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Published online before print February 6, 2008, 10.1097/PSY.0b013e3181642a0b
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Psychosomatic Medicine 70:197-204 (2008)
© 2008 American Psychosomatic Society

ORIGINAL ARTICLES

Depressive Symptoms Moderate the Influence of Hostility on Serum Interleukin-6 and C-Reactive Protein

Jesse C. Stewart, PhD, Denise Janicki-Deverts, PhD, Matthew F. Muldoon, MD, MPH and Thomas W. Kamarck, PhD

From the Department of Psychology (J.C.S.), Indiana University-Purdue University Indianapolis, Indianapolis, Indiana; Department of Psychology (D.J.-D.), Carnegie Mellon University, Pittsburgh, Pennsylvania; Department of Medicine (M.F.M.), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and the Department of Psychology (T.W.K.), University of Pittsburgh, Pittsburgh, Pennsylvania.

Address correspondence and reprint requests to Jesse C. Stewart, Department of Psychology, Indiana University-Purdue University Indianapolis, 402 North Blackford Street, LD 100E, Indianapolis, IN 46202. E-mail: jstew{at}iupui.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Objective: Recent evidence suggests that depressive symptoms and hostility may act together, as interacting factors, to have an effect on the circulating levels of inflammatory markers relevant to coronary artery disease. Further research, however, is needed to clarify the nature of this interaction and to determine whether previous findings extend to older adults. In this report we examined the cross-sectional associations of depressive symptoms, hostility, and their interaction with circulating levels of two such inflammatory markers—interleukin-6 (IL-6) and C-reactive protein (CRP).

Methods: A total of 316 healthy, older adults underwent a blood draw for the assessment of serum IL-6 and CRP and completed the Beck Depression Inventory-II and the Cook-Medley Hostility Scale. Regression analyses were performed to examine depressive symptoms, hostility, and their interaction as predictors of serum IL-6 and CRP.

Results: After adjustment for demographic factors, cardiovascular risk factors, and health behaviors, we detected depressive symptoms x hostility interactions for serum IL-6 ({Delta}R2 = .027, p < .01) and CRP ({Delta}R2 = .015, p < .05). Simple slope analyses revealed that hostility was positively related to serum IL-6 only among individuals with higher depressive symptoms. The pattern of results was similar for serum CRP, although none of the simple slopes was significant.

Conclusions: Our findings suggest that depressive symptoms may moderate the hostility-inflammation relationship such that hostility may augment inflammatory processes relevant to coronary artery disease only in the presence of depressive symptoms. Our results also extend previous findings from younger adults to older adults from the general community.

Key Words: depression • hostility • inflammation • interleukin-6 • C-reactive protein • coronary artery disease

Abbreviations: IL-6 = interleukin-6; CRP = C-reactive protein; CAD = coronary artery disease; BDI = Beck Depression Inventory; Ho Scale = Cook-Medley Hostility Scale; TNF-{alpha} = tumor necrosis factor-{alpha}; PHHP = Pittsburgh Healthy Heart Project; SBP = systolic blood pressure; DBP = diastolic blood pressure; MAP = mean arterial pressure; BMI = body mass index; HDL = high-density lipoprotein; LDL = low-density lipoprotein.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Although depression and hostility have both been linked to the subsequent development of coronary artery disease (CAD) (1–3), the mechanisms underlying these associations have yet to be elucidated. Recently, interest in inflammation as a potential mediator of these relationships has increased for two reasons. First, atherosclerosis is currently conceptualized as a chronic inflammatory disease; it is believed that inflammation plays a key role in both the earlier and the later stages of this condition (4). Consistent with this view, elevated circulating levels of inflammatory markers, such as the proinflammatory cytokine interleukin-6 (IL-6) and the acute-phase reactant C-reactive protein (CRP), have been found to predict future CAD among initially healthy individuals (5–9). Second, mounting evidence suggests that psychological factors, including depression and hostility, may be associated with augmented inflammatory processes relevant to CAD. Although there are notable exceptions (10,11), several recent investigations have found that individuals with a depressive disorder or depressive symptoms have higher circulating levels of IL-6 and CRP (12–21) and exhibit greater expression of proinflammatory cytokines after mitogen stimulation (22–25). Similar results have also been observed among hostile persons (18,19, 23,26–28), although this literature is smaller than that for depressed or dysphoric individuals. For instance, Graham and colleagues (27) recently found that hostility was related to circulating levels of CRP (but not IL-6) among older adults, even after controlling for depressive symptoms.

Even though depression and hostility have been separately related to indicators of inflammation, few studies have explored whether these psychological factors might act together to have an effect on inflammatory processes. This possibility warrants further investigation for at least two reasons. First, depressive symptoms and hostility are moderately associated (r values usually range from .25 to .50; 29–32) and therefore tend to co-occur within individuals. Second, depression and hostility have been linked with various physiological and psychological changes that are potentially complementary or synergistic in their effects (see Discussion).

To our knowledge, only two previous studies have simultaneously examined the main effects of depressive symptoms and hostility as well as their interaction as predictors of circulating levels of inflammatory markers relevant to CAD. Suarez (33) measured plasma IL-6 in a sample of 90 healthy, younger men who also completed the Beck Depression Inventory (BDI) and the Cook-Medley Hostility (Ho) Scale during the same laboratory session. Although BDI and Ho Scale main effects on plasma IL-6 were not observed, a significant BDI x Ho Scale interaction was detected. Follow-up analyses indicated that hostility was positively related to plasma IL-6 among men with higher depressive symptoms, though it was not related to plasma IL-6 among men with lower depressive symptoms. In a sample of 100 physically healthy men and women, Miller and colleagues (34) also detected significant BDI x Ho Scale interactions for two proinflammatory cytokines, IL-6 and tumor necrosis factor-{alpha} (TNF-{alpha}). The results of follow-up analyses for these interactions differed considerably from those obtained by Suarez. Specifically, hostility was positively associated with serum IL-6 and TNF-{alpha} among individuals with minimal depressive symptoms but was only weakly or not associated among those with more severe symptoms. It is worth noting that half of the participants in the study by Miller et al. met the diagnostic criteria for either major or minor depressive disorder.

As the aforementioned studies demonstrate, previous research investigating the depressive symptoms x hostility interaction for CAD-relevant inflammatory processes has yielded conflicting results and has involved relatively small and select samples of younger adults. Consequently, additional studies are needed to clarify the nature of this interaction and to determine whether the existing findings extend to other populations. To address these needs, we examined the cross-sectional associations of depressive symptoms, hostility, and their interaction with serum IL-6 and CRP in a larger sample of older adults from the general community.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 
Participants
Participants were 316 healthy, older, community-dwelling adults involved in the Pittsburgh Healthy Heart Project (PHHP), a cohort study examining biobehavioral factors as predictors of subclinical atherosclerosis. This study received the approval of the University of Pittsburgh Institutional Review Board. Participants provided their written informed consent and were paid $450. Details regarding participant recruitment and selection are provided elsewhere (35). Individuals were eligible for the PHHP if they were between 50 and 70 years of age, were peri- or postmenopausal (women only), had clinic blood pressure levels of <180/110 mm Hg, and reported no history of chronic medical disorders, no history of schizophrenia or bipolar disorder, no use of lipid-lowering or antihypertensive medication in the past year, no regular use of medications with autonomic effects, and no excessive alcohol consumption (≥5 drinks, ≥3 times/week). There were important exceptions to the chronic medical disorders exclusion criterion. Specifically, individuals with diabetes who were not taking insulin, those with a history of cancer but no treatment in the past 2 years, and those with mild or moderate rheumatoid arthritis were eligible. Assays for IL-6 and CRP were performed on blood samples from 344 of the 464 adults enrolled in the PHHP. From this subsample, we excluded 22 persons because they had serum CRP levels of ≥10 mg/L, five persons because they had missing data for one or more of the variables listed in Table 1, and one person because the estimate of physical activity level was a very extreme value.


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  		TABLE 1. Characteristics of Participants (N = 316)

 

Measures and Procedure

Overview
All data examined in this report were obtained during the baseline phase of the PHHP (September 1998–April 2000). Participants attended the 11 baseline visits in the following order: a medical screen, three visits for ambulatory monitoring training and questionnaire assessments, one visit for cardiovascular reactivity testing, two visits for ultrasound assessments of subclinical cardiovascular disease, and four visits for additional ambulatory monitoring training and questionnaire assessments. The average duration from enrollment to completion of the baseline visits was 5 months.

Depression and Hostility
Using a computer, participants completed the 21-item Beck Depression Inventory-II (BDI-II) (36) at the third baseline visit and the 50-item Ho Scale (37) at the fourth baseline visit. The BDI-II and the Ho scale are widely used self-report measures of depressive symptom severity and cynical hostility, respectively. Both instruments have been shown to possess good psychometric characteristics, including moderate-to-high internal consistency, test-retest reliability, and construct validity (32,36,38–40). It should be noted that, due to an oversight while constructing the computerized version of the BDI-II, participants were asked to rate the severity of their depressive symptoms over the past week (the timeframe for the original BDI) instead of the past 2 weeks (the usual timeframe for the BDI-II). In addition, one item of the Ho Scale was accidentally omitted; the value for this item was imputed by taking the mean of the other 49 items.

Descriptive statistics for BDI-II and Ho Scale are shown in Table 1. The BDI-II variable was log transformed to reduce positive skew. Consistent with previous reports (29–32), scores on BDI-II and Ho Scale were moderately correlated, r(314) = .22, p < .01. The BDI-II and Ho Scale variables were centered by subtracting the mean from each value, and a cross-product interaction term was created by multiplying these centered variables.

Inflammatory Markers
Blood samples for the assessment of serum IL-6 and CRP were obtained between 8 AM and 12 PM at the medical screens. Participants were told to fast and to avoid caffeine for 12 hours before this visit. When the participants were seated, a research nurse drew 65 ml of blood from a vein in the antecubital region. Blood samples for the IL-6 and CRP assays were collected in 15-ml tubes with no additives and were stored at room temperature for 40 minutes to allow the samples to clot. Within 3 hours of collection, samples were centrifuged to isolate serum, and serum aliquots were frozen at –70°C.

Serum samples were sent to the Laboratory for Clinical Biochemistry Research at the University of Vermont. Serum IL-6 was measured using ultra-sensitive enzyme-linked immunosorbent assay kits (R&D Systems, Minneapolis, MN). The detection range was 0.16 to 12.0 pg/ml. The routine inter-assay coefficient of variation for this method is 6.3% at the University of Vermont. According to the manufacturer, the expected normal range for this assay is 0.24 to 12.5 pg/ml. Serum CRP was measured with a BNII nephelometer using a particle-enhanced immunonepholometric assay (Dade Behring, Deerfield, IL). The detection range was 0.16 to 1100 mg/L. The routine inter-assay coefficient of variation for this method is 5% at the University of Vermont. For healthy individuals, expected values for CRP are ≤3 mg/L (5).

Mean serum IL-6 and CRP are shown in Table 1. Individuals with serum CRP ≥10 mg/L (n = 22) were excluded. We were concerned that CRP levels above this value may be due to noncardiovascular sources, such as infection or trauma, and therefore may not be reflective of cardiovascular risk (5). In addition, persons with IL-6 levels above the upper detection limit (n = 2) were assigned a value of 12.0 pg/ml, and persons with CRP levels below the lower detection limit (n = 5) were assigned a value of 0.15 mg/L. Because the distributions for serum IL-6 and CRP were both positively skewed and because some participants had values between 0 and 1, these variables were log (Xi + 1) transformed. As expected, IL-6 and CRP levels were moderately correlated r(314) = .33, p < .01.

Other Factors
During the PHHP baseline, information about several additional factors was obtained (Table 1). Participants completed questionnaires and an interview at the medical screen to assess the following variables: age (years); sex (0 = male, 1 = female); race-ethnicity (1 = White, 2 = Black, 3 = Asian, 4 = Hispanic, 5 = other); education level (1 = high school or less, 2 = technical school or some college, 3 = Bachelor’s degree, 4 = Master’s degree or higher); smoking status (0 = nonsmoker, 1 = current smoker); daily alcohol intake; physical activity level; and history of various medical conditions (including diabetes, cancer, and rheumatoid arthritis). Race-ethnicity was coded as a binary variable (0 = White, 1 = non-White) because only five participants selected the Asian, Hispanic, or other categories. Daily alcohol intake (g/day) was computed using the quantity-frequency method (41), and this variable was log transformed to reduce positive skew. An estimate of physical activity level was calculated using responses on the Paffenbarger Physical Activity Questionnaire (42). Specifically, the number of blocks walked and stairs climbed per day were first converted to kilocalories per week and then they were summed. One person was excluded because the physical activity level estimate was a very extreme value and was disconnected from the distribution.

At the medical screen, participants also underwent a blood pressure assessment, anthropometric measurements, and a blood draw. Following the American Heart Association guidelines (43), three blood pressure readings were taken at 2-minute intervals using a standard mercury sphygmomanometer. Systolic (SBP) and diastolic blood pressure (DBP) were computed by averaging the last two readings. From these values, mean arterial pressure (MAP) was calculated using the following equation: DBP + (SBP – DBP)/3. Body mass index (BMI) was computed as weight (kg) divided by height (m) squared. Standard assays were performed to determine serum total cholesterol (44), high-density lipoprotein (HDL) cholesterol (45), and triglycerides (46). The Friedewald equation was used to calculate low-density lipoprotein (LDL) cholesterol (47). Fasting serum glucose and insulin were measured by standard colorimetry (48) and radioimmunoassay, respectively. Triglycerides, fasting glucose, and fasting insulin were each log transformed to reduce positive skew.

Data Analysis
Three sets of multiple regression analyses—unadjusted, adjusted, and exploratory—were performed to examine the associations of depressive symptoms, hostility, and their interaction with serum IL-6 and CRP. In the unadjusted analysis, the main effects of BDI-II (centered) and Ho Scale (centered) were first entered into the model (Step 1) followed by the BDI-II x Ho Scale cross-product interaction term (Step 2). In the adjusted analysis, control variables were entered into the model (Step1) before entering the BDI-II and Ho Scale main effects (Step 2) and the interaction term (Step 3). Control variables were demographic factors (age, sex, race-ethnicity, and education level) as well as cardiovascular risk factors (MAP, BMI, HDL cholesterol, triglycerides, fasting glucose, and fasting insulin) and health behaviors (smoking status, daily alcohol intake, and physical activity level) that have previously been associated with circulating levels of IL-6 and CRP (5,7,8,49,50). We entered only MAP (instead of both SBP and DBP) and HDL cholesterol (instead of both LDL and HDL cholesterol) into the models to limit the number of control variables and to minimize collinearity among the predictors. Additionally, we selected HDL cholesterol because it is a stronger correlate than total or LDL cholesterol of IL-6 and CRP levels (7,8). Significant BDI-II x Ho Scale interactions were explored using the procedures (i.e., simple slope analyses) recommended by Aiken and West (51). In the simple slope analyses, high, intermediate, and low values for each factor corresponded to 1 standard deviation (SD) above the mean, the mean, and 1 SD below the mean, respectively.

Other factors that could confound any observed relationships were examined in exploratory analyses. Specifically, we repeated the adjusted analyses after excluding the participants (n = 48) who reported a history of a medical condition (diabetes, cancer, or rheumatoid arthritis) associated with inflammation (5,52) that was not part of the PHHP exclusion criteria as well as participants (n = 5) for whom history of these conditions could not be determined due to missing or incomplete data. In addition, we tested the three-way interaction between BDI-II, Ho Scale, and sex to determine whether any observed relationships varied among men and women.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 NOTES
 REFERENCES
 
Interleukin-6
The unadjusted regression analysis revealed that the main effect of Ho Scale1 (β = 0.117, p = .04) and the BDI-II x Ho Scale interaction (β = 0.145, p = .01) were both significant predictors of serum IL-6, although the main effect of BDI-II1 was not significant (β = –0.005, p = .93). As seen in Table 2, the adjusted analysis indicated that only BMI and smoking status were independent predictors of serum IL-6, as the levels were higher among persons with greater BMI and among current smokers (Step 1). After controlling for demographic factors, cardiovascular risk factors, and health behaviors, the BDI-II and Ho Scale main effects were both nonsignificant (Step 2). However, the BDI-II x Ho Scale interaction remained a significant predictor of serum IL-6 (Step 3). As is shown in the upper panel of Figure 1, the simple slope analysis for this interaction demonstrated that the Ho Scale score was positively associated with serum IL-6 at high (β = 0.247, p = .002) and intermediate (β = 0.072, p = .23) BDI-II values but was negatively associated with serum IL-6 at low BDI-II values (β = –0.104, p = .22). It should be noted that only the simple slope at high BDI-II values was significant.


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  		TABLE 2. Results of Adjusted Regression Analyses Predicting Serum Interleukin-6

 

Figure 110
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  		Figure 1. Simple regression lines for serum interleukin-6 (IL-6; upper panel) and C-reactive protein (CRP; lower panel) regressed on Cook-Medley Hostility (Ho) Scale score at high, intermediate, and low BDI-II scores. High, intermediate, and low scores for each factor correspond to 1 standard deviation (SD) above the mean, the mean, and 1 SD below the mean, respectively.

 

The exploratory analyses revealed that the BDI-II x Ho Scale interaction remained a significant predictor of serum IL-6 after excluding the participants with a history of diabetes, cancer, or rheumatoid arthritis and those for whom disease history could not be determined (β = 0.169, p = .007). In addition, the results of the simple slope analyses were similar to those of the adjusted analyses. The exploratory analyses also indicated that the three-way interaction between BDI-II, Ho Scale, and sex was not significant (β = 0.014, p = .86).

C-Reactive Protein
Comparable results were observed for serum CRP, although the relationships were not as strong as those found for serum IL-6. In the unadjusted regression analysis, the main effects of BDI-II1 (β = 0.032, p = .58) and Ho Scale1 (β = 0.001, p = .98) as well as their interaction (β = 0.095, p = .10) were all nonsignificant. As shown in Table 3, the adjusted analysis revealed that sex, BMI, triglycerides, and smoking status were independent predictors of serum CRP; levels were higher among females, persons with greater BMI, persons with higher triglyceride levels, and current smokers (Step 1). Although the BDI-II and Ho Scale main effects both remained nonsignificant (Step 2), the BDI x Ho Scale interaction became a significant predictor of serum CRP in the adjusted analyses (Step 3). Similar to serum IL-6, the simple slope analysis for the BDI-II x Ho Scale interaction (see lower panel of Figure 1) indicated that the Ho Scale score was positively related to serum CRP at high BDI-II values (β = 0.106, p = .16) but was negatively related at low BDI-II values (β = –0.152, p = .06), although neither of these relationships was significant. At intermediate BDI-II values, the simple slope (β = –0.023, p = .67) was virtually zero.


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  		TABLE 3. Results of Regression Analyses Predicting Serum C-Reactive Protein

 

In exploratory analyses, the BDI-II x Ho Scale interaction fell just short of statistical significance after excluding the participants with a history of diabetes, cancer, or rheumatoid arthritis and those for whom disease history could not be determined (β = 0.106, p = .06). Simple slope analyses yielded results similar to those of the adjusted analyses. Once again, the BDI-II x Ho Scale x sex interaction was not significant (β = –0.006, p = .93).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
NOTES
 REFERENCES
 
Recent results suggest that depressive symptoms and hostility may interact and exert a combined effect on circulating levels of inflammatory markers relevant to CAD; however, further research is needed to clarify the nature of this interaction and to determine whether existing findings extend to older adults. In a sample of healthy adults aged 50 to 70 years, we detected depressive symptoms x hostility interactions for two such inflammatory markers—serum IL-6 and CRP. The interactions we found were disordinal in form (Figure 1), as hostility was positively related to serum IL-6 and CRP among individuals with higher depressive symptoms but tended to be negatively related among those with lower depressive symptoms. In general, the observed interactions remained significant after adjusting for demographic factors, cardiovascular risk factors, and health behaviors as well as after excluding participants with a history of diabetes, cancer, or rheumatoid arthritis. Furthermore, the 3-way interactions between depressive symptoms, hostility, and sex were not significant, indicating that the combined effect of depressive symptoms and hostility was similar among men and women. Taken together, our findings suggest that hostility may augment inflammatory processes relevant to CAD only in the presence of increased, albeit modest, depressive symptoms.

We found that depressive symptoms moderated the relationship between hostility and inflammatory marker levels in a manner comparable to that reported by Suarez (33). In that study, a positive association between hostility and plasma IL-6 was observed among younger men with higher (BDI ≥10), but not lower (BDI ≤9), depressive symptoms. Importantly, the present study extends the findings of Suarez to older adults, to women, and to another marker of CAD-relevant inflammatory processes (i.e., CRP). Our results, in conjunction with those of Suarez, also suggest that the inconsistent findings of past studies examining the hostility-inflammation relationship (20,27) may have resulted from not considering depressive symptoms. Perhaps hostility is strongly and positively related to indices of inflammation only when at least modest depressive symptoms are present. Thus, it may be more difficult to detect a main effect of hostility in samples that include many individuals with minimal depressive symptoms, such as the present sample.

As is the case with Suarez’s results (33), our findings are not in line with those of Miller and colleagues (34). In that investigation, a depressive symptoms x hostility interaction of the opposite form was observed—i.e., as depressive symptoms increased, the strength of the hostility-inflammation relationship decreased. Although the reason for these discrepant findings is unknown, Miller’s sample did differ from Suarez’s and from ours on an important characteristic—severity of depression. The mean score on the BDI was 12.3 (original version) in Miller’s study, 4.9 (original version) in Suarez’s study, and 4.0 (second edition) in the present study. These differences are due to the fact that half of Miller’s participants met the diagnostic criteria for major or minor depressive disorder, whereas it is likely that few of Suarez’s participants or ours were clinically depressed. For reasons that have yet to be identified, the nature of the depression x hostility interaction may differ at higher (i.e., clinical) versus lower (i.e., subclinical) levels of depressive symptoms. Our finding that hostility tended to be negatively related to inflammatory marker levels among individuals with lower depressive symptoms was unexpected and also contrasts with existing evidence (19,23,26–28). However, these results should not be overinterpreted, given that the simple slope for the Ho Scale at low BDI-II values was not significant for either serum IL-6 (p = .22) or CRP (p = .06).

Despite the paucity of research examining depression x hostility interactions, there are several plausible mechanisms that could explain how depressive symptoms moderate the hostility-inflammation relationship. On the one hand, it has been suggested that the influence of hostility on inflammatory processes may be mediated by increased sympathetic nervous system activation in response to stress (28). On the other hand, depressed patients and individuals with subclinical levels of depressive symptoms exhibit evidence of dysfunction in two systems that normally exert anti-inflammatory effects—the hypothalamic-pituitary-adrenocortical (HPA) axis and the parasympathetic nervous system. Depression has been associated with various indicators of HPA axis hyperactivity, including elevated levels of the glucocorticoid cortisol (53,54). Although glucocorticoids acutely suppress inflammation (55), chronic elevation of these hormones may lead to downregulation or desensitization of the glucocorticoid receptors of macrophages, ultimately resulting in attenuated anti-inflammatory responses to these hormones (56,57). Depression has also been linked with diminished parasympathetic nervous system activity, as indicated by reduced heart rate variability (58,59). Like glucocorticoids, parasympathetic activation seems to have anti-inflammatory effects, as vagal stimulation inhibits proinflammatory cytokine synthesis, vagotomy is associated with increased proinflammatory cytokine production, and acetylcholine reduces proinflammatory cytokine release from macrophages (60). When considered together, the aforementioned findings raise the possibility that, in the presence of depression-related glucocorticoid insensitivity and/or diminished parasympathetic activity, the influence of hostility on inflammatory processes might be augmented because there are fewer mechanisms to counteract the proinflammatory effects of hostility-related sympathetic activation.

Another plausible mechanism that could explain our results is that the magnitude or duration of hostility-related sympathetic activation (and the associated proinflammatory effects) may be greater among individuals with higher depressive symptoms. There are at least two possible explanations for why such an effect might be observed. First, recent studies suggest that depression is associated with reduced sensitivity of the arterial baroreflex (58,61), an important regulator of autonomic outflow to the heart and vasculature. When functioning properly, the baroreflex decreases sympathetic outflow and increases parasympathetic outflow during phasic elevations in blood pressure (62). Among individuals with higher depressive symptoms, this baroreceptor-mediated negative feedback may be attenuated, which could give rise to larger and more prolonged sympathetic responses to stress. Second, it is well established that depression is inversely related to social support (63). Given that social support has been shown to decrease cardiovascular reactivity to psychological stress (64), reductions in this protective factor could bring about larger and more prolonged stress-related sympathetic responses. It should be noted that the possible mechanisms discussed above are very speculative. Because these mechanisms were not directly evaluated in the present study, there is no reason to favor one over any other at this time.

In addition to these causal models, two other possibilities warrant discussion. First, reverse causality is especially important to consider in this instance because of the well-documented bidirectional communication between the brain and the immune system (65). Of particular relevance, it has been observed that increases in proinflammatory cytokines can produce striking changes in affect, cognition, and behavior (66). Thus, based on our cross-sectional data alone, it is not possible to draw valid inferences regarding the directionality of these associations. Second, a third factor (i.e., confounder) associated with both the psychological constructs and the inflammatory markers could account for the relationships we observed. However, the fact that we detected depressive symptoms x hostility interactions after adjusting for several control variables (demographic factors, cardiovascular risk factors, and health behaviors) and after excluding a subset of participants (those with a history of a medical condition associated with inflammation) rules out these factors as potential confounders. Nonetheless, it is still possible that the associations we observed resulted from unmeasured third factors, such as shared genetic factors (67).

To summarize, our findings suggest that depressive symptoms may moderate the hostility-inflammation relationship such that hostility is associated with circulating levels of CAD-relevant inflammatory markers only in the presence of depressive symptoms. To establish the directionality of these associations, future research should investigate the relationship between these psychological constructs and changes in inflammatory marker levels over time. Along with Suarez (33), we believe that another important avenue for future research is to simultaneously examine depressive symptoms, hostility, and their interaction as predictors of hard CAD end points (e.g., myocardial infarction and sudden cardiac death) in prospective epidemiologic studies. If a similar pattern of results is observed, it would indicate that individuals with comorbid depressive symptoms and hostility are at substantially increased risk for CAD and, therefore, may be a subpopulation in which early pharmacological and/or psychological intervention is warranted.

We thank the entire project staff of the Pittsburgh Healthy Heart Project for their assistance with data collection.


   NOTES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
REFERENCES
 
1 The BDI-II and Ho Scale main effects were examined before entering the BDI-II x Ho Scale interaction term into the models. Back

This research was supported by the National Heart, Lung, and Blood Institute Grant HL56346 (T.W.K., Principal Investigator), the National Institutes of Health Training Grant HL07560, and the Pittsburgh Mind-Body Center Grants HL076852 and HL076858. Some of these data were presented at the 64th annual meeting of the American Psychosomatic Society, March, 2006, Denver, Colorado.

Received for publication March 13, 2007; revision received September 28, 2007.

DOI:10.1097/PSY.0b013e3181642a0b


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 NOTES
 REFERENCES
 

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Y. Chida and A. Steptoe
The association of anger and hostility with future coronary heart disease: a meta-analytic review of prospective evidence.
J. Am. Coll. Cardiol., March 17, 2009; 53(11): 936 - 946.
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