Shingo KUROKAWA, MD, Haruhiko OKURI, MD, Taishi SASAOKA, MD, Yohji MACHIDA, MD, Kazuyuki OSADA, MD, and Ryuichi KIKAWADA, MD

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1 Doppler Echocardiographic Method to Determine Early and Late Diastolic Filling Volume Separately Validation and Relationship between Filling Velocity and Volume Shingo KUROKAWA, MD, Haruhiko OKURI, MD, Taishi SASAOKA, MD, Yohji MACHIDA, MD, Kazuyuki OSADA, MD, and Ryuichi KIKAWADA, MD SUMMARY We devised a pulsed Doppler echocardiographic method of separately calculating early diastolic filling volume (EDFV) and late diastolic filling volume during atrial contraction (LDFV) and observed a relationship between diastolic filling volume and velocity in thirty patients with coronary artery disease. By analysing the transmitral flow velocity curve and mitral valve motion, EDFV and LDFV were measured on the basis of the equality of left ventricular inflow and outflow volumes. The Doppler-determined EDFV and LDFV correlated well with those obtained from the left ventricular filling curve produced by left ventriculography. Angiographic EDFV and LDFV were measured from the time (t)-volume (V) curve, using the t-dv/dt curve to define early and late diastolic phases. A good correlation was found between Doppler and angiographic EDFV (y= x, r=0.98, p=0.0001, n=20), Doppler and angiographic LDFV (y= x, r=0.86, p=0.0001), and also between Doppler and angiographic EDFV/LDFV (y= x, r=0.93, p=0.0001). EDFV and the peak early diastolic filling velocity were significantly correlated (E velocity; y= x, r=0.48, p=0.0068), while LDFV and the peak late diastolic filling velocity during atrial contraction (A velocity) were not. Our results validate the method of calculating EDFV and LDFV separately and suggest that early diastole in the left ventricle has flow volume dependency, but that the late diastole filling velocity during atrial contraction may be regulated by other factors such as increased left atrial contraction. (Jpn Heart J 1998; 39: ) Key words: Doppler echocardiography, Early diastolic filling volume, Late diastolic filling volume, E velocity, A velocity A BNORMALITIES of both diastolic filling and systolic dysfunction of the left ventricle play an important role in heart failure.1) Doppler echocardio- From the Department of Internal Medicine, Kitasato University School of Medicine, Sagamihara, Japan. Address for correspondence: Shingo Kurokawa, MD, Department of Internal Medicine, Kitasato University School of Medicine, Kitasato, Sagamihara , Japan. Received for publication March 23, Revised and accepted April 30,

2 490 KUROKAWA, ET AL Jpn Heart J July 1998 graphic indices obtained from the transmitral flow velocity have been used to evaluate left ventricular diastolic filling.2-4) In a wide variety of cardiac disease states, transmitral flow velocity patterns distinctly different from those of normal subjects have been observed. These abnormal patterns were characterized by a prolonged left ventricular isovolumic relaxation time, a decreased peak early diastolic filling velocity (E velocity), but a normal or increased late diastolic filling velocity during atrial contraction (A velocity) resulting in a reduced ratio of the E velocity to the A velocity.5-9) This reduced ratio can represent the reduced magnitude of early diastolic filling in the left ventricle. However, volume changes in the left ventricle during diastole are not totally equivalent to changes in transmitral velocity. It is necessary to calculate left ventricular filling volume and velocity during different portions of diastole at the same time. When transmitral velocity patterns and their relationship to the characteristics of ventricular diastole and to loading conditions were investigated recently,10-16) the E velocity was higher when there was increased chamber stiffness and elevated preload, a finding that may be attributed to higher left ventricular filling pressure. We believe that a higher left ventricular filling pressure may result in a greater left ventricular filling volume. We therefore devised a method for determining separately early diastolic filling volume (EDFV) and late diastolic filling volume during atrial contraction (LDFV) and examined the relationship between diastolic filling volume and filling velocity in the left ventricle. METHODS Patients: The present study was performed in 30 patients with coronary artery disease (aged 55 }6 years [mean }standard deviation], range 44 to 69 years). Twenty of the patients underwent catheterization in our laboratory to evaluate the severity of their coronary artery disease and cardiac function. Echocardiography was performed one day before catheterization. Clinical and echocardiographic examinations confirmed that none of the patients had valvular disease or an intracardiac shunt. Doppler and M-mode examinations: Doppler and M-mode echocardiograms were recorded with a Hewlett Packard phased-array system (Hewlett Packard Co., Andover, MA, USA) equipped with a 2.5 or 3.5MHz transducer (Hewlett Packard model AC). The patients were examined in the lateral decubitus position during normal respiration. In the apical long-axis plane, the sample volume was positioned near the tips of the mitral valve leaflet and transmitral flow velocity was recorded over several cardiac cycles at a paper speed of 100 mm/sec. The sample volume was then placed in the middle of the left ventricular outflow tract just proximal to the aortic valve ring, and the left ventricular ejec-

3 Vol 39 No 4 DOPPLER MEASUREMENT OF LV FILLING VOLUMES 491 t ion flow velocity was recorded. Finally, in the parasternal long-axis plane, M- mode echocardiograms of the left ventricular outflow tract and of mitral valve motion were recorded at a paper speed of 50 or 100mm/sec. Measurements and calculations: All measurements were made by a computer system with a digitizer designed for graphic analysis (PC-9801, Graphtec- 510mk2, NEC Co., Tokyo, Japan). Three consecutive cardiac cycles of the Doppler flow pattern and the M-mode echocardiogram were averaged. The diameter of the left ventricular outflow tract was measured by M-mode echocardiography at the point of the peak of the R wave on the ECG being recorded simultaneously. The cross-sectional area of the left ventricular outflow tract (CSAE) was calculated as Ĕ ~ć2, where r is half the diameter of the left ventricular outflow tract. The time velocity integrals of the left ventricular ejection flow (TVIE) and transmitral flow (TVID) were calculated by digitizing the area under the respective velocity curve (Figure 1). The time velocity integrals of early diastolic filling (TVIED) and late diastolic filling during atrial contraction (TVILD) were also calculated (Figure 1). The left ventricular ejection volume was calculated as the product of CSAE and TVIE. Since a good agreement has been found between the left ventricular ejection volume and left ventricular inflow volume,17) we have the following equation: Figure 1. Doppler patterns of left ventricular ejection velocity and transmitral flow velocity. The time velocity integral of the left ventricular ejection flow (TVIE) and of transmitral flow (TVID) were calculated by digitizing the area under the velocity curve. The time velocity integrals in early and in late diastolic filling (TVIED and TVILD) were also calculated.

4 492 KUROKAWA, ET AL Jpn Heart J July 1998 stroke volume=csae ~TVIE =[mean mitral orifice area] ~TVID The mean mitral orifice area during diastole (CSAD) was then calculated by the equation CSAD=stroke =CSAE ~TVIE/TVID volume/tvid On the M-mode echocardiogram recorded simultaneously with a phonocardiogram, the time intervals of early and late diastolic filling (TED and TLD) were defined as the times from the onset of early diastolic opening of the Figure 2. The pattern of mitral valve motion in diastole recorded by M-mode echocardiography. The area enclosed between the anterior and posterior mitral leaflets (AD) was calculated by a computer with a digitizer. The diastolic period was defined as the time from the start of early mitral valve opening to the beginning of the first heart sound (TD). The early diastolic filling period (TED) was defined as the time from the start of early mitral valve opening to the f point and the late diastolic filling period (TLD) as the start of late mitral valve opening to the beginning of the first heart sound. The areas enclosed between the anterior and posterior mitral valve leaflets during the latter two (AED and ALD) were also calculated. The mean amplitudes of mitral valve separation (h) during the three periods hd, hed, and hld were calculated as AD/TD, AED/TAD and ALD/TLD, respectively. Thus, the ratio of the mitral cross-sectional areas in these periods (diastole, CSAD; early diastole, CSAED; late diastole, CSALD) was taken as hd: hed: hld.

5 Vol 39 DOPPLER MEASUREMENT OF LV FILLING VOLUMES 493 No 4 mitral valve (d point) to the f point and from the onset of late diastolic opening of the mitral valve to the beginning of the first heart sound, respectively (Figure 2). In cases in which the slope from e to f was not straight, the end of early diastolic filling was defined as a point where the slope changes abruptly (f' point). In the M-mode pattern of mitral valve motion, CSAD corresponds to the area enclosed between anterior and posterior mitral valve traces during diastole (AD; Figure 2). The averaged cross-sectional areas during early diastolic filling and during atrial contraction (CSAED and CSALD) corresponded to that enclosed between the anterior and posterior mitral valve traces during early diastolic filling and during atrial contraction, respectively (AED and ALD; Figure 2). Therefore, the ratio CSAD: CSAED: CSALD is considered to be the ratio of the mean amplitude of mitral valve separation on M-mode echocardiograms during the three periods of diastole, early diastole, and late diastole during atrial contraction (hd: hed: hld; Figure 2). Finally early diastolic filling volume and late diastolic filling volume during atrial contraction (EDFV and LDFV) were calculated as follows: Figure 3. A typical graph of left ventricular volume change over time and the first derivative of the changes in volume obtained from left ventriculography. A rapid filling phase occurs in early diastole, during which the volume increases rapidly; this phase is followed by a slower rate of filling through mid-diastole and finally by a rapid increase in volume at the end of diastole due to atrial contraction. The time intervals of early diastolic filling and of late diastolic filling due to atrial contraction were decided by reference to the first derivative of the volume curve, and the differences in volume during these intervals were calculated as early and late diastolic filling volumes (EDFV and LDFV).

6 494 KUROKAWA, ET AL Jpn Heart J July 1998 Cardiac catheterization: Cardiac catheterization was performed within 24 hours of the echocardiographic examination. After routine measurements of left ventricular and pulmonary wedge pressures, single-plane left ventriculograms were obtained in the 30-degree right anterior oblique projection at a frame rate of 60/sec using a Siemens image intensification system. First, several cardiac cycles were excluded to avoid the effects of contrast medium injection and a representative cardiac cycle in which the left ventricle was well opacified was selected for analysis. A computer system (nac-cardias computer system, Seiko, Tokyo) was used to manually trace the left ventricular contour for every other diastolic frame, and the angiographic volume was calculated for each traced contour using the Kennedy formula.18) The volume data were stored and the first derivatives of the volume (dv/dt) over diastole were calculated by the computer system. Finally, left ventricular time-volume and time-dv/dt curves were obtained. A typical graph of volume change over time and the first derivatives of the change in volume are shown in Figure 3. By referring to the dv/dt curve, the early and late diastolic filling intervals were determined and the angiographic EDFV and LDFV were measured. Statistical analysis: Results are given as mean }standard deviation. Student's paired t test was used to compare echocardiographic and angiographic data. Linear regression analysis was performed by the least-squares method. A p value less than 0.05 was considered significant. RESULTS Comparison between Doppler and angiographic methods: There was no significant difference between the echocardiographic EDFV (55.3 }19.2ml) and Figure 4. Early diastolic filling volume (EDFV) obtained by Doppler and angiographic methods. There was good agreement between the Doppler and angiographic EDFVs (y=-3.0 {1.0x, r=0.98, p=0.0001).

7 Vol 39 No 4 DOPPLER MEASUREMENT OF LV FILLING VOLUMES 495 Figure 5. Late diastolic filling volume (LDFV) obtained by Doppler and angiographic methods. There was good agreement between the Doppler and angiographic LDFVs (y=1.6 {1.0x, r=0.86, p=0.0001). Figure 6. The ratio of early and late diastolic filling volume (EDFV/LDFV) obtained by Doppler and angiographic methods. A good correlation was found between the Doppler and angiographic EDFV/LDFV ratios (y=0.05 {0.9x, p=0.0001). angiographic EDFV (52.5 }15.0ml). Also, no difference was found between echocardiographic LDFV (28.4 }7.8ml) and angiographic LDFV (26.6 }6.0 ml). The ratio of EDFV to LDFV (EDFV/LDFV) obtained echocardiographically was 2.0 }0.60, and the value of EDFV/LDFV obtained angiographically was 2.0 }0.59, Thus there was no significant difference for this parameter between these two methods. The echocardiographic EDFV was in good agreement with the angiographic EDFV (y=-3.0 {1.0x, r=0.98, p ~0.0001; Figure 4), and there was similarly good agreement between the two measurement methods for LDFV (y= 1.6 {1.0x, r=0.86, p=0.0001; Figure 5). The EDFV/LDFV ratios were also well correlated (y=0.05 {0.9x, r=0.93, p=0.0001; Figure 6). Relationship between filling volume and filling velocity: A significant corre-

8 496 KUROKAWA, ET AL Jpn Heart J July 1998 Figure 7. Relationship between early diastolic filling volume (EDFV) obtained by the Doppler method, and peak E velocity. A significant correlation was found between Doppler EDFV and peak E velocity (y=25.1 {0.51x, r=0.48, p=0.0068). Figure 8. Relationship between late diastolic filling volume (LDFV) during atrial contraction obtained by the Doppler method and peak A velocity. There was no statistically significant correlation between the two parameters. lation was observed between EDFV obtained by the Doppler method and E velocity (y=25 {0.51x, r=0.48, p=0.0068; Figure 7), but there was no such relationship between LDFV obtained by the Doppler method and A velocity (Figure 8). Therefore, early diastolic filling is a volume-dependent event which is likely influenced by left ventricular filling pressure. Late diastolic filling appears to be independent of left ventricular filling pressure. A wide scatter was seen in EDFV even at approximately the same E velocity value. DISCUSSION In this study we devised a new method for the volumetric evaluation of left

9 Vol 39 No 4 DOPPLER MEASUREMENT OF LV FILLING VOLUMES 497 ventricular diastolic filling and observed the relationship between the Doppler peak filling velocity and filling volume. Significant correlation between EDFV and the E velocity may indicate that Doppler filling volume influences the magnitude of E velocity but its relatively weak correlation coefficient may be interpreted as a result of the complexity of diastolic filling. Validation of Doppler method for calculation of EDFV and LDFV: With the advent of Doppler echocardiography, it has been possible to assess physiologic parameters noninvasively. We can calculate cardiac output easily by means of Doppler echocardiography.19-24) But there has been no study to calculate early diastolic filling volume (EDFV) and late diastolic filling volume during atrial contraction (LDFV) separately using Doppler echocardiography. The aim of this study was to validate the method for calculating EDFV and LDFV in comparison with the left ventricular filling curve obtained from left ventriculography. The major difficulty in calculating EDFV and LDFV is how to determine the area of the mitral orifice through which the blood flows into the left ventricle. There is substantial variation in mitral valve opening throughout diastole so that calculation of the mitral orifice area is very complex.25,26) Ferguson et al.27) developed a method of characterizing the time course of left ventricular filling using a single diastolic estimation of mitral annulus area. They found morphological similarities between Doppler-determined left ventricular filling curves and angiographically-measured left ventricular filling curves. However, changes in filling area during diastole are not negligible when absolute volumetric flow is calculated during different portions of diastole. There is thought to be equality between left ventricular inflow volume and ejection volume.17) Once the stroke volume is calculated from left ventricular ejection flow velocity, the mean mitral orifice area in diastole (CSAD) can be obtained by dividing the stroke volume by the time velocity integral of transmitral flow velocity. Since the amplitude of mitral valve separation on an M- mode echocardiogram should represent the change in mitral orifice area throughout diastole, the mean mitral orifice area during early and late diastole (CSAED and CSALD) can be calculated as CSAD ~hed/hd and CSAD ~hld/hd. Finally, EDFV is calculated as the product of CSAED and the time velocity integral of transmitral flow velocity during early diastole (TVIED), and LDFV is calculated in a similar manner. The problem in determining cross sectional area from a diameter is that small errors in diameter measurement causes greater errors when multiplied. Our method makes it possible to determine the filling area in the left ventricle without measuring the diameter of the mitral orifice or annulus. A good correlation in the EDFV and LDFV obtained from Doppler and angiographic techniques was found, so the results of this study validate our method of determining EDFV and LDFV separately.

10 498 KUROKAWA, ET AL Jpn Heart J July 1998 Relationship between left ventricular filling volume and velocity: There existed a significant but weak correlation between EDFV and the E velocity. No correlation was found between LDFV and the A velocity. These findings suggest that the early diastolic filling is partially influenced by the quantity of left ventricular filling volume which may be dependent on preload condition, but the late diastolic filling during atrial contraction may be regulated by other factors such as increased left atrial contraction. Doppler transmitral flow velocity patterns provide important information on left ventricular diastolic function. The relationship between transmitral flow velocity patterns and the type of disease process have been investigated.5-9) These abnormal patterns are useful for evaluating diastolic function. Recent advances in the technology of echocardiography has provided a transesophageal echocardiography and its application to the hemodynamics in left ventricular diastole has been widely conducted.28) However, conventional echocardiographic techniques are still useful and more easily applied to patients with heart disease. The studies in which the transmitral flow velocity curve was compared with the first derivative of the volume changes by cardiac catheterization,2) and by radionuclide angiography3,4) demonstrated a fair correlation. Therefore, it has been proposed that the transmitral flow velocity reflects the rate of change in the volume flowing into the left ventricle. However, diastolic filling of the left ventricle is a complex sequence of interrelated events and the Doppler filling pattern is influenced not only by intrinsic myocardial properties, such as left ventricular relaxation11,11-16) and stiffness,13) but also by loading conditions,10-12) heart rate, and the contractile state of the heart. The transmitral flow velocity pattern is considered to be related to the left atrial and left ventricular pressure gradients. The pressure gradient between the left atrium and the left ventricle, which is generated by left ventricular relaxation and diastolic suction,10,29,30) produces a driving force across the mitral valve and rapidly accelerates blood flow into the left ventricle.11) Consequently, the E velocity may represent in part left ventricular relaxation when left atrial pressure is not elevated. However, in patients with elevated left atrial pressure, which causes a higher pressure gradient between the left atrium and the left ventricle, a relaxation abnormality is masked by normalizing the early diastolic filling pattern.31) Left atrial pressure plays an important role in left ventricular filling dynamics even in patients with impaired relaxation or chamber stiffness. Also it is widely recognized that the E velocity is enhanced under conditions of restriction or constriction.32) In these cases, we are interested in determining whether or not higher E velocity is equivalent to higher left ventricular filling volume. Therefore, it is necessary to evaluate left ventricular filling volume and filling velocity at the same time. Our results demonstrate the existence of a significant but weak corre-

11 Vol 39 DOPPLER MEASUREMENT OF LV FILLING VOLUMES 499 No 4 lation between EDFV and the E velocity, and a wide scatter of EDFV was found at approximately the same E velocity. The discrepancy between EDFV and the E velocity may be caused by the difference in left ventricular filling pressure. This finding suggests that the E velocity increases with EDFV, which may be affected by left ventricular filling pressure. On the other hand, the A velocity was supposed to be determined by the contractile state of the left atrium and the preload condition of the left atrium. If the A velocity was greatly influenced by the preload condition, it should be correlated with LDFV due to Starling's low. In this study, no significant correlation was found between the A velocity and LDFV. This observation suggests that the A velocity is mainly regulated by the contractile state of the left atrium. In normal subjects with normal left ventricular filling pressure, the E velocity may represent the relaxation property of the left ventricle. However, in patients with a diseased heart who have elevated left ventricular filling pressure after atrial contraction, the E velocity is mainly determined by the filling pressure of the left ventricle and never represents its relaxation property. To evaluate intrinsic left ventricular diastolic function from Doppler transmitral flow velocity, we have to take account of preload conditions. Our method makes it possible to determine EDFV, which may change with the preload condition. Thus, there is a possibility of evaluating left ventricular diastolic function by correction of the E velocity with EDFV. In the present study, we validated a method for evaluating EDFV and LDFV. This method can be used to ascertain the relationship between left ventricular filling volume and velocity. Although further studies are needed, this filling volume-velocity relationship may provide a further understanding of left ventricular filling dynamics. REFERENCES 1. Dougherty AH, Naccarelli GV, Gray EL, Hicks CH, Goldstein RA. Congestive heart failure with normal systolic function. Am J Cardiol 1984; 54: Rokey R, Kuo LC, Zoghbi WA, Limacher MC, Quinones MA. Determination of parameters of left ventricular diastolic filling with pulsed Doppler echocardiography: comparison with cineangiography. Circulation 1985; 71: Friedman BJ, Drinkovic N, Miles H, Shih W -J, Mazzoleni A, DeMaria AN. Assessment of left ventricular diastolic function: comparison of Doppler echocardiography and gated blood pool scintigraphy. J Am Coll Cardiol 1986; 8: Spirito P, Maron BJ, Borrow RO. Noninvasive assessment of left ventricular diastolic function: comparative analysis of Doppler echocardiographic and radionuclide angiographic techniques. J Am Coll Cardiol 1986; 7: Labovitz AJ, Lewen MK, Kern M, Vandormael M, Deligonal U, Kennedy HL. Evaluation of left ventricular systolic and diastolic dysfunction during transient myocardial ischemia produced by angioplasty. J Am Coll Cardiol 1987; 10: Pearson AC, Labovitz AJ, Mrosek D, Williams GA, Kennedy HL. Assessment of diastolic function in

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