DOI: 10.1111/eci.12262

ORIGINAL ARTICLE Depressive symptoms and cardiovascular burden-related mortality among the aged Matti Hiltunen*,†, Tuomo Nieminen‡,§, Raimo Kettunen†, Sirpa Hartikainen¶, Raimo Sulkava**,††, Olli Vuolteenaho‡‡ and Tuomas Kerola† * Department of Clinical Neurophysiology, Helsinki University Central Hospital, Helsinki, †Department of Internal Medicine, €ija €t-Ha €me Central Hospital, Lahti, §Division of Cardiology, Helsinki University Lahti, ‡Department of Internal Medicine, Pa ¶ Central Hospital, Helsinki, Faculty of Pharmacy, University of Kuopio and Kuopio Research Centre of Geriatric Care, €virta Health Centre, Leppa €virta, **Division of Geriatrics, School of Public Health and Clinical Nutrition, University of Leppa †† Kuopio, Kuopio, Department of Neurology, Kuopio University Hospital, Kuopio, ‡‡Department of Physiology, Faculty of Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland

ABSTRACT Background Depressive symptoms have been linked to increased cardiovascular mortality among the elderly. This study was aimed to test the independent and additive predictive value of depressive symptoms and B-type natriuretic peptide (BNP), a marker of direct cardiovascular stress and a strong predictor of mortality, together with traditional cardiovascular risk markers on total and cardiovascular mortalities in a general elderly population. Methods A total of 508 subjects aged 75 or older participated in the study. The prognostic capacity of depressive symptoms and BNP in regard to total and cardiovascular mortalities was assessed with Cox regression analyses. Depressive symptoms were handled as a dichotomous variable based on the Zung selfrated depression scale score with a cut-off point of 40. Results The median follow-up time was 84 months with an interquartile range of 36–99 months. Depressive symptoms reflected susceptibility to all-cause (HR 1
60; 95% CI 1
26–2
04) and cardiovascular mortalities (HR 1
81; 95% CI 1
30–2
52) only in univariable analyses. When cardiovascular illnesses and risk markers were taken into account, depressive symptoms lost their significance as an independent predictor of mortality. BNP as a continuous variable was a significant predictor of both all-cause (HR 1
44; 95% CI 1
22–1
69) and cardiovascular mortalities (HR 1
79; 95% CI 1
44–2
22) in fully adjusted models including depressive symptoms as a covariate. Conclusions The prognostic capacity of depressive symptoms is closely linked to cardiovascular morbidity and has no independent power in an elderly general population. BNP remains a strong harbinger of death regardless of depressive symptoms status. Keywords B-type natriuretic peptide, cardiovascular burden, depressive symptoms, elderly population, mortality. Eur J Clin Invest 2014; 44 (5): 486–492

Introduction Depressive symptoms are common in patients with heart disease, and studies also connect depressive symptoms with increased cardiovascular morbidity and mortality among the elderly [1–4]. However, more information is needed on the interplay between depressive symptoms and cardiovascular risk factors in terms of their effect on prognosis among the aged. Natriuretic peptides, markers of direct cardiovascular stress, outperform traditional cardiovascular risk markers in the aged

486

general population as a predictor of mortality [5–7]. One study has suggested that aminoterminal pro-B-type natriuretic peptide (NT-proBNP) and depressive symptoms have additive value in predicting poor prognosis in patients with diagnosed heart failure [8]. To our knowledge, the independent prognostic power of depressive symptoms and natriuretic peptides has not been studied simultaneously in a general elderly population. This study was aimed to test the predictive capacities of depressive symptoms and B-type natriuretic peptide (BNP) together with established cardiovascular risk markers on mortality in a general elderly population.

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DEPRESSIVE SYMPTOMS

Methods This study is a part of the population-based, multidisciplinary Kuopio 75+ health study focusing on the clinical epidemiology and functional capacity in elderly persons aged 75 years or older [9]. The population is an age-stratified random sample of the 4518 inhabitants ≥75 years of age in the City of Kuopio in eastern Finland. The cohort included 700 participants. Seventy-nine persons refused to participate, five could not be contacted, and fifteen expired before the examination. Of the available 601 persons, a Zung self-rated depression scale (SDS) score [10] was available for 508 persons, who formed the final study population. A structured clinical examination and an interview were conducted by a geriatrician and a trained nurse during the year 1998. Brain imaging by computer tomography or magnetic resonance imaging was performed for participants with a suspicion of dementive illness without prior imaging. Clinical and demographic data were recorded and laboratory tests were analysed as detailed elsewhere [11]. Depressive symptoms were assessed with the Zung SDS [10]. The cut-off score for depressive symptoms was set at ≥ 40, as scores of 40–80 cover various grades of depressive symptoms. Mortality data were obtained from Statistics Finland without losses during follow-up. All deaths between March 1998 and November 2006 were recorded. Lifespan was from the examination date in 1998 to death or 30 November 2006. The causes of deaths were classified according to the International Classification of Disease (ICD-10) with codes I00–99 classified as cardiovascular. Written informed consent was obtained from the participants or their relatives as stipulated in the Declaration of Helsinki. The study was approved by the ethics committee of the Hospital District of Northern Savo and the Kuopio University Hospital.

Statistical analyses Baseline characteristics are given for participants divided into two groups by their depressive symptoms. Comparisons of characteristics between the groups were made with ANOVA or the Kruskal–Wallis test as appropriate. Blood levels of BNP were divided into tertiles for the categorical formulation for BNP: the highest tertile was considered BNPhigh with the cut-off point of 53
2 pg/mL, while the rest formed the group BNPlow. The 15 risk factors with potential stratifier capacity for mortality and cardiovascular mortality, separately, were subjected to univariable Cox proportional hazard models (Table 2). The variables with a significant outcome were included in the fully adjusted models. Hazard ratios (HR) for BNP and Zung SDS as continuous variable were calculated for a 1-SD increase.

Additional models were used to assess risks related to the different combinations of depressive symptoms (Zung SDS ≥ 40 or < 40) and blood levels of BNP (high and low). A P < 0
05 was considered statistically significant. All analyses were performed with PASW release 17.0 for Windows (SPSS Inc., Chicago, IL, USA). Reporting of the study conforms to the STROBE statement [12].

Results Baseline characteristics The baseline data are given in Table 1. The follow-up lasted up to 106 months (median 84 months, interquartile range 36–99). In the depressive symptoms group, 146 (59
8%) persons died during the follow-up; 85 (34
8%) fatalities were considered cardiovascular deaths. In the nondepressive symptoms group, the total mortality was 120 individuals (45
4%) and cardiovascular mortality 61 individuals (23
1%).

Predictors of total mortality Predictors of mortality in the entire Kuopio 75+ study population (n = 601) have been reported previously [5]. The variables that predicted total and cardiovascular mortalities in univariable Cox regression in the present study population are summarized in Table 2. BNP was also a significant predictor of mortality in an ageand sex-adjusted (data not shown) as well as in a multivariable Cox regression model, even when depressive symptoms were included as a covariate (HR 1
44; 95% CI 1
22–1
69). Depressive symptoms had significant prognostic value for total mortality in a univariable analysis (Table 2) as well as in an age- and sexadjusted model (HR 1
39; 95% CI 1
08–1
78). In a multivariable model including BNP, however, depressive symptoms lost their significance as a predictor of total mortality as either a dichotomous (HR 1
21; 95% CI 0
91–1
63, Fig. 1a) or continuous variable (HR 1
04 95% CI 0
82–1
32). The relative importance of BNP and depressive symptoms in the prediction of mortality is illustrated in Fig. 1c. The unadjusted, age- and sex-adjusted, and fully adjusted HRs for mortality in groups divided by the variable combining depressive symptoms and BNP levels are presented in Table 3.

Predictors of cardiovascular mortality The variables that predicted cardiovascular mortality in univariable analyses are presented in Table 2. In a multivariable model, when depressive symptoms were included as a covariate, continuous BNP had significant prognostic value for cardiovascular mortality (HR 1
79; 95% CI 1
44–2
22). Depressive symptoms had significant prognostic value for cardiovascular mortality in an unadjusted model (Table 2) as well as in

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Table 1 Baseline characteristics of the participants in groups divided by their status of depressive symptoms Nondepressed (n = 264) (%)

Depressed (n = 244) (%)

P-value

Female, n (%)

186 (70
5)

185 (75
8)

Age, mean (SD)

79
5 (3
9)

81
0 (4
6)

Total mortality, n (%)

120 (45
5)

146 (59
8)

0
001

85 (34
8)

0
004

Cardiovascular mortality, n (%) BMI, mean (SD)

61 (23
1)

0
103 < 0
001

26
4 (4
1)

26
2 (5
0)

0
749

Length of education, years (SD)

7
3 (3
7)

6
3 (3
2)

0
002

History of smoking, n (%)

70 (26
6)

58 (24
0)

0
539

154
2 (23
5)

149
7 (24
3)

0
038

32 (12
1)

40 (19
6)

0
203

134 (50
8)

150 (61
5)

0
015

Heart failure, n (%)

46 (17
4)

83 (34
0)

< 0
001

Peripheral vascular disease, n (%)

17 (6
4)

37 (15
2)

0
001

Stroke, n (%)

25 (9
5)

29 (11
9)

0
391

TIA, n (%)

39 (14
8)

35 (14
3)

0
901

Myocardial infarction, n (%)

92 (34
8)

73 (29
9)

0
236

Atrial fibrillation, n (%)

32 (12
1)

45 (18
4)

0
047

NYHA class III–IV, n (%)

34 (13
4)

83 (37
9)

< 0
001

Diabetes, n (%)

45 (17
0)

56 (23
0)

0
119

224 (84
8)

235 (96
3)

< 0
001

ACE inhibitor, n (%)

48 (18
2)

54 (22
1)

0
270

Diuretics, n (%)

78 (29
5)

106 (43
4)

0
001

Statin, n (%)

14 (5
3)

8 (3
3)

0
284

Calcium channel blocker, n (%)

44 (16
7)

40 (16
4)

1
000

107 (40
5)

114 (46
7)

0
179

17 (6
4)

21 (8
1)

0
354

6 (2
3)

9 (3
7)

0
435

Systolic blood pressure, mean (SD) Previous illnesses Dementive illness, n (%) Cardiovascular disease, n (%)

Medication Regular medication, n (%)

Beta-blocker, n (%) Oral diabetes medication, n (%) Insulin, n (%) Laboratory data Creatinine clearance, mean (SD) mL/min

< 0
001

54
4 (15
3)

48
9 (15
5)

Cholesterol, mean (SD) mM

5
8 (1
1)

5
5 (1
3)

0
005

HDL cholesterol, mean (SD) mM

1
5 (0
4)

1
4 (0
4)

0
003

BNP, median (IQR) pg/mL Haemoglobin, mean (SD) g/L Glucose, mean (SD) mM

30
9 (18
2–57
3)

40
3 (20
4–75
6)

0
006

135
0 (12
5)

131
4 (13
7)

0
002

5
6 (1
2)

5
6 (1
3)

0
950

BMI, body mass index; TIA, transient ischaemic attack; NYHA, New York Heart Association; ACE, angiotensin-converting enzyme; HDL, high-density lipoprotein; BNP, B-type natriuretic peptide; IQR, interquartile range.

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Table 2 Univariable hazard ratios (HR; with 95% confidence interval [CI]) of variables regarding prognostic value for total and cardiovascular mortalities Total mortality HR (95% CI)

Cardiovascular mortality HR (95% CI)

Age

1
87 (1
69–2
08)

2
00 (1
75–2
29)

Sex

1
15 (0
91–1
46)

1
30 (0
95–1
78)

Diabetes

1
19 (0
92–1
55)

1
41 (1
00–1
98)

Systolic blood pressure

0
71 (0
64–0
80)

0
69 (0
59–0
80)

History of myocardial infarction

1
31 (1
05–1
63)

1
40 (1
04–1
88)

History of stroke

2
20 (1
66–2
90)

2
34 (1
61–3
40)

History of heart failure

2
10 (1
68–2
62)

2
70 (2
01–3
62)

Atrial fibrillation

1
73 (1
33–2
26)

1
91 (1
34–2
72)

Creatinine clearance

0
67 (0
59–0
76)

0
67 (0
56–0
80)

Body mass index

0
80 (0
71–0
91)

0
89 (0
75–1
05)

Blood haemoglobin

0
85 (0
76–0
95)

0
96 (0
83–1
11)

NYHA class III–IV vs. I–II

1
78 (1
38–2
30)

2
59 (1
86–3
60)

HDL cholesterol

0
72 (0
64–0
81)

0
73 (0
55–0
76)

Depressive symptoms

1
60 (1
26–2
04)

1
81 (1
30–2
52)

BNP, continuous

1
52 (1
36–1
70)

1
73 (1
49–2
00)

1
98 (1
60–2
47)

2
52 (1
88–3
38)

BNP

high,

dichotomous

NYHA, New York Heart Association; HDL, high-density lipoprotein; BNP, Btype natriuretic peptide.

an age- and sex-adjusted model (HR 1
52, CI 1
08–2
13). As for total mortality, depressive symptoms did not predict cardiovascular mortality in a fully adjusted model as either a dichotomous (HR 1
27; 95% CI 0
88–1
85, Fig. 1b) or continuous variable (HR 0
86 95% CI 0
62–1
19). The effects of BNP and depressive symptoms on cardiovascular mortality are depicted in Fig. 1d. Unadjusted, age- and sex-adjusted, and fully adjusted risks for cardiovascular mortality in groups divided by the combinatory variable of depressive symptoms and BNP are presented in Table 3.

Discussion Although depressive symptoms reflected the susceptibility to all-cause and cardiovascular mortalities, it had no independent predictive power in an aged general population when cardiovascular traits were taken into account. As reported previously [5], BNP was independently associated with excess total and cardiovascular mortalities.

Depressive symptoms and total mortality Depressive symptoms are common among older people [13] and these symptoms are independently associated with increased mortality (n = 5201 [14]; n = 254 [15]). One recent study demonstrated that depression and NT-proBNP are independent and additive predictors of cardiovascular and allcause mortalities in patients with diagnosed heart failure (n = 208) [8]. Although being common, only a minority of our study population were diagnosed with heart failure. This may partly explain differences in our findings compared with those in subjects with diagnosed heart failure [8]. In our data, depressive symptoms associated with mortality in the univariable and the age- and sex-adjusted models. Adjustment with cardiovascular illnesses and risks, however, negated the association. Participants with depressive symptoms were prone to several conditions with an unfavourable prognosis (Table 1), and BNP levels were higher among depressed individuals. These findings suggest that the previously reported excess mortality related to depressive symptoms is connected to cardiovascular diseases, possibly to heart failure in particular.

Depressive symptoms, cardiovascular morbidity and mortality Depressive symptoms are common and connected with an adverse outcome in patients with heart failure [16–19]. There is also convincing evidence [20,21] that depression is a predictor of future heart disease. Stroke remains as a major cause of mortality among older people despite the decreasing stroke mortality rates due to improved treatment [22]. Poststroke depressive symptoms are common among stroke survivors [23], and depressive symptoms increase mortality among stroke patients [24]. However, as is the case with heart diseases, depressive symptoms have also been addressed as a risk factor for stroke [25]. The mechanisms associating depressive symptoms and cardiovascular mortality are still incompletely understood, although inflammatory mechanisms have been proposed to link depressive symptoms and heart failure [26]. In addition, impaired immune function as well as dysfunction of the autonomic nervous system, endothelial function and hypothalamic– pituitary–adrenocortical axis function link depressive symptoms to cardiovascular disease [27,28]. Importantly, depressed people have higher rates of noncompliance with medication and are less likely to improve their physical activity or stop smoking than nondepressed people [29,30]. Somatic conditions are common among older people, which increases prevalence of depressive symptoms [31].

BNP and mortality BNP has shown predictiveness on total and cardiovascular mortalities [6,7,32]. In one study, BNP and anti-inflammatory

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(b)

(c)

Figure 1 Multivariable Cox regression model for total and cardiovascular mortalities, groups divided by levels of BNP and status of depressive symptoms. (a) Depressive symptoms and total mortality. (b) Depressive symptoms and cardiovascular mortality. (c) Depressive symptoms and levels of BNP and total mortality. (d) Depressive symptoms and levels of BNP and cardiovascular mortality. In the multivariable model for total mortality, parameters included were age, systolic blood pressure, creatinine clearance, haemoglobin, body mass index, history of myocardial infarction, history of stroke, atrial fibrillation, heart failure, New York Heart Association class I-II or III-IV, high-density lipoprotein. In the multivariable model for cardiovascular mortality, parameters included were age, systolic blood pressure, creatinine clearance, history of myocardial infarction, history of stroke, atrial fibrillation, heart failure, diabetes, New York Heart Association class III or III-IV, high-density lipoprotein.

(d)

Table 3 Hazard ratios (HR) and 95% confidence intervals (CI) for groups divided by their levels of BNP and status of depressive symptoms against the group ‘BNPlow without depressive symptoms’ Total mortality HR (95% CI)

Cardiovascular mortality HR (95% CI)

BNPlow with depressive symptoms

1
49 (1
08–2
08)

1
67 (1
04–2
69)

BNPhigh without depressive symptoms

2
17 (1
50–3
15)

2
91 (1
75–4
84)

BNPhigh with depressive symptoms

3
17 (2
28–4
40)

4
51 (2
87–7
07)

BNPlow with depressive symptoms

1
42 (1
02–1
98)

1
58 (0
98–2
55)

BNPhigh without depressive symptoms

2
04 (1
71–2
94)

2
71 (1
63–4
50)

BNPhigh with depressive symptoms

2
41 (1
71–3
40)

3
26 (2
04–5
22)

BNPlow with depressive symptoms

1
29 (0
88–1
88)

1
24 (0
71–2
17)

BNPhigh without depressive symptoms

1
90 (1
25–2
88)

2
77 (1
56–4
90)

BNPhigh with depressive symptoms

2
12 (1
39–3
22)

2
67 (1
50–4
76)

Unadjusted

Age- and sex-adjusted

Multivariable

In the multivariable model for total mortality, the parameters included were age, systolic blood pressure, creatinine clearance, haemoglobin, body mass index, history of myocardial infarction, history of stroke, atrial fibrillation, heart failure, New York Heart Association class I–II or III–IV and high-density lipoprotein.

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cytokine interleukin-10 levels predicted an adverse outcome for heart failure patients with depressive symptoms (n = 300, mean age 65  12) [33]. In the present multivariable Cox regression, depressive symptoms did not augment the predictive power of BNP as demonstrated in Fig. 1c,d. BNP was clearly superior to depressive symptoms as a predictor of mortality, and depressive symptoms were only a modulating factor in the prognosis. Systolic blood pressure also had predictive capacity. These findings demonstrate the importance of BNP, a direct marker of cardiovascular stress, as a predictor of mortality among the aged.

Haartmaninkatu 4, FI-00290 Helsinki, Finland (T. Nieminen); Faculty of Pharmacy, Kuopio Research Centre of Geriatric Care, University of Kuopio Yliopistonranta 1 C, P.O. Box 1627, FI70210 Kuopio, Lepp€ avirta Health Centre, Savonkatu 17, 79100 Lepp€ avirta, Finland (S. Hartikainen); Division of Geriatrics, School of Public Health and Clinical Nutrition, University of Kuopio, P.O. Box 1627, FI-70211 Kuopio, Finland and Department of Neurology, Kuopio University Hospital, P.O Box 100, FI-70029 Kuopio, Finland (R. Sulkava); Department of Physiology, Faculty of Medicine, Biocenter Oulu, University of Oulu, P.O.Box 5000, FI-90014 Oulu, Finland (O. Vuolteenaho).

Study limitations, strengths and conclusions

Correspondence to: Dr Matti Hiltunen, MD, Department of Clinical Neurophysiology, Helsinki University Central Hospital, Haartmaninkatu 4, FI-00290 Helsinki, Finland. Tel.: +358-947180500; fax: +358-9-47174003; e-mail: [email protected]

A minor independent connection between depressive symptoms and mortality cannot be excluded due to the size of the study population. However, the total number of participants was superior to an earlier report on the predictive value of natriuretic peptides and depressive symptoms (n = 208) [8], and the present mortality rate was remarkable. Our solely Caucasian participants were ≥75 years of age, and the extrapolation of the results to other age or ethnic groups should be attempted with caution. The strengths of our study include the population-based approach and the extensive characterization of the study population. In conclusion, the prognostic capacity of depressive symptoms is closely linked to cardiovascular morbidity and has no independent power in an elderly general population. On the other hand, BNP remains a strong harbinger of death regardless of depressive symptoms status.

Acknowledgements This work was supported by the Finnish Cultural Foundation. The authors report no conflict of interests.

Contributions Matti Hiltunen wrote paper, designed study and analysed data. Tuomo Nieminen and Tuomas Kerola designed study, analysed data, and involved in important intellectual comments on paper and supervision. Raimo Kettunen and Raimo Sulkava collected data and involved in important intellectual comments on paper. Sirpa Hartikainen involved in important intellectual comments on paper and analysed data. Olli Vuolteenaho involved in important intellectual comments on paper. Address Department of Clinical Neurophysiology, Helsinki University Central Hospital, Haartmaninkatu 4, FI-00290 Helsinki, Finland (M. Hiltunen); Department of Internal Medicine, P€aij€at-H€ ame Central Hospital, Keskussairaalankatu 7, 15850 Lahti, Finland (M. Hiltunen, T. Nieminen, R. Kettunen, T. Kerola); and Division of Cardiology, Helsinki University Central Hospital,

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