Echocardiographic speckle-tracking based strain imaging for rapid cardiovascular phenotyping in mice

Abstract

Rationale: High-sensitivity in vivo phenotyping of cardiac function is essential for evaluating genes of interest and novel therapies in small animal models of cardiovascular disease. Transthoracic echocardiography is the principal method currently used for assessing cardiac structure and function; however, standard echocardiographic techniques are relatively insensitive to early or subtle changes in cardiac performance, particularly in mice.

Objective: To develop and validate an echocardiographic strain imaging methodology for sensitive and rapid cardiac phenotyping in small animal models.

Methods and results: Herein, we describe a modified echocardiographic technique that uses speckle-tracking based strain analysis for the noninvasive evaluation of cardiac performance in adult mice. This method is found to be rapid, reproducible, and highly sensitive in assessing both regional and global left ventricular (LV) function. Compared with conventional echocardiographic measures of LV structure and function, peak longitudinal strain and strain rate were able to detect changes in adult mouse hearts at an earlier time point following myocardial infarction and predicted the later development of adverse LV remodeling. Moreover, speckle-tracking based strain analysis was able to clearly identify subtle improvement in LV function that occurred early in response to standard post-myocardial infarction cardiac therapy.

Conclusions: Our results highlight the utility of speckle-tracking based strain imaging for detecting discrete functional alterations in mouse models of cardiovascular disease in an efficient and comprehensive manner. Echocardiography speckle-tracking based strain analysis represents a method for relatively high-throughput and sensitive cardiac phenotyping, particularly in evaluating emerging cardiac agents and therapies in mice.

Figure 1. Speckle-tracking based strain analysis

Normal ventricular function involves myocardial deformation along the longitudinal, radial, and circumferential axes (Panel A). Speckle-tracking based strain analysis uses acoustic back scatter on echocardiographic images as tissue markers, which are tracked frame-to-frame throughout the cardiac cycle (Panel B). Timed tracking of myocardial deformation allows for the direct measurement of myocardial strain in the longitudinal, circumferential, and radial axes. For each axis, separate strain curves (representing strain measures over time) are generated for each of the six standard myocardial regions, with a 7^th line (black) denoting the average (global) strain at each time point (Panel C). Regional and global strain curves are altered in a typical fashion following MI and with ACEi treatment.

Figure 2. Echocardiographic assessment of post-MI LV function and remodeling

Among animals that underwent MI, changes in echocardiographic measures are shown at baseline (BL) and at 1 week post-MI (1). LV end-diastolic dimension (Panel A) was increased post-MI, whereas fractional shortening (Panel B), global peak longitudinal strain (Panel C), and global peak longitudinal strain rate (Panel D) all decreased with cardiac injury. Percent change in strain measures was greater than for conventional measures (Panel E). A schematic of myocardial regions identified from the parasternal long axis view is shown in Panel F: BA, basal anterior; MA, mid anterior; AA, apical anterior; AI, apical inferior; MI, mid inferior; BI, basal inferior. Peak longitudinal strain across these regions was normally distributed at baseline but globally reduced at 1 week post-MI (Panel G). *=p<0.05; **=p<0.01.

Figure 3. Longitudinal changes in LV function and remodeling post-MI with cardiac therapy

Echocardiographic measures are shown at baseline and at 1 week and at 3 weeks post-MI, for animals treated with vehicle (open bars) or ACE inhibition (filled bars). Conventional echocardiographic measures, including LVEDD (Panel A) and FS (Panel B) were unchanged in the early post-MI period with ACEi treatment, whereas both longitudinal strain (Panel C) and strain rate (Panel D) were significantly higher in ACEi treated versus untreated animals at 3 weeks. At 3 weeks, longitudinal strain rate was improved not only globally, but also across all segmental myocardial regions in ACEi treated compared to untreated animals (Panel E). Abbreviations for myocardial regions used in Panel E are previously defined in Figure 2, Panel F. *=p<0.05.