Journal of Clinical Epidemiology 62 (2009) 452e456

Anxiety predicted premature all-cause and cardiovascular death

in a 10-year follow-up of middle-aged women
Johan Denolleta,*, Kristel Maasa, Andre Knottnerusb, Jules J. Keyzerc, Victor J. Popa
a
CoRPS e Center of Research on Psychology in Somatic diseases, Tilburg University, Tilburg, The Netherlands
b
Department of General Practice, University of Maastricht, Maastricht, The Netherlands
c
Diagnostic Center Eindhoven, Eindhoven, The Netherlands
Accepted 9 August 2008

Abstract
Objective: Research on emotional distress and mortality has largely focused on depression in men and in elderly populations. We
examined the relation between anxiety and mortality in women at midlife, adjusting for depression.
Study Design and Setting: At baseline, 5,073 healthy Dutch women aged 46e54 years (mean 5 50.4 6 2.1) and living in Eindhoven,
completed a three-item anxiety scale (‘‘being anxious/worried,’’ ‘‘feeling scared/panicky,’’ ‘‘ruminating about things that went wrong;’’
Cronbach’s a 5 0.77). The primary outcome was all-cause mortality at 10-year follow-up; secondary outcomes were cardiovascular and
lung/breast cancer death.
Results: At follow-up, 114 (2.2%) women had died at the mean age of 56.4 6 3.1 years. Lung cancer (23%), cardiovascular disease
(18%), and breast cancer (15%) were the major causes of death. Smoking, living alone, and lower education were related to mortality, but
depression was not. Adjusting for these variables, anxiety was associated with a 77% increase in mortality risk (hazard ratio [HR] 5 1.77,
95% confidence interval [CI]: 1.14e2.74, P 5 0.011). Anxiety was related to cardiovascular death (HR 5 2.77, 95% CI: 1.17e6.58,
P 5 0.021); there was also a trend for lung cancer death (HR 5 1.91, 95% CI: 0.90e4.06, P 5 0.095) but not for breast cancer death.
Conclusion: Anxiety predicted premature all-cause and cardiovascular death in middle-aged women, after adjustment for standard risk
factors and depression. Ó 2009 Elsevier Inc. All rights reserved.
Keywords: Women; Anxiety; Depression; Mortality; Cardiovascular death; Cancer death

1. Introduction women this is less evident [19]. Further, psychological fac-

tors may be more important for late than early stages of heart
Smoking, physical inactivity, body mass index (BMI)
disease in women [20] and behavioral research has largely
O30, hypertension, and diabetes adversely affect health
focused on mortality in older women [13,21e24]. Finally,
[1e5], but more research is needed to study modifiable risk
there is a need for studies on anxiety and health that control
factors for mortality in women [6]. Of note, emotional dis-
for depression [9], and for prospective studies that confirm
tress also predicts mortality and heart disease in the general
findings from retrospective [18] or caseecontrol [7] studies.
population [7]. Although most emphasis is on depression
Therefore, we prospectively examined the relation be-
[8], less is known about the associations between anxiety
tween anxiety and risk of premature death in middle-aged
and somatic diseases [9] such as heart disease [3,5,7] or women, adjusting for the effect of depression.
cancer [10].
Anxiety occurs in relation to worry [11] and has been re-
lated to mortality [12e18] but less is known about its health
effects in women. Although some studies found that anxiety 2. Methods
was related to cardiac death in women [4,5,18], others did not
replicate this finding [12] or found only a marginally elevated 2.1. Participants
risk [3]. Anxiety promotes atherosclerosis in men, but for Between September 1994 and September 1995, 6,574 out
of 8,098 (81%) Caucasian women agreed to participate in the
* Corresponding author. CoRPS, Department of Medical Psychology,
Tilburg University, Warandelaan 2, P.O. Box 90153, 5000 LE Tilburg, Eindhoven Perimenopausal Osteoporosis Study [25]. They
The Netherlands. Tel.: þ31-13-466-2390; fax: þ31-13-466-2370. were all born between 1941 and 1947, and living in Eind-
E-mail address: denollet@uvt.nl (J. Denollet). hoven, the Netherlands. Of these women, 5,428 (83%) gave
0895-4356/09/$ e see front matter Ó 2009 Elsevier Inc. All rights reserved.
doi: 10.1016/j.jclinepi.2008.08.006
 J. Denollet et al. / Journal of Clinical Epidemiology 62 (2009) 452e456 453

the time and causes of death (using ICD-10 criteria). The

What is new? primary outcome was total mortality; secondary outcomes
Most prior studies suggested that anxiety may be less were cardiovascular and lung/breast cancer death.
important for health in women than in men, but these
studies focused on older populations and failed to con- 2.3. Covariates
trol for depression. Demographic features and standard risk factors that have
In this study of women aged 46e54 years anxiety was been associated with poor health in women [1e5] were se-
clearly related to an increased risk of premature mor- lected as covariates, including higher age, lower education
tality, predominantly cardiovascular, after controlling (no high school education), living alone, smoking (current
for standard risk factors and depression. smoker), excessive alcohol consumption, physical inactiv-
ity (exercising less than 2 h/wk), BMI O30, hypertension
(use of antihypertensive drugs), diabetes (use of antidia-
betic drugs), and the Edinburgh Depression Scale (EDS)
written informed consent for the follow-up study and com- [27e29]. The EDS was originally developed for assessing
pleted anxiety and depression scales. At baseline, standard postpartum depression [29] but has also been validated in
risk factors for mortality and a medical history were also middle-aged women [27,28]. Scores on all 10 items of the
assessed. History of cancer was checked in 1995 with the EDS were summed (range, 0e30); a cut-off score of 12
aid of the local Netherlands Cancer Registry [26] center identifies women with mild-to-severe depressive symptoms
(IKZ Eindhoven). In this study, respondents with a personal and this dichotomous variable was used in this study. Cron-
history of cancer (n 5 274) or cardiovascular disease bach’s a of the EDS was 0.89.
(n 5 81) were excluded, resulting in a total of 5,073 women
with a mean age of 50.4 6 2.1 years (Table 1). This study 2.4. Anxiety
was approved by the medical ethical committee of the
Anxiety was assessed using a three-item anxiety subscale
Maxima Medical Centre Hospital of Eindhoven/Veldhoven.
[28] of the EDS. These items refer to anxiety (‘‘being anxious
or worried for no good reason’’, ‘‘feeling scared or panicky
2.2. Study outcomes
for no good reason’’) and rumination/worry (‘‘blaming
In September 2005, with the aid of the Dutch National myself unnecessarily when things went wrong’’). Cronbach’s
Institute of Statistics, the number of women who died dur- a in this study was 0.77. A score >5 corresponds to the upper
ing the 10-year follow-up period was assessed, as well as tertile of the anxiety score (mean 5 3.25 6 2.61; range,
0e9), and was used to define women with increased anxiety.
Table 1
Characteristics of 5,073 middle-aged women, stratified by baseline 2.5. Statistical analyses
anxiety
Principal component analysis was used to examine load-
Low High
Total anxious anxious P- ings of the EDS items onto different anxiety and depression
group (n 5 3,409) (n 5 1,664) value factors. Differences in covariates between anxious and
Continuous: mean 6 SD nonanxious women were analyzed using paired t-test (con-
Anxiety (range, 0e9) 3.3 6 2.6 1.7 6 1.5 6.4 6 1.3 0.0001 tinuous data) and chi-square tests (categorical data). Cox
Depression (range, 7.3 6 6.1 4.4 6 4.0 13.1 6 5.4 0.0001 regression analyses were used to investigate the impact of
0e30) anxiety on mortality, adjusting for covariates, and depres-
Age 50.4 6 2.1 50.4 6 2.0 50.5 6 2.1 0.25
sion. All variables were entered at the same time. We ad-
Dichotomous: % (n) justed for age, education, and living alone because they
Lower education 46% (2,344) 42% (1,447) 54% (897) 0.0001 have been associated with substantial variation in health sta-
Living alone 7% (361) 7% (253) 6% (108) 0.27
Oral contraceptive 13% (662) 13% (427) 14% (235) 0.11
tus; hormone intake was included to control for its effect on
medication anxiety; smoking, alcohol, physical activity, BMI, hyperten-
Hormone replacement 15% (755) 14% (476) 17% (279) 0.008 sion, and diabetes were included to control for standard risk
therapy factors; depression was included to control for this estab-
Smoking 35% (1,779) 33% (1,112) 40% (667) 0.0001 lished psychological risk factor [9]. All statistical tests were
Alcohol O20 3% (160) 3% (101) 4% (59) 0.265
drinks/wk
two-tailed (P ! 0.05), and were performed using SPSS 12.0.
Physical activity 42% (2,138) 45% (1,530) 37% (608) 0.0001
>2 h/wk
BMI O 30 14% (719) 13% (434) 17% (285) 0.0001 3. Results
Hypertension 8% (410) 7% (244) 10% (166) 0.001
Diabetes mellitus 2% (116) 2% (68) 3% (48) 0.047 Factor analysis confirmed that the anxiety scale mea-
Number of subjects appears within parentheses. sured a distress dimension that was distinctly different from
454 J. Denollet et al. / Journal of Clinical Epidemiology 62 (2009) 452e456

depression. All anxiety items loaded on one factor (load- HR=2.74* HR=2.21† HR=0.86‡
p=.023 p=.040 p=.78
ings 5 0.80, 0.78, and 0.75), whereas all depression items
loaded on another factor (mean loading 5 0.68). Anxious 60 12/21
55 14/27 Alive
women were more likely to have depressive symptoms,
50 Dead
a lower education, and an unhealthy lifestyle (smoking, in-

Anxious Women (%)

45
activity, BMI O30, hypertension, diabetes) than nonanxi- 40 1652 1650 1659
ous women (Table 1). 35 / 5052 / 5046 / 5056
After 10 years of follow-up, 114 (2.2%) women had died 30
5/17
at an average age of 56.4 (63.1) years; 108 deaths were due 25
to natural causes. Cardiovascular disease (18%; ischemic 20
heart disease [n 5 8], stroke [n 5 6], cardiac arrest [n 5 4], 15
other [n 5 3]), lung cancer (23%), and breast cancer (15%) 10
were frequent causes of death. Anxiety was associated with 5
total mortality (Table 2a); that is, 51 out of 1,664 anxious 0
Cardiovascular Lung cancer Breast cancer
women had died vs. 63 out of 3,409 nonanxious women Death Death Death
(P 5 0.007). Using continuous levels of anxiety confirmed
Fig. 1. Percentage of middle-aged women with high baseline anxiety,
this association with mortality (hazard ratio [HR] 5 1.10, stratified by cardiovascular, lung cancer death, and breast cancer death.
95% confidence interval [CI]: 1.03e1.17, P 5 0.008). De- *95% CI: 1.15e6.49, adjusting for age. y95% CI: 1.04e4.70, adjusting
pressive symptoms were not related to mortality (P 5 0.41). for age. z95% CI: 0.30e2.45, adjusting for age.
Smoking (HR 5 1.67, 95% CI: 1.16e2.42, P 5 0.006), living
alone (HR 5 2.15, 95% CI: 1.27e3.65, P 5 0.004), and 4. Discussion
lower education (HR 5 1.45, 95% CI: 1.00e2.09, P 5 0.05)
also predicted mortality. In multivariate analysis, anxiety was Anxiety was related to an increased risk of premature
independently associated with a more than 70% increase in mortality in community-dwelling women aged 46e54
risk of death (HR 5 1.77); living alone (HR 5 2.19) and years. This relationship remained significant after adjust-
smoking (HR 5 1.50) were other predictors (Table 2b). ment for standard risk factors and depression, and was ob-
Anxiety was related to cardiovascular and lung cancer served with reference to total and cardiovascular death.
death, controlling for age (Fig. 1). Anxiety also predicted There was also a trend for lung cancer death, even after ad-
cardiovascular death (HR 5 2.72, 95% CI: 1.14e6.48, justment for smoking. Hence, self-reported anxiety had
P 5 0.024) after adjustment for living alone and smoking. a major negative effect on longevity in these relatively
Anxiety predicted lung cancer death after adjustment for young women.
living alone (P 5 .038), but the effect of anxiety was atten- The cumulative mortality rate of 2.2% at 10-year follow-
uated (HR 5 1.91, 95% CI: 0.90e4.06, P 5 0.095) when up corresponded to the national death rate (annual mortality
smoking was controlled for. Anxiety was not related to incidence between 1995 and 2005 in the Netherlands was
breast cancer death. 0.26% for middle-aged women) but the small event rate
of the end points precludes definitive conclusions. Because
the three anxiety items were also retained in the original set
Table 2 of 10 EDS items to assess depression, this overlap may
Predictors of mortality in 5,073 middle-aged womena
have caused overadjustment of anxiety in multivariate anal-
HR [95% CI] P-value yses. However, exclusion of these items from the depres-
2a. Univariate analysis sion variable would have resulted in a nonvalidated
Symptoms of anxiety 1.67 [1.15e2.41] 0.007 depression scale. Finally, this study did not include a psy-
Symptoms of depression 1.19 [0.79e1.81] 0.41
chiatric diagnosis of anxiety disorders and was limited to
2b. Multivariate model Caucasian women. This study also has a number of
Symptoms of anxiety 1.77 [1.14e2.74] 0.011 strengths. Although most prior studies on the health conse-
Symptoms of depression 0.74 [0.45e1.21] 0.23
Age 1.06 [0.97e1.16] 0.18
quences of emotional distress in women have focused on
Lower education 1.36 [0.93e1.99] 0.11 depression in older populations [12,22e24], did not include
Living alone 2.19 [1.28e3.74] 0.004 both anxiety and depression measures [9], or had retrospec-
Oral contraceptive medication 1.29 [0.77e2.14] 0.33 tive or caseecontrol design [7,18], the present research
Hormone replacement therapy 1.04 [0.63e1.73] 0.88 focused on women at midlife, adjusted for the effect of
Smoking 1.50 [1.03e2.20] 0.036
Alcohol O20 drinks/wk 1.48 [0.64e3.40] 0.36
depression, and used a prospective study design.
Physical Activity >2 h/wk 0.78 [0.52e1.17] 0.23 Previous research on cardiac death found that anxious
BMI O 30 1.13 [0.68e1.88] 0.64 women were only at marginally elevated risk [3], if any
Hypertension 1.18 [0.63e2.21] 0.62 [12], and suggests that anxiety may be less important for
Diabetes mellitus 1.06 [0.33e3.80] 0.92 atherosclerosis in women than in men [19,20]. The use of
a
All-cause mortality coded as 1. anxiolytic drugs was associated with cardiac death in
 J. Denollet et al. / Journal of Clinical Epidemiology 62 (2009) 452e456
women, but the authors reported that this ‘‘incidental’’ find-
ing required further investigation [18]. Our study seems to
corroborate their finding; anxiety was associated with
a more than twofold increased risk of cardiac death. Little
is known about the association of anxiety with cancer death
in women. In this study, there was a trend for lung cancer
but not breast cancer death.
Anxiety was related to an unhealthy lifestyle (smoking,
BMI O 30, inactivity), hypertension, and diabetes. These
factors were used as covariates, but they may also mediate
the anxietyemortality relationship. Anxiety has previously
been related to an unhealthy lifestyle in the context of car-
diovascular disease [30]. Anxious individuals may smoke
as a way of managing their level of distress [31], and the
effect of anxiety on lung cancer death was attenuated after
adjustment for smoking in this study. Anxiety is also related
to biological mechanisms such as high norepinephrine and
cortisol levels in middle-aged women [32]. Living alone
also predicted mortality; this factor has previously been re-
lated to poor prognosis in cardiac patients [33].
Although much of the previous studies on emotional
distress and mortality focused on men [14e16] or had an
emphasis on depression [21], clear evidence for a link be-
tween anxiety and mortality in women is largely absent.
In contrast to the negative findings of others [12] and the
notion that anxiety has more health effects in men than in
women [2,21], our findings indicate that anxiety predicts
mortality and call for more research on the health conse-
quences of anxiety in women.
Acknowledgment
This study was supported by VICI grant #453-04-004
from the Netherlands Organization for Scientific Research
(The Hague, The Netherlands) to Dr. Johan Denollet.
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