Pulmonary hypertension (PH) is a life-threatening disease characterized by an increased pulmonary vascular resistance, leading to right ventricular failure, exercise limitation, and, ultimately, death. During the past 20 yr, improvements in treatment have prolonged survival and improved quality of life, but there is currently no cure (11). The median survival from the time of diagnosis varies between 3 and 10 yr (6,16).
Mortality in PH is largely associated with right ventricular dysfunction (16), but accurate determination of hemodynamic parameters requires right-heart catheterization. Noninvasive markers predicting survival in PH could be helpful to monitor patients and to guide treatment. Variables derived during exercise testing have been proposed for this purpose (19). The 6-min walk test is relatively simple to perform, and the total distance walked in this test (6MWD) predicts survival in PH (12). However, the strength of the prediction is modest, and the 6MWD is only weakly correlated to hemodynamic parameters (12).
In heart failure from other causes, prognostic information is obtained through comprehensive cardiopulmonary exercise testing (CPET) with measurements of ventilatory efficiency and peak oxygen consumption (V˙O2peak) (7,14,20). The latter parameter has also been shown to predict survival in PH (24), but it remains unproven if CPET yields additional prognostic information after determination of the 6MWD. Therefore, we conducted a study to determine the additional prognostic value of CPET to 6MWD in a cohort of PH patients.
METHODS
Patients.
We performed a retrospective analysis of all patients referred to our institute between June 2002 and June 2007, meeting the following criteria: 1) diagnosis of pulmonary arterial hypertension or chronic thromboembolic PH; 2) aged <70 yr; 3) mean pulmonary arterial pressure (mPAP) > 20 mm Hg and a pulmonary capillary wedge pressure < 15 mm Hg on baseline right-heart catheterization; and 4) ability to perform exercise testing. A total of 127 patients fulfilled these criteria, and their classification according to the Venice criteria (17) is shown in Table 1.
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TABLE 1: PH cohort: classification according to the Venice criteria (
9).
Treatment strategies were standardized. Medications included anticoagulants and oxygen supplementation when necessary in all patients. Patients referred to our institution in 2002 and subsequent years were treated with prostacyclin analogs (epoprostenol and treprostenil) and oral compounds such as bosentan, sildenafil, and, more recently, sitaxentan. The usual practice was to start with an oral compound and to add a prostacyclin analog in case of clinical worsening. The study protocol was approved by the VU University Medical Center Institutional Review Board, and informed consent was waived due to the retrospective nature of this study.
Hemodynamic studies.
Baseline hemodynamic parameters were measured in all patients by diagnostic right-heart catheterization and included right arterial pressure (RAP), mPAP, total pulmonary vascular resistance (TPVR), wedge pressure, and cardiac output (CO). CO was measured by the direct Fick method. TPVR was calculated by dividing mPAP by CO. CO was indexed (CI) by dividing it by the body surface area.
Six-minute walk distance.
6MWD was measured in all patients according to a standardized protocol that follows the American Thoracic Society guidelines (9). Patients were instructed to walk as far as they could for 6 min at a pace that was comfortable to them. During the 6 min, they stopped and rested when necessary. The elapsed time was read to the patient every 2 min. No other encouragement or conversation was permitted.
Cardiopulmonary exercise testing.
One day before the baseline right-heart catheterization, a physician-supervised CPET was performed on an electromagnetically braked cycle ergometer (Rehcor, Lode Groningen, The Netherlands) adhering to the American Thoracic Society guidelines (1). Three minutes of upright rest were followed by 3 min of unloaded pedaling (0 W) and subsequently a progressive increase in workload (5-20 W·min−1) to maximum tolerance. The rate of workload increase was empirically determined by the supervising physician on the basis of the medical history, clinical data, and the result of a previous 6MWD, if available. Test duration was between 8 and 12 min (from unloaded pedaling to peak exercise) in all patients.
Minute ventilation (V˙E), V˙O2, and carbon dioxide output (V˙CO2) were measured breath by breath using a metabolic cart (Vmax 229; Viasys, Yorba Linda, CA) and analyzed as 20-s averages. Peak RER, as a measure of maximal metabolic effort, was calculated by dividing V˙CO2 by V˙O2 values at peak exercise (20-s average). Anaerobic threshold (AT) was determined by the V-slope method (4). Oxygen saturation of arterial blood (SaO2) was measured by a pulse oximeter (9600; Nonin, Plymouth, MN). No patients were using supplemental oxygen during CPET.
Before each test, the equipment was calibrated according the manufacturer's specifications. Briefly, the flow sensor was calibrated and verified by a calibrated 3-L syringe. Gas analyzers were calibrated by a two-point calibration (0% CO2, 26% O2 and 4% CO2, 16% O2, respectively) and ambient air (0% CO2, 20.9% O2). HR was measured by electrocardiography (Eagle 4000; Marquette). O2 pulse was calculated as V˙O2 divided by HR. CPET was measured on a separate day but within 1 wk of the 6MWD.
Survival estimates.
At least every 3 months, all patients were seen in the outpatient clinic or were contacted by telephone by our PH nurse. Follow-up data were available from all patients. From our initial cohort of 127 patients with 23 nonsurvivors, we excluded 8 patients with congenital heart disease (Fig. 1). From the 119 remaining patients, 21 patients had died by June 30, 2007, 18 of whom from cardiopulmonary causes. The other three deaths were not included in the analyses. Finally, one patient was excluded because there was no baseline 6MWD available.
FIGURE 1: Patients' flowchart from the initial cohort with the included and excluded patients.
Statistical analysis.
Statistical analysis was performed with the SPSS 14.0 package (SPSS, Inc., Chicago, IL). All data are expressed as mean ± SD. The unpaired Student's t-test was used to check for differences in age, body mass index (BMI), RAP, mPAP, CO, CI, TPVR, CPET, and 6MWD characteristics.
The CPET characteristics that were evaluated were peak RER, V˙O2, and HR, ΔO2 pulse (calculated as the change in V˙O2/HR from rest to maximal exercise), ventilatory equivalents for O2, end-tidal CO2 (PetCO2), and SaO2 at rest and during maximal exercise. In addition, the ventilatory response to exercise was quantified in five ways: 1) the slope of the plot describing the relationship between V˙E and V˙CO2 from rest to peak exercise (V˙E/V˙CO2slope); 2) the V˙E/V˙CO2slope calculated from rest to the AT (V˙E/V˙CO2slopeAT); 3) the difference between these two slopes (ΔV˙E/V˙CO2slope); 4) the nadir in the plot describing the ratio of V˙E to V˙CO2 versus time (V˙E/V˙CO2nadir); and 5) the V˙E/V˙CO2 ratio at peak exercise (V˙E/V˙CO2peak).
Pearson correlations were calculated to check for linear associations between noninvasive diagnostic tests (6MWD and CPET characteristics) and invasive hemodynamic parameters (RAP, mPAP, CI, and TPVR). For the variables that were significantly different between survivors and nonsurvivors, optimal cutoff points for predicting survival were identified by determining the receiver operating characteristic (ROC) on the basis of the highest sum of sensitivity and (1 − specificity) values. Areas under the curve (AUC) are presented with a 95% confidence interval (CI).
For those tests with an AUC significantly different from 0.5, univariate Kaplan-Meier survival curves were calculated. For the continuous values of the different diagnostic tests, hazard ratios, and their 95% CI were calculated by univariate Cox proportional risk analysis. Multivariate Cox regression with a forward selection procedure was used to check for significant additional predictive value of survival from CPET parameters to the 6MWD. In all analyses, values <0.05 (two-tailed) were considered significant.
RESULTS
Survival.
No patients were scheduled for transplantation (lung or heart-lung) or pulmonary end-arterectomy during the follow-up period. Of 115 patients, 18 died after a mean ± SD follow-up of 846 ± 461 d. Mean ± SD follow-up time of the 97 survivors was 907 ± 462 d (range = 31-1465 d). The cumulative proportional survival of all patients was 93 ± 2% at 1 yr, 84 ± 4% at 2 yr, 81 ± 4% at 3 yr, and 78 ± 5% at 4yr.
No significant differences in age, BMI, RAP, mPAP, CI, and TPVR were found between survivors and nonsurvivors. CO was significantly lower in the nonsurvival group. On the basis of peak RER (Table 2), patients in this study showed maximal (metabolic) effort during the CPET. V˙O2peak, PetCO2 at AT, ΔO2 pulse, and 6MWD were significantly higher, whereas V˙E/V˙CO2slope, V˙E/V˙CO2slopeAT, V˙E/V˙CO2nadir, and V˙E/V˙CO2peak were significantly lower in survivors compared with nonsurvivors (Table 2). Peak HR, ventilatory equivalents for O2, SaO2, and PetCO2 at rest were not predictive of survival and are therefore not included in the subsequent sections.
TABLE 2: Summary of baseline demographics, hemodynamics, CPET variables, and 6MWD.
Relations between hemodynamic with 6MWD and CPET parameters.
Table 3 shows that most 6MWD and CPET parameters correlated modestly with resting hemodynamic parameters. V˙E/V˙CO2nadir had the strongest correlations with the clinically important variables of RAP, CI, and TPVR, but the maximum variance that could be explained was still only 25%.
TABLE 3: Correlation matrix between hemodynamic, 6MWD, and CPET parameters.
Receiver operating characteristics.
ROC curves from resting hemodynamic parameters and 6MWD and CPET characteristics showed that only V˙E/V˙CO2slope, V˙E/V˙CO2nadir,V˙E/V˙CO2peak, V˙O2peak, ΔO2 pulse, and 6MWD were accurate predictors of 4-yr survival in our cohort (Table 4). The optimal cutoff point was determined by the largest sum of sensitivity and (1 − specificity) from the ROC plots of the V˙E/V˙CO2slope, V˙E/V˙CO2nadir, V˙E/V˙CO2peak, V˙O2peak, ΔO2 pulse, and 6MWD (≥48, ≥52, ≥49, <13.2 mL·kg−1·min−1, <3.3 mL·beat−1, and <399 m, respectively).
TABLE 4: Receiver operating characteristics.
Kaplan-Meier survival analysis.
PH patients with a V˙E/V˙CO2slope < 48 had a significantly better prognosis (P < 0.05) at 4 yr (cumulative survival = 90%, 95% CI = 81-98) compared with PH patients with a slope of ≥48 (cumulative survival = 68%, 95% CI = 53-83). PH patients with a V˙E/V˙CO2nadir < 52 had a significantly better prognosis (P < 0.01) at 4 yr (cumulative survival = 89%, 95% CI = 82-97) compared with PH patients with a nadir of ≥52 (cumulative survival = 58%, 95% CI = 38-77). PH patients with a V˙E/V˙CO2peak < 49 showed no significantly better prognosis (P = 0.33) at 4 yr (cumulative survival = 88%, 95% CI = 78-98) compared with PH patients with a V˙E/V˙CO2peak of ≥49 (cumulative survival = 73%, 95% CI = 60-87). PH patients with a V˙O2peak > 13.2 mL·kg−1·min−1 had a significantly better prognosis (P < 0.05) at 4 yr (cumulative survival = 83%, 95% CI = 66-99) compared with PH patients with a V˙O2peak of <13.2 mL·kg−1·min−1 (cumulative survival = 71%, 95% CI = 56-85). PH patients with a ΔO2 pulse > 3.3 mL·beat−1 had a significantly better prognosis (P < 0.01) at 4 yr (cumulative survival = 88%, 95% CI = 76-99) compared with PH patients with a ΔO2 pulse of <3.3 mL·beat−1 (cumulative survival = 60%, 95% CI = 42-78). PH patients with a 6MWD > 399 m had a significantly better prognosis (P < 0.01) at 4 yr (cumulative survival = 87%, 95% CI = 76-98) compared with PH patients with a 6MWD < 399 m (cumulative survival = 63%, 95% CI = 46-80; Fig. 2).
FIGURE 2: Kaplan-Meier cumulative survival curves for (A) mean regression slope relating minute ventilation to carbon dioxide production until maximum exercise (V˙E/V˙CO2slope), (B) the nadir in the relationship between the V˙E/V˙CO2 ratio and time (V˙E/V˙CO2nadir), (C) V˙E/V˙CO2 ratio at peak exercise (V˙E/V˙CO2peak), (D) peak oxygen consumption (V˙O2peak), (E) V˙O2 difference from rest to maximum exercise per heartbeat (ΔO2 pulse), and (F) 6-min walk distance (6MWD).
Cox proportional hazard analysis.
Table 5 shows that by univariate Cox proportional hazard analysis, only the noninvasive exercise parameters V˙E/V˙CO2slope, V˙E/V˙CO2nadir, V˙E/V˙CO2peak, V˙O2peak, ΔO2 pulse, and 6MWD were significant predictors of impaired survival (here shown as continuous variables). Multivariable Cox regression with a forward selection procedure, forcing 6MWD as the first predictor, showed that from all the separately included CPET parameters, only ΔO2 pulse significantly improved the univariate 6MWD prediction model (P < 0.05; Table 6).
TABLE 5: Univariate Cox proportional hazard analysis.
TABLE 6: Multivariate forward Cox regression each step starting with 6MWD.
DISCUSSION
In this study, we demonstrate that ventilatory and gas exchange CPET parameters predict survival in PH patients. However, from all CPET parameters, only ΔO2 pulse added a significant, but modest, prognostic value to the 6MWD. All the noninvasive CPET parameters as well as 6MWD showed a significant AUC to estimate an optimal cutoff point for making the results dichotomous (to predict survivors vs nonsurvivors) by ROC analysis (Table 4). We found by Kaplan-Meier survival analysis a significantly better prognosis for survival at 4 yr for patients with a V˙E/V˙CO2slope < 48, a V˙E/V˙CO2nadir < 52, a V˙O2peak > 13.2 mL·kg−1·min−1, a ΔO2 pulse > 3.3 mL·beat−1, or a 6MWD > 399 m (Fig. 2).
Univariate Cox proportional hazard analysis showed that all included noninvasive exercise parameters (as continuous variables) were significant predictors of impaired survival (Table 5). Furthermore, from the CPET parameters, only the ΔO2 pulse improved the univariate 6MWD prediction model significantly (Table 6).
Exercise capacity, whether assessed during a walk test or during CPET (6MWD and V˙O2peak, respectively), is a well-established predictor of survival in heart failure and pulmonary arterial hypertension (5,8,15,24). The fact that a low ΔO2 pulse was also a strong predictor in our pulmonary arterial hypertension cohort confirms earlier findings of a relationship between a reduced stroke volume response and exercise intolerance in these patients (10). Rearrangement of the Fick equation [V˙O2 = CO × arterial and mixed venous blood oxygen content differences (C(a-vO2))] shows that O2 pulse (V˙O2/HR) is equal to the product of stroke volume and C(a-vO2). Agostoni et al. (2) showed that, in chronic heart failure patients, C(a-vO2) reaches normal values at maximal exercise. Patients in this study showed no severe desaturation, and we can therefore assume that their peak exercise C(a-vO2) was normal as well and that their low peak O2 pulse indicate a low stroke volume at maximal exercise (18,23). In the multivariate analysis, a low increase in O2 pulse and a low 6MWD were independent predictors of mortality. This could indicate that the 6MWD in these patients is not determined by the stroke volume or CO response only. The relatively limited number of events in our cohort prevents us from drawing firm conclusions, however.
In addition to exercise capacity and the stroke volume response, excessive ventilation (out of proportion of the metabolic rate) predicted survival in our cohort of PH patients. We quantified the ventilatory response during exercise using five different methodologies, which theoretically have different predictive values (3). The V˙E/V˙CO2slope is the mean regression slope in the relationship between V˙E (y-axis) and V˙CO2 (x-axis). In accordance with other investigators and for the sake of methodological simplicity and a better prognostic value (20), we first included all the data until peak exercise in the regression analysis. Our second approach was to include only the linear data that are obtained during the first part of the exercise test until the AT. Because the V˙E increases out of proportion of the V˙CO2 after the AT, the first method yields higher slopes than the second does. The difference between these two slopes (ΔV˙E/V˙CO2) has been described as a predictor by itself (3). This was not the case in our cohort, however (Table 2). We subsequently used two alternative quantifications of the ventilatory response to exercise, the V˙E/V˙CO2nadir and the peak V˙E/V˙CO2peak, and obtained very similar results. V˙E/V˙CO2nadir, which is the nadir in the relationship between the V˙E/V˙CO2 ratio and time, is virtually equal to the V˙E/V˙CO2 ratio at AT and both have been proposed as prognostic tools in PH (19).
Excessive ventilation in PH is due either to increased dead space ventilation (inadequate perfusion of ventilated lung areas) or to alveolar hyperventilation due to a decreased PaCO2 set point (19). This set point is affected by a) metabolic acidosis due to an impaired stroke volume response to exercise (10,22); b) exercise-induced hypoxemia; c) sympathetic over stimulation (21); and d) increased stimulation of blood pressure-responsive receptors in the pulmonary vasculature. Our data provide no insight into the relative contributions of these different factors in the excessive exercise ventilation in PH.
Surprisingly, RAP, CI, and CO did not predict survival in our cohort, which is in contrast with previous studies (6,16,24). We speculate that the main explanation for this contrasting finding is our high survival rate compared with the rates that were found in the reports from Sandoval and Wensel (12,16,24). These studies included only idiopathic PH patients, and anticoagulant therapy was not used as a routine (16). Furthermore, our patients seemed in a relatively better clinical condition, as evidenced by a higher mean V˙O2peak and a lower mPAP and TPVR at baseline. Wensel et al. (24) proposed systolic blood pressure at peak exercise as an additional independent predictor of survival in PH. We did not include blood pressure measurements in our study protocol because accurate noninvasive determination of this parameter is frequently not feasible during routine clinical exercise testing.
No significant differences in baseline hemodynamics were found between survivors and nonsurvivors except for CO which was marginally higher in survivors. There was insufficient follow-up data in our cohort to determine the predictive value of subsequent repeat catheterizations. Possibly, changes in hemodynamics would have had predictive value. In agreement with previous studies, the 6MWD, V˙E/V˙CO2slope, and V˙O2peak were significantly correlated with right ventricular function (12,19,24). However, the rather weak correlations show that these parameters are not exclusively determined by the pulmonary vascular resistance.
Treatment strategies in our hospital are highly standardized; baseline CPET characteristics and 6MWD do not determine the choice of initial treatment that usually consists of an oral single agent (sildenafil, bosentan or sitaxentan). It is therefore unlikely that the predictive values of baseline V˙O2peak, ΔO2 pulse, V˙E/V˙CO2nadir, V˙E/V˙CO2slope, and 6MWD are explained by differences in treatment strategies between survivors and nonsurvivors. A change in6MWD after follow-up may lead to a change in treatment, but the limited size of our cohort prohibits the assessment of the prognostic value of changes in exercise data over time.
Smoking could have influenced V˙E/V˙CO2slope by increasing dead space ventilation. In our cohort, there were very few current smokers, and pulmonary function testing and high-resolution computed tomography scanning (which are both routinely performed in all patients) did not suggest emphysema in any of our patients. Therefore, the effects of smoking or associated chronic obstructive pulmonary disease should have been negligible.
The 6-min walk test is much easier to perform than CPET with ventilatory measurements because it is less technically demanding and less time consuming. The test is therefore frequently used as a primary end point for clinical studies (13). From our data, derived from a cohort of 115 patients with only 18 deaths, which is a limitation of this study, it is difficult to determine which of the five noninvasive parameters (V˙O2peak, ΔO2 pulse, V˙E/V˙CO2nadir, V˙E/V˙CO2slope, and 6MWD) provides the strongest prediction of survival.
We conclude that ventilatory and gas exchange parameters measured during maximal CPET predict survival in PH patients with moderate hemodynamic abnormalities. However, the additional prognostic value of CPET in PH patients that performed a 6MWD previously is only marginal.
Harm Jan Bogaard received a grant from the Netherlands Heart Foundation (Nederlandse Hartstichting, grant no. 2006022). The results of the present study do not constitute endorsement by ACSM.
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