Echocardiographic evaluation of diastolic function in mouse models of heart disease

Moritz Schnelle, Norman Catibog, Min Zhang, Adam A Nabeebaccus, Grace Anderson, Daniel A Richards, Greta Sawyer, Xiaohong Zhang, Karl Toischer, Gerd Hasenfuss, Mark J Monaghan, Ajay M Shah, Moritz Schnelle, Norman Catibog, Min Zhang, Adam A Nabeebaccus, Grace Anderson, Daniel A Richards, Greta Sawyer, Xiaohong Zhang, Karl Toischer, Gerd Hasenfuss, Mark J Monaghan, Ajay M Shah

Abstract

Background: Mouse models of heart disease are extensively employed. The echocardiographic characterization of contractile function is usually focused on systolic function with fewer studies assessing diastolic function. Furthermore, the applicability of diverse echocardiographic parameters of diastolic function that are commonly used in humans has not been extensively evaluated in different pathophysiological models in mice.

Methods and results: We used high resolution echocardiography to evaluate parameters of diastolic function in mouse models of chronic pressure overload (aortic constriction), volume overload (aorto-caval shunt), heart failure with preserved ejection fraction (HFpEF; DOCA-salt hypertension), and acute sarcoplasmic reticulum dysfunction induced by thapsigargin - all known to exhibit diastolic dysfunction. Left atrial area increased in all three chronic models while mitral E/A was difficult to quantify at high heart rates. Isovolumic relaxation time (IVRT) and Doppler E/E' increased significantly and the peak longitudinal strain rate during early filling (peak reverse longitudinal strain rate) decreased significantly after aortic constriction, with the changes being proportional to the magnitude of hypertrophy. In the HFpEF model, reverse longitudinal strain rate decreased significantly but changes in IVRT and E/E' were non-significant, consistent with less severe dysfunction. With volume overload, there was a significant increase in reverse longitudinal strain rate and decrease in IVRT, indicating a restrictive physiology. Acute thapsigargin treatment caused significant prolongation of IVRT and decrease in reverse longitudinal strain rate.

Conclusion: These results indicate that the combined measurement of left atrial area plus reverse longitudinal strain rate and/or IVRT provide an excellent overall assessment of diastolic function in the diseased mouse heart, allowing distinction between different types of pathophysiology.

Keywords: Diastolic function; Echocardiography; Hypertrophy; Mouse.

Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Fig. 1
Fig. 1
LV hypertrophy and echocardiographic assessment of LV function in murine models of pressure and volume overload. Left ventricular weight versus body weight ratio (LV/BW), heart rate, ejection fraction and longitudinal strain rate were compared in mice after AAB (A–D) and Shunt (E–H) or the respective control procedures (ShamA and ShamS). n = 6–7/group; ** p < 0.01; n.s., not significant.
Fig. 2
Fig. 2
LV diastolic function in mouse models of pressure and volume overload. Isovolumic relaxation time (IVRT), E/E´, reverse longitudinal strain rate (rLSR) and left atrial (LA) area were measured after AAB (A–D) or Shunt (E–H). ShamA and ShamS denote the respective control groups. n = 6–7/group; ** p < 0.01; n.s., not significant.
Fig. 3
Fig. 3
Representative Doppler flow profiles for measurement of IVRT and apical 4-chamber views for measurement of left atrial area. A. IVRT measurement (in blue) from the aortic outflow and mitral inflow profiles in the AAB and Shunt groups. B. Left atrial area measurement (red lines) in the AAB and Shunt groups compared to their respective controls (ShamA and ShamS). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Correlation of diastolic parameters and cardiac hypertrophy in models of pressure overload. The % change in IVRT relative to the control Sham group was computed and plotted against the % change in E/E′ (A) or reverse longitudinal strain rate (rLSR) (B). The AAB (black symbols) and TAC (red symbols) groups were combined. (C–F). Correlation of changes in diastolic function parameters (rLSR, IVRT, E/E´ and left atrial (LA) area) with the relative increases in heart weight/body weight ratio. n = 11–13/group. The coefficients of determination (r2) from linear regression analysis and p-values are shown on the graphs. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
Invasive LV pressure-volume analysis of systolic and diastolic function in a mouse DOCA-salt model of HFpEF. A. Heart rate; B. Ejection fraction; C. LV dP/dtmin; D. Isovolumic relaxation time constant, Tau (Mirsky); E. LV end-diastolic pressure (EDP); F. LV dP/dtmax/normalized by end-diastolic volume (EDV). n = 3–7/group; * p < 0.05.
Fig. 6
Fig. 6
Non-invasive echocardiographic assessment of diastolic function in a mouse DOCA-salt model of HFpEF. A. Heart rate; B. Ejection fraction; C. Reverse longitudinal strain rate (rLSR); D. Isovolumic relaxation time (IVRT); E. E/E´ ratio; F. Left atrial (LA) area. n = 6–8/group; * p < 0.05, ** p < 0.01.
Fig. 7
Fig. 7
Effect of acute thapsigargin treatment on diastolic function. A–F. Effect of thapsigargin (Thapsig.; 0.75 mg/kg intraperitoneally) on heart rate, ejection fraction (EF), IVRT, reverse longitudinal strain rate (rLSR), left atrial (LA) area and E/E′ respectively. n = 5–6/group; ** p < 0.01.
Fig. 8
Fig. 8
Algorithm for assessment of chronic LV diastolic dysfunction in mice. If the left atrial (LA) area is unchanged compared to control mice, chronic diastolic dysfunction is unlikely. If the LA area is increased, subsequent assessment of the isovolumic relaxation time (IVRT) and reverse longitudinal strain rate (rLSR) can be used to distinguish between “usual” and “restrictive” diastolic dysfunction.

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