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Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension
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ORIGINAL ARTICLE
Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension Alexandra Arvanitaki, MD, MSc a, Sophia Anastasia Mouratoglou, MD, PhD a, Alexandros Evangeliou, MD a, Vasilios Grosomanidis, MD, PhD b, Stavros Hadjimiltiades, MD, PhD a, Lemonia Skoura, MD, PhD c, Christos Feloukidis, MD a, Dimitrios Farmakis, MD a,d, Haralambos Karvounis, MD, PhD a, George Giannakoulas, MD, PhD a* a
Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece Department of Anesthesiology and Intensive Care Medicine, AHEPA University Hospital, Thessaloniki, Greece c Department of Microbiology, AHEPA University Hospital, Thessaloniki, Greece d Cardiology Department, Papageorgiou General Hospital, Thessaloniki, Greece b
Received 3 July 2018; accepted 10 December 2018; online published-ahead-of-print xxx
Background
Precapillary pulmonary hypertension (PH) is characterised by compromised functional capacity and impaired quality of life. Assessment of haemodynamics is routinely used for initial diagnosis, follow-up, and risk stratification in these patients. The purpose of this study was to investigate the relation of health-related quality of life (HRQoL) as assessed by emPHasis-10 score, a self-assessment questionnaire assessing breathlessness, fatigue, control, and confidence, to haemodynamic and neurohormonal indices in patients with precapillary PH.
Method
This was a prospective cross-sectional study which included stable patients with precapillary PH. All patients underwent right heart catheterisation, 6-minute walk test, N-terminal pro–brain natriuretic peptide (NT-proBNP) measurement, and assessment of HRQoL with the emPHasis-10 scale.
Results
Overall, 54 patients were included (32 women; mean age, 58.4 14.6 yr). Mean emPHasis-10 score was 19.2 12.0. EmPHasis-10 score correlated with World Health Organization functional class (r = 0.52, p < 0.001), 6-minute walk distance (r=–0.56, p < 0.001), and log10(NT-proBNP) (r = 0.41, p < 0.01). A positive correlation of emPHasis-10 score with mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) and a negative correlation with mixed venous oxygen saturation and cardiac index was observed, after adjustment for age, sex, body mass index, and PH group. In a subgroup analysis of patients with pulmonary arterial hypertension (n = 34) there was a stronger correlation of emPHasis-10 score with mPAP (r = 0.86, p < 0.001) and PVR (r = 0.69, p < 0.01), but no correlation with cardiac index and mixed venous oxygen saturation.
Conclusions
Self-assessment of quality of life with the use of the emPHasis-10 score reflects functional capacity and is correlated with haemodynamic and neurohormonal indices of right heart dysfunction in patients with precapillary PH.
Keywords
Precapillary pulmonary hypertension Quality of life Haemodynamics NT- proBNP
*Corresponding author at: Department of Cardiology, AHEPA University Hospital, St. Kiriakidi 1, Thessaloniki, 54636, Greece. Tel.: +30 2310994830, Fax: +30 2310994673., Email: [email protected] © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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Introduction Pulmonary hypertension (PH) is associated with a variety of symptoms, such as breathlessness, fatigue, decreased exercise tolerance, syncope, and chest pain, as well as psychological impairment, that adversely affect patients’ health-related quality of life (HRQoL) [1,2]. Current medical targeted treatment has managed to alleviate symptoms, hinder disease progression, and improve survival. However, the burden of the disease on patients’ lives remains heavy and similar to that of other severe conditions, such as heart failure and chronic obstructive pulmonary disease [3]. In addition to symptoms, frequent hospitalisations, several adverse drug reactions, their route of ad28212821ministration (e.g., parenteral prostanoids), and oxygen therapy may have a negative impact on patients’ HRQoL [4]. The assessment of these patients relies mainly on baseline and serial functional and haemodynamic indices [5]. However, the need for repeated right heart catheterisations (RHC) and the limitations of the 6-minute walk test have led to the emergence of HRQoL as a potential useful tool in clinical practice [4]. Health-related quality of life has been increasingly acknowledged as a significant measure of the disease burden and overall wellbeing, since it is composed of both physical and mental parameters, the assessment of which may allow physicians to better understand the nature of the disease [4,6–8]. Various HRQoL questionnaires have been developed to measure the effects of PH on patients’ daily lives, such as the Cambridge Pulmonary Hypertension Outcome Survey (CAMPHOR) [8], the medical outcome study 36-Item Short Form (SF-36) [9], the Nottingham Health Profile [10], the Minnesota Living with Heart Failure Questionnaire (MLHFQ) [7], and the Euro Quality of Life (EuroQoL) [11,12]. However, the multidimensional nature of these tools limits their use in clinical practice. EmPHasis-10 is a recently developed, diseasespecific questionnaire that is easier to use and simple to score, as it consists of only 10 questions, assessing breathlessness, fatigue, control, and confidence [13]. In this cross-sectional study, we aimed to evaluate HRQoL in patients with stable precapillary PH using the emPHasis10 scale and to investigate its association with haemodynamics and neurohormonal indices of severity of right heart dysfunction.
Methods Study Design, Participants and Data Collection This was a prospective cross-sectional study conducted in a single PH centre. Patients aged 18 years with haemodynamically confirmed precapillary PH, according to the current guidelines [5], were eligible to participate in the study. Patients with postcapillary PH due to left heart disease were excluded. In addition, patients with serious mobility problems due to previous stroke, surgery, or musculoskeletal disease were also excluded.
Eligible patients were asked to complete a HRQoL questionnaire during an outpatient visit. Demographic, clinical, functional, and haemodynamic data were collected and N-terminal pro–brain natriuretic peptide (NT-proBNP) serum levels were also measured on the same day. In patients with cyanotic congenital heart disease a repeat RHC was not performed. The emPHasis-10 questionnaire was used for the evaluation of HRQoL in patients with precapillary PH. This is a PHspecific HRQoL questionnaire, which consists of 10 items, each on a scale of 0 - 5. Each patient had a score of 0 - 50. Higher scores indicate worse health status and quality of life. Important components of the impact of PH are covered in emPHasis-10, including breathlessness, fatigue and lack of energy, social restrictions, and concerns regarding effects on patients’ relatives [13]. A translated version of emPHasis-10 was used. The translation was carried out using translation– back translation and was approved by the original English developers. Each patient answered the questionnaire after optimal clarification was provided. The study personnel reviewed and ensured completeness and readability of entries prior to the participant leaving the site. The participant completed the questionnaire by using a normal pen (no pencil or whiteout/correction fluid was allowed). Written informed consent was obtained from all participants. The study was approved by the local ethics committee and performed according to the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.
Statistical Analysis Data are presented as mean standard deviation for continuous variables or as median (range) as appropriate. Categorical variables are presented as absolute count and percentage (%). Univariable linear regression analysis was used to explore the linear correlation between emPHasis-10 score and functional, haemodynamic, and neurohormonal parameters. Then, a multivariable regression analysis was performed to adjust for age, sex, PH group, and body mass index (BMI). A subgroup analysis was conducted for patients with pulmonary arterial hypertension (PAH), in which the same correlations were sought. N-terminal pro–brain natriuretic peptide did not follow the normal distribution neither in the initial nor in the PAH analysis and therefore normal distribution was achieved using the common logarithm, log10(NT-proBNP). A p-value <0.05 was considered statistically significant. Data were analysed using SPSS version 24.0. for Windows (SPSS, Armonk, NY, USA).
Results Demographics Demographics of the total PH population and PAH (group 1 PH) are presented in Table 1. The study included
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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54 consecutive patients with precapillary PH, of whom 32 (59%) were women. Mean age and BMI were 58.4 years and 24.8 kg/m2, respectively. Almost two-thirds of the patient population suffered from PAH. The median duration of disease since diagnosis was 2 years. The most common comorbidities were arterial hypertension, smoking, and obesity. The majority of patients with PAH (65%) were under monotherapy, while 18% received a triple combination.
Table 1. (continued). Total
CI (L/min/m2) PVR (WU)
2.9 0.8 6.1 3.1
3.1 0.9 6.1 3.4
SvO2 (%)
69.2 7.4
70.3 6.4
HR (bpm)
79.5 16.0
78.3 15.3
PAH-specific treatment
Table 1 Patients’ characteristics. Total
PAH
PAH
PH population (n = 34) (n = 54)
n = 34
Monotherapy
22 (65)
Double combination
6 (18)
Triple combination
6 (18)
PH population (n = 34) (n = 54)
Categorical variables are presented as n (%). Continuous variables are presented as mean standard deviation or as median (range).
Age (yr)
58.4 14.6
57.9 16.3
Female sex
32 (59)
22 (65)
BMI (kg/m2)
24.8 5.9
26.9 6.3
Duration of disease (yr)
2.0 (0.5 - 10.0)
2.0 (0.5 - 10.0)
PH classification Group 1 Idiopathic
34 (63)
or multifactorial mechanisms; WHO FC; World Health Organization
5 (15)
Functional Class; 6MWD, 6-minute walk distance; NT-proBNP, N-term-
Group 1, pulmonary arterial hypertension; Group 3, pulmonary hypertension due to lung disease; Group 4, chronic thromboembolic pulmonary hypertension; Group 5, pulmonary hypertension with unclear and/
Heritable 1 (3) Connective tissue disease 13 (38) Congenital heart disease 12 (35) Portal hypertension
3 (9)
Group 3
7 (13)
Group 4 Group 5
10 (18) 3 (6)
inal pro–brain natriuretic peptide; RAP; right atrial pressure; mPAP; mean pulmonary artery pressure; PAWP; pulmonary artery wedge pressure; CI; cardiac index; PVR; pulmonary vascular resistance; WU, Wood units; SvO2; oxygen saturation in pulmonary artery; HR, heart rate; bpm, beats per min.
Comorbidities Atrial fibrillation
4 (7)
2 (6)
Arterial hypertension
37 (69)
10 (29)
Diabetes mellitus
7 (13)
7 (21)
Dyslipidaemia
11 (20)
5 (15)
Coronary artery disease
3 (6)
1 (3)
Chronic kidney disease Liver disease
2 (4) 6 (11)
0 4 (12)
History of pulmonary
9 (17)
1 (3)
Thyroid disease
9 (17)
5 (15)
Obesity
18 (33)
11 (32)
Smoking
22 (41)
10 (29)
Depression
3 (6)
1 (3)
embolism
Functional and neurohormonal indices WHO FC I
7 (13)
3 (9)
II
35 (65)
24 (70)
III
10 (18)
5 (15)
IV
2 (4)
2 (6)
6MWD (m)
438.3 123.6
451.7 113.3
NT-proBNP (pg/mL)
244 (37 - 4651)
238 (37 - 2994)
19.2 12.0 n = 47
19.1 11.4 n = 27
RAP (mmHg)
6.8 3.1
6.8 2.8
mPAP (mmHg)
40.7 12.6
42.0 13.9
PAWP (mmHg)
11.0 2.7
11.3 2.5
emPHasis-10 score Haemodynamics
Abbreviations: PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; BMI, body mass index; PH, pulmonary hypertension;
Functional, Neurohormonal, and Haemodynamic Indices Functional, neurohormonal, and haemodynamic parameters are presented in Table 1. The majority of patients (78%) reported no or mild symptoms [World Health Organization Functional Class (WHO FC) I/II], while mean 6minute walk distance (6MWD) was 438.3 metres. Based on functional, neurohormonal, and haemodynamic parameters, such as right atrial pressure and cardiac index, the majority of patients with PAH were classified as low risk (1-year mortality risk <5%) according to 2015 European PH guidelines [5].
Correlations of emPHasis-10 Score with Functional and Neurohormonal Indices All participants completed the emPHasis-10 without difficulties. Mean emPHasis-10 score was 19.2 (range, 1– 42). In the study population there was a correlation between emPHasis-10 score and WHO FC (r = 0.54, p < 0.001), 6MWD (r=–0.50, p < 0.001), and log10(NT-proBNP) (r = 0.30, p = 0.03) (Figure 1A,B; Table 2). After adjustment for age, sex, and BMI, these correlations were maintained, while the correlation between emPHasis-10 score and log10(NT-proBNP) became stronger (r = 0.41, p < 0.01). In the PAH group, similar correlations were observed (Table 3).
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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Figure 1 Correlation of emPHasis-10 score with functional, neurohormonal, and haemodynamic parameters in the total population of patients with precapillary pulmonary hypertension. (A) Scatterplot presents the correlation of emPHasis-10 score with 6-minute walk distance (6MWD). (B) Scatterplot presents the correlation of emPHasis-10 score with log10[N-terminal pro–brain natriuretic peptide (NT-proBNP)]. (C) Scatterplot presents the correlation of emPHasis-10 score with mean pulmonary artery pressure (mPAP). (D) Scatterplot presents the correlation of emPHasis-10 score with pulmonary vascular resistance (PVR).
In the PAH subgroup emPHasis-10 score correlated with the number of administered PAH-specific drugs (r = 0.45, p < 0.01).
Correlations of emPHasis-10 Score with Haemodynamic Parameters In the study population there was a correlation between emPHasis-10 score and mean pulmonary artery pressure (mPAP; r = 0.51, p < 0.001), pulmonary vascular resistance (PVR; r = 0.51, p < 0.001), and oxygen saturation in pulmonary artery (SvO2%; r=–0.32, p = 0.03) (Figure 1C,D; Table 2). After adjustment for age, sex, and BMI, these correlations were maintained, while a negative correlation between emPHasis-10 score and cardiac index also emerged (r=–0.33, p = 0.037). In the PAH subgroup, there were stronger correlations between emPHasis-10 score and mPAP and PVR, but no correlation with SvO2 was noted (Table 3).
Discussion This study investigated the relation of HRQoL, as assessed with emPHasis-10, a validated, disease-specific and simpleto-use scoring tool, with the haemodynamic parameters of disease severity in patients with precapillary PH. In addition, we explored the relation of emPHasis-10 score with NTproBNP and markers of functional capacity in a population of patients with precapillary PH, as well as in a subgroup of patients with PAH. EmPHasis-10 score correlated with haemodynamic severity of the disease, as assessed by mPAP and PVR, as well as with prognostic markers of PAH, such as SvO2, and cardiac index. In the subgroup analysis of patients with PAH, no correlation with SvO2 was noted. This result may be attributed to the small sample size and is in line with findings from studies assessing other HRQoL questionnaires [14]. Our results possibly reflect the impact of haemodynamic profile
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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Table 2 Correlation between emPHasis-10 score with functional, neurohormonal, and haemodynamic parameters in patients with precapillary pulmonary hypertension. Parameters
Coefficient (r)
p-valuea
p-valuea
Adjusted coefficient (r)
b
WHO FC
0.54
<0.001
0.52
<0.001
6MWD (m)
–0.50
<0.001
–0.55
<0.001
Log10(NT-proBNP)
0.30
0.03
0.41
<0.01
RAP (mmHg)
0.025
0.86
0.002
0.99
mPAP (mmHg)
0.51
<0.001
0.52
0.001
CI (L/min/m2)
–0.24
1.12
–0.33
0.037
PVR (WU)
0.51
<0.001
0.56
<0.001
SvO2 (%)
–0.32
0.03
–0.36
0.022
Abbreviations: WHO FC, World Health Organization Functional Class; 6MWD; 6-minute walk distance; log10(NT-proBNP); N-terminal pro–brain natriuretic peptide; RAP, right atrial pressure; mPAP, mean pulmonary artery pressure; CI, cardiac index; PVR, pulmonary vascular resistance; WU, Wood units; SvO2, oxygen saturation in pulmonary artery. a
A p-value <0.05 is considered statistically significant.
b
Coefficient (r) is adjusted for age, sex, pulmonary hypertension group, and body mass index.
on quality of life and the effect of disease severity on functional and psychological aspects of daily life. In our study, PH patients’ HRQoL, as assessed by emPHasis score, was satisfactory and in accordance with patients’ functional status. WHO FC and 6MWD are known determinants of HRQoL in patients with PAH [2,7,8,15,16], indicating the great impact of functional capacity on patients’ everyday life. As patients may perceive the effects of impaired 6MWD differently, influenced by their premorbid status, comorbidities, lifestyle, and expectations, the correlation of emPHasis score with functional status probably reflects the influence of the latter on patients’
emotional status. This assumption could be validated with the use of various HRQoL questionnaires in patients with worse clinical and functional status, in whom the disease restricts their emotional status to a greater extent, a limitation that remains even after the initiation of advanced PAH treatment and improvement of indices of functional capacity [7,8,16,17]. In line with our results, generic, non–PH-specific HRQoL questionnaires, such as the MLHFQ and SF-36, apart from functional assessment of psychosocial parameters of daily life, have been found to be correlated with haemodynamics, such as cardiac index, SvO2, and right atrial pressure
Table 3 Correlation of emPHasis-10 score with functional, neurohormonal, and haemodynamic parameters in patients with pulmonary arterial hypertension. Parameters
Coefficient (r)
p-valuea
Adjusted coefficient (r)b
p-valuea
WHO FC
0.50
<0.01
0.52
<0.01
6MWD (m)
–0.42
0.016
–0.51
0.012
Number of PAH-specific drugs
0.41
<0.01
0.42
<0.01
Log10(NT-proBNP)
0.34
0.054
0.45
0.02
RAP (mmHg) mPAP (mmHg)
0.02 0.69
0.94 <0.001
0.06 0.86
0.80 <0.001
CI (L/min/m2)
–0.04
0.85
–0.11
0.60
PVR (WU)
0.58
<0.01
0.69
<0.01
SvO2 (%)
–0.36
0.065
–0.35
0.09
Abbreviations: WHO FC, World Health Organization Functional Class; 6MWD; 6-minute walk distance; PAH, pulmonary arterial hypertension; NT-proBNP, Nterminal pro–brain natriuretic peptide; RAP, right atrial pressure; mPAP, mean pulmonary artery pressure; CI, cardiac index; PVR, pulmonary vascular resistance; WU, Wood units; SvO2, oxygen saturation in pulmonary artery. a
A p-value <0.05 is considered statistically significant.
b
Coefficient (r) is adjusted for age, sex, and body mass index.
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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[7,12,16,18,19]. Mathai et al. [20] associated SF-36 score with survival; however, no association was found with haemodynamics. In addition, we demonstrated a significantly positive correlation between emPHasis-10 score and NTproBNP levels, highlighting that high values of NT-proBNP are indicative of poorer disease-related quality of life. However, the majority of scales that have been used to evaluate HRQoL are not PH specific and, thus, may not accurately capture the PH burden and also be less sensitive to change in HRQoL after treatment [4]. The CAMPHOR scale is the most widely used disease-specific scale for assessing HRQoL, but has limited application in routine clinical practice given its length (65 items), cost, and its limited availability [21]. EmPHasis-10 score is a disease-specific scale, which assesses HRQoL via only 10 items, a characteristic that makes it easy to deliver and evaluate [13]. Its relation with haemodynamics is of major clinical importance for the management of our patients with PH, because theoretically this could probably facilitate the reduction of repetition of RHCs in patients with lower scores or to unmask the need for a repeat RHC in certain populations, such as in patients with preserved indices of prognosis but unchanged high emPHasis scores after the initiation of advanced treatment for PAH. However, parameters such as socio-economic status and educational level have also been acknowledged as predictors of PAH, indicating the need to implement HRQoL measures in the clinical routine. To this extent, the emPHasis-10 scale might serve as a clinical endpoint in clinical trials, such as the 6MWD and WHO FC, enabling physicians to monitor patients more closely and optimise medical treatment.
Study Limitations A possible limitation of the study could be the fact that all participants came from a single tertiary referral centre. However, this is an expert centre in northern Greece, so the sample is considered to be representative of the population. The study population may be considered heterogeneous, as it includes patients from different PH groups, including patients with chronic lung disease who are usually excluded from similar studies [2,7,8,13,16]. However, the emPHasis-10 score was designed to assess HRQoL in all PH classification groups [13]. The lack of validation of the emPHasis-10 score for the Greek population may be considered a study limitation; however, the translation conducted was approved by the developers.
Conclusion This study indicates a relation of HRQoL, as evaluated with emPHasis-10 score, to major haemodynamic parameters in patients with precapillary PH and in the PAH subgroup. Further prospective studies are needed to evaluate whether emPHasis-10 score could be used as an endpoint to monitor response to PH-specific treatment and overall prognosis.
Disclosures This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author Contributions All authors have contributed equally to the manuscript.
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[19] Taichman DB, Shin J, Hud L, Archer-Chicko C, Kaplan S, Sager JS, et al. Health-related quality of life in patients with pulmonary arterial hypertension. Respir Res 2005;6:92. [20] Mathai SC, Suber T, Khair RM, Kolb TM, Damico RL, Hassoun PM. Health-related quality of life and survival in pulmonary arterial hypertension. Ann Am Thorac Soc 2016;13:31–9.
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ORIGINAL ARTICLE
Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension Alexandra Arvanitaki, MD, MSc a, Sophia Anastasia Mouratoglou, MD, PhD a, Alexandros Evangeliou, MD a, Vasilios Grosomanidis, MD, PhD b, Stavros Hadjimiltiades, MD, PhD a, Lemonia Skoura, MD, PhD c, Christos Feloukidis, MD a, Dimitrios Farmakis, MD a,d, Haralambos Karvounis, MD, PhD a, George Giannakoulas, MD, PhD a* a
Department of Cardiology, AHEPA University Hospital, Aristotle University of Thessaloniki, Greece Department of Anesthesiology and Intensive Care Medicine, AHEPA University Hospital, Thessaloniki, Greece c Department of Microbiology, AHEPA University Hospital, Thessaloniki, Greece d Cardiology Department, Papageorgiou General Hospital, Thessaloniki, Greece b
Received 3 July 2018; accepted 10 December 2018; online published-ahead-of-print xxx
Background
Precapillary pulmonary hypertension (PH) is characterised by compromised functional capacity and impaired quality of life. Assessment of haemodynamics is routinely used for initial diagnosis, follow-up, and risk stratification in these patients. The purpose of this study was to investigate the relation of health-related quality of life (HRQoL) as assessed by emPHasis-10 score, a self-assessment questionnaire assessing breathlessness, fatigue, control, and confidence, to haemodynamic and neurohormonal indices in patients with precapillary PH.
Method
This was a prospective cross-sectional study which included stable patients with precapillary PH. All patients underwent right heart catheterisation, 6-minute walk test, N-terminal pro–brain natriuretic peptide (NT-proBNP) measurement, and assessment of HRQoL with the emPHasis-10 scale.
Results
Overall, 54 patients were included (32 women; mean age, 58.4 14.6 yr). Mean emPHasis-10 score was 19.2 12.0. EmPHasis-10 score correlated with World Health Organization functional class (r = 0.52, p < 0.001), 6-minute walk distance (r=–0.56, p < 0.001), and log10(NT-proBNP) (r = 0.41, p < 0.01). A positive correlation of emPHasis-10 score with mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) and a negative correlation with mixed venous oxygen saturation and cardiac index was observed, after adjustment for age, sex, body mass index, and PH group. In a subgroup analysis of patients with pulmonary arterial hypertension (n = 34) there was a stronger correlation of emPHasis-10 score with mPAP (r = 0.86, p < 0.001) and PVR (r = 0.69, p < 0.01), but no correlation with cardiac index and mixed venous oxygen saturation.
Conclusions
Self-assessment of quality of life with the use of the emPHasis-10 score reflects functional capacity and is correlated with haemodynamic and neurohormonal indices of right heart dysfunction in patients with precapillary PH.
Keywords
Precapillary pulmonary hypertension Quality of life Haemodynamics NT- proBNP
*Corresponding author at: Department of Cardiology, AHEPA University Hospital, St. Kiriakidi 1, Thessaloniki, 54636, Greece. Tel.: +30 2310994830, Fax: +30 2310994673., Email: [email protected] © 2019 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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Introduction Pulmonary hypertension (PH) is associated with a variety of symptoms, such as breathlessness, fatigue, decreased exercise tolerance, syncope, and chest pain, as well as psychological impairment, that adversely affect patients’ health-related quality of life (HRQoL) [1,2]. Current medical targeted treatment has managed to alleviate symptoms, hinder disease progression, and improve survival. However, the burden of the disease on patients’ lives remains heavy and similar to that of other severe conditions, such as heart failure and chronic obstructive pulmonary disease [3]. In addition to symptoms, frequent hospitalisations, several adverse drug reactions, their route of ad28212821ministration (e.g., parenteral prostanoids), and oxygen therapy may have a negative impact on patients’ HRQoL [4]. The assessment of these patients relies mainly on baseline and serial functional and haemodynamic indices [5]. However, the need for repeated right heart catheterisations (RHC) and the limitations of the 6-minute walk test have led to the emergence of HRQoL as a potential useful tool in clinical practice [4]. Health-related quality of life has been increasingly acknowledged as a significant measure of the disease burden and overall wellbeing, since it is composed of both physical and mental parameters, the assessment of which may allow physicians to better understand the nature of the disease [4,6–8]. Various HRQoL questionnaires have been developed to measure the effects of PH on patients’ daily lives, such as the Cambridge Pulmonary Hypertension Outcome Survey (CAMPHOR) [8], the medical outcome study 36-Item Short Form (SF-36) [9], the Nottingham Health Profile [10], the Minnesota Living with Heart Failure Questionnaire (MLHFQ) [7], and the Euro Quality of Life (EuroQoL) [11,12]. However, the multidimensional nature of these tools limits their use in clinical practice. EmPHasis-10 is a recently developed, diseasespecific questionnaire that is easier to use and simple to score, as it consists of only 10 questions, assessing breathlessness, fatigue, control, and confidence [13]. In this cross-sectional study, we aimed to evaluate HRQoL in patients with stable precapillary PH using the emPHasis10 scale and to investigate its association with haemodynamics and neurohormonal indices of severity of right heart dysfunction.
Methods Study Design, Participants and Data Collection This was a prospective cross-sectional study conducted in a single PH centre. Patients aged 18 years with haemodynamically confirmed precapillary PH, according to the current guidelines [5], were eligible to participate in the study. Patients with postcapillary PH due to left heart disease were excluded. In addition, patients with serious mobility problems due to previous stroke, surgery, or musculoskeletal disease were also excluded.
Eligible patients were asked to complete a HRQoL questionnaire during an outpatient visit. Demographic, clinical, functional, and haemodynamic data were collected and N-terminal pro–brain natriuretic peptide (NT-proBNP) serum levels were also measured on the same day. In patients with cyanotic congenital heart disease a repeat RHC was not performed. The emPHasis-10 questionnaire was used for the evaluation of HRQoL in patients with precapillary PH. This is a PHspecific HRQoL questionnaire, which consists of 10 items, each on a scale of 0 - 5. Each patient had a score of 0 - 50. Higher scores indicate worse health status and quality of life. Important components of the impact of PH are covered in emPHasis-10, including breathlessness, fatigue and lack of energy, social restrictions, and concerns regarding effects on patients’ relatives [13]. A translated version of emPHasis-10 was used. The translation was carried out using translation– back translation and was approved by the original English developers. Each patient answered the questionnaire after optimal clarification was provided. The study personnel reviewed and ensured completeness and readability of entries prior to the participant leaving the site. The participant completed the questionnaire by using a normal pen (no pencil or whiteout/correction fluid was allowed). Written informed consent was obtained from all participants. The study was approved by the local ethics committee and performed according to the Declaration of Helsinki. Informed consent was obtained from all individual participants included in the study.
Statistical Analysis Data are presented as mean standard deviation for continuous variables or as median (range) as appropriate. Categorical variables are presented as absolute count and percentage (%). Univariable linear regression analysis was used to explore the linear correlation between emPHasis-10 score and functional, haemodynamic, and neurohormonal parameters. Then, a multivariable regression analysis was performed to adjust for age, sex, PH group, and body mass index (BMI). A subgroup analysis was conducted for patients with pulmonary arterial hypertension (PAH), in which the same correlations were sought. N-terminal pro–brain natriuretic peptide did not follow the normal distribution neither in the initial nor in the PAH analysis and therefore normal distribution was achieved using the common logarithm, log10(NT-proBNP). A p-value <0.05 was considered statistically significant. Data were analysed using SPSS version 24.0. for Windows (SPSS, Armonk, NY, USA).
Results Demographics Demographics of the total PH population and PAH (group 1 PH) are presented in Table 1. The study included
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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54 consecutive patients with precapillary PH, of whom 32 (59%) were women. Mean age and BMI were 58.4 years and 24.8 kg/m2, respectively. Almost two-thirds of the patient population suffered from PAH. The median duration of disease since diagnosis was 2 years. The most common comorbidities were arterial hypertension, smoking, and obesity. The majority of patients with PAH (65%) were under monotherapy, while 18% received a triple combination.
Table 1. (continued). Total
CI (L/min/m2) PVR (WU)
2.9 0.8 6.1 3.1
3.1 0.9 6.1 3.4
SvO2 (%)
69.2 7.4
70.3 6.4
HR (bpm)
79.5 16.0
78.3 15.3
PAH-specific treatment
Table 1 Patients’ characteristics. Total
PAH
PAH
PH population (n = 34) (n = 54)
n = 34
Monotherapy
22 (65)
Double combination
6 (18)
Triple combination
6 (18)
PH population (n = 34) (n = 54)
Categorical variables are presented as n (%). Continuous variables are presented as mean standard deviation or as median (range).
Age (yr)
58.4 14.6
57.9 16.3
Female sex
32 (59)
22 (65)
BMI (kg/m2)
24.8 5.9
26.9 6.3
Duration of disease (yr)
2.0 (0.5 - 10.0)
2.0 (0.5 - 10.0)
PH classification Group 1 Idiopathic
34 (63)
or multifactorial mechanisms; WHO FC; World Health Organization
5 (15)
Functional Class; 6MWD, 6-minute walk distance; NT-proBNP, N-term-
Group 1, pulmonary arterial hypertension; Group 3, pulmonary hypertension due to lung disease; Group 4, chronic thromboembolic pulmonary hypertension; Group 5, pulmonary hypertension with unclear and/
Heritable 1 (3) Connective tissue disease 13 (38) Congenital heart disease 12 (35) Portal hypertension
3 (9)
Group 3
7 (13)
Group 4 Group 5
10 (18) 3 (6)
inal pro–brain natriuretic peptide; RAP; right atrial pressure; mPAP; mean pulmonary artery pressure; PAWP; pulmonary artery wedge pressure; CI; cardiac index; PVR; pulmonary vascular resistance; WU, Wood units; SvO2; oxygen saturation in pulmonary artery; HR, heart rate; bpm, beats per min.
Comorbidities Atrial fibrillation
4 (7)
2 (6)
Arterial hypertension
37 (69)
10 (29)
Diabetes mellitus
7 (13)
7 (21)
Dyslipidaemia
11 (20)
5 (15)
Coronary artery disease
3 (6)
1 (3)
Chronic kidney disease Liver disease
2 (4) 6 (11)
0 4 (12)
History of pulmonary
9 (17)
1 (3)
Thyroid disease
9 (17)
5 (15)
Obesity
18 (33)
11 (32)
Smoking
22 (41)
10 (29)
Depression
3 (6)
1 (3)
embolism
Functional and neurohormonal indices WHO FC I
7 (13)
3 (9)
II
35 (65)
24 (70)
III
10 (18)
5 (15)
IV
2 (4)
2 (6)
6MWD (m)
438.3 123.6
451.7 113.3
NT-proBNP (pg/mL)
244 (37 - 4651)
238 (37 - 2994)
19.2 12.0 n = 47
19.1 11.4 n = 27
RAP (mmHg)
6.8 3.1
6.8 2.8
mPAP (mmHg)
40.7 12.6
42.0 13.9
PAWP (mmHg)
11.0 2.7
11.3 2.5
emPHasis-10 score Haemodynamics
Abbreviations: PH, pulmonary hypertension; PAH, pulmonary arterial hypertension; BMI, body mass index; PH, pulmonary hypertension;
Functional, Neurohormonal, and Haemodynamic Indices Functional, neurohormonal, and haemodynamic parameters are presented in Table 1. The majority of patients (78%) reported no or mild symptoms [World Health Organization Functional Class (WHO FC) I/II], while mean 6minute walk distance (6MWD) was 438.3 metres. Based on functional, neurohormonal, and haemodynamic parameters, such as right atrial pressure and cardiac index, the majority of patients with PAH were classified as low risk (1-year mortality risk <5%) according to 2015 European PH guidelines [5].
Correlations of emPHasis-10 Score with Functional and Neurohormonal Indices All participants completed the emPHasis-10 without difficulties. Mean emPHasis-10 score was 19.2 (range, 1– 42). In the study population there was a correlation between emPHasis-10 score and WHO FC (r = 0.54, p < 0.001), 6MWD (r=–0.50, p < 0.001), and log10(NT-proBNP) (r = 0.30, p = 0.03) (Figure 1A,B; Table 2). After adjustment for age, sex, and BMI, these correlations were maintained, while the correlation between emPHasis-10 score and log10(NT-proBNP) became stronger (r = 0.41, p < 0.01). In the PAH group, similar correlations were observed (Table 3).
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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Figure 1 Correlation of emPHasis-10 score with functional, neurohormonal, and haemodynamic parameters in the total population of patients with precapillary pulmonary hypertension. (A) Scatterplot presents the correlation of emPHasis-10 score with 6-minute walk distance (6MWD). (B) Scatterplot presents the correlation of emPHasis-10 score with log10[N-terminal pro–brain natriuretic peptide (NT-proBNP)]. (C) Scatterplot presents the correlation of emPHasis-10 score with mean pulmonary artery pressure (mPAP). (D) Scatterplot presents the correlation of emPHasis-10 score with pulmonary vascular resistance (PVR).
In the PAH subgroup emPHasis-10 score correlated with the number of administered PAH-specific drugs (r = 0.45, p < 0.01).
Correlations of emPHasis-10 Score with Haemodynamic Parameters In the study population there was a correlation between emPHasis-10 score and mean pulmonary artery pressure (mPAP; r = 0.51, p < 0.001), pulmonary vascular resistance (PVR; r = 0.51, p < 0.001), and oxygen saturation in pulmonary artery (SvO2%; r=–0.32, p = 0.03) (Figure 1C,D; Table 2). After adjustment for age, sex, and BMI, these correlations were maintained, while a negative correlation between emPHasis-10 score and cardiac index also emerged (r=–0.33, p = 0.037). In the PAH subgroup, there were stronger correlations between emPHasis-10 score and mPAP and PVR, but no correlation with SvO2 was noted (Table 3).
Discussion This study investigated the relation of HRQoL, as assessed with emPHasis-10, a validated, disease-specific and simpleto-use scoring tool, with the haemodynamic parameters of disease severity in patients with precapillary PH. In addition, we explored the relation of emPHasis-10 score with NTproBNP and markers of functional capacity in a population of patients with precapillary PH, as well as in a subgroup of patients with PAH. EmPHasis-10 score correlated with haemodynamic severity of the disease, as assessed by mPAP and PVR, as well as with prognostic markers of PAH, such as SvO2, and cardiac index. In the subgroup analysis of patients with PAH, no correlation with SvO2 was noted. This result may be attributed to the small sample size and is in line with findings from studies assessing other HRQoL questionnaires [14]. Our results possibly reflect the impact of haemodynamic profile
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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Table 2 Correlation between emPHasis-10 score with functional, neurohormonal, and haemodynamic parameters in patients with precapillary pulmonary hypertension. Parameters
Coefficient (r)
p-valuea
p-valuea
Adjusted coefficient (r)
b
WHO FC
0.54
<0.001
0.52
<0.001
6MWD (m)
–0.50
<0.001
–0.55
<0.001
Log10(NT-proBNP)
0.30
0.03
0.41
<0.01
RAP (mmHg)
0.025
0.86
0.002
0.99
mPAP (mmHg)
0.51
<0.001
0.52
0.001
CI (L/min/m2)
–0.24
1.12
–0.33
0.037
PVR (WU)
0.51
<0.001
0.56
<0.001
SvO2 (%)
–0.32
0.03
–0.36
0.022
Abbreviations: WHO FC, World Health Organization Functional Class; 6MWD; 6-minute walk distance; log10(NT-proBNP); N-terminal pro–brain natriuretic peptide; RAP, right atrial pressure; mPAP, mean pulmonary artery pressure; CI, cardiac index; PVR, pulmonary vascular resistance; WU, Wood units; SvO2, oxygen saturation in pulmonary artery. a
A p-value <0.05 is considered statistically significant.
b
Coefficient (r) is adjusted for age, sex, pulmonary hypertension group, and body mass index.
on quality of life and the effect of disease severity on functional and psychological aspects of daily life. In our study, PH patients’ HRQoL, as assessed by emPHasis score, was satisfactory and in accordance with patients’ functional status. WHO FC and 6MWD are known determinants of HRQoL in patients with PAH [2,7,8,15,16], indicating the great impact of functional capacity on patients’ everyday life. As patients may perceive the effects of impaired 6MWD differently, influenced by their premorbid status, comorbidities, lifestyle, and expectations, the correlation of emPHasis score with functional status probably reflects the influence of the latter on patients’
emotional status. This assumption could be validated with the use of various HRQoL questionnaires in patients with worse clinical and functional status, in whom the disease restricts their emotional status to a greater extent, a limitation that remains even after the initiation of advanced PAH treatment and improvement of indices of functional capacity [7,8,16,17]. In line with our results, generic, non–PH-specific HRQoL questionnaires, such as the MLHFQ and SF-36, apart from functional assessment of psychosocial parameters of daily life, have been found to be correlated with haemodynamics, such as cardiac index, SvO2, and right atrial pressure
Table 3 Correlation of emPHasis-10 score with functional, neurohormonal, and haemodynamic parameters in patients with pulmonary arterial hypertension. Parameters
Coefficient (r)
p-valuea
Adjusted coefficient (r)b
p-valuea
WHO FC
0.50
<0.01
0.52
<0.01
6MWD (m)
–0.42
0.016
–0.51
0.012
Number of PAH-specific drugs
0.41
<0.01
0.42
<0.01
Log10(NT-proBNP)
0.34
0.054
0.45
0.02
RAP (mmHg) mPAP (mmHg)
0.02 0.69
0.94 <0.001
0.06 0.86
0.80 <0.001
CI (L/min/m2)
–0.04
0.85
–0.11
0.60
PVR (WU)
0.58
<0.01
0.69
<0.01
SvO2 (%)
–0.36
0.065
–0.35
0.09
Abbreviations: WHO FC, World Health Organization Functional Class; 6MWD; 6-minute walk distance; PAH, pulmonary arterial hypertension; NT-proBNP, Nterminal pro–brain natriuretic peptide; RAP, right atrial pressure; mPAP, mean pulmonary artery pressure; CI, cardiac index; PVR, pulmonary vascular resistance; WU, Wood units; SvO2, oxygen saturation in pulmonary artery. a
A p-value <0.05 is considered statistically significant.
b
Coefficient (r) is adjusted for age, sex, and body mass index.
Please cite this article in press as: Arvanitaki A, et al. Quality of Life is Related to Haemodynamics in Precapillary Pulmonary Hypertension. Heart, Lung and Circulation (2019), https://doi.org/10.1016/j.hlc.2018.12.005
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[7,12,16,18,19]. Mathai et al. [20] associated SF-36 score with survival; however, no association was found with haemodynamics. In addition, we demonstrated a significantly positive correlation between emPHasis-10 score and NTproBNP levels, highlighting that high values of NT-proBNP are indicative of poorer disease-related quality of life. However, the majority of scales that have been used to evaluate HRQoL are not PH specific and, thus, may not accurately capture the PH burden and also be less sensitive to change in HRQoL after treatment [4]. The CAMPHOR scale is the most widely used disease-specific scale for assessing HRQoL, but has limited application in routine clinical practice given its length (65 items), cost, and its limited availability [21]. EmPHasis-10 score is a disease-specific scale, which assesses HRQoL via only 10 items, a characteristic that makes it easy to deliver and evaluate [13]. Its relation with haemodynamics is of major clinical importance for the management of our patients with PH, because theoretically this could probably facilitate the reduction of repetition of RHCs in patients with lower scores or to unmask the need for a repeat RHC in certain populations, such as in patients with preserved indices of prognosis but unchanged high emPHasis scores after the initiation of advanced treatment for PAH. However, parameters such as socio-economic status and educational level have also been acknowledged as predictors of PAH, indicating the need to implement HRQoL measures in the clinical routine. To this extent, the emPHasis-10 scale might serve as a clinical endpoint in clinical trials, such as the 6MWD and WHO FC, enabling physicians to monitor patients more closely and optimise medical treatment.
Study Limitations A possible limitation of the study could be the fact that all participants came from a single tertiary referral centre. However, this is an expert centre in northern Greece, so the sample is considered to be representative of the population. The study population may be considered heterogeneous, as it includes patients from different PH groups, including patients with chronic lung disease who are usually excluded from similar studies [2,7,8,13,16]. However, the emPHasis-10 score was designed to assess HRQoL in all PH classification groups [13]. The lack of validation of the emPHasis-10 score for the Greek population may be considered a study limitation; however, the translation conducted was approved by the developers.
Conclusion This study indicates a relation of HRQoL, as evaluated with emPHasis-10 score, to major haemodynamic parameters in patients with precapillary PH and in the PAH subgroup. Further prospective studies are needed to evaluate whether emPHasis-10 score could be used as an endpoint to monitor response to PH-specific treatment and overall prognosis.
Disclosures This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Author Contributions All authors have contributed equally to the manuscript.
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