Novel echocardiographic method to assess left ventricular chamber stiffness and elevated end-diastolic pressure based on time–velocity integral measurements of pulmonary venous and transmitral flows

Novel echocardiographic method to assess left ventricular chamber stiffness and elevated... Abstract Aims The detection of increased left ventricular (LV) chamber stiffness may play an important role in assessing cardiac patients with potential but not overt heart failure. A non-invasive method to estimate it is not established. We investigated whether the echocardiographic backward/forward flow volume ratio from the left atrium (LA) during atrial contraction reflects the LV chamber stiffness. Methods and results We studied 62 patients who underwent cardiac catheterization and measured their left ventricular end-diastolic pressure (LVEDP) and pressure increase during atrial contraction (ΔPa) from the LV pressure waveform. Using the echocardiographic biplane method of disks, we measured the LV volume change during atrial contraction indexed to the body surface area (ΔVa), and ΔPa/ΔVa was calculated as a standard for the LV operating chamber stiffness. Using pulsed Doppler echocardiography, we measured the time–velocity integral (TVI) of the backward pulmonary venous (PV) flow during atrial contraction (IPVA) and the ratio of IPVA to the PV flow TVI throughout a cardiac cycle (FPVA). We also measured the TVI of the atrial systolic forward transmitral flow (IA) and the ratio of the IA to the transmitral TVI during a cardiac cycle (FA) and calculated IPVA/IA and FPVA/FA. IPVA/IA and FPVA/FA were well correlated with ΔPa/ΔVa (r = 0.79 and r = 0.81) and LVEDP (r = 0.73 and r = 0.77). The areas under the ROC curve to discriminate LVEDP >18 mmHg were 0.90 for IPVA/IA and 0.93 for FPVA/FA. Conclusion The FPVA/FA, the backward/forward flow volume ratio from the LA during atrial contraction, is useful for non-invasive assessments of LV chamber stiffness and elevated LVEDP. left ventricular chamber stiffness , left ventricular end-diastolic pressure , pulmonary venous flow , heart failure Introduction It is well known that the left ventricular (LV) diastolic pressure rises more steeply as the LV volume increases in a curvilinear relation and becomes the highest during atrial contraction up to end-diastole. A pathological increase in chamber stiffness, usually associated with a prominent ‘A’-wave and elevated LV end-diastolic pressure, may precede an elevation of mean left atrial (LA) pressure and resultant pulmonary congestion.1,2 Thus, even in patients without apparent symptoms of heart failure, the detection of increased chamber stiffness and elevated LV end-diastolic pressure may play a key role in managing patients with potential heart failure in order to prevent the development of overt heart failure.1–5 At present, the measurement of LV operating chamber stiffness requires both an invasive pressure recording and the volume measurement using conductance catheter volumetry, sonomicrometry, or echocardiography,3,4,6,7 but cardiac catheterization is invasive and not entirely free from complications. A completely non-invasive method to precisely assess LV chamber stiffness could thus be extremely valuable in clinical practice, but such a method has not yet been established. An increase in LV chamber stiffness results in a decrease in forward transmitral flow and an increase in the pulmonary venous (PV) backward flow during atrial contraction. Based on this phenomenon, it was reported that the velocity of the atrial systolic backward PV flow8 and the difference between the PV and transmitral flow durations during atrial contraction5,9 reflect the LV pressure increase during atrial contraction and LV end-diastolic pressure. However, there are some questions regarding the diagnostic power of these parameters.10–12 We speculate that the backward/forward flow volume ratio from the LA during atrial contraction would reflect the LV chamber stiffness more accurately than the conventional indices. The aim of this study was to determine the clinical usefulness of a novel non-invasive index reflecting the backward/forward flow volume ratio from the LA during atrial contraction, which was derived from time–velocity integral measurements of the PV and transmitral flows, for estimating LV operating chamber stiffness and identifying patients with elevated LV end-diastolic pressure. Methods Subjects We retrospectively examined consecutive patients who were admitted to Hokkaido University Hospital from January 2013 to December 2015 and underwent echocardiographic examination and left heart catheterization under stable clinical condition within 1 week. In regard to the study enrolment, we carefully excluded patients with changes in clinical condition such as symptoms and signs of heart failure, body weight and plasma BNP level or in cardiovascular medications between echocardiography and catheterization. Patients with atrial fibrillation, frequent premature beats, advanced atrioventricular block, congenital heart disease, any degree of mitral stenosis, or severe mitral regurgitation were also excluded. Among the remaining 71 patients, an adequate Doppler flow velocity waveform of PV flow could not be obtained in five patients, and transmitral flow Doppler flow velocity measurements could not be made in other four patients due to the summation of the early-diastolic and atrial systolic waves caused by tachycardia. Thus, the measurements of both PV flow and transmitral flow waveforms were successful in 62 of the 71 patients (87%). This study was approved as a retrospective observational study by both the Research Ethics Committee of Hokkaido University Hospital and the Ethics Committee of the Faculty of Health Sciences at Hokkaido University. Instead of obtaining informed consent, the program of the present study was opened to the public both through the home page and on the bulletin board of Hokkaido University Hospital. Echocardiographic measurements Echocardiography was performed using an Artida system equipped with a 3.0 MHz probe (Toshiba Medical Systems, Otawara, Japan), a Vivid E9 system with an M4S probe (GE Healthcare, Buckinghamshire, UK), or an iE33 system with an S4 probe (Philips Medical Systems, Eindhoven, The Netherlands). In accord with the guidelines of the American Society of Echocardiography (ASE),13 the LV end-diastolic dimension and the thicknesses of the interventricular septum and the LV-posterior wall were measured in the end-diastolic parasternal long- and short-axis images at the chordal level, and the LV mass index was calculated. The LA volume index was measured from apical two-chamber and four-chamber images using the biplane disk-summation method. The LV end-diastolic volume, end-systolic volume, and pre-atrial systolic volume were also measured using the biplane disk-summation method, and the left ventricular ejection fraction (LVEF) and the volume change during atrial contraction were calculated. The latter was corrected for each patient’s body surface area (ΔVa). With standard transthoracic pulsed-Doppler echocardiography using the apical approach, we measured the peak early-diastolic and atrial systolic transmitral flow velocities (E and A, respectively), the deceleration time of the E wave (DT), the peak systolic and diastolic forward PV flows (S and D), and the backward PV flow during atrial contraction (VPVA), and we calculated the E/A and S/D. In addition, we measured the duration and time–velocity integral of the atrial systolic forward transmitral flow (DA and IA, respectively) and the ratio of the IA to the transmitral flow time–velocity integral throughout a cardiac cycle (FA). We also measured the duration and time–velocity integral of the backward PV flow during atrial contraction (DPVA and IPVA, respectively) and the ratio of the IPVA to the PV flow time–velocity integral during a cardiac cycle (FPVA), and then we calculated DPVA − DA, IPVA/IA, and FPVA/FA (Figure 1). Tissue Doppler imaging of the mitral annulus was performed in the apical four-chamber view. The peak systolic and early-diastolic annular velocity (s′ and e′, respectively) was measured at the septal and lateral sides of the annulus. They were averaged, and E/e′ was calculated. Figure 1 View largeDownload slide Measurements of the pulmonary venous flow and transmitral flow parameters. From the PV flow waveform (left upper panel), the velocity, duration, and time–velocity integral of the backward flow during atrial contraction (VPVA, DPVA, and IPVA, respectively) were measured, and the ratio of IPVA to the time–velocity integral of PV flow through a cardiac cycle (FPVA) was calculated (right upper panel). From the transmitral flow waveform (left lower panel), the duration and time–velocity integral of the forward flow during atrial contraction (DA and IA, respectively), and the ratio of the IA to the transmitral time–velocity integral during a cardiac cycle (FA) were calculated (right lower panel). The DPVA − DA, IPVA/IA, and FPVA/FA values were then calculated. Figure 1 View largeDownload slide Measurements of the pulmonary venous flow and transmitral flow parameters. From the PV flow waveform (left upper panel), the velocity, duration, and time–velocity integral of the backward flow during atrial contraction (VPVA, DPVA, and IPVA, respectively) were measured, and the ratio of IPVA to the time–velocity integral of PV flow through a cardiac cycle (FPVA) was calculated (right upper panel). From the transmitral flow waveform (left lower panel), the duration and time–velocity integral of the forward flow during atrial contraction (DA and IA, respectively), and the ratio of the IA to the transmitral time–velocity integral during a cardiac cycle (FA) were calculated (right lower panel). The DPVA − DA, IPVA/IA, and FPVA/FA values were then calculated. Measurements of LV end-diastolic pressure and LV operating chamber stiffness LV catheterization was performed using a fluid-filled catheter. From the LV pressure records, we measured the LV pre-atrial contraction pressure, the LV pressure increase during the atrial contraction (ΔPa), and the LV end-diastolic pressure (Figure 2). Averaged values of five consecutive beats during end-expiratory breath-holding were used for the analysis. Then, using the catheterization ΔPa and echocardiographic ΔVa, we calculated the ΔPa/ΔVa ratio as an index for LV operating chamber stiffness during late-diastole.1 Figure 2 View largeDownload slide Measurements of ΔPa and LVEDP. Figure 2 View largeDownload slide Measurements of ΔPa and LVEDP. Statistical analysis The statistical analysis was performed with standard statistical software (SPSS ver. 22 for Windows, SPSS, Chicago, IL, USA). All numerical data are presented as the mean ± SD. Relationships between pairs of parameters were assessed by the linear correlation and regression analysis. A stepwise multiple regression analysis was performed to find independent determinants of the ΔPa/ΔVa ratio and LV end-diastolic pressure among multiple parameters. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability to predict the elevation of the catheterization LV end-diastolic pressure (>18 mmHg). The areas under the ROC curves were compared using the Z-test. Inter- and intra-observer reproducibilities for the VPVA, DPVA − DA, IPVA/IA, and FPVA/FA were studied in 25 randomly selected patients. For all statistical tests, a P-value <0.05 was considered significant. Results Patient characteristics The clinical, echocardiographic and haemodynamic parameters of the study patients are summarized in Table 1. Among the 62 patients, LV hypertrophy (LV mass index >115 g/m2 for males, >95 g/m2 for females) was present in 33 (53%) patients; reduced LV pump function (LVEF  < 50%) was present in 24 (39%) patients; LA dilatation (LA volume index >34 mL/m2) was identified in 37 (60%) patients, and elevated LV end-diastolic pressure was present in 12 (19%) patients. Table 1 Patient characteristics   Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0    Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0  Table 1 Patient characteristics   Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0    Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0  Relationships between Doppler parameters for estimating LV chamber stiffness and haemodynamic data The correlations between the Doppler parameters for estimating LV chamber stiffness and the ΔPa/ΔVa are shown in Figure 3. The VPVA and DPVA − DA were significantly correlated with the ΔPa/ΔVa (r = 0.38 and r = 0.56, respectively), but the correlations were relatively weak. The IPVA/IA and FPVA/FA were significantly and well correlated with the ΔPa/ΔVa (r = 0.79 and r = 0.81, respectively). Similarly, correlations between the Doppler parameters and LV end-diastolic pressure are shown in Figure 4. The VPVA did not significantly correlate with the LV end-diastolic pressure and the DPVA − DA significantly but relatively weakly correlated with the LV end-diastolic pressure (r = 0.52). The IPVA/IA and FPVA/FA were significantly and well correlated with the LV end-diastolic pressure (r = 0.73 and r = 0.77, respectively). The DT was significantly but only weakly correlated with the ΔPa/ΔVa (r =  −0.28, P = 0.028) and LV end-diastolic pressure (r = −0.37, P = 0.003). The s′ and e′ did not significantly correlate with ΔPa/ΔVa (r = −0.20 and r = −0.05, respectively) and LV end-diastolic pressure (r = −0.18 and r = −0.16, respectively). The E/e′ significantly correlated with LV end-diastolic pressure (r = 0.53, P < 0.01), but did not significantly correlate with ΔPa/ΔVa (r = 0.25). Figure 3 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LV stiffness during atrial contraction. Figure 3 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LV stiffness during atrial contraction. Figure 4 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LVEDP. Figure 4 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LVEDP. The stepwise multivariate analysis to find determinants of ΔPa/ΔVa and LV end-diastolic pressure among systolic blood pressure, heart rate, LV mass index, LVEF, degree of mitral regurgitation, and FPVA/FA revealed that the FPVA/FA was identified as the single independent determinant of ΔPa/ΔVa (β = 0.82, P < 0.001) and LV end-diastolic pressure (β = 0.78, P < 0.001). Utility for discriminating patients with elevated LV end-diastolic pressure The utility of the Doppler parameters for discriminating patients with LV end-diastolic pressure >18 mmHg from those without is summarized in Table 2. The area under the ROC curve (AUC) values were 0.93 for the FPVA/FA and 0.90 for the IPVA/IA, and these values were tended to be greater than the AUC of 0.86 for the DPVA − DA (P = 0.42 and P = 0.63, respectively) and significantly greater than that of 0.49 for the VPVA (both P < 0.001) (Figure 5). The IPVA/IA > 0.51 showed 83% sensitivity and 80% specificity, and FPVA/FA > 0.47 showed 83% sensitivity and 82% specificity, and these values were greater than the corresponding values of the DPVA − DA > 1 ms. In addition, after adjusting for the systolic blood pressure, heart rate, LV mass index, LVEF, and degree of mitral regurgitation, the AUC was 0.93 for the FPVA/FA and 0.91 for the IPVA/IA, which were tended to be greater than the AUC of 0.84 for the DPVA − DA (P = 0.37 and P = 0.52, respectively) and significantly greater than that of 0.68 for the VPVA (both P < 0.05). Table 2 Performance of pulmonary venous and transmitral flow Doppler parameters for discriminating elevated left ventricular end-diastolic pressure   AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82    AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82  Table 2 Performance of pulmonary venous and transmitral flow Doppler parameters for discriminating elevated left ventricular end-diastolic pressure   AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82    AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82  Figure 5 View largeDownload slide ROC curve analyses of various Doppler parameters. ROC curves of DPVA-DA, IPVA/IA, and FPVA/FA have been plotted for the differentiation of patients with LV end-diastolic pressure >18 mmHg from those without. Figure 5 View largeDownload slide ROC curve analyses of various Doppler parameters. ROC curves of DPVA-DA, IPVA/IA, and FPVA/FA have been plotted for the differentiation of patients with LV end-diastolic pressure >18 mmHg from those without. Reproducibility of measurements The inter- and intra-observer reproducibilities are summarized in the Table 3. The intraclass correlation coefficients for the inter- and intra-observer comparisons were good or excellent for VPVA (0.91 and 0.97, respectively), IPVA (0.89 and 0.92, respectively), FPVA (0.83 and 0.94), IA (0.92 and 0.96), FA (0.96 and 0.96), IPVA/IA (0.92 and 0.94) and FPVA/FA (0.88 and 0.96), whereas they were inadequate for DPVA − DA (0.50 and 0.53). Table 3 Inter- and intra-observer reproducibility   Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001    Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001  ICC, intraclass correlation coefficient. Table 3 Inter- and intra-observer reproducibility   Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001    Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001  ICC, intraclass correlation coefficient. Discussion Our present findings demonstrated that our new echocardiographic parameters for LV chamber stiffness using the time–velocity integral of the backward PV and forward transmitral flows during atrial contraction, i.e. IPVA/IA and FPVA/FA, can more accurately reflect late-diastolic LV chamber stiffness and could be more useful to detect an elevation of LV end-diastolic pressure compared to conventional non-invasive parameters such as VPVA and DPVA − DA in patients with different cardiac diseases. Comparison with previous investigations of Doppler parameters for estimating LV chamber stiffness Several investigators have reported the utility of the DT of the transmitral flow for estimating LV chamber stiffness. Little et al.14 demonstrated that the DT was significantly inversely correlated with an invasive parameter of LV operating chamber stiffness during the total filling period (KLV) in an experiment using eight conscious dogs. Subsequently, Garcia et al.15 showed that the DT was significantly and inversely correlated with KLV and also LV end-diastolic pressure in 18 adult patients with cardiac diseases undergoing open-heart surgery. On the other hand, Yamamoto et al.16 reported that the DT was correlated with LV end-diastolic pressure in patients with reduced ejection fraction, but not in patients with preserved ejection fraction. The DT is an early-to-mid-diastolic parameter, and can be greatly influenced also by an elevated mean LA pressure. In the present study, the DT did not correlate well with the ΔPa/ΔVa. Although e′ and E/e′ are also important diastolic parameters, their correlations with invasive LV chamber stiffness parameters were weak. We considered that e′ and E/e′ reflect LV relaxation and mean LA pressure, respectively, rather than the LV chamber stiffness. Nakatani et al.8 reported a good correlation between the VPVA and the LV end-diastolic pressure in 34 patients with various cardiac diseases. In their study, patients with LA dilatation (LA diameter > 35 mm) were excluded because VPVA can be strongly influenced by LA contractility. However, LA dilatation is frequently present in patients with left heart disease because almost all of such patients have LV diastolic dysfunction. The VPVA did not significantly correlate with LV end-diastolic pressure in our patient population, more than half of whom had LA dilatation. Moreover, the VPVA may be greatly affected by LA preload (i.e. the LA volume before atrial contraction) and the Doppler incident angle. The usefulness of the parameter DPVA–DA was reported by several investigators and cited as a parameter reflecting the LV end-diastolic pressure by the ASE/EACVI guidelines.1,2,5,9,16 However, this parameter requires delicate timing measurements and does not use the velocity information. In the present study, the relationships of the DPVA–DA with LV chamber stiffness and LV end-diastolic pressure were modest, and the inter- and intra-observer reliability was not adequate. The IPVA/IA, one of our novel parameters, which uses both the velocity and duration information, was well correlated with the LV chamber stiffness and LV end-diastolic pressure, much better than the VPVA and DPVA–DA were. However, the IPVA/IA is not a backward/forward flow volume ratio because it is simply a time–velocity integral ratio and depends on the difference in the Doppler incident angle among patients. In contrast, the FPVA/FA is considered to represent a backward/forward flow volume ratio during LA contraction because the FPVA theoretically represents a backward flow fraction and the FA does a forward flow fraction during LA contraction, respectively. Thus, the FPVA/FA, which may be free from angle dependency, was actually best correlated with the LV chamber stiffness and LV end-diastolic pressure among the Doppler parameters in this study. Clinical importance of assessing LV chamber stiffness In patients with increased chamber stiffness but without apparent left heart failure, the LV end-diastolic pressure and mean LA pressure may be dissociated because the LV end-diastolic pressure can distinctly exceed the mean LA pressure due to the prominent pressure rise during atrial contraction (Figure 6).2,17 Although parameters reflecting the mean LA pressure, such as E/A and E/e′, are widely used to evaluate patients with heart failure, the estimation of LV stiffness may have a role independent from them in the assessment of cardiac patients and may be useful to predict overt heart failure before its onset.1,2 Figure 6 View largeDownload slide Pulmonary venous and transmitral Doppler recordings in a patient with increased LV chamber stiffness. This figure shows pulmonary venous (upper panels) and transmitral (lower panels) flow velocity waveforms in a 47-years-old male patient with hypertensive heart disease and with increased LV chamber stiffness (LV end-diastolic pressure of 24 mmHg, ΔPa/ΔVa of 1.89 mmHg·m2/mL, and FPVA/FA of 1.16) but without any increase in mean pulmonary artery wedge pressure (8 mmHg). Figure 6 View largeDownload slide Pulmonary venous and transmitral Doppler recordings in a patient with increased LV chamber stiffness. This figure shows pulmonary venous (upper panels) and transmitral (lower panels) flow velocity waveforms in a 47-years-old male patient with hypertensive heart disease and with increased LV chamber stiffness (LV end-diastolic pressure of 24 mmHg, ΔPa/ΔVa of 1.89 mmHg·m2/mL, and FPVA/FA of 1.16) but without any increase in mean pulmonary artery wedge pressure (8 mmHg). For example, in patients with abnormally increased LV stiffness but without a mean LA pressure rise, greater venous return to the heart induced by exercise or excessive circulatory volume load may cause a further increase in LV stiffness and LV end-diastolic pressure. A further increase in preload or myocardial damage may lead to an elevation of the mean LA pressure and pulmonary congestion. Our new index FPVA/FA may be useful in such a situation for making decisions regarding the therapeutic strategy. Several investigators have reported that the detection of increased chamber stiffness18 and elevated LV end-diastolic pressure,19–22 evaluated using cardiac catheterization, were useful to predict poor prognosis or future cardiac events in patients with coronary artery disease,19,20 non-coronary artery disease,18 and various heart diseases.21 Among them, Watanabe et al.18 reported that increased LV chamber stiffness was the strongest prognostic marker for cardiac death or admission for decompensation in patients with chronic heart failure. Using Doppler echocardiography, Dini et al.22 reported that the DPVA − DA had a prognostic value independent of the mean LA pressure in patients with LV systolic dysfunction. Clinical implications Our present findings demonstrated that our parameters FPVA/FA and IPVA/IA were more accurate indices for chamber stiffness and LV end-diastolic pressure than the DPVA − DA. Thus, the non-invasive estimation of LV stiffness by using our parameters, especially FPVA/FA, may have utility for stratifying cardiac patients for the risk of heart failure before their mean LA pressure distinctly rise. Limitations There are several limitations in this study. First, left heart catheterization and echocardiography were not performed simultaneously. Although we carefully excluded patients with unstable haemodynamics and/or loading conditions between cardiac catheterization and echocardiography, the possibility of haemodynamic alteration might not be completely excluded. Second, the Doppler parameters for estimating LV chamber stiffness could not be obtained in 13% of the initial candidates. This percentage, however, is smaller than that reported in past studies (13%–38%)8,9,11,16,22 and seems to be acceptable for clinical practice. Further advancement of ultrasound technology may increase the detection rate of PV Doppler waveform. Third, patients with elevated LV end-diastolic pressure are relatively few. This can limit the findings of this study. Fourth, our method cannot be applied to patients without synchronized atrial activity due to arrhythmias such as atrial fibrillation, atrial flutter and complete atrioventricular block. Conflict of interest: None declared. References 1 Nagueh SF, Smiseth OA, Appleton CP, Byrd BF3rd, Dokainish H, Edvardsen T et al.   Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging  2016; 17: 1321– 60. Google Scholar CrossRef Search ADS PubMed  2 Hadano Y, Murata K, Liu J, Oyama R, Harada N, Okuda S et al.   Can transthoracic Doppler echocardiography predict the discrepancy between left ventricular end-diastolic pressure and mean pulmonary capillary wedge pressure in patients with heart failure? Circ J  2005; 69: 432– 8. Google Scholar CrossRef Search ADS PubMed  3 Grossman W, Stefadouros MA, McLaurin LP, Rolett EL, Young DT. Quantitative assessment of left ventricular diastolic stiffness in man. Circulation  1973; 47: 567– 74. Google Scholar CrossRef Search ADS PubMed  4 Ambrose JA, Teichholz LE, Meller J, Weintraub W, Pichard AD, Smith HJr et al.   The influence of left ventricular late diastolic filling on the A wave of the left ventricular pressure trace. Circulation  1979; 60: 510– 9. Google Scholar CrossRef Search ADS PubMed  5 Rossvoll O, Hatle LK. Pulmonary venous flow velocities recorded by transthoracic Doppler ultrasound: relation to left ventricular diastolic pressures. J Am Coll Cardiol  1993; 21: 1687– 96. http://dx.doi.org/10.1016/0735-1097(93)90388-H Google Scholar CrossRef Search ADS PubMed  6 Klotz S, Hay I, Dickstein ML, Yi GH, Wang J, Maurer MS et al.   Single-beat estimation of end-diastolic pressure-volume relationship: a novel method with potential for noninvasive application. Am J Physiol Heart Circ Physiol  2006; 291: H403– 12. Google Scholar CrossRef Search ADS PubMed  7 Urheim S, Bjørnerheim R, Endresen K, Vatne K, Rabben SI, Sørhus V et al.   Quantification of left ventricular diastolic pressure-volume relations during routine cardiac catheterization by two-dimensional digital echo quantification and left ventricular micromanometer. J Am Soc Echocardiogr  2002; 15: 225– 32. Google Scholar CrossRef Search ADS PubMed  8 Nakatani S, Yoshitomi H, Wada K, Beppu S, Nagata S, Miyatake K. Noninvasive estimation of left ventricular end-diastolic pressure using transthoracic Doppler-determined pulmonary venous atrial flow reversal. Am J Cardiol  1994; 73: 1017– 8. Google Scholar CrossRef Search ADS PubMed  9 Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using two-dimensional and Doppler echocardiography in adult patients with cardiac disease. Additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol  1993; 22: 1972– 82. Google Scholar CrossRef Search ADS PubMed  10 Tabata T, Thomas JD, Klein AL. Pulmonary venous flow by Doppler echocardiography: revisited 12 years later. J Am Coll Cardiol  2003; 41: 1243– 50. http://dx.doi.org/10.1016/S0735-1097(03)00126-8 Google Scholar CrossRef Search ADS PubMed  11 Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM et al.   Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation  2000; 102: 1788– 94. Google Scholar CrossRef Search ADS PubMed  12 Nagueh SF, Lakkis NM, Middleton KJ, Spencer WH3rd, Zoghbi WA, Quiñones MA. Doppler estimation of left ventricular filling pressures in patients with hypertrophic cardiomyopathy. Circulation  1999; 99: 254– 61. Google Scholar CrossRef Search ADS PubMed  13 Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L et al.   Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging  2015; 16: 233– 70. Google Scholar CrossRef Search ADS PubMed  14 Little WC, Ohno M, Kitzman DW, Thomas JD, Cheng CP. Determination of left ventricular chamber stiffness from the time for deceleration of early left ventricular filling. Circulation  1995; 92: 1933– 9. Google Scholar CrossRef Search ADS PubMed  15 Garcia MJ, Firstenberg MS, Greenberg NL, Smedira N, Rodriguez L, Prior D et al.   Estimation of left ventricular operating stiffness from Doppler early filling deceleration time in humans. Am J Physiol Heart Circ Physiol  2001; 280: H554– 61. Google Scholar PubMed  16 Yamamoto K, Nishimura RA, Chaliki HP, Appleton CP, Holmes DRJr, Redfield MM. Determination of left ventricular filling pressure by Doppler echocardiography in patients with coronary artery disease: critical role of left ventricular systolic function. J Am Coll Cardiol  1997; 30: 1819– 26. Google Scholar CrossRef Search ADS PubMed  17 Halpern SD, Taichman DB. Misclassification of pulmonary hypertension due to reliance on pulmonary capillary wedge pressure rather than left ventricular end-diastolic pressure. Chest  2009; 136: 37– 43. http://dx.doi.org/10.1378/chest.08-2784 Google Scholar CrossRef Search ADS PubMed  18 Watanabe S, Shite J, Takaoka H, Shinke T, Tanino Y, Otake H et al.   Predictive importance of left ventricular myocardial stiffness for the prognosis of patients with congestive heart failure. J Cardiol  2011; 58: 245– 52. Google Scholar CrossRef Search ADS PubMed  19 Bagai A, Armstrong PW, Stebbins A, Mahaffey KW, Hochman JS, Weaver WD et al.   Prognostic implications of left ventricular end-diastolic pressure during primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: findings from the Assessment of Pexelizumab in Acute Myocardial Infarction study. Am Heart J  2013; 166: 913– 9. Google Scholar CrossRef Search ADS PubMed  20 Nagendran J, Norris CM, Appoo JJ, Ross DB, Nagendran J. Left ventricular end-diastolic pressure predicts survival in coronary artery bypass graft surgery patients. Ann Thorac Surg  2014; 97: 1343– 7. Google Scholar CrossRef Search ADS PubMed  21 Liang HY, Cauduro SA, Pellikka PA, Bailey KR, Grossardt BR, Yang EH et al.   Comparison of usefulness of echocardiographic Doppler variables to left ventricular end-diastolic pressure in predicting future heart failure events. Am J Cardiol  2006; 97: 866– 71. Google Scholar CrossRef Search ADS PubMed  22 Dini FL, Michelassi C, Micheli G, Rovai D. Prognostic value of pulmonary venous flow Doppler signal in left ventricular dysfunction: contribution of the difference in duration of pulmonary venous and mitral flow at atrial contraction. J Am Coll Cardiol  2000; 36: 1295– 302. http://dx.doi.org/10.1016/S0735-1097(00)00821-4 Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal – Cardiovascular Imaging Oxford University Press

Novel echocardiographic method to assess left ventricular chamber stiffness and elevated end-diastolic pressure based on time–velocity integral measurements of pulmonary venous and transmitral flows

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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Aims The detection of increased left ventricular (LV) chamber stiffness may play an important role in assessing cardiac patients with potential but not overt heart failure. A non-invasive method to estimate it is not established. We investigated whether the echocardiographic backward/forward flow volume ratio from the left atrium (LA) during atrial contraction reflects the LV chamber stiffness. Methods and results We studied 62 patients who underwent cardiac catheterization and measured their left ventricular end-diastolic pressure (LVEDP) and pressure increase during atrial contraction (ΔPa) from the LV pressure waveform. Using the echocardiographic biplane method of disks, we measured the LV volume change during atrial contraction indexed to the body surface area (ΔVa), and ΔPa/ΔVa was calculated as a standard for the LV operating chamber stiffness. Using pulsed Doppler echocardiography, we measured the time–velocity integral (TVI) of the backward pulmonary venous (PV) flow during atrial contraction (IPVA) and the ratio of IPVA to the PV flow TVI throughout a cardiac cycle (FPVA). We also measured the TVI of the atrial systolic forward transmitral flow (IA) and the ratio of the IA to the transmitral TVI during a cardiac cycle (FA) and calculated IPVA/IA and FPVA/FA. IPVA/IA and FPVA/FA were well correlated with ΔPa/ΔVa (r = 0.79 and r = 0.81) and LVEDP (r = 0.73 and r = 0.77). The areas under the ROC curve to discriminate LVEDP >18 mmHg were 0.90 for IPVA/IA and 0.93 for FPVA/FA. Conclusion The FPVA/FA, the backward/forward flow volume ratio from the LA during atrial contraction, is useful for non-invasive assessments of LV chamber stiffness and elevated LVEDP. left ventricular chamber stiffness , left ventricular end-diastolic pressure , pulmonary venous flow , heart failure Introduction It is well known that the left ventricular (LV) diastolic pressure rises more steeply as the LV volume increases in a curvilinear relation and becomes the highest during atrial contraction up to end-diastole. A pathological increase in chamber stiffness, usually associated with a prominent ‘A’-wave and elevated LV end-diastolic pressure, may precede an elevation of mean left atrial (LA) pressure and resultant pulmonary congestion.1,2 Thus, even in patients without apparent symptoms of heart failure, the detection of increased chamber stiffness and elevated LV end-diastolic pressure may play a key role in managing patients with potential heart failure in order to prevent the development of overt heart failure.1–5 At present, the measurement of LV operating chamber stiffness requires both an invasive pressure recording and the volume measurement using conductance catheter volumetry, sonomicrometry, or echocardiography,3,4,6,7 but cardiac catheterization is invasive and not entirely free from complications. A completely non-invasive method to precisely assess LV chamber stiffness could thus be extremely valuable in clinical practice, but such a method has not yet been established. An increase in LV chamber stiffness results in a decrease in forward transmitral flow and an increase in the pulmonary venous (PV) backward flow during atrial contraction. Based on this phenomenon, it was reported that the velocity of the atrial systolic backward PV flow8 and the difference between the PV and transmitral flow durations during atrial contraction5,9 reflect the LV pressure increase during atrial contraction and LV end-diastolic pressure. However, there are some questions regarding the diagnostic power of these parameters.10–12 We speculate that the backward/forward flow volume ratio from the LA during atrial contraction would reflect the LV chamber stiffness more accurately than the conventional indices. The aim of this study was to determine the clinical usefulness of a novel non-invasive index reflecting the backward/forward flow volume ratio from the LA during atrial contraction, which was derived from time–velocity integral measurements of the PV and transmitral flows, for estimating LV operating chamber stiffness and identifying patients with elevated LV end-diastolic pressure. Methods Subjects We retrospectively examined consecutive patients who were admitted to Hokkaido University Hospital from January 2013 to December 2015 and underwent echocardiographic examination and left heart catheterization under stable clinical condition within 1 week. In regard to the study enrolment, we carefully excluded patients with changes in clinical condition such as symptoms and signs of heart failure, body weight and plasma BNP level or in cardiovascular medications between echocardiography and catheterization. Patients with atrial fibrillation, frequent premature beats, advanced atrioventricular block, congenital heart disease, any degree of mitral stenosis, or severe mitral regurgitation were also excluded. Among the remaining 71 patients, an adequate Doppler flow velocity waveform of PV flow could not be obtained in five patients, and transmitral flow Doppler flow velocity measurements could not be made in other four patients due to the summation of the early-diastolic and atrial systolic waves caused by tachycardia. Thus, the measurements of both PV flow and transmitral flow waveforms were successful in 62 of the 71 patients (87%). This study was approved as a retrospective observational study by both the Research Ethics Committee of Hokkaido University Hospital and the Ethics Committee of the Faculty of Health Sciences at Hokkaido University. Instead of obtaining informed consent, the program of the present study was opened to the public both through the home page and on the bulletin board of Hokkaido University Hospital. Echocardiographic measurements Echocardiography was performed using an Artida system equipped with a 3.0 MHz probe (Toshiba Medical Systems, Otawara, Japan), a Vivid E9 system with an M4S probe (GE Healthcare, Buckinghamshire, UK), or an iE33 system with an S4 probe (Philips Medical Systems, Eindhoven, The Netherlands). In accord with the guidelines of the American Society of Echocardiography (ASE),13 the LV end-diastolic dimension and the thicknesses of the interventricular septum and the LV-posterior wall were measured in the end-diastolic parasternal long- and short-axis images at the chordal level, and the LV mass index was calculated. The LA volume index was measured from apical two-chamber and four-chamber images using the biplane disk-summation method. The LV end-diastolic volume, end-systolic volume, and pre-atrial systolic volume were also measured using the biplane disk-summation method, and the left ventricular ejection fraction (LVEF) and the volume change during atrial contraction were calculated. The latter was corrected for each patient’s body surface area (ΔVa). With standard transthoracic pulsed-Doppler echocardiography using the apical approach, we measured the peak early-diastolic and atrial systolic transmitral flow velocities (E and A, respectively), the deceleration time of the E wave (DT), the peak systolic and diastolic forward PV flows (S and D), and the backward PV flow during atrial contraction (VPVA), and we calculated the E/A and S/D. In addition, we measured the duration and time–velocity integral of the atrial systolic forward transmitral flow (DA and IA, respectively) and the ratio of the IA to the transmitral flow time–velocity integral throughout a cardiac cycle (FA). We also measured the duration and time–velocity integral of the backward PV flow during atrial contraction (DPVA and IPVA, respectively) and the ratio of the IPVA to the PV flow time–velocity integral during a cardiac cycle (FPVA), and then we calculated DPVA − DA, IPVA/IA, and FPVA/FA (Figure 1). Tissue Doppler imaging of the mitral annulus was performed in the apical four-chamber view. The peak systolic and early-diastolic annular velocity (s′ and e′, respectively) was measured at the septal and lateral sides of the annulus. They were averaged, and E/e′ was calculated. Figure 1 View largeDownload slide Measurements of the pulmonary venous flow and transmitral flow parameters. From the PV flow waveform (left upper panel), the velocity, duration, and time–velocity integral of the backward flow during atrial contraction (VPVA, DPVA, and IPVA, respectively) were measured, and the ratio of IPVA to the time–velocity integral of PV flow through a cardiac cycle (FPVA) was calculated (right upper panel). From the transmitral flow waveform (left lower panel), the duration and time–velocity integral of the forward flow during atrial contraction (DA and IA, respectively), and the ratio of the IA to the transmitral time–velocity integral during a cardiac cycle (FA) were calculated (right lower panel). The DPVA − DA, IPVA/IA, and FPVA/FA values were then calculated. Figure 1 View largeDownload slide Measurements of the pulmonary venous flow and transmitral flow parameters. From the PV flow waveform (left upper panel), the velocity, duration, and time–velocity integral of the backward flow during atrial contraction (VPVA, DPVA, and IPVA, respectively) were measured, and the ratio of IPVA to the time–velocity integral of PV flow through a cardiac cycle (FPVA) was calculated (right upper panel). From the transmitral flow waveform (left lower panel), the duration and time–velocity integral of the forward flow during atrial contraction (DA and IA, respectively), and the ratio of the IA to the transmitral time–velocity integral during a cardiac cycle (FA) were calculated (right lower panel). The DPVA − DA, IPVA/IA, and FPVA/FA values were then calculated. Measurements of LV end-diastolic pressure and LV operating chamber stiffness LV catheterization was performed using a fluid-filled catheter. From the LV pressure records, we measured the LV pre-atrial contraction pressure, the LV pressure increase during the atrial contraction (ΔPa), and the LV end-diastolic pressure (Figure 2). Averaged values of five consecutive beats during end-expiratory breath-holding were used for the analysis. Then, using the catheterization ΔPa and echocardiographic ΔVa, we calculated the ΔPa/ΔVa ratio as an index for LV operating chamber stiffness during late-diastole.1 Figure 2 View largeDownload slide Measurements of ΔPa and LVEDP. Figure 2 View largeDownload slide Measurements of ΔPa and LVEDP. Statistical analysis The statistical analysis was performed with standard statistical software (SPSS ver. 22 for Windows, SPSS, Chicago, IL, USA). All numerical data are presented as the mean ± SD. Relationships between pairs of parameters were assessed by the linear correlation and regression analysis. A stepwise multiple regression analysis was performed to find independent determinants of the ΔPa/ΔVa ratio and LV end-diastolic pressure among multiple parameters. A receiver operating characteristic (ROC) curve analysis was performed to evaluate the ability to predict the elevation of the catheterization LV end-diastolic pressure (>18 mmHg). The areas under the ROC curves were compared using the Z-test. Inter- and intra-observer reproducibilities for the VPVA, DPVA − DA, IPVA/IA, and FPVA/FA were studied in 25 randomly selected patients. For all statistical tests, a P-value <0.05 was considered significant. Results Patient characteristics The clinical, echocardiographic and haemodynamic parameters of the study patients are summarized in Table 1. Among the 62 patients, LV hypertrophy (LV mass index >115 g/m2 for males, >95 g/m2 for females) was present in 33 (53%) patients; reduced LV pump function (LVEF  < 50%) was present in 24 (39%) patients; LA dilatation (LA volume index >34 mL/m2) was identified in 37 (60%) patients, and elevated LV end-diastolic pressure was present in 12 (19%) patients. Table 1 Patient characteristics   Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0    Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0  Table 1 Patient characteristics   Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0    Mean ± SD (n = 62)  Range  Clinical characteristics       Age (years)  63.6 ± 14.8  21–87   Male/female  38/24     Body surface area (m2)  1.62 ± 0.23  1.18–2.12   Systolic blood pressure (mmHg)  122 ± 21  83–190   Diastolic blood pressure (mmHg)  68 ± 14  36–106   Heart rate (bpm)  68.5 ± 11.9  51–100   Underlying heart disease, n (%)        Ischaemic heart disease  23 (37%)      Cardiomyopathy  13 (21%)      Valvular heart disease  11 (18%)      Hypertensive heart disease  5 (8%)      Pericardial disease  2 (3%)      Others  8 (13%)    Two-dimensional echocardiographic parameters     LV end-diastolic dimension (mm)  50.9 ± 9.0  33–79   LV ejection fraction (%)  53.0 ± 15.9  17–82   LV mass index (g/m2)  112 ± 35  45–216   Left atrial volume index (mL/m2)  40.7 ± 15.0  12–76  Transmitral and pulmonary venous flow parameters     E (cm/s)  71.3 ± 22.4  30.7–155.0   A (cm/s)  74.4 ± 22.5  18.2–127.8   E/A  1.10 ± 0.71  0.36–5.07   DT (ms)  205 ± 51  127–364   S (cm/s)  58.8 ± 17.8  32.9–121.0   D (cm/s)  48.1 ± 16.5  17.1–102.8   S/D  1.34 ± 0.52  0.36–2.78   VPVA (cm/s)  35.1 ± 15.4  17.9–115.0   DPVA − DA (ms)  −6.7 ± 24.8  −52–66   IPVA/IA  0.51 ± 0.31  0.21–1.83   FPVA/FA  0.44 ± 0.24  0.13–1.28  Haemodynamic parameters       LV pre-A pressure (mmHg)  10.1 ± 4.7  2.5–28.7   ΔPa (mmHg)  5.7 ± 3.3  0.9–14.7   ΔPa/ΔVa (mmHg·m2/mL)  0.49 ± 0.41  0.07–1.89   LV end-diastolic pressure (mmHg)  15.2 ± 5.7  6.6–35.0  Relationships between Doppler parameters for estimating LV chamber stiffness and haemodynamic data The correlations between the Doppler parameters for estimating LV chamber stiffness and the ΔPa/ΔVa are shown in Figure 3. The VPVA and DPVA − DA were significantly correlated with the ΔPa/ΔVa (r = 0.38 and r = 0.56, respectively), but the correlations were relatively weak. The IPVA/IA and FPVA/FA were significantly and well correlated with the ΔPa/ΔVa (r = 0.79 and r = 0.81, respectively). Similarly, correlations between the Doppler parameters and LV end-diastolic pressure are shown in Figure 4. The VPVA did not significantly correlate with the LV end-diastolic pressure and the DPVA − DA significantly but relatively weakly correlated with the LV end-diastolic pressure (r = 0.52). The IPVA/IA and FPVA/FA were significantly and well correlated with the LV end-diastolic pressure (r = 0.73 and r = 0.77, respectively). The DT was significantly but only weakly correlated with the ΔPa/ΔVa (r =  −0.28, P = 0.028) and LV end-diastolic pressure (r = −0.37, P = 0.003). The s′ and e′ did not significantly correlate with ΔPa/ΔVa (r = −0.20 and r = −0.05, respectively) and LV end-diastolic pressure (r = −0.18 and r = −0.16, respectively). The E/e′ significantly correlated with LV end-diastolic pressure (r = 0.53, P < 0.01), but did not significantly correlate with ΔPa/ΔVa (r = 0.25). Figure 3 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LV stiffness during atrial contraction. Figure 3 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LV stiffness during atrial contraction. Figure 4 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LVEDP. Figure 4 View largeDownload slide Correlation of Doppler parameters of pulmonary venous and transmitral flows with the LVEDP. The stepwise multivariate analysis to find determinants of ΔPa/ΔVa and LV end-diastolic pressure among systolic blood pressure, heart rate, LV mass index, LVEF, degree of mitral regurgitation, and FPVA/FA revealed that the FPVA/FA was identified as the single independent determinant of ΔPa/ΔVa (β = 0.82, P < 0.001) and LV end-diastolic pressure (β = 0.78, P < 0.001). Utility for discriminating patients with elevated LV end-diastolic pressure The utility of the Doppler parameters for discriminating patients with LV end-diastolic pressure >18 mmHg from those without is summarized in Table 2. The area under the ROC curve (AUC) values were 0.93 for the FPVA/FA and 0.90 for the IPVA/IA, and these values were tended to be greater than the AUC of 0.86 for the DPVA − DA (P = 0.42 and P = 0.63, respectively) and significantly greater than that of 0.49 for the VPVA (both P < 0.001) (Figure 5). The IPVA/IA > 0.51 showed 83% sensitivity and 80% specificity, and FPVA/FA > 0.47 showed 83% sensitivity and 82% specificity, and these values were greater than the corresponding values of the DPVA − DA > 1 ms. In addition, after adjusting for the systolic blood pressure, heart rate, LV mass index, LVEF, and degree of mitral regurgitation, the AUC was 0.93 for the FPVA/FA and 0.91 for the IPVA/IA, which were tended to be greater than the AUC of 0.84 for the DPVA − DA (P = 0.37 and P = 0.52, respectively) and significantly greater than that of 0.68 for the VPVA (both P < 0.05). Table 2 Performance of pulmonary venous and transmitral flow Doppler parameters for discriminating elevated left ventricular end-diastolic pressure   AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82    AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82  Table 2 Performance of pulmonary venous and transmitral flow Doppler parameters for discriminating elevated left ventricular end-diastolic pressure   AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82    AUC  P-value  Optimal cut-off value  Sensitivity (%)  Specificity (%)  Accuracy (%)  VPVA (cm/s)  0.49  0.28          DPVA − DA (ms)  0.86  <0.001  1 ms  76  75  76  IPVA/IA  0.90  <0.001  0.51  83  80  81  FPVA/FA  0.93  <0.001  0.47  83  82  82  Figure 5 View largeDownload slide ROC curve analyses of various Doppler parameters. ROC curves of DPVA-DA, IPVA/IA, and FPVA/FA have been plotted for the differentiation of patients with LV end-diastolic pressure >18 mmHg from those without. Figure 5 View largeDownload slide ROC curve analyses of various Doppler parameters. ROC curves of DPVA-DA, IPVA/IA, and FPVA/FA have been plotted for the differentiation of patients with LV end-diastolic pressure >18 mmHg from those without. Reproducibility of measurements The inter- and intra-observer reproducibilities are summarized in the Table 3. The intraclass correlation coefficients for the inter- and intra-observer comparisons were good or excellent for VPVA (0.91 and 0.97, respectively), IPVA (0.89 and 0.92, respectively), FPVA (0.83 and 0.94), IA (0.92 and 0.96), FA (0.96 and 0.96), IPVA/IA (0.92 and 0.94) and FPVA/FA (0.88 and 0.96), whereas they were inadequate for DPVA − DA (0.50 and 0.53). Table 3 Inter- and intra-observer reproducibility   Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001    Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001  ICC, intraclass correlation coefficient. Table 3 Inter- and intra-observer reproducibility   Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001    Inter-observer   Intra-observer     ICC  95% CI  P  ICC  95% CI  P  VPVA (cm/s)  0.91  0.77–0.96  <0.001  0.97  0.92–0.98  <0.001  DPVA − DA (ms)  0.50  0.14–0.75  0.002  0.53  0.17–0.77  0.003  IPVA/IA  0.92  0.83–0.97  <0.001  0.94  0.86–0.97  <0.001  FPVA/FA  0.88  0.75–0.95  <0.001  0.96  0.92–0.98  <0.001  ICC, intraclass correlation coefficient. Discussion Our present findings demonstrated that our new echocardiographic parameters for LV chamber stiffness using the time–velocity integral of the backward PV and forward transmitral flows during atrial contraction, i.e. IPVA/IA and FPVA/FA, can more accurately reflect late-diastolic LV chamber stiffness and could be more useful to detect an elevation of LV end-diastolic pressure compared to conventional non-invasive parameters such as VPVA and DPVA − DA in patients with different cardiac diseases. Comparison with previous investigations of Doppler parameters for estimating LV chamber stiffness Several investigators have reported the utility of the DT of the transmitral flow for estimating LV chamber stiffness. Little et al.14 demonstrated that the DT was significantly inversely correlated with an invasive parameter of LV operating chamber stiffness during the total filling period (KLV) in an experiment using eight conscious dogs. Subsequently, Garcia et al.15 showed that the DT was significantly and inversely correlated with KLV and also LV end-diastolic pressure in 18 adult patients with cardiac diseases undergoing open-heart surgery. On the other hand, Yamamoto et al.16 reported that the DT was correlated with LV end-diastolic pressure in patients with reduced ejection fraction, but not in patients with preserved ejection fraction. The DT is an early-to-mid-diastolic parameter, and can be greatly influenced also by an elevated mean LA pressure. In the present study, the DT did not correlate well with the ΔPa/ΔVa. Although e′ and E/e′ are also important diastolic parameters, their correlations with invasive LV chamber stiffness parameters were weak. We considered that e′ and E/e′ reflect LV relaxation and mean LA pressure, respectively, rather than the LV chamber stiffness. Nakatani et al.8 reported a good correlation between the VPVA and the LV end-diastolic pressure in 34 patients with various cardiac diseases. In their study, patients with LA dilatation (LA diameter > 35 mm) were excluded because VPVA can be strongly influenced by LA contractility. However, LA dilatation is frequently present in patients with left heart disease because almost all of such patients have LV diastolic dysfunction. The VPVA did not significantly correlate with LV end-diastolic pressure in our patient population, more than half of whom had LA dilatation. Moreover, the VPVA may be greatly affected by LA preload (i.e. the LA volume before atrial contraction) and the Doppler incident angle. The usefulness of the parameter DPVA–DA was reported by several investigators and cited as a parameter reflecting the LV end-diastolic pressure by the ASE/EACVI guidelines.1,2,5,9,16 However, this parameter requires delicate timing measurements and does not use the velocity information. In the present study, the relationships of the DPVA–DA with LV chamber stiffness and LV end-diastolic pressure were modest, and the inter- and intra-observer reliability was not adequate. The IPVA/IA, one of our novel parameters, which uses both the velocity and duration information, was well correlated with the LV chamber stiffness and LV end-diastolic pressure, much better than the VPVA and DPVA–DA were. However, the IPVA/IA is not a backward/forward flow volume ratio because it is simply a time–velocity integral ratio and depends on the difference in the Doppler incident angle among patients. In contrast, the FPVA/FA is considered to represent a backward/forward flow volume ratio during LA contraction because the FPVA theoretically represents a backward flow fraction and the FA does a forward flow fraction during LA contraction, respectively. Thus, the FPVA/FA, which may be free from angle dependency, was actually best correlated with the LV chamber stiffness and LV end-diastolic pressure among the Doppler parameters in this study. Clinical importance of assessing LV chamber stiffness In patients with increased chamber stiffness but without apparent left heart failure, the LV end-diastolic pressure and mean LA pressure may be dissociated because the LV end-diastolic pressure can distinctly exceed the mean LA pressure due to the prominent pressure rise during atrial contraction (Figure 6).2,17 Although parameters reflecting the mean LA pressure, such as E/A and E/e′, are widely used to evaluate patients with heart failure, the estimation of LV stiffness may have a role independent from them in the assessment of cardiac patients and may be useful to predict overt heart failure before its onset.1,2 Figure 6 View largeDownload slide Pulmonary venous and transmitral Doppler recordings in a patient with increased LV chamber stiffness. This figure shows pulmonary venous (upper panels) and transmitral (lower panels) flow velocity waveforms in a 47-years-old male patient with hypertensive heart disease and with increased LV chamber stiffness (LV end-diastolic pressure of 24 mmHg, ΔPa/ΔVa of 1.89 mmHg·m2/mL, and FPVA/FA of 1.16) but without any increase in mean pulmonary artery wedge pressure (8 mmHg). Figure 6 View largeDownload slide Pulmonary venous and transmitral Doppler recordings in a patient with increased LV chamber stiffness. This figure shows pulmonary venous (upper panels) and transmitral (lower panels) flow velocity waveforms in a 47-years-old male patient with hypertensive heart disease and with increased LV chamber stiffness (LV end-diastolic pressure of 24 mmHg, ΔPa/ΔVa of 1.89 mmHg·m2/mL, and FPVA/FA of 1.16) but without any increase in mean pulmonary artery wedge pressure (8 mmHg). For example, in patients with abnormally increased LV stiffness but without a mean LA pressure rise, greater venous return to the heart induced by exercise or excessive circulatory volume load may cause a further increase in LV stiffness and LV end-diastolic pressure. A further increase in preload or myocardial damage may lead to an elevation of the mean LA pressure and pulmonary congestion. Our new index FPVA/FA may be useful in such a situation for making decisions regarding the therapeutic strategy. Several investigators have reported that the detection of increased chamber stiffness18 and elevated LV end-diastolic pressure,19–22 evaluated using cardiac catheterization, were useful to predict poor prognosis or future cardiac events in patients with coronary artery disease,19,20 non-coronary artery disease,18 and various heart diseases.21 Among them, Watanabe et al.18 reported that increased LV chamber stiffness was the strongest prognostic marker for cardiac death or admission for decompensation in patients with chronic heart failure. Using Doppler echocardiography, Dini et al.22 reported that the DPVA − DA had a prognostic value independent of the mean LA pressure in patients with LV systolic dysfunction. Clinical implications Our present findings demonstrated that our parameters FPVA/FA and IPVA/IA were more accurate indices for chamber stiffness and LV end-diastolic pressure than the DPVA − DA. Thus, the non-invasive estimation of LV stiffness by using our parameters, especially FPVA/FA, may have utility for stratifying cardiac patients for the risk of heart failure before their mean LA pressure distinctly rise. Limitations There are several limitations in this study. First, left heart catheterization and echocardiography were not performed simultaneously. Although we carefully excluded patients with unstable haemodynamics and/or loading conditions between cardiac catheterization and echocardiography, the possibility of haemodynamic alteration might not be completely excluded. Second, the Doppler parameters for estimating LV chamber stiffness could not be obtained in 13% of the initial candidates. This percentage, however, is smaller than that reported in past studies (13%–38%)8,9,11,16,22 and seems to be acceptable for clinical practice. Further advancement of ultrasound technology may increase the detection rate of PV Doppler waveform. Third, patients with elevated LV end-diastolic pressure are relatively few. This can limit the findings of this study. Fourth, our method cannot be applied to patients without synchronized atrial activity due to arrhythmias such as atrial fibrillation, atrial flutter and complete atrioventricular block. Conflict of interest: None declared. References 1 Nagueh SF, Smiseth OA, Appleton CP, Byrd BF3rd, Dokainish H, Edvardsen T et al.   Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging  2016; 17: 1321– 60. Google Scholar CrossRef Search ADS PubMed  2 Hadano Y, Murata K, Liu J, Oyama R, Harada N, Okuda S et al.   Can transthoracic Doppler echocardiography predict the discrepancy between left ventricular end-diastolic pressure and mean pulmonary capillary wedge pressure in patients with heart failure? 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For permissions, please email: journals.permissions@oup.com.

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European Heart Journal – Cardiovascular ImagingOxford University Press

Published: Dec 8, 2017

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