An Index of Early Left Ventricular Filling That Combined With Pulsed Doppler Peak E Velocity May Estimate Capillary Wedge Pressure

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1 448 JACC Vol. 29, No. 2 An Index of Early Left Ventricular Filling That Combined With Pulsed Doler Peak E Velocity May Estimate Caillary Wedge Pressure MARIO J. GARCIA, MD, FACC, MIGUEL A. ARES, MD, CRAIG ASHER, MD, LEONARDO RODRIGUEZ, MD, PIETER VANDERVOORT, MD, JAMES D. THOMAS, MD, FACC Cleveland, Ohio Objectives. This study sought to determine the alicability of the combined information obtained from transmitral Doler flow and color M-mode Doler flow roagation velocities for estimating ulmonary caillary wedge ressure. Background. Although Doler-derived measurements of left ventricular (LV) filling have been alied to determine left atrial ressure, their accuracy has been limited by the variable effect of ventricular relaxation in these indexes. Recently, flow roagation velocity measured by color M-mode Doler echocardiograhy has been suggested as an index of ventricular relaxation. Methods. We studied 45 atients admitted to the intensive care unit who underwent invasive hemodynamic monitoring. We measured eak early (E) and late (A) transmitral Doler velocities, E/A ratio and flow roagation velocity (v ) and comared them by linear regression with ulmonary caillary wedge ressure ( w ). Results. We found a modest ositive correlation between w and E(r 0.62, < 0.001) and the E/A ratio (r 0.52, < 0.001) and a negative correlation between w and v (r 0.34, 0.02). By stewise linear regression, only E and v were statistically significant redictors of w. However, the E/v ratio rovided the best estimate of w (r 0.80, < 0.001; w 5.27 [E/v ] 4.6, SEE 3.1 mm Hg). Conclusions. The ratio of comonent velocity (E) over the color M-mode roagation velocity during early LV filling, by correcting for the effect of LV relaxation, rovides a better estimate of w than standard measurements of transmitral Doler flow. (J Am Coll Cardiol 1997;29:448 54) 1997 by the American College of Cardiology Doler echocardiograhy has been used to estimate diastolic function noninvasively. Several indexes obtained from the transmitral ulsed Doler flow, including eak velocities of early (E) and late (A) filling, the E/A ratio, E wave acceleration and deceleration rates and isovolumetric relaxation time, have been used to characterize atterns of imaired diastolic filling (1 3). Doler-derived measurements of left ventricular (LV) filling have also been shown (4 8) to rovide estimates of LV filling ressure in selected grous of atients with cardiac disease. Because these indexes are also determined by ventricular relaxation (9), they may be inaccurate in estimating left atrial ressure if the rate of relaxation is unknown. Recently, color M-mode Doler echocardiograhy has been From the Veterans Affairs Medical Center, White River Junction, Vermont; Dartmouth Medical School and the Cardiovascular Imaging Center, Deartment of Cardiology of The Cleveland Clinic Foundation, Cleveland, Ohio. This study was suorted in art by Grant-in-Aid from the American Heart Association, Dallas, Texas (Dr. Thomas). Dr. Ares was suorted by a scholarshi from Fondo de Investigaciones Sanitarias, Madrid, Sain. It was resented in art at the 44th Annual Scientific Session of the American College of Cardiology, New Orleans, Louisiana, March Manuscrit received May 21, 1996; revised manuscrit received August 13, 1996, acceted October 9, Address for corresondence: Dr. James D. Thomas, Deartment of Cardiology, Desk F-15, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio thomasj@cesmt.ccf.org. shown (10 13) to rovide unique information about ventricular relaxation. The roagation velocity of transmitral flow during early ventricular filling (v ), or the time difference between maximal velocity at the aex level and at the mitral leaflet tis, measured by color M-mode Doler, has been roved to be related to the time constant of isovolumetric LV relaxation (tau) (10,11); v has also shown a moderate correlation with LV ejection fraction, and in an animal model roved to be indeendent of left atrial ressure and heart rate (11,12). The resent study therefore sought to 1) evaluate the relation between transmitral flow filling velocity atterns and ulmonary caillary wedge ressure ( w ) in a large heterogeneous grou of atients; and 2) test the hyothesis that w could be more accurately estimated by the E/v ratio because mitral flow eak early filling velocity (E) is directly related to w and inversely related to tau (9,14 16), whereas v has been shown (10) to be inversely related to tau. Methods Study grou. We enrolled 65 consecutive atients who were admitted to the intensive care unit at our institution (Cleveland Clinic) and were able to rovide written informed consent. Patients were included if they were in normal sinus rhythm and had a balloon-tied ulmonary artery catheter 1997 by the American College of Cardiology /97/$17.00 Published by Elsevier Science Inc. PII S (96)

2 JACC Vol. 29, No. 2 GARCIA ET AL. COLOR M-MODE FLOW VELOCITY PROPAGATION 449 Abbreviations and Acronyms A late transmitral Doler filling velocity E early transmitral Doler filling velocity LV left ventricular w ulmonary caillary wedge ressure tau time constant of isovolumetric left ventricular relaxation v flow roagation velocity (Swan-Ganz) with an adequate osition confirmed by chest X-ray film and had technically adequate w tracings. Four atients with first-degree atrioventricular block were excluded because a distinct searation could not be established between the E and A waves in the ulsed Doler or color M-mode tracings, or both. Two atients with a rosthetic mitral valve, four with severe mitral regurgitation, two with functional mitral stenosis and eight with inadequate echocardiograhic images were also excluded. The remaining 45 atients (mean [ SD] age years, range 26 to 85) formed our study grou. In 22 atients the rimary diagnosis was an acute ischemic event; 5 had congestive heart failure secondary to idioathic dilated cardiomyoathy; 3 had aortic valve disease; 3 had eriheral vascular surgery; 5 had trauma; and 7 had sesis. Clinical and echocardiograhic characteristics are summarized in Table 1. Doler ultrasound examination. All atients were examined at bedside by two-dimensional guided transthoracic ulsed and color Doler using a Sonos 1500 ultrasound machine (Hewlett-Packard Comany). Recordings were acquired with a 2- or 2.5-MHz Doler transducer laced at the cardiac aical window. Left ventricular ejection fraction was Table 1. Clinical and Echocardiograhic Characteristics of 45 Study Patients Age (yr) Male 26 (58%) Primary diagnosis MI/unstable angina 22 Dilated cardiomyoathy 5 Aortic valve disease 3 Periheral vascular surgery 3 Trauma 5 Sesis 7 w (mm Hg) 15 5 Transmitral Doler velocity E (cm/s) E/A E acceleration rate (m/s) 1, E acceleration time (ms) E deceleration rate (m/s 2 ) E deceleration time (ms) v (cm/s) LVEF (%) Data resented are mean value SD or number (%) of atients. E eak early transmitral Doler flow velocity; E/A early/atrial transmitral Doler flow velocity ratio; LVEF left ventricular ejection fraction; w ulmonary caillary wedge ressure; v flow roagation velocity; MI myocardial infarction. determined using the area length method from two-dimensional echocardiograhic images obtained from the aical four-chamber view. Doler recordings were obtained from the same view with the ulsed samle volume laced at the tis of the mitral leaflets. Transmitral flow velocities were recorded at a horizontal seed of 100 mm/s using a minimized high ass filter. A minimum of 6 beats were stored first in a memory loo and then transferred to a 650-MB magneto-otical disk. From the same echocardiograhic window, the color Doler sector ma of the mitral inflow was dislayed, and fine adjustments were made to obtain the longest column of color flow from the mitral annulus to the aex. An M-mode cursor was ositioned through the center of the flow, avoiding boundary regions and aligning the cursor in the same direction of the inflow jet. The color M-mode sectra were dislayed on the video screen at 100 mm/s. In all cases, color gain was set at subsaturation levels, using the same ma and color rocessing filters. At least 6 cardiac cycles were also recorded and stored on otical disc media and video tae. Determination of w. We estimated w from tracings obtained by means of a ulmonary artery catheter (Swan-Ganz), after confirming osition in a middle-lobe central ulmonary artery by chest X-ray film and gradually inflating the ti balloon until the tyical wedge tracing was obtained. All measurements were obtained at end-exiration after careful calibration and within 5 min of the Doler examination. Pulsed and color Doler measurements. Measurements were done off-line in a workstation (Nova Microsonics) by two indeendent observers (M.J.G., M.A.A.) who had no knowledge of the hemodynamic data. Peak early mitral velocity (E wave) was measured and averaged for all beats. We also measured the color M-mode Doler flow roagation (v ) velocity in all consecutive beats as the sloe of the first aliasing velocity (45 cm/s) during early filling, from the mitral valve lane to 4 cm distally into the LV cavity (Fig. 1). This reresents a modification of the method reviously described by Brun et al. (10), who measured the sloe of the transition no color/color because we found that the latter could not be uniformly seen in all cases. When eak E was 0.45 cm/s, and there was no aliasing, we adoted the first well demarcated isovelocity sloe of the second hase of early filling. It has been roosed by other investigators (11) that the first hase of early filling reresents isovolumetric flow in the aical regions of the left ventricle. We averaged the results of all beats measured in each subject and then comared and averaged the results obtained by both observers indeendently. Intraobserver and interobserver variability was calculated for color M-mode roagation velocity measurements. Data analysis. For all atients, eak E velocity was comared with v by aired t tests and linear regression. The relation between w and E, the E/A ratio, E acceleration and deceleration times and rates, LV ejection fraction and v were tested with linear regression. Stewise multilinear regression analysis was used to test the indeendent additive redictive value of each of these variables. Because E has been shown theoretically (14) and emirically (15,16) to be linearly related to w /tau, whereas v has been shown (10) to be inversely

3 450 GARCIA ET AL. JACC Vol. 29, No. 2 COLOR M-MODE FLOW VELOCITY PROPAGATION Figure 1. Measurement of flow roagation velocity (v ) from color M-mode Doler: v is determined by the sloe of the first clearly demarcated isovelocity line during early filling, from the mitral valve lane to 4 cm distally into the left ventricular cavity (see text for details). related to tau, we hyothesized that the dimensionless ratio E/v would be linearly related to w. This hyothesis was tested by linear regression in the first 15 atients, using E/v as the indeendent variable and w as the deendent variable. We then alied the linear regression equation obtained to estimate w in the next 30 atients. The Student t test for aired data and Bland-Altman analysis of agreement were used to comare the differences between the measured and the estimated w from E/v. All variables were also comared between atients with w 15 versus 15 mm Hg using the t test for unaired data and one-way analysis of variance with Bonferroni adjustments. Results are exressed as mean value SD. Results Figure 2 illustrates the v, transmitral flow velocity and resective w obtained in three reresentative cases. In case A, there is a high eak E velocity in the transmitral flow, yet the w is the lowest (14 mm Hg). The high E is due to the faster rate of relaxation, as indicated by the v measured by color M-mode Doler. This attern is found in a atient with normal LV function. In case B, a higher w (17 mm Hg) in the resence of a low E velocity is due to the slower rate of relaxation as indicated by the low v. This attern is seen in a atient with LV dysfunction who received diuretic drugs. Case C reresents a tyical seudonormal filling attern. A high E combined with a low v corresond to the highest w (20 mm Hg). This attern is found in a atient with LV dysfunction and volume overload. Determinants of w. Mean w was 15 5mmHginour study grou. Univariate and multivariate correlates of w are shown in Table 2. Peak E velocity measured by ulsed Doler (74 24 cm/s) had a ositive correlation (r 0.62, 0.001) with w (Fig. 3), whereas v (40 14 cm/s) showed a negative correlation (r 0.35, 0.02), indeendent of E. The correlation between E and w was greater in atients with LV ejection fraction 40% than in those with LV ejection fraction 40%. Other variables obtained from the transmitral ulsed Doler velocities, including the E/A ratio (r 0.52), E acceleration (r 0.31) and deceleration rates (r 0.37) and LV ejection fraction (r 0.40), did not achieve indeendent statistical significance by multivariate analysis; w was best estimated by the E/v ratio (r 0.80, 0.001; y 5.27x 4.6, SEE 3.1) (Fig. 4). From the linear regression equation obtained from the first 15 study atients, we estimated w rosectively in the remaining 30 atients ( w 5.9 [E/v ] 2.5). The difference between the measured and estimated values was mm Hg. In 26 (87%) of 30 atients, the estimated w was within 5 mm Hg of the w measured invasively. In only one atient was the difference between the estimated and measured w values 10 mm Hg. Patients with w 15 mm Hg had a lower E (62 16 vs cm/s, 0.004), E/A ratio ( vs , 0.001), E deceleration rate ( vs m/s 2, 0.04), and E acceleration time (68 20 vs ms, 0.05) and a higher LV ejection fraction (45 17 vs %, 0.02) than those with w 15 mm Hg. Determinants of v. Flow roagation velocity was cm/s in the study grou, significantly lower than eak E velocity ( 0.001). Similar values for v have been reviously reorted (10) in atients with normal to severe LV dysfunction, even though our methods of measurement were slightly modified from those of Brun et al. (10). The correlations between the measured echocardiograhic variables and v are shown in Table 3. By univariate analysis, the only statistically significant correlates of v were LV ejection fraction (r 0.40, 0.007) and w (r 0.35, 0.02). Only LV ejection fraction was found to be indeendently significant by stewise linear regression. Intraobserver and interobserver variability. There was a good interobserver correlation for measurement of v (r 0.94, 0.001), with a variability of 4 18%. Intraobserver variability for the same measurements was 2 16%. Variability was greater for faster velocities because of the greater relative value of errors in measurements in the horizontal axis (time).

4 JACC Vol. 29, No. 2 GARCIA ET AL. COLOR M-MODE FLOW VELOCITY PROPAGATION 451 Discussion As reviously shown (17), our results indicate that Doler variables of LV filling rovide a modest estimate of w when they are alied to a heterogeneous cohort. The limited alication of these indexes may be exlained by the variable effect of LV relaxation on transmitral Doler velocities. We were able to demonstrate in this study that by combining the Doler eak E velocity with the color-m mode roagation velocity v used as an index of LV relaxation, we may obtain better estimates of w than those derived from conventional transmitral ulsed Doler measurements alone. Assessment of w from ulsed transmitral Doler velocities. Several investigators (4 8) have attemted to assess left atrial ressure noninvasively using the transmitral flow velocity variables measured by Doler echocardiograhy. In atients with reserved systolic erformance in sinus rhythm, the E/A ratio has shown to be redictive of LV filling ressures (4,6). On the basis of data obtained from atients undergoing cardiac catheterization, other investigators (6) have roosed combining several Doler mitral flow velocity measurements with the isovolumetric relaxation time, atrial filling fraction and time from termination of the mitral flow to the electrocardiograhic R wave. All methods that have attemted to estimate left atrial ressure from transmitral Doler flow are alicable only to atients with homogeneity of LV relaxation because they assume that a reduction in isovolumetric relaxation time, atrial filling fraction and deceleration time will arallel an elevation in LV end-diastolic ressure. In a recent study (7) that analyzed the correlation between the E/A ratio and w in atients with structural heart disease, it was noted that atients in whom Doler overestimated w had small myocardial Figure 2. Flow roagation velocity (v ) and transmitral flow velocity obtained in three reresentative cases. In case A, there is a high eak E velocity in the transmitral flow, yet the caillary wedge ressure ( w ) is the lowest (14 mm Hg). The high E is due to the faster rate of relaxation, as indicated by the v measured by color M-mode Doler. This attern is found in a atient with normal LV function. In case B, a higher w (17 mm Hg) in the resence of a low E velocity is due to the slower rate of relaxation, as indicated by the low v. This attern is seen in a atient with LV dysfunction who had received diuretic drugs. Case C reresents a tyical seudonormal filling attern. A high E combined with a low v corresonds to the highest w (20 mm Hg). This attern is found in a atient LV dysfunction and volume overload. infarctions and no or minimal wall motion abnormalities. Changes in the rate of isovolumetric relaxation may not only be due to the resence of structural heart disease, but also to other variables, such as age. Therefore, the accuracy of Doler variables of transmitral flow in estimating left atrial ressure deends on the characteristics of the atients in whom they are alied. Nagueh et al. (8) recently studied the accuracy of Doler estimation of w in atients admitted to the intensive care unit. Their study, involving a less selected atient grou, showed a weaker correlation between w and E, E/A, isovolumetric relaxation time or atrial filling fraction, alone or in combination. Determinants of eak early transmitral flow velocity (E). Mitral E velocity is rimarily determined by the early transmitral ressure gradient. Theoretic models, comuter simulations and exerimental animal models redict that left atrial ressure, rate of isovolumetric ventricular relaxation (tau), endsystolic volume and LV minimal ressure are the main determinants of E (9,15 18). Imairment of LV relaxation results in a rolongation of the isovolumetric relaxation time and a reduction in the early transmitral flow velocity (E) with

5 452 GARCIA ET AL. JACC Vol. 29, No. 2 COLOR M-MODE FLOW VELOCITY PROPAGATION Table 2. Univariate and Multivariate Correlates of Pulmonary Caillary Wedge Pressure Univariate Multivariate R MultR Age 0.07 Transmitral Doler velocity E A 0.16 E/A E acceleration rate E acceleration time 0.19 E deceleration rate E deceleration time 0.07 v LVEF *Statistical significance, Regression equation: log w (E) 0.17 (v ). A eak transmitral Doler flow velocity during atrial contraction; MultR correlation coefficient () for multile regression; R Pearson correlation coefficient; other abbreviations as in Table 1. rolongation of the E wave deceleration time (3,18,19). In contrast, increasing filling ressures result in shortening of the isovolumetric relaxation time, increased early transmitral gradient and, consequently, early transmitral flow velocity, shortening of deceleration time and reduction in atrial flow velocity (3,18 20). Because the mitral flow Doler rofile deends on both variables, rogressive elevation of left atrial ressure in ventricles with reduced isovolumetric relaxation will reverse the classic changes in low E, low acceleration and deceleration rates, reduced E/A ratio and rolonged isovolumetric relaxation time, resulting in a seudonormal filling attern. This attern has been clinically demonstrated (21) in atients with cardiac amyloidosis who exerience a transition from an early hase with imaired relaxation (low E/A ratio) to a restrictive hase with severe heart failure (high E/A ratio) in which LV filling ressure becomes elevated. Figure 3. Overall correlation between eak early (E) transmitral flow velocity and caillary wedge ressure ( w ). The correlation between E and w was greater in atients with an LVEF 40% (solid circles, r 0.82, 0.001) than in those with an LVEF 40% (oen circles, r 0.47, 0.01). Figure 4. A, Linear regression between the dimensionless index: eak early transmitral flow velocity/flow roagation velocity (E/v ) and caillary wedge ressure ( w ) (see text for details). B, Bland-Altman analysis of agreement between the estimated and measured w. Color M-mode measurement of flow roagation velocity. Color M-mode Doler is a ulsed Doler technique in which brief bursts of ultrasound are emitted, and the returning echoes are amlified and digitized for the entire scan line. By analyzing reeated airs of ulses, it is ossible to obtain a satiotemoral velocity ma with a temoral resolution of Table 3. Univariate and Multivariate Correlates of Color M-Mode Flow Proagation Velocity R Univariate MultR Multivariate Age 0.02 w Transmitral Doler velocity E 0.16 A 0.13 E/A 0.08 E acceleration rate 0.12 E acceleration time 0.01 E deceleration rate 0.01 E deceleration time 0.03 LVEF *Statistical significance, Abbreviations as in Tables 1 and 2.

6 JACC Vol. 29, No. 2 GARCIA ET AL. COLOR M-MODE FLOW VELOCITY PROPAGATION ms, a satial resolution 1 mm and a velocity measurement with an average error 5 cm/s. Using digital rocessing, numerical velocity values can be obtained in addition to satial and temoral information (22). A major difference exists between color M-mode Doler and normal ulsed Doler. Whereas normal ulsed Doler ermits us to obtain information on time and velocity at a fixed satial oint, color M-mode Doler allows the acquisition of information on velocity, time and sace along an entire cursor line. There are two general color Doler M-mode indexes reorted in ublished reorts. In the first aroach, v is determined by the sloe of the flow wave front; the tracing of the sloe is done manually and uses the transition between no color and color (10). In the second method, the time delay between maximal velocity at the mitral leaflet tis and ventricular aex has been roosed (11) to overcome the difficulties of manually measuring v by using dedicated comuter software to decode the maximal velocities at various oints along the LV inflow tract. In our study we measured v with certain modifications that try to overcome the difficulties noted reviously. When the leading edge of the second hase of early filling was irregular, we measured the contour of the first isovelocity line that roduced an uninterruted contour. When there were two hases of early filling, we traced the sloe of the second hase because the initial sloe is thought to reflect movement of the blood already within the ventricle before diastole. Alying these two criteria yielded reasonable interobserver and intraobserver variability in v. Color M-mode v has been shown to correlate well with the tau (10,11) and moderately with LV ejection fraction in atients with coronary artery disease (12). Two mechanisms that determine v have been roosed, namely the resence of intraventricular ressure gradients (23) and the formation of vortexes (24 27). Courtois and Ludbrook (28) roosed that intraventricular gradients result from active myocardial events, suggesting a model of diastolic function that treats the aex as a rominent source of recoil during early diastole, contributing to the rocess of filling by actively drawing blood from the mid and basal levels of the heart into the aical region. In their carefully obtained tracings, they show a consistent aex base gradient in ressure during early filling in the left ventricle. Using ulsed Doler echocardiograhy, Thomas et al. (29) found that eak E velocity increases in the normal left ventricle and reaches its maximum closer to the aex, whereas the highest eak A velocity occurs near the mitral leaflet tis. However, in dilated hyocontractile ventricles, eak E velocity decreases as it travels toward the aex. In situations associated with athologic nonhomogeneity, such as ischemia, the outward movement of normal segments would be balanced for an inward movement of ischemic segments (30) during isovolumetric relaxation (31), resulting in a decrease in the rate of isovolumetric relaxation and the loss of mechanical suction during early filling (32). In vitro exeriments have recently shown (33) that increasing suction force results in a faster v. Vortex formation may exlain why flow eak E velocity may be higher than v. Steen and Steen (33), in an in vitro model of a left ventricle, demonstrated that the eak velocity of the fluid articles may be twice as high as the roagation velocity of the wave. Their observation is exlained by the hydrodynamic rinciles of flow in a vortex ring, in which the fluid velocity in the center of the ring exceeds the roagation velocity because of intrinsic circulation of fluid around the axis of the ring. Vorticity is generated by shear between inflowing blood and the stationary blood already in the ventricle. Vortex formation increases in smaller mitral orifice sizes and dilated ventricles, resulting in a slower v. Beu et al. (27) showed that in dogs with normal LV function, contrast medium injected into the left atrium reaches the aex quickly and with little vortex formation, whereas in those with aical akinesia or dyskinesia, the contrast medium does not reach the aex within one diastole, but turns uward to the outflow tract in the middle of the cavity. In summary, normal ventricles, because of smaller size, higher suction force and higher relative mitral orifice size have a faster v than ventricles with abnormal relaxation. It is unknown whether in humans v may be influenced by loading conditions in the same manner as conventional Doler indexes. However, a recent study (34) showed that atients with abnormal LV relaxation, E/A ratio 1 and normal w had a low v similar to those with abnormal LV relaxation, E/A ratio 1 and elevated w, indicating that v is not seudonormalized by the elevation in left atrial ressure. Estimation of w from combined Doler indexes. As reviously indicated, left atrial ressure and LV relaxation are the main determinants of eak E velocity. Left ventricular relaxation during early diastole is best characterized by tau, with lower values for tau indicating faster rates of relaxation. Studies in atients with normal LV function and in atients with ressure overload hyertrohy (35,36) demonstrated that this index is not affected by modest changes in loading conditions. A ositive linear relation between E and left atrial ressure and a negative but still linear inverse relation between E and tau have been shown in animal exeriments. Because there is a strong (negative) linear correlation between v and tau, we substituted v 1/tau in E w /tau to yield E w v and then rearranged w E/v. Limitations of the study. We used w as an estimate of left atrial ressure. Several factors may affect the relation between w and direct left atrial ressure, articularly in atients who are critically ill, such as incomlete occlusion by the air-filled balloon, regional variations in the ulmonary vasculature, underestimation due to air in the fluid-filled catheters or inaccurate calibration. It is ossible that error in left atrial ressure estimation may account for the lack of a stronger correlation of our data. We did not consider the effects of variables, such as eak LV systolic ressure and left atrial comliance, both shown to affect left atrial ressure and eak E wave velocity in comuter and animal models. Left ventricular geometry (dilated sherical vs. nondilated or conical ventricular shaes) and mitral valve orifice diameter could also affect v (32). Vortex formation is more likely with smaller orifice sizes, resulting in slower v. Most of our atients had abnormal LV function because

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