INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

NORMAL DIASTOLIC FUNCTION of the left ventricle can be defined as the ability of the ventricle to adequately fill under low filling pressures. Diastolic dysfunction is present in a number of cardiac diseases and often precedes left ventricular systolic dysfunction, leading to symptoms of heart failure in patients with preserved systolic function. Whereas regional pressure differences between the left ventricle, the left ventricular outflow tract, and the aorta during ejection have been recognized for some time (10), the importance of regional pressure differences within the ventricle during diastole has only recently gained attention. Although the presence of such intraventricular pressure differences between the left ventricular base and apex during early diastole was first reported in canine models by Ling et al. (9) in 1979 and Falsetti et al. (4) in 1980, the possible clinical implications of these observations have not been fully appreciated. Falsetti et al. (4) also observed a gradual increase in the magnitude of the intraventricular pressure differences with graded infusions of isoproterenol and a decrease of these intraventricular pressure differences with propanolol. Courtois et al. (2) found in an animal model that these intraventricular diastolic pressure differences disappeared during ischemia induced by coronary occlusion. More recently, Smiseth et al. (13) demonstrated a relationship between early filling and the pressure difference between the left ventricular apex and outflow tract. Work from this group has also demonstrated that the delay of apical filling in acute ischemic failure was attributed to a decrease in the intraventricular driving pressure (15). Whereas these findings suggest the critical importance of the diastolic intraventricular pressure gradients in assuring adequate left ventricular filling, this information can only be obtained currently during invasive left heart catheterization with careful pressure measurements in the left atrium (LA) and multiple points in the left ventricle, a very impractical procedure for diagnosis and follow-up of patients in the clinical setting.

In recent years, color Doppler M-mode echocardiography has been proposed as a new and promising approach to evaluate left ventricular diastolic function noninvasively. Color Doppler M-mode provides velocity information, not only at a single point as seen with traditional pulsed Doppler methods, but along the entire inflow tract from the LA across the mitral valve into the left ventricle and this throughout the entire diastolic filling period. Several studies (1, 3, 5, 14, 16, 18) observed differences in the left ventricular inflow patterns as detected by color Doppler M-mode echocardiography in different disease states and physiological conditions. Multiple parameters have been proposed to describe these differences in filling patterns, but all of these proposed methods have the following similar disadvantages: 1) only a very limited amount of the velocity information available is used, 2) some measurements are difficult and rather subjective, and 3) the methods are only indirectly related to diastolic function. We (7) recently developed a novel concept to calculate transmitral pressure differences across a normal mitral valve incorporating the inertial forces into the unsteady flow form of the Bernoulli equation by using the full digital velocity map. In this study, we extend this concept and apply basic hydrodynamic principles to the noninvasively obtained spatiotemporal velocity distribution of left ventricular inflow to calculate intraventricular pressure gradients. This approach provides unique information on left ventricular filling dynamics in an entirely noninvasive way that has never been available before.

Glossary

v	Three-component vector of local blood velocity
P	Local pressure
B	Body forces (such as gravity) acting on the fluid
	Blood density, 1.05 g/cm3
µ	Blood viscosity, 0.02 cm2/s
s	Distance along the central streamline from the left atrium to left ventricle
v/t	Partial derivative of velocity with respect to time
v/s	Partial derivative of velocity with respect to space (left atrium to left ventricle)
P/s	Partial derivative of pressure with respect to space
IV	Doppler-derived instantaneous intraventricular pressure difference
MV	Instantaneous transmitral pressure difference derived from Doppler measurements
T	Instantaneous total pressure difference derived from Doppler measurements
vN	Nyquist velocity
PRF	Pulse-repetition frequency
PLA(t)	Instantaneous left atrial pressure (catheter)
Pbase(t)	Instantaneous basal left ventricular pressure (catheter)
Papex(t)	Instantaneous apical left ventricular pressure (catheter)
PT	Instantaneous total pressure difference based on catheter measurements
PMV	Instantaneous transmitral pressure difference based on catheter measurements
PIV	Instantaneous intraventricular pressure difference based on catheter measurements

	METHODS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Theoretical Background

Fluid dynamics of diastolic intraventricular flow. Three-dimensional (3-D) flow across a normal mitral valve, from the LA to the left ventricular apex (LV_apex), is governed by the Navier-Stokes equations for incompressible fluid as shown in Eq. 1, where v is a three-component vector of local blood velocity, P is the local pressure, B represents body forces (such as gravity) acting on the fluid, and  and µ are blood density and viscosity, respectively. Note that Eq. 1 is the differential form of the continuity equation

(1)

This complex set of coupled differential equations can be simplified by the following assumptions: 1) the viscous term, µ²v, is very small and can be neglected (19, 22); and 2) the gravitational force is balanced by hydrostatic buoyancy, and thus B = 0. If we consider flow along a streamline, this becomes the one-dimensional Euler equation as shown in Eq. 2, where the vector notation has been dropped as the focus has shifted to the velocity in one direction

(2)

Integrating the Euler equation along an inflow streamline, from the LV base (LV_base) to apex, yields the nonsteady Bernoulli equation, a noninvasive estimate of the intraventricular pressure difference as shown in Eq. 3

(3)

The instantaneous pressure difference is the sum of convective and inertial components.

Animal Model

High-fidelity pressure measurements. In the first experiment, we used a combination of single- and dual-sensor micromanometer catheters (Millar Instruments; Houston, TX) to obtain pressure measurements from the LA, LV_base, and LV_apex. A catheter with dual pressure sensors separated by 5 cm was used to record the intraventricular pressures. The catheters were positioned so that the spacing between the LA and LV_base sensors was ~2 cm. This was achieved by advancing the dual catheter 1 cm past an initial position, where the pressure signal from the proximal sensor switched from LA to LV, and then pulling back 1 cm on the single- sensor catheter from a similar initial position. In the subsequent experiments, we used a multisensor catheter with 5-cm spacing between LV pressure measurements and 2-cm spacing between the sensors for the LA and LV_base pressures. Before introduction, the catheters were immersed in a saline solution for over 1 h to minimize "drift" and calibrated relative to atmospheric pressure, 20 and 100 mmHg, respectively. To account for hydrostatic pressure differences, LA and LV pressures were aligned during a long diastolic time interval on a postextrasystolic beat. The pressure signals were amplified by using a universal amplifier (Gould; Valley View, OH) with a flat frequency response up to 500 Hz. LA and LV pressures were digitized at 1,000 Hz by using a multifunction data-acquisition card (model AT-MIO-16, National Instruments; Austin, TX) and transferred for storage on a 486/50 personal computer (Gateway; N. Sioux City, SD) with the use of a custom-designed acquisition program developed in the LabView (National Instruments) environment.

Doppler ultrasound measurements. Velocity estimation is made in color Doppler echocardiography by comparing the phase shifts in a series of ultrasound pulses by using autocorrelation techniques along the scanline (8). Visualization of the spatial distribution is provided as an overlay of color- encoded velocity data over structural information. In contrast to the low temporal resolution of two-dimensional (2-D) color imaging (10-20 Hz), color M-mode directs successive pulses in a constant direction, allowing the velocity along a single scanline to be recorded at 200 Hz. Color Doppler imaging obtained using this M-mode format provides the spatial velocity distribution along the Doppler scanline (y-axis) and its temporal changes during the cardiac cycle (x-axis).

Data Analysis

1

1

Calculation of the Invasive Pressure Differences

[P(T)]max

[P(IV)]max

{[P(T)]max}

{[P(T)]max}

Calculation of the Noninvasive Pressure Differences

Preprocessing of color Doppler M-mode images. Assuming that the Doppler M-mode cursor closely approximates an inflow streamline, the color-coded Doppler velocity map provides the spatiotemporal velocity distribution (v[s,t]) along an inflow streamline from the LV_base to LV_apex. The velocity distribution was extracted from the raw image file by using a customized analysis program developed in LabView (National Instruments). The program allows the user to identify regions within the image where the flow velocities have aliased beyond v_N. With these regions identified, an unaliasing algorithm is used to convert the color scale into true velocities given the Nyquist limit stored with the image. Final calibration of the velocity distribution is based on the spatial and temporal resolution coded in the header of the raw image file.

(4)

(5)

View larger version (49K): [in this window] [in a new window]   Fig. 1.   Left: two-dimensional echocardiographic (ECG) sector image showing the position of the scanline from the left ventricular apex (LVapex), across the mitral valve (MV), and into the left atrium (LA). Middle: color Doppler M-mode spatiotemporal velocity distribution of diastolic inflow in two cardiac cycles, each with early (E) and atrial (A) filling waves. Right: simultaneous intraventricular pressure measurements for these cardiac cycles after alignment with the velocity distribution.

View larger version (50K): [in this window] [in a new window]   Fig. 2.   Graphical solution to the one-dimensional Euler equation. The pressure gradient (P/s) is computed from the color Doppler M-mode velocity distribution (v) and its partial derivatives in time (v/t) and space (v/s). Spatiotemporal velocity distribution of E filling (v) shows diastolic inflow propagating from the LA to the LVapex. Spatial range, or image height, is 5 cm and the temporal range, or image width, is 300 ms. Acceleration (+v/t or v/s) is color coded in yellow, whereas deceleration (v/t or v/s) is coded in blue. Brightness of the color display indicates the magnitude of acceleration or deceleration. Acceleration of the E wave, as indicated by the yellow region in the v/t image, is followed by a period of deceleration shown in blue. v/s also provides a similar pattern, with acceleration of blood from the LA through the MV and deceleration within the ventricle.

Statistical Analysis

In addition to comparing the maximum pressure differences, the instantaneous pressure difference waveforms were also compared to assess the accuracy of the methodology throughout diastole. The mean error () and mean absolute error () were computed during early filling (_E, _E) and throughout diastole (_E+A, _E+A) for both the intraventricular and total pressure differences.

The intraventricular pressure differences were also compared with standard indices of diastolic function. [P_IV]_max was compared with Doppler early and atrial filling velocities (E, A, and E/A), peak negative first derivative of pressure development over time (dP/dt) and the relaxation time constant () by linear regression analysis. Statistical significance was defined at P < 0.05. Data are expressed as means ± SD.

Numerical Simulation

	RESULTS

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

Under baseline conditions, the [P_IV]_max by direct catheter measurement was 1.80 ± 0.47 mmHg. This represented 71.1 ± 12.6% of the [P_T]_max, which was 2.58 ± 0.66 mmHg. The percentage of the intraventricular pressure difference at the time of peak total pressure difference ([P_IV]_{[P(T)]max}) was slightly less (68.1 ± 12.1%).

The average noninvasive estimate of the [_IV]_max for the baseline data was 1.77 ± 0.53 mmHg, representing 68.0 ± 7.2% of the [_T]_max. Again the percentage of the intraventricular pressure difference at the time of peak total pressure difference was slightly less (66.1 ± 7.8%). Linear regression analysis comparing catheter (x) and Doppler-derived (y) measurements demonstrated significant agreement for both intraventricular [y = 0.97x + 0.031, r = 0.84, standard error of the estimate (SEE) = 0.34 mmHg, P < 0.001] and total (y = 1.06x  0.12, r = 0.95, SEE = 0.31 mmHg, P < 0.001) maximum pressure differences. Figure 3A demonstrates this agreement at baseline between invasive and noninvasive measurements of the intraventricular pressure difference. A paired t-test demonstrated that the difference, or , between invasive and noninvasive estimates of both the intraventricular (_IV = [_IV]_max  [P_IV]_max = 0.03 ± 0.29 mmHg) and total (_T = [_T]_max  [P_T]_max= 0.04 ± 0.23 mmHg) pressure differences were not significantly different from zero. The standard deviations of these differences provide an indication of the unsigned scatter in the error. The time to peak filling pressure differences was also measured and used to compute the temporal errors (t) between the invasive and noninvasive measures for both the maximum total
and intraventricular pressure differences
After we administered isoproterenol to four of the six animals, the invasive measurement of the maximum total and intraventricular pressure difference increased significantly ([P_T]_max, 2.82 ± 0.42 to 5.32 ± 1.52 mmHg; [P_IV]_max, 1.89 ± 0.3 to 4.43 ± 1.29 mmHg; P < 0.01). The relative contribution of the intraventricular pressure difference to the total difference also increased significantly from 68.0 ± 12.1% at baseline to 83.3 ± 5.3% during isoproterenol infusion. These changes were also tracked well by the noninvasive Doppler-derived estimates. The errors between the Doppler-derived estimates and catheter measurements were not significantly different (_T, 0.04 ± 0.23 at baseline vs. 0.12 ± 0.49 mmHg with isoproterenol; _IV, 0.03 ± 0.29 at baseline vs. 0.35 ± 0.49 mmHg with isoproterenol). Data from both conditions (baseline and isoproterenol) were compared with the simultaneously measured pressure differences by catheter using linear regression analysis. Figure 3B demonstrates the relationship for the combined intraventricular pressure differences at both conditions. Linear regression results for each animal (animals 1, 2, 3, and 6) are provided along with the overall relationship of [_IV]_max versus [P_IV]_max; y = 0.87x + 0.22, SEE = 0.35 mmHg, r = 0.96, P < 0.001. 

View larger version (18K): [in this window] [in a new window]   Fig. 3.   Relationship between the magnitude of catheter and Doppler-derived peak intraventricular pressure differences for data obtained from all animals at baseline (A) and data from four animals at baseline and after administration of isoproterenol (B). Results from linear regression analysis in B are shown for each animal as well as the aggregate. See text for definitions of abbreviations.

In addition to comparing the peak pressure differences, the instantaneous estimates of intraventricular (_IV[t]) and total (_T[t]) pressure differences throughout diastole were also evaluated and compared with the catheter-based waveforms. The  and  during early filling and throughout diastole were computed for both the intraventricular and total pressure differences. The _IV[t] closely tracked the catheter-based profile during early filling (r_E(IV) = 0.88 ± 0.16, _E(IV) = 0.40 ± 0.18 mmHg, _E(IV) = 0.22 ± 0.30 mmHg) and throughout diastole (r_E+A(IV) = 0.72 ± 0.14, _E+A(IV) = 0.67 ± 0.36 mmHg, _E+A(IV) = 0.16 ± 0.53 mmHg). Close agreement between _T[t] and P_T[t] was also observed during early filling (r_E(T) = 0.95 ± 0.04, _E(T) = 0.44 ± 0.21 mmHg, _E(T) = 0.10 ± 0.40 mmHg) and throughout diastole (r_E+A(T) = 0.89 ± 0.08, _E+A(T) = 0.59 ± 0.32 mmHg, _E+A(T) = 0.03 ± 0.41 mmHg). Figure 4 shows an example of the correlation between instantaneous estimated pressure differences (A, _IV[t]; B, _T[t]) and the direct catheter measurements.

View larger version (18K): [in this window] [in a new window]   Fig. 4.   Example of the estimated instantaneous intraventricular (A) and total pressure difference waveforms (B) (dashed curves) with the simultaneously recorded catheter-based pressure differences (solid curves).

The maximum intraventricular pressure difference ([P_IV]_max, x, mmHg) was related to standard Doppler indices of diastolic filling (E, y [cm/s] = 8.394x + 29.0, r = 0.84; E/A, y [dimensionless] = 0.36x + 1.003, r = 0.68) as well as the maximal rate of pressure decrease over time (dP/dt_max) (y [mmHg/s] = 238.4x + 577.7, r = 0.51) and  (y [ms] = 11.2x + 90.2, r = 0.54).

Numerical Simulation

View larger version (17K): [in this window] [in a new window]   Fig. 5.   Numerical simulation results comparing the modeled intraventricular pressure difference distribution and the pressure distribution computed by using velocity data extracted along a simulated scanline. Mean squared error and correlation coefficient are displayed as a function of the displacement of the scanline from the centerline axis (A) and the angulation of the scanline through the mitral orifice (B).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION REFERENCES

The diagnosis of LV diastolic dysfunction remains a challenge in clinical practice. The most complete information on LV relaxation and compliance can be obtained from intraventricular pressure measurements combined with simultaneous volume measurements to reconstruct pressure-volume loops. Because this requires an invasive procedure with high-fidelity pressure measurements in the LV and tedious tracing of ventricular contours on angiograms to obtain LV volume estimates, this is rarely performed in clinical practice. The most commonly used technique to assess LV diastolic function clinically is the pulsed-Doppler measurement of the LV inflow velocities at the level of the mitral valve. Although characteristic inflow patterns have been described, this method is limited because the transmitral velocity profile is also affected by several parameters other than LV diastolic function, such as heart rate, atrioventricular conduction interval, and left atrial pressure.

The use of color Doppler M-mode echocardiography to assess LV inflow was introduced by Brun et al. (1) in 1992 and has been shown to provide information on LV diastolic function in addition to traditional measurements of the transmitral pulsed-Doppler velocity profile. Stugaard et al. (16) noticed a significant change in the color Doppler M-mode inflow pattern with delayed apical filling during ischemia caused by balloon occlusion of the left anterior descending coronary artery. We hypothesized that color Doppler M-mode profiles, representing flow velocities within the ventricle between base and apex, could provide information on intraventricular pressure gradients.

The presence of these intraventricular gradients during early diastole was first reported by Ling et al. (9) in an animal model. Falsetti et al. (4) showed an increase in intraventricular gradients during -stimulation and a decrease in the magnitude of the intraventricular gradients during -blockade, suggesting the close linkage between the LV rate of relaxation and intraventricular pressure gradients. Courtois et al. (2) subsequently showed the disappearance of these intraventricular gradients in an ischemic model during left anterior descending occlusion. Smiseth et al. (13) showed in both animals and humans that the pressure gradient between the ventricular apex and outflow tract strongly correlated with peak early transmitral flow and stroke volume. These observations suggest the critical importance of intraventricular pressure gradients to ensure efficient LV diastolic filling and its close linkage with more traditional parameters of LV diastolic function.

In this study, we propose a novel concept to apply basic hydrodynamic principles to the color Doppler M-mode spatiotemporal velocity distribution to reconstruct noninvasively the intraventricular pressure gradients present between LV base and apex during diastole. Color Doppler echocardiography is usually used in a qualitative way to assess normal and abnormal blood flows in the cardiac chambers. Although quantitative algorithms have been developed using color Doppler images to calculate cardiac output (17, 20) or to quantify severity of regurgitant valves (12, 21), these are relatively simplistic. This study uses the local spatial and temporal velocity distribution measured by color Doppler M-mode echocardiography to calculate local pressure gradients using the Euler equation, integration of which allows us to calculate a pressure difference between two points along the inflow tract. In this study we focused on the intraventricular component of the filling gradient, integrating the pressure gradient between the base and apex of the left ventricle and comparing the results of this estimate with direct catheter measurement. This Doppler-derived pressure difference closely matched the invasive measurement. The magnitude and timing of these noninvasively reconstructed pressure gradients between the LA and different levels in the ventricle closely matched the invasive measurements and also correspond well with data previously published in the literature. We also showed that this approach not only provides accurate information under baseline conditions but is also able to detect relatively small changes in transmitral and intraventricular gradients induced by pharmacologically altering LV relaxation. During isoproterenol infusion, we observed an increase in the reconstructed intraventricular gradients, similar to observations of Falsetti et al. (4) and consistent with the finding by Brun et al. (1) of increased flow propagation into the left ventricle in patients during intracoronary dobutamine infusion.

This new application of color Doppler M-mode echocardiography allows us to reconstruct small intraventricular pressure gradients completely noninvasively, thus avoiding the risk and expense of a cardiac catheterization. This method also enables us to detect changes in these small intraventricular gradients induced by changing LV relaxation and is therefore a promising tool that may help us understand and evaluate the complex phenomena underlying LV filling. This new method is particularly attractive because it can provide much more information than could ever be obtained during an invasive procedure. Because color Doppler M-mode velocities are measured as a continuum between the LA and the LV_apex at 0.5-mm spatial resolution, the derived pressure gradient distribution along a scanline (P/s) can be integrated over space to produce a pressure map. This pressure information can be displayed in a surface plot where pressure (relative to LA pressure) is graphed (z-axis) from the LA to the LV apex (y-axis) throughout the early diastolic filling wave (x-axis) (Fig. 6). This type of information on LV filling pressures has never been available before to researchers or clinicians and opens up entirely new perspectives to evaluate LV diastolic filling and function.

View larger version (72K): [in this window] [in a new window]   Fig. 6.   Relationship between the derived intraventricular pressure distribution (surface with red and blue representing positive and negative pressure differences, respectively) and the direct catheter pressure differences between the LA and the LV base (white) and apex (green).

The time required for the color Doppler M-mode image analysis and extraction of pressure waveforms is ~1 min using the customized software we developed. The processing time is much quicker (a few seconds) after the semiautomatic preprocessing of the color Doppler M-mode data. The preprocessing step requires the user to identify regions within the color Doppler M-mode image where aliasing has occurred. By using this information, the software performs an unaliasing procedure and provides v[s,t] for the calculation of P/s by using the Euler equation. With known locations for the spatial sample locations (depths corresponding to LA, LV_base, and LV_apex pressure transducer locations), transmitral and intraventricular pressure difference waveforms are instantly calculated. Because there is a potential of clinical application of this method, we have extended this methodology to allow pressure differences to be calculated from digital echocardiographic images collected by a variety of equipment, including Acuson and ATL. For these sources, however, a color lookup table is generated from the color bar to provide quantitative velocity data because current implementations of the DICOM (digital imaging and communications in medicine) standard do not provide information to calculate the velocity associated with this mapping.

The accuracy of pressure difference estimates results in part from the accuracy of color Doppler M-mode velocity data used in the noninvasive calculation of pressure differences. Shandas et al. (11) compared ultrasound color Doppler imaging to the reference standard laser Doppler velocimetry technique, establishing the accuracy of using models of steady and pulsatile flow acceleration. By using data from this paper, we estimate the standard error between laser and color Doppler to be 6.8 cm/s, nearly equal to the resolution of color Doppler with a Nyquist velocity of 81 cm/s. In addition to this velocity resolution, the temporal and spatial resolutions of color Doppler M-mode images are important as they determine the degree of accuracy for the partial derivative terms of the Euler equation. The accuracy of the pressure estimate is also related to the degree to which the ultrasound scanline approximates an inflow streamline through the center of the mitral valve. We have shown through the computational model described in this paper that accurate results are achieved when the scanline is placed within the central 60% of the valve orifice ( < 0.26 mmHg, r = 0.93) or when an angular misalignment is made up to 20° ( < 0.18 mmHg, r = 0.95).

Pressure difference estimates can be made reproducibly using this technique. The average absolute difference in the noninvasive peak intraventricular pressure differences calculated by two users was only 0.05 mmHg. This small degree of variability between users is due to the limited steps required to compute the noninvasive pressure differences from color Doppler M-mode images, namely selecting aliased regions and defining spatial locations (or transducer positions) over which the pressure gradient is integrated.

Limitations

The numerical model used to evaluate the impact of scanline misalignment is also a simplification of the 3-D/4-D actual valvular geometry by using 2-D cross-sectional geometry obtained by echocardiography. Limitations of the modeling tools available also required that ventricular cavity was not dynamically changing during diastole. Whereas the resulting spatiotemporal velocity distributions were somewhat representative of actual color Doppler M-mode images, actual fluid-structure interactions may provide a step in realizing a more accurate model.

Other noninvasive imaging modalities may offer the possibility to acquire 3-D velocity data and calculate pressure differences on the basis of a less simplified version of the Navier-Stokes equations. Whereas real-time 3-D echocardiographic assessment of flow velocities is possible, the necessary tradeoffs result in a greatly decreased temporal resolution (10 frames/s). Magnetic resonance imaging techniques such as phase encoding and particle tracking have been utilized to determine ventricular flow characteristics including streamline assessment, but these procedures are generally not available and also have tradeoffs in terms of temporal resolution. More advanced models of ventricular filling utilizing interactions between structural mechanics and fluid dynamics may provide a less simplified analysis of potential errors in our methodology.

Hemodynamic data were available only at three points within the LV inflow tract, and thus we were able to assess the ability of color M-mode to measure pressure differences within the ventricle rather than true spatial pressure gradient. Future work with the multisensor Millar catheter may refine this validation, but this remains fundamentally an issue of an inadequate gold standard against which to compare our noninvasive findings. These results were obtained in canine model with open chest and open pericardium and thus full validation in humans in a clinical setting awaits further work.

In conclusion, it is very encouraging that though sophisticated, through very straightforward application of basic hydrodynamic principles to color Doppler M-mode data, we are able to measure accurately and noninvasively intraventricular pressure differences throughout diastole. The potential for applying this approach in physiological research and clinical practice appears very significant, because noninvasive diastolic filling gradients have previously been available with only the most meticulous invasive technique.