Regular ArticleInefficient exercise gas exchange identifies pulmonary hypertension in chronic thromboembolic obstruction following pulmonary embolism
Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) lies within Group IV of the Dana Point classification of pulmonary hypertension (PH) and may be an uncommon sequela of acute pulmonary embolism (PE) [1], [2], [3], [4], [5], [6]. However, up to 75% of patients with CTEPH suffer an antecedent PE with presentation occurring often months after acute thrombotic insult despite a period of therapeutic anticoagulation [7], [8]. Patients present with effort dyspnoea predominantly related to incapacity of the right ventricle (RV) to increase cardiac output on exercise. Untreated this condition typically leads to progressive RV dysfunction and death so early detection, ideally using non-invasive methods, prior to physiological decompensation may be advantageous.
CTEPH is haemodynamically defined by a resting mean pulmonary artery pressure (mPAP) > 25 mmHg at right heart catheterisation in the presence of chronic thromboembolic pulmonary vascular obstruction confirmed by radiological criteria [9]. However despite exercise related symptoms, a proportion of patients demonstrate mPAP values < 25 mmHg at rest despite persistent chronic pulmonary thromboembolic obstructions. These patients may be labelled as having chronic thromboembolic disease (CTED) and usually present with preserved resting RV contractility and normal cardiac chamber morphology. Hence, investigations conducted at rest such as echocardiography may lack power to detect changes suggestive of progression to CTEPH. Assessment of potential attenuation in cardiac output on exercise therefore requires an exercise-based assessment method.
Cardiopulmonary exercise testing (CPET) demonstrates a characteristic profile in pulmonary arterial hypertension (PAH) [10], [11]. However patients with chronic thromboembolic obstruction are less well described. Six minute walk distance (6MWD) reflects haemodynamic severity in CTEPH but does not inform on mechanisms of exercise limitation [12]. Therefore, we hypothesised that CPET could be used to differentiate the exercise profiles of patients with CTED and CTEPH compared to sedentary controls. Following this, we aimed to establish which exercise parameters were predictive of a diagnosis of CTEPH and potentially therefore of value in the follow up of patients with unresolved PE who are at risk of deterioration. To account for a potential association between proximal thrombotic burden and pulmonary haemodynamics, we quantified thrombotic obstruction in these groups to evaluate for any effect of greater thrombotic load.
Section snippets
Study Protocol
Patients underwent incremental symptom limited CPET and right heart catheterisation (RHC) within 72 hours. Radiological evaluation with CT pulmonary angiogram was carried out prior to RHC in patients with CTED and CTEPH to confirm a radiological pattern consistent with chronic thromboembolic obstruction. Patients with chronic thromboembolic obstruction were grouped by diagnosis following RHC: mPAP > = 25 mmHg (CTEPH), mPAP < 25 mmHg (CTED) and compared with age and sex-matched sedentary controls
Subject Characteristics
Demographics and RHC data are shown in Table 1. At RHC, 15 patients fulfilled diagnostic criteria for CTEPH. A further 15 had a resting mean pulmonary artery pressure < 25 mmHg despite substantial thrombotic burden. Compliance, estimated using the pulse pressure method, was lower in CTEPH. There were 12 ex-smokers in total although none had greater than a 10 pack year smoking exposure. No patients with CTED or CTEPH were taking supplemental oxygen. Patients with CTED and CTEPH suffered both acute
Discussion
Our results describe changes in peak exercise gas exchange and ventilatory efficiency in patients with confirmed chronic thromboembolic obstruction following PE stratified by haemodynamic criteria for pulmonary hypertension. Vd/Vt at peak predicts a diagnosis of CTEPH in this setting with acceptable sensitivity and specificity. Furthermore, Aa gradient at peak exercise and Ve/VCO2 (AT) harbour similar predictive value. Reduced exercise capacity in CTED and CTEPH and elevated Ve/VCO2 ratio
Conclusions
The major finding of this study was the distinction on CPET between patients with chronic thromboembolic obstruction with and without PH compared to sedentary controls. The mechanism of exercise impairment in CTED centres on impaired RV adaptation on exercise without apparent significant influence from the degree of proximal thromboembolic obstruction. CPET, unlike routinely employed exercise assessments such as 6MWD, offers diagnostic insight into patients suffering persistent symptoms after
Disclosures
JPZ has received reimbursements of travel expenses to congresses and speakers’ fees from Actelion, Pfizer, Glaxo, Bayer, LungRX and United Therapeutics, has participated to advisory boards for Actelion, Bayer, Pfizer, GSK, United Therapeutics, and has received funds for research from Actelion and Pfizer. All other authors have no significant conflicts of interest.
Acknowledgements and Support Statement
CM is the principle writer of the manuscript, designed the study, performed the statistical analysis and created the tables and figures. GD performed the CPET analyses and contributed to writing of the manuscript. IH performed the CPET testing and contributed to the manuscript preparation. RMR assisted in the statistical design and contributed to the data analysis and manuscript preparation. DG and NS performed the CT pulmonary angiography analysis. JPZ reviewed the manuscript, contributed to
References (37)
- et al.
Incidence of chronic pulmonary hypertension in patients with previous pulmonary embolism
Thromb Res
(2009) - et al.
Incidence of chronic thromboembolic pulmonary hypertension after a first episode of pulmonary embolism
Chest
(2006) - et al.
Chronic thromboembolic pulmonary hypertension
Clin Chest Med
(1995) - et al.
Updated clinical classification of pulmonary hypertension
J Am Coll Cardiol
(2009) - et al.
Reproducibility of cardiopulmonary exercise measurements in patients with pulmonary arterial hypertension
Chest
(2004) - et al.
Six-minute walk distance as parameter of functional outcome after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension
J Thorac Cardiovasc Surg
(2007) - et al.
Differences in ventilatory inefficiency between pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
Chest
(2011) Ventilation-perfusion inequality and overall gas exchange in computer models of the lung
Respir Physiol
(1969)- et al.
Pulmonary gas exchange and exercise performance in pulmonary hypertension
Chest
(1985) - et al.
Right ventricular load at exercise is a cause of persistent exercise limitation in patients with normal resting pulmonary vascular resistance after pulmonary endarterectomy
Chest
(2011)
Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients
Ann Thorac Surg
Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism
N Engl J Med
Survival and restoration of pulmonary perfusion in a long-term follow-up of patients after acute pulmonary embolism
Medicine
Patient outcomes after acute pulmonary embolism. A pooled survival analysis of different adverse events
Am J Respir Crit Care Med
Incidence of recurrent venous thromboembolism and of chronic thromboembolic pulmonary hypertension in patients after a first episode of pulmonary embolism
J Thromb Thrombolysis
Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry
Circulation
Exercise pathophysiology in patients with primary pulmonary hypertension
Circulation
ATS/ACCP Statement on cardiopulmonary exercise testing
Am J Respir Crit Care Med
Cited by (0)
- 1
JPZ is the overall guarantor of the manuscript.