Elsevier

Thrombosis Research

Volume 132, Issue 6, December 2013, Pages 659-665
Thrombosis Research

Regular Article
Inefficient exercise gas exchange identifies pulmonary hypertension in chronic thromboembolic obstruction following pulmonary embolism

https://doi.org/10.1016/j.thromres.2013.09.032Get rights and content

Abstract

Introduction

Persistent obstruction in the pulmonary artery following acute pulmonary embolism (PE) can give rise to both chronic thromboembolic pulmonary hypertension (CTEPH) and chronic thromboembolic disease without PH (CTED). We hypothesised that cardiopulmonary exercise testing (CPET) may be able to differentiate patients with CTEPH and CTED following unresolved PE which may help guide patient assessment.

Materials and Methods

Fifteen patients with CTEPH and 15 with CTED all diagnosed after PE underwent CT pulmonary angiography, CPET and resting right heart catheterisation. Exercise variables were compared between patients with CTEPH, CTED and 10 sedentary controls and analysed as predictors of a CTEPH diagnosis. Proximal thrombotic burden in CTEPH and CTED was quantified using CT criteria.

Results

Physiological dead space (Vd/Vt) (34.5 ± 11.4 vs 50.8 ± 6.6 %, p < 0.001) and alveolar-arterial oxygen gradient (29 ± 16 vs 46 ± 12 mmHg, p < 0.001) at peak exercise strongly differentiated CTED and CTEPH groups respectively. Resting ventilatory efficiency also differed from control subjects. In both univariate and multivariate analyses, peak exercise Vd/Vt predicted a diagnosis of CTEPH (ROC AUC > 0.88, 0.67 - 0.97) despite a similar degree of proximal thrombotic obstruction to the CTED group (67.5, 55 - 70% and 72.5, 60 - 80% respectively, p = 0.08).

Conclusions

Gas exchange at peak exercise differentiates CTED and CTEPH after PE that can present with no apparent relation to the degree of proximal thrombotic burden. A potential role for CPET exists in guiding further clinical investigations in this setting.

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

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