Article Text

Original research
Restoration of right ventricular function in the treatment of pulmonary arterial hypertension
  1. Lucas R Celant1,2,
  2. Jeroen N Wessels1,2,
  3. Azar Kianzad1,2,
  4. J Tim Marcus2,3,
  5. Lilian J Meijboom2,3,
  6. Harm Jan Bogaard1,2,
  7. Frances S de Man1,2,
  8. Anton Vonk Noordegraaf1,2
  1. 1 Department of Pulmonary Medicine, Amsterdam UMC, location Vrije Universiteit, Amsterdam, Netherlands
  2. 2 Pulmonary Hypertension and Thrombosis, Cardiovascular Sciences, Amsterdam, the Netherlands
  3. 3 Department of Radiology and Nuclear Medicine, Amsterdam UMC, location Vrije Universiteit, Amsterdam, Netherlands
  1. Correspondence to Professor Anton Vonk Noordegraaf, VU Medisch Centrum, Amsterdam, 1117, Netherlands; a.vonk{at}amsterdamumc.nl

Abstract

Objective A 45% threshold of right ventricular ejection fraction (RVEF) is proposed clinically relevant in patients with pulmonary arterial hypertension (PAH). We aim to determine treatment response, long-term right ventricular (RV) functional stability and prognosis of patients with PAH reaching or maintaining the RVEF 45% threshold.

Methods Incident, treatment-naive, adult PAH patients with cardiac magnetic resonance imaging at baseline and first follow-up were included (total N=127) and followed until date of censoring or death/lung transplantation. Patients were categorised into two groups based on 45% RVEF. Baseline predictors, treatment response and prognosis were assessed with logistic regression analyses, two-way analysis of variance and log-rank tests.

Results Patients were 50±17 years old, 73% female, of which N=75 reached or maintained the 45% RVEF threshold at follow-up (RVEF≥45%@FU), while N=52 patients did not (RVEF<45%@FU). RV end-diastolic volume and N-terminal pro-B-type natriuretic peptide at baseline were multivariable predictors of an RVEF ≥45% at follow-up. A 40% pulmonary vascular resistance (PVR) reduction resulted in greater improvement in RV function (ΔRVEF 17±11 vs. 5±8; pinteraction<0.001) compared to a PVR reduction <40%, but did not guarantee an RVEF ≥45%. Finally, the 45% RVEF threshold was associated with stable RV function during long-term follow-up and better survival (HR: 1.91 (95% CI: 1.11 to 3.27)). Patients failing to reach or maintain the 45% RVEF threshold at first follow-up mostly stayed below this threshold over the next consecutive visits.

Conclusion After treatment initiation, 60% of patients with PAH reach or maintain the 45% RVEF threshold, which is associated with a long-term stable RV function and favourable prognosis.

  • Pulmonary Arterial Hypertension
  • Heart Failure

Data availability statement

Data are available upon reasonable request. Certain requests can be done by contacting the first/corresponding author.

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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: http://creativecommons.org/licenses/by-nc/4.0/.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Preservation of right ventricular (RV) function in patients with pulmonary arterial hypertension (PAH) is of great clinical importance since it determines morbidity and mortality.

WHAT THIS STUDY ADDS

  • Treatment-naive patients with PAH reaching a 45% right ventricular ejection fraction (RVEF) mostly remain above this threshold during long-term follow-up and have a favourable prognosis. Patients that fail to reach a 45% RVEF rarely exceed this threshold and are more likely to experience a clinical event related to progressive RV failure.

  • Exceeding 40% pulmonary vascular resistance (PVR) reduction guarantees improvement in RV function.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

  • Current findings advocate for a treatment strategy aiming for at least a reduction of 40% in PVR in the first year to improve the RV and survival.

  • The 45% RVEF threshold as treatment target results in survival benefit and long-term RV functional stability.

Introduction

Pulmonary arterial hypertension (PAH) is characterised by progressive remodelling of the pulmonary vasculature resulting in right ventricular (RV) pressure overload.1 Preservation of RV function in patients with PAH is of great clinical importance since it determines morbidity and mortality.2 The general treatment goal in patients with PAH is to reduce the afterload of the right ventricle to improve RV function and maintain stability in the long-term.3 Cardiac magnetic resonance (CMR) imaging is the recognised gold standard for assessment of RV function.4 The prognostic value of CMR at baseline and during follow-up has been established in patients with PAH.5–8 Based on clinical and physiological studies, a threshold of 45% for the right ventricular ejection fraction (RVEF) is considered clinically relevant in patients with PAH, whereas an RVEF below 45% at follow-up is associated with poor outcome.9 10 Additionally, in non-PH conditions, a similar threshold for RVEF was found.11–16 Nevertheless, recent ESC/ERS 2022 guidelines propose an RVEF 54% cut-off for identifying patients at low risk of 1-year mortality at baseline.17 This cut-off is based on a single-centre study and requires external validation. At present, more extensive rationale is provided to use an RVEF 45% cut-off. However, the treatment response and long-term benefit of patients that reach an RVEF of 45% or maintain their RVEF above this threshold are currently elusive. In this study, we aim to understand the impact of RV baseline conditions and unloading in reaching the RVEF 45% threshold and in particular how this translates to long-term RV functional stability and prognosis.

Methods

Study design and patient selection

This study retrospectively analysed data from incident patients with PAH diagnosed between 2000 and 2020 at the Amsterdam UMC, location VUmc, the Netherlands, a tertiary referral centre for PAH. All patients routinely underwent right-sided heart catheterisation (RHC) and CMR for clinical purposes. These measurements were repeated during follow-up at the discretion of the treating pulmonologist. This study did not fall within the scope of the Medical Research Involving Human Subjects act. No informed consent or additional approval was required (confirmed by the Medical Ethics Review Committee of the VU University Medical Centre: approval number 2012288).

All patients were assessed for eligibility by the following criteria: (1) newly diagnosed patients with PAH, (2) age ≥18 years, (3) treatment-naive, (4) available CMR at baseline and 1-year follow-up (0.5–1.5 years), (5) initiation of PAH-specific treatment. Baseline RHC and CMR were performed within a maximum time interval of 2 weeks, most patients had their CMR and RHC on the same day. Patients with inferior quality CMR images were excluded from this analysis. In total, 127 patients with PAH diagnosed between 2000 and 2020 fulfilled the study criteria and were included in the present study. An overview of study participant selection is presented in online supplemental figure 1.

Supplemental material

Right heart catheterisation

Haemodynamic assessment was performed with a balloon-tipped, flow-directed, 7.5F triple-lumen Swan-Ganz catheter (Edwards Lifesciences LLC, Irvine, California, USA). Measured parameters include mean pulmonary arterial pressure (mPAP), right atrial pressure (RAP), pulmonary arterial wedge pressure (PAWP), heart rate and mixed venous oxygen saturation (SvO2). Cardiac output (CO) was measured by direct Fick or thermodilution method. CO was indexed to body surface area (BSA) shown as cardiac index (CI). Pulmonary vascular resistance (PVR) was derived as followed: PVR=80×(mPAP – PAWP)/CO.

Cardiac magnetic resonance

Imaging was performed on a 1.5T Avanto or Sonata scanner equipped with a 6-element phased array coil (Siemens Medical Solutions, Erlangen, Germany). Acquisition and analysis of images were performed as described previously.7 18 Until 2019, MRI scans were analysed by MASS software package (MEDIS Medical Imaging Systems, Leiden, the Netherlands), later on via commercially available software (Circle CVI42). Stroke volume (SV) was calculated as end-diastolic volume (EDV) minus end-systolic volume (ESV), on the basis of left ventricular volumes.19 Papillary muscles and trabeculations were included in the mass of the ventricles. The RVEF was calculated as following: RVEF= (RVEDV – RVESV)/RVEDV×100%). Volume and mass measurements were indexed to BSA.

Statistical analysis

Statistical analyses were carried out using R, V.4.1.2 (https://cran.r-project.org/). Histograms and qqplots were used to visually assess normal distribution for all variables (rcompanion; https://CRAN.R-project.org/package=rcompanion). Continuous data are reported as mean±SD or median (IQR) depending on distribution, unless stated otherwise. Logarithmic transformation was performed in case of non-normally distributed data. Categorical variables are presented as absolute numbers and relative frequencies (percentage). General characteristics of patients at baseline and follow-up, but also stratified subgroup analysis, were calculated with R package tableone (https://cran.r-project.org/web/packages/tableone/index.html). Comparison between baseline and follow-up was tested by paired t-tests for continuous variables and by McNemar test for categorical variables using rstatix (https://cran.r-project.org/package=rstatix). Patients were divided in groups based on reaching the 45% RVEF threshold or maintaining their RVEF above this threshold at first follow-up. Changes in haemodynamics or CMR parameters between groups over time were compared with a two-way repeated measures analysis of variance (https://cran.r-project.org/web/packages/ez/index.html). Univariable logistic regression analysis was performed to identify univariable predictors of reaching or maintaining an RVEF of 45% at follow-up (p<0.10). A multivariable regression model was established by backward elimination of variables until significant (https://cran.r-project.org/web/packages/dplyr/index.html). Survival was evaluated using Kaplan-Meier analysis and differences were tested by the log-rank test (https://cran.r-project.org/web/packages/survminer/index.html). Also, the hypothesis that a relative reduction in PVR of at least 40% on therapy is associated with improvement in RV function was tested by dividing patient subgroups into quintiles of PVR response.7 20–22 Risk stratification at baseline (non-invasive French three strata) and follow-up (four strata) was calculated as previously described.23 24 All visualisations were generated with ggplot2 (https://cran.r-project.org/web/packages/ggplot2/index.html). No imputations were made for missing data. A p-value <0.05 was considered statistically significant.

Results

Baseline characteristics

Mean age of the study population was 50±17 years; most patients were female (73%), and the majority of patients were diagnosed with idiopathic pulmonary arterial hypertension (59%; online supplemental table 1). Most patients were in New York Heart Association functional class III (50%), the mean 6 min walking distance was 411±145 m and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were 1360 ng/L (358–2625). Patients presented with an mPAP of 55±14 mm Hg, mixed venous oxygen saturation of 63%±9%, mean right atrial pressure (mRAP) of 8±5 mm Hg and PVR of 843±384 dynes/sec/cm−5. CMR imaging showed RV dilatation reflected by an indexed RVEDV of 83±21 mL/m2 and indexed RVESV of 55±21 mL/m2 resulting in a mean RVEF of 35%±12% at initial presentation. An overview of disease severity is presented in online supplemental table 2.

RVEF≥45%@FU patients versus RVEF<45%@FU patients

The first follow-up was performed after a median time of 1.0 year (0.9–1.1). At first follow-up, 75 patients (59%) reached an RVEF of 45% or maintained above this threshold (RVEF≥45%@FU patients), whereas in 52 patients (41%) RVEF remained below 45% (RVEF<45%@FU patients; figure 1). Three out of 29 patients failed to maintain their RVEF above the 45% threshold. RVEF≥45%@FU patients had a less severe RV phenotype at baseline, characterised by greater RVEF (p<0.001), moderate RV dilatation (77±18 mL/m2 vs 91±21 mL/m2; p<0.001) and lower PVR (785±397 dynes/sec/cm−5 vs 947±341 dynes/sec/cm−5; p=0.034). There were no differences in gender and age between RVEF<45%@FU and RVEF≥45%@FU patients (online supplemental table 3). Baseline multivariable predictors of an RVEF≥45%@FU are RVEDVi (OR (95% CI): 0.96 (0.94 to 0.98), p<0.001) and NT-proBNP (OR (95% CI): 0.999 (0.9992 to 0.0.9998), p<0.001) (online supplemental table 4).

Figure 1

Longitudinal visualisation of RVEF stratified for patients who reach or maintain the 45% threshold. P-values represent the change over time within each group. The red dotted line indicates the 45% cut-off. Dots and whiskers represent the mean±SEM. CMR, cardiac magnetic resonance; FU, follow-up; RVEF, right ventricular ejection fraction; RVEF≥45%@FU, patients with an RVEF ≥45% at first FU; RVEF<45%@FU, patients with an RVEF <45% at first FU.

Haemodynamic determinants

At first follow-up, both groups showed haemodynamic and functional improvement. An overview is presented in online supplemental table 3. PVR, mRAP and mPAP significantly decreased in both groups. However, the magnitude of mPAP decrease was larger in RVEF≥45%@FU patients (figure 2A; pinteraction <0.001). Also, RVEF≥45%@FU patients showed a greater decrease in PVR (figure 2B; pinteraction=0.04). Both groups had a similar improvement in CI (pinteraction=0.37). Naturally, RVEF improvement was greater in RVEF≥45%@FU patients (pinteraction<0.001), as well as SV; greater reductions in RV remodelling were observed in RVEF≥45%@FU patients for RVEDVi (pinteraction<0.01), RVESVi (pinteraction<0.001) and RV mass (pinteraction<0.001) than in RVEF<45%@FU patients. This was reflected in a greater reduction of NT-proBNP levels for RVEF≥45%@FU patients (pinteraction=0.03). No differences in LV function improvement could be observed between RVEF≥45%@FU patients and RVEF<45%@FU patients.

Figure 2

Changes in mPAP and PVR as stratified by an RVEF of 45% @ FU. (A) Longitudinal visualisation of mPAP in RVEF≥45%@FU patients and RVEF<45%@FU patients. (B) Longitudinal visualisation of PVR in RVEF≥45%@FU patients and RVEF<45%@FU patients. P-values represent the change over time within each group by two-way repeated measures analysis of variance. Dots and whiskers represent the mean±SEM. FU, first follow-up; mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; RHC, right heart catheterisation; RVEF, right ventricular ejection fraction; RVEF≥45%@FU patients, patients with a right ventricular ejection fraction ≥45% at first FU; RVEF<45%@FU patients, patients with an RVEF<45% at first FU.

RV phenotype

RVEF≥45%@FU patients were characterised by less severe RV dilatation at initial presentation compared with RVEF<45%@FU patients. Remarkably, improvement of RV volume and function can be achieved, even in patients with severely dilated right ventricles. Figure 3 displays the improvement of RVEF from baseline to follow-up, stratified by RVEDVi and RVESVi quintiles. The proportion of patients reaching the 45% RVEF threshold declines when the RV is more dilated at baseline. Haemodynamic profiles between RVEDVi quintiles were comparable (online supplemental table 5, RVESVi quintiles; online supplemental table 6).

Figure 3

Absolute change in RVEF for baseline RVEDVi and RVESVi quintiles. (A) Absolute change in RVEF for baseline RVEDVi subdivided into quintiles. (B) Absolute change in RVEF for baseline RVESVi subdivided into quintiles. P-values represent significant change in RVEF for each RVEDVi and RVESVi quintile determined through pairwise t-tests. Values above the x-axis represent portion of patients reaching the 45% RVEF threshold. The red dotted line indicates the 45% cut-off. Dots and whiskers represent the mean±SEM. CMR, cardiac magnetic resonance; FU, first follow-up; RVEDVi, right ventricular end-diastolic volume index; RVEF, right ventricular ejection fraction; RVESVi, right ventricular end-systolic volume index.

Pulmonary vascular resistance and pulmonary arterial pressure

We divided our study population into quintiles based on relative PVR change from baseline to follow-up to assess the corresponding RVEF improvement. In all quintiles, individual improvement of RVEF is seen. However, the proportion of patients reaching the 45% RVEF threshold was lower when PVR reduction is smaller (online supplemental figure 2A). Additionally, we tested the hypothesis of 40% relative PVR reduction in restoring RV function. Exceeding 40% PVR reduction improves RV function in near all patients, but does not guarantee an RVEF≥45%@FU. Of interest, 56 patients had a reduction in PVR of more than 40% at follow-up. In almost all patients (53/56), RV function improved significantly (table 1). As stated previously, RVEF≥45%@FU patients also have greater reduction in mPAP. A similar approach to assess the corresponding RVEF change within each relative quintile of mPAP reduction was used (online supplemental figure 2B). A greater reduction in pulmonary artery pressure resulted in an increased proportion of patients reaching the 45% RVEF threshold.

Table 1

Change in RVEF for PVR reduction of 40%

Long-term follow-up

During follow-up, 45 (36%) patients died and 10 (7%) patients underwent lung transplantation. The second follow-up was performed after 2.1 years (1.9–3.0) and the third follow-up after 3.3 years (2.8–5.2). Between the first and second follow-up, 2 patients received a lung transplantation and 26 patients died. Between the second and third follow-up, 4 patients received a lung transplantation and 11 patients died. Importantly, reaching or maintaining an RVEF of at least 45% at first follow-up was associated with better 1-year, 3-year and 5-year survival rates. The survival rates after first follow-up were 96%, 87% and 74% for the RVEF≥45%@FU patients and 92%, 67% and 63% for RVEF<45%@FU patients (p=0.018, HR: 1.91 (95% CI: 1.11 to 3.27), figure 4). At first follow-up, 15 (20%) RVEF≥45%@FU patients received treatment intensification compared with 16 (31%) RVEF<45%@FU patients. A significantly different RVEF trajectory was seen between RVEF≥45%@FU patients and RVEF<45%@FU patients. Furthermore, reaching or maintaining a 45% RVEF at first follow-up was associated with a stable RVEF over the next consecutive visits. Patients failing to reach or maintain this 45% RVEF threshold at first follow-up, mostly stayed below this threshold (figure 5).

Figure 4

Survival stratified for patients with RVEF≥45%@FU compared with RVEF<45%@FU patients. FU, first follow-up; PAH, pulmonary arterial hypertension; RVEF, right ventricular ejection fraction. Log-rank test shows a significant different survival between both groups starting from first follow-up (p=0.018).

Figure 5

Longitudinal visualisation of RVEF in RVEF≥45%@FU patients and RVEF<45%@FU patients. (A) RVEF trajectory during follow-up for RVEF≥45%@FU patients and RVEF<45%@FU patients at two consecutive follow-up visits. (B) RVEF trajectory during follow-up for RVEF≥45%@FU patients and RVEF<45%@FU patients at three consecutive follow-up visits. The red dotted line indicates the 45% cut-off. Dots and whiskers represent the mean±SEM. CMR, cardiac magnetic resonance; FU 1, first follow-up visit; FU 2, second follow-up visit; FU 3, third follow-up visit; RVEF, right ventricular ejection fraction; RVEF≥45%@FU, patients with a right ventricular ejection fraction ≥45% at first FU; RVEF<45%@FU, patients with an RVEF<45% at first FU. Repeated measures analysis of variance shows a significant different trajectory between both groups (p<0.001).

Clinical events

An event of death or lung transplantation occurred in 23/75 (31%) RVEF≥45%@FU patients compared with 32/50 (64%) RVEF<45%@FU patients. Although survival rates were in favour of the RVEF≥45%@FU patients, a substantial amount still deceased or was listed for lung transplantation. In RVEF≥45%@FU patients, only 9/23 (39%) experienced a clinical event due to progressive RV failure. In contrast, a clinical event in 23/32 (72%) RVEF<45%@FU patients was caused by progressive RV failure. Additionally, the mean age of diagnosis in RVEF≥45%@FU patients experiencing a clinical event was 60±19 years vs 50±15 years, resulting in less lung transplantations. Data for each individual experiencing a clinical event are summarised in online supplemental table 7 (RVEF≥45%@FU patients) and online supplemental table 8 (RVEF<45%@FU patients).

Discussion

By assessing the treatment response of the right ventricle in patients with PAH, we were able to demonstrate the following:

  1. After treatment initiation, 60% of patients can reach or maintain a 45% RVEF threshold. Most of these patients remain above this threshold during long-term follow-up and have a favourable prognosis. In contrast, patients who fail to reach the 45% RVEF threshold rarely exceed this threshold during long-term follow-up (figure 6) and more likely experience a clinical event related to progressive RV failure.

  2. Restoration of RV function is associated with baseline RV condition and magnitude of PVR and mPAP reduction. In particular, exceeding 40% PVR reduction guarantees improvement in RV function.

Figure 6

Summary of longitudinal results for RVEF≥45%@FU patients vs. RVEF<45%@FU patients. Of 127 treatment-naive patients with PAH who underwent RHC and CMR during initial diagnostic work-up and first follow-up, n=75 reach the RVEF 45% threshold. During long-term clinical monitoring with CMR, these patients mostly stay above the RVEF 45% threshold and have a more favourable prognosis. CMR, cardiac magnetic resonance imaging; FU 1, first follow-up visit; FU 2, second follow-up visit; FU 3, third follow-up visit.; mPAP, mean pulmonary arterial pressure; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; RHC, right heart catheterisation; RV, right ventricular; RVEF, right ventricular ejection fraction; RVEF≥45%@FU, patients with a right ventricular ejection fraction ≥45% at first FU; RVEF<45%@FU, patients with an RVEF<45% at first FU. The red dotted line indicates the RVEF 45% threshold.

Reverse remodelling of the RV

In this study, we characterised the RV response of treatment-naive patients with PAH. By dichotomising patient by an RVEF cut-off of 45% at first follow-up, we identified two patient subgroups with different clinical outcome, thus confirming the prognostic value of CMR in patients with PAH.5–7 25 26 Patients who failed to reach or maintain the 45% cut-off already presented with a more severe RV phenotype at baseline and displayed less PVR and mPAP reduction on treatment. Greater afterload reduction in RVEF≥45%@FU patients resulted in more pronounced reverse remodelling of the RV but also greater CI and mixed venous oxygen saturation, implying sufficient CO to meet tissue oxygen need. As previously stated, baseline RV condition is a main determinant of RV function at follow-up. However, a PVR reduction of more than 40% can restore RV function, although not all patients reached the RVEF 45% threshold. This confirms the hypothesis that a reduction of more than 40% in PVR is required to guarantee reverse remodelling of the RV.21 27 28 The physiological explanation for this critical threshold is that a modest reduction in PVR will increase CO to fulfil the requirements of the body, keeping pulmonary artery pressure unchanged not benefitting the right ventricle. Only if CO is normalised, pulmonary artery pressure will drop at a further reduction in PVR which will lead to reverse remodelling of the right ventricle. This explains why a PVR reduction below a certain threshold or a reduction in pulmonary artery pressure predicts reverse remodelling of the RV in our study.

Therapy approach

Notably, during the study period treatment strategies changed, since more treatments became available in the last 10 years and more often aggressive upfront combination therapy was started. This fits with the current evidence that improved survival in patients with PAH can only be reached if PVR is reduced significantly.7 The beneficial effects of aggressive upfront therapy to drastically reduce PVR was underlined by reverse remodelling of the RV in patients with PAH treated with either combination or upfront triple therapy.22 28 Also, patients who fail to reach the RVEF 45% threshold are more likely to experience a clinical event caused by progressive RV failure. This underlines the urgency to facilitate extensive reverse remodelling of the RV. Taken together, these studies and our results emphasise a treatment strategy aiming for at least a reduction of 40% in PVR in the first year to improve the right ventricle and survival.

Strengths and limitations

A strength of this study is the availability of multiple follow-up visits in treatment-naive patients with PAH initiated on different treatment regimens. More importantly, this is the first study applying the 45% RVEF cut-off in patients with PAH, identifying a subgroup of patients at baseline that do not display RV reverse remodelling after treatment initiation. But also demonstrate the reverse remodelling abilities of the right ventricle after exceeding 40% PVR reduction. Future research should investigate whether this threshold reduction in PVR also leads to a low-risk status. However, the present study has certain limitations. Not all patients have complete follow-up data, and this retrospective analysis was performed in a single centre limiting its generalisability. Although, general characteristics are comparable to larger cohorts, such as the REVEAL registry.29 Currently, there is no consensus on postprocessing CMR images in pulmonary hypertension. Future collaborative studies should address the implementation of automated approaches, as manual inclusion of trabeculations is time-consuming.

At last and ideally, a prospective cohort study should validate the discriminative and prognostic properties of the RVEF 45% cut-off and assess implementation in daily clinical practice.

Conclusion

After treatment initiation, 60% of patients with PAH reach or maintain the 45% RVEF threshold, which is associated with long-term stable RV function and favourable prognosis. Restoration of RV function is associated with baseline RV condition and magnitude of PVR and mPAP reduction.

Data availability statement

Data are available upon reasonable request. Certain requests can be done by contacting the first/corresponding author.

Ethics statements

Patient consent for publication

References

Supplementary materials

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Footnotes

  • Twitter @fsdeman

  • Contributors LC is responsible for the overall content as guarantor, had full access to all data and takes responsibility for the integrity of the data and accuracy of data analysis. JW, AK, TM, LM, HJB, FdM and AVN contributed substantially to the study design, data analysis and interpretation, and writing and reviewing of the manuscript.

  • Funding HJB, AVN and FSM were supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-2012-08 PHAEDRA, CVON-2018-29 PHAEDRA-IMPACT and CVON-2017-10 Dolphin-Genesis). AVN and FSM were further supported by The Netherlands Organization for Scientific Research (NWO-VICI: 918.16.610, NWO-VIDI: 917.18.338). FSM was supported by the Dutch Heart Foundation Dekker senior post doc grant (2018T059).

  • Competing interests HJB and AVN were supported by research grants from Actelion, GSK and Ferrer (Therabel). The remaining authors have nothing to disclose.

  • 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.