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Original Research: Pulmonary Vascular Disease |

Echocardiography Combined With Cardiopulmonary Exercise Testing for the Prediction of Outcome in Idiopathic Pulmonary Arterial Hypertension FREE TO VIEW

Roberto Badagliacca, MD, PhD; Silvia Papa, MD; Gabriele Valli, MD; Beatrice Pezzuto, MD; Roberto Poscia, MD, PhD; Giovanna Manzi, MD; Elisa Giannetta, MD, PhD; Susanna Sciomer, MD; Paolo Palange, MD; Robert Naeije, MD; Francesco Fedele, MD; Carmine Dario Vizza, MD
Author and Funding Information

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

aDepartment of Cardiovascular and Respiratory Science, Sapienza University of Rome, Italy

bDepartment of Experimental Medicine, Sapienza University of Rome, Italy

cDepartment of Clinical Medicine, Sapienza University of Rome, Italy

dDepartment of Cardiology, Erasme University Hospital, Brussels, Belgium

CORRESPONDENCE TO: Roberto Badagliacca, MD, PhD, Department of Cardiovascular and Respiratory Science, I School of Medicine, Sapienza University of Rome, Policlinico Umberto I, Viale del Policlinico 155 - 00161 Rome, Italy


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(6):1313-1322. doi:10.1016/j.chest.2016.07.036
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Background  Right ventricular (RV) function is a major determinant of exercise intolerance and outcome in idiopathic pulmonary arterial hypertension. The aim of the study was to evaluate the incremental prognostic value of echocardiography of the right ventricle and cardiopulmonary exercise testing (CPET) on long-term prognosis in these patients.

Methods  One hundred and thirty treatment-naïve patients with idiopathic pulmonary arterial hypertension were enrolled and prospectively followed. Clinical worsening (CW) was defined by a reduction in 6-min walk distance plus an increase in functional class, or nonelective hospitalization for PAH, or death. Baseline evaluation included clinical, hemodynamic, echocardiographic, and CPET variables. Cox regression modeling with c-statistic and bootstrapping validation methods were done.

Results  During a mean period of 528 ± 304 days, 54 patients experienced CW (53%). Among demographic, clinical, and hemodynamic variables at catheterization, functional class and cardiac index were independent predictors of CW (model 1). With addition of echocardiographic and CPET variables (model 2), peak O2 pulse (peak o2/heart rate) and RV fractional area change (RVFAC) independently improved the power of the prognostic model (area under the curve, 0.81 vs 0.66, respectively; P = .005). Patients with low RVFAC and low O2 pulse (low RVFAC + low O2 pulse) and high RVFAC + low O2 pulse showed a 99.8 and 29.4 increase in the hazard ratio, respectively (relative risk, 41.1 and 25.3, respectively), compared with high RVFAC + high O2 pulse (P = .0001).

Conclusions  Echocardiography combined with CPET provides relevant clinical and prognostic information. A combination of low RVFAC and low O2 pulse identifies patients at a particularly high risk of clinical deterioration.

Figures in this Article

Pulmonary arterial hypertension (PAH) is a life-threatening and still incurable syndrome caused by an unexplained progressive increase in pulmonary vascular resistance (PVR). PAH exercise symptomatology and outcome are mainly determined by right ventricular (RV) function adaptation to increased afterload.

The diagnosis of PAH requires a right heart catheterization with measurement of the mean pulmonary arterial pressure (mPAP) ≥ 25 mm Hg and a PVR of > 3 Wood units. However, the procedure allows only an indirect decription of RV function, with right atrial pressure to estimate RV end-diastolic volume, or preload, mPAP or PVR to estimate afterload, and stroke volume (SV) to reflect contractility. Echocardiography provides indices of systolic and diastolic function, structural changes, RV-left ventricular (LV) interactions in addition to estimations of afterload. On the other hand, cardiopulmonary exercise testing (CPET) allows for indirect assessment of RV functional contractile reserve determining maximum cardiac output and related maximum workload and oxygen uptake.,,

Recent studies have shown the incremental value and prognostic relevance of echocardiography of the RV combined with CPET variables in predicting outcome in patients with heart failure. This has not been yet assessed in PAH. Furthermore, the added value of echocardiography and CPET with respect to invasive hemodynamic predictors of outcome is not exactly known. Therefore, the aim of the present study was to evaluate the incremental prognostic value of echocardiography and CPET on long-term prognosis compared with traditional clinical and hemodynamic variables.

Population and Study Design

This study enrolled 130 consecutive patients with idiopathic PAH (IPAH) referred for pulmonary hypertension to our center over a 3-year period and who gave an informed written consent. This study was conducted in accordance with the amended Declaration of Helsinki and was approved by the local Institutional Review Board (Protocol no. 42412). The diagnosis of IPAH relied on right heart catheterization showing precapillary pulmonary hypertension (mPAP ≥ 25 mm Hg, pulmonary artery wedge pressure ≤ 15 mm Hg) and the use of an algorithm incorporating respiratory function tests, perfusion lung scan, CT scan and echocardiography to exclude secondary causes, in agreement with updated guidelines. Patients were then treated with endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and prostanoids.

Clinical worsening (CW) was defined as a reduction from baseline in the 6-min walk (6MW) distance by 15%, confirmed by two tests done within 2 weeks, plus worsening of World Health Organization (WHO) functional class, or nonelective hospitalization for PAH (need for IV diuretic or inotropic drugs, need for new PAH therapies, lung transplantation, or septostomy), or all-cause mortality.

All patients were prospectively followed-up with phone calls (every month) and clinical examinations (every 1 to 3 months) by two physicians (R. P. and B. P.) blinded to the echocardiographic and CPET results. The first episode of CW was taken into consideration for the analysis.

Echocardiographic Assessment

Baseline echocardiographic studies were performed within 24 hours of the right heart catheterization (RHC) using commercially available equipment (Vivid S6, GE), with a 3.5-MHz transducer at a depth of 16 cm in the standard views and in agreement with the American Society of Echocardiography Guidelines.

The following standard parameters and derived measures were considered in the analysis: apical four-chamber view: right atrial (RA) area, RV end-diastolic area (RVEDA), RV end-systolic area (RVESA), RV fractional area change % (RVFAC = [RVEDA - RVESA]/RVEDA × 100) and tricuspid annular plane systolic excursion (TAPSE); parasternal view: LV systolic and diastolic eccentricity index (LV-EIs and LV-EId, respectively) and presence of pericardial effusion.

Intraobserver and interobserver variabilities were assessed using a Bland-Altman analysis for RVEDA and RVESA, the two determinants of RVFAC: for RVEDA, the intraobserver variability was 0.18 ± 0.66 cm2 (95% CI, -1.09 to 1.45) and interobserver variability was 0.31 ± 0.98 cm2 (95% CI, −1.37 to 1.99); for RVESA, the intraobserver variability was 0.16 ± 0.50 cm2 (95% CI, −0.77 to 1.09) and the interobserver variability was 0.05 ± 0.55 cm2 (95% CI, −1.10 to 1.20).

Six-min Walk Test

At baseline, all patients performed a nonencouraged 6MW test in a 25-m-long corridor in the same environmental conditions and at about the same time of day (±2 h).

The best distance covered on two consecutive tests performed after 60 to 90 minutes was considered for the analysis.

Cardiopulmonary Exercise Test
All patients performed a symptom-limited incremental cycle ergometer CPET with 10 to 15 watt/min workload increments. No patient performed the test on supplemental O2. Oxygen uptake (V˙ o2), carbon dioxide output (V˙ co2), minute ventilation (V˙ E), and end-tidal carbon dioxide partial pressure (PETco2) were measured breath-by-breath (Quark CPET) and averaged every 5 s for subsequent analysis. Heart rate (HR) was monitored via 12-lead ECG. The O2 pulse was calculated as the V˙ o2/HR ratio at peak exercise. Tests were considered maximal if peak respiratory exchange ratio was greater than 1.1. The anaerobic threshold was detected by the V-slope method.
Peak work rate, peak V˙ o2, and peak V˙ E were defined, respectively, as the highest level of exercise and the highest V˙ o2 and V˙ E that could be sustained for at least 15 s during the last stage of incremental exercise. The slope of V˙ E over V˙ co2V˙ EV˙ co2) during incremental test was measured from unloaded pedalling to the ventilatory compensation point; for patients who did not reached the ventilatory compensation point, it was measured from unloaded pedalling to peak exercise. The dead space volume of the facemask was subtracted from the total V˙ E before calculating individual V˙ E/V˙ co2 slopes and ratios.
The occurrence of a right-to-left exercise-induced shunt through a patent foramen ovale was detected by brisk increase in V˙ E/V˙ co2 and other criteria as previously described.
Statistical Analysis

Continuous data were expressed as mean ± SD, and categorical data were expressed as counts and proportions. Two-group comparisons were done with unpaired or paired, two-tailed t tests for means if the data were normally distributed or with Wilcoxon rank sum tests if the data were not normally distributed. Fisher exact χ2 tests were used to analyze the categorical data. Linear regression analysis was performed to assess the relationship between RVFAC and PVR and expressed as a Pearson correlation coefficient.

Actuarial freedom from episodes of CW was determined by the Life Table method. Kaplan-Meier (product-limit) graphs were used to demonstrate clinical worsening over time. Patients who were without CW were censored on the date of the conclusion of the study.

Cox proportional hazards regression methods were used to identify risk factors for CW and to determine the association among baseline patient characteristics and outcomes. Time to clinical worsening was selected as the primary outcome. Univariate proportional hazards analyses were performed, and Wald χ2P values were calculated. The likelihood ratio method was used to determine hazard ratios. After all Cox univariate analyses were performed, the covariates were inversely ordered by P value (smallest to largest).

Because of the large number of variables and relatively low number of events (54), a strict univariate P value criterion (P < .05) was used to select the variables initially entered into the multivariable model. Thus, these variables were included in the multivariable model if they improved the likelihood ratio statistic by an amount that corresponded to a P value of < .05.

Finally, collinearity was assessed by using bivariate linear regression between continuous variables or using Wilcoxon tests across categorical variables. When two or more selected variables were intimately associated (correlation coefficient > 0.60, as between CI, 6MW test, pulmonary arterial pressure, PVR, peak V˙ o2, V˙ E/V˙ co2 slope, and between RVEDA, RVESA, RVFAC, TAPSE, LV-EI, and between right atrial pressure, RA area, pericardial effusion), the one chosen was that with the greatest Wald statistic (ie, the ratio of the square of the regression coefficient to the square of the standard error of the coefficient). The Wald statistic, analogous to the t test in linear regression, is used to assess the significance of coefficients; thus, the contribution of individual predictors in a given model and is asymptotically distributed as a χ2 distribution.

This approach allowed to restrict the candidate variables for the multivariate analysis to the CI, right atrial pressure, WHO class, 6MW test for model 1 building and to the CI, WHO class, PETco2, peak pulse O2, RVFAC, pericardial effusion for model 2 construction.

Finally, internal validation of the Cox proportional hazard analysis model was based on bootstrapping, using 10,000 bootstrap samples and 95% percentile CIs. The c statistic was calculated for each model and the comparison of the two values was tested by the method of DeLong et al to determine the incremental prognostic information of model 2.

Receiver operating characteristic curves were used to identify the optimal RVFAC and peak O2 pulse cut-points for CW detection. Survival curves were generated using the Kaplan-Meier method, and the log-rank test was used to evaluate differences between groups.

All statistical analyses were performed using SPSS software (version 20.0, IBM) and Stata 13 (StataCorp). All statistical tests were two-sided, and a P value < .05 was considered statistically significant.

Among 130 patient with IPAH initially enrolled, 13 were excluded as being unable to perform the CPET, 8 because of an exercise gas exchange pattern indicating opening of a foramen ovale, and 7 because of severe tricuspid regurgitation. The remaining 102 were 62 women and 40 men, aged 52 ± 14 years with a BMI of 25.5 ± 4, a WHO functional class of 2.7 ± 0.4, a 6MW distance 430 ± 6 m, and severely impaired hemodynamics, echocardiography, and exercise capacity (Table 1)., Most relevant comorbidities were diabetes (5 patients; 5%), hypercholesterolemia (10 patients; 10%), thyroid diseases (6 patients; 6%), and clinical depression (7 patients; 7%).

Table Graphic Jump Location
Table 1 Hemodynamic, Imaging, and Exercise Characteristics of the Study Population

Normal values for echocardiographic parameters are reported from reference 5.

Normal values for cardiopulmonary exercise test have been calculated from previous reported equations and reports considering sex, age, height, and weight.,

CI = cardiac index; HR = heart rate; LV-EId = left ventricular end-diastolic eccentricity index; LV-EIs = left ventricular end-systolic eccentricity index; mPAP = mean pulmonary arterial pressure; PAWP = mean pulmonary artery wedge pressure; PETco2 peak = end-tidal CO2 pressure; PVR = pulmonary vascular resistance; RA area = right atrium area; RAP = mean right atrial pressure; RVEDA = right ventricular end-diastolic area; RVESA = right ventricular end-systolic area; RVFAC = right ventricular fractional area change; TAPSE = tricuspid anular plane systolic excursion; V˙ co2 peak = peak carbon dioxide production; V˙ E = minute ventilation; V˙ E/V˙ co2 slope = ventilation to CO2 production slope; V˙ o2 peak = peak oxygen uptake; WU = Wood unit.

Treatments instituted after diagnostic workup were calcium channel blockers in 9, endothelin receptor antagonists in 37, phosphodiesterase 5 inhibitors in 6, and SC treprostinil in 16 patients.

During a follow-up of 528 ± 304 days, 54 patients experienced CW (53%) (Table 2). The event-free survival rates were, respectively, 72%, 51%, and 30% at 1, 2, and 3 years (Fig 1). As shown in Table 3, patients with a CW had worse WHO functional class, shorter 6MW test, worse hemodynamics, worse RV function on echocardiography and CPET with lower V˙ o2 peak and increased V˙ E/V˙ coO2.
Table Graphic Jump Location
Table 2 Description of Different Clinical Worsening Endpoints During Follow-up

6MW test = isolated worsening in 6-min walk test > 15% compared with previous test; 6MW test + WHO = worsening in both 6MW test and WHO class; RHF = right heart failure; WHO class = isolated worsening in World Health Organization functional class.

Figure 1
Figure Jump LinkFigure 1 The event-free survival rates for the overall population included in the study: 72%, 51%, and 30% at 1, 2, and 3 years, respectively, from baseline.Grahic Jump Location
Table Graphic Jump Location
Table 3 Demographic, Clinical, Hemodynamic, Imaging, and Exercise Differences Between Patients With and Without CW

Ca = calcium; CW = clinical worsening; ERA = endothelin receptor antagonist; NS = not significant; PDE5i = phosphodiesterase 5 inhibitor. See Table 1 and 2 legends for expansion of abbreviations.

At univariate analysis the following variables resulted predictive of CW (Table 4): WHO functional class, 6MW distance, RAP, CI, PVR, RA area, LV-EId, LV-EIs, RVEDA, RVESA, RVFAC, TAPSE, pericardial effusion, peak exercise HR, V˙ o2 peak, V˙ o2 pulse peak, V˙ E peak, V˙ E/V˙ co2 slope, peak workload.
Table Graphic Jump Location
Table 4 Univariate Analysis of Baseline Parameters for Clinical Worsening Prediction

See Table 1 and 2 legends for expansion of abbreviations.

Cox regression model 1 for CW prediction was constructed, with those variables significantly resulting from univariate analysis excluding echocardiographic and CPET variables. Among demographic, clinical, and hemodynamic parameters, WHO functional class and CI emerged as independent predictors of CW (Table 5). Adding echocardiographic and CPET variables from univariate analysis, model 2 was generated, in which only peak O2 pulse and RVFAC emerged as additional independent predictors of outcome. Figures 2 and 3 highlight that, among patients with preserved RVFAC at rest, there was a proportion of them with low peak O2 pulse.

Table Graphic Jump Location
Table 5 Cox Regression Models for Clinical Worsening Prediction (Models 1 and 2) and Bootstrap Estimates of Cox Proportional Hazard Analysis

WHO IV: WHO functional class IV. See Table 1 and 2 legends for expansion of abbreviations.

Figure 2
Figure Jump LinkFigure 2 Correlation between RVFAC and PVR (linear model, r = 0.60, P = .0001, y = 47.7-1.0×). Patients with low peak O2 pulse (<8.0 mL/beat) and high peak O2 pulse (≥8.0 mL/beat) are reported in the same scatterplot (red circles and blue circles, respectively). PVR = pulmonary vascular resistance; RVFAC = right ventricular fractional area change; WU = Wood unit.Grahic Jump Location
Figure 3
Figure Jump LinkFigure 3 RVFAC and the corresponding peak O2 pulse pattern during the cardiopulmonary exercise test, in two different IPAH patients. (A) Preserved RVFAC (42.3%) and good exercise performance with adequate-performing O2 pulse (peak, 14.2 mL/beat); (B) preserved RVFAC (40.4%) and poor exercise performance with low O2 pulse (peak, 7.0 mL/beat). IPAH = idiopathic pulmonary arterial hypertension; O2 pulse: peak oxygen pulse. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

The c-statistic accuracy comparison between the two models demonstrated incremental prognostic power of model 2 vs model 1 for CW (area under the curve, 0.81 vs 0.66, respectively; P = .005, 95% CI, 0.02-0.11) (Fig 4). Sensitivity analysis of the Cox proportional hazard analysis for a parsimonious model 2 (including CI, WHO class, PETco2, peak pulse O2, RVFAC, and pericardial effusion) using bootstrapping (Table 5) confirmed the main results in terms of both statistical magnitude and direction.

Figure 4
Figure Jump LinkFigure 4 Comparison of the receiver operating characteristic curves for prediction of clinical worsening between model 1 (dashed black line), including demographic, clinical, and hemodynamic parameters, and model 2 (solid red line) adding echocardiographic and cardiopulmonary exercise test parameters. A significant improvement in accuracy is observed for model 2 in predicting clinical worsening (AUC 0.80 vs 0.66, P = .0004). AUC = area under the curve.Grahic Jump Location

Receiver operating characteristic curve analysis revealed that RVFAC and peak O2 pulse at a cutoff point of 36.5% and 8.0 mL/beat, respectively, were indicators of CW with the best predictive values (RVFAC: area under the curve [AUC], 0.89, P = .0001; peak O2 pulse: AUC, 0.91, P = .0001). Figure 5 shows Kaplan-Meier event-free survival curves based on the combination of the cutoff values of RVFAC and peak O2 pulse. Patients with high RVFAC + high peak O2 pulse (group 1) had a better prognosis compared with patients with high RVFAC + low peak O2 pulse (group 2) and low RVFAC + low peak O2 pulse (group 3).

Figure 5
Figure Jump LinkFigure 5 Kaplan-Meier event-free survival curves based on the combination of the cutoff values of RVFAC and peak O2 pulse. Patients with high RVFAC + high peak O2 pulse (group 1) had significantly a better prognosis compared with patients with high RVFAC + low peak O2 pulse (group 2; P = .0001) and low RVFAC + low peak O2 pulse (group 3; P = .0001). Group 2 patients had a better prognosis compared with group 3 (P = .0001), but a worse outcome compared with group 1 (P = .0001). See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Bivariate Cox regression analysis applied to the combination of the binary values of RVFAC and peak O2 pulse showed a progressive increase in the hazard ratio from group 2 to 3: HR 29.4 (95 CI, 3.8-224; P = .001) (relative ratio, 25.3) and hazard ratio, 99.8 (95% CI, 13.5-737; P = .0001) (relative ratio, 41.1), respectively, compared with high RVFAC + high peak O2 pulse group (log-likelihood -2, 323; χ2, 80.6; P = .0001).

The present results show that echocardiography and CPET are important additions to right heart catheterization to assess disease severity and predict outcome in patients with IPAH.

The present study is original by the analysis of predictors of outcome of combined cardiac catheterization, echocardiography, and CPET measurements. Only two variables emerged as additional independent predictors: RVFAC and peak O2 pulse. RVFAC is a surrogate of RV ejection fraction and accordingly reflects systolic function at a given level of preload and afterload., MRI measurements of changes, not absolute values of RV ejection fraction, have been shown to be of prognostic relevance. The new finding here is that RVFAC outperformed other echocardiographic indices of systolic function. Each of these measurements has of course limitations and, as previously shown, whether or not a variable emerges as an independent predictor of outcome is also dependent on size and characteristics of source population. As for peak O2 pulse, this variable is thought to assess maximum SV. MRI-determined SV has been previously shown to be an important predictor of survival in PAH.

Right heart catheterization variables have long been known to predict survival in patients with PAH, with more effective prognostication from variables assessing RV function (SV, RAP) than from variables assessing pulmonary vascular function (pulmonary arterial pressure, PVR).,,,,,, It is not surprising therefore that several echocardiographic variables that estimate RV function have also been reported as independent predictors of outcome in PAH.,,,,,,,,,,,,,, However, in all these studies, there was no evaluation of the relevance and added value of each of them with respect to right heart catheterization measurements. Only one study, by incremental modeling analysis using the c-index, has shown that the incorporation of invasive hemodynamic variables in a model that already include echocardiographic measures may not be of incremental value to prognostic evaluation.

CPET is another important tool for the assessment of PAH severity and outcome, with variables emerging as independent predictors being the 6MW distance, peak V˙ o2, V˙ E/V˙ co2, and HR reserve.,,, These CPET variables of predictive capability are the same as reported in heart failure, and are therefore assumed to be determined by RV function. However, as for echocardiography, the added value of CPET variables with respect to a right heart catheterization is not clearly determined. Only one study addressed this issue and showed PVR, peak V˙ o2, and heart rate reserve as independent predictors of survival.

A limitation to this study is that IPAH patients with exercise-induced opening of a foramen ovale were excluded to preserve the relevance of ventilator measurements. These patients may have a worse prognosis. A reanalysis of our population with inclusion of patients with exercise-induced right-to-left shunting showed the same independent predictors of outcome with the same levels of significance. However, 15% (20 patients) of the initial cohort were excluded, which indeed is a limitation of the study. Another limitation is that there was no independent adjudication committee for clinical events. Finally, most parameters used in the evaluation of pulmonary hypertension patients are to some extent physiologically linked, and this may not be sufficiently accounted for in a multivariate analysis.

In conclusion, the present results strongly suggest that noninvasive measurements related to RV function obtained by combining resting echocardiography and CPET are of added value to right heart catheterization in the assessment of severity and prognostication of PAH.

Author contributions: Each author of this study has made substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; has drafted the submitted article or revised it critically for important intellectual content; has provided final approval of the version to be published; has agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. R. B. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following: R. B. and C. D. V. have received fees for speaking activities and advisory boards from United Therapeutics, Dompe, GSK, and Bayer. None declared (S. P., G. V., B. P., R. P., G. M., E. G., S. S., P. P., R. N., F. F.).

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Humbert M. .Sitbon O. .Chaouat A. .et al Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156-163 [PubMed]journal. [CrossRef] [PubMed]
 
Benza R.L. .Miller D.P. .Gomberg-Maitland M. .et al Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164-172 [PubMed]journal. [CrossRef] [PubMed]
 
Eysmann S.B. .Palevsky H.I. .Reichek N. .Hackney K. .Douglas P.S. . Two-dimensional and Doppler-echocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension. Circulation. 1989;80:353-360 [PubMed]journal. [CrossRef] [PubMed]
 
Raymond R.J. .Hinderliter A.L. .Willis P.W. .et al Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214-1219 [PubMed]journal. [CrossRef] [PubMed]
 
Brierre G. .Blot-Souletie N. .Degano B. .et al New echocardiographic prognostic factors for mortality in pulmonary arterial hypertension. Eur J Echocardiogr. 2010;11:516-522 [PubMed]journal. [CrossRef] [PubMed]
 
Fine N.M. .Chen L. .Basztiansen P.M. .et al Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging. 2013;6:711-721 [PubMed]journal. [CrossRef] [PubMed]
 
Bustamante-Labarta M. .Perrone S. .De La Fuente R.L. .et al Right atrial size and tricuspid regurgitation severity predict mortality or transplantation in primary pulmonary hypertension. J Am Soc Echocardiogr. 2002;15:1160-1164 [PubMed]journal. [CrossRef] [PubMed]
 
Ghio S. .Klersy C. .Magrini G. .et al Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension. Int J Cardiol. 2010;140:272-278 [PubMed]journal. [CrossRef] [PubMed]
 
Ghio S. .Pazzano A.S. .Klersy C. .et al Clinical and prognostic relevance of echocardiographic evaluation of right ventricular geometry in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol. 2011;107:628-632 [PubMed]journal. [CrossRef] [PubMed]
 
Utsunomiya H. .Nakatani S. .Nishihira M. .et al Value of estimated right ventricular filling pressure in predicting cardiac events in chronic pulmonary arterial hypertension. J Am Soc Echocardiogr. 2009;22:1368-1374 [PubMed]journal. [CrossRef] [PubMed]
 
Forfia P.R. .Fisher M.R. .Mathai S.C. .et al Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1034-1041 [PubMed]journal. [CrossRef] [PubMed]
 
Ameloot K. .Palmers P.J. .Vandebruane A. .et al Clinical value of echocardiographic Doppler-derived right ventricular dp/dt in patients with pulmonary arterial hypertension. Eur Heart J Cardiovas Imaging. 2014;15:1411-1419 [PubMed]journal. [CrossRef]
 
Ernande L. .Cottin V. .Leroux P.Y. .et al Right isovolumic contraction velocity predicts survival in pulmonary hypertension. J Am Soc Echocardiogr. 2013;26:297-306 [PubMed]journal. [CrossRef] [PubMed]
 
Haeck M.L. .Scherptong R.W. .Marsan N.A. .et al Prognostic value of right ventricular longitudinal peak systolic strain in patients with pulmonary hpertension. Circ Cardiovasc Imaging. 2012;5:628-636 [PubMed]journal. [CrossRef] [PubMed]
 
Smith B.C. .Dobson G. .Dawson D. .Charalampopoulos A. .Grapsa J. .Nihoyannopoulos P. . Three-dimensional speckle tracking of the right ventricle: toward optimal quantification of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol. 2014;64:41-51 [PubMed]journal. [CrossRef] [PubMed]
 
Tei C. .Dujardin K.S. .Hodge D.O. .et al Doppler echocardiographic index for assessment of global right ventricular function. J Am Soc Echocardiogr. 1996;9:838-847 [PubMed]journal. [CrossRef] [PubMed]
 
Yeo T.C. .Dujardin K.S. .Tei C. .Mahoney D.W. .McGoon M.D. .Seward J.B. . Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol. 1998;81:1157-1161 [PubMed]journal. [CrossRef] [PubMed]
 
Wensel R. .Opitz C.F. .Anker S.D. .et al Assessment of survival in patients with primary pulmonary hypertension. Importance of cardiopulmonary exercise testing. Circulation. 2002;106:319-324 [PubMed]journal. [CrossRef] [PubMed]
 
Kane G.C. .Maradit-Kremers H. .Slusser J.P. .et al Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial hypertension. Chest. 2011;139:1285-1293 [PubMed]journal. [CrossRef] [PubMed]
 
Deboeck G. .Scoditti C. .Huez S. .et al Exercise testing to predict outcome in idiopathic versus associated pulmonary arterial hypertension. Eur Respir J. 2012;40:1410-1419 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 The event-free survival rates for the overall population included in the study: 72%, 51%, and 30% at 1, 2, and 3 years, respectively, from baseline.Grahic Jump Location
Figure Jump LinkFigure 2 Correlation between RVFAC and PVR (linear model, r = 0.60, P = .0001, y = 47.7-1.0×). Patients with low peak O2 pulse (<8.0 mL/beat) and high peak O2 pulse (≥8.0 mL/beat) are reported in the same scatterplot (red circles and blue circles, respectively). PVR = pulmonary vascular resistance; RVFAC = right ventricular fractional area change; WU = Wood unit.Grahic Jump Location
Figure Jump LinkFigure 3 RVFAC and the corresponding peak O2 pulse pattern during the cardiopulmonary exercise test, in two different IPAH patients. (A) Preserved RVFAC (42.3%) and good exercise performance with adequate-performing O2 pulse (peak, 14.2 mL/beat); (B) preserved RVFAC (40.4%) and poor exercise performance with low O2 pulse (peak, 7.0 mL/beat). IPAH = idiopathic pulmonary arterial hypertension; O2 pulse: peak oxygen pulse. See Figure 2 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 4 Comparison of the receiver operating characteristic curves for prediction of clinical worsening between model 1 (dashed black line), including demographic, clinical, and hemodynamic parameters, and model 2 (solid red line) adding echocardiographic and cardiopulmonary exercise test parameters. A significant improvement in accuracy is observed for model 2 in predicting clinical worsening (AUC 0.80 vs 0.66, P = .0004). AUC = area under the curve.Grahic Jump Location
Figure Jump LinkFigure 5 Kaplan-Meier event-free survival curves based on the combination of the cutoff values of RVFAC and peak O2 pulse. Patients with high RVFAC + high peak O2 pulse (group 1) had significantly a better prognosis compared with patients with high RVFAC + low peak O2 pulse (group 2; P = .0001) and low RVFAC + low peak O2 pulse (group 3; P = .0001). Group 2 patients had a better prognosis compared with group 3 (P = .0001), but a worse outcome compared with group 1 (P = .0001). See Figure 2 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Hemodynamic, Imaging, and Exercise Characteristics of the Study Population

Normal values for echocardiographic parameters are reported from reference 5.

Normal values for cardiopulmonary exercise test have been calculated from previous reported equations and reports considering sex, age, height, and weight.,

CI = cardiac index; HR = heart rate; LV-EId = left ventricular end-diastolic eccentricity index; LV-EIs = left ventricular end-systolic eccentricity index; mPAP = mean pulmonary arterial pressure; PAWP = mean pulmonary artery wedge pressure; PETco2 peak = end-tidal CO2 pressure; PVR = pulmonary vascular resistance; RA area = right atrium area; RAP = mean right atrial pressure; RVEDA = right ventricular end-diastolic area; RVESA = right ventricular end-systolic area; RVFAC = right ventricular fractional area change; TAPSE = tricuspid anular plane systolic excursion; V˙ co2 peak = peak carbon dioxide production; V˙ E = minute ventilation; V˙ E/V˙ co2 slope = ventilation to CO2 production slope; V˙ o2 peak = peak oxygen uptake; WU = Wood unit.

Table Graphic Jump Location
Table 2 Description of Different Clinical Worsening Endpoints During Follow-up

6MW test = isolated worsening in 6-min walk test > 15% compared with previous test; 6MW test + WHO = worsening in both 6MW test and WHO class; RHF = right heart failure; WHO class = isolated worsening in World Health Organization functional class.

Table Graphic Jump Location
Table 3 Demographic, Clinical, Hemodynamic, Imaging, and Exercise Differences Between Patients With and Without CW

Ca = calcium; CW = clinical worsening; ERA = endothelin receptor antagonist; NS = not significant; PDE5i = phosphodiesterase 5 inhibitor. See Table 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
Table 4 Univariate Analysis of Baseline Parameters for Clinical Worsening Prediction

See Table 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
Table 5 Cox Regression Models for Clinical Worsening Prediction (Models 1 and 2) and Bootstrap Estimates of Cox Proportional Hazard Analysis

WHO IV: WHO functional class IV. See Table 1 and 2 legends for expansion of abbreviations.

References

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Groepenhoff H. .Vonk-Noordegraaf A. .Boonstra A. .Spreeuwenberg M.D. .Postmus P.E. .Bogaard H.J. . Exercise testing to estimate survival in pulmonary hypertension. Med Sci Sports Exerc. 2008;40:1725-1732 [PubMed]journal. [CrossRef] [PubMed]
 
Fuster V. .Steele P.M. .Edwards W.D. .Gersh B.J. .McGoon M.D. .Frye R.L. . Primary pulmonary hypertension: natural history and the importance of thrombosis. Circulation. 1984;70:580-587 [PubMed]journal. [CrossRef] [PubMed]
 
D'Alonzo G.E. .Barst R.J. .Ayres S.M. .et al Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med. 1991;115:343-349 [PubMed]journal. [CrossRef] [PubMed]
 
Sandoval J. .Bauerle O. .Palomar A. .et al Survival in primary pulmonary hypertension. Validation of a prognostic equation. Circulation. 1994;89:1733-1744 [PubMed]journal. [CrossRef] [PubMed]
 
Sitbon O. .Humbert M. .Nunes H. .et al Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol. 2002;40:780-788 [PubMed]journal. [CrossRef] [PubMed]
 
Humbert M. .Sitbon O. .Chaouat A. .et al Survival in patients with idiopathic, familial, and anorexigen-associated pulmonary arterial hypertension in the modern management era. Circulation. 2010;122:156-163 [PubMed]journal. [CrossRef] [PubMed]
 
Benza R.L. .Miller D.P. .Gomberg-Maitland M. .et al Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010;122:164-172 [PubMed]journal. [CrossRef] [PubMed]
 
Eysmann S.B. .Palevsky H.I. .Reichek N. .Hackney K. .Douglas P.S. . Two-dimensional and Doppler-echocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension. Circulation. 1989;80:353-360 [PubMed]journal. [CrossRef] [PubMed]
 
Raymond R.J. .Hinderliter A.L. .Willis P.W. .et al Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension. J Am Coll Cardiol. 2002;39:1214-1219 [PubMed]journal. [CrossRef] [PubMed]
 
Brierre G. .Blot-Souletie N. .Degano B. .et al New echocardiographic prognostic factors for mortality in pulmonary arterial hypertension. Eur J Echocardiogr. 2010;11:516-522 [PubMed]journal. [CrossRef] [PubMed]
 
Fine N.M. .Chen L. .Basztiansen P.M. .et al Outcome prediction by quantitative right ventricular function assessment in 575 subjects evaluated for pulmonary hypertension. Circ Cardiovasc Imaging. 2013;6:711-721 [PubMed]journal. [CrossRef] [PubMed]
 
Bustamante-Labarta M. .Perrone S. .De La Fuente R.L. .et al Right atrial size and tricuspid regurgitation severity predict mortality or transplantation in primary pulmonary hypertension. J Am Soc Echocardiogr. 2002;15:1160-1164 [PubMed]journal. [CrossRef] [PubMed]
 
Ghio S. .Klersy C. .Magrini G. .et al Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension. Int J Cardiol. 2010;140:272-278 [PubMed]journal. [CrossRef] [PubMed]
 
Ghio S. .Pazzano A.S. .Klersy C. .et al Clinical and prognostic relevance of echocardiographic evaluation of right ventricular geometry in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol. 2011;107:628-632 [PubMed]journal. [CrossRef] [PubMed]
 
Utsunomiya H. .Nakatani S. .Nishihira M. .et al Value of estimated right ventricular filling pressure in predicting cardiac events in chronic pulmonary arterial hypertension. J Am Soc Echocardiogr. 2009;22:1368-1374 [PubMed]journal. [CrossRef] [PubMed]
 
Forfia P.R. .Fisher M.R. .Mathai S.C. .et al Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med. 2006;174:1034-1041 [PubMed]journal. [CrossRef] [PubMed]
 
Ameloot K. .Palmers P.J. .Vandebruane A. .et al Clinical value of echocardiographic Doppler-derived right ventricular dp/dt in patients with pulmonary arterial hypertension. Eur Heart J Cardiovas Imaging. 2014;15:1411-1419 [PubMed]journal. [CrossRef]
 
Ernande L. .Cottin V. .Leroux P.Y. .et al Right isovolumic contraction velocity predicts survival in pulmonary hypertension. J Am Soc Echocardiogr. 2013;26:297-306 [PubMed]journal. [CrossRef] [PubMed]
 
Haeck M.L. .Scherptong R.W. .Marsan N.A. .et al Prognostic value of right ventricular longitudinal peak systolic strain in patients with pulmonary hpertension. Circ Cardiovasc Imaging. 2012;5:628-636 [PubMed]journal. [CrossRef] [PubMed]
 
Smith B.C. .Dobson G. .Dawson D. .Charalampopoulos A. .Grapsa J. .Nihoyannopoulos P. . Three-dimensional speckle tracking of the right ventricle: toward optimal quantification of right ventricular dysfunction in pulmonary hypertension. J Am Coll Cardiol. 2014;64:41-51 [PubMed]journal. [CrossRef] [PubMed]
 
Tei C. .Dujardin K.S. .Hodge D.O. .et al Doppler echocardiographic index for assessment of global right ventricular function. J Am Soc Echocardiogr. 1996;9:838-847 [PubMed]journal. [CrossRef] [PubMed]
 
Yeo T.C. .Dujardin K.S. .Tei C. .Mahoney D.W. .McGoon M.D. .Seward J.B. . Value of a Doppler-derived index combining systolic and diastolic time intervals in predicting outcome in primary pulmonary hypertension. Am J Cardiol. 1998;81:1157-1161 [PubMed]journal. [CrossRef] [PubMed]
 
Wensel R. .Opitz C.F. .Anker S.D. .et al Assessment of survival in patients with primary pulmonary hypertension. Importance of cardiopulmonary exercise testing. Circulation. 2002;106:319-324 [PubMed]journal. [CrossRef] [PubMed]
 
Kane G.C. .Maradit-Kremers H. .Slusser J.P. .et al Integration of clinical and hemodynamic parameters in the prediction of long-term survival in patients with pulmonary arterial hypertension. Chest. 2011;139:1285-1293 [PubMed]journal. [CrossRef] [PubMed]
 
Deboeck G. .Scoditti C. .Huez S. .et al Exercise testing to predict outcome in idiopathic versus associated pulmonary arterial hypertension. Eur Respir J. 2012;40:1410-1419 [PubMed]journal. [CrossRef] [PubMed]
 
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