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C-Reactive Protein Is Associated With Psychological Risk Factors of Cardiovascular Disease in Apparently Healthy Adults

From the Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.

Address correspondence and reprint requests to Dr. Suarez at Duke University Medical Center, PO Box 3328, Durham, NC 27710. E-mail: suare001{at}mc.duke.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
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 (ß = 0.05, p = .011), BPAQ anger (ß = 0.05, p = .007), and the PRF composite score (ß = 0.27, p = .005), but not BPAQ hostility (ß = 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

Abbreviations: 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 inflammatory protein-1a;; NHANES III = Third National Health and Nutrition Examination Survey;; OTC = over-the-counter;; PRF = psychological risk factor;; TNF- = tumor necrosis factor-.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
Inflammatory processes play key roles in the initiation and progression of atherosclerosis and its clinical sequelae (1,2). The relevance of inflammation to atherosclerotic cardiovascular disease (CVD) is such that plasma levels of various inflammatory biomarkers are emerging as important prognostic 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’ subpopulations 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 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 mortality and severity of CHD in coronary patients (33–36). Severity of depressive symptoms, independent of clinical diagnosis, 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, separately and in combination, have been associated with enhanced lipopolysaccharide (LPS)-stimulated expression of monocyte-associated interleukin (IL)-1ß, 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 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 episode (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 association between CRP and depressive moods in univariate analysis, but not in multivariate analyses that controlled for age, body mass index (BMI), smoking, and other sociodemographic variables (49). Another study using multivariate techniques to control for gender, age, smoking, BMI, and socio-economic status also failed to observed a significant association between CRP and severity of depressive symptoms 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 individuals 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

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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 distributed 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, myocardial 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 medications used to treat the aforementioned diseases. All participants also reported a negative history of psychiatric ailments; 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 procedures during the 2 weeks before their laboratory session. Also during those 2 weeks, subjects remained free of all prescription medications and over-the-counter (OTC) preparations, including daily low-dose aspirin. All female participants reported not using oral contraceptives during the 6 months before study participation. Written informed consent was obtained before study participation. The Institutional Review Board of Duke University Medical Center approved this protocol.

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 menses. 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 medications or OTC, presence of physical injury, recent medical conditions (eg, sore throat, cold, sinus problems, flu-like symptoms), or having undergone any medical/dental procedures in the 2 weeks before laboratory session were rescheduled. 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 refrigerated 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 reliability = 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-validated and frequently used 21-item scale designed to measure severity of depressive symptomatology with scores significantly associated with clinical measures of depression (63). The BDI has been widely used in cardiovascular populations, and prior evidence has suggested that the risk of future cardiac events is associated with the magnitude of depressive symptoms along a gradient (28,43,64). Each item on the BDI is scored on a 0 to 3 scale, with the total score ranging from 0 to 63 and Cronbach’s alpha of 0.89.

Participants also completed a health history questionnaire which included items assessing alcohol use (never, former user, infrequently, frequently, regularly), exercise regularly (yes/no), and family history of CVD before age 60 (yes/no).

Measures of Cardiovascular Risk Factors: Blood Pressure and Fasting Lipids
Blood pressure readings were taken using the Dinamap automated blood pressure monitor (Model 1876X, Critikon Corporation, Tampa, FL). Blood pressures were taken in the nondominant arm while the subject relaxed for 10 minutes. Two blood pressure readings were taken approximately 5 minutes apart and the average blood pressure reading was used in the analyses to represent basal blood pressure. Fasting lipids were determined by enzymatic methods.

High Sensitivity C-reactive Protein Measure
CRP was assessed in duplicate with an ultrasensitive, enzyme-linked, immunometric latex-enhanced assay (Diagnostic Products Corporation, Los Angeles, CA) using purified protein and polyclonal anti-CRP antibodies from Diagnostic Products Corporation (Los Angeles, CA) (65). This system has a lower detection threshold of < 0.10 mg/L with coefficients of variation ranging from 6.6% to 9.3%. Measurements of CRP were done on fasting venous blood samples collected between the hours of 8:30 AM and 9:30 AM while subjects were seated in a reclined position. Blood samples were spun, refrigerated, and transferred to the laboratory where CRP assays were performed on fresh samples. It has been shown that a one-time measure of CRP is a reliable and stable measure of CRP over an extended period of time (65).

Statistical Analyses
Statistical Analysis System statistical software (SAS Institute, Cary, NC) was utilized for all analyses. To insure a normal distribution, CRP values were logarithmically transformed. Initial analyses used univariate procedures to examine the relation of log-transformed CRP to anger, hostility, and severity of depressive symptoms.

Multivariate analysis was then utilized to examine the independent associations between psychological factors and log-normalized CRP. For each psychological factor, the analytic model contained the same set of covariates. Statistical adjustments were made for gender, age, BMI, the ratio of fasting total cholesterol (TC) to high-density lipoprotein (HDL), alcohol use (ie, none/former user, occasionally, frequently), exercise regularly (yes/no) and family history of premature (< 60 years of age) CHD (yes/no); factors previously reported to be associated with higher levels of CRP (5,66–71). Given that the inclusion criteria insured that participants were free of all medications and OTC preparations, were nonsmokers with no previous or current medical conditions or physical injury that could affect CRP, these factors were not included in the regression model.

Four independent multivariate regression analyses were conducted. The first analysis examined the association between log-transformed CRP and severity of depressive symptoms, entered either as a continuous score or as a dichotomous depressed/non-depressed group variable. The second and third analyses examined the relation of BPAQ-anger and hostility scores, entered as continuous variables, to log-transformed CRP. The last analysis examined the relation of log-transformed CRP to the summary effect of anger, hostility, and severity of depressive symptoms. The analysis of the summary effect of all three factors combined utilized a factor score derived from a principal component analysis. This analytically-derived factor score represents a composite summary indicator of BDI, BPAQ-anger and hostility scores, with higher summary scores indicating higher scores on all three scales.

	RESULTS

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Univariate Analyses: Psychological Risk Factors and Their Associations With Log-Normalized CRP
Characteristics of the study participants are presented in Table 1. BDI depression scores ranged from 0 to 27 (mean 4.2 ± 4.7). Scores on the BPAQ-anger scale ranged from 7 to 29 (mean 14.1 ± 5.1) and scores on the BPAQ-hostility scale ranged from 8 to 33 (mean 16.3 ± 5.9). All CRP values were under 10.0 mg/L, a level suggestive of an ongoing acute inflammatory condition (72). Log-transformed CRP was significantly 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).

High Sensitivity CRP and Anger
The BPAQ-anger score was entered as a continuous variable in a multiple regression model with statistical adjustments for gender, age, BMI, TC:HDL ratio, exercise regularity, reported alcohol use, and family history of premature CHD. Results indicated that higher BPAQ-anger scores were associated with elevated concentrations of CRP (ß = 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 (ß = 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 (ß = 0.271, SE = 0.095, p = .005).

	DISCUSSION

TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 
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 analyses 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, CRP was positively and significantly associated with a composite summary indicator of anger, hostility, and severity of depressive symptoms. These latter observations are particularly important because of clinical and empirical evidence suggesting that these psychological factors tend to cluster within individuals (80–82), and that the clustering of psychological 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 samples 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 association between CRP and severity of depressive symptoms in both univariate and multivariate analysis adjusting for various potential confounding factors. What may account for the differences between the results of the current study and those of previous studies that failed to observe a significant multivariate 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 depressive 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 significantly 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 significantly 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 psychiatrically 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). Although 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 elevated 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-analytically derived composite summary indicator of anger, hostility, and severity of depressive symptoms is a significant and independent predictor of CRP. The combination of these psychological factors has relevance for several reasons. First, it is well recognized that severity of depressive symptoms, hostility, and anger are statistically correlated and share a significant proportion of variance (45). It has been suggested, however, 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, therefore, 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 symptoms 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 effect of anger, hostility, and depressive symptoms on inflammatory biomarkers appears to go beyond merely statistical covariation. Epidemiological evidence is clearly needed in 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 inflammatory 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 associations between these same psychological factors and monocyte-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 possibilities 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 injury, or medical procedures; all factors associated with elevated CRP. Thus, how anger and severity of depressive symptoms, alone and in combination with hostility, contribute to CRP elevations is open to speculation. One possible explanation 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 norepinephrine responses and norepinephrine dysregulation (93–97). Preliminary evidence suggests that norepinephrine-dependent adrenergic stimulation results in activation of the nuclear factor (NF)-B, a transcription factor known to increase gene expression for cytokines, such as IL-1ß 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 independent 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-induced sympathetic activation that triggers an NF-b-dependent 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 associated 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 represented 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 infarction 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.

	ACKNOWLEDGMENTS

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This study was supported by grants HL56105 and HL67459 from the National Heart, Lung and Blood Institute to the author.

The author gratefully acknowledges the assistance of Wilma Young, Shina Miller and Andrew Weiman in the collection of the data.

Received for publication November 14, 2003.

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TOP ABSTRACT INTRODUCTION METHODS RESULTS DISCUSSION ACKNOWLEDGMENTS REFERENCES

 

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