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ORIGINAL CLINICAL SCIENCE

Emotional symptoms and quality of life in patients with pulmonary arterial hypertension Jasper M.M. Vanhoof, MSN,a Marion Delcroix, MD, PhD,b Ellen Vandevelde, MSN,b Kris Denhaerynck, MSN, PhD,c Wim Wuyts, MD, PhD,b Catharina Belge, MD, PhD,b and Fabienne Dobbels, PhDa From the aHealth Services and Nursing Research, Department of Public Health and Primary Care; bRespiratory Division, University Hospitals, and Department of Clinical and Experimental Medicine, University of Leuven, (KU Leuven) Leuven, Belgium; and the cTriloStatistical Consultancy, Basel, Switzerland.

KEYWORDS: Pulmonary arterial hypertension; psychological functioning; mood problems; quality of life

BACKGROUND: Limited evidence exists on the nature and degree of emotional problems in pulmonary arterial hypertension (PAH) and their association with patients’ health-related quality of life (HRQOL). METHODS: This cross-sectional study examined the presence of depression, anxiety, and stress symptoms, and their association with disease-specific and generic HRQOL. A total of 101 patients (73% women) with PAH (age, 55.4 ⫾ 16.4 years; 42.6% in New York Heart Association [NYHA] class II) completed the Depression, Anxiety, and Stress Scale, the generic Medical Outcomes Study Short-Form 36-Item (SF-36) Health Survey, and the disease-specific Minnesota Living With Heart Failure Questionnaire (MLHFQ) HRQOL instrument. The association between emotional problems and HRQOL was determined using multivariable linear regression analyses, controlling for demographic and disease-related characteristics. RESULTS: Of the patients, 32.6%, 48%, and 27.6% experienced depressive, anxiety or stress symptoms, respectively. HRQOL was 41 standard deviation below population norms for the SF-36 Physical Component Summary. Depressive symptoms, NYHA class, and being disabled explained 46% of the total variance of the MLHFQ. Emotional problems did not contribute to the SF-36 Physical Component Summary but explained part of the variance of the physical sub-scales of the SF-36 role limitations due to physical problems, bodily pain, and general health. CONCLUSIONS: The high presence of emotional problems warrants regular screening and appropriate psychotherapeutic and/or pharmacological treatment. Which strategies could improve PAH patients’ HRQOL remains to be investigated. J Heart Lung Transplant ]]]];]:]]]–]]] r 2014 International Society for Heart and Lung Transplantation. All rights reserved.

Pulmonary arterial hypertension (PAH) is a rare, complex, hemodynamic and pathophysiological condition with a poor prognosis.1 Symptoms, especially in the beginning, are vague and nonspecific, including fatigue, Reprint requests: Fabienne Dobbels, PhD, Health Services and Nursing Research, Department of Public Health and Primary Care, University of Leuven, Kapucijnenvoer 35/4, B-3000 Leuven, Belgium. Telephone: þ3216-33-69-81. E-mail address: [email protected]

shortness of breath, palpitations, edema of the lower limbs, and syncope.2 Diagnosis might take years, which can result in anxiety and stress.3 When PAH is finally diagnosed, new stressors may occur. Worries about heredity, disease progression, and outcome are just a few examples.3 Patients are also physically strongly limited and need to follow a complex and sometimes painful pharmacotherapy, all of which might significantly affect their health-related quality of life (HRQOL).4 This, together with the fact that patients

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often do not look sick to outsiders, can cause problems in their professional and personal lives.3 Newer treatments are improving life expectancy, but survival is still sub-optimal, and patients must learn to manage their complex treatments and the accompanying feelings of anxiety, depression, and insecurity in their daily lives.3,4 Although most clinicians are aware of the illness burden, surprisingly little evidence exists on the exact nature and degree of psychologic problems and their relationship with the PAH patient’s HRQOL. Recent articles found prevalences of depressive disorder of between 7.5% and 26%5–8 and depressive symptoms ranging from 10% to 55%.9–12 Only 4 reports focused on anxiety, describing moderate to severe anxiety in 9% to 20.5% of patients.5,6,8,9 No studies on feelings of stress could be found. It is important to emphasize that all of the few studies were conducted in the United States,5–12 used relatively small samples of approximately 50 patients only,5,6,7,12 and did not focus exclusively on PAH patients7,8,12 or also enrolled pediatric patients.8,12 Moreover, although some reports describe their HRQOL,5,9,13 the association between depressive, anxiety and stress symptoms with PAH patients’ HRQOL is not well described. We therefore aimed to (1) quantify the presence of depressive, anxiety, and stress symptoms in adults with PAH and (2) investigate their HRQOL and its association with psychologic symptoms.

Methods Design, sample, and setting This cross-sectional study included all Dutch-speaking patients monitored at the outpatient clinic of the Center for Pulmonary Vascular Diseases of the University Hospitals of Leuven who were aged Z 18 years, gave written informed consent, and had PAH (i.e., idiopathic, heritable, drug-induced, toxin-induced, or associated with connective tissue disease, HIV infection, portal hypertension, or congenital heart disease). Diagnosis of PAH was set by standard criteria of a mean pulmonary artery pressure Z 25 mm Hg and a pulmonary capillary wedge pressure r 15 mm Hg at right-sided heart catheterization. Excluded were patients with pulmonary hypertension due to left-sided heart disease, lung diseases, and/or hypoxemia, chronic thromboembolic pulmonary hypertension, and pulmonary hypertension with unclear and/or multifactorial mechanisms.

Depression, anxiety, and stress The Depression Anxiety Stress Scale (DASS) is a validated selfreport instrument consisting of 3 sub-scales measuring symptoms of depression, anxiety, and stress on 7 items each. Items have 4 response options increasing in degree of severity, and scores are summed and multiplied by 2, with higher scores reflecting higher severity. The cutoffs to classify patients as having no, mild, moderate, severe, and extremely severe symptoms are presented in Table 2.14

HRQOL assessment State-of-the-art measurement recommends the use of both a disease-specific and a generic HRQOL instrument. In the absence of a validated Dutch PAH-specific instrument, we used the Dutch version of the Minnesota Living With Heart Failure Questionnaire (MLHFQ).15,16 Although the MLHFQ was originally developed for heart failure patients, previous studies have used it in PAH patients.13,17 It consists of 21 statements measuring the effects of symptoms, psychologic distress, and functional limitation on HRQOL, expressed on a 6-point Likert scale, ranging from 0 to 5. Item scores are summed, yielding a total score between 0 and 105, with higher scores reflecting a poorer HRQOL.16 The Medical Outcomes Study Short-Form 36-Item Health Survey (SF-36) is a well-validated, generic questionnaire18,19 consisting of physical functioning, physical role functioning, bodily pain, and general health, and the four mental sub-scales of vitality, social functioning, emotional role functioning, and mental health. Sub-scale scores range from 0 to 100, with higher scores indicating a better HRQOL. Sub-scales can be further grouped in 2 summary measures, a physical component summary (PCS) and a mental component summary (MCS) measure, with a mean score of 50 and a standard deviation (SD) of 10, representing a HRQOL comparable to that of the general population.19 The SF36 physical sub-scale scores of patients were compared with gender-matched and age-matched SF-36 scores derived from the general Dutch population norms.20

Procedure

Variables and measurement

The study was approved by the hospital’s Ethics Committee and conducted in concordance with the Declaration of Helsinki and the guideline of “Good Clinical Practice.”21,22 Eligible patients were contacted by telephone between January and March 2012 and informed about the study in a standardized way. Patients could participate in 2 ways: by completing the questionnaire during a scheduled appointment or at home using a paper and pencil version or by a secured e-mail link. Patients who did not respond were contacted by phone once. All patients provided written informed consent. Questionnaires were coded, allowing for anonymous analyses.

Demographic and clinical characteristics

Statistical analysis

Demographic characteristics and information on past or current psychiatric hospitalizations and/or ambulatory psychotherapy were collected by self-report. Employment status and use of psychopharmacotherapy was obtained by medical record review, as well as clinical characteristics, including date of diagnosis, type of PAH, New York Heart Association (NYHA) functional class, 6-minute walking distance (6MWD), and type of therapy (Table 1 provides a detailed list).

Descriptive statistics were used as appropriate to describe the sample and to quantify the presence of depressive, anxiety and stress symptoms, as well as the patients’ disease-specific and generic HRQOL. Analyses were done with SPSS 20 software (IBM Corp, Armonk, NY). The difference between patients with and without emotional symptoms regarding demographics, clinical characteristics and HRQOL was explored by independent t-testing, Mann Whitney U-test or the chi-square/Fisher’s exact test,

Vanhoof et al. Table 1

Emotional Problems and HRQOL in PAH

Demographics and Clinical Characteristics

Characteristics Women, No. (%) Age, mean ⫾ SD, years Time from PAH diagnosis, median (IQR) range, years Marital status, No. (%) Single Married/living together Divorced Widow/widower Living situation, No. (%) Living alone Living together With partner With partner and children With parents With children Children, median (IQR) range, No. Employment (n ¼ 100), No. (%) Retired Disabled Unemployed Student Housewife Employed Half-time Full-time Type of PAH, No. (%) Idiopathic Connective tissue diseases Congenital heart disease Drugs and/or toxins induced Portal hypertension Heritable NYHA classes, No. (%) I II III IV 6MWD, mean ⫾ SD, meters RAPa (n ¼ 91), mean ⫾ SD mm Hg MPAPa (n ¼ 99), mean ⫾ SD mm Hg CIa (n ¼ 88), mean ⫾ SD liters/min/m PVRa (n ¼ 95), mean ⫾ SD dyn  sec  cm-5 TAPSE, mean ⫾ SD mm Pericardial effusion (n ¼ 74), No. (%) Absent Trace Diastolic separation 4 1cm CRPb (n ¼ 77), mean ⫾ SD mg/1iter Type of therapy, No. (%) Prostacyclin analogs Intravenous Subcutaneous Inhalation None Endothelin receptor antagonists Phosphodiesterase 5 inhibitors Combination Oral therapies

Total PAH group (N ¼ 101) 74 (73.3) 55.4 ⫾ 16.4 4 (1–9) 0–23

25 61 6 9

(24.8) (60.4) (5.9) (8.9)

23 (22.8) 45 19 8 6 2

(44.6) (18.8) (7.9) (5.9) (0–3) 0–5

26 35 4 5 16 14 3 11

(26.0) (35.0) (4.0) (5.0) (16.0) (13.9) (3.0) (11.0)

33 18 17 13 12 8

(32.7) (17.8) (16.8) (12.9) (11.9) (7.9)

19 (18.8) 43 (42.6) 32 (31.7) 7 (6.9) 392 ⫾ 162 9⫾5 53 ⫾ 16 2.26 ⫾ 0.67 977 ⫾ 544 10 ⫾ 23 65 (87.8) 7 (9.5) 2 (2.7) 3.64 ⫾ 3.76

8 8 1 84 70 57

(7.9) (7.9) (1.0) (83.2) (69.3) (56.4)

26 (25.7)

3 Table 1 (Continued )

Characteristics 1 oral and 1 prostacyclin analog 2 oral and 1 prostacyclin analog None Study medication Oral medication Intravenous prostacyclin analog None Current smoking behavior (n ¼ 71), No. (%) Oxygen (n ¼ 100), No. (%) Use Frequency Continuously Night Evening Use of psychopharmacological drugs, No. (%) Anti-psychotics Benzodiazepines Anti-depressants Hypnotics Former hospitalization in psychiatric hospital, No. (%) Consultation of psychologist in past year, No. (%) Currently in therapy with psychologist/ psychiatrist, No. (%)

Total PAH group (N ¼ 101) 1 (1.0) 16 (15.8) 58 (57.4) 18 4 79 8

(17.8) (4.0) (78.2) (11.3)

26 19 6 1

(26.0) (19.0) (6.0) (1.0)

5 27 17 12 8

(5.0) (26.7) (16.8) (11.9) (7.9)

12 (11.9) 6 (5.9)

6MWD, 6-minute walking distance; CI, cardiac index; CRP, C-reactive protein; IQR, interquartile range (25th percentile–75th percentile); mPAP, mean pulmonary arterial pressure; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; RAP, right atrial pressure; SD, standard deviation; TAPSE, tricuspid annular plane systolic excursion. a At time of PAH diagnosis. b Owing to the detection limits of the CRP measurement test, CRP values of o 0.6 mg/liter were arbitrarily assigned as 0.6 mg/liter.

depending on the measurement level and the distribution of the variable under scrutiny. Patients’ SF-36 scores were compared with the matched general population scores by independent t-test. A p o 0.05 represented statistical significance. Three general linear models were built to determine the association of demographic and clinical characteristics and depression, anxiety, and stress, with the (1) total MLHFQ, (2) SF-36 PCS, and (3) SF-36 MCS, respectively. Yet, given the substantial correlation between the DASS scores and the SF-36 MCS (r ¼ –0.815 for depressive, r ¼ –0.608 for anxiety, and r ¼ –0.661 for stress symptoms), suggesting conceptual overlap, the MCS model is only model presented for sake of completeness. Next, general linear models were subsequently built for the 4 physical sub-scales constituting the PCS. Underlying assumptions of linearity, constant variance, and normality were evaluated, transformations were applied, if needed, and variables were screened for colinearity. All variables with a p o 0.20 in the univariable models were entered in each multivariable model. Next, the least significant variable was excluded from the model until only significant variables remained.

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Table 2 Severity of Depressive, Anxiety, and Stress Symptoms in Pulmonary Arterial Hypertension Patients According to the Depression Anxiety Stress Scalea Severity of symptoms Depressive symptoms No symptoms Mild Moderate Severe Extremely severe Total score Anxiety symptoms No symptoms Mild Moderate Severe Extremely severe Total score Stress symptoms No symptoms Mild Moderate Severe Extremely severe Total score

Score range

Patients, No (%)

0–9 10–13 14–20 21–27 Z28

(n ¼ 98) 66 (67.4) 12 (12.2) 5 (5.1) 7 (7.1) 8 (8.2)

0–7 8–9 10–14 15–19 Z20

(n ¼ 100) 52 (52) 7 (7.0) 17 (17.0) 10 (10.0) 14 (14.0)

0–14 15–18 19–25 26–33 Z34

(n ¼ 98) 71 (72.5) 11 (11.2) 8 (8.2) 4 (4.1) 4 (4.1)

Mean ⫾ SD

(p ¼ 0.03), anxious patients had lower 6MWD scores than non-anxious patients (p ¼ 0.02), and stressed patients had higher baseline cardiac indices (p ¼ 0.036), used more endothelin receptor antagonists (p ¼ 0.049), and more frequently visited a psychologist in the past year (p ¼ 0.017) than patients without stress. NYHA class was also worse in patients with depressive (p ¼ 0.01), anxiety (p o 0.001), or stress symptoms (p ¼ 0.006) than in those without these symptoms (data not shown).

HRQOL assessments 20.19 ⫾ 9.02

16.54 ⫾ 7.69

Total MLHFQ score was 36.47 ⫾ 23.46 (range, 0–96; n ¼ 94). The mean SF-36 PCS score was 33.53 ⫾ 10.43 (range 14.68–53.13; n ¼ 99), which is more than 1 SD lower than the general population. The MCS was 49.81 ⫾ 12.66 (range 13.96–70.88; n ¼ 99), which closely resembles the general population mean. The age-matched and gender-matched data derived from the Dutch population for the 8 SF-36 subscales are depicted in Figure 1A–C.

Association between depression, anxiety, stress, and HRQOL 22.89 ⫾ 7.22

SD, Standard deviation. a Some patients had incomplete data.

Results Patient characteristics Of 142 patients who were contacted, 32 did not meet the inclusion criteria, 8 refused to participate, and 1 patient did not return the questionnaire, yielding a response rate of 101 of 110 (91.8%). Most patients (73.3%) were women, mean age was 55.4 ⫾ 16.4 years, and only a minority were employed. Median time from PAH diagnosis was 4 years (25th percentile, 1; 75th percentile, 9; range, 0–23 years). Idiopathic PAH was present in 32.7%, and 42.6% were in NYHA class II. Table 1 summarizes patient demographic and clinical characteristics.

Presence of emotional symptoms Thirty-two patients (32.6%) experienced depressive symptoms, 48 (48.0%) symptoms of anxiety, and 27 (27.6%) stress symptoms (Table 2). A high correlation was observed between depressive and anxiety (r ¼ 0.778; p o 0.001), depressive and stress (p o 0.800), and anxiety and stress symptoms (r ¼ 0.776; p o 0.001) was observed (data not shown). Of the 32 depressed patients, 7 (21.9%) took antidepressants, 6 (18.8%) had consulted a psychologist in the past year, and 4 (12.5%) were presently receiving psychotherapy. Depressed patients used more phosphodiesterase 5 inhibitors than patients without depressive symptoms

The MLHFQ and the SF-36 HRQOL scores in patients with and without emotional symptoms are described in Table 3 and in Figure 1A–C, respectively. The mean total MLHFQ score differed significantly between patients with and without depressive symptoms (t ¼ 5.45, p o .001). For the SF-36, lower mean sub-scale MCS and PCS scores were found between both groups, although the physical functioning subscale (t ¼ 1.57, p ¼ .120) and PCS (t ¼ –1.13, p ¼ 0.26) did not reach statistical significance. All physical functioning subscales were significantly lower for patients with and without depressive symptoms compared with their age-matched and gender-matched counterparts (Figure 1A), with the exception of bodily pain, which was not statistically different in the nondepressed group (data available upon request). Lower mean MLHFQ and SF-36 HRQOL scores were also observed for patients with vs those without anxiety symptoms, as well as between those with and without elevated stress. Yet again, no significant difference was found for physical functioning and the PCS between patients with and without elevated stress levels. SF-36 physical sub-scale scores of patients with or without anxiety symptoms (Figure 1B) and of patients with or without stress symptoms (Figure 1C) were again significantly lower than those of a gender-matched and age-matched general population, except for bodily pain, which was similar in the non-stress group (p ¼ 0.318) and significantly better in the non-anxious group (p ¼ 0.025). Table 4 reports the general linear models for the 3 HRQOL outcomes. The model for MLHFQ shows that NYHA class (β ¼ 6.36, p ¼ .011), depressive symptoms (β ¼ 1.25, p o .001), and being disabled compared with those who were employed (β ¼ 10.90, p ¼ .050) explained 46% of the total variance (adjusted R2 ¼ 0.464). In this model, depressive symptomatology can be replaced by anxiety or stress

Vanhoof et al.

Emotional Problems and HRQOL in PAH

symptoms, yielding similar results. In the PCS model, only NYHA class (β ¼ –4.47, p ¼ .001) and the 6MWD (β ¼ .02, p ¼ .025) explained 26% (adjusted R2 ¼ 0.259) of the variance. Table 5 illustrates that depressive symptoms, besides NYHA and/or 6MWD, explained part of the variance in all

5 models of the SF-36 physical sub-scales, except for physical functioning.

Discussion Our study yields some innovative insights. Symptoms of stress, depression, and especially anxiety seem to affect approximately 25% to almost 50% of the patients. Moreover, PAH patients’ HRQOL, particularly in view of physical functioning, is poor and more than 1 SD lower than that of the general population. Very few studies have examined the presence of emotional problems in PAH. The 32.6% rate of depressive symptoms in our sample is in line with published data, ranging from 10% to 55%.9–12 Symptoms were severe or very severe in 15.3% of our patients, suggestive of depressive disorder, which corresponds to the few studies published,5–8 although they mostly used smaller samples,5,6,7,12 included pediatric patients8,12 or those with conditions other than PAH,7,8,12 or did not describe how they classified patients in the depression group. Two recent meta-analyses documented a prevalence of depressive symptoms in 21.5% in heart failure and 24.6% in chronic obstructive pulmonary disease, highlighting that depressive symptoms are more frequent in patients with PAH.23,24 The reasons for the high presence of anxiety symptoms (48%) in our study should not be considered farfetched, given the nature and progression of PAH, but is nevertheless much higher than the numbers documented in 4 other studies (i.e., 20.5%,5 19.6%,6 10.4%,8 and 9%9). Comparisons are difficult, however, because the first 2 studies only represented the “moderate to severe” ratings. Our score from moderate to extremely severe would be 41%, which is still much higher. One study8 focused on panic attacks exclusively, covering only a small portion of the anxiety spectrum, and included patients aged o 18 years as well, and the latter used a non-validated measure or at least did not describe how they classified patients into the anxious Figure 1 (A) Comparison of means between patients with and without (A) depressive symptoms, (B) anxiety symptoms, and (C) stress symptoms and Dutch norm data for the 8 Medical Outcome Study Short-Form 36-Item Health Survey sub-scales (BP, bodily pain; GH, general health; MH, mental health; PF, physical functioning; RE, role-emotional; RP, role-physical; SF, social functioning; and VT, vitality). Higher scores indicate betterperceived health status. Comparison between patients with and without symptoms and norm data, unpaired t-test, level of significance: p o .05 (2-tailed). (A) A, significant difference between depressed and non-depressed patients; B, significant difference between depressed patients and matched norm data; C, significant difference between non-depressed patients and matched norm data. (B) A, significant difference between anxious and nonanxious patients; B, significant difference between anxious patients and matched norm data; C, significant difference between nonanxious patients and matched norm data. (C) A, significant difference between stressed and non-stressed patients; B, significant difference between stressed patients and matched norm data; C, significant difference between non-stressed patients and matched norm data.

o0.001 (–6.069)

0.107 (–1.626)

n ¼ 71 34.61 ⫾ 10.05 (14.71–53.13) n ¼ 71 53.90 ⫾ 10.05 (17.08–70.88) o0.001 (–4.146)

n ¼ 26 30.73 ⫾ 11.38 (14.68–51.49) n ¼ 26 38.95 ⫾ 12.49 (13.96–57.14) o0.001 (–7.557)

0.260 (–1.130)

n ¼ 52 36.97 ⫾ 9.96 (18.39–53.13) n ¼ 52 54.53 ⫾ 9.40 (29.53–69.67) n ¼ 47 29.72 ⫾ 9.67 (14.68–51.49) n ¼ 47 44.59 ⫾ 13.79 (13.96–70.88) n ¼ 65 34.53 ⫾ 10.53 (14.71–53.13) n ¼ 65 55.68 ⫾ 8.07 (32.00–70.88)

o0.001 (–3.666)

n ¼ 68 o0.001 29.18 ⫾ 19.02 (0–73) (5.549) n ¼ 25 55.72 ⫾ 24.01 (4–96) n ¼ 44 n ¼ 50 o0.001 50.16 ⫾ 21.68 (14–96) 24.42 ⫾ 17.75 (0–65) (6.325) n ¼ 64 o0.001 28.30 ⫾ 19.44 (0–72) (5.446)

MLHFQb Total n ¼ 29 52.76 ⫾ 21.41 (4–96) SF-36c PCS n ¼ 32 31.97 ⫾ 10.32 (14.68–51.49) MCSd n ¼ 32 37.93 ⫾ 12.03 (13.96–62.30)

p-value (t-value)a Mean ⫾ SD (range) Mean ⫾ SD (range) Scale

Mean ⫾ SD (range)

p-value (t-value)a Mean ⫾ SD (range)

Mean ⫾ SD (range)

p-value (t-value)a

Mean ⫾ SD (range)

Non-stressed) Stressed Non-anxious Anxious Non-depressed Depressed

Health-Related Quality of Life as Measured by the Minnesota Living With Heart Failure Questionnaire (MLHFQ) and the Medical Outcome Study Short-Form 36-Item Health Survey (SF-36) Table 3

MCS, mental component summary; PCS, physical component summary. a Comparison between patients with and without depressive symptoms, with and without anxiety symptoms, and with and without stress symptoms, unpaired t-test, level of significance: p o 0.05 (2-tailed). b Lower scores indicate better health-related quality of life. c Higher scores indicate better health status. d The MCS results are only presented for sake of completeness, given the conceptual overlap between the Depression Anxiety Stress Scale and the MCS.

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group.9 Our questionnaire is well-validated, and closely resembles the Diagnostic and Statistical Manual for Mental Disorders–Fourth Edition (DSM-IV) symptoms of various anxiety disorders,14,25 which is a more comprehensive and methodologically much stronger approach. We also showed that the presence of stress cannot be underestimated, because 27% of patients suffer from difficulties relaxing, nervous arousal, being easily upset or agitated, being irritable or over-reactive, and being impatient.14 Unfortunately, we cannot compare this unique observation because literature on PAH-related stress is absent. Only a small portion of the patients were taking antidepressants or had consulted a psychologist, suggesting that presence of emotional problems remains undetected and untreated, which is consistent with observations from other studies.11 In contrast, the level of benzodiazepines (medication with sedating and anxiolytic effects) was higher (26.7%), but given the high presence of anxiety, this may not be sufficient. Although depressed patients had a significantly higher NYHA class and used more phosphodiesterase 5 inhibitors than non-depressed patients, suggesting higher disease severity, no differences in 6MWD or other disease-related characteristics were revealed. We also found a significantly lower 6MWD in anxious patients and higher NYHA classes in anxious and stressed patients, again suggesting higher disease severity, although further research to understand why emotional symptoms are much more frequent in PAH compared with other serious illnesses, such as heart failure or chronic obstructive pulmonary disease, might be interesting.23,24 It is also possible that pulmonary vasodilators, such as endothelin receptor antagonists and phosphodiesterase 5 inhibitors, have a currently undocumented influence on mental status, similarly to systemic vasodilators.26,27 The disease-specific and generic instruments both confirm results from other studies, showing that the HRQOL of patients with PAH is extremely poor,5–7,9,12,13 especially with regard to physical functioning, with the PCS being more than 1 SD below the population mean, and the SF-36 physical sub-scales being significantly lower than an agematched and gender-matched general population. This was the case for patients both with and without emotional symptoms, although patients without symptoms for bodily pain had scores approaching those of the general population. To our knowledge, no other HRQOL study in PAH patients used matched general population norms. Interestingly, our multivariable analyses showed that depressive symptomatology explained most of the variance of disease-specific HRQOL. Not surprisingly, a higher NYHA class and worse 6MWD were significant correlates of both disease-specific and physical HRQOL. Mental problems were no longer significantly associated with the PCS, although depressive symptomatology seem to explain part of the variance of the SF-36 physical sub-scales underpinning PCS, including role limitations due to physical problems, bodily pain, and general health, suggesting that emotional problems should not be overlooked as a relevant correlate of physical HRQOL.

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Emotional Problems and HRQOL in PAH

7

Table 4 General Linear Models Showing the Dependent Variable for the Minnesota Living With Heart Failure Questionnaire (MLHFQ) and the Medical Outcomes Study Short-Form 36-Item Health Survey Mental Component Summary (MCS) and Physical Component Summary (PCS) Parameter Total score MLHFQ Intercept NYHA Depressive symptomsb Employment

Label

R2

Adjusted R2

Estimate (95% CI)

SE

t-test

p-value

0.494

0.464

4.44 6.36a 1.25 9.04 10.90 5.40 0d

(–7.75 to 16.64) (1.49 to 11.23) (0.86 to 1.65) (–3.41 to 21.50) (–0.02 to 21.83) (–6.02 to 16.83)

6.134 2.451 0.198 6.265 5.495 5.749 …

0.724 2.596 6.339 1.443 1.984 0.940 …

0.471 0.011 o0.001 0.153 0.050 0.350 …

0.664

0.660

58.38 (56.44 to 60.32) –1.03 (–1.18 to –0.88)

0.977 0.075

59.777 –13.687

o0.001 o0.001

0.274

0.259

37.77 (28.28 to 47.27) –4.47 (–6.96 to –1.99) 0.02 (0.002 to 0.028)

4.783 1.251 0.007

7.897 –3.575 2.271

o0.001 0.001 0.025

Retired Disabled Otherc Workers

MCSe Intercept Depressive symptomsb PCS Intercept NYHA 6MWD

6MWD, 6-minute walk distance; CI, confidence interval; NYHA, New York Heart Association; SE, standard error. a Example to read this estimate: If NYHA-class increases with 1 measurement unit (e.g., from NYHA class II to III), the MLHFQ score will increase with 6.36 points (i.e., worse disease-specific health-related quality of life). b Depressive symptoms can be replaced by anxiety or stress symptoms, yielding similar results. c Includes student, housewife, or unemployed. d This parameter was used as the reference value and therefore set at 0. e These results are presented for sake of completeness, as the results are trivial given the conceptual overlap between the Depression Anxiety Stress Scale and MCS and its mental subscales.

To our knowledge, one other study has used multivariable analyses to predict HRQOL,7 observing that depressive symptoms contributed to poorer physical functioning; however, the authors enrolled a mixed population of PAH patients along with those with left-sided heart disease.

Given the paucity of data, especially in view of multivariable models taking disease-characteristics into consideration, further research is needed to confirm our findings. Our results suggest that screening and treatment of depressive, anxiety, and stress symptoms might be helpful

Table 5 General Linear Models Showing the 4 Physical Sub-scales of the Medical Outcome Study Short-form 36-item Health Survey as Dependent Variables Parameter Physical functioning Intercept NYHA 6MWD Role limitations due to physical problems Intercept 6MWD NYHA Depressive symptomsa Bodily pain Intercept 6MWD Depressive symptomsa General health Intercept NYHA Gender Depressive symptomsb

R2

Adjusted R2

Estimate (95% CI)

SE

t-test

p-value

0.350

0.336

52.85 (28.84 to 76.86) –13.85 (–20.11 to –7.56) 0.04 (0.01 to 0.08)

12.098 3.153 0.016

4.369 –4.393 2.613

o0.001 o0.001 0.010

0.38

0.317

39.65 0.08 –11.91 –0.85

18.689 0.026 5.073 0.382

2.121 3.082 –2.348 –2.222

0.037 0.003 0.021 0.029

0.205

0.188

62.06 (44.99 to79.13) 0.04 (0.03 to 0.08) –1.06 (–1.63 to –0.49)

8.598 0.018 0.287

7.218 2.163 –3.682

o0.001 0.033 o0.001

0.341

0.320

42.29 –5.92 8.11 –0.63

8.559 2.048 3.571 0.167

4.941 –2.892 2.271 –3.770

o0.001 0.005 0.025 o0.001

(2.54 to 76.76) (0.03 to 0.13) (–21.99 to –1.84) (–1.61 to –0.09)

(25.30 to 59.29) (–9.99 to –1.86) (1.02 to 15.20) (–0.960 to –0.30)

6MWD, 6-minute walking distance test; CI, confidence interval; NYHA, New York Heart Association classification; SE, standard error. a Can be replaced by stress symptoms, yielding similar results. b Can be replaced by anxiety symptoms, yielding similar results.

8

The Journal of Heart and Lung Transplantation, Vol ], No ], Month ]]]]

strategies to improve patients’ HRQOL, yet further research is warranted to explore whether patients’ HRQOL is indeed benefitting from these, alongside other interventions. In the light of some methodologic limitations, our results should, however, be interpreted with caution. Our singlecenter approach limited generalizability, and this crosssectional study does not allow inferring causality: emotional symptoms might negatively affect HRQOL or vice versa, necessitating prospective studies to disentangle the direction of the relationship between both concepts. We also used a relatively small sample size; yet, our study is among the largest ever published on related topics6,7,12 and had a participation rate of more than 90%, minimizing the risk of selection bias. The combination of a generic and diseasespecific HRQOL instrument is a strength; yet, our diseasespecific instrument was originally designed for patients with heart failure.16 Although other studies have used the same instrument, whether this instrument sufficiently captures HRQOL aspects that are relevant for PAH patients is unknown.13,17 A PAH disease-specific scale, the Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) has been published but is not available for a Dutch-speaking population.28 We presented the univariable and multivariable associations between the DASS scores and the SF-36 MCS; yet, this might be perceived as redundant. Because both instruments target the same underlying concept (emotional problems indicative of psychiatric disorder), one could argue that correlating 2 similar questionnaires does not make sense. Finally, we examined an extensive list of demographic, patient, and disease-related determinants; yet, prospective, multicenter studies could help to better understand which characteristics influence onset of emotional problems. Moreover, whether the presence of mild emotional symptoms is clinically relevant needs to be demonstrated. Other studies in cardiovascular illness showed that mild depressive or anxiety symptoms, even when controlling for potential confounders, already increased the risk for mortality.29,30 It would be interesting to investigate whether the presence of emotional problems predicts morbidity and mortality, and which DASS cutoff represents clinically meaningful emotional symptomatology. Despite these limitations, our study nevertheless suggests that symptoms of depression, anxiety, and stress should be regularly screened for, using standardized, validated questionnaires. The DASS is a relatively short, easy to use instrument to identify patients that need psychologic treatment. However, intervention studies are needed to evaluate whether psychotherapeutic or psychopharmacologic interventions are helpful to alleviate emotional symptoms and improve PAH patients’ HRQOL.

Disclosure statement The authors thank all of the patients for their participation. W.W. is a senior Clinical Investigator of the Research Foundation–Flanders (1.8.325.12N).

None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript or other conflicts of interest to disclose.

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Emotional symptoms and quality of life in patients with pulmonary arterial hypertension.

Limited evidence exists on the nature and degree of emotional problems in pulmonary arterial hypertension (PAH) and their association with patients' h...
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