Author + information
- Received March 9, 2018
- Revision received July 20, 2018
- Accepted July 23, 2018
- Published online September 12, 2018.
- Mathias Claeys, MDa,b,∗ (, )@ClaeysMathias,
- Guido Claessen, MD, PhDa,b,
- Andre La Gerche, MD, PhDa,c,
- Thibault Petit, MDa,b,
- Catharina Belge, MD, PhDd,e,
- Bart Meyns, MD, PhDa,f,
- Jan Bogaert, MD, PhDg,h,
- Rik Willems, MD, PhDa,b,
- Piet Claus, MSc, PhDa and
- Marion Delcroix, MD, PhDd,e
- aDepartment of Cardiovascular Sciences, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
- bDepartment of Cardiology, University Hospitals Leuven, Leuven, Belgium
- cBaker IDI Heart and Diabetes Institute, Melbourne, Australia
- dDepartment of Pneumology, University Hospitals Leuven, Leuven, Belgium
- eDivision of Pneumology, Department of Chronic Diseases, Metabolism and Aging, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
- fDepartment of Cardiac Surgery, University Hospitals Leuven, Leuven, Belgium
- gDepartment of Radiology, University Hospitals Leuven, Leuven, Belgium
- hDepartment of Imaging and Pathology, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
- ↵∗Address for correspondence:
Dr. Mathias Claeys, Department of Cardiovascular Medicine, University Hospitals Leuven, Herestraat 49, B-3000 Leuven, Belgium.
Objectives This study was a comprehensive evaluation of cardiopulmonary function in patients with chronic thromboembolic (pulmonary vascular) disease (CTED) during exercise.
Background Exertional dyspnea is frequent following pulmonary embolism, but only a minority of patients eventually develops chronic thromboembolic pulmonary hypertension (CTEPH). Better understanding of the factors that limit exercise capacity in patients with persistent pulmonary artery obstruction could help to further define the entity of CTED.
Methods Fifty-two subjects (13 healthy control subjects, 14 CTED patients, and 25 CTEPH patients) underwent cardiopulmonary exercise testing and exercise cardiac magnetic resonance with simultaneous invasive pressure registration. Pulmonary vascular function and right ventricular contractile reserve were assessed through combined invasive pressure measurements and magnetic resonance imaging volume measures.
Results Exercise capacity was reduced by 29% and 57% in patients with CTED and CTEPH respectively, compared with control subjects. Both CTED (3.48 [interquartile range: 2.24 to 4.36] mm Hg × l−1 × min−1) and CTEPH patients (8.85 [interquartile range: 7.18 to 10.4] mm Hg × l−1 × min−1) had abnormal total pulmonary vascular resistance. Right ventricular contractile reserve was reduced in CTED patients compared with control subjects (2.23 ± 0.55 vs. 3.72 ± 0.94), but was still higher than that in CTEPH patients (1.34 ± 0.24; p < 0.001). As opposed to patients with CTEPH in whom right ventricular ejection fraction declined with exercise, right ventricular ejection fraction still increased in patients with CTED, albeit to a lesser extent than in healthy control subjects (interaction p < 0.001), which illustrated the distinct patterns of ventricular−arterial coupling.
Conclusions CTED represents an intermediate clinical phenotype. Exercise imaging unmasks cardiovascular dysfunction not evident at rest and identifies hemodynamically significant disease that results from reduced contractile reserve or increased vascular load.
- cardiac magnetic resonance imaging
- chronic thromboembolic pulmonary hypertension
- pulmonary hypertension
- right ventricle
Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of pulmonary embolism. Proximal fibrothrombotic pulmonary vascular obstructions and microvasculopathy cause progressive pulmonary hypertension, which leads to right heart failure and ultimately death if left untreated (1). CTEPH is defined by a mean pulmonary artery pressure of >25 mm Hg and an abnormal ventilation perfusion scan, together with abnormal computed tomography or pulmonary angiography showing typical anomalies after at least 3 months of anticoagulation. Surgical pulmonary endarterectomy represents a potential cure for patients with CTEPH. Because the degree of pulmonary hypertension at diagnosis of pulmonary thromboembolism correlates with mortality, timely diagnosis and treatment may prevent the development of microvasculopathy and right heart dysfunction (2,3).
Chronic thromboembolic (pulmonary vascular) disease (CTED) has recently been recognized as a separate entity and corresponds to the presence of persistent perfusion defects in the absence of pulmonary hypertension at rest (4). It can cause significant exercise limitations and pulmonary endarterectomy may also be beneficial in selected patients (5,6). Nevertheless, because the long-term prognosis in CTED may be favorable even without treatment, and because of the peri-operative risk, the decision to perform surgery in these patients requires a careful workup that takes into account the symptoms and functional limitations of the patient, and the mechanism of functional limitation (2,7). This is particularly important because exertional dyspnea is frequent following acute pulmonary embolism, and anatomic resolution is often incomplete with evidence of persistent thrombi in up to 30% of patients (8,9).
To gain insight into the pathophysiology of exertional dyspnea with the aim of establishing diagnostic tests that may identify significant pathology, we conducted a comprehensive evaluation of cardiopulmonary function during exercise, a time of maximal hemodynamic stress and most profound symptoms, and compared CTED with both age-matched control subjects and patients with established CTEPH. We hypothesized that exercise intolerance in CTED patients is caused by impaired augmentation of right ventricular ejection fraction (RVEF) function during exercise as a consequence of abnormal vascular load and reduced contractile reserve. Therefore, exercise evaluation might unmask clinically significant pulmonary vascular disease that is not evident at rest.
CTED and CTEPH patients were recruited from the center for pulmonary vascular diseases at our institution. CTED patients were eligible for inclusion if the following criteria were met: 1) history of acute pulmonary embolism; 2) persistent mismatched segmental perfusion defects on ventilation and perfusion scan despite therapeutic anticoagulation for ≥6 months; 3) chronic dyspnea and New York Health Association functional class II or more; 4) absence of significant respiratory disease and normal ventilatory reserve (>11 l/min); and 5) mean pulmonary artery pressure <25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg on right heart catheterization. CTEPH patients were diagnosed in accordance with contemporary clinical practice guidelines (7). Thirteen healthy control subjects without previous cardiac or pulmonary disease volunteered to participate. All were asymptomatic and had a normal electrocardiogram, transthoracic echocardiogram, and right heart catheterization at rest. All participants had to able to perform at least 50 W on an upright bicycle stress test. The study conformed to the Declaration of Helsinki and was approved by the local ethics committee. All participants provided written informed consent before inclusion.
Cardiopulmonary exercise testing with continuous monitoring of expiratory gases was performed on an upright cycle ergometer (Jaeger Oxycon Pro [CareFusion], Hoechberg, Germany). Through breath-by-breath analysis minute ventilation, oxygen consumption and carbon dioxide production were assessed. Other measures included peak heart rate, peak power and ventilatory efficiency (VE/VCO2 slope). The dead space fraction (i.e., ratio of physiological dead space ventilation to tidal volume) was calculated using arterial carbon dioxide pressures and the Enghoff modification of the Bohr equation (10). Within 24 h, all subjects underwent exercise cardiac magnetic resonance imaging (exCMR) with simultaneous invasive pressure measurements (Online Figure 1). Right heart catheterization was performed in the catheterization laboratory. A 7-F magnetic resonance imaging compatible pulmonary artery catheter (Edwards Lifesciences, Irvine, California) was inserted into the pulmonary artery, and a 20-gauge arterial catheter was inserted into the radial artery. In the exCMR suite, the catheters were connected through magnetic resonance imaging compatible transducers to a Powerlab recording system (AD Instruments, Oxford, United Kingdom) and recalibrated. Right atrial pressures, and pulmonary and systemic artery pressures were continuously monitored during the protocol and analyzed offline using LabChart V6.1.1 (AD Instruments). For safety reasons, pulmonary capillary wedge pressure was only measured at rest in CTED and CTEPH patients. All pressure measurements were obtained during unrestricted respiration and averaged over 10 consecutive cardiac cycles. Images were acquired during free breathing both at rest and during exercise at 25%, 50%, and 66% of peak power achieved during CPET. Workloads were imposed nearly instantaneously and were maintained for ≈3 min at each stage—30 s to achieve a physiological steady state and then 2 to 3 min for image acquisition. Because supine exercise at 66% of peak power closely corresponds to maximal sustainable upright exercise, these workloads will hereinafter be referred to as rest, low, moderate, and peak intensity.
Cardiac magnetic resonance equipment, image acquisition, and analysis
Biventricular volumes were measured using a free-breathing, real-time cardiac magnetic resonance (CMR) method that we previously validated against invasive standards and that has been described extensively elsewhere (11,12). Detailed information regarding the exCMR examination can be found in the Online Appendix. In brief, subjects performed supine bicycle exercise within the CMR (Achieva 1.5-T, Philips Medical Systems, Best, the Netherlands) using a cycle ergometer with adjustable electronic resistance (Lode, Groningen, the Netherlands). Left ventricular (LV) and RV contours were manually traced using in-house−developed software (RightVol, Leuven, Belgium) (Online Figure 1). Cardiac volumes were calculated through a summation of the disk method and indexed for body surface area. LV and RV contractility were assessed through the LV and RV end-systolic pressure−volume relationship, respectively (13,14). Pulmonary vascular load was evaluated through the relationship between mean pulmonary artery pressure and cardiac output (P/Q slope). Abnormal RV contractile reserve was defined as the ratio of peak exercise to resting RV end-systolic pressure−volume relationship of <2, and abnormal pulmonary vascular load during exercise was defined as a P/Q slope >3 mm Hgl/min (15,16).
Arterial and central venous blood samples were collected at rest and at peak exercise during the exCMR protocol and were analyzed using an automated blood gas analyzer (ABL 700, Radiometer, Copenhagen, Denmark). N-terminal pro–B-type natriuretic peptide was analyzed from standard blood samples.
Sample size calculation was based on the previous observation that patients with only mild pulmonary hypertension at rest had an inadequate stroke volume (SV) response to exercise; the detailed calculation can be found in the Online Appendix (17). Data were analyzed using SPSS version 24 (IBM Corporation, Armonk, New York). Normality was ensured using the Shapiro-Wilk test, and variables are presented as mean ± SD or as median (interquartile range). Continuous variables were compared using a chi-square test for categorical data and either a Kruskal-Wallis H test or a 1-way analysis of variance with the Bonferroni post hoc correction. Rest and peak dead space fraction were compared using a related-samples Wilcoxon signed-rank test. The cardiac volume response to exercise was assessed using repeated measures analysis of variance, with exercise intensity as a within-subject effect and subject group as between-subject effect. Pressure-flow relationships (i.e., P/Q slopes) were calculated through linear regression of the individual multiple mean pulmonary artery pressure−cardiac output points obtained during incremental exercise. A p value of <0.05 was considered statistically significant. The relationship between different physiological parameters and peak oxygen uptake in patients with chronic thromboemboli (i.e., CTEPH and CTED combined) was evaluated with Pearson correlation coefficients.
Fifty-two subjects (13 control subjects, 14 CTED patients, and 25 CTEPH patients) were included in the study. The baseline characteristics and the results of the cardiopulmonary exercise test and right heart catheterization at rest are summarized in Table 1. The 3 groups had similar age and body size distributions, but there was a slight sex imbalance (larger proportion of female CTED patients and male control subjects). CTEPH patients had a lower 6-min walking distance and higher N-terminal pro–B-type natriuretic peptide levels compared with CTED patients (p = 0.033 and p < 0.001, respectively). One inoperable CTEPH patient received pulmonary vasodilator therapy (sildenafil and ambrisentan) because of a previous episode of RV failure. Five CTEPH patients and 1 CTED patient were treated with a beta-blocker, which was withheld at least 24 hours before exCMR. Thromboembolic history, comorbidities, and baseline echocardiographic parameters are listed in Online Table 1. Coronary artery disease was present in 1 older CTEPH patient. None of the participants had evidence of significant left heart disease at rest.
Cardiopulmonary exercise test and right heart catheterization
Compared with controls, peak oxygen consumption and peak power were significantly reduced in CTED patients (p = 0.002 and p = 0.007, respectively), and were even lower in CTEPH patients (both p < 0.001 compared with controls; p = 0.001 and p = 0.004 compared with patients with CTED). CTEPH patients had a lower ventilatory efficiency (i.e., higher VE/VCO2 slope; p < 0.001) and a higher dead space fraction (p = 0.003 at rest and p < 0.001 at peak exercise), which did not change with exercise (p = 0.167). In CTED patients, the dead space fraction decreased with exercise (p = 0.015), but ventilatory efficiency (p = 0.229) and the dead space fraction (p = 0.376 at rest and p = 0.680 at peak exercise) were similar to that in control subjects. When the ventilatory equivalent at peak exercise was plotted against end-tidal carbon dioxide pressures, CTED patients had intermediate ventilatory efficiency (Figure 2A). Similarly, when the ventilatory equivalent was plotted against the arterial carbon dioxide pressure (Figure 2B), the CTED curve lay between the control subjects and CTEPH patients for a given arterial carbon dioxide pressure, which suggested a gradual difference in the dead space fraction. On right heart catheterization, CTEPH patients had a lower cardiac index (p = 0.001), higher pulmonary pressures, and higher pulmonary vascular resistance (all p < 0.001) relative to CTED and control subjects. CTED patients had lower right atrial pressures. Representative pressure traces during exercise are shown in Online Figure 2.
Biventricular function at rest and during exercise
Ventricular volumes, pressures, and oxygen saturations are shown in Online Table 2. The biventricular volume response to exercise differed in the 3 groups (Figure 3). In control subjects, LV end-diastolic volume (indexed for body surface area) (EDVi) did not change with exercise (p = 0.14), whereas the RVEDVi declined (p = 0.014 for exercise intensity), and both LV and RV end-systolic volume (indexed for body surface area) (ESVi) decreased significantly (p = 0.003 and p < 0.001 respectively). LV and RVEDVi did not change with exercise in CTED patients (p = 0.433 and p = 0.787, respectively), whereas LVESVi decreased (p = 0.001) and RVESVi remained unchanged (p = 0.17). In CTEPH patients, LVEDVi and LVESVi declined (p < 0.001) whereas both RVEDVi and RVESVi increased (p < 0.001). Relative to control subjects, the LV stroke volume (indexed for body surface area) (SVi) was lower in CTED and CTEPH patients throughout exercise. LVSVi increased with exercise in control subjects and CTED patients (p = 0.001 and p = 0.011) but declined in CTEPH patients (p = 0.01 for exercise intensity, p < 0001 for interaction) (Figure 4A). Similarly, RVSVi was lower in CTED and CTEPH patients relative to control subjects. During exercise, RVSVi increased in control subjects (p = 0.001), tended to increase in CTED patients (p = 0.049), and remained unchanged in CTEPH patients (p = 0.606 for exercise intensity, interaction p = 0.008) (Figure 4B).
As evident from Table 2 and Figure 4C, LVEF increased during exercise in all groups (interaction p = 0.194). In contrast, the change in RVEF during exercise differed among the groups (p < 0.001 for the among groups interaction), with an attenuated increase in CTED patients and a decline during exercise in CTEPH patients. In other words, there was an intermediate RVEF response to exercise in CTED patients (Figure 4D). Right atrial pressures increased in all 3 groups, although the increase was most pronounced in CTEPH patients (interaction p < 0.001) (Online Figure 3). The cardiac index increased more in control subjects (interaction p < 0.001) (Figure 5A). Heart rate at peak exercise was also significantly higher in control subjects (interaction p < 0.001) (Figure 5B). LV contractility increased to a similar extent in all groups (interaction p = 0.882). Therefore, LV contractile did not differ among the different groups (p = 0.239). In contrast, RV contractility was elevated at rest in CTED and CTEPH patients compared with the control subjects. With exercise, it quickly reached a plateau in CTEPH patients, whereas it increased linearly in CTED and control subjects (interaction p < 0.001). Therefore, RV contractile reserve (RV end-systolic) was abnormal in CTEPH patients (1.35 ± 0.23) and borderline in CTED patients (2.23 ± 0.55), but both were significantly lower compared with control subjects (3.72 ± 0.94; p < 0.001 for between group difference) (Figure 5C). Because of the slight sex imbalance, separate analyses were performed for men and women, which showed consistent results in both sexes (Online Figures 4 and 5). Female CTED patients had a more preserved RV contractile reserve and RV response to exercise.
Pulmonary vascular function at rest and during exercise
Total pulmonary vascular resistance was significantly higher throughout exercise in CTEPH patients (p < 0.001 compared with both control subjects and CTED patients; interaction p = 0.816). In contrast, pulmonary arterial compliance declined with exercise intensity in all groups, was lower in CTED patients, and was even more reduced in CTEPH patients. Although the absolute decrease with exercise was greatest in control subjects, compliance at peak exercise remained higher (p < 0.001 for interaction). Pulmonary vascular load was significantly increased in CTEPH patients (8.85 [interquartile range (IQR): 7.18 to 10.40] mm Hg × l−1 × min), and although the difference in P/Q slope between control subjects (0.99 [IQR: 0.88 to 2.60] mm Hg × l−1 × min) and CTED patients (3.48 [IQR: 2.24 to 4.36] mm Hg × l−1 × min) was not significant (p = 0.443), RV load increased disproportionally in most of the CTED patients (8 of 14) (i.e., P/Q slope >3 mm Hg × l−1 × min (interaction p < 0.001) (Figure 5D). Both men and women had an increased P/Q slope (Online Figures 4 and 5).
Determinants of exercise capacity
Peak oxygen consumption in patients with chronic thromboembolic pulmonary vascular obstructions (i.e., CTED and CTEPH combined) correlated weakly with the dead space fraction (r = −0.345; p = 0.039), correlated more significantly with P/Q slope and ventilatory inefficiency (r = −0.479 and r = −0.535, respectively, both p < 0.01), and correlated strongly with RV contractile reserve and cardiac index at peak exercise (r = 0.664 and r = 0.694, respectively; both p < 0.001). Two-dimensional scatterplots of all subjects revealed that RV contractile reserve, pulmonary vascular load, and the dead space fraction increased proportionally to disease severity, with CTED patients appearing as an intermediary group (Online Figure 6).
Persistent exertional dyspnea is common following an acute pulmonary embolism. However, it has many potential causes, and only a minority of patients develop CTEPH. Nevertheless, CTED patients often have measurable limitations in cardiopulmonary function, and evolving evidence raises the possibility that some could benefit from intervention even in the absence of pulmonary hypertension at rest (6). In the present study, we provided data that suggested that CTED represents an intermediate phenotype with RV contractile impairment and abnormal pulmonary vascular load relative to healthy control subjects but is less pronounced than in CTEPH patients (Figure 1). Exercise measures are known predictors of outcome in pulmonary hypertension; thus, the data presented here are a first step in identifying those CTED patients who may benefit from therapeutic intervention.
Cardiopulmonary function during exercise
In pulmonary hypertension, exercise capacity is limited by ventilation−perfusion mismatch, exertional hypoxemia, and insufficient cardiac output augmentation. Recently, Held et al. (5) demonstrated that CTED patients had a similar degree of functional impairment as that in CTEPH patients. However, in our study, exercise capacity was reduced to a lesser extent, potentially reflecting the younger age of CTED patients in our cohort. Consistent with previous data, the dead space fraction of CTEPH patients did not decline, even during strenuous exercise, and contributed to ventilatory inefficiency (18). CTED patients also had lower ventilatory efficiency compared with healthy control subjects, which could be explained in part by the higher dead space fraction, which was mildly elevated at rest but still decreased with exercise.
Pulmonary vascular obstruction also profoundly influences RV function during exercise (12). An increased pulmonary vascular load during exercise was previously identified in CTED patients (19). In our study, cardiac output augmentation of both CTED and CTEPH patients was limited by chronotropic incompetence and a blunted SV increase. The former could be explained by the slightly older age of CTEPH patients, previous use of rate-slowing medication, beta-adrenoreceptor pathway downregulation, or even adverse right atrial remodeling. In contrast, the reduction in SV during exercise is an established feature of pulmonary hypertension linked to altered ventricular−arterial coupling (i.e., mismatching of contractility to afterload) (17,20). In control subjects, the increased RV afterload was matched by a substantial increase in contractility; hence, SV was maintained and RVEF increased. Conversely, in CTEPH patients, and in line with a recent study by Spruijt et al. (21), RVEF and SV declined during exercise as a consequence of the severely reduced contractile reserve and disproportionate afterload increase. As in the study of McCabe et al. (22), we showed that contractility was elevated at rest in CTED patients, possibly to maintain ventricular−arterial coupling in the setting of subtle increases in pulmonary vascular load. However, with exercise, contractility did not increase to the same degree as that in control subjects. Thus, exercise measures enabled us to identify subtle RV contractile impairment when resting measures gave the false impression of preserved or even enhanced RV function.
During exercise, venous return is enhanced through the concerted effects of venoconstriction, respiration, and skeletal muscle contraction. Venous obstruction potentially reduces pre-load and impairs cardiac function through the Frank-Starling mechanism. Although right atrial pressures of CTED patients were low at rest, they increased significantly during exercise and were higher than previously suggested cutoffs for pre-load insufficiency (23).
Interestingly, the disproportionate afterload increase in CTED patients was mainly caused by reduced compliance, whereas no significant differences were observed in total pulmonary vascular resistance. Lower compliance increases pulse pressure, is associated with more severe disease, and has been shown to be a better predictor of outcome than pulmonary vascular resistance (24,25). Our data would seem to support previous observations that reduced compliance is a more sensitive indicator of pulmonary vascular disease (26,27). However, these results should be interpreted with caution because exercise by definition accentuates pulsatile metrics (e.g., compliance). Furthermore, the decrease in pulmonary vascular resistance is more limited in supine exercise versus upright exercise, and an increase in pulmonary capillary wedge pressure during exercise cannot be fully excluded (28,29).
Exercise imaging in pulmonary vascular disease
In recent years, it has become clear that the right ventricle and its interplay with pulmonary circulation are important determinants of exercise capacity even in healthy individuals (30). In pulmonary hypertension, in which RV contractile reserve has been shown to be an independent predictor of outcome, exercise evaluation is of prime clinical relevance (31). Previously, we and others have linked persistent exercise intolerance after pulmonary endarterectomy to impaired pulmonary vascular reserve and altered ventricular−arterial coupling (12,32). In the present study, we extended these findings to patients with pulmonary vascular disease without pulmonary hypertension at rest. We showed that standard measurements at rest provided little insight into disease mechanisms and did not accurately identify those CTED patients with hemodynamically significant disease. In our study, RV load increased disproportionally with exercise in more than one-half of CTED patients, and there was evidence of reduced RV contractile reserve relative to healthy subjects. This strongly supports the notion that exercise testing is critical for accurate assessment of cardiopulmonary pathophysiology in CTED. Based on previous reports that linked borderline pulmonary hypertension with worse outcomes, it would seem appropriate that CTED patients with impaired pulmonary vascular or contractile reserve are closely monitored (33). Whether therapeutic intervention would be beneficial remains to be proven, but preliminary reports, combined with our results, provide a rationale for patient selection based on exercise hemodynamics. Certainly, with the advent of less invasive techniques, like balloon pulmonary angioplasty, accurate discrimination will become even more important.
Because of its accuracy and simultaneous evaluation of cardiac function and load, exCMR with simultaneous invasive pressure measurements would seem to be the preferred method to use. Nevertheless, its additional value for clinical decision making requires further validation and practical considerations currently limit its widespread availability. However, guidelines recommend evaluation of pulmonary vascular diseases in expert reference centers where such a technique would not be unattainable. In addition, we previously demonstrated that echocardiographic evaluation of RV contractile or pulmonary vascular function during exercise is feasible and has reasonably accuracy compared with exCMR (15,34). Exercise stress echocardiography might therefore be a valuable and broadly applicable screening tool.
The small sample size might have increased the probability of type 2 statistical errors, whereas multiple comparisons increased the likelihood of type 1 errors. Nevertheless, the accuracy of exCMR measures enabled evaluation of relevant hemodynamic differences with high statistical significance despite the modest cohort size. To account for the sex imbalance, separate analyses were performed for both men and women. Consistent patterns were observed, although female CTED patients seemed to have a more preserved RV contractile reserve. In control subjects, a greater difference was observed between the catheterization laboratory and exCMR pressures at rest, which could be related to differences in the baseline circulatory state (catheterization was performed ambulatory in control subjects) or a small offset in the pressure calibration system (because different rooms were used). However, during the exCMR protocol, there were no methodological differences among subjects regarding the pressure acquisition and calibration.
Due to safety concerns, pulmonary capillary wedge pressure measurements were only obtained in CTED and CTEPH patients at rest. Therefore, we could not ascertain the role of increased left-sided filling pressures, which could have influenced the relationship between resistance and compliance on the observed afterload changes with exercise (28). However, the relatively young age of our cohorts, the absence of left heart disease on baseline echocardiography, and the low wedge pressures at rest made a significant post-capillary component less likely. In addition, the use of fluid-filled catheters could have resulted in measurement artefacts. These were minimized by ensuring that catheters were adequately flushed, by averaging pressures over at least 10 consecutive cycles, and through careful manual selection of the region of interest.
For the calculation of dead space ventilation, gas exchange parameters of the cardiopulmonary exercise test were combined with blood gasses obtained during the magnetic resonance imaging protocol, which might have introduced inconsistencies due to differences in exercise level and posture. Furthermore, because only supine exercise was performed, we could not exclude potential differences in exercise hemodynamics related to posture.
Finally, for the estimation of contractility, we assumed that the volume at zero pressure was zero at all times and used mean pulmonary artery pressure in all groups (35,36). Nevertheless, because RV contractile reserve was derived as a ratio and because of the constant relationship between systolic and mean pulmonary artery pressure, the effect of this modification was probably minimal.
Chronic thromboembolic pulmonary vascular disease represents an intermediate clinical phenotype in which exercise intolerance is linked to reduced cardiac reserve and increased afterload. The slight increase in dead space ventilation correlated with disease severity. Exercise imaging unmasks subtle cardiovascular dysfunction and should be incorporated into future studies to assess its clinical relevance in patient management.
COMPETENCY IN MEDICAL KNOWLEDGE: Exertional dyspnea is common following pulmonary embolism and should be evaluated during exercise (i.e., when patients are symptomatic). Exercise imaging unmasks subtle cardiovascular dysfunction not evident at rest and informs clinicians on the pathophysiological mechanisms underlying exertional breathlessness.
TRANSLATIONAL OUTLOOK: Future studies should address whether the use of exercise hemodynamics in clinical decision making improves patient outcome through tailored interventions.
The authors wish to acknowledge Kris Byloos, Stefan Ghysels, and Guido Putzeys for their assistance with the CMR examinations.
This study was funded by a grant (Project G.0465.10N) from the Fund for Scientific Research Flanders (FWO), Brussels, Belgium.
Dr. La Gerche has received grants from the Fund for Scientific Research Flanders (FWO) and from the National Health and Medical Research Council (NHMRC) of Australia. Dr. Belge has received speaker and consultancy fees from Actelion and GlaxoSmithKline. Dr. Willems has received research funding from Medtronic Belgium and is supported as a postdoctoral clinical researcher by the Fund for Scientific Research Flanders (FWO). Dr. Delcroix has received fees as a speaker, investigator, consultant, or steering committee member for Actelion, Bayer, Bellarophon, Eli Lilly, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, and Reata; and has received a research grant from Actelion. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- cardiac magnetic resonance
- chronic thromboembolic (pulmonary vascular) disease
- chronic thromboembolic pulmonary hypertension
- end-diastolic volume (indexed for body surface area)
- ejection fraction
- end-systolic volume (indexed for body surface area)
- exercise cardiac magnetic resonance imaging
- left ventricular
- P/Q slope
- slope of the mean pulmonary artery pressure to cardiac output relationship
- right ventricular
- stroke volume (indexed for body surface area)
- Received March 9, 2018.
- Revision received July 20, 2018.
- Accepted July 23, 2018.
- 2018 American College of Cardiology Foundation
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