We previously studied HopXTg
mice and found most of these animals develop LV hypertrophy13
with diastolic dysfunction by the age of 14–18 weeks. Therefore, we used these mice as a model of LV hypertrophy and diastolic dysfunction for these studies. We confirmed all HopXTg
mice used in is this investigation had LV hypertrophy, as denoted by a significant increase in diastolic relative wall thickness and LV mass-to-body weight ratio ().
Morphometric measurements of wild-type and HopXTg mice
Evaluation of LV relaxation in HopXTg mice using invasive hemodynamics
While HopXTg mice clearly develop LV hypertrophy, we next sought to determine the extent to which LV diastolic function was affected in these animals. Invasive hemodynamic recordings revealed HopXTg mice had reduced LV relaxation compared to wild-type control mice, where tau (g) and LVEDP were significantly higher and -dP/dtmin was much lower ( & ). These data confirm that HopXTg mice with LV hypertrophy have impairments in LV relaxation. Furthermore, measurements of the LV peak pressure and +dp/dtmax revealed that LV systolic function is preserved in HopXTg mice ().
Fig. 2 Left ventricular relaxation indices in HopXTg and wild-type mice. Invasive hemodynamic recordings reveal HopXTg mice have reduced LV relaxation compared to wild-type mice where -dP/dtmin is significantly decreased (A, B) in HopXTg mice. Similarly, Doppler (more ...)
Echocardiographic and hemodynamic indices from wild-type and HopXTg mice
Evaluation of LV relaxation in HopXTg mice by Doppler echocardiography
Transmitral Doppler echocardiography provided evidence for reduced LV relaxation in HopXTg mice as revealed by a decrease in the E-wave flow velocity and E/A ratio, and an increase in the acceleration time of the transmitral early diastolic peak flow velocity (EAT) ( & ). On the other hand, the deceleration time of the transmitral early diastolic peak flow velocity (EDT), which is a function of LV compliance and typically affected in later stages of diastole dysfunction, was not different between WT and HopXTg mice ().
Doppler interrogation of the pulmonary vein revealed the waveform was composed of a small S-wave, two forward D-waves (D1 and D2) and a small, reversed a-wave in all WT mice examined. While we could obtain pulmonary venous flows from every mouse we studied, approximately 50% of the HopXTg mice examined did not have a D2 wave. Lack of a D2 wave in half of the HopXTg mice probably accounts for the slight, yet significant, decrease in the pulmonary VTI during diastole (PV VTId) in HopXTg mice compared to control littermates (, ).
Comparison of LV relaxation by echocardiography versus invasive hemodynamics in HopXTg mice
In order to validate the Doppler echocardiographic indices for assessing diastolic function in mice, we compared several non-invasive measurements of LV filling and relaxation with invasively measured parameters of LV relaxation. In this model, we found that the EAT by Doppler echocardiography, and RWT and LA area by non-Doppler echocardiography correlated well with -dp/dtmin, tau (g) and LVEDP ( & ). In contrast, the IVRT did not correlate well with -dp/dtmin and the E/A ratio did not show good correlation well with any of the invasive parameters ().
Fig. 3 Linear regression analysis of LV relaxation indices assessed by echocardiography versus invasive hemodynamics in HopXTg and wild type mice. Both –dp/dtmin and tau (g) appear to correlate strongly with EAT (A, B), but less well with the E/A ratio (more ...)
Correlation of echocardiographic and hemodynamic indices
Intra- and inter-observer variability
We saw good agreement between measurements taken by the same observer for Doppler echocardiographic values. It appears there was no difference (0.0 ms) in repeated measurements of IVRT taken by the same observer (). Similarly, when measurements were taken by two independent observers, the mean difference between values was −0.85 ms for IVRT (). We saw similar agreement between values obtained for the acceleration time of the Doppler E-wave for the same () and two independent observers (), as well as those measured for the pulmonary vein D1-wave flow velocity ().
Fig. 4 Intra- and inter-observer variability of Doppler interval measurements. Linear regression analysis shows good agreement between measurements for parameters taken by the same observer for IVRT (A, B) and EAT (E, F). Similarly we saw good agreement exists (more ...)
Fig. 5 Intra- and inter-observer variability of pulmonary venous velocity measurements. Linear regression analysis shows good agreement between measurements by the same observer for PV D1 velocity (A, B). Similarly good agreement also exists for measurements (more ...)