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JQYK ) JOURNAL OF CLINICAL MEDICINE OF KAZAKHSTAN
Original Article
(E-ISSN 2313-1519)
Prognostic value of depression, anxiety disorders and inflammatory markers in patients with reduced and mildly reduced ejection fraction heart failure
Emine Gazi1, Elif Karaahmet2, Hakan Türkön3, Ahmet Barut^u1, Ugur Küfük1
'Department of Cardiology, Faculty of Medicine, Qanakkale Onsekiz Mart University, Qanakkale, Turkey
2 Department of Psychiatry, Saghk Bilimleri University, Okmeydani Research and Education Hospital, istanbul, Turkey
3 Department of Biochemistry, Meddem Hospital, Isparta, Turkey
Abstract
Aim: Patients with heart failure (HF) have greater rates of depression and anxiety than the general public. The researchers wanted to investigate if there was a relationship between depression, anxiety, and inflammatory markers, as well as survival and hospitalization, in HF patients with reduced and mildly reduced ejection fractions (HFrEF and HFmrEF).
Materials and methods: This prospective research comprised 122 consecutive individuals having a left ventricular ejection fraction (LVEF) of less than 50%. The inflammatory system was investigated using the specific markers. Hamilton Depression and Anxiety Rating Scales (HAM-D and HAM-A) were used to diagnose of depression and anxiety.
Results: The median duration of follow-up was 36.4 months. Non-survivors had lower glomerular filtration rate, LVEF, and blood sodium levels than survivors, while they were older. Age, LVEF, and GFR are independent predictors for mortality. No independent relation was found between depression, anxiety, inflammatory parameters and mortality. Anxiety was found as independent predictors for hospitalization.
Conclusion: Anxiety, depression, and inflammatory conditions indicators were not associated with mortality in people with HFrEF and HFmrEF. Neutrophil-to-lymphocyte ratio (NLR) and anxiety were found as independent predictors for hospitalization.
Key words: heart failure, depression, anxiety, inflammatory markers, mortality
Received: 2022-05-10. Accepted: 2022-06-09
© ®
This work is licensed under a Creative Commons Attribution 4.0 international License
J Clin Med Kaz 2022; 19(4):4-12
Corresponding author: Ugur Kûçûk.
E-mail: [email protected]; ORCID: 0000-0003-4669-7387
Introduction
Heart failure (HF) still reduces the quality of life because of recurrent hospitalizations, and it has high mortality despite improvements in medical and interventional treatment strategies. HF was reported to be related to psychological stress and incidence of clinically significant anxiety disorders (8%-16%), including general anxiety disorder and panic attack [1,2]. The relationship between HF and depression is a new area in daily practice. The frequency of depression in patients with HF is 2-3 times higher than that in the normal population [3]. Sometimes, depression is overlooked in routine daily practice because these two diseases have many similar symptoms, and HF symptoms may lead to over-reporting in patients with depression who are thought to have worsened perception [4].
Like HF, depression is associated with high morbidity and mortality rates [5]. While some investigations have reported that the concurrence of two disorders has increasing adverse outcomes, others reported the opposite. The mechanism of the relationship between depression with HF progression and mortality is unclear. Inflammation is thought to be a possible mechanism in patients with these conditions [6-9]. High levels of inflammatory markers may be related to the progression of HF [10]. Some studies have supposed that in patients with depression without HF, inflammatory markers are also increased [11,12]. However, it is unknown whether inflammation is the cause or consequence.
Our study aimed to explore the relationship among inflammatory markers, anxiety, and depression and determine the prognostic effects on long-term
mortality, hospitalization, and quality of life in patients having HF with reduced and mildly reduced ejection fraction (HFrEF and HFmrEF) by using objective psychiatric evaluation.
Materials and methods Study population
Consecutive outpatients with HF visiting the cardiology clinic between November 2011 and September 2013 were included. Patients with HF and left ventricular ejection fraction (LVEF) <50%, aged <75 years, and were stable for at least one-month. Patients with malignancy, liver failure, chronic inflammatory disease, and cognitive disorders, aged <18 years and >75 years (quality of life may affect test results in the older population), were excluded. All patients have received appropriate treatment for HF with reduced ejection fraction and other comorbidities.
Of the 160 patients, 131 agreed to participate. 9 individuals were excluded because they did not have a depression score at the time of inclusion and blood was not taken at the time of baseline. Therefore, 122 patients who had complete data at inclusion (blood and questionnaires) were included. Routine controls were performed every 6 months. In this study, the follow-up was completed in December 2015. An interview was used to examine demographic and clinical variables. New York Heart Association (NYHA) functional class information, risk factors, comorbidities, and medication was obtained from the patients through interview by a cardiologist.
Blood sample
Venous blood sample was obtained with a jelly tube at admission. Samples were centrifuged at 4000 rpm. Serum samples were stored -80°C for analysis of B-type natriuretic peptide (BNP), IL-6, tumor necrosis factor (TNF)-a, and high-sensitivity CRP (hs-CRP). IL-6 (Catalog No. KHC0061, Invitrogen Corporation, Camarillo, CA, USA) and TNF-a (Catalog No.: KHC3011, Invitrogen Corporation) levels were studied by enzyme-linked immunosorbent assay (ELISA) in ELX 808 IU model ELISA device. The NT-proBNP level was studied by using the electrochemiluminescence method in Cobas e601 analyzer. The hs-CRP level was examined by the immunoturbidimetric method in Cobas c501 analyzer by using Roche kits (Roche Diagnostics GmbH). All routine biochemical tests were carried out with the Cobas 6000 Integra (Roche) auto-analyzer using the chemiluminescence method at admission. Transthoracic echocardiography was performed on each patient in the outpatient clinic. Simpson's method was used to assess the LVEF.
An independent psychiatrist evaluated patients. The Hamilton Depression Rating Scale for depression (HAM-D), HAM scale for anxiety (HAM-A), and Short-Form 36 (SF-36) quality of life scale were used in the face-to-face interview. HAM-D score >7 indicates depression [13]. HAM-A, which is a standard psychiatric interview commonly used in research and clinical trials, score >11 represents anxiety [14]. The SF-36, which is a self-questionnaire survey, was used to determine the patients' quality of life. Physical health composite score (PCS) and mental health composite score were calculated as follows:
SF-36PCS= £ (z score of each scale x respective physical factor coefficient) x 10 + 50
SF-36 MCS = £ (z score of each scale x respective mental factor coefficient) x 10 + 50 formulas in the SPSS software [15].
After the initial assessment, all patients were periodically referred to our hospital for control checkup. Patients were interviewed (directly or over the phone) to acquire endpoint information, their families, hospital records, or social insurance if patient information cannot be reached.
Depression and anxiety were only assessed at baseline. Cardiovascular death was described as the primary endpoint, and the secondary endpoint was defined as hospitalization because of cardiovascular disease.
All participants agreed and provided consent to participate in the research, and the approval of the local ethics committee was obtained (Date: 09/03/2012, Decision no: 050.99-55). The study follows the principles guided in the Helsinki Declaration.
Statistical analysis
All statistical analyses were carried out with the SPSS program (version 21.0, SPSS, Chicago, IL, USA). Quantitative/ continuous variables with a skewed distribution were summarized as median and interquartile range, continuous variables with a normal distribution were summarized as mean and standard deviation, and Percentages were used to express qualitative characteristics (%). To determine the normality of all measures, the Kolmogorov-Smirnov test was used. The Student T or Mann-Whitney U-test was used to compare continuous variables between the two groups. The Chi-square test was used to compare categorical variables. Correlations between LVEF, BNP, IL-6, hs-CRP, BNP, HAM-A score, HAM-D score, and SF-36 score were evaluated by a Pearson correlation test. A KaplanMeier with the log-rank statistics was used to determine survival rates for depression and anxiety. Cox proportional regression analysis including age, LVEF, GFR, serum sodium level, NLR, inflammatory markers, HAM-A, HAM-D scores and SF-36 parameters was as independent predictors of mortality. A p value <0.05 was accepted significantly.
Results
Baseline demographic and clinical parameters of the study population are summarized in Table 1. Most of the patients were male (77.9%) and hypertensive (69.7%), and 27.9% of the population has atrial fibrillation. Patients were receiving appropriate medications, including renin-angiotensin-aldosterone system blockers and beta-blockers. Moreover, 4.9% and 19.7% of the patients have mild and severe depression according to the HAM-D scale, respectively, and 19.7% and 36.9% of the patients have mild and severe anxiety according to the HAM-A scale, respectively. A total of 39 (32%) patients died; 45 (36.9%) patients were hospitalized at a median follow-up period of 36.4 months.
Depression and anxiety
Results of the comparison of depression and anxiety groups are summarized in Table 2. Baseline demographic parameters, endpoints, and inflammatory marker levels were similar in patients with and without depression except for the use of beta-blockers (91.1% vs. 76.6%, p=0.045). HAM-D and HAM-A scale scores were significantly high, and the SF-36 scores were significantly low in patients with both depression and anxiety. Baseline demographic, laboratory, and inflammatory marker findings were similar in patients with and without anxiety and depression. Patients with anxiety had a greater hospitalization rate (44.9% vs. 26.4%, p=0.036).
Table 1
Demographic, laboratory and psychological parameters of study population
Parameter Value
Age (Years) 63.5 ± 9.8
Male/Female 95/27
Heart Rate (bpm) 76 ± 12
Ejection Fraction (%) 34.3±6.6
BMI (kg/m2) 28.3 ± 5.2
Hypertension % (n) %69.7 (85)
Diabetes Mellitus % (n) %41 (50)
CAD history % (n) 64.8 % (79)
Smoking % (n) 19.7 % (24)
Atrial Fibrillation % (n) 27.9 % (34) Medications % (n)
ACE inhibitor 61.5 % (75)
Beta Blocker 82 % (100)
ARB 20.5 % (25)
Hydrochlorothiazide 43.4% (53)
Furosemide 48.4 % (59)
MRA 46.7 % (57)
Oral anticoagulation 22.9 % (28) Laboratory analysis
Glucose (mg/dl) 136.9 ± 7.7
TG (mg/dl) 141.5 ± 76.2
LDL (mg/dl) 113.7 ± 3.1
HDL (mg/dl) 44.9 ± 12.7
GFR 60.9±20.4
NLR 3.19±1.77
SF physiological function 16.8 ± 10.5
SF physiological role 15.9 ± 8.7
SF pain 28.2 ± 11
SF general health 26.9 ±10.6
SF vital 33.8 ± 13
SF social function 37 ± 13.9
SF mental health 42.1 ± 28.6
HAM-D 6 (1-43)
HAM-D (8-16) 4.9 % (6)
HAM-D (>16) 27 % (33)
HAM-A 14 % (1-40)
HAM-A (11-17) 19.7 % (24)
HAM-A (>17) 36.9 % (45) Follow-up
Time (month) 36.4 (1-41)
Death % (n) 32 % (39)
Hospitalisation % (n) 36.9 (45) Death ± Hospitalisation % (n) 54.1 % (66)
Survival analysis
Kaplan-Meier survival curves of depression and anxiety are shown in Figure 1 and 2. Univariate Cox regression analysis showed that age, LVEF, GFR, serum sodium level, neutrophil-to-lymphocyte ratio (NLR), SF-36 pain, SF-36 general health, and NYHA functional classifications were predictors of mortality. Age, LVEF, and GFR were independent predictors of mortality (Table 4).
Figure 1 - Kaplan-Meier survival curves of the study population according to depression groups.
Figure 2 - KaplaMeier survival curves of the study population according to anxiety groups.
BMI: Body Mass Index, CAD: Coronary Artery Disease, ACE: Angiotensin Converting Enzyme, ARB: Angiotensin Receptor Blocker, MRA: Mineralocorticoid receptor antagonist, TG: Triglyceride, LDL: Low Density Lipoprotein, HDL: High Density Lipoprotein, GFR: Glomerular Filtration Rate, NLR: Neutrophile to Lymphocyte Ratio, SF: Short Form for quality of life, HAM-D: Hamilton D rating scale, HAM-A: Hamilton A rating scale.
Mortality groups
When compared with survivors, non-survivors patients were older (68.6±9.7 vs. 61 ± 8.8 years, p < 0.001) and have lower LVEF (32.5±6.4% vs. 35.1±6.5%, p=0.037), decreased glomerular filtration rate (GFR) (51.3±19.5 vs. 65.6±19.3 ml/ min, p<0.001), and blood sodium level (135±19 vs. 139±2 mEq/ml, p=0.04). NYHA functional capacity was poor in non-survivors (p<0.001) (Table 3).
Figure 3 - Kaplan-Meier survival curve according to the effective cut-off value of the neutrophil-to-lymphocyte ratio
Table 2
Comparisons of demographic, laboratory and psychological parameters of study groups
Parameter Depression (+) Depression (-)
n (45) n (77)
Age (Years) 64.0 ± 9.5 63.1 ± 9.9
Male, % (n) 82.2 % (37) 75.3 % (58)
Heart Rate (bpm) 76±12 76 ± 12
Ejection Fraction (%) 33.6 ± 7.3 34.7 ± 6.1
BMI (kg/m2) 28.3 ± 5.5 28.3 ± 5.1
Hypertension % (n) 68.9 (31) 71.1 (54)
Diabetes Mellitus % (n) 37.8 (17) 43.4 (33)
CAD history % (n) 66.7 (30) 63.6 (49)
Smoking % (n) 20 (9) 19.7 (15)
Atrial Fibrillation % (n) 38.5 (15) 28.4 (19)
Medications % (n)
ACE inhibitor 644 (29) 59.7 (46)
Beta Blocker 91.1 (41) 76.6 (59)
ARB 22.2 (10) 19.5 (15)
ASA 88.9 (40) 76.6 (59)
Hydrochlorothiazide 48.9 (22) 40.3 (31)
Furosemide 51.1 (23) 46.8 (36)
Laboratory analysis
Glucose (mg/dl) 109 (73-394) 112 (72-315)
TG (mg/dl) 140 ± 74 142 ± 77
LDL (mg/dl) 112 ± 29 114 ± 38
HDL (mg/dl) 41 ± 10 47 ± 13
GFR 60.4 ± 18.2 61.2 ± 21.7
NLR 3.49±1.86 3.02±1.7
Hs-CRP 3.7 (0.3-69) 43 (0.4-38)
TNFa 17.3 (6.6-243.1) 16.7 (2.9-237.4)
IL-6 5.6 (1.9-209.9) 5.8 (2.2-452.9)
NT-proBNP 923 (43-13179) 1134(105-134)
Depression and anxiety
SF physiological function 11 ± 6 20 ± 11
SF physiological role 10 ± 5 19 ± 8
SF pain 22 ± 8 31 ± 11
SF general health 21 ± 7 30 ± 10
SF vital 23 ± 6 40 ± 11
SF social function 24 ± 8 44 ± 11
SF mental health 23 ± 11 53 ± 30
HAM-D 21 (7-43) 4 (1-7)
HAM-A 22 (3-43) 8 (1-43)
Baseline NYHA Class
I 8.9 (4) 5.2 (4)
II 71.1 (32) 62.3 (48)
III 20 (9) 31.2 (24)
Follow-up
Time (month) 36.5 (3-41) 36.3 (1-41)
Death % (n) 33.3 (15) 31.2 (24)
Hospitalisation % (n) 44.4 (20) 32.5 (25)
p Anxiety (+) Anxiety (-) p
n (68) n (54)
0.685 63.0 ± 9.6 64.0 ± 9.9 0.593
0.376 76.8 (53) 79.2 (42) 0.748
0.910 75 ± 11 78 ± 14 0.509
0.369 34.7 ± 6.7 33.7 ± 6.4 0.435
0.990 28.4 ± 5.5 28.2 ± 5 0.851
0.801 69.1 (47) 71.7 (38) 0.738
0.542 39.7 (27) 43.4 (23) 0.683
0.735 63.8 (44) 66 (35) 0.795
0.761 19.1 (13) 20.8 (11) 0.775
0.213 66.4 (18) 48.4 (16) 0.647
0.606 62.3 (43) 60.4 (32) 0.827
0.045 87 (60) 75.5 (40) 0.102
0.717 18.8 (13) 22.6 (12) 0.606
0.095 85.5 (59) 75.5 (40) 0.160
0.354 478 (33) 37.7 (20) 0.265
0.642 49.3 (34) 47.2 (25) 0.818
0.716 111 (73-394) 112 (72-315) 0.822
0.895 146 ± 80 135 ± 70 0.463
0.752 113 ± 33 113 ± 37 0.952
0.039 43 ± 11 46 ± 13 0.236
0.840 62.9 ± 20 58.4 ± 20.6 0.234
0.181 3.31±1.78 3.05±1.75 0.430
0.493 4.1 (0.3-69) 4.4 (0.7-18.1) 0.936
0.937 17.3 (2.9-243.1) 16.2 (5.4-139.8) 0.960
0.375 5.3 (2.5-209.9) 6.9 (1.9-452.9) 0.064
0.306 923(43-13179) 1257 (105-35000) 0.106
0.000 12 ± 6 23 ± 11 0.000
0.000 12 ± 6 20 ± 8 0.000
0.000 24 ± 9 32 ±11 0.000
0.000 23 ± 9 31 ± 10 0.000
0.000 28 ± 11 40 ± 11 0.000
0.000 31 ± 14 43 ± 10 0.000
0.000 32 ± 17 54 ± 35 0.000
0.000 13 (1-43) 4 (1-24) 0.000
0.000 22 (11-43) 5 (1-10) 0.000
0.420 0.427
8.7 (6) 3.8 (2)
66.7 (46) 64.2 (34)
24.6 (17) 30.2 (16)
0.934 37 (2-41) 35 (1-41) 0.062
0.805 30.4 (21) 34 (18) 0.679
0.186 44.9 (31) 26.4 (14) 0.036
BMI: Body Mass Index, CAD: Coronary Artery Disease, ACE: Angiotensin Converting Enzyme, ARB: Angiotensin Receptor Blocker, TG: Triglyceride, LDL: Low Density Lipoprotein, HDL: High Density Lipoprotein, GFR: Glomerular Filtration Rate, hs-CRP: High sensitive C-reactive protein, TNFa: Tumor necrosis factor alfa, IL-6: Interleukin-6, NT-proBNP: N-terminal pro-brain natriuretic peptide, NYHA: New York Heart Association, SF: Short Form for quality of life, HAM-D: Hamilton D rating scale, HAM-A: Hamilton A rating scale.
A receiver operating characteristics curve analysis was performed for NLR. The area under the curve was 0.62 (CI 0.500.73, p=0.042), and 2.68 was selected as an optimal effective cut-off point according to sensitivity of 60% and specificity of 60%). Kaplan-Meier's survival curve of NLR is shown in Figure 3.
Hospitalization
Age, LVEF, serum sodium level, SF-36 pain, MCS, NLR, HAM-D score, HAM-A score, and NYHA functional capacity were found as predictors in the univariate analysis. NLR, HAM-A score, serum sodium level, and NYHA functional capacity were found as independent predictors for hospitalization (Table 5).
Table 3
Comparisons of survivors and non-survivors
Parameter Non-Survivors n (39) Survivors n (83) p
Age (Years) 68.6 ± 9.7 61±8.8 0.000
Male 79.5 (31) 77.1 (64) 0.768
Ejection Fraction (%) 32.5 ± 6.4 35.1 ± 6.5 0.037
BMI (kg/m2) 27.6 ± 5.4 28.6 ± 5.2 0.398
Hypertension % (n) 76.9 (30) 67.1 (55) 0.268
Diabetes Mellitus % (n) 46.2 (18) 39 (32) 0.457
CAD history % (n) 59 (23) 67.5 (56) 0.360
Smoking % (n) 35.8 (14) 36.1 (30) 0.569
Atrial Fibrillation % (n) 39.4 (13) 28.8 (21) 0.462
Medications % (n)
ACE inhibitor 56.4 (22) 63.9 (53) 0.431
Beta Blocker 76.9 (30) 84.3 (70) 0.321
ARB 28.2 (11) 16.9 (14) 0.148
ASA 71.8 (28) 85.5 (71) 0.07
Hydrochlorothiazide 46.2 (18) 42.2 (35) 0.679
Furosemide 51.3 (20) 47 (39) 0.658
MRA 43.6 (17) 45.8 (38) 0.820
Laboratory analysis
Glucose (mg/dl) 0.259
TG (mg/dl) 136 ± 72 143 ± 78 0.692
LDL (mg/dl) 116 ± 37 112 ± 34 0.544
HDL (mg/dl) 41 ± 10 46 ± 13 0.116
GFR 51.3 ± 19.5 65.6 ± 19.3 0.000
Sodium 135 ± 19 139 ± 2 0.04
Potassium 4.8 ± 1.1 4.6 ± 0.4 0.131
NLR 3.8 ±2.8 2.8 ± 1.3 0.005
hsCRP 6.4 (0.3-39.8) 4 (2.9-16.2) 0.120
TNF alfa 17.5 (8.3-17.5) 16.2 (2.9-243.1) 0.190
IL-6 6.8 (3.6-367.8) 5.6 (1.9-452.9) 0.290
NT-proBNP 1257 (223-7392) 961 (43-35000) 0.199
Depression and anxiety
SF physiological function 15 ± 9 17 ± 11 0.354
SF physiological rol 13 ± 7 16 ± 9 0.081
SF pain 23 ± 9 30 ± 11 0.003
SF general health 23 ± 8 28 ± 11 0.014
SF vital 33 ± 13 34 ± 13 0.637
SF social function 34 ± 13 38 ± 13 0.123
SF mental health 45 ± 43 40 ± 17 0.435
HAM-D 5 (1-43) 6 (1-38) 0.858
HAM-A 11 (3-43) 13 (1-43) 0.456
NYHA Class I 7.7 (3) 6 (5) 0.000
II 41 (16) 77.1 (64)
III 48.7 (19) 16.9 (14)
Follow-up Time 16 (1-41) 38 (4-41) 0.000
BMI: Body Mass Index, CAD: Coronary artery disease, ACE: Angiotensin Converting Enzyme, ARB: Angiotensin Receptor Blocker, TG: Triglyceride, LDL: Low Density Lipoprotein, HDL: High Density Lipoprotein, GFR: Glomerular Filtration Rate, NLR: Neytrophile to Lymphocyte ratio, hs-CRP: High sensitive C-reactive protein, TNFa: Tumor necrosis factor alfa, IL-6: Interleukin-6, NT-proBNP: N-terminal pro-brain natriuretic peptide, NYHA: New York Heart Association, HAM-D: Hamilton D rating scale, HAM-A: Hamilton A rating scale.
Correlation analysis
A Pearson correlation analysis showed that NLR was negatively correlated with LVEF (r= -0.218, p=0.002) and hs-CRP and IL-6 levels were positively correlated with NT-proBNP (r=0.368, p<0.001 and r=0.650, p<0.001, respectively). Table 6 shows other correlated parameters.
Discussion
In our study including HFrEF and HFmrEF patients we found that 1) Depression and anxiety were not related to mortality 2) NLR, NYHA, and HAM-A scores were independent
predictors for hospitalization 3) Age, LVEF, and GFR were independent predictors of mortality 4) Serum NT-proBNP, IL-6, TNF-a, and hs-CRP levels were not related to mortality, also.
The incidence of depression is nearly 2-3 times increased in patients with HF than in the normal population, and the estimated prevalence is 24%-42% [16]. The prevalence of depression in HF differs by health status, demographic factors, and social factors. In our study population, depression and anxiety occurred in 36.9% and 56.6% of the cases, respectively, similar to that in previous studies. Depression has also been associated with developing HF [17]. Because arguments on
Table 4
Cox regression analysis for cardiovascular mortality
Univariate Multivariate
Variable HR CI 95% p HR CI 95% p
Age (years) 1.08 1.04-1.12 <G.GG1 1.08 1.04-1.14 <G.GG1
EF 0.94 0.9- 0.98 G.G15 0.93 0.89-0.98 G.G14
GFR 0.9б 0.9S-0.98 <G.GG1 0.97 0.9S-0.99 G.G28
Sodium 0.98 0.9б-0.99 G^6
NLR 1.31 1.12-1.S2 <G.GG1
hsCRP 1.01 0.99-1.04 0.21б
TNFa 1.00 0.99-1.01 0.789
IL-6 1.00 0.99-1.00 0.870
NT-proBNP 1.00 1.00-1.00 0.970
SF pain 0.9S 0.92-0.98 G.GG6
SF general health 0.9б 0.93-0.99 G^T
MCS 1.01 0.98-1.0S 0.322
PCS 0.98 0.9б-1.01 0.240
NYHA class 2.77 1.б3-4.7 <G.GG1
HAM-A 1.0 0.97-1.03 0.б22
HAM-D 1.00 0.97-1.03 0.819
EF: Ejection fraction, GFR: Glomerular Filtration Rate, NLR: Neytrophile to Lymphocyte ratio, hs-CRP: High sensitive C-reactive protein, TNFa: Tumor necrosis factor alfa, IL-6: Interleukin-6, NT-proBNP: N-terminal pro-brain natriuretic peptide, SF: Short Form for quality of life, MCS: mental composite health score, PCS: Physical composite health score NYHA: New York Heart Association, HAM-D: Hamilton D rating scale, HAM-A: Hamilton A rating scale.
Cox regression analysis for hospitalization
Univariate Multivariate
Variable HR CI 95% p HR CI 95% p
Age (years) 1.04 1-1.07 G.G2
EF 0.9S 0.91-0.99 G^4
GFR 0.99 0.97-1 0.231
Sodium 0.97 0.9б-0.99 G.GG6 0.97 0.9S-0.99 G.GG6
NLR 1.2S 1-1.0S G.G11 1.32 1.0б-1.б5 G.G12
hsCRP 1.01 0.99-1.03 0.1S7
TNFalfa 1.00 0.99-1.01 0.1бб
IL-6 1.00 0.99-1.01 0.8бб
NT-proBNP 1.00 1.00-1.00 0.88S
SF pain 0.9б 0.93-0.99 G^
SF general healh 0.97 0.94-1.00 0.131
MCS 0.9S 0.91-0.99 G^5
PCS 1.01 0.98-1.0S 0.322
NYHA class 2.47 1.47-4.1б G.GG1 2.48 1.37-4.48 0.003
HAM-A 1.02 1.00-1.0S G^6 1.04 1.01-1.07 G.G1G
HAM-D 1.02 1.00-1.0S G.G49
EF: Ejection fraction, GFR: Glomerular Filtration Rate, NLR: Neytrophile to Lymphocyte ratio, hs-CRP: High sensitive C-reactive protein, TNFa: Tumor necrosis factor alfa, IL-6: Interleukin-6, NT-proBNP: N-terminal pro-brain natriuretic peptide, SF: Short Form for quality of life, MCS: mental composite health score, PCS: Physical composite health score NYHA: New York Heart Association, HAM-D: Hamilton D rating scale, HAM-A: Hamilton A rating scale.
Correlation analysis between some parameters with EF and BNP
EF BNP
Variable r p Variable r p
GFR 0.1б4 0.077 GFR -0.233 0.021
BNP -0.00б 0.S30 Hs-CRP 0.3б8 <0.001
Hs-CRP -0.178 0.072 TNF-a 0.009 0.929
TNF-a -0.0S0 0.605 IL-6 0.650 <0.001
IL-6 0.03S 0.723 NLR 0.561 0.0б
NLR -0.218 0.002 MCS 0.094 0.43б
MCS -0.08б 0.349 PCS 0.078 0.436
PCS 0.048 0.б03 SF physiological function 0.23S 0.017
HAM-D -0.039 0.б71 SF physiological role 0.187 0.0S9
HAM-A 0.007 0.942 SF pain 0.18S 0.0б1
EF: Ejection fraction, GFR: Glomerular Filtration Rate, NT-proBNP: N-terminal pro-brain natriuretic peptide, hs-CRP: High sensitive C-reactive protein, TNFa: Tumor necrosis factor alfa, IL-6: Interleukin-б, NLR: Neytrophile to Lymphocyte ratio, MCS: mental composite health score, PCS: Physical composite health score HAM-D: Hamilton D rating scale, HAM-A: Hamilton A rating scale.
g
depression are related to increased mortality, the combination of systolic HF and depression has become a more important issue nowadays. In the HF population, some investigations have showed that patients with depression and anxiety have higher rates of mortality and morbidity [18]. Moomersteeg et al. [19] reported that depression, CRP, and TNF-a receptors are associated with higher mortality rates in a study including 104 patients with HFrEF. However, in that study, diabetes mellitus was more common in the cardiovascular death group. By contrast, some authors have reported that depression is not an independent predictor of cardiovascular mortality in patients with HF [20,21]. Pelle et al. [22] showed that anxiety and depression symptoms were not related to mortality and was an independent risk factor for hospitalization in a study including 662 patients with HFrHF aged 40 years. In that study, patients were already hospitalized for HF at beginning of the study, were younger, and had follow-up for 1 year. Recently, metaanalysis investigating the relation between anxiety, depression and all-cause mortality in HF patients showed that depression is an independent predictor. However, these meta-analyses including a mixed HF population for reduced, mildly-reduced and preserved EF. Last European Heart Failure Guideline emphasized the depression was related to poor outcomes and worse clinical status in HF patients [23]. Depression and anxiety worsen the symptoms of heart failure and diminish the quality of life. Controversial findings about depression and anxiety's influence on mortality in HF patients and ineffectiveness of antidepressant treatment on clinical outcome may related to HF types, comorbidities, drug-drug interactions, follow-up time and used different depression scales. In our study, we included patients with compensated HFrEF-HFmrEF and the follow-up period was longer than other studies. We found that the depression and anxiety scores were related to hospitalization (HR 1.025 and 1.029, respectively) in the univariate analysis. Anxiety was an independent predictor of repeated hospitalization in our study population.
In most of the studies on depression, inflammatory markers, and HF, investigators used self-questioning scales such as the BDI scale, Patient Health Questionnaire depression module, and Center for Epidemiological Studies Depression-Scale for detecting depression or anxiety. Patients with both HF and depression suffer from reduced exertion tolerance, worsening quality of life, and poor NYHA functional capacity, which are symptoms present in both diseases. Some studies have suggested that depression is minimally related to an objective assessment of HF severity such as peak oxygen consumption, LVEF, and BNP levels; however, it significantly affected symptoms of HF such as NYHA capacity or results of the 6-minute walk test [24,25]. Therefore, we preferred HAM-D and HAM-A scales because they are applied through face-to-face interviews by a specialist and provide an objective assessment of symptoms. Different from previous studies, we used HAM-D and HAM-A to evaluate the presence of depression and anxiety scale by an interview with a physiatrist.
The relationship between the inflammation system and cardiovascular disease is widely known. Neutrophils play a role in the HF process because it is reflected in the pro-inflammatory status. NLR is a worse outcome biomarker for patients with high-risk status. Studies suggest that both HF is characterized by low-grade chronic inflammation [26,27]. In our study, NLR was significantly increased in non-survivors. It was related to a 1.3-fold risk increase for mortality in the univariate regression analysis and a 1.21-fold independent risk increase for hospitalization in the multivariate regression analysis. In this study, NLR of >2.68 is related to decreasing survival rates in
the Kaplan-Meier analysis. In addition, we found a significant correlation between LVEF and NLR. These results emphasized that NLR reflects a low-grade inflammatory status in patients with HFrEF and HFmrEF.
Although increased CRP relates to new, recurring, or long-term depression, the relationship between inflammation and depression is unclear. While some studies suggested that depression and associated autonomic dysfunction might prolong immune activation and resulted in an inflammatory state in patients with HF, others have suggested that increased inflammation might worsen depressive symptoms [28,29].
TNF is a cytokine that promotes inflammation that activates immune cells. Studies have reported that serum IL-6 and TNF-a levels correlated with HF symptoms and poor prognosis [30,31]. Some authors have found that TNF-a receptor but not TNF-a level was related to cardiovascular mortality in their study [32]. Parissis et al. [33] found no relationship between serum IL-6 and TNF-a levels and cardiovascular outcomes; only IL-10 and BNP levels were independent predictors of cardiovascular mortality at 1-year follow-up in patients with HF and hospitalized. In our study serum BNP, TNF-a, hs-CRP, and IL-6 levels are not associated with cardiovascular mortality and hospitalization. Different results of previous studies may be related to the patient's LVEF because of the inflammation appears more prominent in HFpEF patients, functional capacity, compensated or non-compensated status, and immune-compromised status because of aging.
NT-proBNP is an indicator of volume overload as well as a diagnostic biomarker of HF. BNP level is related to the severity of HF and cardiovascular outcomes [34]. In our study, serum BNP levels were not related to cardiovascular mortality and hospitalization. It significantly correlated with IL-6 and hs-CRP levels like in previous studies [35].
This study has limitations. First, limited number of patients and the follow-up period were relatively short. Second, serum inflammatory levels and psychological assessments were evaluated only at baseline. Third, we did not re-evaluate serum biomarkers and LVEF during the study period. Finally, we evaluated functional capacity with an interview and not with the 6-minute walk test.
Conclusion
This study revealed that depression and anxiety are not related to cardiovascular mortality in HFrEF and HFmrEF patients. However, anxiety is an independent predictor for hospitalization. The levels of serum BNP, IL-6, TNF-, and hs-CRP are not associated to cardiovascular outcomes. NLR is related to repeated hospitalization.
Declaration of congress abstract: This study was presented as an 'poster presentation' at Heart Failure 2019 - 6th World Congress on Acute Heart Failure.
Disclosures: There is no conflict of interest for all authors.
Acknowledgements: The study was supported by the Research Fund of the Canakkale Onsekiz Mart University (project No TSA-2014-342).
Funding: The study was supported by the Research Fund of the Canakkale Onsekiz Mart University (project No TSA-2014-342).The research sponsors did not participate in the study design, data collection, analysis, and interpretation, not involved in the writing of the manuscript, and the decision to submit the manuscript for publication
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