Article Text
Abstract
Objectives Heart failure with preserved ejection fraction (HFpEF) is often complicated by pulmonary hypertension (PH), which is mainly characterised by postcapillary PH and occasionally accompanied by a precapillary component of PH. Haemodynamic changes in worsening heart failure (HF) can modify the characteristics of PH. However, the clinical features of PH after HF treatment in HFpEF remain unclear. We investigated the prevalence and clinical significance of the precapillary component of PH after HF treatment in HFpEF, using data from the Prospective Multicentre Observational Study of Patients with HFpEF (PURSUIT-HFpEF).
Methods From the PURSUIT-HFpEF registry, 219 patients hospitalised with acute HF who underwent right heart catheterisation after initial HF treatment were divided into four groups according to the 2015 and 2018 PH definitions: non-PH, isolated postcapillary pulmonary hypertension (Ipc-PH), precapillary PH and combined postcapillary and precapillary pulmonary hypertension (Cpc-PH). The latter two were combined as PH with the precapillary component.
Results Using the 2015 definition, we found that the prevalence of PH after HF treatment was 27% (Ipc-PH: 20%, precapillary PH: 3%, Cpc-PH: 4%). Applying the 2018 definition resulted in a doubled frequency of precapillary PH (6%). PH with a precapillary component according to the 2015 definition was associated with poor clinical outcomes and characterised by small left ventricular dimension and high early diastolic mitral inflow velocity/early diastolic mitral annular tissue velocity.
Conclusion After initial HF treatment, 7% of hospitalised patients with HFpEF had precapillary component of PH according to the 2015 definition. Echocardiographic parameters of the left ventricle can contribute to the risk stratification of patients with HFpEF with a precapillary component of PH.
- heart failure
- haemodynamics
- echocardiography
- hypertension, pulmonary
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
The development of a precapillary component of pulmonary hypertension (PH) is associated with poor clinical outcomes in patients with heart failure with preserved ejection fraction (HFpEF), which can be either a permanent condition or reversible with treatment of acute heart failure (HF).
WHAT THIS STUDY ADDS
PH with the precapillary component after HF treatment was found in 7% of hospitalised patients with HFpEF according to the 2015 PH definition. Small left ventricular (LV) dimension and high early diastolic mitral inflow velocity/early diastolic mitral annular tissue velocity were echocardiographic indicators to determine the presence of a precapillary component of PH.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
Echocardiographic parameters of left ventricle may contribute to identifying a high-risk subgroup of patients with HFpEF in whom a more aggressive treatment to reduce elevated LV filling pressure may help decrease the risk of developing a precapillary component of PH.
Introduction
Heart failure with preserved ejection fraction (HFpEF) accounts for a substantial portion of acute heart failure (HF) hospitalisations worldwide.1 2 Treatment options to reduce morbidity or mortality in patients with HFpEF remain limited.3 4 Therefore, a better understanding and risk stratification of patients with HFpEF can lead to the development of novel therapeutic strategies.
Pulmonary hypertension (PH) in patients with HFpEF is characterised by postcapillary PH associated with elevated left heart filling pressures. However, a subset of patients with HFpEF develops an additional precapillary component of PH, which can be caused by multiple mechanisms, including pulmonary arterial vasoconstriction and vascular remodelling, and may be altered by haemodynamic changes, indicating either a permanent condition or a reversible condition with treatment of acute HF.5 6 The relatively high prevalence of PH and the prognostic implications of the precapillary component of PH have been reported in patients with HFpEF in a chronic setting, including among patients with worsening condition.7 8 However, the prevalence and clinical features of the precapillary component of PH in hospitalised patients with HFpEF after the stabilisation of acute HF and non-invasive indicators for predicting the presence of the precapillary component of PH in patients with HFpEF have not been elucidated.
Previous studies on PH in HFpEF have been conducted using the 2015 European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines, in which PH is defined as mean pulmonary artery pressure (mPAP) of ≥25 mm Hg.9 In the definition updated in 2018, a lower threshold of mPAP of >20 mm Hg is adopted; pulmonary vascular resistance (PVR) of ≥3 Wood units (WU) is required as the definition of the precapillary component, and the diastolic pulmonary artery pressure gradient (DPG) is no longer used.10 The clinical impact of the 2018 definition has not been investigated in HFpEF. Therefore, we investigated the prevalence of PH using right heart catheterisation (RHC) according to the 2015 and 2018 definitions and catalogued the clinical features of patients with a precapillary component of PH, in a prospective multicentre registry of hospitalised patients with HFpEF.
Methods
Study population
The study cohort was derived from the PURSUIT-HFpEF (prospective multicentre observational study of patients with HFpEF) registry (UMIN-CTR ID: UMIN000021831). Details of the PURSUIT-HFpEF registry have been described previously (online supplemental material S1).11 Briefly, individuals were eligible if they were hospitalised with acute decompensated HF with a left ventricular ejection fraction of ≥50%, met the Framingham HF criteria and had levels of N-terminal probrain natriuretic peptide (NT-pro-BNP) of ≥400 pg/mL or levels of BNP of ≥100 pg/mL on admission.
Supplemental material
Between June 2016 and March 2020, 870 patients were enrolled in the PURSUIT-HFpEF registry. Of these, 236 patients underwent RHC. Seventeen patients were excluded, as shown in figure 1, and the final sample included 219 patients.
Patient and public involvement
This research was conducted without patient involvement.
Haemodynamic assessments
The indications for and timing of haemodynamic evaluation by RHC were at the discretion of the treating physicians. RHC was performed using a standard protocol. Further details are provided in the online supplemental methods.
The patients were classified according to the 2015 and 2018 PH definitions9 10: non-PH, precapillary PH, isolated postcapillary pulmonary hypertension (Ipc-PH) and combined postcapillary and precapillary pulmonary hypertension (Cpc-PH). Under the 2015 definition, patients with discrepant DPG and PVR were unclassifiable.12 13 To avoid this, Ipc-PH was defined as mPAP of ≥25 mm Hg, pulmonary artery wedge pressure (PAWP) of >15 mm Hg with DPG of <7 mm Hg and PVR of ≤3 WU in this study. Additionally, patients with mPAP of >20 mm Hg, PAWP of ≤15 mm Hg, and PVR of <3 WU did not meet any PH criteria under the 2018 definition.13 These patients were classified as ‘unclassifiable’ in this study. The PH definitions in our study are summarised in table 1.
Echocardiographic assessments
Echocardiographic data at discharge were available for 216 patients. The conventional and Doppler echocardiographic measurements were obtained according to the recommendations of the American Society of Echocardiography.14 15 LV volumes were calculated using a modified Simpson method. The early diastolic mitral inflow velocity (E)/early diastolic mitral annular tissue velocity (e′) was calculated based on the mean e′ values. Tricuspid annular plane systolic excursion (TAPSE) was measured. Systolic pulmonary artery pressure (SPAP) was an estimate of SPAP on echocardiography. Further details are provided in the online supplemental methods.
Statistical analysis
Continuous variables were expressed as mean±SD or median (IQR), as appropriate. Categorical variables were expressed as frequencies and percentages. The differences between the groups were compared using the χ2 test for categorical variables, and analysis of variance or the Kruskal-Wallis test for continuous variables, and multiple comparisons using the Tukey-Kramer or the Dwass-Steel-Critchlow-Fligner methods, as appropriate. Logistic regression models were used to assess the factors associated with PH with a precapillary component that combined the precapillary PH and Cpc-PH groups. All other groups were combined and used as a control group and the ORs and 95% CIs were calculated. A receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values of echocardiographic parameters to distinguish patients with a precapillary component of PH from those in the other groups. The incidence of the composite endpoint of all-cause death and HF hospitalisation at 1 year in each PH category was evaluated using the Kaplan-Meier method and was compared using the log-rank test. A probability value of <0.05 was considered statistically significant. For multiple comparisons in Kaplan-Meier analysis, p values were adjusted using the Bonferroni correction. Statistical analyses were performed using JMP Pro V.14.3.0 (SAS Institute, Cary, NC, USA).
Results
Study population
Patient characteristics on admission and initial HF treatment for the 219 patients are shown in online supplemental table S1. RHC after the stabilisation of acute HF by initial treatments (median 11 days after admission, IQR 7–14 days) revealed that 60 (27%) patients had PH, including 44 patients (20%) classified as Ipc-PH, 9 (4%) patients classified as Cpc-PH and 7 (3%) patients classified as precapillary PH according to the 2015 definition (figure 1). The clinical characteristics at discharge in each PH category are shown in table 2. Patients classified in the precapillary PH group were mostly elderly women, without coronary artery disease, with high NT-pro-BNP and low estimated glomerular filtration rate. Haemodynamic parameters associated with PH categories are shown in online supplemental table S2 and figure S1. PH was present in only 5% (n=7) of the patients with PAWP of ≤15 mm Hg (n=142). In contrast, 69% (n=53) of the patients with PAWP of >15 mm Hg (n=77) had PH. Notably, the precapillary PH group had a relatively high median PAWP of 14 mm Hg (IQR 13–15).
Echocardiographic parameters and PH category
Echocardiography at discharge was performed at a median of 3 days after RHC and those parameters are summarised in table 3. The precapillary PH and Cpc-PH groups showed smaller LV dimensions among the four categories, which were no longer significant after being indexed by body surface area (BSA) at discharge. The Doppler echocardiographic parameters of E, E/A, and E/e′ tended to be higher in the precapillary PH and Cpc-PH categories.
Determinants of the precapillary component of PH
The Cpc-PH and precapillary PH groups were combined as a group of PH with the precapillary component (n=16). LV dimensions, E, E/A, E/e′, and SPAP, as well as female sex and BSA, were all significantly associated with the PH with the precapillary component in the univariate analysis (table 4), whereas left atrial diameter and TAPSE/SPAP were not (p=0.229 and 0.060, respectively). In the multivariate analysis adjusted for sex, smaller LV dimensions remained significantly associated with an increased risk of PH with the precapillary component (table 4). Conversely, adjustment for BSA resulted in an attenuation of the significant association of LV dimensions with PH with the precapillary component (table 4). The combined Cpc-PH and precapillary PH group had significantly smaller LV end-diastolic dimension (LVDD) than the Ipc-PH group and higher E/e′ than the non-PH group (figure 2). ROC curve analysis for association of LVDD and E/e′ with PH with the precapillary component yielded an area under the curve (AUC) of 0.69 and a cut-off value of 48 mm for LVDD, and an AUC of 0.71 and a cut-off value of 17.6 for E/e′. When LVDD and E/e′ were entered simultaneously in the analysis, the AUC improved to 0.81. By adding SPAP, the AUC further improved to 0.86.
Impact of the 2018 definition of PH in HFpEF
Using the 2018 definition, 54 (25%) patients were re-classified into a different group, including 23 (11%) patients classified as unclassifiable, from that using the 2015 definition, resulting in a significant increase in the prevalence of PH (39% vs 27%, p<0.001), with a doubled frequency of precapillary PH (figure 3). With the 2018 definition, 25 (11%) patients were classified as having PH with a precapillary component.
Prognostic implication of PH with a precapillary component
Among 219 patients, there were no in-hospital deaths, and 1 year follow-up data were available for 201 patients (92%). Thirty-three (16%) patients were re-admitted due to HF and 14 (7%) patients died within 1 year after discharge. The Kaplan–Meier analysis demonstrated that PH with a precapillary component with the 2015 definition was associated with poor clinical outcomes 1 year after discharge (figure 4A), whereas it was no longer relevant with the 2018 definition (figure 4B).
Impact of the 2022 definition of PH in HFpEF
The recently published 2022 ESC/ERS guidelines have adopted a lower threshold of PVR of >2 WU for the definition of precapillary PH (online supplemental table S3), resulting in an increase in the number of patients with a precapillary component of PH to 58 (26%) (figure 3). Applying the 2022 definition, we found that clinical outcomes 1 year after discharge did not differ across the PH groups (online supplemental figure S2), unlike the results based on the 2015 definition (figure 4A).
Discussion
In this prospective multicentre registry of patients with HFpEF who required hospitalisation for acute decompensated HF, we found that (1) the prevalence of PH after acute treatment defined by mPAP of ≥25 mm Hg was unexpectedly low (27%), within which the PH with precapillary component was observed in 7% of cases; (2) PH with a precapillary component after HF treatment was highly predictable by echocardiographic parameters (E/e′ and LV dimension); and (3) the 2018 definition of PH resulted in an increased prevalence of PH in HFpEF, with a doubled frequency of precapillary PH. To the best of our knowledge, this is the first report describing the prevalence and clinical features of the precapillary component of PH after HF treatment with the 2015 and 2018 definition of PH, which was invasively assessed in a real-world registry of hospitalised patients with HFpEF.
Several studies in patients with HFpEF, mainly in a chronic setting, have reported the prevalence of PH defined by mPAP of >25 mm Hg, ranging widely from 53% to 81%.7 8 16 17 Some studies further investigated the prevalence of the precapillary component of PH, and a relatively high prevalence was reported, ranging from 12% to 31%.7 8 In our population, we also found a similarly high prevalence of PH (69%) among patients with elevated PAWP. However, patients with elevated PAWP represented only 35% of our cohort after initial HF treatment, despite the fact that all patients were considered to have elevated LV filling pressure on admission based on the Framingham HF criteria, together with elevated NT-pro-BNP or BNP levels.
The precapillary PH and Cpc-PH categories showed several similarities in clinical and echocardiographic features. It was reported that patients with a borderline PAWP between 12 mm Hg and 15 mm Hg at rest were 4.5 times more likely to have elevated levels of PAWP at exercise.18 Therefore, we postulate that the presence of the postcapillary component of PH in patients in the precapillary PH group may have been masked at the resting haemodynamic evaluation after acute treatment to reduce congestion, and that these patients may share similar pathophysiology to Cpc-PH. Smaller LV dimension was significantly associated with an increased risk of the precapillary component of PH, which may be mediated by smaller BSA rather than sex. Higher E, E/A and E/e′ were also found to be significant determinants of the precapillary component of PH, suggesting that LV diastolic dysfunction may be involved in the elevation of PVR in patients with HFpEF.
We also demonstrated that small LVDD and high E/e′ were significant echocardiographic indicators to determine the presence of precapillary component of PH. Previous reports suggested that a reduced TAPSE/SPAP can help to identify the presence of precapillary component of PH.7 8 However, in our population, TAPSE/SPAP was relatively preserved and only weakly associated with the precapillary component of PH. We assume that our population was in a less advanced stage of PH compared with that in the previous reports, and that our findings may contribute to early non-invasive risk stratification of patients with HFpEF.
The impact of the 2018 definition has been reported in different populations.13 19 20 A recent study in patients with severe aortic stenosis reported that the 2018 definition contributed to accurate identification of high-risk patients with precapillary PH by excluding patients with PH with borderline PAWP without elevated PVR classified as precapillary PH according to the 2015 definition.13 In contrast, in our HFpEF cohort, which did not include severe valvular disease, the 2018 definition resulted in an increased proportion of precapillary PH including more patients with lower mPAP and failed to show the prognostic implication of PH with the precapillary component. Furthermore, the number of patients defined as having a precapillary component of PH is expected to increase under the 2022 definition. Long-term observations are needed to clarify the prognostic implications of the new definition of PH and the trajectory of PH classification in the course of HF progression in HFpEF.
Limitations
This study has several limitations. First, RHC was performed in 27% of all participants in the PURSUIT-HFpEF registry. Because in our aged population the indications for invasive haemodynamic evaluation were determined by the treating physicians, selection bias may exist. However, it should be noted that the prevalence of suspected PH on echocardiography was not different between patients who did and did not undergo RHC (online supplemental table S1). In addition, due to the small number of patients with a precapillary component of PH, the possibility of statistical error cannot be excluded. Second, the haemodynamic measurements and echocardiographic parameters were not simultaneously obtained in this cohort, although echocardiography at discharge was performed at a median of 3 days after RHC, suggesting that the haemodynamic measurements were obtained in a relatively stable condition after acute treatment in this cohort. Third, there were no data available on haemodynamic parameters after fluid loading or exercise testing. We could not make a clear distinction between isolated precapillary PH and masked PH due to left heart disease. In addition, a comprehensive evaluation for other PH aetiologies (ie, respiratory function test) was not readily available. Considering the heterogeneous nature of HFpEF, it is possible that several aetiologies were associated with the development of PH. Finally, although our study patients are representative of a real-world population of hospitalised HFpEF in Japan, our cohort was significantly older than patients in other HFpEF studies.21 22 Therefore, the results of the present study may not be generalisable to other populations with different demographics.
Conclusion
In our prospective multicentre registry of hospitalised patients with HFpEF, the prevalence of PH with a precapillary component after initial HF treatment was 7% according to the 2015 definition and 11% according to the 2018 definition. After the stabilisation of acute HF in the hospitalised patients with HFpEF, PH with a precapillary component according to the 2015 definition was associated with poor clinical outcomes. LV echocardiographic parameters can contribute to risk stratification of patients with HFpEF with a precapillary component of PH.
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 involves human participants and was approved by Kansai Rosai Hospital Institutional Review Board (approval ID: 16co10g), Kawachi General Hospital Ethics Committee (approval ID was not available, but approved on 26 April 2016), Osaka Rosai Hospital Ethics Committee (approval ID: 28-5), Higashiosaka City Medical Center Institutional Review Board (approval ID: 02-0313), Osaka Prefectural Hospital Organization Osaka General Medical Center Institutional Review Board (approval ID: 28-2002), Hyogo Prefectural Nishinomiya Hospital Ethics Committee (approval ID: H28-3), Ikeda Municipal Hospital Ethics Committee (approval ID: 3280), Kawanishi City Hospital Institutional Review Board (approval ID: 28001), Rinku General Medical Center Ethics Committee (approval ID: 27-40), Saiseikai Senri Hospital Ethics Committee (approval ID: 280304), Yao Municipal Hospital Institutional Review Board (approval ID: H28-6), Kawasaki Hospital Ethics Committee (approval ID was not available, but approved on 12 May 2016), Minoh City Hospital Ethics Committee (approval ID was not available, but approved on 24 May 2016), National Hospital Organization Osaka National Hospital Second Institutional Review Board (approval ID: 16024), Kano General Hospital Ethics Committee (approval ID was not available, but approved on 9 June 2016), Toyonaka Municipal Hospital Ethics Committee (approval ID: 2016-04-02), Kinan Hospital Ethics Committee 121, Japan Community Health Care Organization Osaka Hospital Ethics Committee (approval ID: 2016-2), Kobe Ekisaikai Hospital Ethics Committee (approval ID: 2016-3), Sakurabashi Watanabe Hospital Ethics Committee (approval ID: 16-15), Sumitomo Hospital Research Ethics Committee (approval ID: 28-01), Suita Municipal Hospital Institutional Review Board (approval ID: 2017-8), Kinki Central Hospital Ethics Committee (approval ID: 288), Osaka Police Hospital Institutional Review Board (approval ID: 593), Japan Community Health Care Organization Hoshigaoka Medical Center Institutional Review Board (approval ID: 1618), National Hospital Organization Osaka Minami Medical Center Institutional Review Board (approval ID: 28-3), Japan Community Health Care Organization Osaka Minato Central Hospital Ethics Committee (approval ID was not available, but approved on 10 June 2016), Amagasaki Chuo Hospital Ethics Committee (approval ID was not available, but approved on 1 August 2017), Otemae Hospital Institutional Review Board (approval ID: 2017-020), Osaka University Hospital Clinical Research Review Committee (approval ID: 15471) and Osaka International Cancer Institute Institutional Review Board (No. 20097). The investigation conforms with the principles outlined in the Declaration of Helsinki and was approved by the institutional review boards of Osaka University and each participating hospital. Written informed consent was obtained from all study participants.
Acknowledgments
The authors thank Sugako Mitsuoka, Masako Terui, Yasue Imagawa, Nagisa Yoshioka, Satomi Kishimoto, Kyoko Tatsumi and Noriko Murakami for their excellent assistance in data collection, data management and secretarial work.
References
Supplementary materials
Supplementary Data
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Footnotes
Collaborators On behalf of Osaka Cardiovascular Conference Heart Failure Investigators.
Contributors FS: conception, design of analysis, interpretation of data and manuscript drafting. TO: guarantor, conception, design of analysis, interpretation of data and revision of the manuscript for important intellectual content. ST, MY, TH, AN, YN and KY-T: interpretation of data and revision of the manuscript for important intellectual content. DN: project administration and revision of the manuscript for important intellectual content. TY and YY: supervision and revision of the manuscript for important intellectual content. SH: funding acquisition, project administration, interpretation of data and critical revision of the manuscript for important intellectual content. YS: funding acquisition, supervision and revision of the manuscript for important intellectual content. All authors read and gave the final approval of the manuscript.
Funding SH and YS were supported by Roche Diagnostics K.K. and Fuji Film Toyama Chemical Co., and FS was supported by JSPS KAKENHI (JP18K08070).
Competing interests FS received modest lecture fees from Actelion Pharmaceuticals, Pfizer and Nippon Boehringer Ingelheim. TO received modest lecture fees from Bristol-Myers Squibb, Daiichi Sankyo Company, Nippon Boehringer Ingelheim and Otsuka Pharmaceutical, as well as significant medical advisory fees from Takeda Pharmaceutical. SH received modest personal fees from Daiichi Sankyo Company, Bayer and Astellas Pharma, as well as a modest grant from Actelion Pharmaceuticals. KY-T received a modest lecture fee from Actelion Pharmaceuticals. YS received significant personal fees from Otsuka Pharmaceutical and Daiichi Sankyo Company, and modest personal fees from Actelion Pharmaceuticals, Ono Pharmaceutical, Astellas Pharma, AstraZeneca, Novartis Pharma, Bayer, Pfizer and TOA EIYO. The other authors have no conflicts of interest 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.
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