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CLINICAL STUDIES

Color M-mode Doppler flow propagation velocity is a preload insensitive index of left ventricular relaxation: animal and human validation

^a Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
^b Department of Cardiothoracic Surgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA

Manuscript received March 25, 1999; revised manuscript received July 22, 1999, accepted September 21, 1999.

Reprint requests and correspondence: Dr. Mario J. Garcia, Desk F-15, Division of Cardiology, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195.
garciam{at}ccf.org

	Abstract

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

 
OBJECTIVES

To determine the effect of preload in color M-mode Doppler flow propagation velocity (v_p).

BACKGROUND

The interpretation of Doppler filling patterns is limited by confounding effects of left ventricular (LV) relaxation and preload. Color M-mode v_p has been proposed as a new index of LV relaxation.

METHODS

We studied four dogs before and during inferior caval (IVC) occlusion at five different inotropic stages and 14 patients before and during partial cardiopulmonary bypass. Left ventricular (LV) end-diastolic volumes (LV-EDV), the time constant of isovolumic relaxation (tau), left atrial (LA) pre-A and LV end-diastolic pressures (LV-EDP) were measured. Peak velocity during early filling (E) and v_p were extracted by digital analysis of color M-mode Doppler images.

RESULTS

In both animals and humans, LV-EDV and LV-EDP decreased significantly from baseline to IVC occlusion (both p < 0.001). Peak early filling (E) velocity decreased in animals from 56 ± 21 to 42 ± 17 cm/s (p < 0.001) without change in v_p (from 35 ± 15 to 35 ± 16, p = 0.99). Results were similar in humans (from 69 ± 15 to 53 ± 22 cm/s, p < 0.001, and 37 ± 12 to 34 ± 16, p = 0.30). In both species, there was a strong correlation between LV relaxation (tau) and v_p (r = 0.78, p < 0.001, r = 0.86, p < 0.001).

CONCLUSIONS

Our results indicate that color M-mode Doppler v_p is not affected by preload alterations and confirms that LV relaxation is its main physiologic determinant in both animals during varying lusitropic conditions and in humans with heart disease.

Abbreviations and Acronyms   A = peak atrial contraction velocity   E = peak early transmitral flow velocity   IVC = inferior vena cava   LA = left atrium   LV = left ventricle or ventricular   LV-EDP = left ventricular end-diastolic pressure   LV-EDV = left ventricular end-diastolic volume   LV-EF = left ventricular ejection fraction   LV-ESP = left ventricular end-systolic pressure   LV-ESV = left ventricular end-systolic volume   tau = time constant of isovolumic relaxation   TD = time delay   TEE = transesophageal echocardiography   vp = color M-mode flow propagation velocity

The propagation velocity of early flow into the LV cavity (v_p) measured by color M-mode Doppler was first proposed by Brun et al. (8) as an index of left ventricular relaxation. Animal and human studies have since confirmed that v_p is closely related to tau (9,10). In addition, earlier animal studies indicated that v_p was relatively insensitive to small alterations in left atrium (LA) pressure and heart rate (9).

The objectives of the following study were: 1) to evaluate the influence of preload on E and v_p measured by color M-mode, and 2) to determine the relationship between these Doppler indexes and physiologic parameters of systolic and diastolic function in healthy animals during varying lusitropic conditions and in humans with cardiac disease.

	Methods

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

 
Animal study.   Four healthy mongrel dogs weighting 27.5 ± 0.4 kg (range 26.5 to 29 kg) were anesthetized with sodium pentobarbital (30 mg/kg IV for induction, 1.0 mg/kg/h for maintenance) and ventilated with room air by a Mark 7 Respirator (Bird Products, Palm Springs, California). The protocol was approved by the Institutional Animal Care and Research Committee and conformed to the position of the American Heart Association on research animal use. The right femoral and carotid arteries and the right internal jugular vein were isolated and cannulated with valve sheaths (USCI, Billerica, Massachusetts; Hemaquet 8F). A 6 Fr 11-pole combination multielectrode conductance catheter with dual high-fidelity pressure sensors (Millar Instruments, Houston, Texas) was advanced after adequate calibration from the right carotid artery to the LV apex using echocardiographic guidance. The electrical impedance measured by five pairs of conductance electrodes was analyzed by a conductance data processor (Leycom Sigma 5DF, Leyden, Netherlands) as previously described (11). The pressure transducers were positioned in the LV cavity and the proximal ascending aorta. A 23-mm Mansfield balloon catheter (Boston Scientific, Maple Grove, Minnesota) was introduced through the femoral vein and advanced to the upper limit of the inferior vena cava (IVC) under fluoroscopic guidance. The balloon catheter was inflated intermittently throughout the experiment to occlude caval flow. Arterial blood pressure and central venous pressure were monitored via fluid-filled catheters together with a single ECG lead coupled to an oscilloscopic multichannel recorder (EM models M1101C and M2101B, Honeywell, Pleasantville, New York). Two-dimensional and Doppler echocardiographic studies were performed with an Acuson Sequoia (Mountain View, California) ultrasound machine using a multifrequency transducer (Model 3V2c). From the apical four-chamber view, pulsed Doppler recordings of the LV inflow were acquired. From the same echocardiographic window, the color Doppler map of the mitral inflow was displayed, and M-mode recordings were acquired after aligning the cursor in the direction of the inflow jet. Pulsed and color M-mode Doppler were recorded at a horizontal sweep speed of 100 mm/s and stored digitally. A timing signal marker was coupled to the echocardiographic system and to the data acquisition board in order to match pressure, volume and Doppler signals for each corresponding heart beat. Left ventricular volume and pressure, ECG and timing marker signals were digitally acquired with 1 ms resolution using a multifunction I/O (input/output) board (AT-MIO-16, National Instruments, Austin, Texas) interfaced with a computer workstation (Pentium 200 MHz PC, Gateway, Sioux Falls, North Dakota) using customized software developed using LabVIEW v. 5.0 (National Instruments, Austin, Texas). From the LV pressure waveform, the time constant of isovolumic relaxation (tau) was determined using Weiss’ (12) monoexponential equation ; whereas P is LV pressure at time t, P₀ is LV pressure at peak negative dP/dt and t is time after negative dP/dt) and after curve fitting by use of the Levenberg-Marquardt nonlinear least-squares parameter estimation technique (13). A basic assumption of a zero-asymptote was adopted as suggested by Yellin et al. (14).

A total of five different inotropic-lusitropic conditions were available in each animal including 1) baseline, 2) dobutamine at 5 µg/kg/min, 3) dobutamine at 10 µg/kg/min, 4) esmolol at 50 µg/kg/min, and 5) esmolol at 100 µg/kg/min. A period of stabilization was allowed between each stage (range 3 to 20 min). All animals received 1,000 ml of Ringer’s lactate before the initiation of the experiment. Volume and pressure data were collected continuously before and during caval occlusion. Color M-mode Doppler images were acquired immediately before and 5–10 seconds after each occlusion. From color M-mode Doppler images, the magnitude and location of velocities were determined at each color pixel. The position and magnitude of maximal velocity in the early filling waveform was automatically located (Fig. 1). Pixels containing velocity magnitudes corresponding to 25%, 50% and 75% of the maximal velocity were connected creating several isovelocity contour lines. Flow propagation velocity (v_p) was measured as the slope of the first 50% isovelocity contour line. In order to analyze v_p and early filling (E) simultaneously from the same heart beats, E and atrial contraction (A) velocity components were extracted at mitral leaflet tips from the color M-mode Doppler data. In order to validate the accuracy of peak component E and A velocities derived by digital analysis from color M-mode Doppler images, these were compared against pulsed Doppler velocities obtained sequentially during each stage in the human experiments. The correlation between both methods was excellent (r = 0.97, y = 0.91x + 2.5 cm/s, p < 0.001, SEE = 5.7 cm/s, delta = 2.9 ± 6.0 cm/s). In those cases when separation of E and A waves was not possible (n = 7, 35%) we measured v_p as the slope of the single wavefront and E as the peak velocity of the single filling wave. Intra- and interobserver variability of v_p measurements were 8% and 12%, respectively (r = 0.95, p < 0.001).

View larger version (70K): [in this window] [in a new window]   Figure 1 Automated method of determining flow propagation velocity (vp). A color M-mode Doppler image obtained by transesophageal echocardiography is shown at the left. The value of each color pixel is decoded. The maximum velocity value obtained during early filling (E) is detected. Isovelocity lines connecting pixels that encode values of 25% (yellow line), 50% (red line), 75% (green line) and 100% (blue line) of the maximum value are displayed in the right panel. The slope of the 50% isovelocity line is then determined. See text for details.

Data analysis.   Statistical analysis was performed using commercially available software (Sigmastat version 6.0). In the animal study, peak E and A velocities, E/A ratio, color M-mode Doppler v_p, LV end-diastolic (LV-EDV), end-systolic (LV-ESV) volumes, ejection fraction (LV-EF), end-systolic (LV-ESP) and end-diastolic (LV-EDP) pressures and tau were compared between baseline, peak dobutamine stimulation and maximum esmolol dose using one-way ANOVA for repeated measurements with Dunnett’s test for post-hoc analysis. The same indexes were also compared before and during IVC occlusion in dogs and before and during partial bypass in humans using Student t test for paired data. The association between v_p and other variables was tested using simple and multiple linear regression in both dogs and humans. Statistical significance was defined as p < 0.05. Data are expressed as mean ± standard deviation.

To test the hypothesis that v_p is independent of preload, v_p was compared pre- and post-preload reduction. The effect of preload reduction on E and v_p was compared by paired t-testing. A p < 0.05 was taken as evidence that v_p is less preload dependent than E.

To test the hypothesis that v_p is an index of LV relaxation (tau), linear and nonlinear regression using test functions such as polynomial, power and exponential were used to determine the optimal function relating these variables. To test whether these relations were similar for both the canine and human data, one-way analysis of covariance was used, where tau was the independent variable, v_p was the covariate, and canine versus human was the discrete variable.

	Results

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

 
Animal study.   Baseline LV-ESP and LV-EF increased at peak dobutamine dose volume and decreased with maximum dose of esmolol. Left ventricular end-diastolic pressure decreased with dobutamine and increased with esmolol. Changes in lusitropy were also induced with tau decreasing with dobutamine and increasing with esmolol. Other parameters are shown in Table 1. Figure 2 is a representative example of color M-mode recording of the LV inflow obtained at baseline and during dobutamine and esmolol infusion. Color M-mode v_p increased from baseline to dobutamine and decreased with esmolol.

View larger version (44K): [in this window] [in a new window]   Figure 2 Color M-mode Doppler of left ventricular filling obtained during esmolol, at baseline and during dobutamine infusion showing the changes in E and vp. Peak E is given by the maximum color encoded velocity value during early filling (inside enclosed circle), while vp is given by the slope of the isovelocity lines (white line). E = peak early transmitral flow velocity; vp = flow propagation velocity. See text for details.

View larger version (43K): [in this window] [in a new window]   Figure 3 Color M-mode Doppler of left ventricular filling obtained before (first image) and during caval occlusion (second and third images). Peak early filling component velocity decreases together with left ventricular end-diastolic pressure (LV-EDP), as demonstrated by the changes in pixel colors from yellow to red. In contrast the slope of the early filling wavefront which determines flow propagation velocity (vp) is unchanged. See text for details. LV-EDP = left ventricular end-diastolic pressure; vp = flow propagation velocity.

View larger version (21K): [in this window] [in a new window]   Figure 4 Animal study: effect of preload reduction in E and color M-mode vp IVC occlusion. E = peak early transmitral flow velocity; IVC = inferior vena cava; vp = flow propagation velocity.

	Human study

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

 
Left ventricular end-diastolic volume decreased from 92.5 ± 37.4 ml before cardiopulmonary bypass to 78.1 ± 43.9 ml during partial cardiopulmonary bypass (p < 0.001) while mean LA pressure decreased from 15.1 ± 6.2 to 10.3 ± 6.1 mm Hg (p < 0.001). There was no significant change in LV relaxation (tau = 58 ± 16 before vs. 63 ± 25 ms during partial bypass, p = 0.28). Peak Doppler E velocity decreased from 69 ± 15 to 53 ± 22 cm/s (p < 0.001) with no significant change observed in peak A velocity. As in the animal experiments, v_p did not decrease during preload reduction (from 37 ± 12 to 34 ± 16 cm/s, p = 0.30), confirming also the preload independence of this index in humans (Fig. 5). Overall, E showed a 17.4 ± 16.4 cm/s decrease with preload reduction compared with v_p (2.8 ± 9.7 cm/s, p < 0.0001, Table 3).

View larger version (20K): [in this window] [in a new window]   Figure 5 Human study: effect of preload reduction in E and color M-mode vp during partial circulatory bypass. E = peak early transmitral flow velocity; vp = flow propagation velocity.

View larger version (18K): [in this window] [in a new window]   Figure 6 Correlation between flow propagation velocity (vp) and the tau in the combined animal (solid circles) and human (open circles) group (trendline fitted to a power function). tau = time constant of isovolumetric relaxation; vp = flow propagation velocity. R = –0.78; y = 592.21x–0.6838; p < 0.001.

	Discussion

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

Several studies have related specific Doppler LV filling patterns to diastolic function abnormalities in patients with heart disease (1–4). Older patients and those with hypertensive heart disease and early restrictive cardiomyopathy in whom LV relaxation is impaired, typically present with decreased transmitral E velocity and E/A (early-to-atrial filling) ratio as well as increased pulmonary venous systolic flow. The opposite changes occur when LV relaxation is enhanced during cathecolamine stimulation, as shown in our animal experiment (Table 1). At the same time, increasing LV filling pressure results in a linear increase in peak E velocity (5,6,15). Therefore, in patients with advanced diastolic dysfunction, the compensatory or overcompensatory elevation in LA pressure that occurs in order to maintain an adequate cardiac output opposes the effects produced by impaired relaxation causing pseudonormalization of the transmitral filling pattern. This dual dependency limits the utility of conventional Doppler indexes frequently leading to an incorrect diagnosis.

Color M-mode Doppler differs from spectral pulsed Doppler in that it allows the acquisition of spatial information in addition to velocity and time. Earlier studies using color M-mode Doppler have found that in patients with dilated cardiomyopathy the wavefront of early ventricular filling reaches the apex much later than in patients with normal LV function (16). Previous investigators have measured the delay in apical filling as the slope of the color wavefront (v_p) or the time delay (TD) for the wavefront to pass from the mitral annulus to the LV apex (8,9). Previous experimental and clinical studies have demonstrated that color M-mode Doppler indexes of LV filling are related to LV relaxation and systolic function (8–10). In normal subjects, v_p has been reported between 55 and 100 cm/s (8,17).

The relation between LV relaxation and v_p may be explained by the presence of regional pressure gradients within the LV cavity. Courtois et al. (18) initially reported the presence of intraventricular gradients in the normal LV, showing consistent apex-to-base gradients in pressure during early filling. Intraventricular pressure gradients are responsible for the mechanism of suction in ventricles with normal relaxation, allowing adequate LV filling and cardiac output even at near-zero LA pressure. Falsetti et al. (19) later demonstrated in a canine model that these gradients increase with isoproterenol and decrease with propanolol. Through Euler’s hydrodynamic equation:

(whereas p = pressure, s = space, t = time and v = velocity), pressure gradients may be related to color M-mode Doppler spatiotemporal velocity distribution providing a physical foundation for the relationship between LV relaxation and v_p (20).

Several studies have previously shown that tau is not affected by modest changes in loading conditions when heart rate is maintained constant (21,22) and when the decrease in preload is not profound enough to cause alterations in afterload. Although in our animal experiment there was a small decrease in tau suggesting improvement in relaxation, the difference was of no clinical significance. In previously reported animal experiments, volume loading and caval constriction caused only minor, nonstatistical changes in v_p, suggesting that this index was relatively independent of preload (9). In these previous studies, however, the magnitude of volume change obtained during caval occlusion resulted only in a modest decrease in LA pressure and was not sufficient to cause a statistically significant change in LV-EDP. Volume loading, on the other hand, resulted in a 50% prolongation of TD (not statistically significant). These results may be attributed to the confounding effect of other hemodynamic changes occurring during the longer interval required for volume infusion, as suggested by the observed 40% increase in heart rate. In our animal model, we performed IVC occlusions after volume loading in order to obtain larger alterations in preload. By using a closed-chest model, we avoided hemodynamic perturbations that may be caused by blood loss and lack of pericardial constraint. In addition, we collected our data earlier during IVC occlusion to minimize the effect of compensatory increases in sympathetic tone, as demonstrated by the lack of significant increase in heart rate.

We, as well as other investigators, previously suggested that v_p was a preload independent index in humans (17,23), based on indirect evidence (lack of correlation between v_p and LV-EDP in groups of patients with heart disease). However, confounding variables could have accounted for the lack of correlation observed in these previous studies. In this study, preload alterations were caused while carefully avoiding other hemodynamic alterations in our controlled experimental setting.

In this study, a semiautomatic method was implemented in order to objectively measure v_p, consisting of identifying multiple isovelocity lines within the wavefront of LV filling. We chose arbitrarily the line that connected points where velocity was 50% of the maximum, since this was easily identifiable in all cases. If digital velocity output is available from the ultrasound machine, this semiautomatic method is easily implemented and helps to reduce operator bias compared with the previously reported manual methods.

Differences between animal and human results.   Although the effects of preload were similar, the relation between v_p and other parameters was different in both species. These differences may be attributed to different experimental settings (open vs. closed pericardium, IVC occlusion vs. partial circulatory bypass, inotropic modulation in the dogs but not the patients) but are most likely related to underlying pathophysiological differences among both groups (healthy dogs vs. humans with cardiac disease). The association between end-diastolic volume and v_p observed in humans may reflect a high prevalence of LV hypertrophy and coronary artery disease without impaired systolic function since these tend to have impaired relaxation and small LV cavity. This relation would be different, however, if more patients with dilated LV and low ejection fraction were included in this study.

Our study showed a remarkably low correlation between pulsed mitral Doppler E and tau. This finding likely reflects the effect of pseudonormalization caused by increased LA pressure in some patients. On the other hand, the lack of association between LV-EDP and E in dogs could be attributed to the effect of a concomitant change in LV relaxation that was induced by pharmacological maneuvers. This would also explain the negative correlation observed between LV-EDP and v_p. The association between E, v_p and heart rate in the animal study most likely reflect differences in inotropic conditions induced by dobutamine and esmolol and not a direct effect of heart rate changes. This is supported by Stugaard’s (9) study in which changes in heart rate during atrial pacing failed to show similar association.

	Study limitations

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

 
In this study we determined component E and A velocities from color M-mode Doppler digital analysis. Such approach was necessary in order to compare the effect of preload on both E and v_p in the same heart beat and under the same physiologic conditions. In addition, this method allowed obtaining component velocities at the sample depth at the level of the mitral leaflet tips. We validated the accuracy of color M-mode Doppler against pulsed Doppler component velocities in the human study where similar hemodynamic conditions were maintained during independent acquisition of color M-mode and pulsed Doppler recordings.

In animals, separation of E and A waves was not possible in 7 of the 20 (35%) available animal conditions. In such cases, we measured v_p as the slope of the single wavefront and E as the peak velocity of the single filling wave. The results of preload alterations were similar, however, when we analyzed the cases with distinct E and A waves separately.

Finally, the accuracy of TEE determined LV volumes may be limited. Although we paid careful attention in order to avoid LV foreshortening during these studies, LV volumes may have been underestimated. This underestimation should have affected volumes obtained at high and low preload in a similar manner, and, therefore, the magnitude of change should still be accurate.

	Conclusions

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

 
Color M-mode Doppler v_p may be easily obtained with modern ultrasound systems during a routine echocardiographic examination. This index can be useful in the routine clinical evaluation of diastolic function as it provides a preload independent estimate of LV relaxation. For example, v_p may be used to differentiate patients with normal from those with "pseudonormal" filling (17) and to estimate the effect of LV filling pressure when combined with pulsed Doppler indexes (23). Therefore, color M-mode v_p should be incorporated into the routine echocardiographic assessment of diastolic function.

	Footnotes

 
This study was supported by Grant-in-aid #NEO-97-225-BGIA from the American Heart Association, North-East Ohio Affiliate (M.G.), National Aeronautics Space Administration Grant #NCC9-60, Houston, Texas (J.D.T., M.G., N.L.G.) and National Institutes of Health Grant #RO1 HL56688-01A1, Bethesda, Maryland (J.D.T.).

	References

Top Abstract Methods Results Human study Discussion Study limitations Conclusions References

 

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				P. Reant, S. Lafitte, P. Jais, K. Serri, R. Weerasooriya, M. Hocini, X. Pillois, J. Clementy, M. Haissaguerre, and R. Roudaut Reverse Remodeling of the Left Cardiac Chambers After Catheter Ablation After 1 Year in a Series of Patients With Isolated Atrial Fibrillation Circulation, November 8, 2005; 112(19): 2896 - 2903. [Abstract] [Full Text] [PDF]

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				M. Slama, J. Ahn, M. Peltier, J. Maizel, D. Chemla, J. Varagic, D. Susic, C. Tribouilloy, and E. D. Frohlich Validation of echocardiographic and Doppler indexes of left ventricular relaxation in adult hypertensive and normotensive rats Am J Physiol Heart Circ Physiol, September 1, 2005; 289(3): H1131 - H1136. [Abstract] [Full Text] [PDF]

				C. Schmidt, F. Hinder, H. Van Aken, G. Theilmeier, C. Bruch, S. P. Wirtz, H. Burkle, T. Guhs, M. Rothenburger, and E. Berendes The Effect of High Thoracic Epidural Anesthesia on Systolic and Diastolic Left Ventricular Function in Patients with Coronary Artery Disease Anesth. Analg., June 1, 2005; 100(6): 1561 - 1569. [Abstract] [Full Text] [PDF]

				L. H Naylor, L. F Arnolda, J. A Deague, D. Playford, A. Maurogiovanni, G. O'Driscoll, and D. J Green Reduced ventricular flow propagation velocity in elite athletes is augmented with the resumption of exercise training J. Physiol., March 15, 2005; 563(3): 957 - 963. [Abstract] [Full Text] [PDF]