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Abstract
Background Pulmonary endarterectomy (PEA) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH), while balloon pulmonary angioplasty (BPA) is an alternative for inoperable patients. We aimed to compare right ventricular (RV) remodelling and late survival after PEA and BPA.
Methods In this prospective observational cohort study, we performed echocardiography at baseline and follow-up in patients with CTEPH treated with PEA (n=54) or BPA (n=44) between 2011 and 2022.
Results Follow-up echocardiography was performed at 5 months (IQR 4–7) after PEA and 3 months (IQR 2–4) after the last BPA. Both groups showed significant improvements in left ventricular end-systolic eccentricity index, RV basal diameter and RV fractional area change (RV FAC). Tricuspid regurgitation pressure decreased by 26±18 mm Hg after PEA and 13±21 mm Hg after BPA (p=0.02 for between-group difference). Tricuspid annular systolic excursion (TAPSE) decreased by 4±5 mm after PEA but increased by 1±4 mm after BPA (p<0.001). The TAPSE/systolic pulmonary artery pressure ratio improved similarly in both groups. Five-year survival was 96% (95% CI 86% to 99%) for PEA and 79% (95% CI 61% to 89%) for BPA (p=0.25). Change in RV FAC was an independent predictor of survival (HR 0.9, 95% CI 0.82 to 0.99, p=0.03).
Conclusions Both PEA and BPA led to significant RV reverse remodelling, with no clear evidence of a difference in survival rates. Improvement in RV function, particularly RV FAC, was associated with better outcomes, highlighting the importance of RV recovery in CTEPH treatment.
- pulmonary arterial hypertension
- pulmonary embolism
- cardiac surgical procedures
- treatment outcome
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
Chronic thromboembolic pulmonary hypertension (CTEPH) carries high morbidity and mortality.
Pulmonary endarterectomy (PEA) and balloon pulmonary angioplasty (BPA) reduce pulmonary pressures and improve functional capacity.
WHAT THIS STUDY ADDS
This study demonstrates excellent long-term survival, with similar improvements in right ventricular (RV) geometry and function after BPA as well as PEA.
The change in RV fractional area was independently associated with survival.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
This study adds to the increasing body of data suggesting that BPA is a good alternative to PEA in patients with CTEPH who are deemed unsuitable for surgery.
Introduction
Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disorder. The reported yearly incidence is approximately 3–5 cases per 100 000 persons in the USA and Europe, whereas the incidence seems to be lower in Japan.1 Untreated CTEPH can lead to progressive right ventricular (RV) failure and eventual death. Three-year survival in untreated patients is <70%.2 Higher pulmonary artery pressures are associated with increased mortality.3 The treatment of choice for CTEPH is pulmonary endarterectomy (PEA), which improves mortality and is potentially curative.2 Balloon pulmonary angioplasty (BPA) is a treatment alternative for up to 40% of patients who are inoperable. Multiple studies demonstrate improvements of haemodynamics and functional capacity after BPA.4–7 In the 2022 guidelines for the diagnosis and treatment of pulmonary hypertension from the European Society of Cardiology and the European Respiratory Society,8 PEA is recommended as first-line treatment in operable patients. On the other hand, BPA is recommended in technically inoperable patients, and in case of residual pulmonary hypertension after PEA (both with recommendation class I, evidence level B).
The current understanding of the pathophysiological mechanism behind CTEPH is incomplete resolution and fibrotic transformation of the thromboembolic material.9 In addition to the resulting large vessel disease, a secondary pulmonary microangiopathy is present in both obstructed and non-obstructed parts of the pulmonary vasculature. This microangiopathy is characterised by smooth muscle hypertrophy, intimal fibrosis and plexiform lesions,10 similar to the histopathological changes seen in pulmonary arterial hypertension. The resulting chronic pressure overload leads to RV hypertrophy and ventriculoarterial decoupling, leading to progressive RV dilatation and decompensation.11 CTEPH represents a unique opportunity to study the effects of pressure overload on the RV, because removal of the obstruction facilitates rapid unloading of the right heart. Several studies describe RV reverse remodelling after PEA.12–16 Reports on RV remodelling after BPA are fewer.17–19
Few studies describe RV remodelling in both BPA and PEA from the same centre. As far as we are aware, only one other study has combined such results with survival analyses.20 In this study, we aimed to quantify and compare echocardiographic parameters of right heart remodelling after PEA and BPA, and explore the relationship between right heart remodelling and long-term prognosis after BPA or PEA in patients with CTEPH.
Methods
Patient cohort and treatment selection
Our centre has national responsibility for the treatment of CTEPH in Norway. We included patients who were treated for CTEPH at our centre between 2011 and 2022. All patients underwent right heart catheterisation, CT pulmonary angiography, conventional pulmonary angiography, echocardiography and cardiopulmonary exercise testing. Patients were evaluated by our CTEPH team, including cardiologists, cardiothoracic surgeons, radiologists and anaesthesiologists. Operable patients were offered PEA. Patients deemed inoperable, or who declined PEA, were offered BPA. We performed follow-up examination 3 months after the last BPA session and 5 months after PEA. The reason for the longer follow-up interval after PEA was to allow for proper rehabilitation after cardiothoracic surgery, as we also analysed peak oxygen consumption before and after treatment.21
Transthoracic echocardiography
Echocardiography was performed at our echocardiography lab as part of the routine clinical follow-up. Images were acquired using a GE Vivid E9 or E95 scanner (GE Vingmed Ultrasound, Horten, Norway). All images were reanalysed post hoc for the present study by a single observer (HR), who was blinded to the baseline data and clinical characteristics of each patient. Left ventricular (LV) dimensions were measured in the left parasternal view. The LV end-systolic eccentricity index was calculated by dividing the anteroposterior and transverse inner diameter of the left ventricle, measured in the left parasternal short axis view at the level of the papillary muscles in end-systole. Right atrial (RA) and RV dimensions, RV free wall strain, tricuspid annular systolic excursion (TAPSE) and lateral tricuspid annular peak systolic velocity were measured in an RV-focused apical four-chamber view. Tricuspid regurgitation pressure (TRP) was estimated by Doppler measurement of the peak tricuspid valve regurgitation jet velocity from the apical four-chamber view. LV stroke volume was measured by pulsed wave Doppler in the LV outflow tract from the apical four-chamber view. Free wall thickness was measured using M-mode from the subcostal view. We performed the analyses according to the 2015 recommendations for cardiac chamber quantification22 and the 2010 guidelines for echocardiographic assessment of right heart in adults,23 from the American Society of Echocardiography.
Right heart catheterisation
Right heart catheterisation was performed at baseline and follow-up. We inserted a Swan-Ganz catheter (Edwards Lifesciences, Irvine, California, USA) via the internal jugular vein. We recorded pressures from the right atrium, the right ventricle, the pulmonary artery and in the pulmonary artery wedge position. Cardiac output was measured three times by thermodilution (five times in case of atrial fibrillation). We obtained blood samples for mixed venous oxygen saturation from the pulmonary artery.
Pulmonary endarterectomy
We performed a median sternotomy, and established cardiopulmonary bypass. The patient was cooled to 20°C. The pulmonary artery was incised, and subintimal dissection was performed, removing the thromboembolic material. Deep hypothermic circulatory arrest was started after the initial subintimal dissection, and continued for a maximum of 20 min. The arteriotomy was closed, and cardiopulmonary bypass resumed. The procedure was then repeated on the contralateral side.
Balloon pulmonary angioplasty
The procedure has been previously described in detail.24 Briefly, venous access was via the femoral vein. A guide catheter was advanced to the pulmonary arteries. Balloon catheters were advanced over a guide-wire to the stenotic or occluded pulmonary artery. After demonstrating stenosis by super-selective angiography, the balloon was inflated. Angiography was repeated after deflation to verify the successful effect of BPA and exclude vessel perforation. A maximum of three pulmonary segments were treated in any one session, to reduce the risk of vascular injury. The procedure was repeated every 5–8 weeks until all available stenotic segments were treated or pressure was normalised.
Statistical analysis
Data are presented as mean±SD unless otherwise specified. Differences in variables that were approximately normally distributed were calculated using Student’s t-test. We analysed differences in categorical variables using Fischer’s exact test. A two-sided p value of <0.05 was considered statistically significant. Survival analysis was performed using univariable and multivariable Cox proportional hazards regression. Survival was analysed from the time of diagnosis (ie, the time of diagnostic right heart catheterisation), to avoid bias when comparing the treatment modalities. The proportional hazards assumption was tested by visual assessment of the Kaplan-Meier curves. All statistical analyses were performed using STATA V.17.0 SE (StataCorp, College Station, Texas, USA).
Patient and public involvement
Patients were not involved in the planning of this study.
Results
A total of 54 patients were treated with PEA, and 44 patients with BPA. Figure 1 shows an overview of patient recruitment and follow-up, including loss to follow-up. The reason for inoperability was peripheral lesion distribution (n=26), significant comorbidity (n=7), patient choice (n=2) and residual pulmonary hypertension after prior PEA (n=9). Table 1 shows baseline characteristics for patients treated with PEA and patients treated with BPA as first-line treatment (n=35). Most patients were not on pulmonary arterial hypertension-specific medical therapy at baseline.
Overview of patient recruitment and follow-up. BPA, balloon pulmonary angioplasty; CTEPH, chronic thromboembolic pulmonary hypertension; PEA, pulmonary endarterectomy; PH, pulmonary hypertension.
Population characteristics at baseline
The median time from PEA or last BPA procedure to follow-up echocardiography was 5 months (IQR 4–7) in the PEA group, and 3 months (IQR 2–4) in the BPA group. Changes in echocardiographic parameters between baseline and follow-up are shown in table 2. LV dimensions increased after treatment in both groups. The LV eccentricity index increased.
Changes in echocardiographic parameters
TRP fell in both groups, but the improvement was larger in patients treated with PEA. RV dimensions improved in both groups. RV systolic function as measured by fractional area change (FAC) improved in both groups. TAPSE did not change significantly after BPA, but was significantly reduced after PEA. The ratio of TAPSE to systolic pulmonary artery pressure (TAPSE/sPAP ratio) improved in both groups. Improvements in pulmonary artery pressures and pulmonary vascular resistance (PVR) were significantly larger in the PEA group compared with the BPA group. An overview of haemodynamic changes from baseline to follow-up is available in online supplemental file 1.
Supplemental material
Figure 2 shows echocardiographic images from one patient, demonstrating change in LV eccentricity index and RV dimensions before and after PEA. Figure 3 shows the change in RV basal diameter and RV free wall strain plotted against the relative change in PVR. There were moderate but significant correlations between the change in RV basal diameter and the percentage change in PVR (R=0.33, p=0.003) and between the change in RV free wall strain and the percentage change in PVR (R=0.36, p=0.009).
Example images taken from the same patient before and after pulmonary endarterectomy. (A) Left ventricular (LV) end-systolic eccentricity index at baseline of 0.48. (B) LV end-systolic eccentricity index at follow-up has improved to 0.95. (C) Right ventricular (RV) end-diastolic diameter at baseline. (D) RV end-diastolic diameter at follow-up.
(A) Scatter plot of the change in right ventricular (RV) basal diameter relative to the percentage change in pulmonary vascular resistance (PVR) in all patients. The solid line represents the linear regression line. (B) Scatter plot of the change in RV free wall strain relative to the percentage change in PVR in all patients. The solid line represents the linear regression line.
Figure 4 shows Kaplan-Meier estimates of patient survival from the time of diagnosis for patients stratified by treatment group. The 30-day mortality was 3.7% in the PEA group (n=2) and 2.3% (n=1) in the BPA group. Over the study period, six patients died in the PEA group and eight patients in the BPA group. Median observation time was 6 years (IQR 3–9). Estimated survival at 3, 5 and 10 years was 96% (95% CI 86% to 99%), 96% (95% CI 86% to 99%) and 80% (95% CI 58% to 91%) in the PEA group and 89% (95% CI 72% to 96%), 79% (95% CI 61% to 89%) and 75% (95% CI 56% to 87%) in the BPA group. There were no deaths in the subset of patients who were treated with BPA after prior PEA. There were no differences in survival between treatment groups (p=0.25). Table 3 shows the results of univariable and multivariable Cox regression for the entire cohort.
Univariable and multivariable Cox regression for all-cause mortality
Kaplan-Meier plot of long-term survival from time of diagnosis, stratified by treatment group. BPA, balloon pulmonary angioplasty; PEA, pulmonary endarterectomy.
On univariable Cox regression, age and the change in RV FAC were significant predictors of survival. When performing a multivariable Cox regression, only the change in RV FAC remained a significant predictor of survival.
Discussion
In an attempt to standardise the BPA procedure, a clinical consensus statement was recently published by a working group of the European Society of Cardiology.25 Despite an increasing number of publications on BPA in last 5 years, more data are still needed on long-term outcomes after BPA. The best treatment option in patients with location of thrombi intermediary between those optimal for PEA and for BPA is still unknown. While a true comparison of PEA and BPA can only be performed in a large multicentre randomised clinical trial, our single-centre observational study demonstrates similar improvements of RV dimensions and function after either procedure. Long-term survival was excellent in both groups, with improvement in RV FAC as an independent predictor of survival.
TAPSE did not change significantly after BPA, but was reduced after PEA. TAPSE measures longitudinal systolic motion of the RV, and is among the most widely used echocardiographic parameters of RV systolic function. In normal subjects, about 75% of the RV cardiomyocytes are longitudinally oriented.11 In line with this, there is evidence that longitudinal shortening accounts for the majority of RV systolic function in healthy individuals.26 Reduction of TAPSE after cardiac surgery is a well-known phenomenon. Tamborini et al demonstrated that despite worsening of longitudinal RV function after surgery, real-time three-dimensional ejection fraction was unchanged.27 Unsworth et al showed that the reduction in RV longitudinal motion occurs within minutes after pericardiotomy.28 Zanobini et al found a significantly larger reduction in TAPSE with anterior pericardiotomy compared with a lateral approach.29 This might point to loss of structural support from the pericardium as a possible mechanism behind reduced longitudinal RV function. Reduced TAPSE has also been reported after PEA, and while there is a trend towards improvement over time, TAPSE does not reach normal levels 12 months after surgery.13 30
The ratio of TAPSE/sPAP has been proposed as a non-invasive marker of RV-pulmonary artery coupling. The TAPSE/sPAP ratio improved in both groups in our study, despite reduction in TAPSE in the PEA group, reflecting the significant improvement of pulmonary artery pressures. The fact that TAPSE is reduced after PEA despite improvement of RV dimensions and function suggests that the TAPSE/sPAP ratio might be less useful as a measure of RV-pulmonary artery coupling after PEA compared with other non-surgical pulmonary hypertension cohorts.
We demonstrate increased LV end-diastolic dimensions in both groups at follow-up, as well as improved LV end-systolic eccentricity index. These observations point to improved LV working conditions by dual mechanisms: improved LV geometry on account of reduced RV pressures, and increased LV preload as a result of improved RV systolic function.
Long-term survival was excellent in both groups, with no difference in survival between the BPA group and the PEA group. The only independent predictor of survival in our study was the change in RV FAC from baseline to follow-up, strongly suggesting that RV reverse remodelling is associated with improved survival.
The current study has some limitations. First, this is a single-centre study, and the number of patients is relatively small, increasing the risk of a type II error. Second, we report echocardiographic changes at follow-up after 3–5 months. Further changes might be present at a later stage. Third, the chosen difference in median time from treatment to follow-up between the PEA group and the BPA group might influence comparisons. The PEA group had longer time from completion of treatment for reverse remodelling to occur, while BPA treatment is performed over a longer period. Hence, the time since the last procedure alone might not reflect the true time course of RV remodelling in patients with BPA. Fourth, very few patients in our study were treated with riociguat. Following the publication of theRACE trial in 2022,31 riociguat is recommended before BPA in patients with unfavourable haemodynamics.8 Lastly, our study is observational, and does not allow causal interpretations of the observed differences between the groups.
In conclusion, our study demonstrates similar RV reverse remodelling after BPA and PEA, with no clear evidence of a difference in survival rates. Although PEA remains the gold standard treatment for CTEPH, our findings add to the data suggesting that BPA is a good alternative for selected patients.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
Ethics statements
Patient consent for publication
Ethics approval
This study was approved by the Norwegian Regional Committee for Medical and Health Research ethics, South-East (application number 454247). This study was performed in accordance with the Declaration of Helsinki. The ethics committee gave an exemption from the requirement for prior written consent. All patients were given written information about the research project, with the option to decline participation.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Presented at An abstract of this manuscript was presented at Heart Failure conference, 20–23 May 2023, in Prague, Czechia (Abstracts of the Heart Failure 2023 and the World Congress on Acute Heart Failure, 20–23 May 2023, Prague, Czechia. Eur J Heart Fail. 2023 Jul;25 Suppl 2:3-457. doi: 10.1002/ejhf.2927. PMID: 37415090).
Contributors HR is the guarantor for this manuscript. HR, AKA, KB and J-PEK produced the initial draft of the manuscript. KM, NM, RA, MS, EGj, SB, PSL, EGu and LG helped interpret the data and provided substantial revision of the manuscript. All authors have revised the manuscript, and have approved the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.