Murine pressure overload models: a 30-MHz look brings a whole new "sound" into data interpretation.

Abstract

Transverse aortic constriction (TAC) and angiotensin II (ANG II) subcutaneous osmotic pump infusion are frequently used murine models of pressure overload hypertrophy. The aim of this paper is to investigate time- and stressor-dependent functional and structural changes using echocardiographic B-mode, M-mode, and Doppler characterization. Ten-week-old male C57BL6/J wild-type mice received 4-wk ANG II (1.5 mg·kg(-1)·day(-1), n = 19) or saline (n = 10) infusion followed by echocardiography (Vevo2100, Visual Sonics), or underwent TAC (n = 63) or a sham operation (n = 30). In the TAC protocol, echocardiography was performed after 2 wk (n = 22 TAC, n = 10 sham), after 4 wk (n = 20 TAC, n = 10 sham), and after 10 wk (n = 21 TAC, n = 10 sham). ANG II infusion was associated with a mixed pressure and volume overload, with a variable contribution of volume overload caused by aortic valve insufficiency (grade 0.5-3.5/4). The degree of aortic valve insufficiency correlated with the degree of left ventricular dilation (r(2) = 0.671, P < 0.001). After TAC, all hypertrophic remodeling patterns known in human disease were observed: 1) low-flow, low-gradient with preserved ejection fraction (EF); 2) concentric hypertrophy with normal EF and flow; 3) concentric hypertrophy with moderately decreased EF and/or flow; 4) eccentric hypertrophy with normal EF and flow; 5) eccentric hypertrophy with moderately decreased EF and/or flow; and 6) eccentric hypertrophy with severely depressed EF. Eccentric remodeling was time dependent, with 5% of mice developing this phenotype at 2 wk, 39% at 4 wk, and 59% at 10 wk. Comprehensive echocardiographic analysis allows identification of homogeneous subgroups of mice subjected to hypertrophic stress, reducing variability in experimental results and facilitating clinical translation.