C-Reactive Protein Is Associated With Psychological Risk Factors of

Cardiovascular Disease in Apparently Healthy Adults

EDWARD C. SUAREZ, PHD
Objective: The current study examined the relation of anger, hostility, and severity of depressive symptoms, alone and in
combination, to C-reactive protein (CRP) in healthy men and women. Methods: A high sensitivity enzyme linked immuno sorbent
assay (ELISA) was used to evaluate CRP levels in a multiethnic sample of 127 healthy, nonsmoking men and women. Fasting blood
samples were collected the same day the assessments were done of anger and hostility using the Buss-Perry Aggression
Questionnaire (BPAQ) and depressive symptomatology using the Beck Depression Inventory (BDI). A psychological risk factor
(PRF) score representing a composite summary indicator of BDI and BPAQ-anger and -hostility was generated using principal
component analysis. Log-transformed CRP values were examined using univariate and multivariate analyses adjusting for control
variables of age, gender, body mass index (BMI), alcohol use, exercise frequency, ratio of total to high-density lipoprotein
cholesterol, and family history of premature coronary heart disease (CHD). Results: Log-normalized CRP was correlated with BDI
(r ⫽ 0.21, p ⫽ .02) and BPAQ anger (r ⫽ 0.20, p ⫽ .02), but not with BPAQ hostility. After adjustment for control variables, BDI
(␤ ⫽ 0.05, p ⫽ .011), BPAQ anger (␤ ⫽ 0.05, p ⫽ .007), and the PRF composite score (␤ ⫽ 0.27, p ⫽ .005), but not BPAQ hostility
(␤ ⫽ 0.03, p ⫽ .11), were significantly associated with log-normalized CRP. Conclusions: Greater anger and severity of depressive
symptoms, separately and in combination with hostility, were significantly associated with elevations in CRP in apparently healthy
men and women. These associations were independent of potential confounding factors. Key words: C-reactive protein, anger,
hostility, severity of depressive symptoms, men, women.

BDI ⫽ Beck Depression Inventory; BMI ⫽ body mass index;
BPAQ ⫽ Buss-Perry Aggression Questionnaire; CHD ⫽ coronary
heart disease; CVD ⫽ cardiovascular disease; ELISA ⫽ enzyme
linked immuno sorbent assay; hsCRP ⫽ high sensitivity C-reactive
protein; IL ⫽ interleukin; MCP-1 ⫽ monocyte chemoattractant
protein-1; MI ⫽ myocardial infarction; MIP-1a ⫽ monocyte inflam-
matory protein-1a; NHANES III ⫽ Third National Health and
Nutrition Examination Survey; OTC ⫽ over-the-counter; PRF ⫽
psychological risk factor; TNF-␣ ⫽ tumor necrosis factor-␣.
INTRODUCTION
I nflammatory processes play key roles in the initiation and
progression of atherosclerosis and its clinical sequelae (1,2).
The relevance of inflammation to atherosclerotic cardiovas-
cular disease (CVD) is such that plasma levels of various
inflammatory biomarkers are emerging as important prognos-
tic indicators of future risk of CVD in initially healthy men
and women (3). One such biomarker is C-reactive protein
(CRP), a sensitive but nonspecific acute phase reactant (4). In
a number of studies of initially healthy individuals, CRP has
been associated with an increased risk of coronary heart
disease (CHD) (5–11), peripheral vascular disease (12,13),
and stroke (9,14). The strengths of these associations are such
that CRP predicts future risk of CVD in ‘high risk’ subpopu-
lations such as current smokers, diabetics, and hypertensives
(9), as well as in subgroups considered at ‘low risk’ such as
premenopausal women with no evidence of hypertension,
hyperlipidemia, diabetes, or family history of CHD (10), and
men who are not current smokers (9). It has been suggested
that the role of CRP in CVD goes beyond simply a predictor
From the Department of Psychiatry and Behavioral Sciences, Duke Uni-
versity Medical Center, Durham, North Carolina.
Address correspondence and reprint requests to Dr. Suarez at Duke Uni-
versity Medical Center, PO Box 3328, Durham, NC 27710. E-mail:
suare001@mc.duke.edu
Received for publication November 14, 2003; revision received May 6,
2004.
This study was supported by grants HL56105 and HL67459 from the
National Heart, Lung and Blood Institute to the author.
DOI: 10.1097/01.psy.0000138281.73634.67
of future risk or a biomarker of preclinical disease (15).
Recent evidence suggests that CRP plays an active role in
atherothrombogenesis by inducing the expression of cellular
molecules interleukin (IL)-6, endothelin-1 by endothelial cells
(16,17), and monocyte chemoattractant protein (MCP)-1 (18).
Thus, CRP is not only an important biomarker of the future
risk of CVD, but also a potential contributor to atherosclerosis
and its clinical sequelae (15).
The prognostic and pathophysiological relevance of CRP to
vascular diseases raises the question whether psychological
risk factors (PRF) known to predict an increased risk of CVD
are associated with CRP. Numerous studies have shown that
anger, hostility, and clinical depression are independently and
significantly associated with an increased risk of CHD in
initially healthy populations (19 –32), as well as cardiac mor-
tality and severity of CHD in coronary patients (33–36).
Severity of depressive symptoms, independent of clinical di-
agnosis, has also been shown to predict both future risk of
CHD in initially healthy persons (37,38) and the outcome
following acute cardiac events in clinical patients
(21,28,34,39). Severity of depressive symptoms and anger
have also been independently associated with increased risk of
stroke (40,41). Anger has been associated with an increased
risk of premature CVD, defined as incidence of disease before
age 60 (25,42). Although the pathophysiological pathways
whereby these factors contribute to poor cardiovascular health
are not fully understood (43), one relevant hypothesis posits
that inflammation may be a potential pathway whereby anger,
hostility (44 – 47), and severity of depressive symptoms (48 –
50) contribute to CVD. Evidence from a number of recent
studies has supported this general hypothesis. For example,
anger, hostility, and severity of depressive symptoms, sepa-
rately and in combination, have been associated with en-
hanced lipopolysaccharide (LPS)-stimulated expression of
monocyte-associated interleukin (IL)-1␤, IL-8, tumor necrosis
(TNF)-␣, monocyte chemoattractant protein (MCP)-1 and
monocyte inflammatory protein (MIP)-1a in healthy young
men (46,47) and women (51), as well as higher levels of

684 Psychosomatic Medicine 66:684 – 691 (2004)

0033-3174/04/6605-0684
Copyright © 2004 by the American Psychosomatic Society
CRP AND PSYCHOLOGICAL RISK FACTORS
circulating IL-6 in healthy young men (45). In healthy older
adults, the level of depressive moods and symptoms, even in
the mild ranges, has been associated with elevated IL-6
(50,52,53). Studies that have assessed CRP have shown that
patients diagnosed with major depressive disorder (48,54 –57)
and persons with a positive history of major depressive epi-
sode (58) have higher CRP levels. The relationship between
CRP and severity of depressive symptoms has been studied
less extensively with results being inconsistent (28,49,59).
One study of elderly men and women has shown an associa-
tion between CRP and depressive moods in univariate analy-
sis, but not in multivariate analyses that controlled for age,
body mass index (BMI), smoking, and other sociodemo-
graphic variables (49). Another study using multivariate tech-
niques to control for gender, age, smoking, BMI, and socio-
economic status also failed to observed a significant
association between CRP and severity of depressive symp-
toms in middle-aged men and women (59). Of the three
studies to date, only one has shown that elevated CRP is
significantly associated with greater severity of depressive
symptoms in an analysis that adjusted for various confounding
variables (52). To date, no study has examined the relation of
CRP to either anger or hostility. Clearly, evidence for an
association between CRP and PRF in apparently healthy in-
dividuals not only strengthens the notion that inflammation is
an important process mediating the relationship between CVD
and PRF, but also underscores the importance of evaluating
the role of PRF in the early stages of CVD.
The current study determined whether levels of CRP were
associated with anger, hostility, and severity of depressive
symptoms among apparently healthy individuals. The current
study also sought to determine whether these associations
were independent of other cardiovascular risk factors known
to be associated with both CRP and psychological risk factors.
METHODS
Subjects
A total of 127 healthy adults (male ⫽ 70, female ⫽ 57)
were enrolled in the study. Participants were nonsmoking,
normotensive (casual blood pressure ⬍ 140/90 mm Hg) men
and women between the ages of 18 and 65 (mean age ⫽ 27.6
years). Subjects were recruited from the general community
via advertisements placed in local newspapers and fliers dis-
tributed throughout the community. Participants received
monetary compensation for their participation.
Interested individuals were screened using a short self-
report health questionnaire. Individuals who enrolled in the
study were healthy with no past or current medical conditions.
Medical conditions screened were asthma, allergies, chronic
pain, diabetes, rheumatoid arthritis, cancer of any kind, and
cardiovascular diseases that included hypertension, myocar-
dial infarction, stroke, angina, and any other conditions that
could influence CRP. A positive history of any of these
diseases was based on self-report or prior use of any medica-
tions used to treat the aforementioned diseases. All partici-
pants also reported a negative history of psychiatric ailments;
Psychosomatic Medicine 66:684 – 691 (2004)
none reported ever using antidepressants. All participants
were free of acute infections and injuries occurring within the
last 30 days and none had undergone medical/dental proce-
dures during the 2 weeks before their laboratory session. Also
during those 2 weeks, subjects remained free of all prescrip-
tion medications and over-the-counter (OTC) preparations,
including daily low-dose aspirin. All female participants re-
ported not using oral contraceptives during the 6 months
before study participation. Written informed consent was ob-
tained before study participation. The Institutional Review
Board of Duke University Medical Center approved this pro-
tocol.
Procedures
To control for possible diurnal variation in CRP, study
sessions were scheduled between the hours of 8:00 AM and
9:30 AM following an overnight fast. To reduce menstrual
cycle related fluctuation of CRP (60), female participants were
scheduled during the follicular phase (days 5–10) of the men-
ses. After written informed consents were obtained, subjects
were interviewed about recent health status, physical injuries,
medical conditions, and use of prescribed medications and
OTC preparations. Participants who reported use of any med-
ications or OTC, presence of physical injury, recent medical
conditions (eg, sore throat, cold, sinus problems, flu-like
symptoms), or having undergone any medical/dental proce-
dures in the 2 weeks before laboratory session were resched-
uled. Following the interview, subjects were taken to the
laboratory where they were seated in a recliner and a blood
pressure cuff was attached to their nondominant arm. Two
blood pressure readings were taken at 5-minute intervals while
the subject sat quietly in the chair. After blood pressure
readings were taken, a 21-gauge butterfly needle was inserted
into a forearm vein and venous blood samples were collected.
Blood samples were centrifuged for 10 minutes, then refrig-
erated until transferred to the laboratory where assays were
conducted. Subjects then completed the packet of paper-and-
pencil questionnaires.
Measures of Anger, Hostility, Severity of Depressive
Symptoms, and Health-Related Behaviors
Anger and hostility were measured using subscales of the
Buss and Perry Aggression Questionnaire (BPAQ) (61). The
7-item BPAQ-anger subscale, which yields a score ranging
from 7 to 35, measures the emotional and affective component
of anger that involves physiological arousal and preparation
for aggression. The BPAQ-hostility subscale is comprised of
8-items that yield scores ranging from 8 to 40. The BPAQ-
hostility scale assesses an individual’s feelings of ill-will and
injustice. Psychometric properties of both BPAQ subscales
suggest good test-retest reliability (9-week test-retest reliabil-
ity ⫽ 0.72 for both BPAQ hostility and anger) and internal
consistency (Cronbach’s alphas ⫽ 0.77 and 0.83, for hostility
and anger, respectively) (61).
Severity of depressive symptoms was assessed using the
Beck Depression Inventory (BDI) (62). The BDI is a well-
685
 E. C. SUAREZ

validated and frequently used 21-item scale designed to mea- premature (⬍ 60 years of age) CHD (yes/no); factors previ-
sure severity of depressive symptomatology with scores sig- ously reported to be associated with higher levels of CRP
nificantly associated with clinical measures of depression (5,66 –71). Given that the inclusion criteria insured that par-
(63). The BDI has been widely used in cardiovascular popu- ticipants were free of all medications and OTC preparations,
lations, and prior evidence has suggested that the risk of future were nonsmokers with no previous or current medical condi-
cardiac events is associated with the magnitude of depressive tions or physical injury that could affect CRP, these factors
symptoms along a gradient (28,43,64). Each item on the BDI were not included in the regression model.
is scored on a 0 to 3 scale, with the total score ranging from Four independent multivariate regression analyses were
0 to 63 and Cronbach’s alpha of 0.89. conducted. The first analysis examined the association be-
Participants also completed a health history questionnaire tween log-transformed CRP and severity of depressive symp-
which included items assessing alcohol use (never, former toms, entered either as a continuous score or as a dichotomous
user, infrequently, frequently, regularly), exercise regularly depressed/non-depressed group variable. The second and third
(yes/no), and family history of CVD before age 60 (yes/no). analyses examined the relation of BPAQ-anger and hostility
scores, entered as continuous variables, to log-transformed
Measures of Cardiovascular Risk Factors: Blood CRP. The last analysis examined the relation of log-trans-
Pressure and Fasting Lipids formed CRP to the summary effect of anger, hostility, and
Blood pressure readings were taken using the Dinamap severity of depressive symptoms. The analysis of the summary
automated blood pressure monitor (Model 1876X, Critikon effect of all three factors combined utilized a factor score
Corporation, Tampa, FL). Blood pressures were taken in the derived from a principal component analysis. This analytical-
nondominant arm while the subject relaxed for 10 minutes. ly-derived factor score represents a composite summary indi-
Two blood pressure readings were taken approximately 5 cator of BDI, BPAQ-anger and hostility scores, with higher
minutes apart and the average blood pressure reading was summary scores indicating higher scores on all three scales.
used in the analyses to represent basal blood pressure. Fasting
lipids were determined by enzymatic methods. RESULTS
Univariate Analyses: Psychological Risk Factors and
High Sensitivity C-reactive Protein Measure Their Associations With Log-Normalized CRP
CRP was assessed in duplicate with an ultrasensitive, en- Characteristics of the study participants are presented in
zyme-linked, immunometric latex-enhanced assay (Diagnostic Table 1. BDI depression scores ranged from 0 to 27 (mean
Products Corporation, Los Angeles, CA) using purified pro- 4.2 ⫾ 4.7). Scores on the BPAQ-anger scale ranged from 7 to
tein and polyclonal anti-CRP antibodies from Diagnostic 29 (mean 14.1 ⫾ 5.1) and scores on the BPAQ-hostility scale
Products Corporation (Los Angeles, CA) (65). This system ranged from 8 to 33 (mean 16.3 ⫾ 5.9). All CRP values were
has a lower detection threshold of ⬍ 0.10 mg/L with coeffi-
cients of variation ranging from 6.6% to 9.3%. Measurements
TABLE 1. Subject Characteristics (N ⴝ 127)
of CRP were done on fasting venous blood samples collected
between the hours of 8:30 AM and 9:30 AM while subjects Age (yrs) 27.6 ⫾ 9.6
were seated in a reclined position. Blood samples were spun, Men 70 (55.1%)
refrigerated, and transferred to the laboratory where CRP Women 57 (44.9%)
assays were performed on fresh samples. It has been shown Caucasian 60 (47.4%)
African-American 40 (31.5%)
that a one-time measure of CRP is a reliable and stable Other 27 (21.1%)
measure of CRP over an extended period of time (65). Body Mass Index (kg/m2) 25.2 ⫾ 4.6
Systolic blood pressure (mm Hg) 110.5 ⫾ 14
Statistical Analyses Diastolic blood pressure (mm Hg) 62.8 ⫾ 8
Statistical Analysis System statistical software (SAS Insti- Ratio of total cholesterol to high density 3.50 ⫾ 1
lipoprotein cholesterol
tute, Cary, NC) was utilized for all analyses. To insure a Alcohol Use
normal distribution, CRP values were logarithmically trans- Never/Former 35 (27.6%)
formed. Initial analyses used univariate procedures to examine Occasionally 36 (28.4%)
the relation of log-transformed CRP to anger, hostility, and Frequently 56 (44.0%)
severity of depressive symptoms. Exercise Regularly
No 19 (15%)
Multivariate analysis was then utilized to examine the Yes 108 (85%)
independent associations between psychological factors and Family history of Premature CHD
log-normalized CRP. For each psychological factor, the ana- (⬍ 60 yrs.)
lytic model contained the same set of covariates. Statistical No 111 (87.4%)
adjustments were made for gender, age, BMI, the ratio of Yes 16 (12.6%)
High sensitivity C-reactive proteina 0.60 (0.25–1.63)
fasting total cholesterol (TC) to high-density lipoprotein
(HDL), alcohol use (ie, none/former user, occasionally, fre- a
Median and interquartile range.
quently), exercise regularly (yes/no) and family history of Values are expressed as mean ⫾ SD or number (%).

686 Psychosomatic Medicine 66:684 – 691 (2004)

CRP AND PSYCHOLOGICAL RISK FACTORS
under 10.0 mg/L, a level suggestive of an ongoing acute
inflammatory condition (72). Log-transformed CRP was sig-
nificantly correlated with age (r ⫽ 0.29, p ⫽ .01), BMI (r ⫽
0.39, p ⬍ .001) and TC:HDL ratio (r ⫽ 0.23, p ⬍ .01). No
group differences in CRP were observed for alcohol (F(2,
125) ⫽ 0.72, ns), gender (F(1, 126) ⫽ 0.07, ns), or exercise
regularity (F(1, 126) ⫽ 1.33, ns). There was a statistical trend
for subjects with a positive family history of premature CHD
to have higher CRP (geometric mean ⫽ 1.20 mg/L) relative to
subjects with a negative family history (geometric mean ⫽
0.62 mg/L), (F(1, 126) ⫽ 2.93, p ⫽ .08).
Table 2 presents adjusted and unadjusted correlations be-
tween log-normalized CRP and psychological risk factor
scores. Unadjusted correlations indicated that log-transformed
CRP was significantly associated with BPAQ-anger (p ⫽
.020) and BDI (p ⫽ .019), but not with BPAQ hostility (p ⫽
.49). After adjusting for age and BMI, log-normalized CRP
was significantly correlated with BDI (p’s ⬍ 0.02) and
BPAQ-anger (p’s ⬍ 0.01). The correlation between CRP and
BPAQ-hostility was marginally significant only after adjust-
ing for both age and BMI (p ⫽ .09). Elevated BDI scores
(BDI ⱖ 10) suggesting clinically relevant depressive symp-
tomatology were observed in 17 participants (13.4%) (62).
Using this classification, results indicated a significant depres-
sive group effect (t(126) ⫽ ⫺2.18, p ⫽ .03) such that the
geometric CRP mean for the depressed group (unadjusted
geometric mean ⫽ 1.21 mg/L) was significantly higher than
the mean for the nondepressed participants (unadjusted geo-
metric mean ⫽ 0.61 mg/L).
Multivariate Analysis of Psychological Risk Factors
and Log-Normalized CRP
High Sensitivity CRP and Severity of Depressive
Symptoms
The results of regression analyses adjusting for control
variables revealed a significant effect for the BDI score (␤ ⫽
0.053, SE ⫽ 0.021, p ⫽ .011). Similarly, analyses comparing
depression groups established by a priori criteria for the BDI
(⬍ 10, ⱖ 10) revealed a significant group effect (F(1, 117) ⫽
6.65, p ⫽ .01) such that participants who were depressed (n ⫽
17, BDI ⱖ 10) exhibited significantly higher CRP (adjusted
geometric mean CRP ⫽ 1.47 mg/L) relative to nondepressed
subjects (n ⫽ 110, adjusted geometric mean CRP ⫽ 0.66
mg/L). Given the number of individuals scoring 10 and above
on the BDI, analyses were repeated using the criteria BDI ⱖ
TABLE 2. Adjusted and Unadjusted Correlations Between Log-Normalized C-reactive Protein and Psychological Scales
Unadjusted
BDI 0.21**
BPAQ-Hostility 0.06
BPAQ-Anger 0.20*
** p ⬍ 0.01; * p ⬍ 0.05; a p ⬍ 0.10.
BPAQ ⫽ Buss Perry Aggression Questionnaire; BDI ⫽ Beck Depression Inventory; BMI ⫽ Body Mass Index.
Psychosomatic Medicine 66:684 – 691 (2004)
6, approximately the highest tercile in the distribution of BDI
scores in this sample. Results again confirmed that high scor-
ing individuals (BDI ⱖ 6, n ⫽ 40) had higher CRP (adjusted
geometric mean CRP ⫽ 1.07 mg/L) relative to low scoring
participants (BDI ⬍ 6, n ⫽ 87, adjusted geometric mean
CRP ⫽ 0.32 mg/L).
High Sensitivity CRP and Anger
The BPAQ-anger score was entered as a continuous vari-
able in a multiple regression model with statistical adjust-
ments for gender, age, BMI, TC:HDL ratio, exercise regular-
ity, reported alcohol use, and family history of premature
CHD. Results indicated that higher BPAQ-anger scores were
associated with elevated concentrations of CRP (␤ ⫽ 0.051,
SE ⫽ 0.019, p ⫽ .007).
High Sensitivity CRP and Hostility
The BPAQ-hostility score was entered as a continuous
variable in a multiple regression that controlled confounding
variables. Results indicated a positive, but not significant,
BPAQ-hostility main effect (␤ ⫽ 0.027, SE ⫽ 0.017, p ⫽
.11).
High Sensitivity CRP and the Combined Effect of Anger,
Hostility, and Severity of Depressive Symptoms
As expected, scores on the BPAQ-anger, BPAQ-hostility,
and BDI were significantly inter-correlated (rs ⬎ 0.37, ps ⬍
0.0001). Results of the principal component yielded a single
factor, PRF, (Eigenvalue ⫽ 1.87) which accounted for 62.3%
of the total variance. Analysis of log-normalized hsCRP using
multivariate regression revealed that increasing PRF scores
were associated with increasing levels of CRP (␤ ⫽ 0.271,
SE ⫽ 0.095, p ⫽ .005).
DISCUSSION
In this cross-sectional study of apparently healthy adult
men and women, higher levels of anger and greater severity of
depressive symptoms, previously shown to predict future risk
of CHD, peripheral artery disease, and stroke, were found to
be significantly associated with higher levels of baseline CRP.
These associations were also confirmed in multivariate anal-
yses that were statistically adjusted for various factors known
to increase CRP, gender (73), age (74 –76), BMI (71,73),
alcohol use (77), exercise (78), and lipids (79). As important,
in analysis adjusting for the aforementioned confounders,
Log-normalized CRP
Age-adjusted Age- and BMI-adjusted
0.21** 0.22**
0.12* 0.15a
0.24** 0.23**
687

CRP was positively and significantly associated with a com-
posite summary indicator of anger, hostility, and severity of
depressive symptoms. These latter observations are particu-
larly important because of clinical and empirical evidence
suggesting that these psychological factors tend to cluster
within individuals (80 – 82), and that the clustering of psycho-
logical factors may incur greater risk than any one single
factor alone (83). It is worth noting that individuals who
smoke, reported any previous or current medical conditions,
had acute physical injury or trauma, were currently taking
medications including low-dose aspirin, reported a history of
psychiatric illness, and women using oral contraceptives, were
not enrolled in the study, thus excluding the possibility that
these factors account for the current observations. Thus, these
observations show that theoretically driven and empirically
justified psychological factors associated with increased risk
of CVD are significantly and independently associated with
CRP, an important biomarker of inflammation and predictor
of future CVD in initially healthy men and women.
Prior data evaluating the association between CRP and
measures of depressive symptom severity in nonclinical sam-
ples are sparse, with only one study reporting a significant
association in both univariate and multivariate analyses
(49,52,59). The current study observed a significant associa-
tion between CRP and severity of depressive symptoms in
both univariate and multivariate analysis adjusting for various
potential confounding factors. What may account for the dif-
ferences between the results of the current study and those of
previous studies that failed to observe a significant multivar-
iate association is opened to speculation. One possibility is the
differences in the ages of the participants and lifestyle factors
associated with PRF. Due to the fact that age-related medical
conditions are often associated with elevated levels of depres-
sive symptoms (e.g.,53,84), studies with older individuals may
have a greater problem with confounding (59). Furthermore,
individuals with greater severity of depressive symptoms and
higher hostility are more likely to smoke and to be physically
inactive (85,86), thus the potential for confounding associated
with these factors. Thus, it may be that differences across
studies are due to age-related confounding and lifestyle factors
associated with some of these PRF.
A number of studies in patients have reported elevated
levels of CRP in individuals with major depressive disorder
(48,56,87). The current observations, however, suggest that
mild to moderate levels of depressive symptoms in nonpatient
samples are also associated with elevated levels of CRP.
Using the well-established BDI cut-off criteria of 10 and
above to indicate the presence of depression (62), comparison
between depressed and nondepressed individuals revealed sig-
nificantly higher CRP in depressed adults. Significant group
differences also emerged when comparing subjects who
scored in the top tercile relative to the bottom terciles, with
individuals scoring 6 and above on the BDI having signifi-
cantly higher baseline CRP. The health relevance of these
findings rests on a growing body of evidence indicating that
levels of depressive symptomatology that are not psychiatri-
688
E. C. SUAREZ
cally significant are associated with increased future risk of
CHD in initially healthy individuals (38,43) and with disease
severity and outcome in cardiac patients (21,28,33,39). Al-
though replications of these findings are warranted with a
larger and more diverse sample, the current findings may
partially explain the gradient relationship between severity of
depressive symptoms and the future risk of CVD in initially
health persons by suggesting that inflammation is also evident
among individuals with mild to moderate levels of symptoms
of depression.
The current observations also confirm that anger, and to a
lesser extent hostility, are independently associated with ele-
vated baseline CRP. Previous studies from this laboratory
have shown that anger and hostility, alone or in combination
with severity of depression, predict higher circulating levels of
IL-6 in healthy men (45). This study, however, is the first to
provide empirical evidence of an association between CRP
and anger/hostility. As with the relationship between CRP and
severity of depressive symptoms, these associations remained
statistically significant in analyses controlling for age, gender,
alcohol use, exercise frequency, family history of premature
CHD, lipids, and BMI. Although preliminary, these current
data support the general hypothesis that hostility and anger are
associated with the low-grade inflammation characterizing
atherosclerotic CVD.
Lastly, the current study also confirms that a factor-analyt-
ically derived composite summary indicator of anger, hostil-
ity, and severity of depressive symptoms is a significant and
independent predictor of CRP. The combination of these psy-
chological factors has relevance for several reasons. First, it is
well recognized that severity of depressive symptoms, hostil-
ity, and anger are statistically correlated and share a signifi-
cant proportion of variance (45). It has been suggested, how-
ever, that these associations are important beyond the merely
statistical relationships. Individuals with depressed symptoms
may evaluate their social environment in a cynically hostile
manner and thus respond with greater anger as a consequence
of their negative affective state (81,88 –90). On the other hand,
individuals who are hostile and anger-prone may be at greater
risk for depression due to a lack of social support and/or
greater experience of stress (81,89). It is not unusual, there-
fore, that these factors tend to cluster within an individual.
Thus, higher summary scores, indicative of an individual
scoring high on all three scales, suggests a person that is
hostile, is prone to anger, and has elevated symptoms of
depression. Secondly, and equally as important, it is unlikely
that only one psychological factor working alone increases the
risk of cardiac events (91). Consistent with this assumption,
preliminary evidence suggests that persons who show symp-
toms of depression and anger are at an even greater risk of
coronary artery disease (CAD) when compared with persons
who are either depressed or angry (83). Given the present
findings, the appropriateness of examining the combined ef-
fect of anger, hostility, and depressive symptoms on inflam-
matory biomarkers appears to go beyond merely statistical
covariation. Epidemiological evidence is clearly needed in
Psychosomatic Medicine 66:684 – 691 (2004)
CRP AND PSYCHOLOGICAL RISK FACTORS
determining the combined effects of these factors on CVD
risk; the current observations argue for such an evaluation.
Limitations of these data should be considered. First, the
current study is cross-sectional and not prospective in design
and the sample size is relatively small compared with other
studies that have examined similar associations. Like all cross-
sectional studies, no conclusions regarding directionality can
be substantiated. The issue of directionality is particularly
relevant given the possibility that inflammation may precede
the presence of depressive symptoms (92). Secondly, the
current study only examined CRP. Although other inflamma-
tory markers are predictive of disease and participate in the
atherogenic process (15), CRP appears to be the strongest
predictor of relative risk of future cardiovascular events in
comparison to other inflammatory markers, such as IL-6 (8),
and other acute phase proteins, such as fibrinogen (13). It is
important to also note that independent studies from this
laboratory using different study samples have shown associ-
ations between these same psychological factors and mono-
cyte-associated expressions of chemokines and cytokines in
men and women (46,47,51) and between IL-6 and hostility/
severity of depressive symptoms in healthy men (44). That the
current study does not assess other relevant inflammatory
markers does not detract from the significance of the findings.
In contrast, the current study is unique in measuring three
psychological factors that have been independently and jointly
associated with increased risk of future CVD.
The current study also did not address possible underlying
mechanisms that may account for these observations. It can be
said, however, that statistical and methodological procedures
implemented in the current study argue against the possibili-
ties that these results are due to confounding factors such as
BMI, age, lipids, gender, exercise, alcohol use, smoking,
various medical conditions, use of medications, physical in-
jury, or medical procedures; all factors associated with ele-
vated CRP. Thus, how anger and severity of depressive symp-
toms, alone and in combination with hostility, contribute to
CRP elevations is open to speculation. One possible explana-
tion is that in individuals with high levels of PRF, stress-
activated pathways contribute to increases in CRP (75). It is
recognized that hostility and anger, as well as depressive
symptoms, are associated with enhanced stress-induced nor-
epinephrine responses and norepinephrine dysregulation (93–
97). Preliminary evidence suggests that norepinephrine-de-
pendent adrenergic stimulation results in activation of the
nuclear factor (NF)-␬B, a transcription factor known to in-
crease gene expression for cytokines, such as IL-1␤ and
TNF-␣, and chemokines, such as IL-8, MCP-1 and MIP-1a
(98). Similarly, NF-␬B activation also promotes IL-6 gene
expression (99). As noted, this laboratory has conducted in-
dependent studies suggesting that severity of depressive
symptoms, anger, and hostility, alone and in combination, are
associated with increased gene expression of proinflammatory
cytokines and chemokines (46,47,51) and elevated plasma
IL-6 (44). Thus, individuals who show elevated levels of PRF
may respond to daily-life stressors with excessive stress-in-
Psychosomatic Medicine 66:684 – 691 (2004)
duced sympathetic activation that triggers an NF-␬b-depen-
dent cascade of proinflammatory events that contribute to
increases in CRP.
In summary, anger and severity of depressive symptoms,
alone and in combination with hostility, are significantly as-
sociated with CRP. These associations are independent of
various factors known to increase levels of CRP, such as the
presence of cardiovascular diseases, smoking, diabetes, age,
gender, BMI, TC:HDL ratio, exercise , and alcohol use. These
data further suggest that a clustering of these factors repre-
sented as a summary score is positively and significantly
associated with CRP. Given mounting evidence suggesting
that CHD is not simply a disease of lipid deposit but rather an
inflammatory condition, and that CRP is the single strongest
inflammatory biomarker of risk for future myocardial infarc-
tion and stroke in healthy persons (11,100), these data provide
evidence for biological associations between psychological
risk factors and CRP, a biomarker of vascular inflammation
that has been linked with increased risk of future CHD in
initially healthy persons and is believed to characterize and
promote CVD.
The author gratefully acknowledges the assistance of Wilma Young,
Shina Miller and Andrew Weiman in the collection of the data.
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