Journal of the American College of Cardiology 2003 by the American College of Cardiology Foundation Published by Elsevier Science Inc.

Vol. 41, No. 6, 2003 ISSN 0735-1097/03/$30.00 doi:10.1016/S0735-1097(02)02973-X

Pulmonary Hypertension

A Simple Method for Noninvasive Estimation of Pulmonary Vascular Resistance

Amr E. Abbas, MD,* F. David Fortuin, MD,* Nelson B. Schiller, MD, FACC, Christopher P. Appleton, MD, FACC,* Carlos A. Moreno, BS,* Steven J. Lester, MD, FACC* San Francisco, California; and Scottsdale, Arizona
We sought to test whether the ratio of peak tricuspid regurgitant velocity (TRV, ms) to the right ventricular outow tract time-velocity integral (TVIRVOT, cm) obtained by Doppler echocardiography (TRV/TVIRVOT) provides a clinically reliable method to determine pulmonary vascular resistance (PVR). BACKGROUND Pulmonary vascular resistance is an important hemodynamic variable used in the management of patients with cardiovascular and pulmonary disease. Right-heart catheterization, with its associated disadvantages, is required to determine PVR. However, a reliable noninvasive method is unavailable. METHODS Simultaneous Doppler echocardiographic examination and right-heart catheterization were performed in 44 patients. The ratio of TRV/TVIRVOT was then correlated with invasive PVR measurements using regression analysis. An equation was modeled to calculate PVR in Wood units (WU) using echocardiography, and the results were compared with invasive PVR measurements using the Bland-Altman analysis. Using receiver-operating characteristics curve analysis, a cutoff value for the Doppler equation was generated to determine PVR 2WU. RESULTS As calculated by Doppler echocardiography, TRV/TVIRVOT correlated well (r 0.929, 95% condence interval 0.87 to 0.96) with invasive PVR measurements. The Bland-Altman analysis between PVR obtained invasively and that by echocardiography, using the equation: PVR TRV/TVIRVOT 10 0.16, showed satisfactory limits of agreement (mean 0 0.41). A TRV/TVIRVOT cutoff value of 0.175 had a sensitivity of 77% and a specicity of 81% to determine PVR 2WU. CONCLUSIONS Doppler echocardiography may provide a reliable, noninvasive method to determine PVR. (J Am Coll Cardiol 2003;41:10217) 2003 by the American College of Cardiology Foundation OBJECTIVES

Pulmonary vascular resistance (PVR) is a hemodynamic variable that contributes to the management of patients with advanced cardiovascular and pulmonary conditions. It is used to evaluate the response to pharmacologic therapy in patients with congestive heart failure (1). Also, PVR is an essential component of heart- and liver- transplant candidate evaluation (2) and in predicting both early and late clinical outcomes (3,4). Moreover, PVR is an important variable in deciding the surgical outcome of patients with congenital heart disease (5). Pulmonary vascular resistance is calculated invasively by the ratio of transpulmonary pressure gradient (p) to transpulmonary ow (Qp) (6). Doppler echocardiography has signicantly impacted clinical medicine by its ability to determine intracardiac hemodynamics noninvasively. Since ow and pressure variables can be measured, we hypothesized that a measure of PVR might be accurately obtained by Doppler-derived variables.
From the *Division of Cardiovascular Diseases, Mayo Clinic, Scottsdale, Arizona; and the Division of Cardiology, University of California, San Francisco, California. Manuscript received June 20, 2002; revised manuscript received October 15, 2002, accepted November 11, 2002.

METHODS
This study was approved by the Institutional Review Board. A sample of 44 patients who had a pulmonary artery catheter in place was evaluated. Each subject provided written, informed consent. The patients demographic and clinical characteristics are shown in Table 1. Doppler and invasive measurements were obtained within 45 min of each other. Tricuspid regurgitation grade 2, as determined by Doppler echocardiography, was exclusionary. Invasive measurements. A Swan-Ganz catheter was used for hemodynamic measurements. Pulmonary capillary wedge pressure (PCWP), pulmonary artery systolic pressure (PASP), pulmonary artery diastolic pressure, and mean pulmonary artery pressure (MPAP) were measured. Cardiac output was calculated by thermodilution as a mean of three consecutive measurements not varying by more than 10%. The PVR in Wood units (WU) was calculated using the equation:
PVR MPAP PCWP/cardiac output

Doppler measurements. Doppler echocardiography was performed using the GE Vivid FiVe (GEMS, Milwaukee,

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Abbreviations and Acronyms CI condence interval ICC intraclass correlation coefcient MPAP mean pulmonary artery pressure PASP pulmonary artery systolic pressure PCWP pulmonary capillary wedge pressure PVR pulmonary vascular resistance PVRCATH invasive pulmonary vascular resistance PVRECHO pulmonary vascular resistance calculated by echocardiography Qp transpulmonary ow p transpulmonary pressure gradient RAP right atrial pressure TRV peak tricuspid regurgitant velocity TVIRVOT right ventricular outow tract time-velocity integral WU Wood units

Wisconsin) or Acuson Sequoia (Acuson, Mountain View, California) ultrasound systems. The right ventricular outow tract time-velocity integral (TVIRVOT) (cm) was obtained by placing a 1- to 2-mm pulsed wave Doppler sample volume in the proximal right ventricular outow tract just within the pulmonary valve 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. Pulsed wave Doppler was used rather than continuous wave Doppler to eliminate cases with increased pulmonary velocities secondary to either pulmonary valve or peripheral pulmonary artery stenosis. Continuous wave Doppler was used to determine the
Table 1. Clinical and Demographic Characteristics of the Patients
Characteristics Gender (M/F) Mean age (range) in yrs Mean ejection fraction (range) (%) Mean of the mean pulmonary artery pressure (range) (mm Hg) Pulmonary capillary wedge pressure Mean (range) (mm Hg) 12 mm Hg (n) 1319 mm Hg (n) 20 mm Hg (n) Right atrial pressure 8 mm Hg (n) 8 mm Hg (n) Mean PVRCATH (range) (WU) Referral diagnosis Valvular heart disease Chest pain and exertional dyspnea CAD and exertional dyspnea Renal and liver transplant Acute respiratory failure Postoperative Cardiomyopathy Findings 32/12 67 (4790) 54 (2075) 25 (1057)

peak tricuspid regurgitant velocity (TRV) (m/s). The highest velocity obtained from multiple views was used. Agitated saline was used to enhance suboptimal Doppler signals (7). In patients with atrial brillation (n 3), the average of ve measurements were used. The TRV/TVIRVOT ratio was then calculated (Figs. 1A, 1B, 2A, and 2B). Individuals in whom both invasive measurements and Doppler variables were obtained were blinded to each others calculations. Statistical analysis. SAS version 8.0 software was used for statistical computations (SAS Institute Inc., Cary, North Carolina). Linear regression analysis was generated between invasive PVR (WU) (PVRCATH) and TRV/TVIRVOT, and Pearsons correlation coefcient was obtained. A regression equation was derived in which a value for PVR (WU) was modeled based on TRV/TVIRVOT (PVRECHO). Furthermore, a plot of PVRECHO compared with PVRCATH was generated using the Bland-Altman analysis. Using receiver-operating characteristics curves, a dichotomized PVR was analyzed based on TRV/TVIRVOT. A logistic model was generated, and a cutoff value for TRV/ TVIRVOT with balanced sensitivity and specicity values was obtained to predict elevated PVR values (PVR 2 WU). Condence intervals were calculated for the sensitivity and specicity values by using the exact binomial method. Another cutoff value was then generated to determine a higher specicity of predicting PVR 2 WU. Twenty percent of the Doppler images were re-evaluated to quantify the intra- and interobserver reliability by calculating the intraclass correlation coefcient (ICC 2patients/ [2patients 2error]). Condence intervals for the ICC were calculated using the method of Shrout and Fleiss (8).

RESULTS
Thirteen of our patients had increased right atrial pressure (RAP) (8 mm Hg), whereas 20 had elevated mean left atrial pressure (PCWP 12 mm Hg). The linear regression analysis between PVRCATH and TRV/TVIRVOT revealed a good correlation (r 0.93, 95% condence interval [CI] 0.87 to 0.96) for all patients (Fig. 3). The equation derived from the linear regression was:
PVR ECHO 0.1618 10.006 TRV/TVIRVOT error

14 (338) 24 8 12 31 13 2 (0.76) (n (n (n (n (n (n (n 12) 9) 8) 6) 4) 3) 2)

CAD coronary artery disease; PVRCATH invasive pulmonary vascular resistance; WU Woods unit.

Patients with elevated PCWP and RAP were evenly distributed among the patient population (Fig. 4). Using the Bland-Altman analysis, PVRECHO measurements derived from this equation showed satisfactory limits of agreement with PVRCATH (Fig. 5), with a mean value of 0.0 0.41 (SD). The PVRECHO and PVRCATH values were well within one standard deviation (Figs. 1 and 2). The area under the receiver-operating characteristics curve was calculated at 0.916 (Fig. 6). A TRV/TVIRVOT cutoff value of 0.175 provided the best-balanced sensitivity (77%; 95% CI 46% to 96%) and specicity (81%; 95% CI 63% to 93%) to determine PVR 2 WU. A TRV/TVIRVOT cutoff value of 0.2 provided a speci-

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Figure 1. Images showing peak tricuspid regurgitant velocity (TRV) and right ventricular outow time-velocity integral (TVIRVOT) in a patient with normal pulmonary vascular resistance (PVR). (A) TRV is 2.86 m/s. (B) TVIRVOT is 20.8 cm. The ratio of TRV/TVIRVOT 2.86/20.8 0.1375. PVRECHO 0.1375 10 0.16 1.53 Woods units (WU) . This patients invasive PVR measurement was within 0.4 WU of the echocardiographic value (PVRCATH 1.3 WU). PVRECHO PVR in WU calculated based on the linear regression equation in which a value for PVR in WU was modeled based on TRV/TVIRVOT. PVRCATH invasive PVR.

Figure 2. Images showing TRV and TVIRVOT in a patient with elevated PVR. (A) TRV is 3.64 m/s. (B) TVIRVOT shows a clear deceleration of pulmonary ow before the pulmonic valve closure click and is calculated at 6.5 cm. The ratio of TRV/TVIRVOT 3.64/6.5 0.56. PVRECHO 0.56 10 0.16 5.76 WU . This patients invasive PVR measurement is also within 0.4 WU of the echocardiographic value (PVRCATH 6.0 WU). Abbreviations as in Figure 1.

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Figure 3. Linear regression analysis between PVRCATH and TRV/TVIRVOT. The circle highlights the PVR cutoff value of 2 WU (r 0.929, 95% condence interval 0.87 to 0.96). Abbreviations as in Figure 1.

Figure 4. Linear regression analysis between PVRCATH and TRV/TVIRVOT. The correlation remained robust among all groups of patients. Patients with normal left atrial pressure (LAP) and right atrial pressure (RAP) (open squares), elevated LAP and RAP (solid squares), elevated LAP and normal RAP (solid triangles), and elevated RAP and normal LAP (open triangles) were evenly distributed among the study population. Abbreviations as in Figure 1.

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Figure 5. Bland-Altman analysis showing the limits of agreement between PVRECHO and PVRCATH. Abbreviations as in Figure 1.

Figure 6. Receiver-operating characteristics curve. A TRV/TVIRVOT cutoff value of 0.175 provided the best-balanced sensitivity (77%) and specicity (81%) to determine patients with a PVR value 2 WU. (Area under the curve 0.916.) Abbreviations as in Figure 1.

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city of 94% and a sensitivity of 70% to determine PVR 2 WU. Thus, by using a TRV/TVIRVOT cutoff value of 0.2, the PVR could have been determined noninvasively to be 2 WU in 94% of patients. The ICC and CI for inter- and intraobserver reliabilities were 0.99 (95% CI 0.95 to 1.0) and 0.99 (95% CI 0.98 to 1.0), respectively.

DISCUSSION
Pulmonary vascular resistance is directly related to p and inversely related to Qp (6). Thus, TRV and TVIRVOT can be used as correlates of p and Qp, respectively (9,10). As PVR increases, changes in TVIRVOT and TRV occur in opposite directions (9,11). In accordance with the Bernoulli equation, TRV will increase as the PASP increases (9,12,13). However, both hyperdynamic ow states and true pulmonary vascular disease can elevate PASP; therefore, a measure of Qp is crucial. As PVR increases, there is earlier and enhanced reection of the pressure wave propagated from the RVOT into the pulmonary trunk. This is reected by a conformational change in TVIRVOT, where midsystolic notching and premature deceleration of pulmonary ow occur, leading to a decreased right ventricular ejection time (11,14 17). The Doppler-derived ratio of TRV/ TVIRVOT was hence hypothesized as a good correlate of PVR. Previous investigators have described the use of various Doppler parameters to evaluate PVR (11,1523). These efforts have focused primarily on the timing of events such as right ventricular pre-ejection and ejection times, acceleration time of the RVOT velocity, and ow propagation velocities. These studies support the notion that a conformational change in TVIRVOT occurs with increasing PVR. However, these methods require obtaining additional information than routinely acquired with less robust test characteristics. Based on our results, we propose a simplied equation for noninvasive calculation of PVR:
PVR(WU) 10 TRV/TVI RVOT

Heart rate correction may be required for extreme variations. Possible confounding hemodynamic variables that were not included in our Doppler equation include correlates of RAP and PCWP. Patients in whom the results of this study may be benecial will likely have elevated RAP and PCWP. However, despite the presence of these patients in our study, the correlation remained robust (Fig. 4). Thermodilution was used to calculate cardiac output, which may be inaccurate in the presence of moderate or severe tricuspid regurgitation; thus, those patients were excluded. Further studies will be needed to determine the applicability of this formula to those groups of patients in whom the Fick method was used for calculation of cardiac output. Anatomic variations of the right-heart structures may interfere with Doppler variables. Further studies will be needed to determine the applicability of this formula to patients with congenital heart disease, shunts, or pulmonary artery dilation who were not included in our study. Conclusions. Noninvasive determination of PVR is possible using variables that are routinely obtained by Doppler echocardiography. Increased PASP may be secondary to increased transpulmonary ow or abnormal PVR. Patients with TRV/TVIRVOT 0.2 are likely to have low PVR values (2 WU), and pulmonary vascular disease may be excluded despite increased PASP by Doppler. We propose that the term increased pulmonary pressures may be preferred to describe all patients with increased PASP. However, the term pulmonary hypertension may be more appropriately used in patients who also have increased PVR. Acknowledgments We thank the Echocardiography Laboratory (Rochelle Loftus, Ronald Buono, Steven Schneck, and Rose Simpson), Biostatistics Department, and Library Department (Eliane Purchase) for their assistance.
Reprint requests and correspondence: Dr. Steven J. Lester, Division of Cardiovascular Diseases, Mayo Clinic, 13400 East Shea Boulevard, Scottsdale, Arizona 85259. E-mail: lester.steven@ mayo.edu.

We also propose that in patients with increased PASP on Doppler echocardiography and TRV/TVIRVOT 0.2, an elevated PVR is suggested, and these patients may require further invasive workup. However, in patients with TRV/ TVIRVOT 0.2, PVR values are likely to be normal, even in the presence of Doppler evidence of increased PASP. Study limitations. Proper alignment of the ultrasound beam is a crucial factor to ensure adequate determination of TRV and TVIRVOT. Detection of TRV is crucial. The TRV signal could not be obtained in only one patient and was excluded. Agitated saline and ultrasound contrast agents can also enhance the Doppler signal when needed (7). A correction for heart rate in TVIRVOT was not made, as all patients had a heart rate between 60 and 100 beats/min.

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