- Email: [email protected]
Noninvasive Assessment of Pulmonary Vascular Resistance by Doppler Echocardiography
PULMONARY HEMODYNAMICS
Noninvasive Assessment of Pulmonary Vascular Resistance by Doppler Echocardiography Amr E. Abbas, MD, FACC, Laura M. Franey, MD, Thomas Marwick, MD, PhD, Micha T. Maeder, MD, David M. Kaye, MD, FACC, Antonios P. Vlahos, MD, PhD, Walter Serra, MD, Karim Al-Azizi, MD, Nelson B. Schiller, MD, FACC, and Steven J. Lester, MD, FRCP(C), Royal Oak, Rochester, and Pontiac, Michigan; Hobart and Melbourne, Australia; St. Gallen, Switzerland; Ioannina, Greece; Parma, Italy; San Francisco, California; Scottsdale, Arizona
Background: The ratio of tricuspid regurgitation velocity (TRV) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) has been studied as a reliable measure to distinguish elevated from normal pulmonary vascular resistance (PVR). The equation TRV/TVIRVOT 10 + 0.16 (PVRecho) has been shown to provide a good noninvasive estimate of PVR. However, its role in patients with significantly elevated PVR (> 6 Wood units [WU]) has not been conclusively evaluated. The aim of this study was to establish the validity of the TRV/TVIRVOT ratio as a correlate of PVR. The role of TRV/TVIRVOT was also compared with that of a new ratio, TRV2/TVIRVOT, in patients with markedly elevated PVR (>6 WU). Methods: Data from five validation studies using TRV/TVIRVOT as an estimate of PVR were compared with invasive PVR measurements (PVRcath). Multiple linear regression analyses were generated between PVRcath and both TRV/TVIRVOT and TRV2/TVIRVOT. Both PVRecho and a new derived regression equation based on TRV2/TVIRVOT: 5.19 TRV2/TVIRVOT - 0.4 (PVRecho2) were compared with PVRcath using Bland-Altman analysis. Logistic models were generated, and cutoff values for both TRV/TVIRVOT and TRV2/TVIRVOT were obtained to predict PVR > 6 WU. Results: One hundred fifty patients remained in the final analysis. Linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92). There was a better correlation between PVRcath and TRV2/TVIRVOT (r = 0.79, P < .0001, Z = 0.01) in the entire cohort as well as in patients with PVR > 6 WU. Moreover, PVRecho2 compared better with PVRcath than PVRecho using Bland-Altman analysis in the entire cohort and in patients with PVR > 6 WU. TRV2/TVIRVOT and TRV/TVIRVOT both predicted PVR > 6 WU with good sensitivity and specificity. Conclusions: TRV/TVIRVOT is a reliable method to identify patients with elevated PVR. In patients with TRV/TVIRVOT > 0.275, PVR is likely > 6 WU, and PVRecho2 derived from TRV2/TVIRVOT provides an improved noninvasive estimate of PVR compared with PVRecho. (J Am Soc Echocardiogr 2013;26:1170-7.) Keywords: Pulmonary vascular resistance, Doppler echocardiography, Pulmonary hypertension
From the Department of Cardiology, Beaumont Health System, Royal Oak, Michigan (A.E.A., L.M.F.); Oakland University/William Beaumont School of Medicine, Rochester, Michigan (A.E.A.); Menzies Research Institute of Tasmania, Hobart, Australia (T.M.); Baker IDI Heart and Diabetes Institute, Melbourne, Australia (M.T.M., D.M.K.); Heart Center, Alfred Hospital, Melbourne, Australia (M.T.M., D.M.K.); the Cardiology Division, Kantonsspital St. Gallen, St. Gallen, Switzerland (M.T.M.); the Pediatric Cardiology Division, University of Ioannina, Ioannina, Greece (A.P.V.); the Cardiopulmonary Department, University Hospital, Parma, Italy (W.S.); the Department of Internal Medicine, St. Joseph Mercy Oakland, Pontiac, Michigan (K.A.); the University of San Francisco, San Francisco, California (N.B.S.); and the Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona (S.J.L.). Reprint requests: Amr E. Abbas, MD, Beaumont Health System, Department of Cardiology, 1315 West Thirteen Mile Road, Royal Oak, MI 48073 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2013 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2013.06.003
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The noninvasive determination of pulmonary vascular resistance (PVR) has been the subject of multiple reports.1-10 In 2003, we reported a novel index obtained by Doppler echocardiography, which reliably distinguished between patients with elevated and normal PVR.11 Invasively, PVR is derived from the ratio of transpulmonary pressure gradient to transpulmonary flow.12 The noninvasive index presented was the ratio of the peak tricuspid regurgitation velocity (TRV) (m/sec) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) (cm), where TRV represents a surrogate for transpulmonary pressure and TVIRVOT a surrogate for transpulmonary flow.11 In our original study, all patients had PVR # 6 Wood units (WU), and the equation TRV/TVIRVOT 10 + 0.16 (PVRecho) was shown to provide a good estimate of invasively derived PVR (PVRcath).11 The ratio was further simplified to TRV/TVI RVOT 10 and was subsequently evaluated in three different groups of studies. The first group consisted of validation studies, confirming the validity of the ratio as
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a noninvasive correlate of PVR and included patients with varyCI = Confidence interval ing pathologies.13-16 The second group included prognostic PCWP = Pulmonary capillary studies, which used the ratio as wedge pressure a prognostic indicator in various PVR = Pulmonary vascular clinical scenarios.17-40 Finally, the resistance last group consisted of modification studies with adjustments TPR = Total pulmonary resistance to the original ratio and equation in an attempt to provide TRV = Tricuspid regurgitation improved accuracy in exchange velocity for complexity.13,15,20,30,31,41 This TVIRVOT = Time-velocity was, in part, because some of the integral of the right ventricular above studies noted that outflow tract PVRecho became less accurate in patients with significantly WU = Wood units elevated PVR (>6 WU). The goals of our present study were to confirm the validity of TRV/ TVIRVOT in a larger group of patients collected from multiple centers and to include patients with markedly elevated PVR (>6 WU). In addition, we compared the TRV/TVI RVOT ratio with a proposed modified ratio, TRV2/TVIRVOT, as an improved noninvasive correlate of PVR. As has been studied, TRV/TVIRVOT discriminates normal from elevated PVR, provides a noninvasive estimate when PVR is #6 WU, and provides a prognostic marker in patients with myriad pathologies. We hypothesized that the modified ratio, TRV2/TVIRVOT, might perform better in situations of markedly elevated PVR (>6 WU). The latter ratio was introduced because, according to the convective acceleration component of the Bernoulli equation, a quadratic relationship between pressure and velocity exists.42 Abbreviations
METHODS In an effort to create a larger database of noninvasive Doppler correlates of PVRcath, we corresponded with authors who had published validation studies using the TRV/TVIRVOT ratio, or a derivative thereof, and compared these values with PVRcath. We were able to obtain the anonymous raw data from five centers, including our original data set.11,13,31,39,43 Analysis was performed by combining preexisting data from the original databases. Original echocardiographic images were not reanalyzed, but an independent review of each data worksheet was performed. We included only patients with complete sets of Doppler and hemodynamic data. Of note, not all patients in the studies included had simultaneous right heart catheterization and Doppler interrogation as outlined in the original publication.11 The institutional review boards of the respective institutions approved the published studies. Doppler variables including TRV and TVIRVOT were obtained as previously described.11 Briefly, Doppler echocardiography was performed using the following ultrasound systems: Vivid 5 and Vivid 7 (GE Medical Systems, Milwaukee, WI), Acuson Sequoia (Acuson, Mountain View, CA; Siemens Healthcare, Erlangen, Germany), and iE33 (Philips Healthcare, North Ryde, Australia; Philips Medical Systems, Andover, MA). TVIRVOT (cm) was obtained by placing a 1-mm to 2-mm pulsedwave Doppler sample volume in the proximal right ventricular outflow tract when imaged from the parasternal short-axis view. The sample volume was placed so that the closing but not opening click of the pulmonary valve was visualized. Continuous-wave Doppler was used to determine the peak TRV (m/sec). The highest velocity
obtained from multiple views was used. Agitated saline was used to enhance suboptimal Doppler signals. In patients with atrial fibrillation, the average of five measurements were used. The TRV/TVIRVOT and TRV2/TVIRVOT ratios were then calculated. Invasive PVR measures were also obtained as previously described and recorded from their respective studies.11,13,31,39,43 Briefly, a flow-directed pulmonary artery catheter was used for hemodynamic measurements. Pulmonary capillary wedge pressure (PCWP), pulmonary artery systolic pressure, pulmonary artery diastolic pressure, and mean pulmonary artery pressure were measured. Cardiac output was calculated by thermodilution as a mean of three consecutive measurements not varying by >10%. PVR (WU) was calculated using the equation PVR = mean pulmonary artery pressure PCWP/cardiac output. Individuals interpreting invasive and Doppler variables were blinded to each other’s results. Statistical Methods Multiple linear regression analyses were generated, the first between the entire cohort of PVRcath and TRV/TVIRVOT and the second between the same PVRcath cohort and TRV2/TVIRVOT. Spearman’s correlation coefficient was obtained for each analysis. The patients were then divided into two groups, the first with PVRcath # 6 WU and the second with PVRcath > 6 WU. Linear regression analysis was then performed for each of the two groups with both TRV/TVIRVOT and subsequently TRV2/TVIRVOT. Spearman’s correlation coefficient was obtained for each analysis. A plot of PVRecho (TRV/TVIRVOT 10 + 0.16)11 compared with PVRcath was generated using Bland-Altman analysis. A new regression equation was derived on the basis of the modified ratio TRV2/TVIRVOT (PVRecho2 = 5.19 TRV2/TVIRVOT 0.4). A second plot for PVRecho2 compared with PVRcath was then generated using Bland-Altman analysis. Using receiver operating characteristic curves, dichotomized PVR was analyzed based first on TRV/TVIRVOT and then TRV2/TVIRVOT. A logistic model was generated, and cutoff values for both TRV/TVIRVOT and TRV2/TVIRVOT, with balanced sensitivity and specificity, were obtained to predict elevated PVR > 6 WU. Confidence intervals (CIs) were calculated for the sensitivity and specificity values using the binomial method. In an attempt to determine the effect of left atrial pressure, patients were divided into two subgroups, those with elevated and normal PCWP (>15 and #15 mm Hg, respectively). Moreover, both ratios were also correlated with invasively derived PVR and with total pulmonary resistance (TPR). The latter is an invasively obtained variable that excludes left atrial pressure in determining pulmonary resistance (TPR = mean pulmonary artery pressure/cardiac output). BlandAltman analysis was performed for both ratios (TRV/TVIRVOT and TRV2/TVIRVOT) in patients with PCWP # 15 and > 15 mm Hg. Similarly, in an attempt to determine the effect of flow, patients were divided into two subgroups, those with normal or diminished TVIRVOT (>15 or # 15 cm, respectively). TVIRVOT was used as a surrogate of stroke volume. A second Bland-Altman analysis was performed for patients with TVIRVOT # 15 and > 15 cm.
RESULTS Thirty patients were excluded because of incomplete data. A total of 150 patients remained in the final analysis. The baseline demographics are listed in Table 1. A total of 126 patients had PVRcath # 6 WU,
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Table 1 Clinical and hemodynamic variables in patients and referral diagnoses
Table 2 Invasive and echocardiographically derived PVR correlates in various patient groups
Variable
Value
Variable
Women Age (y) Left ventricular ejection fraction (%) Mean pulmonary artery pressure (mm Hg) PCWP (mm Hg) Right atrial pressure (mm Hg) PVR (WU) Referral diagnosis Valvular heart disease Exertional dyspnea Renal and liver transplantation Acute respiratory failure Postoperative Cardiomyopathy Primary pulmonary hypertension Congestive heart failure Scleroderma Asymptomatic Other
82 62 6 13 58 6 13 25 6 11 13 6 6 866 3.47 6 3.63
TRV/TVIRVOT All patients PVRcath # 6 WU PVRcath > 6 WU TRV2/TVIRVOT All patients PVRcath # 6 WU PVRcath > 6 WU PVRcath (WU) (all patients) PVRecho (WU) (all patients) PVRecho2 (WU) (all patients) PVRcath # 6 WU PVRecho (WU) (PVRcath # 6) PVRecho2 (WU) (PVRcath # 6) PVRcath > 6 WU PVRecho (WU) (PVRcath > 6) PVRecho2 (WU) (PVRcath > 6)
12 17 6 4 3 2 20 15 23 8 40
Data are expressed as mean 6 SD or as numbers.
while 24 patients had PVRcath > 6 WU. The mean, median, and standard deviation of invasive PVR and noninvasive correlates are shown in Table 2. The linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92; Figure 1A). There was a better correlation between PVRcath and TRV2/TVIRVOT (r = 0.79, P < .0001, Z = 0.01; Figure 1B). PVRecho was derived as previously described ([TRV/TVIRVOT 10] + 0.16).11 PVRecho2 was derived from the regression analysis involving TRV2/TVIRVOT: PVRecho2 ¼ 5:19 TRV2 =TVIRVOT 0:4
As we hypothesized, for patients with PVRcath # 6 WU, there were similar correlations with both TRV/TVIRVOT and TRV2/TVIRVOT (r = 0.69, P < .0001, Z = 0.16 and r = 0.70, P < .0001, Z = 0.24, respectively; Figures 1C and 1D). However, in patients with PVR > 6 WU, the correlation markedly improved with TRV2/ TVIRVOT compared with TRV/TVIRVOT (r = 0.48, P = .01, Z = 0.57 and r = 0.33, P = .11, Z = 4.46, respectively; Figures 1E and 1F). This suggests that both methods correlate similarly for patients with lower PVR values. However, for PVR > 6 WU, the correlation appeared stronger with TRV2/TVIRVOT compared with TRV/TVI RVOT. Using Bland-Altman analysis, PVRecho showed satisfactory limits of agreement with PVRcath, with a mean of 0.04 6 2.38 for the entire cohort. However, the limits of agreement were better for patients with PVRcath # 6 WU, with a mean of 0.05 6 0.85, compared with those with PVRcath > 6 WU (mean, 6.35 6 3.75) (Figure 2A). On the other hand, the limits of agreement between PVRecho2 and PVRcath (mean, 0.03 6 2.08) for the entire cohort were similar or perhaps slightly better than for PVRecho. The limits of agreement between PVRecho2 and patients with PVRcath # 6 WU were comparable with those of PVRecho, with a mean of 0.36 6 1.18. However, in patients with PVRcath > 6 WU, the mean value for the limits of agreement of PVRecho2 and PVRcath was 2.06 6 3.93, which was much improved compared with that between PVRecho and PVRcath
Mean
Median
SD
Range
0.22 0.19 0.4
0.18 0.17 0.41
0.11 0.06 0.14
0.08–0.71 0.08–0.48 0.13–0.71
0.74 0.55 1.72 3.47 2.4 3.44 2.11 2 2.47 10.59 4.25 8.53
0.49 0.45 2.02 2 2 2.16 1.8 1.89 1.96 9.83 4.32 10
0.57 0.29 0.69 3.63 1.16 2.97 1.09 0.69 1.5 4 1.42 3.59
0.1–2.84 0.1–1.86 0.45–2.84 0.31–21 1.04–7.26 0.11–14.33 0.31–6 1.04–4.99 0.11–9.29 6.07–21 1.45–7.26 1.95–14.33
Z scores were calculated for PVRecho versus PVRecho2 in the entire PVRcath cohort (0.92 vs 0.01), in patients with PVRcath # 6 WU (0.16 vs 0.24), and in patients with PVRcath > 6 WU (4.46 vs 0.57), respectively.
(Figure 2B). In summary, the limits of agreement were comparable, or slightly better, between PVRcath and PVRecho compared with PVRecho2 in patients with PVRcath # 6 WU. However, for patients with higher PVRcath (>6 WU), the reverse was true. It should be noted that for both PVRecho and PVRecho2, the limits of agreement were worse for patients with PVRcath > 6 WU than for patient with lower PVRcath values (#6 WU). The area under the receiver operating characteristic curve was calculated at 0.90 (95% CI, 0.82–0.98) for TRV/TVIRVOT (Figure 3). A cutoff value of 0.275 provided the best-balanced sensitivity (83.3%) and specificity (88.9%) to determine PVRcath > 6 WU. For TRV2/TVIRVOT, the area under the receiver operating characteristic curve was calculated at 0.93 (95% CI, 0.86–0.98). A cutoff value of 0.95 provided the best-balanced sensitivity (83.3%) and specificity (89.7%) to determine PVRcath > 6 WU. No statistical significance was noted between the receiver operating characteristic curves using the Hanley and McNeil method (SE, 0.046 and 0.041, respectively; SED, 0.06; Z = 0.36; P = NS). TRV of 3.1 m/sec had slightly higher sensitivity of 87.5% and much lower specificity of 74.6% to predict PVR > 6 WU (area under the curve, 0.92) compared to either ratio. The patients were divided into two groups, selected at random, to test the predictive value of the cutoff level for either equation; a derivation group (n = 100) and a validation group (n = 50). In the derivation group, TRV/TVIRVOT > 0.275 had sensitivity of 86.7% and specificity of 91.8%, to predict PVRcath > 6 WU. In addition, TRV2/TVIRVOT > 0.95 had sensitivity of 86.7% and specificity of 89.4% to predict PVRcath > 6 WU. In the validation group, TRV/ TVIRVOT > 0.275 had sensitivity of 77.8% and specificity of 82.9% to predict PVRcath > 6 WU. TRV2/TVIRVOT > 0.95 had sensitivity of 77.8% and specificity of 90.2% to predict PVRcath > 6 WU. Bland-Altman analysis was also performed between PVRcath and both PVRecho and PVRecho2 in patients with TRV/ TVIRVOT > 0.275. PVRecho revealed a mean of 3.76 6 4.5 in comparison with PVRecho2, which showed a mean value of 0.05 6 3.5,
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Figure 1 Linear regression analysis and Spearman’s correlation coefficients between PVRcath and both TRV/TVIRVOT and TRV2/ TVIRVOT in the entire PVRcath cohort (A,B), in patients with PVRcath # 6 WU (C,D), and in patients with PVRcath > 6 WU (E,F). suggesting a better comparison between PVRcath and PVRecho2 at TRV/TVIRVOT > 0.275. With regard to the evaluation of left atrial pressure contributions, Bland-Altman analysis was performed for PVRcath and both PVRecho and PVRecho2, respectively, in patients with PCWP # 15 mm Hg (n = 100) and > 15 mm H g (n = 50). For patients with PCWP # 15 mm Hg, comparison of PVRecho and PVRcath revealed a mean of 1.4 6 3.3, while comparison of PVRecho2 and PVRcath revealed a mean of 0.3 6 2.3, suggesting an improved comparison with the latter. There appeared to be a better comparison between PVRcath and both PVRecho and PVRecho2 in patients with PCWP > 15 mm Hg. As such, mean values were 0.3 6 1.4 using PVRecho and 0.6 6 1.2 using PVRecho2, which were comparable. Both ratios were also correlated with PVRcath and with the invasively derived TPR. We found that TRV/TVIRVOT showed improved correlation with PVRcath compared with TPR (r = 0.71 for TPR vs r = 0.76 for PVRcath; Figure 4). Similarly, TRV2/TVIRVOT had improved correlation with PVR compared with TPR (r = 0.78 versus r = 0.71). This suggests that both PVRecho and PVRecho2 perform well in patients with elevated PCWPs, whereas PVRecho2 performs better than PVRecho in patients with low PCWPs. Moreover, it appears that both ratios correlate better with PVR than TPR. With regard to the effect of cardiac output, Bland-Altman analysis was again performed for both equations PVRecho and PVRecho2 in
patients with TVIRVOT # 15 (n = 86) and > 15 (n=64) cm. We found that Both PVRecho and PVRecho2 performed better for patients with increased stroke volumes (TVIRVOT > 15 cm) compared with lower stroke volumes (TVIRVOT # 15 cm). For patients with TVIRVOT # 15 cm, mean values were 1.6 6 3.5 using PVRecho and 0.02 6 2.5 using PVRecho2. For patients with TVIRVOT > 15 cm, mean values were 0.3 6 1.2 using PVRecho and 0.05 6 1.3 using PVRecho2. DISCUSSION Multiple studies have attempted to obtain a noninvasive measure of PVR.1-10 Among the most studied is the ratio of TRV to TVIRVOT. As described previously, with increasing pulmonary pressure, TRV increases via an exponential correlation, whereas TVIRVOT undergoes conformational changes with decline in its value.11 Thus, in our original study, we noted an excellent correlation between the TRV/TVIRVOT ratio and PVRcath.11 TRV/TVIRVOT > 0.175 was shown to distinguish normal from elevated PVR (>2 WU) with good sensitivity of 77% (95% CI, 46%–96%) and specificity of 81% (95% CI, 63%–93%). Moreover, a simplified formula, TRV/TVI RVOT 10, has been suggested to provide a noninvasive estimate of PVR in the population of patients we studied, in whom all had PVR # 6 WU.11
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Figure 2 Bland-Altman analysis showing the limits of agreement between PVRcath and both PVRecho derived from TRV/TVIRVOT (A) and PVRecho2 derived from TRV2/TVIRVOT (B) in patients with PVRcath > 6 WU. TRV/TVIRVOT has been validated in various studies as an estimate of PVRcath.13-16 However, further ‘‘adjustments’’ were proposed to the method, including indexing the ratio to right ventricular outflow tract diameter, substituting TVIRVOT with the time-velocity integral of the left ventricular outflow tract, using the transtricuspid valve gradient (4TRV2), using the estimated right ventricular systolic pressure, using the product of pulmonary artery systolic pressure and heart rate, and subtracting the E/e0 ratio (a ratio of early mitral inflow velocity to early diastolic annular velocity as an estimate of left atrial pressure).13,15,20,30,31,41 The rationale was that the equation did not include a correlate of left atrial pressure and appeared to have poor limits of agreement with more elevated invasive measures of PVR. However, these methods traded simplicity for complexity with limited reproducibility. Other studies have used the TRV/TVI RVOT ratio as a prognostic indicator for multiple clinical syndromes.17-40 Our present study confirms the validity of our technique as a noninvasive correlate of PVR. TRV/TVIRVOT was shown to correlate well with a wide range of invasive PVR measurements in a large group of
patients from various institutions.11,13,31,39,42 The basis for this correlation is outlined in Figure 5. Moreover, in our study TRV/ TVIRVOT appears to correlate better with PVR than TPR contrary to previous critique. In our original study, further simplifying the equation to TRV/ TVIRVOT was shown to correlate well with invasive PVR in the population studied.11 Although this did not seem to matter in patients with lower estimated pulmonary pressure (lower TRV and PVR), as the pressure increased, so did the TRV and the absolute difference between velocity and the square of velocity. As demonstrated by our analysis of 150 patients, both models operate well for patients with relatively lower PVR (<6 WU). Our revised equation correlates better for patients with higher PVR (>6 WU). This may be explained by the fact that the Bernoulli equation identifies a quadratic relationship between pressure and velocity rather than a linear or direct relationship; thus, with lower velocities, this makes little difference. With higher velocities, the quadratic relationship must be taken into account to improve noninvasively derived PVR estimates. When
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Figure 3 Receiver operating characteristic (ROC) curve. A TRV/ TVIRVOT ratio of 0.275 (blue) and a TRV2/TVIRVOT ratio of 0.95 (red) provided the best-balanced sensitivity and specificity to determine patients with PVR > 6 WU (areas under the curve [AUCs], 0.90 and 0.93, respectively). No difference was noted between ROC curves (SE, 0.046 vs 0.041; SED, 0.06; Z = 0.369; P = NS). TRV/TVIRVOT is >0.275, PVR is likely markedly elevated to >6 WU, and the findings of our present study suggest that using a derivative of TRV2/TVIRVOT, rather than TRV/TVIRVOT, provides an improved noninvasive estimation of PVRcath. A novel simplified equation is thus suggested in patients with TRV/TVIRVOT > 0.275, namely, PVRecho2 = TRV2/TVIRVOT 5. We propose that for the sake of identifying patients with abnormal PVR (>2 WU), TRV/TVI RVOT > 0.175 remains an excellent cutoff, with sensitivity of 77% (95% CI, 46%–96%) and specificity of 81% (95% CI, 63%–93%) and an area under the curve of 0.916.11 A TRV/TVIRVOT ratio of 0.2 correctly identifies patients with PVR < 2 WU 94% of the time.11 Moreover, Farzaneh-Far et al.16 concluded that a TRV/TVIRVOT value of 0.12 had 100% sensitivity and negative predictive value for PVR > 1.5 WU in patients awaiting liver transplantation. In this study, the cutoff of TRV/TVIRVOT > 0.275 had excellent sensitivity and specificity to identify patients with PVR > 6 WU. If patients have TRV/TVI RVOT < 0.275, the original simplified equation TRV/TVIRVOT 10 may provide a reliable noninvasive estimate of PVR with good limits of agreement. However, if TRV/TVIRVOT is >0.275, the newly proposed equation, TRV2/TVIRVOT 5, is best used to estimate invasive PVR values (Figure 6). We do believe that with extremely high PVR values (>12 WU) and/or marked variations in heart rate or right ventricular outflow tract diameter, the noninvasive estimate may be unreliable by either equation. It is in this select group of patients that invasive values would best be used for accuracy. Limitations inherent to the Doppler technique are related to proper alignment of the ultrasound beam and have been reported elsewhere. Inability to obtain the tricuspid regurgitation jet is also a concern and has been addressed in the respective publications. Also, the peak TRV may vary with respiration, so using an average of multiple beats, rather than the maximum velocity obtained during
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Figure 4 Linear regression analysis and Spearman’s correlation coefficients between TRV/TVIRVOT and PVRcath and TPR.
Figure 5 Equation derivation. sinus rhythm, may be a more appropriate representation of this parameter. Additionally, not all patients in the studies included underwent simultaneous right heart catheterization and Doppler interrogation, so an error of different hemodynamic states may have confounded the results. Another limitation of the present study was that our analysis was performed by combining preexisting data from the original databases without independent reanalysis of the echocardiographic images. Moreover, we were not able to receive data from all the authors; some authors did not have the data stored, while others did not respond to our communications. Finally, we acknowledge that the number of patients in whom PVR > 6 WU is not large (n = 24); studying a patient population solely with PVR values > 6 WU may be the focus of a future, prospective study.
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Figure 6 Algorithm for noninvasive estimation of PVR. CONCLUSIONS The TRV/TVIRVOT ratio is a reliable method to identify patients with elevated PVR. Moreover, a noninvasive estimate of PVR may be provided in those with ratios < 0.275 by using the simplified equation PVR = TRV/TVIRVOT 10. In patients with TRV/TVIRVOT ratios > 0.275, indicative of markedly elevated PVR (>6 WU), a noninvasive estimate is best obtained using the equation TRV2/TVIRVOT 5 (Figure 6). However, TRV/TVIRVOT and PVRecho are clear prognostic indicators in multiple clinical syndromes and may be used to aid in determining prognosis for all patients with cardiac and systemic diseases that affect right ventricular function, particularly in the previously studied patient populations.17-40 The value of TRV2/TVIRVOT in patients with extremely high PVR values (>12 WU), as well in follow-up for individual patients with elevated PVR, may require further study.
REFERENCES 1. Okamoto M, Miyatake K, Kinoshita N, Sakakibara H, Nimura Y. Analysis of blood flow in pulmonary hypertension with the pulsed Doppler flowmeter combined with cross-sectional echocardiography. Br Heart J 1984;51:407-15. 2. Hirschfeld S, Meyer R, Schwartz DC, Kofhagen J, Kaplan S. The echocardiographic assessment of pulmonary artery pressure and pulmonary vascular resistance. Circulation 1975;52:642-50. 3. Matsuda M, Sekiguchi T, Sugishita Y, Kuwako K, Iida K, Ito I. Reliability of non-invasive estimates of pulmonary hypertension by pulsed Doppler echocardiography. Br Heart J 1986;56:158-64. 4. Chan KL, Currie PJ, Seward JB, Hagler DJ, Mair DD, Tajik AJ. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol 1987;9:549-54. 5. Murata I, Sonoda M, Morita T, Nakamura F, Takenaka K, Nagai R. The Clinical Significance of reversed flow in the main pulmonary artery detected by Doppler color flow imaging. Chest 2000;118:336-41. 6. Riggs T, Hirschfeld S, Borkat G, Knoke J, Leibman J. Assessment of the pulmonary vascular bed by echocardiographic right ventricular systolic time intervals. Circulation 1978;57:939-47. 7. Scapellato F, Temporelli PL, Eleuteri E, Corra U, Imparato A, Gianuzzi P. Accurate noninvasive estimation of pulmonary vascular resistance by Doppler echocardiography in patients with chronic failure heart failure. J Am Coll Cardiol 2001;37:1813-9.
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8. Shandas R, Weinberg C, Ivy DD, Nicol E, DeGroff CG, Hertzberg J, et al. Development of a noninvasive ultrasound color M-mode means of estimating pulmonary vascular resistance in pediatric pulmonary hypertension: mathematical analysis, in vitro validation, and preliminary clinical studies. Circulation 2001;104:908-13. 9. Tahara M, Tanaka H, Nakao S, Yoshimura H, Sakurai S, Tei C, et al. Hemodynamic determinants of pulmonary valve motion during systole in experimental pulmonary hypertension. Circulation 1981;64:1249-55. 10. Ebeid MR, Ferrer PL, Robinson B, Weatherby N, Gebland H. Doppler echocardiographic evaluation of pulmonary vascular resistance in children with congenital heart disease. J Am Soc Echocardiogr 1996;9:822-31. 11. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol 2003;41:1021-7. 12. Willard JEL, Richard A, Hillis LD. Cardiac catheterization. In: Kloner RA, ed. The guide to cardiology. 3rd ed. Greenwich, CT: Le Jacq Communications; 1995. p. 151. 13. Vlahos AP, Feinstein JA, Schiller NB, Silverman NH. Extension of Dopplerderived echocardiographic measures of pulmonary vascular resistance to patients with moderate or severe pulmonary vascular disease. J Am Soc Echocardiogr 2008;21:711-4. 14. Rajagopalan N, Simon MA, Suffoletto MS, Shah H, Edelman K, Mathier MA, et al. Noninvasive estimation of pulmonary vascular resistance in pulmonary hypertension. Echocardiography 2009;26:489-94. 15. Roule V, Labombarda F, Pellissier A, Sabatier R, Lognone T, Gomes S, et al. Echocardiographic assessment of pulmonary vascular resistance in pulmonary arterial hypertension. Cardiovasc Ultrasound 2010;8:21. 16. Farzaneh-Far R, McKeown BH, Dang D, Roberts J, Schiller NB, Foster E. Accuracy of Doppler-estimated pulmonary vascular resistance in patients before liver transplantation. Am J Cardiol 2008;101:259-62. 17. Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, et al. A randomised controlled trial of bosentan in severe COPD. Eur Respir J 2008;32:619-28. 18. Kalambokis GN, Pappas K, Tsianos V. Differential effects of terlipressin on pulmonary and systemic hemodynamics in patients with cirrhosis and pulmonary hypertension: an echo study. Angiology 2012;63:199-205. 19. Kalambokis GN, Mouzaki A, Rodi M, Pappas K, Korantzopoulos P, Tsianos EV. Circulating endotoxin and interleukin-6 levels are associated with Doppler-evaluated pulmonary vascular resistance in cirrhotic patients. Hepatol Int 2012;6:783-9. 20. Ajami GH, Cheriki S, Amoozgar H, Borzouee M, Soltani M. Accuracy of Doppler-derived estimation of pulmonary vascular resistance in congenital heart disease: an index of operability. Pediatr Cardiol 2011;32:1168-74. 21. Cevik A, Kula S, Olgunturk R, Tunaoglu FS, Oguz AD, Pektas A, et al. Quantitative evaluation of right ventricle function by transthoracic echocardiography in childhood congenital heart disease patients with pulmonary hypertension. Echocardiography 2012;29:840-8. 22. Kuppahally SS, Michaels AD, Tandar A, Gilbert EM, Litwin SE, Bader FM. Can echocardiographic evaluation of cardiopulmonary hemodynamics decrease right heart catheterizations in end-stage heart failure patients awaiting transplantation? Am Journal Cardiology 2010;106:1657-62. 23. Lam KM, Ennis S, O’Driscoll G, Solis JM, Macgillivray T, Picard MH. Observations from non-invasive measures of right heart hemodynamics in left ventricular assist device patients. J Am Soc Echocardiogr 2009; 22:1055-62. 24. Farzaneh-Far R, Na B, Whooley MA, Schiller NB. Usefulness of noninvasive estimate of pulmonary vascular resistance to predict mortality, heart failure, and adverse cardiovascular events in patients with stable coronary artery disease (from the Heart and Soul Study). Am J Cardiol 2008;101: 762-6. 25. Yan GH, Wang M, Yue WS, Yiu KH, Siu CW, Lee SW, et al. Elevated pulmonary artery systolic pressure in patients with coronary artery disease and left ventricular dyssynchrony. Eur J Heart Fail 2010;12:1067-75. 26. Choi EY, Shim J, Kim SA, Shim CY, Yoon SJ, Kang SM, et al. Value of echoDoppler derived pulmonary vascular resistance, net-atrioventricular compliance and tricuspid annular velocity in determining exercise capacity in patients with mitral stenosis. Circ J 2007;71:1721-7.
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27. Oliveira W, Poyares D, Cintra F, Vieira ML, Fischer CH, Moises V, et al. Impact of continuous positive airway pressure treatment on right ventricle performance in patients with obstructive sleep apnea, assessed by threedimensional echocardiography. Sleep Med 2012;13:510-6. 28. Albers J, Ister D, Kayhan N, Vahl CF. Postoperative non-invasive assessment of pulmonary vascular resistance using Doppler echocardiography. Interact Cardiovasc Thorac Surg 2011;13:579-84. 29. Pirat B, McCulloch ML, Zoghbi WA. Evaluation of global and regional right ventricular systolic function in patients with pulmonary hypertension using a novel speckle tracking method. Am J Cardiol 2006;98:699-704. 30. Kouzu H, Nakatani S, Kyotani S, Kanzaki H, Nakanishi N, Kitakaze M. Noninvasive estimation of pulmonary vascular resistance by Doppler echocardiography in patients with pulmonary arterial hypertension. Am J Cardiol 2009;103:872-6. 31. Dahiya A, Vollbon W, Jellis C, Prior D, Wahi S, Marwick T. Echocardiographic assessment of raised pulmonary vascular resistance: application to diagnosis and follow-up of pulmonary hypertension. Heart 2010;96: 2005-9. 32. Lopez-Candales A, Edelman K, Gulyasy B, Candales MD. Differences in the duration of total ejection between right and left ventricles in chronic pulmonary hypertension. Echocardiography 2011;28:509-15. 33. Hoit BD, Dalton ND, Gebremedhim A, Janocha A, Zimmerman PA, Zimmerman AM, et al. Elevated pulmonary artery pressure among Amhara highlanders in Ethiopia. Am J Hum Biol 2011;23:168-76. 34. Maignan M, Rivera-Ch M, Privat C, Le on-Velarde F, Richalet JP, Pham I. Pulmonary pressure and cardiac function in chronic mountain sickness patients. Chest 2009;135:499-504. 35. Richalet JP, Rivera-Ch M, Maignan M, Privat C, Pham I, Macarlupu JL, et al. Acetazolamide for Monge’s disease: efficacy
36.
37.
38.
39.
40.
41.
42. 43.
and tolerance of 6-month treatment. Am J Respir Crit Care Med 2008;177:1370-6. Kim SH, Yi MZ, Kim HD, Song JM, Kang DH, Lee SD, et al. Prognostic value of echocardiographic estimation of pulmonary vascular resistance in patients with acute pulmonary thromboembolism. J Am Soc Echocardiogr 2011;24:693-8. Rydman R, Larsen F, Caidahl K, Alam M. Right Ventricular function in patients with pulmonary embolism: early and late findings using Doppler tissue imaging. J Am Soc Echocardiogr 2010;23:531-7. Chaudry RA, Cikes M, Karu T, Hutchinson C, Ball S, Sutherland G, et al. Paediatric sickle cell disease: pulmonary hypertension but normal vascular resistance. Arch Dis Child 2011;96:131-6. Serra W, Chetta A, Santilli D, Mozzani F, Dall’Aglio PP, Olivieri D, et al. Echocardiography may help detect pulmonary vasculopathy in the early stages of pulmonary artery hypertension associated with systemic sclerosis. Cardiovasc Ultrasound 2010;8:25. Frea S, Capriolo M, Marra WG, Cannillo M, Fusaro E, Libertucci D, et al. Echo Doppler predictors of pulmonary artery hypertension in patients with systemic sclerosis. Echocardiography 2011;28:860-9. Haddad F, Zamanian R, Beraud AS, Schnittger I, Feinstein J, Peterson T, et al. A novel non-invasive method of estimating pulmonary vascular resistance in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr 2009;22:523-9. Armstrong WF, Ryan T. Feigenbaum’s echocardiography. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:212. Maeder MT, Karapanagiotidis S, Dewar EM, Gamboni SE, Htun N, Kaye DM. Accuracy of Doppler echocardiography to estimate key hemodynamic variables in subjects with normal left ventricular ejection fraction. J Card Fail 2011;17:405-12.
Noninvasive Assessment of Pulmonary Vascular Resistance by Doppler Echocardiography Amr E. Abbas, MD, FACC, Laura M. Franey, MD, Thomas Marwick, MD, PhD, Micha T. Maeder, MD, David M. Kaye, MD, FACC, Antonios P. Vlahos, MD, PhD, Walter Serra, MD, Karim Al-Azizi, MD, Nelson B. Schiller, MD, FACC, and Steven J. Lester, MD, FRCP(C), Royal Oak, Rochester, and Pontiac, Michigan; Hobart and Melbourne, Australia; St. Gallen, Switzerland; Ioannina, Greece; Parma, Italy; San Francisco, California; Scottsdale, Arizona
Background: The ratio of tricuspid regurgitation velocity (TRV) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) has been studied as a reliable measure to distinguish elevated from normal pulmonary vascular resistance (PVR). The equation TRV/TVIRVOT 10 + 0.16 (PVRecho) has been shown to provide a good noninvasive estimate of PVR. However, its role in patients with significantly elevated PVR (> 6 Wood units [WU]) has not been conclusively evaluated. The aim of this study was to establish the validity of the TRV/TVIRVOT ratio as a correlate of PVR. The role of TRV/TVIRVOT was also compared with that of a new ratio, TRV2/TVIRVOT, in patients with markedly elevated PVR (>6 WU). Methods: Data from five validation studies using TRV/TVIRVOT as an estimate of PVR were compared with invasive PVR measurements (PVRcath). Multiple linear regression analyses were generated between PVRcath and both TRV/TVIRVOT and TRV2/TVIRVOT. Both PVRecho and a new derived regression equation based on TRV2/TVIRVOT: 5.19 TRV2/TVIRVOT - 0.4 (PVRecho2) were compared with PVRcath using Bland-Altman analysis. Logistic models were generated, and cutoff values for both TRV/TVIRVOT and TRV2/TVIRVOT were obtained to predict PVR > 6 WU. Results: One hundred fifty patients remained in the final analysis. Linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92). There was a better correlation between PVRcath and TRV2/TVIRVOT (r = 0.79, P < .0001, Z = 0.01) in the entire cohort as well as in patients with PVR > 6 WU. Moreover, PVRecho2 compared better with PVRcath than PVRecho using Bland-Altman analysis in the entire cohort and in patients with PVR > 6 WU. TRV2/TVIRVOT and TRV/TVIRVOT both predicted PVR > 6 WU with good sensitivity and specificity. Conclusions: TRV/TVIRVOT is a reliable method to identify patients with elevated PVR. In patients with TRV/TVIRVOT > 0.275, PVR is likely > 6 WU, and PVRecho2 derived from TRV2/TVIRVOT provides an improved noninvasive estimate of PVR compared with PVRecho. (J Am Soc Echocardiogr 2013;26:1170-7.) Keywords: Pulmonary vascular resistance, Doppler echocardiography, Pulmonary hypertension
From the Department of Cardiology, Beaumont Health System, Royal Oak, Michigan (A.E.A., L.M.F.); Oakland University/William Beaumont School of Medicine, Rochester, Michigan (A.E.A.); Menzies Research Institute of Tasmania, Hobart, Australia (T.M.); Baker IDI Heart and Diabetes Institute, Melbourne, Australia (M.T.M., D.M.K.); Heart Center, Alfred Hospital, Melbourne, Australia (M.T.M., D.M.K.); the Cardiology Division, Kantonsspital St. Gallen, St. Gallen, Switzerland (M.T.M.); the Pediatric Cardiology Division, University of Ioannina, Ioannina, Greece (A.P.V.); the Cardiopulmonary Department, University Hospital, Parma, Italy (W.S.); the Department of Internal Medicine, St. Joseph Mercy Oakland, Pontiac, Michigan (K.A.); the University of San Francisco, San Francisco, California (N.B.S.); and the Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona (S.J.L.). Reprint requests: Amr E. Abbas, MD, Beaumont Health System, Department of Cardiology, 1315 West Thirteen Mile Road, Royal Oak, MI 48073 (E-mail: [email protected]). 0894-7317/$36.00 Copyright 2013 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2013.06.003
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The noninvasive determination of pulmonary vascular resistance (PVR) has been the subject of multiple reports.1-10 In 2003, we reported a novel index obtained by Doppler echocardiography, which reliably distinguished between patients with elevated and normal PVR.11 Invasively, PVR is derived from the ratio of transpulmonary pressure gradient to transpulmonary flow.12 The noninvasive index presented was the ratio of the peak tricuspid regurgitation velocity (TRV) (m/sec) to the time-velocity integral of the right ventricular outflow tract (TVIRVOT) (cm), where TRV represents a surrogate for transpulmonary pressure and TVIRVOT a surrogate for transpulmonary flow.11 In our original study, all patients had PVR # 6 Wood units (WU), and the equation TRV/TVIRVOT 10 + 0.16 (PVRecho) was shown to provide a good estimate of invasively derived PVR (PVRcath).11 The ratio was further simplified to TRV/TVI RVOT 10 and was subsequently evaluated in three different groups of studies. The first group consisted of validation studies, confirming the validity of the ratio as
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a noninvasive correlate of PVR and included patients with varyCI = Confidence interval ing pathologies.13-16 The second group included prognostic PCWP = Pulmonary capillary studies, which used the ratio as wedge pressure a prognostic indicator in various PVR = Pulmonary vascular clinical scenarios.17-40 Finally, the resistance last group consisted of modification studies with adjustments TPR = Total pulmonary resistance to the original ratio and equation in an attempt to provide TRV = Tricuspid regurgitation improved accuracy in exchange velocity for complexity.13,15,20,30,31,41 This TVIRVOT = Time-velocity was, in part, because some of the integral of the right ventricular above studies noted that outflow tract PVRecho became less accurate in patients with significantly WU = Wood units elevated PVR (>6 WU). The goals of our present study were to confirm the validity of TRV/ TVIRVOT in a larger group of patients collected from multiple centers and to include patients with markedly elevated PVR (>6 WU). In addition, we compared the TRV/TVI RVOT ratio with a proposed modified ratio, TRV2/TVIRVOT, as an improved noninvasive correlate of PVR. As has been studied, TRV/TVIRVOT discriminates normal from elevated PVR, provides a noninvasive estimate when PVR is #6 WU, and provides a prognostic marker in patients with myriad pathologies. We hypothesized that the modified ratio, TRV2/TVIRVOT, might perform better in situations of markedly elevated PVR (>6 WU). The latter ratio was introduced because, according to the convective acceleration component of the Bernoulli equation, a quadratic relationship between pressure and velocity exists.42 Abbreviations
METHODS In an effort to create a larger database of noninvasive Doppler correlates of PVRcath, we corresponded with authors who had published validation studies using the TRV/TVIRVOT ratio, or a derivative thereof, and compared these values with PVRcath. We were able to obtain the anonymous raw data from five centers, including our original data set.11,13,31,39,43 Analysis was performed by combining preexisting data from the original databases. Original echocardiographic images were not reanalyzed, but an independent review of each data worksheet was performed. We included only patients with complete sets of Doppler and hemodynamic data. Of note, not all patients in the studies included had simultaneous right heart catheterization and Doppler interrogation as outlined in the original publication.11 The institutional review boards of the respective institutions approved the published studies. Doppler variables including TRV and TVIRVOT were obtained as previously described.11 Briefly, Doppler echocardiography was performed using the following ultrasound systems: Vivid 5 and Vivid 7 (GE Medical Systems, Milwaukee, WI), Acuson Sequoia (Acuson, Mountain View, CA; Siemens Healthcare, Erlangen, Germany), and iE33 (Philips Healthcare, North Ryde, Australia; Philips Medical Systems, Andover, MA). TVIRVOT (cm) was obtained by placing a 1-mm to 2-mm pulsedwave Doppler sample volume in the proximal right ventricular outflow tract when imaged from the parasternal short-axis view. The sample volume was placed so that the closing but not opening click of the pulmonary valve was visualized. Continuous-wave Doppler was used to determine the peak TRV (m/sec). The highest velocity
obtained from multiple views was used. Agitated saline was used to enhance suboptimal Doppler signals. In patients with atrial fibrillation, the average of five measurements were used. The TRV/TVIRVOT and TRV2/TVIRVOT ratios were then calculated. Invasive PVR measures were also obtained as previously described and recorded from their respective studies.11,13,31,39,43 Briefly, a flow-directed pulmonary artery catheter was used for hemodynamic measurements. Pulmonary capillary wedge pressure (PCWP), pulmonary artery systolic pressure, pulmonary artery diastolic pressure, and mean pulmonary artery pressure were measured. Cardiac output was calculated by thermodilution as a mean of three consecutive measurements not varying by >10%. PVR (WU) was calculated using the equation PVR = mean pulmonary artery pressure PCWP/cardiac output. Individuals interpreting invasive and Doppler variables were blinded to each other’s results. Statistical Methods Multiple linear regression analyses were generated, the first between the entire cohort of PVRcath and TRV/TVIRVOT and the second between the same PVRcath cohort and TRV2/TVIRVOT. Spearman’s correlation coefficient was obtained for each analysis. The patients were then divided into two groups, the first with PVRcath # 6 WU and the second with PVRcath > 6 WU. Linear regression analysis was then performed for each of the two groups with both TRV/TVIRVOT and subsequently TRV2/TVIRVOT. Spearman’s correlation coefficient was obtained for each analysis. A plot of PVRecho (TRV/TVIRVOT 10 + 0.16)11 compared with PVRcath was generated using Bland-Altman analysis. A new regression equation was derived on the basis of the modified ratio TRV2/TVIRVOT (PVRecho2 = 5.19 TRV2/TVIRVOT 0.4). A second plot for PVRecho2 compared with PVRcath was then generated using Bland-Altman analysis. Using receiver operating characteristic curves, dichotomized PVR was analyzed based first on TRV/TVIRVOT and then TRV2/TVIRVOT. A logistic model was generated, and cutoff values for both TRV/TVIRVOT and TRV2/TVIRVOT, with balanced sensitivity and specificity, were obtained to predict elevated PVR > 6 WU. Confidence intervals (CIs) were calculated for the sensitivity and specificity values using the binomial method. In an attempt to determine the effect of left atrial pressure, patients were divided into two subgroups, those with elevated and normal PCWP (>15 and #15 mm Hg, respectively). Moreover, both ratios were also correlated with invasively derived PVR and with total pulmonary resistance (TPR). The latter is an invasively obtained variable that excludes left atrial pressure in determining pulmonary resistance (TPR = mean pulmonary artery pressure/cardiac output). BlandAltman analysis was performed for both ratios (TRV/TVIRVOT and TRV2/TVIRVOT) in patients with PCWP # 15 and > 15 mm Hg. Similarly, in an attempt to determine the effect of flow, patients were divided into two subgroups, those with normal or diminished TVIRVOT (>15 or # 15 cm, respectively). TVIRVOT was used as a surrogate of stroke volume. A second Bland-Altman analysis was performed for patients with TVIRVOT # 15 and > 15 cm.
RESULTS Thirty patients were excluded because of incomplete data. A total of 150 patients remained in the final analysis. The baseline demographics are listed in Table 1. A total of 126 patients had PVRcath # 6 WU,
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Table 1 Clinical and hemodynamic variables in patients and referral diagnoses
Table 2 Invasive and echocardiographically derived PVR correlates in various patient groups
Variable
Value
Variable
Women Age (y) Left ventricular ejection fraction (%) Mean pulmonary artery pressure (mm Hg) PCWP (mm Hg) Right atrial pressure (mm Hg) PVR (WU) Referral diagnosis Valvular heart disease Exertional dyspnea Renal and liver transplantation Acute respiratory failure Postoperative Cardiomyopathy Primary pulmonary hypertension Congestive heart failure Scleroderma Asymptomatic Other
82 62 6 13 58 6 13 25 6 11 13 6 6 866 3.47 6 3.63
TRV/TVIRVOT All patients PVRcath # 6 WU PVRcath > 6 WU TRV2/TVIRVOT All patients PVRcath # 6 WU PVRcath > 6 WU PVRcath (WU) (all patients) PVRecho (WU) (all patients) PVRecho2 (WU) (all patients) PVRcath # 6 WU PVRecho (WU) (PVRcath # 6) PVRecho2 (WU) (PVRcath # 6) PVRcath > 6 WU PVRecho (WU) (PVRcath > 6) PVRecho2 (WU) (PVRcath > 6)
12 17 6 4 3 2 20 15 23 8 40
Data are expressed as mean 6 SD or as numbers.
while 24 patients had PVRcath > 6 WU. The mean, median, and standard deviation of invasive PVR and noninvasive correlates are shown in Table 2. The linear regression analysis between PVRcath and TRV/TVIRVOT revealed a good correlation (r = 0.76, P < .0001, Z = 0.92; Figure 1A). There was a better correlation between PVRcath and TRV2/TVIRVOT (r = 0.79, P < .0001, Z = 0.01; Figure 1B). PVRecho was derived as previously described ([TRV/TVIRVOT 10] + 0.16).11 PVRecho2 was derived from the regression analysis involving TRV2/TVIRVOT: PVRecho2 ¼ 5:19 TRV2 =TVIRVOT 0:4
As we hypothesized, for patients with PVRcath # 6 WU, there were similar correlations with both TRV/TVIRVOT and TRV2/TVIRVOT (r = 0.69, P < .0001, Z = 0.16 and r = 0.70, P < .0001, Z = 0.24, respectively; Figures 1C and 1D). However, in patients with PVR > 6 WU, the correlation markedly improved with TRV2/ TVIRVOT compared with TRV/TVIRVOT (r = 0.48, P = .01, Z = 0.57 and r = 0.33, P = .11, Z = 4.46, respectively; Figures 1E and 1F). This suggests that both methods correlate similarly for patients with lower PVR values. However, for PVR > 6 WU, the correlation appeared stronger with TRV2/TVIRVOT compared with TRV/TVI RVOT. Using Bland-Altman analysis, PVRecho showed satisfactory limits of agreement with PVRcath, with a mean of 0.04 6 2.38 for the entire cohort. However, the limits of agreement were better for patients with PVRcath # 6 WU, with a mean of 0.05 6 0.85, compared with those with PVRcath > 6 WU (mean, 6.35 6 3.75) (Figure 2A). On the other hand, the limits of agreement between PVRecho2 and PVRcath (mean, 0.03 6 2.08) for the entire cohort were similar or perhaps slightly better than for PVRecho. The limits of agreement between PVRecho2 and patients with PVRcath # 6 WU were comparable with those of PVRecho, with a mean of 0.36 6 1.18. However, in patients with PVRcath > 6 WU, the mean value for the limits of agreement of PVRecho2 and PVRcath was 2.06 6 3.93, which was much improved compared with that between PVRecho and PVRcath
Mean
Median
SD
Range
0.22 0.19 0.4
0.18 0.17 0.41
0.11 0.06 0.14
0.08–0.71 0.08–0.48 0.13–0.71
0.74 0.55 1.72 3.47 2.4 3.44 2.11 2 2.47 10.59 4.25 8.53
0.49 0.45 2.02 2 2 2.16 1.8 1.89 1.96 9.83 4.32 10
0.57 0.29 0.69 3.63 1.16 2.97 1.09 0.69 1.5 4 1.42 3.59
0.1–2.84 0.1–1.86 0.45–2.84 0.31–21 1.04–7.26 0.11–14.33 0.31–6 1.04–4.99 0.11–9.29 6.07–21 1.45–7.26 1.95–14.33
Z scores were calculated for PVRecho versus PVRecho2 in the entire PVRcath cohort (0.92 vs 0.01), in patients with PVRcath # 6 WU (0.16 vs 0.24), and in patients with PVRcath > 6 WU (4.46 vs 0.57), respectively.
(Figure 2B). In summary, the limits of agreement were comparable, or slightly better, between PVRcath and PVRecho compared with PVRecho2 in patients with PVRcath # 6 WU. However, for patients with higher PVRcath (>6 WU), the reverse was true. It should be noted that for both PVRecho and PVRecho2, the limits of agreement were worse for patients with PVRcath > 6 WU than for patient with lower PVRcath values (#6 WU). The area under the receiver operating characteristic curve was calculated at 0.90 (95% CI, 0.82–0.98) for TRV/TVIRVOT (Figure 3). A cutoff value of 0.275 provided the best-balanced sensitivity (83.3%) and specificity (88.9%) to determine PVRcath > 6 WU. For TRV2/TVIRVOT, the area under the receiver operating characteristic curve was calculated at 0.93 (95% CI, 0.86–0.98). A cutoff value of 0.95 provided the best-balanced sensitivity (83.3%) and specificity (89.7%) to determine PVRcath > 6 WU. No statistical significance was noted between the receiver operating characteristic curves using the Hanley and McNeil method (SE, 0.046 and 0.041, respectively; SED, 0.06; Z = 0.36; P = NS). TRV of 3.1 m/sec had slightly higher sensitivity of 87.5% and much lower specificity of 74.6% to predict PVR > 6 WU (area under the curve, 0.92) compared to either ratio. The patients were divided into two groups, selected at random, to test the predictive value of the cutoff level for either equation; a derivation group (n = 100) and a validation group (n = 50). In the derivation group, TRV/TVIRVOT > 0.275 had sensitivity of 86.7% and specificity of 91.8%, to predict PVRcath > 6 WU. In addition, TRV2/TVIRVOT > 0.95 had sensitivity of 86.7% and specificity of 89.4% to predict PVRcath > 6 WU. In the validation group, TRV/ TVIRVOT > 0.275 had sensitivity of 77.8% and specificity of 82.9% to predict PVRcath > 6 WU. TRV2/TVIRVOT > 0.95 had sensitivity of 77.8% and specificity of 90.2% to predict PVRcath > 6 WU. Bland-Altman analysis was also performed between PVRcath and both PVRecho and PVRecho2 in patients with TRV/ TVIRVOT > 0.275. PVRecho revealed a mean of 3.76 6 4.5 in comparison with PVRecho2, which showed a mean value of 0.05 6 3.5,
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Figure 1 Linear regression analysis and Spearman’s correlation coefficients between PVRcath and both TRV/TVIRVOT and TRV2/ TVIRVOT in the entire PVRcath cohort (A,B), in patients with PVRcath # 6 WU (C,D), and in patients with PVRcath > 6 WU (E,F). suggesting a better comparison between PVRcath and PVRecho2 at TRV/TVIRVOT > 0.275. With regard to the evaluation of left atrial pressure contributions, Bland-Altman analysis was performed for PVRcath and both PVRecho and PVRecho2, respectively, in patients with PCWP # 15 mm Hg (n = 100) and > 15 mm H g (n = 50). For patients with PCWP # 15 mm Hg, comparison of PVRecho and PVRcath revealed a mean of 1.4 6 3.3, while comparison of PVRecho2 and PVRcath revealed a mean of 0.3 6 2.3, suggesting an improved comparison with the latter. There appeared to be a better comparison between PVRcath and both PVRecho and PVRecho2 in patients with PCWP > 15 mm Hg. As such, mean values were 0.3 6 1.4 using PVRecho and 0.6 6 1.2 using PVRecho2, which were comparable. Both ratios were also correlated with PVRcath and with the invasively derived TPR. We found that TRV/TVIRVOT showed improved correlation with PVRcath compared with TPR (r = 0.71 for TPR vs r = 0.76 for PVRcath; Figure 4). Similarly, TRV2/TVIRVOT had improved correlation with PVR compared with TPR (r = 0.78 versus r = 0.71). This suggests that both PVRecho and PVRecho2 perform well in patients with elevated PCWPs, whereas PVRecho2 performs better than PVRecho in patients with low PCWPs. Moreover, it appears that both ratios correlate better with PVR than TPR. With regard to the effect of cardiac output, Bland-Altman analysis was again performed for both equations PVRecho and PVRecho2 in
patients with TVIRVOT # 15 (n = 86) and > 15 (n=64) cm. We found that Both PVRecho and PVRecho2 performed better for patients with increased stroke volumes (TVIRVOT > 15 cm) compared with lower stroke volumes (TVIRVOT # 15 cm). For patients with TVIRVOT # 15 cm, mean values were 1.6 6 3.5 using PVRecho and 0.02 6 2.5 using PVRecho2. For patients with TVIRVOT > 15 cm, mean values were 0.3 6 1.2 using PVRecho and 0.05 6 1.3 using PVRecho2. DISCUSSION Multiple studies have attempted to obtain a noninvasive measure of PVR.1-10 Among the most studied is the ratio of TRV to TVIRVOT. As described previously, with increasing pulmonary pressure, TRV increases via an exponential correlation, whereas TVIRVOT undergoes conformational changes with decline in its value.11 Thus, in our original study, we noted an excellent correlation between the TRV/TVIRVOT ratio and PVRcath.11 TRV/TVIRVOT > 0.175 was shown to distinguish normal from elevated PVR (>2 WU) with good sensitivity of 77% (95% CI, 46%–96%) and specificity of 81% (95% CI, 63%–93%). Moreover, a simplified formula, TRV/TVI RVOT 10, has been suggested to provide a noninvasive estimate of PVR in the population of patients we studied, in whom all had PVR # 6 WU.11
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Figure 2 Bland-Altman analysis showing the limits of agreement between PVRcath and both PVRecho derived from TRV/TVIRVOT (A) and PVRecho2 derived from TRV2/TVIRVOT (B) in patients with PVRcath > 6 WU. TRV/TVIRVOT has been validated in various studies as an estimate of PVRcath.13-16 However, further ‘‘adjustments’’ were proposed to the method, including indexing the ratio to right ventricular outflow tract diameter, substituting TVIRVOT with the time-velocity integral of the left ventricular outflow tract, using the transtricuspid valve gradient (4TRV2), using the estimated right ventricular systolic pressure, using the product of pulmonary artery systolic pressure and heart rate, and subtracting the E/e0 ratio (a ratio of early mitral inflow velocity to early diastolic annular velocity as an estimate of left atrial pressure).13,15,20,30,31,41 The rationale was that the equation did not include a correlate of left atrial pressure and appeared to have poor limits of agreement with more elevated invasive measures of PVR. However, these methods traded simplicity for complexity with limited reproducibility. Other studies have used the TRV/TVI RVOT ratio as a prognostic indicator for multiple clinical syndromes.17-40 Our present study confirms the validity of our technique as a noninvasive correlate of PVR. TRV/TVIRVOT was shown to correlate well with a wide range of invasive PVR measurements in a large group of
patients from various institutions.11,13,31,39,42 The basis for this correlation is outlined in Figure 5. Moreover, in our study TRV/ TVIRVOT appears to correlate better with PVR than TPR contrary to previous critique. In our original study, further simplifying the equation to TRV/ TVIRVOT was shown to correlate well with invasive PVR in the population studied.11 Although this did not seem to matter in patients with lower estimated pulmonary pressure (lower TRV and PVR), as the pressure increased, so did the TRV and the absolute difference between velocity and the square of velocity. As demonstrated by our analysis of 150 patients, both models operate well for patients with relatively lower PVR (<6 WU). Our revised equation correlates better for patients with higher PVR (>6 WU). This may be explained by the fact that the Bernoulli equation identifies a quadratic relationship between pressure and velocity rather than a linear or direct relationship; thus, with lower velocities, this makes little difference. With higher velocities, the quadratic relationship must be taken into account to improve noninvasively derived PVR estimates. When
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Figure 3 Receiver operating characteristic (ROC) curve. A TRV/ TVIRVOT ratio of 0.275 (blue) and a TRV2/TVIRVOT ratio of 0.95 (red) provided the best-balanced sensitivity and specificity to determine patients with PVR > 6 WU (areas under the curve [AUCs], 0.90 and 0.93, respectively). No difference was noted between ROC curves (SE, 0.046 vs 0.041; SED, 0.06; Z = 0.369; P = NS). TRV/TVIRVOT is >0.275, PVR is likely markedly elevated to >6 WU, and the findings of our present study suggest that using a derivative of TRV2/TVIRVOT, rather than TRV/TVIRVOT, provides an improved noninvasive estimation of PVRcath. A novel simplified equation is thus suggested in patients with TRV/TVIRVOT > 0.275, namely, PVRecho2 = TRV2/TVIRVOT 5. We propose that for the sake of identifying patients with abnormal PVR (>2 WU), TRV/TVI RVOT > 0.175 remains an excellent cutoff, with sensitivity of 77% (95% CI, 46%–96%) and specificity of 81% (95% CI, 63%–93%) and an area under the curve of 0.916.11 A TRV/TVIRVOT ratio of 0.2 correctly identifies patients with PVR < 2 WU 94% of the time.11 Moreover, Farzaneh-Far et al.16 concluded that a TRV/TVIRVOT value of 0.12 had 100% sensitivity and negative predictive value for PVR > 1.5 WU in patients awaiting liver transplantation. In this study, the cutoff of TRV/TVIRVOT > 0.275 had excellent sensitivity and specificity to identify patients with PVR > 6 WU. If patients have TRV/TVI RVOT < 0.275, the original simplified equation TRV/TVIRVOT 10 may provide a reliable noninvasive estimate of PVR with good limits of agreement. However, if TRV/TVIRVOT is >0.275, the newly proposed equation, TRV2/TVIRVOT 5, is best used to estimate invasive PVR values (Figure 6). We do believe that with extremely high PVR values (>12 WU) and/or marked variations in heart rate or right ventricular outflow tract diameter, the noninvasive estimate may be unreliable by either equation. It is in this select group of patients that invasive values would best be used for accuracy. Limitations inherent to the Doppler technique are related to proper alignment of the ultrasound beam and have been reported elsewhere. Inability to obtain the tricuspid regurgitation jet is also a concern and has been addressed in the respective publications. Also, the peak TRV may vary with respiration, so using an average of multiple beats, rather than the maximum velocity obtained during
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Figure 4 Linear regression analysis and Spearman’s correlation coefficients between TRV/TVIRVOT and PVRcath and TPR.
Figure 5 Equation derivation. sinus rhythm, may be a more appropriate representation of this parameter. Additionally, not all patients in the studies included underwent simultaneous right heart catheterization and Doppler interrogation, so an error of different hemodynamic states may have confounded the results. Another limitation of the present study was that our analysis was performed by combining preexisting data from the original databases without independent reanalysis of the echocardiographic images. Moreover, we were not able to receive data from all the authors; some authors did not have the data stored, while others did not respond to our communications. Finally, we acknowledge that the number of patients in whom PVR > 6 WU is not large (n = 24); studying a patient population solely with PVR values > 6 WU may be the focus of a future, prospective study.
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Figure 6 Algorithm for noninvasive estimation of PVR. CONCLUSIONS The TRV/TVIRVOT ratio is a reliable method to identify patients with elevated PVR. Moreover, a noninvasive estimate of PVR may be provided in those with ratios < 0.275 by using the simplified equation PVR = TRV/TVIRVOT 10. In patients with TRV/TVIRVOT ratios > 0.275, indicative of markedly elevated PVR (>6 WU), a noninvasive estimate is best obtained using the equation TRV2/TVIRVOT 5 (Figure 6). However, TRV/TVIRVOT and PVRecho are clear prognostic indicators in multiple clinical syndromes and may be used to aid in determining prognosis for all patients with cardiac and systemic diseases that affect right ventricular function, particularly in the previously studied patient populations.17-40 The value of TRV2/TVIRVOT in patients with extremely high PVR values (>12 WU), as well in follow-up for individual patients with elevated PVR, may require further study.
REFERENCES 1. Okamoto M, Miyatake K, Kinoshita N, Sakakibara H, Nimura Y. Analysis of blood flow in pulmonary hypertension with the pulsed Doppler flowmeter combined with cross-sectional echocardiography. Br Heart J 1984;51:407-15. 2. Hirschfeld S, Meyer R, Schwartz DC, Kofhagen J, Kaplan S. The echocardiographic assessment of pulmonary artery pressure and pulmonary vascular resistance. Circulation 1975;52:642-50. 3. Matsuda M, Sekiguchi T, Sugishita Y, Kuwako K, Iida K, Ito I. Reliability of non-invasive estimates of pulmonary hypertension by pulsed Doppler echocardiography. Br Heart J 1986;56:158-64. 4. Chan KL, Currie PJ, Seward JB, Hagler DJ, Mair DD, Tajik AJ. Comparison of three Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol 1987;9:549-54. 5. Murata I, Sonoda M, Morita T, Nakamura F, Takenaka K, Nagai R. The Clinical Significance of reversed flow in the main pulmonary artery detected by Doppler color flow imaging. Chest 2000;118:336-41. 6. Riggs T, Hirschfeld S, Borkat G, Knoke J, Leibman J. Assessment of the pulmonary vascular bed by echocardiographic right ventricular systolic time intervals. Circulation 1978;57:939-47. 7. Scapellato F, Temporelli PL, Eleuteri E, Corra U, Imparato A, Gianuzzi P. Accurate noninvasive estimation of pulmonary vascular resistance by Doppler echocardiography in patients with chronic failure heart failure. J Am Coll Cardiol 2001;37:1813-9.
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8. Shandas R, Weinberg C, Ivy DD, Nicol E, DeGroff CG, Hertzberg J, et al. Development of a noninvasive ultrasound color M-mode means of estimating pulmonary vascular resistance in pediatric pulmonary hypertension: mathematical analysis, in vitro validation, and preliminary clinical studies. Circulation 2001;104:908-13. 9. Tahara M, Tanaka H, Nakao S, Yoshimura H, Sakurai S, Tei C, et al. Hemodynamic determinants of pulmonary valve motion during systole in experimental pulmonary hypertension. Circulation 1981;64:1249-55. 10. Ebeid MR, Ferrer PL, Robinson B, Weatherby N, Gebland H. Doppler echocardiographic evaluation of pulmonary vascular resistance in children with congenital heart disease. J Am Soc Echocardiogr 1996;9:822-31. 11. Abbas AE, Fortuin FD, Schiller NB, Appleton CP, Moreno CA, Lester SJ. A simple method for noninvasive estimation of pulmonary vascular resistance. J Am Coll Cardiol 2003;41:1021-7. 12. Willard JEL, Richard A, Hillis LD. Cardiac catheterization. In: Kloner RA, ed. The guide to cardiology. 3rd ed. Greenwich, CT: Le Jacq Communications; 1995. p. 151. 13. Vlahos AP, Feinstein JA, Schiller NB, Silverman NH. Extension of Dopplerderived echocardiographic measures of pulmonary vascular resistance to patients with moderate or severe pulmonary vascular disease. J Am Soc Echocardiogr 2008;21:711-4. 14. Rajagopalan N, Simon MA, Suffoletto MS, Shah H, Edelman K, Mathier MA, et al. Noninvasive estimation of pulmonary vascular resistance in pulmonary hypertension. Echocardiography 2009;26:489-94. 15. Roule V, Labombarda F, Pellissier A, Sabatier R, Lognone T, Gomes S, et al. Echocardiographic assessment of pulmonary vascular resistance in pulmonary arterial hypertension. Cardiovasc Ultrasound 2010;8:21. 16. Farzaneh-Far R, McKeown BH, Dang D, Roberts J, Schiller NB, Foster E. Accuracy of Doppler-estimated pulmonary vascular resistance in patients before liver transplantation. Am J Cardiol 2008;101:259-62. 17. Stolz D, Rasch H, Linka A, Di Valentino M, Meyer A, Brutsche M, et al. A randomised controlled trial of bosentan in severe COPD. Eur Respir J 2008;32:619-28. 18. Kalambokis GN, Pappas K, Tsianos V. Differential effects of terlipressin on pulmonary and systemic hemodynamics in patients with cirrhosis and pulmonary hypertension: an echo study. Angiology 2012;63:199-205. 19. Kalambokis GN, Mouzaki A, Rodi M, Pappas K, Korantzopoulos P, Tsianos EV. Circulating endotoxin and interleukin-6 levels are associated with Doppler-evaluated pulmonary vascular resistance in cirrhotic patients. Hepatol Int 2012;6:783-9. 20. Ajami GH, Cheriki S, Amoozgar H, Borzouee M, Soltani M. Accuracy of Doppler-derived estimation of pulmonary vascular resistance in congenital heart disease: an index of operability. Pediatr Cardiol 2011;32:1168-74. 21. Cevik A, Kula S, Olgunturk R, Tunaoglu FS, Oguz AD, Pektas A, et al. Quantitative evaluation of right ventricle function by transthoracic echocardiography in childhood congenital heart disease patients with pulmonary hypertension. Echocardiography 2012;29:840-8. 22. Kuppahally SS, Michaels AD, Tandar A, Gilbert EM, Litwin SE, Bader FM. Can echocardiographic evaluation of cardiopulmonary hemodynamics decrease right heart catheterizations in end-stage heart failure patients awaiting transplantation? Am Journal Cardiology 2010;106:1657-62. 23. Lam KM, Ennis S, O’Driscoll G, Solis JM, Macgillivray T, Picard MH. Observations from non-invasive measures of right heart hemodynamics in left ventricular assist device patients. J Am Soc Echocardiogr 2009; 22:1055-62. 24. Farzaneh-Far R, Na B, Whooley MA, Schiller NB. Usefulness of noninvasive estimate of pulmonary vascular resistance to predict mortality, heart failure, and adverse cardiovascular events in patients with stable coronary artery disease (from the Heart and Soul Study). Am J Cardiol 2008;101: 762-6. 25. Yan GH, Wang M, Yue WS, Yiu KH, Siu CW, Lee SW, et al. Elevated pulmonary artery systolic pressure in patients with coronary artery disease and left ventricular dyssynchrony. Eur J Heart Fail 2010;12:1067-75. 26. Choi EY, Shim J, Kim SA, Shim CY, Yoon SJ, Kang SM, et al. Value of echoDoppler derived pulmonary vascular resistance, net-atrioventricular compliance and tricuspid annular velocity in determining exercise capacity in patients with mitral stenosis. Circ J 2007;71:1721-7.
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27. Oliveira W, Poyares D, Cintra F, Vieira ML, Fischer CH, Moises V, et al. Impact of continuous positive airway pressure treatment on right ventricle performance in patients with obstructive sleep apnea, assessed by threedimensional echocardiography. Sleep Med 2012;13:510-6. 28. Albers J, Ister D, Kayhan N, Vahl CF. Postoperative non-invasive assessment of pulmonary vascular resistance using Doppler echocardiography. Interact Cardiovasc Thorac Surg 2011;13:579-84. 29. Pirat B, McCulloch ML, Zoghbi WA. Evaluation of global and regional right ventricular systolic function in patients with pulmonary hypertension using a novel speckle tracking method. Am J Cardiol 2006;98:699-704. 30. Kouzu H, Nakatani S, Kyotani S, Kanzaki H, Nakanishi N, Kitakaze M. Noninvasive estimation of pulmonary vascular resistance by Doppler echocardiography in patients with pulmonary arterial hypertension. Am J Cardiol 2009;103:872-6. 31. Dahiya A, Vollbon W, Jellis C, Prior D, Wahi S, Marwick T. Echocardiographic assessment of raised pulmonary vascular resistance: application to diagnosis and follow-up of pulmonary hypertension. Heart 2010;96: 2005-9. 32. Lopez-Candales A, Edelman K, Gulyasy B, Candales MD. Differences in the duration of total ejection between right and left ventricles in chronic pulmonary hypertension. Echocardiography 2011;28:509-15. 33. Hoit BD, Dalton ND, Gebremedhim A, Janocha A, Zimmerman PA, Zimmerman AM, et al. Elevated pulmonary artery pressure among Amhara highlanders in Ethiopia. Am J Hum Biol 2011;23:168-76. 34. Maignan M, Rivera-Ch M, Privat C, Le on-Velarde F, Richalet JP, Pham I. Pulmonary pressure and cardiac function in chronic mountain sickness patients. Chest 2009;135:499-504. 35. Richalet JP, Rivera-Ch M, Maignan M, Privat C, Pham I, Macarlupu JL, et al. Acetazolamide for Monge’s disease: efficacy
36.
37.
38.
39.
40.
41.
42. 43.
and tolerance of 6-month treatment. Am J Respir Crit Care Med 2008;177:1370-6. Kim SH, Yi MZ, Kim HD, Song JM, Kang DH, Lee SD, et al. Prognostic value of echocardiographic estimation of pulmonary vascular resistance in patients with acute pulmonary thromboembolism. J Am Soc Echocardiogr 2011;24:693-8. Rydman R, Larsen F, Caidahl K, Alam M. Right Ventricular function in patients with pulmonary embolism: early and late findings using Doppler tissue imaging. J Am Soc Echocardiogr 2010;23:531-7. Chaudry RA, Cikes M, Karu T, Hutchinson C, Ball S, Sutherland G, et al. Paediatric sickle cell disease: pulmonary hypertension but normal vascular resistance. Arch Dis Child 2011;96:131-6. Serra W, Chetta A, Santilli D, Mozzani F, Dall’Aglio PP, Olivieri D, et al. Echocardiography may help detect pulmonary vasculopathy in the early stages of pulmonary artery hypertension associated with systemic sclerosis. Cardiovasc Ultrasound 2010;8:25. Frea S, Capriolo M, Marra WG, Cannillo M, Fusaro E, Libertucci D, et al. Echo Doppler predictors of pulmonary artery hypertension in patients with systemic sclerosis. Echocardiography 2011;28:860-9. Haddad F, Zamanian R, Beraud AS, Schnittger I, Feinstein J, Peterson T, et al. A novel non-invasive method of estimating pulmonary vascular resistance in patients with pulmonary arterial hypertension. J Am Soc Echocardiogr 2009;22:523-9. Armstrong WF, Ryan T. Feigenbaum’s echocardiography. 7th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:212. Maeder MT, Karapanagiotidis S, Dewar EM, Gamboni SE, Htun N, Kaye DM. Accuracy of Doppler echocardiography to estimate key hemodynamic variables in subjects with normal left ventricular ejection fraction. J Card Fail 2011;17:405-12.