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European Journal of Heart Failure 2009 11(2):163-169; doi:10.1093/eurjhf/hfn032
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Self-assessment of health status is associated with inflammatory activation and predicts long-term outcomes in chronic heart failure

John T. Parissis*, Maria Nikolaou, Dimitrios Farmakis, Ioannis A. Paraskevaidis, Vassiliki Bistola, Koula Venetsanou, Dimitrios Katsaras, Gerasimos Filippatos and Dimitrios T. Kremastinos

Heart Failure Clinic, Second Department of Cardiology, Attikon University Hospital, Navarinou 13, Maroussi, 15122 Athens, Greece

* Corresponding author. Tel: +30 210 6123720, Fax: +30 210 5832195, Email: jparissis{at}yahoo.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 
Aims: Clinicians lack a generally accepted means for health status assessment in chronic heart failure (CHF). We investigated the correlation between health status and inflammation burden as well as its long-term prognostic value in CHF outpatients.

Methods and Results: Kansas City Cardiomyopathy Questionnaires (KCCQ) were completed by 137 CHF outpatients (aged 64 ± 12 years, mean ejection fraction 27 ± 7%). Inflammatory markers [interleukin (IL)-6, IL-10, TNF-{alpha}, soluble Fas, Fas ligand, ICAM-1, VCAM-1], plasma B-type natriuretic peptide (BNP), 6 min walk test (6MWT), Zung self-rating depression scale, and Beck Depression Inventory were also assessed. Patients were followed for major cardiovascular events (death or hospitalization for disease progression) for up to 250 days. Patients with worse KCCQ-summary (KCCQ-s < 50) score had lower 6MWT (P < 0.05), and higher BNP (P < 0.05) and pro-inflammatory markers (P < 0.05) than those with KCCQ-s ≥ 50. Worse health status was also associated with shorter event-free survival (115 ± 12 days for KCCQ-s < 50 vs. 214 ± 15 days for KCCQ-s ≥ 50, P = 0.0179). Separating patients according KCCQ-functional score (KCCQ-f, cut-off 50) showed similar results. In multivariate Cox regression analysis, only LVEF (HR = 0.637, 95% CI 0.450–0.900, P = 0.011) and KCCQ-f (HR = 0.035, 95% CI 0.002–0.824, P = 0.037) were independent predictors of event-free survival at 250 days.

Conclusion: KCCQ-s reflects neurohormonal and inflammatory burden in CHF. Among studied questionnaires, only KCCQ-f is an independent predictor of long-term event-free survival in CHF.

Key Words: Health status • Depression • Kansas City Cardiomyopathy Questionnaire • Minnesota Living with Heart Failure Questionnaire • Heart failure • Cytokines • Prognosis

Received May 30, 2008; Revised August 12, 2008; Accepted November 17, 2008


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusion
 References
 
According to the American College of Cardiology/American Heart Association 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure (CHF) in the adult, patients presenting with CHF should undergo initial assessment of their ability to perform routine and desired activities of daily living (Class I Level of Evidence: C).1 The longitudinal monitoring of patients’ functional capacity is necessary for appropriate treatment management and the standardized scales or assessment tools that have been proposed include the New York Heart Association (NYHA) functional classification of CHF, the Kansas City Cardiomyopathy Questionnaire (KCCQ), the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and the CHF Questionnaire.2

NYHA classification although simple to obtain, cannot discriminate subtle changes in health status and is subjected to inter-observer variability, since it represents the physician’s and not the patient’s perspective. In an attempt to quantify and standardize all the variables that contribute to what we call ‘health status’, including functional capability and quality of life, a number of self-administered questionnaires have been developed, for use in patient management and for estimating the outcome of clinical trials.3–5

Recently, the KCCQ has been shown to reflect clinical changes more accurately than NYHA classification or 6 min walk test (6MWT).6,7 It may independently predict cardiovascular morbidity and mortality in CHF patients, when used either as baseline assessment8 or as change in KCCQ score in serial assessments.9

The present study tries to clarify the clinical, neurohormonal, and inflammatory profile of patients with low health status and to assess the stronger prognostic factors among health status questionnaires (KCCQ, MLHFQ), depression questionnaires [Beck Depression Inventory (BDI) and Zung self-rating depression scale (SDS)], clinical characteristics [left ventricular ejection fraction (LVEF), NYHA class, exercise capacity], neurohormonal activation (B-type natriuretic peptide, BNP), and a wide range of inflammatory markers.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusion
 References
 
Study population and laboratory parameters
All consecutive patients referred to the Heart Failure Clinic of our Department for evaluation, and treatment planning over a period of 6 months was considered for inclusion in the study. Inclusion criteria were (i) history of CHF of at least 6 months; (ii) left ventricular systolic dysfunction (LVEF <40%) as documented by echocardiography; (iii) clinically stable condition for at least 3–4 weeks; (iv) optimum medical treatment according to functional status. Exclusion criteria were (i) acute or chronic infectious or inflammatory diseases; (ii) malignancies and known haematologic, lung, thyroid, or neuromuscular diseases; (iii) symptomatic coronary artery disease. The protocol was approved by the institutional Ethics Committee, and all patients enrolled gave their written informed consent.

At baseline, all patients underwent assessment, which included a clinical, neurohormonal, and inflammatory profile. In detail, patients underwent a medical history interview and physical examination, NYHA classification and a 6MWT, as an indicator of their exercise capacity.

Neurohormonal status was assessed from plasma BNP levels, using the rapid Triage BNP assay (Biosite Inc., San Diego, CA, USA).10 Fasting plasma and serum samples were collected from each patient for the measurement of pro-inflammatory markers, including interleukin (IL)-6 and tumour necrosis factor-{alpha} (TNF-{alpha}), the anti-inflammatory cytokine IL-10, soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), and soluble apoptosis mediators Fas and Fas ligand. Commercially available enzyme-linked immunosorbent assay kits (R&D Systems Inc., Minneapolis, Minnesota, for TNF-{alpha}, IL-6, IL-10, ICAM-1, VCAM-1 and soluble Fas; Diaclone Research, Besancon, France, for soluble Fas ligand) were used. The intra- and inter-assay coefficients of variation were <8% for all assays in our laboratory.

All patients were also asked to complete instruments to assess health status and screen depressive symptoms (KCCQs, BDI, and Zung SDS). In a subpopulation of 56 patients, MLHFQ was also completed. All the above questionnaires have been validated in the Greek language.

Instruments
The KCCQ is a disease-specific, self-administered 23-item questionnaire that quantifies physical limitation and quality of life. It consists of different domains that can be summarized as a functional score (assessing physical activity and symptoms) and as a summary score (functional score and quality of life), which reflect the overall health status. Scale scoring is transformed to a 0–100 range, where lower levels imply worse function and life quality. KCCQ has proven to be valid and reliable and it appears very sensitive in monitoring clinical changes.5

The MLHFQ was developed to assess the perception of the effect of CHF and its treatment on the life of patients. It is made up of 21 items that cover CHF-related physical, psychological, and social impairments. The patient’s perception of such impairments is assessed on a scale ranging from no (score of 0) to very much (score of 5). The total MLHFQ score is obtained by adding the scores for all 21 items (range, 0–105); the higher the score, the worse the health-related quality of life.4 Since the Greek version of the MLHFQ was not available to our Department at the time this study was initiated, this questionnaire was completed only by the last 56 consecutive cases enrolled in the study.

The Zung SDS has been designed to provide a quantitative assessment of the subjective experience of depression. It contains 20 items covering affective, psychological, and somatic features of depression. Non-depressed individuals typically score less than 40, while a score of 40–80 covers various grades of depressive symptomatology.11

The BDI is a self administered 21-item questionnaire that has been established for screening depressive symptoms in various populations. Since only five of its items reflect somatic symptoms, whereas the other 16 reflect non-somatic symptoms of depression, the BDI has been extensively used in heart failure. The standard cut-off point of ≥10 was used to classify patients as depressives.12

After the baseline assessment, patients were followed for up to 250 days for major cardiovascular events, including death or hospitalization due to cardiovascular causes.

Statistical analysis
Statistical analysis was performed using the SPSS 11.0 statistical software package (SPSS Inc., Chicago, IL, USA). Continuous variables are expressed as mean ± standard deviation and categorical variables as percentages of the total population. Continuous variables were compared between groups by the Student’s t-test or the Mann–Whitney U-test, according to whether they followed a normal distribution or not, respectively, as tested by the Kolmogorov–Smirnov test. Categorical variables were compared between groups using the {chi}2test. Linear regression analysis was used to investigate for potential relationships between variables. To identify independent predictors of health status, as assessed by KCCQ, univariate and multivariate linear regression analysis was performed; candidate variables included age, gender, NYHA class, cause of heart failure, 6MWT, LVEF, BNP, and the depression questionnaires BDI and Zung SDS. Event-free survival (expressed as mean ± standard error of the mean) was estimated using the Kaplan–Meier method and compared between groups using the log-rank test. Univariate and multivariate Cox regression analysis was used to identify predictors of outcome; candidate variables included demographics (age, gender), clinical features (NYHA class, heart failure type, exercise capacity as measured by the 6MWT), LVEF, the presence or absence of depressive symptoms (as defined by BDI and Zung SDS questionnaires), health status (as measured by KCCQ-s, KCCQ-f, and MLHFQ), neurohormonal activation (as reflected by BNP plasma levels), and inflammatory burden (including serum levels of IL-6, IL-10, and TNF-{alpha}). Receiver operator characteristics (ROC) analysis was performed to assess the sensitivity and specificity of variables in predicting outcome. A value of P < 0.050 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusion
 References
 
Baseline characteristics
The baseline characteristics of the study population are summarized in Table 1. KCCQ, BDI, and Zung SDS questionnaires were completed by 137 patients, whereas the MLHFQ was only given to a subpopulation of 56 patients. Mean KCCQ summary score (KCCQ-s) was 34 ± 20, while mean KCCQ functional score (KCCQ-f) was 44 ± 21. Separating the population into quartiles, 44 patients had a KCCQ-s < 25, 51 patients had KCCQ-s between 25 and 50, 35 patients had KCCQ-s between 50 and 75, and 7 patients had a KCCQ-s >75. In the subpopulation of 56 patients, mean MLHFQ score was 54 ± 26. Half of our population (49.5%) was characterized as having depressive symptoms according to both depression questionnaires (BDI > 10 and Zung SDS > 40). The mean BDI score in all studied patients was 21 ± 8 and the mean Zung SDS score was 50 ± 7.


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  		Table 1 Baseline characteristics

 
Patients with low vs. high health status according to KCCQ
Using a cut-off limit of 50 for the KCCQ-s, patients were separated into two groups: those with poor health status (KCCQ-s < 50, n = 94) and those with better health status (KCCQ-s ≥ 50, n = 43). The clinical, neurohormonal, and inflammatory profile of these two groups is described in Table 2. Patients with lower health status were more often depressives, with worse NYHA class and reduced exercise capacity, as indicated by the lower 6MWT and a trend towards to lower EF. Concerning their neurohormonal and inflammatory profile, patients with low health status had higher plasma BNP, higher levels of the pro-inflammatory markers IL-6, soluble Fas, soluble Fas ligand and sVCAM-1, and lower levels of the anti-inflammatory cytokine IL-10. Poor health status was also associated with worse prognosis and significantly shorter event-free survival (130 ± 10 vs. 205 ± 15 days, log-rank test P = 0.0009, Figure 1A). Separating patients according to their functional status, using the cut-off value of 50 for KCCQ-f, reported similar results; similarly, poor functional status was associated with significantly shorter event-free survival (113 ± 10 vs. 190 ± 12 days, log-rank test P < 0.0001, Figure 1B). The same findings were encountered when the population was separated into quartiles according to KCCQ-s, although the four groups were not well balanced in terms of the number of patients in each group. Event-free survival differed significantly among the four quartiles of KCCQ-s, no events were encountered in patients with a KCCQ-s >75 (117 ± 13 vs. 138 ± 13 vs. 203 ± 15 vs. 225 ± 13 days, overall log-rank test P = 0.0046).


Figure 1
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  		Figure 1 Kaplan–Meier curves for event-free survival according to Kansas City Cardiomyopathy Questionnaire score. Panel A: Kansas City Cardiomyopathy Questionnaire-summary; Panel B: Kansas City Cardiomyopathy Questionnaire-functional; solid line: score ≥50; dotted line: score <50.

 


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  		Table 2 Patient features by Kansas City Cardiomyopathy Questionnaire score groups

 
Bivariate correlations
Significant correlations were observed between KCCQ-s and clinical parameters, such as 6-MWT (r = 0.3, P = 0.012), NYHA class (r = –0.26, P = 0.017), LVEF (r = 0.304, P = 0.006), biochemical markers such as BNP (r = –0.29, P = 0.012), IL-6 (r = –0.299, P = 0.013), IL-10 (r = 0.292, P = 0.04) and other instruments such as BDI score (r = –0.522, P < 0.001), Zung SDS (r = –0.528, P < 0.001), and MLHFQ (r = –0.733, P < 0.001).

Factors that influence health-related quality of life
According to linear regression analysis, poor exercise capacity, as estimated by 6MWT (P = 0.046) and the presence of depressive symptoms, as screened by the BDI score (0.015), were independently associated with worse health status.

Patients’ prognosis
Ten patients from distant regions of the country were lost to follow-up, since we were not able to contact them. Therefore, 127 of the 137 patients recruited were followed for major cardiovascular events, including death or hospitalization for cardiovascular causes. Of these, 77 patients (60.6%) died or were hospitalized for deteriorating HF symptoms during a follow-up period of up to 250 days, with a mean event-free survival of 145 ± 8 days and a median survival of 120 days.

Univariate Cox regression analyses revealed that NYHA class, LVEF, 6MWT, BDI, Zung SDS, KCCQ-s, KCCQ-f, BNP, and inflammatory cytokines were significantly associated with outcome (Table 3). Worse outcome was also associated with the presence of depression, either screened by the BDI score (P < 0.05) or by the Zung SDS (P < 0.05). Multivariate Cox regression analysis included the following parameters: NYHA class, LVEF, 6MWT, BDI, Zung SDS, KCCQ-s, KCCQ-f, BNP, IL-6, TNF-{alpha}, and IL-10. Of those parameters, only LVEF (HR = 0.637, 95% CI 0.450–0.900, P = 0.011) and KCCQ-f (HR = 0.035, 95% CI 0.002–0.824, P = 0.037) remained as independent predictors of event-free survival at 250 days.


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  		Table 3 Patient features according to outcome

 
Combining the two independent predictors of outcome, event-free survival differed significantly among the four subgroups (KCCQ-f ≥ 50 and LVEF ≥ 29%, 224 ± 14 days; KCCQ-f < 50 and LVEF ≥ 29%, 170 ± 25 days; KCCQ-f ≥ 50 and LVEF < 29%, 143 ± 23 days; KCCQ-f < 50 and LVEF < 29%, 83 ± 13 days; log-rank test P < 0.0001).

ROC curves constructed for each independent prognostic factor revealed that using the previously described cut-off level of 5% for KCCQ-f predicted future events with a sensitivity of 74% and a specificity of 63%. Concerning the LVEF, the best cut-off value for predicting events was 29%, with a sensitivity of 80%, and a specificity of 74%. Combining the two independent predictors of outcome, KCCQ-f with a cut-off of 50 and LVEF with a cut-off of 29% predicted future events with a sensitivity of 63% and a specificity of 83%.

Comparison of the two health status questionnaires-sub-analysis data
The interesting finding that health status when estimated by the KCCQ score, but not by the MLHFQ score, was associated with clinical outcome, raised the question of whether the result was misleading because a smaller group of patients (n = 56) completed the MLHFQ or if KCCQ is a better clinical tool for patient monitoring. Therefore, a sub-analysis that included only the patients that had completed the MLHFQ (n = 56) was conducted. This sub-population had similar baseline characteristics to the entire population, with no evidence of selection bias. KCCQ remained strongly associated with outcome; event-free survival was significantly shorter in patients with KCCQ-s < 50 vs. those with KCCQ-s ≥ 50 (115 ± 12 vs. 214 ± 15 days, log-rank test P = 0.0179, Figure 2A). In contrast, event-free survival did not differ significantly between patients in the low and those in the high MLHFQ 50% percentile (118 ± 15 vs. 152 ± 18, log-rank test P = 0.1292, Figure 2B).


Figure 2
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  		Figure 2 Kaplan–Meier curves for event-free survival in a subpopulation of 56 patients; Panel A, according to Kansas City Cardiomyopathy Questionnaire-summary score (solid line: score ≥50; dotted line: score <50); Panel B: according to Minnesota Living with Heart Failure Questionnaire score (solid line: lower 50% percentile; dotted line: upper 50% percentile).

 
Power analysis
Given the observed event rates in patients with KCCQ-s < 50 and those with KCCQ-s ≥ 50 (69% vs. 29%, respectively) during the follow-up period of 250 days, and taking under consideration the rest of study characteristics (accrual period, ratio of samples with KCCQ-s < 50 to ≥50 and loss to follow-up rates), a sample of 133 patients detects a significant survival difference between those two subgroups (KCCQ-s < 50 vs. KCCQ-s ≥ 50) with a power of 97% at a two-sided type I error level of 5%.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusion
 References
 
Congestive heart failure is a chronic condition with a significant impact on patients’ survival and quality of life. Disease progression alternates with periods of clinical stability and treatment strategies aim to prevent rather than treat acute events, in order to ameliorate patient’s quality of life and survival. Although current guidelines underline the need for patient monitoring, the optimal means of assessment remains unclear. According to the literature, a lot of markers seem to have prognostic value and may be used for risk stratification in CHF. However, there is a lack of established patient-defined tools for clinical and prognostic evaluation. Recently, patient self-assessed symptoms have been shown independently to predict hospitalization and mortality.13 It seems that self-assessment of the two main symptoms in CHF, breathlessness and fatigue, may differ from NYHA classification reported by the physician.14,15

The present study investigated for the first time the relationship between health status assessment by KCCQ and neurohormonal and immune activation as well as depressive symptoms in CHF outpatients. Moreover, the prognostic value of the overall KCCQ score was compared with that of its functional subcategory and of the MLHFQ.

Our study supports the concept that ‘ask the patient, he will tell you the truth’ is an essential approach for clinical evaluation and risk stratification in CHF patients. Indeed, KCCQ is a self-administered disease-specific instrument that covers various domains (physical limitation, frequency, severity and change over time of symptoms, self-efficacy and knowledge, social interference, and quality of life). Responses are classified on a Likert scale with clinically meaningful gradations between categories, making the questionnaire comprehensive and quick to complete.5 Reflecting the patient’s perspective, instead of the clinician’s, represents an objective, quantified medical interview. Recently, a lower KCCQ-s has been associated with worse hospitalization and survival rates, when measured either as baseline or as serial assessments, in the sub-analyses of the Eplerenone’s neurohormonal Efficacy and Survival Study (EPHESUS) trial,9,16 and also in populations with a broader range of CHF aetiologies.17 Thus, KCCQ is an easily performed, non-invasive, and low-cost instrument that reflects health status, and could be used for patient risk stratification.18

Furthermore, our study showed for the first time that KCCQ is associated with neurohormonal activation and inflammatory burden, implying a close relationship between health status and the biochemical pathogenetic mechanisms of heart failure progression. Immune activation, expressed by pro-inflammatory/anti-inflammatory cytokine imbalance, has been shown to be associated with increased emotional stress and depressive symptoms,19,20 as well as with peripheral muscular and vascular abnormalities that promoted fatigue and impaired exercise capacity in CHF patients.21 This pathophysiological aspect may possibly explain the development of depression in patients with low KCCQ score, as previously reported,22 as well as the correlation between KCCQ and depression observed in our study. As demonstrated by linear regression analysis, depressive symptoms and exercise capacity are two parameters that may alter the health status score, possibly through the vicious cycle of inflammation and neurohormonal activation.

Another interesting finding of this study was that although KCCQ-s was univariately associated with prognosis in outpatients with CHF, the multivariable model revealed that only the functional score of KCCQ, along with LVEF, were independently associated with long-term outcome. In previous studies, KCCQ-s was reported to be an independent predictor of poor prognosis.8,18 However, such findings may be due to the fact that depression, which is known to be a comorbid condition that influences prognosis in CHF patients,22–25 was not included as a covariate in those analyses. Indeed, in our study, the overall KCCQ score was found to be independently affected by the presence of depressive symptoms, as evaluated by the Zung SDS. The functional subcategory of KCCQ, in contrast, better reflects the somatic components and thus the clinical severity of the disease. Furthermore, according to our data, the combination of the patient-derived KCCQ-f score with the objectively defined LVEF seemed to predict future major cardiovascular events with an enhanced specificity.

Besides KCCQ, several other disease-specific health status instruments have been evaluated in CHF. The MLHFQ is one of the frequently used questionnaires in this setting. However, MLHFQ seems to be less sensitive to clinical changes and this may explain, at least in part, why some clinical trials have failed to demonstrate benefits in quality of life despite improvement in other clinical markers.6,26–28 Although there is no evidence on the superiority of one single questionnaire, according to the present study, KCCQ was associated with long-term event-free survival, while MLHFQ was not. In this context, one may speculate that patients can more easily describe their symptoms, as in the KCCQ, than quantify them on a scale of 0–5, as in the MLHFQ. As a result, KCCQ may reflect the patients’ condition better, hence coding and quantifying more accurately their health status.

Taking into consideration these observations, we may assume that health status assessment by KCCQ is essential for identifying high-risk CHF patients. Patients’ perception of their own disease, coded and calculated by KCCQ, may provide a useful, inexpensive, and easy-to-use tool in monitoring programmes. All patients, especially those with low health score, should be screened for depressive symptoms. Treating depression and improving exercise capacity should be part of treatment optimization in CHF patients, targeting a better quality of life and a longer survival.

Limitations
Since MLHFQ scores were available only for a subpopulation of patients (n = 56), no firm conclusions can be drawn regarding the prognostic value of this questionnaire in heart failure. Moreover, this study concerned a cross-sectional assessment of neurohormonal and inflammatory markers and health status in heart failure and although a strong correlation was identified, a causative relationship cannot be confirmed, as it is not easy to discriminate between the cause and the effect.


   Conclusion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
References
 
Overall health status assessment by the self-rated KCCQ reflects neurohormonal and inflammatory burden as well as depressive symptoms in CHF. Furthermore, the functional subcategory of this questionnaire, compared with the overall score or MLHFQ, represents an independent prognostic factor for long-term event-free survival.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusion
 References
 

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