Methods. Circ J 2005; 69:

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1 Circ J 2005; 69: Can Transthoracic Doppler Echocardiography Predict the Discrepancy Between Left Ventricular End-Diastolic Pressure and Mean Pulmonary Capillary Wedge Pressure in Patients With Heart Failure? Yasuyuki Hadano, MD; Kazuya Murata, MD; Jinyao Liu, MD; Rikimaru Oyama, MD; Nozomu Harada, MD; Shinichi Okuda, MD; Yoko Hamada, MD; Nobuaki Tanaka, MD*; Masunori Matsuzaki, MD Background Left ventricular end-diastolic pressure (LVEDP) is difficult to measure continuously; therefore, pulmonary capillary wedge pressure (PCWP) is frequently used instead for hemodynamic monitoring in patients with heart failure. However, a discrepancy between LVEDP and mean PCWP is sometimes observed. Methods and Results To assess the feasibility of evaluating this discrepancy using echo-doppler indexes, 140 consecutive patients with heart disease were studied. Transthoracic Doppler echocardiography (TTDE) was performed immediately before bilateral-sided cardiac catheterization. We measured peak velocities of early (E: cm/s) and late (A: cm/s) diastolic transmitral flow, and duration of A wave (MAd: ms). We also measured the duration of atrial reversal of pulmonary venous flow (PAd: ms). The difference between PAd and MAd ( d= PAd-MAd: ms) was calculated. The ratio of E to tissue Doppler-derived peak early diastolic velocity of mitral annulus (Ea: cm/s) was also calculated (E/Ea). There was a good positive correlation between LVEDP and d (r=0.77, p<0.001). There was a modest correlation between mean PCWP and E/Ea (r=0.56, p<0.001). When patients were classified by d 10 ms and E/Ea 14, elevated LVEDP ( 17 mmhg) and normal mean PCWP ( 12 mmhg) were predicted with 100% sensitivity and 85% specificity. Conclusions Evaluation of the discrepancy between LVEDP and mean PCWP in patients with heart failure was feasible by separately estimating LVEDP by d and mean PCWP by E/Ea using noninvasive TTDE. Early detection of patients with elevated LVEDP and normal mean PCWP may be useful for preventing acute exacerbation of chronic heart failure. (Circ J 2005; 69: ) Key Words: Doppler echocardiography; Left ventricular end-diastolic pressure; Pulmonary capillary wedge pressure; Tissue Doppler imaging Direct measurement of left ventricular end-diastolic pressure (LVEDP) requires invasive cardiac catheterization and is difficult to be undertaken as a continuous measure. The value of LVEDP is similar to the values of mean pulmonary capillary wedge pressure (PCWP), mean left atrial pressure (LAP), or pulmonary arterial end-diastolic pressure in normal subjects; 1 3 therefore, mean PCWP measured by a balloon-tipped pulmonary artery catheter has been used for continuous hemodynamic monitoring in patients with heart failure instead of LVEDP. However, in patients with heart diseases, including aortic valvular disease, systemic arterial hypertension and coronary artery disease, a discrepancy is sometimes observed between LVEDP and mean PCWP. 1 4 In such patients, early detection of elevated LVEDP may be useful for preventing acute deterioration of chronic heart failure. (Received October 25, 2004; revised manuscript received January 5, 2005; accepted January 12, 2005) Department of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, *Department of Clinical Laboratory, Yamaguchi University Hospital, Yamaguchi, Japan Mailing address: Kazuya Murata, MD, Department of Cardiovascular Medicine, Yamaguchi University Graduate School of Medicine, Minamikogushi, Ube, Yamaguchi , Japan. Recently, it has been reported that transmitral flow (TMF), 5 7 pulmonary venous flow (PVF), 8,9 the combined analysis of TMF and PVF, 10,11 the flow propagation velocity of left ventricular (LV) inflow measured by color M-mode Doppler (Vp), 12,13 and the mitral annular velocity obtained by tissue Doppler imaging (TDI) for evaluating LV diastolic function are useful for the estimation of LV filling pressures in various heart diseases. The present study aimed to: (i) evaluate the relationship between Doppler echocardiographic indexes and hemodynamic variables; and (ii) test the hypothesis that the discrepancy between LVEDP and mean PCWP in patients with heart failure could be noninvasively predicted by transthoracic Doppler echocardiography (TTDE). Methods Initial Study Population One hundred forty consecutive patients (44 females and 96 males, mean age: 66±9 years) referred for clinically indicated cardiac catheterization made up the initial study group. All patients were in sinus rhythm and had a normal PQ interval on an electrocardiogram with no more than mild mitral or aortic regurgitation. The range of LV ejection fraction (LVEF) was 20% to 70% (mean LVEF: 51±

2 Prediction of Discrepancy Between LVEDP and PCWP 433 Table 1 Patient Characteristics All patients LVEF 50% LVEF >50% n=140 n=75 (54%) n=65 (46%) p-value Age (years) 66±9 65±10 66± M/F 96/44 55/20 41/ LVEF (%) 51±14 42±8 60±6 <0.001 Diagnosis Old myocardial infarction 66 (47%) 47 (63%) 19 (29%) <0.001 Stable angina pectoris 25 (18%) 7 (9%) 18 (28%) <0.01 Hypertrophic cardiomyopathy 7 (5%) 3 (4%) 4 (6%) 0.56 Dilated cardiomyopathy 7 (5%) 6 (8%) 1 (1%) 0.08 Unstable angina pectoris 6 (4%) 2 (3%) 4 (6%) 0.31 Aortic stenosis 4 (3%) 1 (1%) 3 (5%) 0.25 Others 25 (18%) 9 (12%) 16 (25%) 0.05 LVH (+) (wall thickness 12 mm) 23 (16%) 9 (12%) 14 (22%) 0.13 Discrepancy (+) (LVEDP 17 mmhg, mean PCWP 12 mmhg) 19 (14%) 13 (17%) 6 (9%) 0.17 LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; LVEDP, left ventricular end-diastolic pressure; PCWP, pulmonary capillary wedge pressure. Fig 1. Measurements of transmitral (A) and pulmonary venous (B) flow velocities, color M-mode Doppler flow propagation velocity during early left ventricular (LV) filling (C), and mitral annular velocity of the lateral wall of LV by tissue Doppler imaging (D). E, peak velocity of early mitral flow; A, peak velocity of late mitral flow; DcT, deceleration time of early mitral flow; MAd, duration of late mitral flow; S, peak systolic velocity of pulmonary venous flow; D, peak diastolic velocity of pulmonary venous flow; PVA, peak velocity of reverse flow at atrial contraction; PVDcT, deceleration time of diastolic pulmonary venous flow; PAd, duration of reverse flow; Vp, flow propagation velocity during early LV filling; Sa, peak systolic velocity of mitral annulus; Ea, peak early diastolic velocity of mitral annulus; Aa, peak late diastolic velocity of mitral annulus. 14%). Clinical and echocardiographic characteristics are summarized in Table 1. The investigational protocol was approved by the Institutional Review Boards of The Yamaguchi University Hospital, and all patients gave written informed consent before participation. Echocardiography All patients were examined by TTDE within 3 h before bilateral-sided cardiac catheterization. Examinations were performed with the patients in a left lateral position. An ultrasonographic instrument with a 2.5-MHz Doppler transducer (System Five, Ving Med, Horten, Norway) was used. All data were recorded during end-expiratory apnea. The TMF and PVF curves were recorded as previously described. 11 Peak velocities of early (E) and late (A) mitral inflow, the deceleration time of the E wave (DcT), and the mitral A duration (MAd) were measured (Fig 1A). Pulmonary venous peak systolic (S) and diastolic (D) forward

3 434 HADANO Y et al. Table 2 Correlation Coefficients Between Left Ventricular End-Diastolic Pressure and Doppler Parameters All patients n=140 LVEF 50% n=75 (54%) LVEF >50% n=65 (46%) r p-value r p-value r p-value TMF: E 0.23 < < A 0.24 < < E/A 0.37 < < <0.05 DcT MAd 0.39 < < <0.01 PVF: S D 0.30 < < <0.05 S/D 0.31 < < <0.05 PVDcT 0.30 < < <0.05 PVA 0.28 < <0.01 PAd 0.50 < < <0.001 d 0.77 < < <0.001 Vp: Vp E/Vp 0.32 < < <0.05 TDI: Ea E/Ea 0.33 < < <0.001 TMF, transmitral flow; E, peak early diastolic transmitral flow; A, peak late diastolic transmitral flow; DcT, deceleration time of the E wave; MAd, mitral A duration; PVF, pulmonary venous flow; S, peak systolic forward flow velocity; D, peak diastolic forward flow velocity; PVDcT, deceleration time of the D wave; PVA, peak atrial reversal flow velocity; PAd, duration of reversal flow during atrial contraction; Vp, flow propagation velocity; TDI, tissue Doppler imaging; Ea, peak early diastolic velocity of mitral annulus. Table 3 Correlation Coefficients Between Mean Pulmonary Capillary Wedge Pressure and Doppler Parameters All patients n=140 LVEF 50% n=75 (54%) LVEF >50% n=65 (46%) r p-value r p-value r p-value TMF: E 0.43 < < <0.001 A < E/A 0.46 < < <0.001 DcT 0.20 < MAd 0.30 < < PVF: S 0.20 < < D 0.40 < < <0.01 S/D 0.40 < < <0.01 PVDcT PVA 0.21 < <0.01 PAd 0.29 < < <0.01 d 0.50 < < <0.001 Vp: Vp E/Vp 0.46 < < <0.001 TDI: Ea 0.24 < < E/Ea 0.56 < < <0.001 Abbreviations see Table 2. flow velocities, peak atrial reversal flow velocity (PVA), the deceleration time of the D wave (PVDcT), and the duration of reversal flow during atrial contraction (PAd) were measured (Fig 1B). The difference in duration between the pulmonary venous reversal wave and the mitral A wave during atrial contraction ( d = PAd MAd) was calculated. We also measured color M-mode Doppler flow propagation velocity of LV inflow (Vp) in all consecutive beats as the slope of the first aliasing velocity (45 cm/s) during early filling, from the mitral valve plane to 4 cm distally into the LV cavity (Fig 1C). The TDI of the mitral annulus was obtained from an apical 4-chamber view, using a 1- to 2- mm sample volume placed in the lateral mitral annulus. The peak systolic velocity (Sa), early (Ea) and late (Aa) diastolic velocities were measured from TDI recordings (Fig 1D). The ratios of E to Vp (E/Vp) and E to Ea (E/Ea) were calculated. Hemodynamic Measurements A 6F high-fidelity manometer-tipped catheter (Millar Instruments, Houston, TX, USA) or 5F pigtail catheter connected with fluid-filled transducer (Terumo Corp, Tokyo, Japan) was introduced across the aortic valve into the LV. The high-fidelity LV pressure was zeroed and calibrated to the fluid-filled LV pressure measured by the fluid-filled lumen of the catheter before recordings. The PCWP was measured with a balloon-tipped pulmonary artery catheter (Swan-Ganz, Baxter Healthcare Corp, Santa Ana, CA, USA) connected to a fluid-filled transducer. All pressures were recorded on a strip chart at a paper speed of 100mm/s. Averaged values of 3 consecutive beats during end-expiratory apnea were used for analysis. Statistical Analysis Results were expressed as mean value ± SD. Statistical analysis was performed using a statistical package (Statview, Berkeley, CA, USA). Linear regression analysis was used to evaluate the correlations of Doppler echocardio-

4 Prediction of Discrepancy Between LVEDP and PCWP 435 Fig 2. Scatter plot of the correlation between left ventricular end-diastolic pressure (LVEDP) and the difference in duration between reverse pulmonary venous and mitral A wave ( d=pad MAd) (A), LVEDP and the ratio of E to tissue Doppler-derived peak early diastolic velocity of mitral annulus (E/Ea) (B), mean pulmonary capillary wedge pressure (PCWP) and d (C), mean PCWP and E/Ea (D), in all patients. A, scatter plot of the correlation between LVEDP and d; B, scatter plot of the correlation between LVEDP and E/Ea; C, scatter plot of the correlation between mean PCWP and d; D, scatter plot of the correlation between mean PCWP and E/Ea. Fig 3. Scatter plot of the correlation between left ventricular end-diastolic pressure (LVEDP) and the difference in duration between reverse pulmonary venous and mitral A wave ( d=pad MAd) (A), LVEDP and the ratio of E to tissue Doppler-derived peak early diastolic velocity of mitral annulus (E/Ea) (B), mean pulmonary capillary wedge pressure (PCWP) and d (C), mean PCWP and E/Ea (D), in patients with left ventricular ejection fraction (LVEF) 50%. A, scatter plot of the correlation between LVEDP and d; B, scatter plot of the correlation between LVEDP and E/Ea; C, scatter plot of the correlation between mean PCWP and d; D, scatter plot of the correlation between mean PCWP and E/Ea.

5 436 HADANO Y et al. Fig 4. Scatter plot of the correlation between left ventricular end-diastolic pressure (LVEDP) and the difference in duration between reverse pulmonary venous and mitral A wave ( d=pad MAd) (A), LVEDP and the ratio of E to tissue Doppler-derived peak early diastolic velocity of mitral annulus (E/Ea) (B), mean pulmonary capillary wedge pressure (PCWP) and d (C), mean PCWP and E/Ea (D), in patients with left ventricular ejection fraction (LVEF) >50%. A, scatter plot of the correlation between LVEDP and d; B, scatter plot of the correlation between LVEDP and E/Ea; C, scatter plot of the correlation between mean PCWP and d; D, scatter plot of the correlation between mean PCWP and E/Ea. Fig 5. Scatter plot of the correlation between the difference in duration between reverse pulmonary venous and mitral A wave ( d=pad MAd) and the ratio of E to tissue Doppler-derived peak early diastolic velocity of mitral annulus (E/Ea). Solid circles, patients with the discrepancy between left ventricular end-diastolic pressure (LVEDP 17mmHg) and mean pulmonary capillary wedge pressure (PCWP 12 mmhg); open circles, patients without the discrepancy between LVEDP and mean PCWP. Horizontal dashed line marks the value of 10ms in d that was found to be the cutoff point in predicting the level of 17 mmhg of LVEDP. Vertical dashed line marks the value of 14 in E/Ea that was found to be the cutoff point in predicting the level of 12mmHg of mean PCWP. graphic parameters with LVEDP and mean PCWP. The correlation study was performed for patients with LVEF 50% and those with LVEF >50% to assess the influence of systolic function on the validity of these methods. A p-value <0.05 was considered significant. Sensitivity and specificity were calculated with standard formulas. Results Initial Study Population Correlations of Echocardiographic Parameters With LVEDP or Mean PCWP Correlations of echocardiographic parameters with LVEDP or mean PCWP are summarized in Tables 2 and 3. There was a good positive correlation between LVEDP and d (r=0.77, p<0.001) (Fig 2A). However, LVEDP was correlated poorly with E/Ea (r=0.33, p<0.001) (Fig 2B). Both d and E/Ea had modest correlations with mean PCWP (r=0.50, r=0.56, p<0.001, respectively) (Fig 2C and 2D). The patient characteristics with LVEF 50% and those with LVEF >50% are outlined and compared in Table 1. In patients with LVEF 50%, there was a good correlation between LVEDP and d and a modest correlation between mean PCWP and E/Ea (Fig 3). There was also a good correlation between LVEDP and d and a modest correla-

6 Prediction of Discrepancy Between LVEDP and PCWP tion between mean PCWP and E/Ea in patients with LVEF >50% (Fig 4). The scatter plot of the correlation between d and E/Ea was shown in Fig 5. Patients with LVEDP 17 mmhg and mean PCWP 12 mmhg (solid circles) were plotted in the left upper quadrant. This discrepancy between elevated LVEDP and normal mean PCWP was observed in patients with coronary artery disease, aortic stenosis, or dilated cardiomyopathy. The cutoff values of 10 ms of d and 14 of E/Ea predicted LVEDP 17 mmhg and mean PCWP 12 mmhg with 100% sensitivity and 85% specificity by receiver operating characteristic (ROC) curve analysis. The area under the ROC curve using d and E/Ea to predict the discrepancy between LVEDP and mean PCWP was Test Study Population The cutoff values of d to estimate LVEDP and E/Ea to estimate mean PCWP were tested prospectively in 63 consecutive patients (17 females and 46 males, mean age: 65±10 years, mean LVEF: 51±18%). As in the initial study group, Doppler echocardiographic parameters and hemodynamic parameters were measured. The criteria for exclusion were the same as in the initial group, and all Doppler measurements and calculations were made without knowledge of the hemodynamic data. Of the 63 patients, 16 had LVEDP 17 mmhg and mean PCWP 12 mmhg. The sensitivity and specificity for prediction of LVEDP 17 mmhg and mean PCWP 12 mmhg were 81% and 85%, respectively. Discussion In patients with normal cardiac function and without mitral valvular disease, mean PCWP closely approximates LVEDP. 1,2 However, the measure of these pressures may be dissimilar in patients with aortic valvular disease, systemic arterial hypertension or coronary artery disease, and in whom LVEDP exceeds mean PCWP 1,3 because of LV noncompliance and the prominent A wave of LV pressure. Although PCWP reflects clinical symptoms and is widely used to manage patients with heart failure, the estimation of LVEDP is also clinically important to predict acute aggravation of chronic heart failure and to decide therapeutic strategy for such cardiac disease. In the current study, we used d and E/Ea to predict the discrepancy between elevated LVEDP and normal mean PCWP with high sensitivity and specificity. Many studies have reported the relationship between echocardiographic indexes and LV filling pressures However, these studies chose selected patients, such as patients with impaired LV systolic function. In the present study we investigated a wide range of LV systolic function and did not take into account the grade of diastolic dysfunction. LVEDP and Durations of Mitral A Wave and Pulmonary Venous A Wave In the present study, and as previously reported, 10,11 d was well correlated with LVEDP and was found to be the best indicator of LVEDP. The left atrial (LA) booster pump function makes a large contribution to LV filling, especially in patients with impaired LV diastolic properties. 3,4,17 In patients with elevated LVEDP, high Pre-A LV pressure and a decrease in LV compliance resulted in an earlier cross of LA-LV pressure and a shortened duration of the mitral A 437 wave. 10 Matsuda et al reported in patients with highly elevated LVEDP that the atrial pressure curve became biphasic and that the second and largest peak occurred at the time of maximal ventricular A wave pressure. 18 They suggested that the duration of the LAP A wave is widened when LVEDP is increased and that with increasing LV filling pressure, the duration of a positive LA-LV pressure gradient during atrial contraction shortened. With the higher second wave, these findings may show results with a shorter duration of MAd and a prolonged duration of PAd. This may in turn result in a prolonged LAP A wave and prolongation of the reverse flow into the pulmonary vein, and may also result in prolongation of the difference in duration between pulmonary venous flow reversal and forward mitral flow during atrial systole ( d). PCWP and the Ratio of Transmitral E Wave Velocity to Early Diastolic Velocity of the Mitral Annulus In the present study, tissue Doppler-derived mitral E/Ea was the best single Doppler predictor of elevated PCWP. The mitral E wave velocity is influenced by multiple interrelated factors, including LV relaxation rate, atrial and ventricular compliance, and LAP. In diseased ventricles, progressive shortening of the transmitral DcT and increasing E/A ratio can be seen with decreasing ventricular compliance and increasing LV filling pressure. 5 7,19 21 To overcome these limitations in mitral inflow parameters, combinations of mitral flow velocity curves with other Doppler parameters have been proposed. The TDI of mitral annular motion has been introduced to correct for the influence of myocardial relaxation on TMF and has been shown to be an excellent predictor of diastolic filling in subsets of patients ,22,23 Dokainish et al have shown that optimal cutoffs for the prediction of PCWP >15mmHg are E/Ea >15 in patients with impaired LV systolic function and >11 in patients with preserved LVEF. 16 The results of the present study confirmed their data in patients with a wide range of LVEF. The early propagation velocity of LV inflow by color M- mode Doppler (Vp) is an index of LV relaxation, and the ratio of the E wave velocity to Vp (E/Vp) relates with mean PCWP. 12,13 In the current study, E/Ea appears more accurate than E/Vp for prediction of mean PCWP. In comparison to Vp, Ea is easily recorded and measured with TDI and is independent of LV systolic function, whereas Vp is currently measured by various methods and appears to have some relation to systolic performance. 12,13 Thus, E/Ea, which is relatively simple to obtain, conceptually has the potential for providing a reasonable estimate of filling pressures throughout a wide range of relaxation abnormalities. In the current study, E/Ea was poorly correlated with LVEDP, which may be strongly influenced by the LA-LV pressure relation during atrial contraction. Therefore, LVEDP may be more faithfully related to d than E/Ea. Clinical Implications The LV diastolic dysfunction is common in patients with heart failure and implies elevated LVEDP. Thus, the assessment of LVEDP provides significant information for evaluating the status of a failing heart. In patients with chronic heart failure with normal mean PCWP and elevated LVEDP, excessive fluid infusion may result in aggravation of the failing heart. Therefore, in such patients, early detection of elevated LVEDP may be useful for preventing acute deterioration of chronic heart failure. Further, Ommen et al

7 438 HADANO Y et al. have suggested that an E/Ea of 8 to 15 is a gray zone for prediction of LV filling pressure. 15 To predict LVEDP accurately by d may overcome this limitation. Study Limitations To accurately elucidate the mechanisms in the relationship between the Doppler indexes and hemodynamics, simultaneous recordings of LV pressure and PCWP would be desirable. Furthermore, the estimation of LA contractility, such as evaluation of LA maximum dp/dt by Doppler parameters, 24 would be required to demonstrate increased LA contractility in patients with prolonged PAd. The measurement of the Doppler indexes and of hemodynamics was not performed simultaneously. However, Doppler echocardiography was recorded within the 3 h before cardiac catheterization and transfusion was withheld minimally. In addition, we confirmed that blood pressure and heart rate did not change significantly during the time of Doppler echocardiography and catheterization recordings. 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