American Journal of Respiratory and Critical Care Medicine

Rationale: Exercise tolerance is decreased in patients with pulmonary hypertension (PH). It is unknown whether exercise intolerance in PH coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility.

Objectives: To investigate in patients with PH the RV exertional contractile reserve, defined as the rest-to-exercise response in end-systolic elastance (ΔEes), and the effects of exercise on the matching of Ees and RV afterload (Ea) (i.e., RV–arterial coupling; Ees/Ea). In addition, we compared ΔEes with a recently proposed surrogate, the rest-to-exercise change in pulmonary artery pressure (ΔPAP).

Methods: We prospectively included 17 patients with precapillary PH and 7 control subjects without PH who performed a submaximal invasive cardiopulmonary exercise test between January 2013 and July 2014. Ees and Ees/Ea were assessed using single-beat pressure–volume loop analysis.

Measurements and Main Results: Exercise data in 16 patients with PH and 5 control subjects were of sufficient quality for analysis. Ees significantly increased from rest to exercise in control subjects but not in patients with PH. Ea significantly increased in both groups. As a result, exercise led to a decrease in Ees/Ea in patients with PH, whereas Ees/Ea was unaffected in control subjects (Pinteraction = 0.009). In patients with PH, ΔPAP was not related to ΔEes but significantly correlated to the rest-to-exercise change in heart rate.

Conclusions: In contrast to control subjects, patients with PH were unable to increase Ees during submaximal exercise. Failure to compensate for the further increase in Ea during exercise led to deterioration in Ees/Ea. Furthermore, ΔPAP did not reflect ΔEes but rather the change in heart rate.

Scientific Knowledge on the Subject

In patients with pulmonary hypertension (PH), exercise tolerance is decreased with respect to control subjects. Whether or not this decreased exercise tolerance coincides with an impaired rest-to-exercise response in right ventricular (RV) contractility is unknown.

What This Study Adds to the Field

In this prospective study we show that, in contrast to subjects with no PH, patients with PH have no exertional contractile reserve (as determined by the rest-to-exercise change in end-systolic elastance) to compensate for increase in load, leading to a decrease in RV–arterial coupling during exercise. An absent inotropic response to submaximal exercise warrants further study of the effects of inotropic drugs in RV dysfunction and failure. Because we also observed that the rest-to-exercise change in pulmonary artery pressure did not describe the exertional contractile reserve, but rather correlated to the heart rate response during exercise, it is also suggested that the rest-to-exercise change in pulmonary artery pressure should not be used as a surrogate measure for the contractile reserve.

Precapillary pulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance (PVR), increasing the load on the right ventricle (RV). The RV’s ability to cope with the increased load is the most important determinant of survival in patients with PH (1). RV dysfunction tends to be more visible during exercise (25) and most patients with PH experience exercise intolerance caused by an inadequate increase in pulmonary blood flow during physical activity (2, 4). In healthy individuals, increased demand of oxygen is met by a proportional increase in cardiac output (CO) caused by an increase in stroke volume (SV) and heart rate (HR). In patients with PH, CO response is truncated during exercise because of a blunted maximal HR response together with an inability to increase SV (3, 510). It is unclear whether exercise intolerance and the impaired CO response to exercise in PH coincide with a failure to increase RV contractility during exercise (i.e., an impaired exertional contractile reserve).

The only way to assess the exertional contractile reserve is by determining end-systolic elastance (Ees): a load-independent measure of contractility that can be derived either from a family of pressure–volume loops or from the so-called single-beat method (11, 12). As such, the exertional contractile reserve can be described as the rest-to-exercise response in Ees (ΔEes). Pressure–volume loop analysis also provides the opportunity to determine arterial elastance (Ea), a measure of RV afterload. The matching of Ees to Ea is known as RV–arterial coupling and its preservation is important in terms of ventricular efficiency (13, 14). Because in PH, Ees is already considerably increased at rest (15), we hypothesized that patients with PH are unable to further increase Ees during exercise. Therefore, the increase in Ea will lead to a deterioration of RV–arterial coupling during exercise.

The aim of this study was to investigate in patients with PH and control subjects with no PH, the effects of exercise on RV contractility (Ees), Ea, and RV–arterial coupling (Ees/Ea). Additionally, the exertional contractile reserve was compared with a recently proposed surrogate measure, the rest-to-exercise change in pulmonary artery pressure (ΔPAP) (16). The findings of this study contribute to a better understanding of exercise intolerance and right heart failure in PH. Some of the results of this study has been previously reported in the form of an abstract (17).


We prospectively included patients with precapillary PH (idiopathic pulmonary arterial hypertension [IPAH], hereditary pulmonary arterial hypertension [HPAH], and chronic thromboembolic PH [CTEPH]) and control subjects without PH who performed an invasive cardiopulmonary exercise test (iCPET) in the VU University Medical Center from January 2013 until July 2014. Subjects with a history of left-sided heart failure, valvular heart disease, arrhythmias, or neuromuscular disease preventing the subject to exercise were excluded.

In total, 24 subjects performed an iCPET, including 17 patients with PH (13 IPAH, one HPAH, and three CTEPH patients) and 7 control subjects. The control group consisted of subjects in whom the iCPET did not confirm a previous suspicion of PH. In nine patients with IPAH, the iCPET was part of an ongoing clinical trial that was approved by the Medical Ethical Review Committee of the VU University Medical Center (Registration number: NL41878.029.13). In the remaining 15 subjects, the iCPET was part of their clinical evaluation. All subjects gave written informed consent for usage of the data for research purposes.

Maximal CPET

The day prior to the invasive exercise test, a maximal CPET was performed in the upright position using an electromagnetically braked cycle-ergometer (Ergoline GmbH, Bitz, Germany) according to the American Thoracic Society guidelines (18). Breath-by-breath measurements were made of V.o2, Vco2, and V.e (Vmax229; Sensormedica, Yorba Linda, CA).


A balloon-tipped, flow-directed 7.5F, triple-lumen Swan-Ganz catheter (Edwards Lifesciences LLC, Irvine, CA) was inserted in the pulmonary artery via the jugular vein under local anesthesia and constant ECG monitoring. The ports of the catheter were placed in the right atrium, RV, and pulmonary artery. The zero reference level for the pressure transducer was placed at midthoracic level in supine position. Subsequently, a second catheter was placed in the radial artery under local anesthesia. After placement of the pulmonary artery and radial artery catheters, patients were positioned on a recumbent bicycle (Lode, Groningen, the Netherlands) in supine position. After calibration of the equipment, resting hemodynamics (right atrial pressure, right ventricular pressure, PAP, and systemic blood pressure) were continuously recorded using a Powerlab data acquisition system (Chart 5 for Windows; AD Instruments, Sydney, Australia); resting mixed venous oxygen and arterial oxygen blood samples were drawn from the pulmonary artery and radial artery catheters; and breath-by-breath measurements were made of V.o2, Vco2, and V.e (Vmax229, Sensormedica).

The exercise protocol consisted of 1 minute of unloaded cycling followed by 2 minutes of submaximal exercise (40% of maximal workload [Wmax] during maximal CPET) with continuous recording of hemodynamics. Near the end of exercise, mixed venous and arterial blood samples were again drawn from the pulmonary artery and radial artery catheters.

For subjects whose Wmax was less than 150 W, submaximal workloads were immediately increased to 40% of Wmax after 1 minute of unloaded exercise. For subjects with a Wmax greater than 150 W, a direct increase to 40% of Wmax was too large and therefore these subjects were exercised at one additional intermediate step of 1 minute of exercise at 35 W in patients with PH and 45 W in control subjects. This intermediate step allowed data comparison at approximately similar absolute work rates in all subjects.


CO at rest and during exercise was measured using the direct Fick method. SV was calculated as CO divided by HR. CO and SV were indexed for body surface area. PAP was averaged over a period of 15 seconds to be sure that the PAP was measured over multiple respiratory cycles.

The Ees, a load-independent measure of RV contractility, was calculated at rest and during submaximal exercise as:

Ees=maximal isovolumic pressure  mean pulmonary artery pressurestroke volume index
The maximal isovolumic pressure (Pmax) was determined using the single-beat method (11, 12). Pressure data were averaged over several beats to reduce respiratory variations.

The load on the RV was calculated as:

Ea=mean pulmonary artery pressurestroke volume index
Subsequently, RV–arterial coupling was calculated as: RV–arterial coupling = Ees/Ea (11, 1315, 1921).

Statistical Methods

Data are presented as mean ± SD unless stated differently. Comparisons of characteristics, CPET parameters, and resting hemodynamics between patients with PH and control subjects were performed using independent t tests for normally distributed data and Mann-Whitney U tests for not normally distributed data. Chi-square tests were used to analyze dichotomous variables. Comparisons of rest-to-exercise responses between patients with PH and control subjects were performed using two-way repeated measures analysis of variance with Bonferroni post hoc correction. The Pinteraction represents the P value for the effect of exercise in patients with PH in comparison with control subjects. Because patients with PH were significantly older than control subjects, the differences between patients with PH and control subjects in rest-to-exercise responses of HR, Ees, Ea, and RV–arterial coupling were adjusted for age using multivariate analysis of covariance. Simple linear regression was performed to describe the relationship between rest-to-exercise responses of different parameters in the PH group. Statistical analyses were performed using Graphpad Prism for Windows version 5 (GraphPad Software, Inc., San Diego, CA) and SPSS for Windows version 20 (IBM Corp., Armonk, NY). A P value less than 0.05 was considered statistically significant.

Of the 24 subjects that performed an iCPET, in 16 patients with PH and 5 control subjects, hemodynamic data at 40% of Wmax was of sufficient quality to analyze. In one patient with IPAH and in two control subjects the pressure signal was lost during exercise because of displacement of the pulmonary artery catheter. Ten of the 16 patients with PH used PH-specific treatment at the moment of the iCPET (Table 1). Final diagnosis and medication of the control subjects are described in Table 2.

Patients with PH were significantly older than the control subjects (Table 1). As expected, patients with PH showed, during maximal CPET, significantly lower maximal oxygen consumption, workload, and HR compared with control subjects (Table 1). Resting hemodynamics showed significantly higher mean PAP (mPAP), PVR, and right atrial pressure and significantly lower cardiac index (CI), arterial, and mixed venous oxygen levels in patients with PH compared with the control subjects (Table 1). Between groups there was no difference in HR at rest. RV contractility (Ees) and RV afterload (Ea) at rest were significantly increased in patients with PH compared with control subjects, whereas no difference was seen in RV–arterial coupling (Table 1).

Table 1. Characteristics, Maximal CPET, and Resting Hemodynamics

 Control Subjects (n = 5)Pulmonary Hypertension (n = 16)P Value
 Age, yr38 (12)57 (14)0.015
 Sex, n female3110.717
 BSA, m21.853 (0.327)1.883 (0.181)0.850
 Diagnosis 12 IPAH, 1 HPAH, 3 CTEPH 
 NYHA, II/III, n 9/7 
Treatment, n   
 None 5 
 ERA 2 
 PDE5I 1 
 Prostanoids 0 
 ERA + PDE5I 8 
 Ca2+ antagonists 1 
 β-Blockers 2 
CPET max   
V.o2/kg, ml/kg/min31 (8)16 (5)<0.001
 Work, W187 (87)90 (44)0.005
 HR, bpm174 (5)139 (15)<0.001
RHC rest   
 HR, bpm75 (14)77 (15)0.785
 CI, L/min4.7 (0.8)3.1 (0.6)<0.001
 mPAP, mm Hg18 (2)53 (8)<0.001
 PAWP, mm Hg11 (2)12 (2)0.475
 PVR, dyn/s/cm569 (14)582 (168)<0.001
 mRAP, mm Hg4 (1)7 (4)0.015
 Sao2, %99 (0.5)95 (2)<0.001
 Sv¯o2, %82 (2)70 (4)<0.001
 RVEDV, ml151 (52) 
 RVESV, ml88 (53) 
 RVEF, %47 (13) 
 LVEF, %61 (15) 
Load-independent RV function rest   
Ees, mm Hg/ml/m20.47 (0.20)2.00 (0.50)<0.001
Ea, mm Hg/ml/m20.29 (0.05)1.36 (0.45)<0.001
Ees/Ea1.63 (0.74)1.61 (0.54)0.963

Definition of abbreviations: BSA = body surface area; CI = cardiac index; CMRI = cardiac magnetic resonance imaging; CPET = cardiopulmonary exercise test; CTEPH = chronic thromboembolic pulmonary hypertension; Ea = arterial elastance (RV afterload); Ees = end-systolic elastance (RV contractility); Ees/Ea = right ventricular–arterial coupling; ERA = endothelin receptor antagonist; HPAH = hereditary pulmonary arterial hypertension; HR = heart rate; IPAH = idiopathic pulmonary arterial hypertension; LVEF = left ventricular ejection fraction; mPAP = mean pulmonary artery pressure; mRAP = mean right atrial pressure; NYHA = New York Heart Association; PAWP = pulmonary artery wedge pressure; PDE5I = phosphodiesterase 5 inhibitors; PVR = pulmonary vascular resistance; RHC = right heart catheterization; RV = right ventricular; RVEDV = right ventricular end-diastolic volume; RVEF = right ventricular ejection fraction; RVESV = right ventricular end-systolic volume; V.o2/kg = oxygen consumption per kilogram.

Data are presented as mean (SD).

Table 2. Final Diagnosis and Medication of Control Subjects

Control SubjectFinal DiagnosisMedication
1High-frequency ventilation and scoliosisLong-acting β-agonist; inhalation glucocorticoid
2Physical deconditioning after PEVitamin K antagonist
3No cause foundNone
4No cause foundNone
5Physical deconditioning after PEVitamin K antagonist

Definition of abbreviation: PE = pulmonary embolism.

Exercise Hemodynamics

In control subjects 40% of Wmax was 70 ± 34 W and in patients with PH this was 39 ± 14 W (P = 0.009). From rest to exercise, both groups showed a significant increase in CI (Figure 1A), with a larger increase in CI in control subjects (Pinteraction = 0.003). During exercise, both groups showed a significant increase in HR, but no change in SVI (Figure 1B). The increase in HR was larger in control subjects compared with patients with PH (Pinteraction = 0.039), but not after correction for age (P = 0.300) (Figure 1C). The mPAP and RV systolic pressures (RV Psys) increased significantly during exercise in control subjects and patients with PH (Figures 1D and 1E), with larger increases seen in the PH group (mPAP, Pinteraction = 0.005; RV Psys, Pinteraction = 0.019). Pmax, derived from the single-beat method, was significantly higher than resting values in both groups (Figure 1F). Total PVR significantly decreased in patients with PH from rest to exercise (Figure 1G).

The Exertional Contractile Reserve (ΔEes)

From rest to exercise, RV contractility (Ees) increased significantly in control subjects, but not in patients with PH (Pinteraction ≤ 0.001), implying an impaired exertional contractile reserve (Figure 2).

Effects of Exercise on RV–Arterial Coupling

RV afterload (Ea) increased significantly during exercise in both groups (Figure 2). As a result, RV–arterial coupling during exercise decreased in patients with PH, but remained stable in control subjects (Pinteraction = 0.013) (Figure 2).

Comparison between ΔEes and ΔPAP

There was no relation between the rest-to-exercise response in Ees (ΔEes) and PAPs (ΔEes and change in systolic PAP [ΔsPAP], r = 0.350, R2 = 0.123, P = 0.184; ΔEes and ΔmPAP, r = 0.182, R2 = 0.033, P = 0.500), and neither was ΔEes related to ΔHR (r = 0.055; R2 = 0.003; P = 0.838) or ΔSVI (r = 0.373; R2 = −0.139; P = 0.155).

ΔsPAP and ΔmPAP were both related to ΔHR (ΔsPAP and ΔHR, r = 0.579, R2 = 0.335, P = 0.019; ΔmPAP and ΔHR, r = 0.788, R2 = 0.621, P < 0.001) (Figure 3), but not to SVI.

This is the first study to describe the RV exertional contractile reserve in patients with PH and the effects of exercise on RV–arterial coupling. We showed that patients with PH have an impaired exertional contractile reserve and that the failure to increase contractility during exercise in response to the increased RV afterload led to a deterioration of RV–arterial coupling.

The RV Exertional Contractile Reserve (ΔEes)

In line with previous studies, RV contractility (Ees) measured at rest was larger in patients with PH than in control subjects (15, 22). Here we show that patients with PH are unable to increase RV contractility during exercise and this suggests that RV contractility is already maximally increased at rest.

As far as we know, the rest-to-exercise response in a load-independent measure of RV contractility has never been studied in healthy subjects. In the left ventricle of healthy humans, the increase in load-independent measures of contractility during exercise (2325) is largely caused by an increase in β-adrenergic stimulation (26). The impaired rest-to-exercise response in RV contractility in patients with PH could relate to the down-regulation and desensitization of β-adrenergic receptors, which has been shown in PH rat models (27) and patients with PH (28). It has been suggested that the increased catecholamine levels at rest in PAH (29) may lead to an inability to increase catecholamine levels during exercise (30). Interestingly, an impaired inotropic RV response was also observed in a recent study using different PH rat models treated with several inotropic agents (27). The impaired exertional contractile reserve found in our study adds to the debate whether it is useful to treat patients with PH with RV failure with inotropic agents (30). Although a degree of caution has to be taken into account regarding the extrapolation of our findings during submaximal exercise to a situation of RV failure, the usefulness of inotropic agents in patients with PH with RV failure should be studied in a randomized controlled trial. Absence of a contractile reserve suggests that it may be more useful to treat RV failure with agents that reverse maladaptive RV remodeling.

The Rest-to-Exercise Response in RV–Arterial Coupling

We found a significant increase in load (Ea) on the RV in patients with PH and control subjects during exercise, whereas total PVR (= Ea ∙ HR) significantly decreased in patients with PH and remained stable in control subjects. Most hemodynamic exercise studies measured load as PVR and showed a decrease or stable PVR during exercise in both patients with PH and healthy control subjects (2, 3134). The difference between both measures of load is explained by the way in which they are calculated: PVR as pressure divided by CO, and Ea as pressure divided by SV. Despite the larger RV afterload in patients with PH at rest, no differences in RV–arterial coupling between patients with PH and control subjects were found, implying that RV–arterial coupling at rest was well maintained. It was shown in a large cohort of patients with IPAH that RV–arterial coupling at rest was maintained in stable patients with PH and decreased in patients with PH with a more progressive disease (15). Another study showed a decrease in RV–arterial coupling at rest in patients with PH compared with control subjects (35). In this study, the calculation of Ees was simplified as end-systolic pressure divided by end-systolic volume (measured by magnetic resonance imaging), assuming the volume at zero pressure (V0) is zero. However, it has been shown that V0 depends on RV dilatation and therefore that the assumption of V0 = 0 leads to an underestimation of Ees and RV–arterial coupling (21).

The insufficient response in RV contractility to the increase in load resulted in a deterioration in RV–arterial coupling during exercise in patients with PH, whereas in control subjects the exertional contractile reserve was sufficient to maintain RV–arterial coupling. Studies of the LV showed that at an Ees/Ea ratio of 1, ventricular stroke work is optimal (14), although maximal ventricular efficiency, defined as ventricular stroke work divided by myocardial oxygen consumption, is reached at an Ees/Ea ratio of 2 (13). Theoretically, the decrease in RV–arterial coupling in patients with PH suggests that the coupling is shifted to an optimal ventricular stroke work at the cost of ventricular efficiency, although this cannot be determined from the current data.

Comparison of ΔEes with the Rest-to-Exercise Change in PAP

A recent study in patients with PH defined the contractile reserve as the increase in systolic PAP during exercise (16). In this study, a larger increase in sPAP was associated with a better survival. The rationale for using ΔsPAP as a measure of contractile reserve was derived from the pressure–flow relation. The authors stated that a greater increase in pressure allows the ejection of a higher SV and that, therefore, the contractile reserve can be described by the increase in pressures. In our study ΔPAP did not correlate with ΔEes or with ΔSVI. Because it is known that the increase in SV in patients with PH during exercise is only minor (3, 59), the increase in CI during exercise is highly HR dependent. Our data showed significant relations between the increases in PAP and ΔHR. This is in line with a recent study showing a strong relation between ΔmPAP and ΔHR during exercise in patients with PAH (7). Therefore, a large increase in PAP during exercise seems not to indicate an intact contractile reserve, but rather a more preserved HR response. The ability to increase HR is a well-known predictor of survival (36, 37) and the better survival found by Grünig and coworkers (16) in patients with PH with a larger increase in PAP during exercise could reflect a relatively intact HR response.

Clinical Implications

Although a direct link between exercise capacity and RV contractile reserve was not investigated in this study, our findings suggest that a decreased exercise capacity in PH is not only the direct result of an increased pressure in the lung circulation, but also caused by intrinsic changes in RV contractility. Moreover, our study results imply that inotropic drugs may have little value in improving RV dysfunction in PH. Studies are warranted to identify interventions that could restore RV contractile reserve by reversing maladaptive remodeling.

Because the rest-to-exercise response in PAP was not related to the rest-to-exercise response in Ees, but rather reflected an intact HR response, the rest-to-exercise response in PAP should not be used as a surrogate measure of the exertional contractile reserve.


For safety reasons, we exercised subjects only at submaximal workloads (40% of Wmax). In a subanalysis hemodynamic data were compared at comparable submaximal workloads of 37 W ± 12 in patients with PH and 46 W ± 5 in control subjects (P = 0.096). Differences between patients with PH and control subjects in rest-to-exercise responses of hemodynamics and load-independent measures of RV function were similar in direction and magnitude as in the data at 40% of Wmax (results not shown). From our results, we cannot determine whether the observed differences at submaximal exercise can be extrapolated to maximal exercise testing.

In the calculation of Ees, we used mPAP as a surrogate for RV end-systolic pressure based on a study of Chemla and coworkers (38) who found that in normal subjects mPAP was closely related to RV end-systolic pressure. It is possible that in a pressure-overloaded RV, RV end-systolic pressure is more closely related to the systolic RV pressure (39), which would have led to an overestimation of Ees. However, mPAP and systolic RV pressure were strongly related at rest and during exercise, implying that the choice of pressure does not influence the direction of the rest-to-exercise response.

Although the single-beat method has been developed and validated for the left ventricle (12), validation of the method in PH has been restricted to animals (11). The results of that study showed, in a wide range of Pmax values, that an excellent relation exists between Pmax determined by the single-beat method and the Pmax values determined after clamping of the pulmonary artery.

We used relatively deconditioned control subjects, because the primary indication to perform iCPET in these subjects was unexplained dyspnea. Based on the literature (3, 4042), including a previous study from our institute (3), we did not expect to find an unchanged SV in healthy subjects during submaximal exercise. The difference in SV response in control subjects between the current study and our previous study (3) can probably be explained by the fact that the control subjects in our previous study were healthy volunteers in good condition. Several previous studies showed physiologic explanations for an unchanged SV from rest to exercise. A reduced filling time caused by an increase in HR can result in an inability to increase SV in healthy subjects. Furthermore, in the upright position, the venous return is increased from rest to exercise via the muscle pump. When exercise is performed in the supine position, the venous return is already increased at rest because of the return of pooled blood caused by gravity, resulting in an inability to increase SV during exercise (6, 4349).

Because we already found large differences in the hemodynamic rest-to-exercise responses between patients with PH and relatively deconditioned control subjects, the inclusion of relatively deconditioned control subjects only strengthens our findings.


Patients with PH had no RV exertional contractile reserve, which resulted in RV–arterial uncoupling during submaximal exercise. Rest-to-exercise responses in PAPs rather reflected the rest-to-exercise response in HR than an exertional contractile reserve and should therefore not be used as a surrogate measure of exertional contractile reserve.

1. van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A. Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 2011;58:25112519.
2. Chaouat A, Sitbon O, Mercy M, Ponçot-Mongars R, Provencher S, Guillaumot A, Gomez E, Selton-Suty C, Malvestio P, Regent D, et al. Prognostic value of exercise pulmonary haemodynamics in pulmonary arterial hypertension. Eur Respir J 2014;44:704713.
3. Holverda S, Gan CT, Marcus JT, Postmus PE, Boonstra A, Vonk-Noordegraaf A. Impaired stroke volume response to exercise in pulmonary arterial hypertension. J Am Coll Cardiol 2006;47:17321733.
4. Lewis GD, Bossone E, Naeije R, Grünig E, Saggar R, Lancellotti P, Ghio S, Varga J, Rajagopalan S, Oudiz R, et al. Pulmonary vascular hemodynamic response to exercise in cardiopulmonary diseases. Circulation 2013;128:14701479.
5. Nootens M, Wolfkiel CJ, Chomka EV, Rich S. Understanding right and left ventricular systolic function and interactions at rest and with exercise in primary pulmonary hypertension. Am J Cardiol 1995;75:374377.
6. Almeida AR, Loureiro MJ, Lopes L, Cotrim C, Lopes L, Repolho D, Pereira H. Echocardiographic assessment of right ventricular contractile reserve in patients with pulmonary hypertension. Rev Port Cardiol 2014;33:155163.
7. Chemla D, Castelain V, Hoette S, Creuzé N, Provencher S, Zhu K, Humbert M, Herve P. Strong linear relationship between heart rate and mean pulmonary artery pressure in exercising patients with severe precapillary pulmonary hypertension. Am J Physiol Heart Circ Physiol 2013;305:H769H777.
8. Deboeck G, Taboada D, Hagan G, Treacy C, Page K, Sheares K, Naeije R, Pepke-Zaba J. Maximal cardiac output determines 6 minutes walking distance in pulmonary hypertension. PLoS One 2014;9:e92324.
9. Groepenhoff H, Westerhof N, Jacobs W, Boonstra A, Postmus PE, Vonk-Noordegraaf A. Exercise stroke volume and heart rate response differ in right and left heart failure. Eur J Heart Fail 2010;12:716720.
10. Provencher S, Chemla D, Hervé P, Sitbon O, Humbert M, Simonneau G. Heart rate responses during the 6-minute walk test in pulmonary arterial hypertension. Eur Respir J 2006;27:114120.
11. Brimioulle S, Wauthy P, Ewalenko P, Rondelet B, Vermeulen F, Kerbaul F, Naeije R. Single-beat estimation of right ventricular end-systolic pressure-volume relationship. Am J Physiol Heart Circ Physiol 2003;284:H1625H1630.
12. Sunagawa K, Yamada A, Senda Y, Kikuchi Y, Nakamura M, Shibahara T, Nose Y. Estimation of the hydromotive source pressure from ejecting beats of the left ventricle. IEEE Trans Biomed Eng 1980;27:299305.
13. Burkhoff D, Sagawa K. Ventricular efficiency predicted by an analytical model. Am J Physiol 1986;250:R1021R1027.
14. Sunagawa K, Maughan WL, Sagawa K. Optimal arterial resistance for the maximal stroke work studied in isolated canine left ventricle. Circ Res 1985;56:586595.
15. Trip P, De Man FS, Raamsteeboers AJ, Westerhof N, vonk-Noordegraaf A. Right ventriculo-arterial coupling in long-term, mid-term and short-term surviving patients with pulmonary arterial hypertension [abstract]. Am J Respir Crit Care Med 2013;187:A2550.
16. Grünig E, Tiede H, Enyimayew EO, Ehlken N, Seyfarth HJ, Bossone E, D’Andrea A, Naeije R, Olschewski H, Ulrich S, et al. Assessment and prognostic relevance of right ventricular contractile reserve in patients with severe pulmonary hypertension. Circulation 2013;128:20052015.
17. Spruijt OA, Bogaard HJ, De Man FS, Oosterveer F, Groepenhoff H, Westerhof N, vonk-Noordegraaf A. The coupling of the right ventricle to its load during exercise in pulmonary hypertension [abstract]. Am J Respir Crit Care Med 2014;189:A4720.
18. Ross RM. ATS/ACCP statement on cardiopulmonary exercise testing. Am J Respir Crit Care Med 2003;167:1451, author reply 1451.
19. Vonk-Noordegraaf A, Westerhof N. Describing right ventricular function. Eur Respir J 2013;41:14191423.
20. Spruijt OA, Bogaard HJ, Vonk-Noordegraaf A. Assessment of right ventricular responses to therapy in pulmonary hypertension. Drug Discov Today 2014;19:12461250.
21. Trip P, Kind T, van de Veerdonk MC, Marcus JT, de Man FS, Westerhof N, Vonk-Noordegraaf A. Accurate assessment of load-independent right ventricular systolic function in patients with pulmonary hypertension. J Heart Lung Transplant 2013;32:5055.
22. Kuehne T, Yilmaz S, Steendijk P, Moore P, Groenink M, Saaed M, Weber O, Higgins CB, Ewert P, Fleck E, et al. Magnetic resonance imaging analysis of right ventricular pressure-volume loops: in vivo validation and clinical application in patients with pulmonary hypertension. Circulation 2004;110:20102016.
23. Chantler PD, Lakatta EG, Najjar SS. Arterial-ventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise. J Appl Physiol (1985) 2008;105:13421351.
24. Chantler PD, Melenovsky V, Schulman SP, Gerstenblith G, Becker LC, Ferrucci L, Fleg JL, Lakatta EG, Najjar SS. The sex-specific impact of systolic hypertension and systolic blood pressure on arterial-ventricular coupling at rest and during exercise. Am J Physiol Heart Circ Physiol 2008;295:H145H153.
25. Najjar SS, Schulman SP, Gerstenblith G, Fleg JL, Kass DA, O’Connor F, Becker LC, Lakatta EG. Age and gender affect ventricular-vascular coupling during aerobic exercise. J Am Coll Cardiol 2004;44:611617.
26. Little WC, Cheng CP. Effect of exercise on left ventricular-arterial coupling assessed in the pressure-volume plane. Am J Physiol 1993;264:H1629H1633.
27. Piao L, Fang YH, Parikh KS, Ryan JJ, D’Souza KM, Theccanat T, Toth PT, Pogoriler J, Paul J, Blaxall BC, et al. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation 2012;126:28592869.
28. Bristow MR, Minobe W, Rasmussen R, Larrabee P, Skerl L, Klein JW, Anderson FL, Murray J, Mestroni L, Karwande SV, et al. Beta-adrenergic neuroeffector abnormalities in the failing human heart are produced by local rather than systemic mechanisms. J Clin Invest 1992;89:803815.
29. Nootens M, Kaufmann E, Rector T, Toher C, Judd D, Francis GS, Rich S. Neurohormonal activation in patients with right ventricular failure from pulmonary hypertension: relation to hemodynamic variables and endothelin levels. J Am Coll Cardiol 1995;26:15811585.
30. Ryan JJ, Archer SL. The right ventricle in pulmonary arterial hypertension: disorders of metabolism, angiogenesis and adrenergic signaling in right ventricular failure. Circ Res 2014;115:176188.
31. Blumberg FC, Arzt M, Lange T, Schroll S, Pfeifer M, Wensel R. Impact of right ventricular reserve on exercise capacity and survival in patients with pulmonary hypertension. Eur J Heart Fail 2013;15:771775.
32. Kovacs G, Olschewski A, Berghold A, Olschewski H. Pulmonary vascular resistances during exercise in normal subjects: a systematic review. Eur Respir J 2012;39:319328.
33. Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced pulmonary arterial hypertension. Circulation 2008;118:21832189.
34. Waxman AB. Exercise physiology and pulmonary arterial hypertension. Prog Cardiovasc Dis 2012;55:172179.
35. Sanz J, García-Alvarez A, Fernández-Friera L, Nair A, Mirelis JG, Sawit ST, Pinney S, Fuster V. Right ventriculo-arterial coupling in pulmonary hypertension: a magnetic resonance study. Heart 2012;98:238243.
36. Groepenhoff H, Vonk-Noordegraaf A, van de Veerdonk MC, Boonstra A, Westerhof N, Bogaard HJ. Prognostic relevance of changes in exercise test variables in pulmonary arterial hypertension. PLoS One 2013;8:e72013.
37. Henkens IR, Van Wolferen SA, Gan CT, Boonstra A, Swenne CA, Twisk JW, Kamp O, van der Wall EE, Schalij MJ, Vonk-Noordegraaf A, et al. Relation of resting heart rate to prognosis in patients with idiopathic pulmonary arterial hypertension. Am J Cardiol 2009;103:14511456.
38. Chemla D, Hébert JL, Coirault C, Salmeron S, Zamani K, Lecarpentier Y. Matching dicrotic notch and mean pulmonary artery pressures: implications for effective arterial elastance. Am J Physiol 1996;271:H1287H1295.
39. Redington AN, Rigby ML, Shinebourne EA, Oldershaw PJ. Changes in the pressure-volume relation of the right ventricle when its loading conditions are modified. Br Heart J 1990;63:4549.
40. Rigaud M, Boschat J, Rocha P, Ferreira A, Bardet J, Bourdarias JP. Comparative haemodynamic effects of dobutamine and isoproterenol in man. Intensive Care Med 1977;3:5762.
41. Roest AA, Kunz P, Lamb HJ, Helbing WA, van der Wall EE, de Roos A. Biventricular response to supine physical exercise in young adults assessed with ultrafast magnetic resonance imaging. Am J Cardiol 2001;87:601605.
42. Surie S, van der Plas MN, Marcus JT, Kind T, Kloek JJ, Vonk-Noordegraaf A, Bresser P. Effect of pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension on stroke volume response to exercise. Am J Cardiol 2014;114:136140.
43. Daley PJ, Sagar KB, Wann LS. Doppler echocardiographic measurement of flow velocity in the ascending aorta during supine and upright exercise. Br Heart J 1985;54:562567.
44. Elstad M, Nådland IH, Toska K, Walløe L. Stroke volume decreases during mild dynamic and static exercise in supine humans. Acta Physiol (Oxf) 2009;195:289300.
45. Elstad M, Toska K, Chon KH, Raeder EA, Cohen RJ. Respiratory sinus arrhythmia: opposite effects on systolic and mean arterial pressure in supine humans. J Physiol 2001;536:251259.
46. Loeppky JA, Greene ER, Hoekenga DE, Caprihan A, Luft UC. Beat-by-beat stroke volume assessment by pulsed Doppler in upright and supine exercise. J Appl Physiol 1981;50:11731182.
47. Puchalska L, Belkania GS. Haemodynamic responses to the dynamic exercise in subjects exposed to different gravitational conditions. J Physiol Pharmacol 2006;57:103113.
48. Steding-Ehrenborg K, Jablonowski R, Arvidsson PM, Carlsson M, Saltin B, Arheden H. Moderate intensity supine exercise causes decreased cardiac volumes and increased outer volume variations: a cardiovascular magnetic resonance study. J Cardiovasc Magn Reson 2013;15:96.
49. Toska K, Eriksen M. Respiration-synchronous fluctuations in stroke volume, heart rate and arterial pressure in humans. J Physiol 1993;472:501512.
Correspondence and requests for reprints should be addressed to Harm-Jan Bogaard, M.D., Ph.D., Department of Pulmonology, VU University Medical Center, de Boelelaan 1117, ZH 4F-010, 1081HV, Amsterdam, the Netherlands. E-mail:

Supported by the NWO, Vidi Grant, project number 91.796.306 (A.V.-N.).

Author Contributions: All authors contributed significantly to the submitted work. O.A.S. and H.-J.B. contributed to the conception and design of the study, the analysis and interpretation of data, and the writing of the manuscript. F.S.d.M., H.G., F.O., N.W., and A.V.-N. contributed to the conception and design of the study, the analysis and interpretation of data, and revising the manuscript. All authors gave their final approval.

This article has an online supplement, which is accessible from this issue's table of contents at

Originally Published in Press as DOI: 10.1164/rccm.201412-2271OC on February 24, 2015

Author disclosures are available with the text of this article at


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