A Simple Echocardiographic Method to Estimate Pulmonary Vascular Resistance

Alexander R. Opotowsky, MD, MPHa,b,*, Mathieu Clair, MDb, Jonathan Alalo, MD, MScc, Michael J. Landzberg, MDa,b, Aaron B. Waxman, MD, PhDa, Lilamarie Moko, BAb, Bradley A. Maron, MDa, Anjali Vaidya, MDd, and Paul R. Fora, MDd
Pulmonary hypertension includes heterogeneous diagnoses with distinct hemodynamic pathophysiologic features. Identifying elevated pulmonary vascular resistance (PVR) is critical for appropriate treatment. We reviewed data from patients seen at referral pulmonary hypertension clinics who had undergone echocardiography and right-side cardiac catheterization within 1 year. We derived equations to estimate PVR using the ratio of estimated pulmonary artery (PA) systolic pressure (PASPDoppler) to right ventricular outow tract velocity time integral (VTI). We validated these equations in a separate sample and compared them with a published model based on the ratio of the transtricuspid ow velocity to right ventricular outow tract VTI (model 1, Abbas et al 2003). The derived models were as follows: PVR [ 1.2 3 (PASP/right ventricular outow tract VTI) (model 2) and PVR [ (PASP/right ventricular outow tract VTI) D 3 if notch present (model 3). The cohort included 217 patients with mean PA pressure of 45.3 11.9 mm Hg, PVR of 7.3 5.0 WU, and PA wedge pressure of 14.8 8.1 mm Hg. Just >1/3 had a PA wedge pressure >15 mm Hg (35.5%) and 82.0% had PVR >3 WU. Model 1 systematically underestimated catheterization estimated PVR, especially for those with high PVR. The derived models demonstrated no systematic bias. Model 3 correlated best with PVR (r [ 0.80 vs r [ 0.73 and r [ 0.77 for models 1 and 2, respectively). Model 3 had superior discriminatory power for PVR >3 WU (area under the curve 0.946) and PVR >5 WU (area under the curve 0.924), although all models discriminated well. Model 3-estimated PVR >3 was 98.3% sensitive and 61.1% specic for PVR >3 WU (positive predictive value 93%; negative predictive value 88%). In conclusion, we present an equation to estimate the PVR, using the ratio of PASPDoppler to right ventricular outow tract VTI and a constant designating presence of right ventricular outow tract VTI midsystolic notching, which provides superior agreement with catheterization estimates of PVR across a wide range of values. 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:873e882) Right-sided cardiac catheterization is the reference standard for hemodynamic evaluation of patients with pulmonary hypertension, including pulmonary vascular resistance (PVR) estimation.1e3 Right-sided cardiac catheterization is invasive and cannot be applied repeatedly to all patients with suspected pulmonary hypertension. The estimated pulmonary artery (PA) systolic pressure (PASPDoppler) from transtricuspid ow velocity (TTFV) is at the core of the echocardiographic evaluation of suspected pulmonary hypertension.4e6 The PASP does not dene PVR, however; patients with vastly
a Cardiovascular Division, Department of Medicine Brigham and Womens Hospital, Boston, Massachusetts; bDepartment of Cardiology, Boston Childrens Hospital, Boston, Massachusetts; cDivisions of Cardiology and Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada; and dCardiovascular Division, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania. Manuscript received February 25, 2013; revised manuscript received and accepted May 2, 2013. This work was supported by grant 5-T32-HL07604-25 from the National Institutes of Health (Bethesda, Maryland) to Dr. Opotowsky and the Dunlevie Fund to Drs. Opotowsky and Landzberg. See page 881 for disclosure information. *Corresponding author: Tel: (617) 355-6508; fax: (617) 739-8632. E-mail address: sasha.opo@gmail.com (A.R. Opotowsky).

different PVR values can have identical PASP. Noninvasive PVR estimation would be useful for diagnosis and monitoring response to therapy. Several investigators have proposed echocardiographic PVR prediction models.7e14 Some have used the timing of the right ventricular outow tract ow to estimate PVR.12 Others have used a ratio of a correlate of PA pressure to PA ow in the denominator. An early model based on the ratio of TTFV to right ventricular outow tract velocity time integral (VTI) has been validated to predict PVR in patients with cirrhosis and adverse outcomes among coronary disease patients.8,15,16 This model, however, was derived in patients with normal or mildly elevated PVR and has poor agreement at higher levels of PVR.17,18 Equations using transtricuspid pressure gradient (4 TTFV2) in place of TTFV have been derived for patients with markedly elevated PVR.9 Others have evaluated a multiparameter approach involving the estimation of all variables involved in calculating the PVR (mean PA pressure, left atrial pressure, stroke volume, and heart rate).11 This approach is time intensive and therefore less clinically useful. Our objectives were to derive and validate a simple equation to accurately estimate PVR for widespread application in a diverse referral population of patients with pulmonary hypertension or suspected pulmonary hypertension.
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0002-9149/13/$ - see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.05.016

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Table 1 Descriptive statistics, including demographics, clinical characteristics, and hemodynamics, for derivation and validation cohorts Parameter Age (yrs) Men (%) White (%) Hypertension (%) Dyslipidemia (%) Coronary artery disease (%) Atrial brillation (%) Pacemaker or debrillator (%) Congenital heart disease (%) Connective tissue disease (%) Sarcoidosis (%) Chronic obstructive lung disease (%) Obstructive sleep apnea (%) Interstitial lung disease (%) Asthma (%) HIV (%) Diabetes mellitus (%) Liver cirrhosis (%) Tobacco, current (%) Tobacco, former (%) WHO group (%) I II III Heart rate (beats/min) Systolic blood pressure (mm Hg) Right atrial pressure (mm Hg) Systolic PA pressure (mm Hg) mPAP (mm Hg) PAWP (mm Hg) PVR (WU) Cardiac output (L/min) Overall (n 217) 60.6 15.2 25.3 85.5 53.9 32.3 22.6 23.0 7.8 6.5 14.7 4.6 21.7 15.2 16.2 4.1 1.8 18.0 5.1 6.5 49.0 30.9 25.8 16.1 76.9 14.6 125.3 20.8 10.7 6.1 72.8 21.2 45.2 13.0 13.8 7.9 7.7 5.1 4.8 1.8 Derivation (n 109) 58.6 15.4 20.2 86.5 52.3 29.3 20.2 19.3 7.3 5.5 13.8 1.8 19.3 16.5 16.5 5.5 1.8 12.8 5.5 9.2 45.7 37.6 22.9 12.8 76.6 15.1 123.2 20.1 10.6 6.0 72.8 19.7 45.4 12.5 13.2 7.4 7.7 5.1 4.9 1.8 Validation (n 108) 62.6 14.8 30.6 84.4 55.6 35.2 25.0 26.9 8.3 7.4 15.7 7.4 24.1 13.9 15.9 2.8 1.9 23.1 4.6 3.7 52.4 24.1 28.7 19.4 77.2 14.2 127.3 21.3 10.8 6.2 72.8 22.6 45.0 13.6 14.4 8.2 7.7 5.1 4.7 1.7 p Value* 0.05 0.09 0.84 0.68 0.39 0.42 0.20 0.81 0.59 0.71 0.06 0.41 0.71 1.00 0.50 1.00 0.05 1.00 0.17 0.41 0.04 0.36 0.20 0.75 0.16 0.78 1.00 0.80 0.25 0.97 0.43

Categorical data are presented as % and continuous data as mean SD. Hypertension refers to a clinical diagnosis of systemic arterial hypertension, consistent with recommendations of the Joint National Committee 7 as either systolic blood pressure !140 mm Hg, diastolic blood pressure !90 mm Hg, or treatment with an antihypertensive medication (except if prescribed for an alternative use such as calcium channel blockers for treatment of Raynauds phenomenon). Dyslipidemia was dened clinically according to the Adult Treatment Panel III guidelines and/or treatment with a lipid medication. Coronary artery disease refers to atherosclerotic coronary disease, either documented signicant epicardial coronary stenosis, with or without previous intervention, or a history of acute coronary syndrome. HIV human immunodeciency virus; mPAP mean pulmonary artery pressure; PAWP PA wedge pressure; WHO World Health Organization. * For differences between derivation and validation cohorts.

Methods The cohort included patients seen by the pulmonary hypertension services at the Hospital of the University of Pennsylvania, Brigham and Womens Hospital, Boston Childrens Hospital, or Massachusetts General Hospital who had undergone right-sided cardiac catheterization and transthoracic echocardiography from March 2002 to January 2012. The exclusion criteria were >12 months between right-sided cardiac catheterization and transthoracic echocardiography, interval initiation of pulmonary vasodilator or loop diuretic or cardiovascular or abdominal surgery or a change in clinical status, unrepaired congenital heart disease, or intravenous inotropes or vasopressors or positive pressure ventilation at the time of either study. We excluded 44 of 261 (17.1%) otherwise eligible patients because of poor-quality tricuspid regurgitation signals. The median interval between right-sided cardiac catheterization and

transthoracic echocardiography was 21.5 days (interquartile range 5 to 55.5). The patients were classied according to the World Health Organization pulmonary hypertension diagnostic groups.2 The patients had undergone clinically indicated transthoracic echocardiography with the Philips Sonos 7500 or IE33 (Philips Medical Systems, Andover, Massachusetts) or GE Vivid 7 Ultrasound (GE, Milwaukee, Wisconsin). The measurements were made by an echocardiographer (A.R.O.), who was unaware of the invasive hemodynamics data, in accordance with the American Society of Echocardiography guidelines19 using AcusonKinetDx (WS3000 Diagnostic Workstation, Siemens Medical Solutions USA, Mountain View, California) or Showcase Premier 5.3 (Trillium Technology, Ann Arbor, Michigan). At least 3 cardiac cycles were measured (5 to 10 with irregular rhythms), and average values were used.

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Figure 1. Bland-Altman plots for the derivation (Left) and validation (Middle) cohorts for model 1 (Top) and model by Kouzu et al9 (Bottom). The average of the PVR value from catheterization and the respective PVR estimation model is plotted on the x axis, and the difference between the catheterization PVR and the PVR estimated by the model is plotted on the y axis. Blue dotted line species mean bias; black dotted lines represent the 95% limits of agreement. (Right) Data for all subjects are plotted for model 1 and model by Kouzou et al,9 with 95% limits of agreement using regression of the absolute value of the residuals to estimate the SD at varying levels of average PVR. These plots demonstrate that model 1 has greater negative bias at higher values of PVR, and the model by Kouzou et al9 overestimates PVR at low PVR values.

Figure 2. Bland-Altman plots for the derivation (Left) and validation (Middle) cohorts for model 2 (Top) and model 3 (Bottom). The average of the PVR value from catheterization and the respective PVR estimation models is plotted on the x axis, and the difference between the catheterization PVR and the PVR estimated by the model is plotted on the y axis. Blue dotted line species mean bias; black dotted lines represent 95% limits of agreement. (Right) Data plotted for all subjects and 95% limits of agreement using regression of the absolute value of the residuals to estimate the SD at varying levels of average PVR for models 2 (Top) and 3 (Bottom). Although both models have minimal bias at all levels of PVR, because of its small positive bias and narrow 95% limits of agreement at low PVR values, model 3 is unlikely to estimate PVR <3 WU for a patient with elevated PVR.

The left atrial anteroposterior end-systolic dimension was measured from the parasternal long-axis view. Right ventricular outow tract pulse wave Doppler interrogation was performed from the basal short-axis views just proximal

to the pulmonic valve. By inspecting the pulse wave Doppler signal from the right ventricular outow tract, the presence of a midsystolic notch was characterized as a distinct notch or nadir within the initial 2/3 of the systolic ejection period.20

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Figure 3. (A) PVR versus estimated PVR using model 2, with red and blue designating the presence of midsystolic notching. The best-t line for patients with midsystolic notching was signicantly higher for a given value of estimated PVR (p 0.0001 for intercept 0). (B,C) PVR versus model 3 estimated PVR (B, red and blue indicate presence of midsystolic notching). Adding a constant of 3 for patients with midsystolic notching resulted in overlapping best-t lines with equal intercepts (p 0.34). (C) The best-t line for model 3.

TTFV was obtained from continuous wave Doppler interrogation in the view that provided the best envelope with the highest estimates. Left ventricular inow pulse wave Doppler was used to measure the peak E/A velocities. Lateral mitral annular tissue Doppler was used to measure e0 velocity.21 Right-sided cardiac catheterization was performed using a balloon-tipped, uid-lled catheter, as previously described.20 No sedation was administered for most catheterizations, and minimal to moderate conscious sedation was used for a subset with spontaneous ventilation. Supplemental oxygen was not administered unless the patient used chronic supplemental oxygen at rest, in which case the same dose was used during right-sided cardiac catheterization. The cardiac output was estimated either by triplicate thermodilution (n 83) or assumed Fick (n 134). Oxygen consumption was assumed to be 125 ml/m2 body surface area. No difference (p 0.74) was seen in the mean cardiac output between the 2 groups, and the method used did not signicantly modify the relationship between the right ventricular outow tract VTI and cardiac output (i.e., no 2-way interaction). Categorical data are expressed as proportions, and continuous data are presented as the mean SD or median and interquartile range, as appropriate. Unpaired t tests and Wilcoxon rank sum test were used to compare the mean values for normally and non-normally distributed continuous variables, respectively. The chi-square test or Fishers exact test was performed to compare the proportions for categorical variables. We compared the derived models to a published model from Abbas et al8 based on the ratio of TTFV to VTI: PVR 10 TTFV 0:16 model 1 RVOT VTI

increased r2 by !0.02. Potential variables included the left atrial anteroposterior dimension, lateral mitral E/e0 , TTFV, 4 TTFV2, estimated PASP using a xed right atrial pressure of 8 mm Hg (PASPDoppler) or variable right atrial pressure of 5, 10, or 15 mm Hg or 3, 8, or 15 mm Hg according to the inferior vena caval diameter and collapse,22,23 PASPDoppler-E/e0 , acceleration time, right ventricular outow tract midsystolic notching, right ventricular outow tract VTI, and ratios of the following variables to VTI: TTFV, 4 TTFV2, and PASPDoppler ( 4 TTFV2 8). Given the potential for model instability in the setting of collinear parameters, we also assessed the predictive value of alternative models to conrm the derived model was associated with the highest r2. The derived model was PVR 0.05 1.0 (PASPDoppler/VTI) 2.8 (midsystolic notching), where midsystolic notching was 1 if present and 0 if absent (partial r2 0.596 for PASPDoppler/VTI and partial r2 0.068 for the midsystolic notching term). To simplify, we rounded the coefcients to the nearest integer, given the clinical insignicance of PVR 0.25 WU. We further evaluated a model that included only PASPDoppler/VTI, given the potential for increased simplicity and to test the value of midsystolic notching in the validation cohort. Sensitivity analyses were performed to assess model performance in specic subsets of patients (e.g., high PA wedge pressure) and whether alternative parameters might improve the model. BlandAltman plots were used to assess the agreement between the derived models and PVR. Model discrimination for clinically relevant levels of PVR (>3 or >5 WU) was assessed using receiver operating characteristic curves, area under the curve, and sensitivity, specicity, and negative and positive predictive values. Thus, the simple PASPDoppler/VTI model was as follows: PVR 1:2 PASP RVOT VTI model 2

The overall sample was divided using random sampling into derivation and validation samples. To derive the model, we used linear regression analysis and forward selection, with p <0.10 for entry. The variables were retained if they

where RVOT is the right ventricular outow tract.

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The comprehensive model was as follows: PVR PASP 3 if notch present model 3 RVOT VTI

where RVOT is the right ventricular outow tract. We also assessed the agreement between PVR and a model derived by Kouzu et al9 in a population enriched for elevated PVR (mPVR 16.2 WU): PVR 1:48 TTFV 2 2:34 RVOT VTI

For simplicity, we have limited the reported results on this equation to Bland-Altman plots illustrating the overestimation of PVR at low values. This equation correlated less well with PVR than did model 3 (r 0.77 vs r 0.80). Statistical analyses were performed using the Statistical Analysis Systems for Windows, version 9.3 (SAS Institute, Cary, North Carolina) and GraphPad Prism, version 5.02, for Windows (GraphPad Software, San Diego, California). Results Demographic, clinical, and hemodynamic data are listed in Table 1. The mean patient age was 60.6 years, and the prevalence of common chronic diseases was high. The mean PA pressure was markedly elevated (45.2 13.0 mm Hg), as was the PVR (7.7 5.1 WU). Just >1/3 (35.5%) had a PA wedge pressure >15 mm Hg, and 10% had a PA wedge pressure of !23 mm Hg. The derivation and validation cohorts were similar, although the validation cohort tended to be older, with a smaller proportion of World Health Organization group I pulmonary hypertension. In the derivation cohort, we found that the published model using TTFV/right ventricular outow tract VTI (model 1) underestimated the PVR, especially at higher PVR values. The best linear approximation using TTFV/ right ventricular outow tract VTI was PVR 22.8 TTFV/ VTI (or PVR 0.76 2.37x, where x is the PVR estimate per model 1), with r2 0.531. Model 1 demonstrated signicant bias (bias 4.1) and increasingly underestimated PVR with higher PVR values (Figure 1). The model derived by Kouzu et al9 (Figure 1) was accurate at high PVR values but overestimated normal to mildly elevated PVR (bias 2.7 3.4, 95% limits of agreement 3.9 to 9.3). Model 2 (PVR 1.2 [PASP/right ventricular outow tract VTI]) correlated more closely with PVR (r2 0.593). Model 3 (PVR [PASP/right ventricular outow tract VTI] 3, if midsystolic notching present) correlated better still (r2 0.669). Figure 2 shows Bland-Altman plots for models 2 and 3 in the derivation cohort. As shown in Figure 3 (data for the entire cohort; equivalent results for the derivation and validation cohorts), lines approximating PVR with and without midsystolic notching are parallel (p 0.07 for difference in slope) but y intercepts at x 0 differed by w3 WU (p <0.0001). Including the additional term for midsystolic notching resulted in equivalent intercepts (p 0.34; Figure 3). We evaluated whether including estimates of PA wedge pressure improved the predictive models. Neither the left atrial dimension nor lateral mitral annular E/e0 met the criteria

Figure 4. Receiver operating characteristic curves for discrimination of PVR >3 WU.

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Figure 5. Tracings from 4 subjects, along with PVR estimates by each model and catheterization PVR. (A) Normal TTFV and right ventricular outow tract VTI without midsystolic notching. Models 1 and 3 accurately estimated PVR, and model 2 overestimated PVR. (B) TTFV was likely underestimated because of signal quality. All models predicted PVR >3 WU, although model 1 underestimated PVR the most. (C) High TTFV with high right ventricular outow tract VTI. (D) Model 1 markedly underestimated PVR with high PVR.

to be included in the model. Given the theoretical benet of including a PA wedge pressure estimate, however, we explored various methods to estimate the transpulmonary pressure gradient (difference between PASPDoppler and correlates of PA wedge pressure). No resulting equation provided statistically signicant improvement in the estimates. For example, using a previously proposed method (numerator PASPDopplerE/e0 ),13 we found the correlation for n 87 with E/e0 data (r2 0.595) was the same as for model 2, with a numerator of PASPDoppler alone (r2 0.596). To understand whether this resulted from variability in estimating the PA wedge pressure or to limited intrinsic value to including PA wedge pressure, we estimated the transpulmonary pressure gradient as PASPDoppleractual (catheterization) PA wedge pressure. Using this as the numerator in model 2, the correlation improved modestly (from r2 0.593 to r2 0.622), but no improvement was seen in model 3 (from r2 0.669 to r2 0.662). We examined how well any 2 of 3 component variables (mean PA pressure, PA wedge pressure, cardiac output) of catheter PVR could explain PVR by substituting the mean value for each parameter as a constant in the equation. Cardiac output and mean PA pressure provided much more information on PVR than did PA wedge pressure. Setting PA wedge pressure at 15, the equation (PVR [mPAP15]/cardiac output) resulted in r2 0.876. Equations substituting a constant for the mean PA pressure and cardiac output, respectively, produced r2 0.653 and r2 0.687. Likewise, the mean PA pressure and cardiac output correlated with PVR much better than did the PA wedge pressure (r2 0.575, r2 0.342, and r2 0.129,

respectively). No single catheter-derived variable predicted PVR as well as did the derived echocardiographic models; even perfect echocardiographic estimation of 1 parameter could not predict PVR as well as did a combination. In the validation cohort, model 3 correlated better with PVR (r2 0.622) than did model 2 (r2 0.597) or model 1 (r2 0.551). The intercept and coefcients of the best-t line did not differ signicantly from the derivation cohort for either model 2 or 3. No additional predictors of PVR achieved statistical signicance (all p >0.15) or provided additional explanatory power (Dr2 <0.02). Figure 1 shows Bland-Altman plots for the validation cohort for model 1 and the model by Kouzu et al.9 Model 1 again displayed bias (bias 4.1 4.1, 95% limits of agreement 12.2 to 4.0) and progressively underestimated PVR at higher PVR values. The model by Kouzu et al9 tended to overestimate lower PVR values (bias 2.7 3.2, 95% limits of agreement 3.7 to 9.0). Figure 2 shows the equivalent data for models 2 and 3, neither of which demonstrated systematic bias (model 2, bias 0.29 3.3, 95% limits of agreement 6.7 to 6.1; model 3, bias 0.03 3.2, 95% limits of agreement 6.2 to 6.2). Figures 1 and 2 show the data for all subjects, but the 95% limits of agreement were estimated using regression of the absolute value of the residuals to estimate the SD at varying levels of average PVR, instead of assuming a model would have the same bias and limits of agreement across the spectrum of PVR values. It can be seen (Figure 1) that model 1 progressively underestimated the PVR at higher values, and the model by Kouzu et al9 overestimated the PVR at low levels. However, models 2 and 3 demonstrated narrow limits

Miscellaneous/Echocardiographic PVR Table 2 Pearson correlation coefcients between pulmonary vascular resistance (PVR) and various predictors Variable Acceleration Time RVOT-VTI TTFV Estimated PASP 1 Derivation PVR Acceleration time RVOT-VTI TTFV Estimated PASP Model 1 Model 2 Validation PVR Acceleration time RVOT-VTI TTFV Estimated PASP Model 1 Model 2 PVR <8 WU* PVR Acceleration time RVOT-VTI TTFV Estimated PASP Model 1 Model 2 0.514 0.549 0.512 0.624 0.457 0.264 0.633 0.444 0.258 0.993 0.733 0.546 0.827 0.607 0.602 Model 2 0.768 0.538 0.736 0.733 0.738 0.978

879

3 0.803 0.604 0.722 0.710 0.712 0.922 0.939 0.789 0.666 0.727 0.707 0.706 0.909 0.934 0.697 0.583 0.603 0.626 0.626 0.824 0.850

0.576

0.545 0.546

0.603 0.528 0.263

0.601 0.510 0.253 0.994

0.743 0.618 0.854 0.586 0.577

0.772 0.622 0.765 0.731 0.732 0.974

0.578

0.397 0.407

0.564 0.368 0.054

0.564 0.362 0.047 0.995

0.579 0.485 0.796 0.552 0.544

0.622 0.483 0.656 0.726 0.725 0.967

RVOT right ventricular outow tract. * Subset of the combined cohort with PVR <8 WU (n 135).

of agreement at low PVR values, with a slight positive bias (Figure 2), consistent with a high sensitivity for PVR >3 WU. Figure 4 shows the receiver operating characteristic curves for PASPDoppler and models 1 to 3 as predictors of PVR >3. The results were similar in the derivation and validation cohorts. Model 3 estimated PVR >3 had 98.3% sensitivity and 61.1% specicity for PVR >3 WU (positive predictive value 93% and negative predictive value 88%), and an estimated PVR >7 had 63.0% sensitivity and 97.2% specicity for PVR >3 (positive predictive value 99% and negative predictive value 34%). All subjects with estimated PVR >8 (n 95) had PVR >3 WU, just as did 94.3% (50 of 53) with an estimated PVR of 5 to 8. Figure 5 gives examples of Doppler tracings and PVR estimates for each model and catheterization PVR. We performed sensitivity analyses to assess the model performance in specic subsets of patients and to determine whether specic physiologic ndings were associated with model performance. First, among patients with PASPDoppler <60 mm Hg (TTFV 3.6 m/s), in whom this equation is most likely to be used clinically, PASPDoppler had lower discriminatory ability for PVR >3 (area under the curve 0.712), and models 1 and 2 had intermediate discriminatory power (area under the curve 0.849 and 0.846, respectively; model 3, area under the curve 0.873). Second, among patients with PVR <8 WU, model 3 again demonstrated the highest correlation with PVR >3 (r 0.70 vs r 0.58 and r 0.62 for models 1 and 2, respectively; Table 2). Third, excluding PVR outliers, patients with PVR in the top or

bottom 5% (n 195, PVR 1.5 to 17.4 WU) produced similar results, albeit with slightly lower correlation coefcients (r 0.55, r 0.64, r 0.67, and r 0.73 for PASPDoppler and models 1 to 3, respectively). Fourth, to assess the effect of the time delay between echocardiography and catheterization, we limited the analysis to studies performed <22 days apart (median). However, this had little effect on the results (n 109, r 0.67, r 0.70, and r 0.76 for models 1 to 3, respectively). Fifth, among the 77 patients with PA wedge pressure >15 mm Hg, the correlation with PVR was slightly lower (r 0.63, r 0.70, r 0.74, and r 0.75 for PASPDoppler and models 1 to 3, respectively). This was also true for the subset with a diagnosis of World Health Organization group II pulmonary hypertension (n 56; r 0.62, r 0.74, r 0.79, and r 0.81 for PASPDoppler and models 1 to 3, respectively). Bland-Altman analysis for model 3 for patients with PA wedge pressure >15 mm Hg suggested minimal systematic bias (bias 0.46 2.62). Finally, to determine whether the heart rate affected the model, we repeated the assessment of model 2, using the product of VTI and heart rate as the denominator. This product and VTI alone correlated similarly with cardiac output among the 209 subjects with heart rate data available (r 0.49 to r 0.50); the resulting PVR estimates performed less well (r2 0.530 vs r2 0.590). Discussion We have described the derivation and validation of an equation to estimate PVR using clinically available

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echocardiographic parameters. The model includes the ratio of estimated PASP (PASPDoppler 8 4 TTFV2) to right ventricular outow tract VTI, with the addition of a constant (3) for patients with right ventricular outow tract Doppler ow envelope midsystolic notching. The equation is simple and easily integrated into clinical practice. In addition, it is as applicable to patients with normal PVR as it is to those with markedly elevated PVR. Previous investigators have demonstrated that an echocardiographic estimate using a ratio of estimated PA pressure to ow can approximate the PVR. Initial models included TTFV as the numerator. Although a direct correlation is present between TTFV/VTI and PVR at any level of PVR,24 the absolute agreement between this ratio and PVR is not robust. TTFV/VTI underestimates PVR at higher levels, because it does not account for the quadratic relation between velocity and pressure. Other models, such as that reported by Kouzu et al,9 were derived from populations with elevated PVR to address this limitation. They used estimates of the transtricuspid pressure gradient or PASP (4 TTFV2 right atrial pressure estimate) in the numerator. Because of the universally high PVR in the derivation samples, however, the equation includes a large constant, resulting in overestimation of the PVR in the normal range.9 The present model provided good agreement with true PVR throughout the range of PVR, addressing a limitation of the previously proposed models. All the models correlated reasonably well with the catheter-derived PVR (r ! 0.7). Although model 3 correlated best with PVR, the small difference makes ease of use and interpretation important considerations in choosing among these options. Most clinical echocardiographic laboratories will report the PASPDoppler or transtricuspid gradient. The units used for PASPDoppler or transtricuspid gradient are consistent (mm Hg), but different options exist for TTFV (cm/s or m/s); thus, consideration must be given to the units in the calculation of model 1. Including midsystolic notching might seem to add complexity, but it resulted in a coefcient of 1 for PASP/VTI (vs 1.2 in model 2). Finally, although a given cutoff of model 1 has similar test characteristics to PVR 3 for model 3, model 3s superior agreement between the absolute values of the estimated PVR makes it a more reliable predictor of the actual numerical PVR in an individual patient, and interpretation is thereby simplied. Because of these considerations, we believe model 3 is preferable. The inclusion of midsystolic notching is useful from a clinical perspective and is consistent with previous data that almost all patients with midsystolic notching have elevated PVR.20 It improves the sensitivity for high PVR, because it provides a second mechanism for the equation to produce a result with elevated PVR; even if the VTI and TTFV have been acquired or measured incorrectly, midsystolic notching will highlight the likelihood of PVR >3 WU. The derived equations include an estimate of pressure in the numerator and ow in the denominator. Both terms are simplications of the physiology captured by catheterization. First, PVR is calculated with the transpulmonary gradient, the difference between the mean PA pressure and PA wedge pressure (or left atrial pressure), as the numerator.

The proposed equations use PASPDoppler as a surrogate. PASP is not equivalent to mean PA pressure, although highly correlated (r 0.95 in this sample). Although mean PA pressure can be estimated using echocardiography, this is more time consuming and not commonly applied in practice. Likewise, PA wedge pressure can be estimated by echocardiography, but including such estimates did not improve model performance. This relates to the imprecision of PASP and PA wedge pressure estimates and the limited relative contribution of PA wedge pressure to the absolute PVR value compared with the greater inuence of PA pressure and cardiac output. Second, the equations use right ventricular outow tract VTI as a marker of ow. VTI reects the average distance traveled by the blood column but only indirectly suggests the stroke volume in the absence of data on area. The right ventricular outow tract VTI varies inversely with the cross-sectional area of the right ventricular outow tract and, presumably, indirectly with PVR.24 The left ventricular outow tract area might be less susceptible to such, and some have suggested the left ventricular outow tract VTI would provide a better marker of stroke volume. One study reported no benet to using the left ventricular outow tract VTI instead of the right ventricular outow tract VTI.10 In addition, cardiac output is the product of stroke volume and heart rate. Integrating heart rate into the equation did not improve the estimates. In patients with elevated PVR, we would expect a larger right ventricular outow tract area and higher heart rate, both of which would result in the VTI underestimating the cardiac output in patients with elevated PVR and would bias the model to overestimate the PVR at high values. Not only did we not observe that in our cohort, such a phenomenon would actually increase the likelihood that patients with high PVR are identied. The absolute value in a patient with very high PVR is less important than that the clinician is alerted to the presence of high PVR. We found a lower correlation between the predicted and actual PVR than in most previous reports. This might have been, in part, owing to use of clinical echocardiograms or the interval between studies. Our sample size and PVR distribution also differed. Most of the 44 subjects used to derive model 1 had normal PVR; only 6 had PVR >3 WU and 3 had PVR >4 WU.8 In small studies, outliers will have undue inuence and inate the correlation. We see several potential uses for the derived equation. First, it can be used to clinically assess whether a patient has importantly elevated PVR. An estimate signicantly <3 WU argues against elevated PVR. Patients with suspected pulmonary hypertension or elevated PASP in whom it would be unclear whether the pulmonary hypertension is due to elevated PVR, ow (e.g., cirrhosis), or left atrial pressure (e.g., left-sided cardiac disease) would be a relevant population. Second, it can be used to assess the treatment response to vasodilators. This would not replace right-sided cardiac catheterization but could supplement information, because right-sided cardiac catheterization is invasive and expensive. Finally, large epidemiologic studies have shown elevated estimated PASP is a predictor of heart failure and poor outcomes in patients with a normal and reduced ejection fraction.25e27 Being able to estimate PVR on a population scale would help distinguish whether this reects the

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adverse prognostic import of elevated left atrial pressure or an independent vascular remodeling, as suggested by 1 study of patients with coronary disease.16 These data were derived from clinical echocardiograms and a time delay was present between the echocardiogram and catheterization. Although empirically we found the model performed equally well whether performed close to catheterization or with many months in between tests, such a delay could in theory increase the nondifferential error and bias the results toward the null. A nondifferential error would be expected to be more of an issue for PASPDoppler than for TTFV, because PASP estimation involves squaring any error. Midsystolic notching can vary with respiration and sample volume placement. With these considerations, we would expect the test characteristics of models 2 and 3 to be more susceptible to random error than model 1. The inclusion of midsystolic notching improved the sensitivity for elevated PVR as outlined; even if the VTI and TTFV underestimate PVR, midsystolic notching will highlight the likelihood of PVR >3 WU. PASP estimation using TTFV requires the addition of the right atrial pressure to transtricuspid gradient. Some have suggested adding a constant value (e.g., 8 or 14 mm Hg), and others have used a clinical estimate from the assessment of the jugular venous pressure or have made a gross estimate based on the features of the inferior vena cava. In choosing a constant, we opted for a middle value (8 mm Hg). The average VTI in the sample in which the PVR was <5 WU (the subset likely to affected by small differences in the numerator) was w15 cm. Omitting the right atrial pressure altogether might be expected to underestimate PVR, on average, by w0.5 WU; adding 14 mm Hg might overestimate it by w0.4 WU. The relevance of such small differences is questionable when considered in light of the intrinsic variability of echocardiographic variables and catheter PVR. Disclosures The authors have no conicts of interest to disclose.
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