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Diurnal Cortisol Decline is Related to Coronary Calcification: CARDIA Study

From the Department of Psychiatry, University of Pittsburgh, Pittsburgh, Pennsylvania (K.M.); the Department of Psychiatry, State University of New York at Stony Brook, Stony Brook, New York (J.S.); the Department of Psychology, Carnegie Mellon University, Pittsburgh, Pennsylvania (S.C.); and the Division of Geriatrics, UCLA School of Medicine, Los Angeles, California (T.S.).

Address correspondence and reprint requests to Karen Matthews, PhD, Department of Psychiatry, University of Pittsburgh, 3811 O'Hara Street, Pittsburgh, PA 15213. E-mail: matthewska{at}upmc.edu

	ABSTRACT

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Objective: Chronic stress may be a risk factor for coronary heart disease and is associated with dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis. We tested the hypotheses that two markers of HPA axis dysregulation, elevated average level (area under the curve, adjusted for time awake) and diurnal decline of salivary cortisol, were associated with presence of coronary calcification (CaC).

Method: Seven hundred eighteen black and white middle-aged adults enrolled in an ancillary study of Coronary Artery Risk Development in Young Adults provided six salivary cortisol samples throughout one full day and had measurements of CaC.

Results: The prevalence of any calcification was low, 8.1% in the participants of the ancillary study, with white men having the highest proportion. Average cortisol did not differentiate groups, means = 2.15 and 2.08. Those with any CaC declined approximately 6% per hour in cortisol over the course of the day, whereas those with no CaC declined more than 8% per hour (p < .003). Those persons with slope scores in the flattest quartile had a greater likelihood of any CaC than did those in the remaining quartiles adjusted for sex–race group, age, smoking, treatment for diabetes, systolic blood pressure, logged triglycerides, average cortisol, and educational attainment (odds ratio = 2.58; 95% confidence interval = 1.26–5.30).

Conclusions: Our results are consistent with the hypothesis that HPA axis dysregulation may affect risk for atherosclerosis.

Key Words: coronary calcification • neuroendocrine • stress • cortisol

Abbreviations: CHD = coronary heart disease; HPA = hypothalamic–pituitary–adrenal; CARDIA = Coronary Artery Risk Development in Young Adults; CaC = coronary artery calcification; BMI = body mass index; LDL-C = low-density lipoprotein cholesterol; HU = Hounsfield unit; BP = blood pressure; HDL = high-density lipoprotein; AUC = area under the curve; SBP = systolic blood pressure.

	INTRODUCTION

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Cumulativeexposure to chronic stressors may be a risk factor for coronary heart disease (CHD (1)). Individuals who are exposed to high levels of demands and low levels of control at work, to distressing marriages, and to low social support are more likely to have incident CHD than their less stressed counterparts (2–4). Dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis is one of the pathways through which chronic stress may affect CHD risk. In healthy individuals, cortisol has a distinct diurnal pattern with the peak cortisol occurring in the early morning, declining throughout the day, and reaching a nadir around 2 or 3 AM (5). Cortisol also exhibits sizable, short-term increases during the first hour after awakening and in response to a lunch meal or a threat-provoking stressor. Aging is associated with increased mean 24-hour plasma cortisol, but the diurnal variation is preserved (5). Dysregulation can take the form of altered overall levels of cortisol or a smaller decline in cortisol throughout the day and evening, i.e., flatter slope.

The literature clearly supports that chronic stress in both animal and human studies alters the ability of the HPA axis to recover from challenges (6). Elevated cortisol levels are associated with depressive symptoms (7), anxiety (8), caregiver stress (9), unemployment (10), and overall negative affect (11). Elevated evening cortisol, resulting from a smaller cortisol decline throughout the day, is associated with unhappy marriages (12), low positive affect (men only (11)) and depressive symptoms, low network diversity, support, feelings of control, and low socioeconomic status (13). No epidemiologic studies have tested the association between cortisol level and pattern and risk for CHD, although a higher level of morning cortisol has been observed among men with moderate to severe coronary atherosclerosis than those with no detectable disease (14). In the ongoing epidemiologic study of young and middle-aged adults called the Coronary Artery Risk Development in Young Adults (CARDIA (15)), we tested the hypothesis that coronary calcification (CaC) is associated with average awake cortisol level and diurnal pattern, i.e., the average rate of decline throughout the day.

	METHODS

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Participants
CARDIA is an ongoing prospective, multicenter study of the natural history of cardiovascular risk development starting in young adulthood. Participants were initially recruited in 1985 to 1986 to achieve a balance at each of four sites by race (black, white), sex, and education (high school degree or less vs. more than a high school degree). Detailed description of the original sampling procedure is available elsewhere (15). Participants were examined at study entry and years 2, 5, 7, 10, and 15 with the reexamination rate among surviving cohort members at year 15 of 73.5%. Comparisons of CARDIA participants in the year 15 examination with nonparticipants showed that nonparticipants were more likely to be black, younger, less educated, and smokers (16). Site institutional review committee approval and informed consent were obtained for each examination. The CARDIA Publications Committee approved this article.

At the year 15 examination conducted in 2000 to 2001, participants at the Oakland and Chicago sites living within 50 miles of the clinic were invited to participate in an ancillary study of socioeconomic status, which included assessment of salivary cortisol. Informed consent was obtained separately for participation in the ancillary study. Of the 1336 participants who were eligible for the ancillary study, 836 (62.6%) agreed to participate and 808 returned salivettes containing saliva. Excluded from analysis were two because of inadequate data on the times that samples were collected, 25 because they awoke after 11 AM and had a distinctly different cortisol pattern from the remainder of the sample, one who reported having had a heart attack, and 62 who did not have CaC measures. The final sample was 151 and 235 black men and women, respectively, and 154 and 178 white men and women, respectively. Among those who participated in the CaC protocol at the two sites, participants in the ancillary study had higher body mass index (BMI), less education, and were more likely to be black compared with nonparticipants in the ancillary study at the two sites; they were similar in age, blood pressure, low-density lipoprotein cholesterol (LDL-C), and percentage of women, current smokers, or those having any calcification.

Coronary Calcification
Coronary calcification was measured by using an Imatron C-150 electron beam scanner. A committee of cardiologists, radiologists, and a physicist developed a scanning protocol to standardize scan acquisition, which included two 2.5- to 3-mm thick electrocardiogram-gated scans completed within 100 to 520 ms on each participant using a hydroxyapatite phantom to allow standardization of image brightness. With the help of specialized image processing software, trained readers identified the presence of CaC in each scan (17). A total CaC score was calculated for each scan by multiplying the area of the focus by a coefficient ranging from 1 to 4 based on the peak density in the focus (1 = 130–200 Hounsfield units [HU], 2 = 201–300 HU, 3 = 301–400 HU, and 4 = 401+ HU) according to the method described by Agatston (18). All readers were blind to participant characteristics. Both between- and within-reader reproducibility were high (17).

Other Relevant Measures
Standardized questionnaires were used to assess age, race, sex, treatment for diabetes, and years of education. At each examination, three seated blood pressure (BP) measurements at 1-minute intervals were taken on the right arm using a Hawksley random zero sphygmomanometer (WA Baum Co., Copaigue, NY) after a 5-minute rest. Systolic BP and diastolic BP were recorded as phase I and phase V Korotkoff sounds, and the latter two measures were averaged. BMI was calculated as measured weight (in kilograms) divided by height squared (in meters). Smoking status was categorized as currently smoking at least five cigarettes per week, yes/no. A fasting blood draw was conducted and total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol were measured (19) with LDL-C calculated by the Friedewald equation.

Cortisol Protocol and Data Reduction
Cortisol was measured in saliva as opposed to plasma because of the epidemiologic and ambulatory nature of the study. Salivary "free" cortisol levels track closely with plasma levels, correlations ranging from 0.70 to 0.90 (20) showing a 1- to 2-minute lag, and have been previously used to monitor cortisol activity in both ambulatory and laboratory challenge paradigms (21–22). Participants were given materials and instructed regarding the collection of the saliva samples at the conclusion of their year 15 follow-up CARDIA clinic visit. Samples were collected from participants on a single weekday, in most cases the Monday after a Friday or Saturday clinic visit. They provided six saliva samples over the course of the day: at awakening ("when your eyes open and you are ready to get up"), 45 minutes, 2.5 hours, 8 hours, and 12 hours after awakening, and at bedtime ("right before getting into bed"). Participants were instructed to record the time they woke up in a log and were provided with alarm watches (preset to their regular wakeup time) to remind them to collect samples; they were also given a form that allowed them to easily recalculate the desired sample times if they woke up at a different time than anticipated.

To provide a saliva sample, participants placed a roll of cotton in their mouths, chewed on it for approximately 30 seconds or until it became saturated, and placed it in a tube called a salivette (Sarstedt, Rommelsdorft, Germany). They then filled in the time of the sample on the tube label. The investigators collected all six salivettes the next morning. Salivettes were refrigerated at each site until they were assayed. Cortisol level was determined by time-resolved immunoassay with fluorometric end point detection (23). Nine samples with levels below the minimum detectable level (0.7 nmol/L) for this assay were assigned values of 0.5 nmol/L. Intra- and interassay variabilities were each less than 12%.

Not every cortisol sample was taken precisely at the intended time. For each of the six targeted times, a window relative to time since awakening was established for considering the sample collected at the appropriate time. This window was narrowest for the morning sample as a result of the typical pattern of a rapid increase in cortisol during the first 30 to 60 minutes after awakening (the "morning rise") followed by a more gradual, but steady, decrease during the rest of the day. The targeted times and windows were as follows: +15 minutes for wakeup, +15 to +90 minutes for +45 minutes, +2 to +3.5 hours for +2.5 hours, +7 to +9 hours for +8 hours, +11 to +13 hours for +12 hours, and +12 to +20 hours for bedtime. The sixth sample was not targeted to a specific time. The window for each target time was determined from preliminary analyses documenting the interval over which there was no systematic tendency for cortisol levels to differ from those obtained within ±5 minutes of the target time. A sample provided outside the acceptable window was excluded from analyses of samples for that targeted time.

Analyses reported subsequently were performed separately on each of the six targeted cortisol samples after natural logarithmic transformation to reduce the positive skewness. However, the main focus was on two summary measures of cortisol: area under the curve (AUC) and slope. AUC, a time-adjusted measure of total cortisol exposure while awake, was calculated as the AUC defined by the plot of log-transformed cortisol values against collection times multiplied by 16 hours and divided by the duration, in hours, between the first and last sample. The AUC measure was computed only for those who had data for the first and/or second sample and a minimum of 12 hours between their first and last samples; 18 were excluded from AUC analyses. The slope was calculated for those who had at least the first or second sample and the fifth or sixth sample; 13 participants were therefore excluded from the slope analyses; six participants had slopes calculated based on the second cortisol sample rather than the first. The slope was estimated by fitting a linear regression line separately for each participant that predicted the log-transformed cortisol values from time (hours) since awakening. To minimize the impact of the morning rise on the estimation of slopes, the second saliva sample was excluded from the calculation of slopes for all but the six otherwise eligible participants who did not have a first cortisol sample collected within 60 minutes of awakening. Because the AUC and slope were based on real time, it was not necessary to exclude available data outside the targeted windows.

Statistical Analyses
Data are reported as means and standard deviations or proportions, and preliminary analyses by t tests were conducted on differences between those with and without any calcification. Because only a small minority of participants had any measurable calcification, we used logistic regression analysis to predict presence/absence of measurable calcification. (Preliminary Tobit conditional regression analysis, which applies linear regression to continuous data [CaC scores] did not reveal a graded relationship with extent of calcification.) Initial models adjusted for race–gender group, treatment for diabetes, and age; subsequent models also adjusted for risk factors that were associated with CaC (p < .10): smoking status, systolic blood pressure (SBP), logged triglycerides, and education attainment. To test whether the relationship between cortisol's diurnal pattern and CaC or AUC was linear or nonlinear, we collapsed the distribution of diurnal slopes into quartiles (using cut points of –0.11758, –0.8775, and –0.049955) and examined their relationship to CaC. To examine if the effect of slope was independent of the level of cortisol, we investigated whether the results changed when also adjusting for AUC.

	RESULTS

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On average, participants were 40 years old with almost 20% smokers (Table 1). Mean BMI of the total and four sex–race subgroups was within the overweight range, except for black women whose mean was in the obese range. The number of participants with measurable calcification was low in this relatively young sample. Men were more likely to have measurable coronary calcification than women with white men having the highest and white women the lowest prevalence. Participants with CaC did not differ in time since awakening at sample collections from those with no CaC (all p > .15).

Although participants with calcification did not differ significantly from those without calcification on any of the six individual cortisol samples, there was a tendency for the last three samples to be higher in those with calcification (all p < .20). As a result, those with calcification had flatter diurnal slopes of cortisol than did those without calcification, although there were no differences by group in cortisol AUC (Table 2). The mean slope of –0.061 for the group with any calcification means that, on average, (untransformed) cortisol decreased at a rate of approximately 6% per hour over the course of the day, whereas the mean slope of –0.084 means that on average cortisol decreased at a rate of more than 8% per hour over the course of the day.

The association between cortisol slopes (continuous) and having any calcification was significant in the logistic regression model adjusting for sex–race group, treatment for diabetes, and age (Table 3, row 1). The analysis based on the four quartiles of the cortisol slope showed that compared with the quartile with the steepest cortisol slopes, the quartile with the flattest slopes was approximately 31/3 times more likely to have any calcification, whereas there were no differences among the remaining quartiles (all p > .70) (controlling for sex–race group, treatment for diabetes, and age; see Fig. 1). Compared with the three other quartiles combined, those in the quartile with the flattest slopes were markedly more likely to have any calcification. A similar analysis using AUC as the predictor variable did not show a nonlinear association with CaC.

View larger version (16K): [in this window] [in a new window]   Figure 1. Probability of detectable coronary artery calcification by quartiles of diurnal slope of salivary cortisol adjusted for sex, race, treatment for diabetes, and age. p values refer to tests for whether the quartile group differs from the reference group.

These associations remained statistically significant when adjusted for race–gender groups, age, current smoking, SBP, triglycerides, and educational attainment (Table 3, row 2). Additionally controlling for AUC, a time-weighted estimate of average cortisol during the day did not substantially alter the relationship.

The Hosmer and Lemeshow goodness-of-fit statistic was used to estimate the validity of the logistic regression models presented in Table 3. For none of these models was there evidence of a poor fit; the significance levels for this test ranged from p = .09 to .90 (mean p = .38), in which a nonsignificant result indicates an adequate or good fit.

	DISCUSSION

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The present article evaluated whether markers of HPA function, i.e., average cortisol or diurnal pattern throughout the day, were related to presence of coronary calcification in young and middle-aged black and European American men and women. Results showed that the flatter the cortisol slopes throughout the day, the greater the likelihood of any coronary calcification with the suggestion that the flatter slopes were the result of elevated afternoon and evening levels as opposed to lower morning levels. Further inspection of the data showed that the relationship was nonlinear. That is, the flattest quartile of cortisol slopes was associated with the presence of calcification. These associations remained statistically significant in models adjusting for sex–race group, age, treatment for diabetes, cigarette smoking, SBP, triglycerides, educational attainment, and average cortisol levels measured across the day. To our knowledge, this is the first epidemiologic study to show that the cortisol pattern is related to risk for coronary atherosclerosis.

To date, cortisol (and dysregulated HPA axis activity more generally) has not been the focus of investigation as a potential contributor to coronary atherosclerosis. The plausibility of a relationship between cortisol patterns and atherosclerosis is in accord with a number of recent findings. Cortisol abnormalities are associated with increased abdominal obesity (24,25). Pharmacologic inhibition of cortisol production prevents mental stress-induced endothelial function and baroreflex impairment, suggesting that cortisol may facilitate these phenomena (26). Growing evidence links dysregulation of the HPA axis with inflammatory processes (27), which then contribute to the pathogenesis of atherosclerosis (28). Finally, and most specific to calcification, animal data suggest that vascular lesions may be less affected by the antiproliferative/antifibrotic effects of cortisol during chronic stress, leading to excessive wound repair processes and calcification (29).

Several features of this study are noteworthy. First, the sample was small, relatively young, and very few had coronary calcification. Thus, the findings should be considered preliminary. Furthermore, the extent to which abnormal cortisol rhythms may be related to calcification in older populations with significant comorbidity and higher levels of calcification is unknown. Second, the study was cross-sectional in design. Although it is unlikely that coronary calcification alters HPA regulation, it is possible that there is a third correlated factor accounting for both. Indeed, we had reasoned that HPA dysregulation in response to stress would increase the risk for calcification. However, in the present sample, a flatter slope was not associated with number of chronic problems, although it was associated with greater depressive symptoms and lower emotional support and network diversity (13). Third, we did not expect average cortisol level summarized throughout the day to be unrelated to calcification. However, it should be noted that average cortisol was related to different and fewer psychosocial factors than was the slope in the same sample (13). Furthermore, some stress-related diseases, e.g., posttraumatic stress disorder, are associated with lower cortisol levels, and some theorists believe that either hyperresponsiveness or hyporesponsiveness of the HPA axis is deleterious (30). This notion is in keeping with the concept of allostatic load in which both excessive responding or the failure to mount an adequate response is considered to be health-damaging consequences of stress (6). Finally, the methods of salivary cortisol collection are demanding in ambulatory populations. Our data would suggest that compliance with the timing of collection, especially in the evening hours, is very important for hypothesis testing.

In summary, we tested the hypothesis that cortisol level and diurnal patterns are related to the risk of any coronary calcification in a multiethnic sample. We found that a relatively flat diurnal pattern is associated with the risk of coronary calcification. These associations are independent of sociodemographic factors and established cardiovascular risk factors. Abnormal cortisol patterns may play a role in understanding why psychosocial factors are linked to risk for coronary disease. This is the first epidemiologic report of cortisol patterns being related to coronary atherosclerosis.

This work was supported by contracts University of Alabama at Birmingham, Coordinating Center, N01-HC-95095 University of Alabama at Birmingham, Field Center, N01-HC-48047 University of Minnesota, Field Center, N01-HC-48048 Northwestern University, Field Center, N01-HC-48049 Kaiser Foundation Research Institute, N01-HC-48050 University of California, Irvine, Echocardiography Reading Center, N01-HC-45134 Harbor-UCLA Research Education Institute, and Computed Tomography Reading Center, N01-HC-05187 from the National Heart, Lung and Blood Institute and by the MacArthur Research Network on SES and Health through grants from the John D. and Catherine T. MacArthur Foundation. Preparation of the manuscript was also facilitated by the Pittsburgh Mind-Body Center (HL65111 and HL65112).

	NOTES

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Received for publication August 25, 2006; revision received May 30, 2006.

DOI:10.1097/01.psy.0000244071.42939.0e

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