Background The relation between psychological variables andclinically evident coronary artery disease has been studiedextensively, although the potential mechanisms of such a relationremain speculative. We studied the relation between multiplepsychological variables and subclinical coronary artery diseaseto assess the possible role of such variables in atherogenesis.
Methods We conducted a prospective study of 630 consecutiveconsenting, active-duty U.S. Army personnel, 39 to 45 yearsof age, without known coronary artery disease. Each participantwas assessed for depression, anxiety, somatization, hostility,and stress. Subclinical coronary artery disease was identifiedby electron-beam computed tomography.
Results The mean (±SD) age of the subjects was 42±2years; 82 percent were male, and 72 percent were white. Theprevalence of coronary-artery calcification was 17.6 percent(mean calcification score, 10±49). The prevalence ofprior or current psychiatric disorders was 12.7 percent. Therewas no correlation between the coronary-calcification scoreand the scores measuring depression (r=–0.07, P=0.08),anxiety (r=–0.07, P=0.10), hostility (r=–0.07, P=0.10),or stress (r=–0.002, P=0.96). Somatization (the numberand severity of durable physical symptoms) was inversely correlatedwith calcification scores (r=–0.12, P=0.003), even afterwe controlled for age and sex. In multivariate logistic-regressionmodels, a somatization score greater than 4 (out of a possible26) was independently associated with the absence of any coronary-arterycalcification (odds ratio, 0.49; 95 percent confidence interval,0.25 to 0.96).
Conclusions Our data suggest that depression, anxiety, hostility,and stress are not related to coronary-artery calcificationand that somatization is associated with the absence of calcification.
An association between psychological traits and coronary arterydisease has been acknowledged for decades but has only recentlybeen validated empirically.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16Depression, anxiety, and hostility have each been demonstratedto be associated with the risk of coronary artery disease5,6,7,8,9,10,14,15and of adverse outcomes after acute coronary events.11,12,13Several hypotheses have been proposed to explain such associations:increased platelet reactivity, decreased heart-rate variability,poor adherence to therapies, or increased atherogenesis.17 Severalstudies have shown minimal or no relation between psychologicalvariables and the degree of coronary stenosis due to plaquesin symptomatic patients undergoing cardiac catheterization.18,19,20,21One study of young adults found a weak relation between hostilityand coronary-artery calcification.22
We undertook this study to explore the relation between multiplepsychological variables (depression, anxiety, somatization,hostility, and multidimensional stress) and subclinical coronary-arterycalcification, as measured by electron-beam computed tomography,in a consecutive sample of an asymptomatic screening population.The a priori hypothesis was that psychological variables previouslyshown to be associated with clinical coronary artery diseasewould be associated with underlying atherosclerosis, as reflectedby coronary-artery calcification.
Methods
Subjects
The methods of the Prospective Army Coronary Calcium Study havebeen described previously.23 Briefly, between October 1998 andOctober 1999, active-duty Army personnel from 39 through 45years of age who were stationed in the Washington, D.C., areawere recruited at the time of a periodic, Army-mandated physicalexamination. Persons who had a history of coronary heart diseaseor who reported a history of angina pectoris on the questionnaireof Rose et al.24 were ineligible. Of 705 eligible subjects,630 gave written informed consent for the study, which includedexamination by electron-beam computed tomography. The 75 personswho did not consent to the study were similar to the participantswith respect to age, sex, education, and factors that affectthe risk of cardiovascular disease (diabetes mellitus, totalcholesterol level, and smoking status). The protocol was approvedby the Department of Clinical Investigation of the Walter ReedArmy Medical Center.
The participants provided information on their personal historieswith respect to hypertension, diabetes mellitus, hypercholesterolemia,and psychiatric disorders; any family history of premature cardiovasculardisease; and their smoking status. Height and weight, body-massindex (the weight in kilograms divided by the square of theheight in meters), and blood pressure were measured in standardfashion. Blood was collected while the patients were fastingfor the measurement of serum glucose, glycosylated hemoglobin,insulin, homocysteine, Lp(a) lipoprotein, and fibrinogen. Low-densitylipoprotein (LDL) cholesterol was measured by direct assay.Standard 12-lead electrocardiograms were obtained and were evaluatedby an investigator who had no knowledge of the subject's coronary-arterycalcification score or other cardiovascular risk factors.
Assessment of Subclinical Atherosclerosis
To determine the presence and amount of subclinical atherosclerosis,coronary-artery calcification was measured by electron-beamcomputed tomography with a scanner (C-150LXP, Imatron). Eachscan included 40 to 50 slices, each 3 mm thick, with image acquisitiongated to 70 to 80 percent of the RR interval during electrocardiographywhile the subject was holding his or her breath. The scans wereinterpreted by an experienced radiologist using the scoringmethod of Agatston et al.25 Scans that had at least four contiguouspixels with more than 130 Hounsfield units were considered tobe positive for coronary-artery calcification, yielding a definitionof "any calcification" as any score greater than 0 (scores canrange into the thousands). A total score was determined fromthe sum of the individual scores for the four major epicardialcoronary arteries. This scoring system has been demonstratedto correlate well with the histologic and angiographic burdenof plaque.26,27,28,29,30 The radiologist who interpreted thescans was unaware of the clinical status of the participants.
Assessment of Psychological Factors
Before undergoing scanning, each participant filled out a questionnairethat included validated instruments to assess functional status,hostility, and stress and to identify depression, anxiety, andsomatoform disorders according to the fourth edition of theDiagnostic and Statistical Manual of Mental Disorders (DSM-IV).31Functional status was measured by the Medical Outcomes Study36-Item Short-Form Health Survey (SF-36).32 Depression, anxiety,and somatization (a durable pattern of physical symptoms causingimpairment for which no physical explanation can be identified)were measured with use of the validated, self-administered versionof the Primary Care Evaluation of Mental Disorders (PRIME-MD).33Depression, anxiety, and somatoform disorders were defined asany such disorders detected on the questionnaire. Continuousscores for depression and anxiety were created on the basisof the number and severity of the symptoms that the participantreported in each domain. Somatization was quantified in termsof the number and severity of bothersome physical symptoms reportedfrom a checklist of the 13 most common symptoms encounteredin primary care (each of the 13 common symptoms was graded asfollows: "bothered not at all"=0, "bothered a little"=1, or"bothered a lot"=2).34 The scores for depression ranged from0 to 27, the scores for anxiety from 0 to 14, and the scoresfor somatization from 0 to 26.
Hostility was measured with use of the Cook–Medley hostilityscale (the 50-item tool,35 as well as the refined version describedby Barefoot et al.36). A comprehensive stress score (range,0 to 18) was calculated on the basis of the number and severityof responses indicating stress in nine different domains (work,finances, relationships, caregiving burden, body image, sexuality,psychological support, health, and traumatic life experiences).For each psychological variable, the validity of the continuousscores was assessed by correlating scores with mental healthfunction as measured by the SF-36.33
Statistical Analysis
Continuous variables were compared with use of a t-test forindependent groups; categorical variables were compared withuse of the chi-square test. Correlation analysis was performedwith use of Spearman's rho, since the coronary-calcificationscores and the psychological scores were not normally distributed.The independent relation between multiple cardiovascular andpsychological factors and the dependent variable, coronary-arterycalcification (defined by a score greater than 0), were assessedwith multivariate logistic-regression models. A two-tailed Pvalue of 0.05 or less was considered to indicate statisticalsignificance.
Results
The demographic characteristics, cardiovascular risk factors,coronary-calcification data, and psychological profiles of the630 participants are shown in Table 1 and Table 2.
Table 1. Demographic Characteristics, Risk Factors for Coronary Artery Disease, and Prevalence of Coronary-Artery Calcification among the 630 Participants.
Table 2. Prevalence of Psychological Disorders, Psychological Scores, and Correlation of Psychological Scores with Coronary-Artery Calcification Scores.
The group was predominantly well educated. Most were white men;18.3 percent were women, and 28.4 percent were nonwhite. Accordingto the Framingham Risk Index,37 the five-year predicted riskof coronary heart disease was relatively low (mean [±SD],1.6±1.2 percent).
Coronary-artery calcification was present in 20.6 percent ofthe men and 4.3 percent of the women. The mean calcificationscores for men and women were 11±53 and 3±25,respectively. Coronary-artery calcification was significantlyrelated to higher total cholesterol, LDL cholesterol, and triglyceridelevels, higher systolic blood pressure, higher body-mass index,a greater degree of somatization, and male sex.
The correlation of each psychological score (from the PRIME-MD)with mental health status was substantial, thus establishingthe internal validity of the psychological measures in thissample: for depression, r=0.69, P<0.001; for anxiety, r=0.61,P< 0.001; for somatization, r=0.51, P<0.001; and for stress,r=0.60, P<0.001.
Eighty participants (12.7 percent) had depression, anxiety,or a somatoform disorder; this prevalence was roughly half thatin clinical populations (Table 2). Depression, anxiety, hostility,and stress were not significantly associated with coronary-arterycalcification. There was no significant difference between thosewith and those without psychological disorders in the prevalenceof coronary-artery calcification (13.8 percent vs. 18.3 percent,P=0.33) (Table 3). However, the somatization score was significantlyand inversely correlated with the calcification score (Figure 1).33 This relation persisted even after we controlled for ageand sex.
Table 3. Scores for Psychological Variables in Subjects with Coronary-Artery Calcification and Those without Calcification on Electron-Beam Computed Tomography.
Figure 1. Inverse Correlation of Somatization Scores and Scores for Coronary-Artery Calcification in 630 Asymptomatic Subjects.
One subject with a calcification score of 790 and a somatization score of 1 is not indicated, owing to the scale of the figure.
Logistic-regression models (with control for body-mass index,LDL cholesterol level, systolic blood pressure, the interactionof systolic blood pressure and antihypertensive treatment,38smoking status, sex, age, education, and each of the psychologicalvariables) identified sex, LDL cholesterol level, body-massindex, and degree of somatization as independent correlatesof coronary-artery calcification (Table 4). A somatization scoreof more than 4 out of a possible 26 was associated with an adjustedodds ratio for coronary calcification of 0.49 (95 percent confidenceinterval, 0.25 to 0.96).
Table 4. Odds Ratios for Coronary-Artery Calcification Associated with Selected Characteristics in a Consecutive Screening Sample of 630 Asymptomatic Subjects.
When the same models were repeated with the inclusion of eitherany psychological disorder (depression, anxiety, or somatization)or individual psychological scores, and the level of Lp(a) lipoprotein,homocysteine, fibrinogen, insulin, glycosylated hemoglobin,or high-density lipoprotein cholesterol, a persistent independentrelation was found between somatization and coronary-arterycalcification.
Discussion
In this consecutive sample of nonreferred, asymptomatic U.S.Army personnel without known coronary disease, there was nopositive association between psychological variables and coronary-arterycalcification, an established marker of atherosclerosis. Therewas, however, an unexpected inverse association between somatizationand coronary-artery calcification, even after we controlledfor multiple potential confounding variables.
Previously, two studies in which the thickness of the intimaand media of the carotid artery was used as a surrogate foratherosclerosis found an independent association between hostilityand subclinical atherosclerosis. One study found an associationbetween hostility and a change in intima–media thicknessover a period of two years,39 and the other found an independentassociation between hostility (but not anxiety) and intima–mediathickness.40
One prospective study of young men and women found an independentrelation between hostility and coronary-artery calcification,but the study did not measure other psychological variablesand had few participants with any coronary-artery calcification.22Our study was substantially larger than those studies, assesseda more comprehensive battery of psychological variables andcoronary risk factors, and had more participants with subclinicaldisease. These features allowed us to perform a richer multivariateassessment of the relation between psychological variables andcoronary-artery calcification. In our study, hostility was notassociated with subclinical coronary-artery disease. A higherdegree of somatization, on the other hand, was independentlyassociated with the absence of coronary-artery calcification,even after we controlled for other psychological variables,including depression and hostility. Our data suggest that anyassessment of psychological variables and subclinical coronaryartery disease must also control for somatization.
Several studies have assessed the association between psychologicalvariables and the burden of coronary atherosclerosis in symptomaticpersons undergoing angiography. The results are conflicting.18,19,20,21However, it is difficult to draw conclusions about the mechanismsof subclinical atherogenesis from angiographic studies of largelysymptomatic patients with clinically manifest disease. Angiographicstudies may not be a suitable method of assessing the relationbetween behavioral variables and coronary artery disease, largelybecause of a skewed population with late-stage, severe disease(disease-spectrum bias).41 Indeed, the strength of our studylies in the use of a consecutive sample of an asymptomatic screeningpopulation, which avoids the selection bias inherent in referredpopulations.
There has been limited research on the relation between somatizationand coronary artery disease, and all of it has been in patientswith clinically manifest disease.21,42,43 One study showed norelation between hypochondriasis and the number and extent ofcoronary stenoses.21 Two studies showed a weak association betweensomatization and new cases of myocardial infarction.42,43
Surprisingly, we found a substantial inverse correlation betweensomatization and coronary-artery calcification. One can onlyspeculate about the explanation for such a relation. Could itbe that patients who have somatization are more likely to havea healthy lifestyle? This would be consistent with the health-beliefmodel, whereby adherence to such a lifestyle is dependent onthe patient's perception of his or her susceptibility to illness.44Also, it is known that enhanced adherence by itself, even adherenceto a regimen of placebo in clinical trials, is associated withbetter health outcomes.45
Somatization is a strong predictor of the absence of noncardiovasculardisease among patients referred for specialty care.46,47 Evenwhere coexisting medical conditions are common, patients donot indicate high numbers of symptoms on symptom checklists.In one analysis of the original PRIME-MD data set, most somatizationwas explained by psychological variables such as depressionand anxiety, and coexisting medical conditions explained only2 percent of the total number of physical symptoms.48 It isimportant to emphasize that although our data show an associationbetween somatization and a healthy outcome — namely, absenceof coronary-artery calcification — somatization was alsostrongly correlated with poor mental health function, a resultconsistent with prior research demonstrating that somatizationis a disorder.34
There are several limitations to our data. It is possible thatcoronary-artery calcification is not a valid surrogate for atheroscleroticplaque.49 However, despite clinical research suggesting thatelectron-beam computed tomography may have a lower sensitivityfor atherosclerotic plaque in younger people with clinical coronaryartery disease than in older ones,50 the preponderance of evidenceindicates that coronary-artery calcification predicts cardiacevents and correlates with the histologic burden of atherosclerosis.28,29,51
There was a relatively low prevalence of coronary-artery calcificationand psychological dysfunction in our study, which could haveled to an underestimation of any relation between these twovariables. It is also possible that our psychometric tools werenot sensitive enough to dynamic psychological states and thusmissed potential associations. However, the PRIME-MD is a widelyused, valid psychometric tool for the detection of depression,anxiety, and somatoform disorders.33 For depression, the PRIME-MDscoring system is sensitive to changes in depressive status(Kroenke K: personal communication). The Cook–Medley questionnaire35is the state-of-the-art tool for the assessment of hostility.It was derived from the Minnesota Multiphasic Personality Inventoryand has been shown to be prospectively associated with adversehealth outcomes.36 Finally, we have shown that these tools haveinternal validity in our sample of participants by demonstratingstrong correlations between the results of each scoring systemand mental health function.
The lack of an association between psychological variables andcoronary-artery calcification is unlikely to be a result ofinsufficient statistical power, given the negative directionsand narrow confidence intervals for all the correlations. Itcould, however, be due to an insufficient "dose" exposure ratherthan to the lack of a cause-and-effect relation. That is, themeasurement of psychological variables at one point in timemay not accurately reflect either the cumulative psychologicalburden or the effect of the psychological factors on atherosclerosisover time. However, it is known that there is substantial stabilityof psychological variables over time.22,40,52 The ProspectiveArmy Coronary Calcium Study will continue to explore this relationin a prospective fashion.23
Our results are based on a sample with a narrow range of agesand may not be generalizable to other age groups. However, theuse of such a sample may have the advantage of controlling forthe powerful effect of age on atherosclerosis and coronary-arterycalcification. Data from larger and more diverse populationswould be needed to verify these findings.
Causal relations are difficult to infer from cross-sectionaldata. The problems tend to be with spurious associations, however,and so the finding of a lack of any association between severalpsychological variables and subclinical coronary artery diseasemakes it unlikely that there is actually a causal associationbetween psychological factors and the formation of atheromatousplaque.53,54
On the assumption that coronary-artery calcification is a validsurrogate marker for subclinical coronary artery disease, thesedata suggest that depression, anxiety, hostility, and stressare not related to atherogenesis and that somatization is amarker for the absence of atherosclerosis. Prospective dataare needed to clarify the specific relation between psychologicalvariables and the progression from subclinical to clinical coronaryartery disease.
The views expressed here are those of the authors and shouldnot be construed as those of the Department of the Army or theDepartment of Defense.
We are indebted to Kurt Kroenke, M.D., and Ann Shaheen O'Malley,M.D., M.P.H., for their critical review of the manuscript andtheir helpful comments.
Source Information
From the Departments of Medicine (P.G.O., D.L.J., A.J.T.) and Radiology (I.M.F.), Walter Reed Army Medical Center, Washington, D.C.; and the Uniformed Services University of the Health Sciences, Bethesda, Md. (P.G.O., D.L.J., I.M.F., A.J.T.).
Address reprint requests to Dr. O'Malley at the General Internal Medicine Service, Department of Medicine (EDP), Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814-4799, or at patrick.omalley{at}na.amedd.army.mil.
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