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Right ventricular functional recovery assessment with stress echocardiography and cardiopulmonary exercise testing after pulmonary embolism: a pilot prospective multicentre study
  1. Chinthaka Bhagya Samaranayake1,2,
  2. John Upham2,3,
  3. Khoa Tran2,4,
  4. Luke S Howard5,6,
  5. Sean Nguyen3,
  6. Myo Lwin1,
  7. James Anderson7,
  8. Sudhir Wahi2,3,
  9. Laura C Price1,6,
  10. Stephen Wort1,6,
  11. Wei Li1,6,
  12. Colm McCabe1,6 and
  13. Gregory J Keir2,3
  1. 1National Pulmonary Hypertension Service, Royal Brompton Hospital, London, UK
  2. 2Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
  3. 3Princess Alexandra Hospital, Woolloongabba, Queensland, Australia
  4. 4Department of Respiratory Medicine, Logan Hospital, Loganholme, Queensland, Australia
  5. 5National Pulmonary Hypertension Service, Hammersmith Hospital, London, UK
  6. 6National Heart and Lung Institute, Imperial College London, London, UK
  7. 7Sunshine Coast University Hospital, Sunshine Coast, Queensland, Australia
  1. Correspondence to Dr Chinthaka Bhagya Samaranayake; c.samaranayake{at}


Background Data on right ventricular (RV) exercise adaptation following acute intermediate and high-risk pulmonary embolism (PE) remain limited. This study aimed to evaluate the symptom burden, RV functional recovery during exercise and cardiopulmonary exercise parameters in survivors of intermediate and high-risk acute PE.

Methods We prospectively recruited patients following acute intermediate and high-risk PE at four sites in Australia and UK. Study assessments included stress echocardiography, cardiopulmonary exercise testing (CPET) and ventilation–perfusion (VQ) scan at 3 months follow-up.

Results Thirty patients were recruited and 24 (median age: 55 years, IQR: 22) completed follow-up. Reduced peak oxygen consumption (VO2) and workload was seen in 75.0% (n=18), with a persistent high symptom burden (mean PEmb-QoL Questionnaire 48.4±21.5 and emPHasis-10 score 22.4±8.8) reported at follow-up. All had improvement in RV-focused resting echocardiographic parameters. RV systolic dysfunction and RV to pulmonary artery (PA) uncoupling assessed by stress echocardiography was seen in 29.2% (n=7) patients and associated with increased ventilatory inefficiency (V̇E/V̇CO2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen desaturation (93.2% vs 98.4%, p=0.01) and reduced peak oxygen pulse (p=0.036) compared with controls. Five out of seven patients with RV–PA uncoupling demonstrated persistent bilateral perfusion defects on VQ scintigraphy consistent with chronic thromboembolic pulmonary vascular disease.

Conclusion In our cohort, impaired RV adaptation on exercise was seen in almost one-third of patients. Combined stress echocardiography and CPET may enable more accurate phenotyping of patients with persistent symptoms following acute PE to allow timely detection of long-term complications.

  • pulmonary embolism
  • exercise
  • primary pulmonary hypertension
  • imaging/CT MRI etc

Data availability statement

Data are available on reasonable request.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See:

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  • Several previous studies have shown that up to 50% of acute pulmonary embolism (PE) survivors report functional limitation, breathlessness and reduced quality of life, which has been termed post-PE syndrome.


  • Using a novel method of combining stress echocardiography with cardiopulmonary exercise testing, this study demonstrated the utility of exercise imaging techniques for assessing right ventricular (RV) functional adaptation during exercise following acute PE. The results for the first time demonstrate impaired exercise RV function and ventricular–vascular uncoupling in a significant proportion of patients, despite having normal RV function at rest.


  • Our results suggest the importance of incorporating exercise imaging modalities to accurately assess the RV adaptation during exercise for thorough non-invasive phenotyping of patients with persistent functional limitation and breathlessness following acute PE.


Acute pulmonary embolism (PE) has previously been regarded as a curable disease with the majority of individuals expected to make a full recovery with appropriate treatment. However, it is now recognised that the functional recovery following acute PE occurs in a wide spectrum, with up to 50% of PE survivors experiencing dyspnoea and impaired exercise capacity.1 2 Patients with intermediate or high-risk PE are recognised as a population with higher risk of incomplete right ventricular (RV) recovery and persistent functional impairment.3 4 Even though anatomical thrombus distribution does not significantly affect pulmonary vascular resistance acutely, proximal PE with a large thrombus burden may have a much greater impact on impedance to pulmonary blood flow and therefore the acute increase in RV afterload, which may impact on the RV recovery.5

Transthoracic echocardiography is a commonly used non-invasive follow-up investigation to detect complications after PE, and has good negative predictive value as a screening test for chronic thromboembolic pulmonary hypertension (CTEPH), when combined with clinical risk assessment and serum brain natriuretic peptide.6 7 However, echocardiography at rest can significantly underestimate the level of RV impairment and overlook impairment in contractile reserve during exercise.8 Additionally, patients with chronic thromboembolic disease without pulmonary hypertension (CTEPD), may have only mild changes in RV structure and function on resting transthoracic echocardiography.9

RV responses during exercise are closely associated with symptom burden and outcomes in patients with pulmonary arterial hypertension.10 11 Previous studies have demonstrated significant changes seen in RV reserve and RV to pulmonary artery (PA) coupling in patients with chronic thromboembolic disease spectrum.12 Non-invasive assessment of RV to PA uncoupling at rest with echocardiography using tricuspid annular plane systolic excursion (TAPSE) to right ventricular systolic pressure (RVSP) ratio is well validated in pulmonary hypertension,13 14 and has been introduced into the comprehensive risk assessment in the recent 2022 European Society of Cardiology/European Respiratory Society guidelines.15 Echocardiographic assessment of RV–PA coupling has also been shown to predict impaired exercise haemodynamics in patients with chronic thromboembolic disease.16 Specifically in PE, reduced TAPSE/RVSP in hospitalised patients during the acute event has been demonstrated to have prognostic significance.17 However, assessment of ventricular vascular coupling during exercise in patients following PE has received little attention. Cardiopulmonary exercise testing (CPET) is helpful for quantifying the physiological limitation following acute PE,18 and is a useful diagnostic test in patients with post-PE syndrome.19 However, studies investigating RV functional recovery following PE are limited and the utility of stress echocardiography for early detection of complications in this patient population remains unexplored.

We hypothesised that combining stress echocardiography with CPET will allow accurate non-invasive phenotyping of patients at risk of developing long-term complications following acute PE. This study aimed to prospectively investigate the persistent symptom burden, exercise capacity, RV structure and function during exercise and ventilation–perfusion (VQ) abnormalities at 3 months in survivors of intermediate and high-risk acute PE.


Study design and recruitment

This was a prospective multisite observational pilot study conducted between June 2020 and January 2022 at four sites: three centres from Australia and one from UK participated. Adult patients admitted with intermediate or high-risk acute PE were eligible. Patients with recurrent PE, significant cardiopulmonary comorbidities, active malignancy, unable to receive uninterrupted anticoagulation or unable to perform exercise testing were excluded. Study investigations were performed after at least 3 months of adequate anticoagulation.

Ethical approval for this study was granted by the Queensland Metro South Human Research Ethics Committee (HREC/2019/QMS/57882) for Australia and Health Research Authority Wales (REC 21/WA/0230) for UK. All participants provided written informed consent before study enrolment.

Study assessments

During the study assessment, all participants underwent clinical review, static lung function tests, resting transthoracic echocardiography, VQ scan and CPET with RV-focused stress echocardiography according to the study protocol as outlined below. Quality of life was assessed using the PE-specific PEmb-QoL Questionnaire20 21 and the emPHasis-10 Questionnaire in all patients.22 Patients who were diagnosed with deconditioning as the predominant contributor to breathlessness during the study assessment underwent an additional follow-up CPET after undergoing a period of rehabilitation at least 6 months after the initial PE.

Cardiopulmonary exercise testing

Maximal symptom-limited tests were performed on an upright cycle ergometer. After a 3‐min period of unloaded exercise and gas exchange measurement to ensure ventilatory equilibration, participants underwent a continuous ramp protocol (10–25 W/min) to volitional fatigue. Gas exchange data were measured breath‐by‐breath using commercially available metabolic carts at study sites. Heart rate was continuously recorded during exercise using a 12‐lead ECG system. Blood pressures were determined by automatic sphygmomanometer before exercise, at 3‐min intervals during exercise and recovery. Capillary blood gas analysis was performed during resting phase and at peak exercise, where available. BORG scores were recorded at rest and at peak exercise.

Stress echocardiography

Transthoracic echocardiogram at rest was performed according to the European/American Society of Echocardiography guidelines prior to exercise. RV-focused two-dimensional, colour Doppler, colour-flow-guided continuous-wave-Doppler and tissue Doppler echocardiographic examinations were performed immediately after peak exercise during the CPET, while the patient remained upright but stationary on the cycle ergometer according to the study protocol. The following echocardiographic variables were recorded pre and post exercise: basal RV diameter, RV dilatation (Y/N), RV systolic impairment (Y/N), tricuspid regurgitation (TR) velocity and estimated RVSP, TAPSE, tricuspid annular systolic velocity (S′), RV outflow Doppler acceleration time, RV outflow tract flow velocity envelope mid-systolic notching and quality of the images acquired. RV systolic dysfunction or elevated RVSP on echocardiography was assessed according to the guidelines,23 24 and was defined as the presence of one or more of: RV basal diameter >4.2 cm, TAPSE <1.6 cm, S′ <10 cm/s and TR velocity ≥2.8 m/s. Based on previous studies in healthy individuals, the RV–PA uncoupling was defined as TAPSE/RVSP <1.0 mm/mm Hg at rest and TAPSE/RVSP <0.6 mm/mm Hg at peak exercise.25–27 Impaired RV adaptation on exercise was defined as development of RV systolic dysfunction or RV–PA uncoupling during exercise.

Statistical analysis

Continuous variables were summarised as mean±SD or median and IQR. Pre and post exercise comparisons were performed using paired sample Wilcoxon signed-rank test. Between-group means were compared using independent sample Kruskal-Wallis tests with post-hoc pair-wise comparisons performed using the Mann-Whitney test. P value of <0.05 was used to establish statistical significance. Statistical analyses were performed using SPSS Statistics V.27 (IBM Corp, Armonk, New Y, USA).


Out of 136 patients screened, 34 were eligible for the study with four declining to participate. Thirty patients were prospectively recruited, and six were lost to follow-up. A total of 24 patients, median age 55 years (IQR: 22) underwent all the study investigations. Baseline clinical characteristics of the study cohort (n=24) are summarised in table 1. All patients had a history of intermediate or high-risk PE at baseline and received at least 3 months of adequate anticoagulation at the time of study assessments.

Table 1

Baseline characteristics of study participants with breathlessness following PE

Exercise assessments

RV parameters at the time of acute PE diagnosis and follow-up are summarised in table 2. During exercise, all patients had adequate image quality for subjective assessment of RV systolic function and basal diameter measurements. Reliable measurements of TAPSE and RVSP at peak upright exercise was available in 17 (70.8%) patients. RV systolic dysfunction and/or RV–PA uncoupling on exercise were seen in 7 (29.2%) patients (table 2).

Table 2

Echocardiographic RV parameters in study cohort

Detailed CPET parameters at rest and peak exercise are summarised in table 3. Reduced peak exercise workload and oxygen uptake was seen in 18 (75.0%) patients, and the patterns of abnormality observed during CPET are summarised in table 4. Impaired exercise RV adaptation (n=7) was associated with increased ventilatory inefficiency (V̇E/V̇CO2 slope 47.6 vs 32.4, p=0.03), peak exercise oxygen saturation (93.2% vs 98.4%, p=0.01) and reduced oxygen pulse (p=0.036). Eight patients diagnosed with deconditioning showed improvement in symptom burden, exercise capacity and peak oxygen consumption (VO2) during a following CPET at 6 months.

Table 3

Cardiopulmonary exercise test results: baseline and peak exercise measurements

Table 4

Causes of functional limitation 3 months after acute intermediate or high-risk PE

VQ scan

Five (20.8%) patients had bilateral or lobar perfusion defects on VQ scans after least 3 months of adequate anticoagulation, all of whom had impaired RV–PA coupling demonstrated on stress echocardiography. All patients with persistent perfusion defects underwent right heart catheterisation and diagnosed with CTEPH (n=1) or CTEPD (n=4). Two patients with evidence of exercise RV dysfunction and RV–PA uncoupling on echocardiography who had normal VQ scans were diagnosed with heart failure with preserved ejection fraction and exercise diastolic dysfunction following further clinical investigations. The combined approach of stress echocardiography and CPET had 100% sensitivity (95% CI: 47.8 to 100.0%) and 89.5% specificity (95% CI: 66.9% to 98.7%) for bilateral or lobar perfusion defects on VQ scans in our study.

Quality of life

This cohort had a high overall symptom burden and impaired quality of life with a mean PEmb-QoL Questionnaire score of 48.4 (SD: 21.5). PEmb-QoL Questionnaire scores and emPHasis-10 scores were elevated in patients irrespective of the cause of exercise limitation, with no significant difference between those with impaired RV adaptation during exercise on echocardiography versus others.


This study evaluated the clinical utility of a novel approach of combined RV-focused stress echocardiography and CPET for evaluating RV functional recovery in patients after acute intermediate and high-risk PE. Despite the presence of right heart strain at presentation with acute PE, all patients had improvement in RV size and function on resting echocardiography during follow-up. However, stress echocardiography demonstrated impaired RV function and RV–PA uncoupling in 29.2% of patients, all of whom had increased ventilatory inefficiency during exercise. The majority of patients with impaired RV adaptation during exercise had chronic thromboembolic disease spectrum (71.4%) in our cohort.

A large proportion of patients (75.0%) in our study had objective exercise limitation, reduced peak VO2 and a significant symptom burden associated with a reduced quality of life despite adequate anticoagulation treatment for at least 3 months. Our results show higher rates of functional impairment and symptom burden compared with previous patients with unselected PE.1 4 28 More specifically in patients with intermediate and high-risk PE, Albaghdadi et al reported a 60% incidence of impaired exercise capacity at 6 months, with most of the functional impairment attributed to deconditioning rather than intrinsic cardiopulmonary limitation.18 The lack of accurate assessment of change in dead-space ventilation during exercise may have underestimated the more subtle features of pulmonary vascular disease in that cohort, particularly given persistent RV impairment on resting echocardiography was demonstrated in 35% of patients.18 In our study, RV-focused stress echocardiography provided additional information on RV systolic response during exercise for more accurate phenotyping of patients. A further novel aspect was the demonstration of RV–PA uncoupling during exercise in patients who had chronic thromboembolic disease, suggesting persistent RV maladaptation during exercise contributing to symptoms despite normal resting echocardiographic parameters. Additionally, our results highlight the importance of accurate assessment of markers of dead-space ventilation on CPET to detect more subtle features of chronic thromboembolic disease as reduced peak VO2 and workload are commonly seen following intermediate and high-risk PE, both with and without chronic thromboembolic disease.

The feasibility of stress echocardiography to assess RV contractile reserve and RV–PA coupling has been established,26 27 29 and may have a role in early detection of pulmonary hypertension in at-risk patients. However, the lack of consensus on the threshold for normal responses in commonly used measures of RV function such as TAPSE/RVSP has prevented wider implementation in clinical practice.30An additional limitation of the more traditional supine or semisupine stress echocardiography is that supine exercise assessment does not predict ventricular performance during upright exercise.31 Therefore, measurements of RV performance used in the investigation of exertional breathlessness post-PE should be assessed during upright exercise, ideally with upright invasive CPET. A further consideration is measurements made during exercise recovery may be unreliable due to rapid normalisation of pulmonary pressures to baseline in more subtle cases of pulmonary vascular disease.29 Therefore, the assessments may be better performed at peak exercise. However, RV pressure–volume analysis with invasive upright CPET is not routinely available and difficult to perform outside expert centres and research settings. More recently, echocardiography has been shown to be a reliable alternative non-invasive imaging modality for this purpose, and has good agreement with invasive pulmonary pressure measurements during upright exercise, particularly in patients with high-quality TR Doppler signal.32

A strength of our study is that the echocardiography was assessed at peak upright exercise. We were able to obtain adequate image quality for subjective assessment of RV systolic function and basal diameter measurements on all patients, and reliable measurements of TAPSE and RVSP at peak upright exercise was possible in a large proportion (70.8%). We recruited patients and performed the study investigations at both district general hospitals and tertiary referral centres, which highlights the feasibility of the approach in variety of clinical settings. All CPETs were performed under both medical and physiologist supervision allowing the tests to be symptom-limited maximal tests, which reduced the possibility of submaximal effort confounding the results.

There are several limitations to this observational study. First, the cohort is small and difficult to draw strong conclusions, and the lack of external validation reduces the generalisability of the proposed approach. However, all patients included in this study were thoroughly phenotyped at baseline and during follow-up, which increases the reliability of the findings in this enriched cohort with intermediate and high-risk PE. To validate the findings of this pilot study, a large study recruiting patients with all risk categories of acute PE is required. Another limitation is the lack of premorbid exercise assessments; therefore, it is difficult to determine the degree of pre-existing functional impairment contributing to the results. Exclusion of patients with underlying cardiopulmonary comorbidities, active malignancy or recurrent PE would have introduced selection bias, however the strict eligibility criteria allowed the investigators to obtain a complete set of unconfounded data and reduced the impact of pre-existing functional limitation on the results. Additionally, the reliability of stress echocardiographic assessment of RV–PA uncoupling in patients with poor TR Doppler signal is low. Accurate assessment of RV systolic function during exercise in patients with inadequate image quality is often challenging and therefore the utility of stress echocardiography in some patients will be limited. A matched non-PE control group would have provided more insights into how much of the exercise limitation is directly attributable to PE. Although this study provides early evidence to support the role of non-invasive functional tests for more selected use of imaging modalities with ionising radiation in post-PE follow-up, the negative predictive value of this approach needs to be established in larger studies. Additionally, the generalisability of this approach maybe limited due to lack of availability of CPET in all clinical settings. Functional recovery following PE in some patients can be prolonged and therefore longer durations of follow-up need to be considered in future larger studies. Longer duration of follow-up will also allow us to determine the prognostic value of impaired RV adaptation during exercise at early stages of disease evolution in chronic thromboembolic disease.

In summary, this is the first study to assess RV function during exercise following acute intermediate and high-risk PE. Even though most patients had recovery of RV dilatation and systolic impairment at rest, 29.2% had RV systolic impairment and RV–PA uncoupling during exercise. Combined stress echocardiography and CPET allowed accurate non-invasive phenotyping of patients with persistent breathlessness following acute PE, and is a potential approach that requires validation in larger cohorts.

Data availability statement

Data are available on reasonable request.

Ethics statements

Patient consent for publication

Ethics approval

Ethical approval for this study was granted by the Queensland Metro South Human Research Ethics Committee (HREC/2019/QMS/57882) for Australia and Health Research Authority Wales (REC 21/WA/0230) for UK. Participants gave informed consent to participate in the study before taking part.


The authors would like to thank the following colleagues for their contribution to this study: Jaron Warner, Scientific Director, Respiratory Laboratory, Princess Alexandra Hospital. Sharna Wilkinson, Scientific Director, Respiratory Laboratory, Logan Hospital. Carly Hughes, Director of Cardiac Investigations, Logan Hospital. Serena Rhamie, Chief Respiratory Physiologist, Lung Function, Royal Brompton Hospital.



  • CM and GJK contributed equally.

  • Contributors All authors contributed to the conception, design and conduct of the study. CBS, CM and GJK performed statistical analysis. CBS, CM, ML, WL and GJK drafted the first version of the manuscript, and all authors contributed to editing the manuscript. CBS compiled edits, and all authors read and approved the final manuscript. CBS acts as the guarantor of this manuscript.

  • Funding Australian component of this study was funded by an internal project grant from Metro South Hospital and Health Service SERTA, Queensland Health.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.