). Basal peak longitudinal strain (endocardial) in the sham and aortic constricted animals at 1 week (D) and in the AAC and de-AAC animals at 7 weeks (E). Apical peak longitudinal strain changes were similar to global peak longitudinal strain changes observed at 1 and 7 weeks (F and G).

Figure 2. Vector angle dyssynchrony differentiates varying levels of exposure to afterload stress.

Dyssynchrony measured as the mean vector angle (for 48 regional curves) for sham, AAC, and de-AAC animals at 7 weeks.

Figure 3. Regional distribution of fibrosis in a model of afterload stress.

A Masson’s trichrome stained longitudinal section of the left ventricle of a representative mouse that underwent aortic banding (without reversal) is shown. Inner sections show regional variation in the degree of interstitial fibrosis across the left ventricular myocardium. The black horizontal scale bars represent 50 micrometers.