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Salivary Cortisol Is Related to Atherosclerosis of Carotid Arteries

Departments of Internal Medicine (M.J.H.J.D., J.W.K., M.O.v.A., H.A.P.P., F.H.d.J., S.W.J.L.), of Epidemiology & Biostatistics (M.J.H.J.D., H.A.P.P., A.H., J.C.M.W., H.T.), and of Child and Adolescent Psychiatry (H.T.), Erasmus Medical Center, 3000 CA Rotterdam, The Netherlands; and Department of Biological Psychology (C.K.), Technical University of Dresden, 01187 Dresden, Germany

Address all correspondence and requests for reprints to: H. Tiemeier, M.D., Ph.D., Department of Epidemiology, Biostatistics, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. E-mail: h.tiemeier{at}erasmusmc.nl.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background: Dysregulation of the hypothalamic-pituitary-adrenal axis has been suggested as an independent risk factor for ischemic heart disease. The aim of our study was to evaluate whether two markers of the hypothalamic-pituitary-adrenal axis activity, the level of salivary cortisol and the diurnal salivary cortisol pattern, are associated with atherosclerosis of the carotid arteries in an elderly population.

Methods and Results: A total of 1866 participants of the Rotterdam Study, a population-based cohort study in the elderly, provided four salivary cortisol samples throughout 1 d, and underwent ultrasonography to examine the presence of plaques in the common, internal, and bifurcation sites of both carotid arteries. Two summary measures of the separate cortisol values were computed: area under the curve (AUC), which is a measure of total cortisol exposure while awake; and the slope, which is a measure of diurnal cortisol decline.

Results: Total cortisol exposure while awake (AUC) was associated with higher plaque scores (β = 0.08 per SD of AUC, 95% confidence interval 0.00–0.16; P = 0.04) in a fully adjusted linear regression model. Persons with an AUC in the highest tertile had a higher number of plaques of carotid arteries compared with those in the lowest tertile (3.08 vs. 2.80, 95% confidence interval of difference 0.09–0.48; P = 0.005). There was no relation between diurnal cortisol decline and plaque score.

Conclusion: Our results support the hypothesis that increased total cortisol exposure is independently associated with atherosclerosis of the carotid arteries.

	Introduction

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For several decades, chronic exposure to psychosocial stressors has been implicated as a risk factor for cardiovascular disease (CVD). For instance, the lack of social support, low socioeconomic status (SES), unhappy marriages, and work stress are consistently associated with an increased incidence of CVD in several epidemiological studies (1, 2, 3, 4, 5).

One of the possible biological mechanisms through which chronic stress may influence the risk of CVD is dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. In healthy persons the HPA axis shows a diurnal rhythm with peak cortisol levels approximately 30 min after awakening, declining cortisol levels throughout the day, and a nadir around midnight (6). In response to physical or psychosocial stress (e.g. physical exercise, having a lunch meal, or emotional arousal), the HPA axis gets activated, and as a result, short-term cortisol increases are observed (7, 8).

Exposure to chronic stressors might dysregulate two different aspects of the HPA axis activity. First, overall levels of cortisol can be increased. This is observed during periods of perceived work stress (9), in men with lower social economic status (10), and in men with overall negative affect (11). Second, a smaller decline of cortisol levels throughout the day, a flatter slope, is seen in persons with marital problems (12), trait negative affect (11), low social economic status (13), unemployed individuals with high financial strain (14), and women undergoing a divorce or separation (15).

Elevated cortisol levels have numerous negative health consequences throughout the human body. Cortisol is implicated in the regulation of the immune system, glucose and lipid metabolism, and maintenance of cardiac output by increasing vascular tone and decreasing vascular permeability. Dysregulation of the HPA axis is associated with hypertension (16, 17), increased heart rate, and increased levels of total and low-density lipoprotein cholesterol and fasting insulin and glucose (18).

Despite the strong hypothetical basis for a causal relationship between cortisol and CVD, and more specifically the development of atherosclerosis, only one large epidemiological study has tested this hypothesis. Matthews et al. (19) showed that flatter cortisol slopes, but not average cortisol levels, correlate with the presence of any coronary calcification in young and middle-aged adults. Although this is an important finding, the prevalence of atherosclerosis was very low in this relatively young age group. The aim of the present study was to evaluate whether HPA axis regulation is associated with atherosclerosis in the elderly. We tested the hypothesis that total cortisol secretion throughout the day and diurnal cortisol decline correlate with atherosclerosis of the carotid arteries using data from the Rotterdam Study, a population-based study in an elderly population.

	Subjects and Methods

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Study population

This investigation is embedded in the Rotterdam Study, an ongoing population-based cohort study aimed at assessing risk factors for chronic diseases in the elderly (20). In 1990, all inhabitants of a suburb of Rotterdam aged 55 yr and older were invited, and 7983 agreed to participate (response 78%). The Rotterdam Study was approved by the Medical Ethics Committee of the Erasmus Medical Center, and written informed consent was obtained from all participants. Assessment of the salivary diurnal cortisol rhythm was added to the fourth survey study protocol, which took place between January 2002 and December 2004.

Of the 3550 persons who participated in the fourth survey, 2569 (74%) returned one or more saliva samples. We excluded 434 persons because they had missing data on salivary cortisol levels or collection times or salivary cortisol levels above the 98th percentile, four persons because they did not collect saliva correctly, 29 persons because they did not undergo ultrasonography of the carotid arteries, and 236 persons because they were using glucocorticoid applications. The final population for analysis consisted of 1866 persons with complete data on ultrasonography and at least one summary cortisol measure: the slope.

Measures of atherosclerosis

Ultrasonography of both carotid arteries was performed with a 7.5-MHz linear-array transducer and a duplex scanner (Acuson 128; Siemens and Esaote, Pie Medical Imaging, Maastricht, The Netherlands).

Both left and right internal carotid arteries, carotid bifurcation, and common carotid artery were examined for the presence of plaques. Plaques were defined as a focal widening relative to adjacent segments with the protrusion into the lumen. The total plaque score reflected the number of sites with plaques ranging from zero to six (21).

Assessment of covariates

During the home interview of the fourth study visit, information on current smoking status, medication, and educational attainment was collected. We defined eight categories of educational attainment: 1, primary education; 2, primary education plus a higher not completed education; 3, lower vocational education; 4, lower secondary education; 5, intermediate vocational education; 6, general secondary education; 7, higher vocational education; and 8, university. In The Netherlands, educational attainment is the best measure for SES. In the Dutch elderly population, income is not the best proxy for differences in SES because in this country, retirement insurances level out differences in income. The same holds for "last occupation" or "highest occupation" because in this generation, it was very common for women to stay at home regardless of SES. Depressive symptoms were evaluated using the validated Dutch version of the Center for Epidemiologic Studies Depression Scale (CES-D) (22). In addition, clinical measures were obtained at the research center. Detailed information on all glucocorticoid applications (including systemic glucocorticoids, intra-articular steroid injections, steroid creams and inhalants), aspirin and statin use, and blood pressure lowering medication was obtained from one or more of the seven pharmacies serving the research area. Nearly all participants (95%) were registered at one of these pharmacies, which are fully automated, and linked to the database of the Rotterdam Study. Fasting blood samples were drawn, and total cholesterol, high-density lipid (HDL) cholesterol, and glucose were determined. We defined diabetes mellitus as a fasting glucose of 7.0 mmol/liter or greater, a nonfasting glucose of 11.1 mmol/liter or greater, or the use of blood glucose lowering medication. Blood pressure was measured at the right brachial artery using a random-zero sphygmomanometer with the participant in sitting position. The body mass index (BMI) was calculated as weight (kg) divided by height squared (m²).

Salivary cortisol protocol

All participants who came to the research center during the fourth study survey were asked to collect saliva samples at home using Salivette sampling devices (Sarstedt, Rommelsdorf, Germany). Participants received detailed oral and written instructions concerning the saliva sampling. They were told to collect four saliva samples during one single weekday at home; directly after awakening (Cort_aw), 30 min later (Cort_aw+30), at 1700 h (Cort_1700h), and at bedtime (Cort_bed) and to write down the exact times and date of saliva collections. Furthermore, they were asked not to brush their teeth and not to eat 15 min before saliva sampling to avoid contamination of saliva with blood caused by microinjuries to the oral cavity. Besides these restrictions, subjects were otherwise free to follow their normal daily routines on the sampling day. One day after the saliva collections, the Salivettes were returned at the research center. Samples were stored in the freezer at –80 C until completing the fourth study survey and sent to the laboratory of Biopsychology, Technical University of Dresden, Germany. Salivary cortisol concentrations were measured using a commercial immunoassay with chemiluminescence detection (CLIA; IBL Hamburg, Hamburg, Germany). Intraassay and interassay coefficients of variation were less than 6 and 9%, respectively. The lower limit of detection was 0.4 nmol/liter. All but two of the saliva samples had detectable levels of cortisol.

Salivary cortisol analysis

Data were screened for quality of cortisol measurements. Due to sampling errors, 28 samples were excluded from the analyses: one because it was clearly contaminated with blood, two because the label on the Salivette was unreadable, 23 because those Salivettes were most likely swapped by the participants, and two because the Salivettes did not contain saliva.

For each time point, cortisol values that were above the 98th percentile in the original cortisol data set were excluded from the final data set to normalize the distribution of cortisol measurements and to exclude misclassification due to possible measurement errors: Cort_aw 46 were excluded, Cort_aw+30 46 were excluded, Cort_1700h 45 were excluded, and Cort_bed 47 were excluded. After this exclusion, cortisol levels followed a normal distribution. This conservative cutoff was chosen due to the high number of outliers. However, using the 99th percentile as a cutoff for outliers did not essentially change the results presented in this paper.

All analyses reported were performed on each of the four separate cortisol measurements. However, the main focus of our study was to evaluate the effects of two markers of the HPA axis activity: the area under the curve (AUC), which is a measure of total cortisol exposure while awake, and the slope, which is a measure of diurnal cortisol decline. The AUC was determined by the total area under the curve given by the cortisol measurements in nmol/liter on the y-axis and the time between the cortisol measurements on the x-axis. To correct for differences in hours being awake, the AUC was divided by the number of hours between the first cortisol measurement (at awakening) and the last cortisol measurement (before going to bed). The AUC was computed only for those who collected four saliva samples and had complete data on collection times at all time points. In this way, we obtained data on the AUC of 1963 participants.

The slope was calculated by fitting a linear regression line for each participant, which predicted the cortisol values from time since awakening. The second sample was excluded to minimize the impact of the morning increase on the estimation of slopes. The final data set consisted of 2016 participants with data on the slope.

Statistical analysis

We compared persons with and without plaques for known risk indicators for CVD: sex, age, smoking status, systolic and diastolic blood pressure, BMI, total cholesterol, HDL cholesterol, diabetes mellitus, blood pressure lowering medication, aspirin and statin use, and educational attainment using the Student’s t test for continuous variables and Pearson’s ² for the categorical variables. Next, we examined the associations of these risk factors with two summary measures of cortisol: AUC and slope using linear regression models.

Linear regression models were used to study the associations between the cortisol measures and the plaque score. First, we adjusted the analyses for age, sex, and time between awakening and saliva collection in the analyses of the separate cortisol measures, and for age, sex, and time between second and third measurement in the analyses of the AUC, to adjust for differences in timing of the sleep-wake cycle (model 1). Second, we adjusted the analyses as for model 1 and additional confounders: current smoking status, month of saliva collection, blood pressure lowering medication, and aspirin and statin use (model 2). Finally, we additionally adjusted the analyses for possible mediators: educational attainment, systolic blood pressure, diabetes mellitus, BMI, and total and HDL cholesterol (model 3). We did not include depressive symptoms in our models because adjustment did not change effect estimates (changes <0.05%).

Next, we divided the AUC and slope distributions into tertiles, and studied the differences in mean plaque score using ANOVA, and risk of having any atherosclerotic plaques using logistical regression analysis, between the tertiles in fully adjusted models. Missing information on covariates was imputed by means. Data are presented as βs and 95% confidence interval (CI), as means and 95% CI, or as odds ratios and 95% CI. Data were analyzed using SPSS for Windows, release 12.0.1 (SPSS, Inc., Chicago, IL).

The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The baseline characteristics for participants with and without atherosclerotic plaques are given in Table 1. Overall, a higher percentage of men had plaques, and persons with plaques were more often smokers. They were older, had higher systolic blood pressure, lower HDL cholesterol, and used statins, aspirin, and antihypertensives more often. Next, we examined the associations of the baseline characteristics with AUC and slope (Table 2). Smoking, systolic blood pressure, diabetes mellitus, educational attainment, and the presence of plaques correlated positively with AUC. Higher age, current smoking, and higher BMI were associated with flatter slopes. There were no associations with the summary measures AUC and slope for the other baseline characteristics.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

Some methodological issues of our study need to be discussed before we can interpret the findings. First, this study is cross-sectional and, therefore, cannot demonstrate the chronology of the observed relationships. Second, studies using saliva sampling to determine the diurnal cortisol pattern rely heavily upon participant adherence to the sampling protocol. Samples taken in the early morning are especially sensitive to deviations from the study protocol because cortisol levels change rapidly after awakening (23, 24). Noncompliance to the study protocol has probably also influenced the salivary cortisol concentrations in our study. However, it is unlikely that noncompliance is related to plaque score and will, therefore, result in random misclassification, which most likely leads to underestimation of the effect. This might explain why we did not find associations of the slope analyses with atherosclerosis because the steepness of the slopes depends heavily on the first cortisol measurement, and it could also explain why we did not observe associations with the separate morning cortisol measures in the adjusted models in our study. Third, although we controlled for major confounders like smoking, we cannot exclude residual confounding by unknown factors.

To the best of our knowledge, the present study is the first to evaluate the effects of HPA axis regulation on atherosclerosis in an elderly population. Previously, only one epidemiological study has examined the effects of HPA axis regulation and atherosclerosis in adults. This study, performed by Matthews et al. (19), was done in a relatively young population, with a mean age of 40 yr. They showed that a reduced diurnal cortisol decline, but not total cortisol exposure, was associated with coronary calcification. However, the prevalence of coronary calcification in this population was only 8.1%. Advantages of our study are the larger sample size and the higher prevalence of atherosclerosis due to an older age of the population: the mean age of our population was 75 yr, and more than 85% of the participants had one or more plaques (mean plaque score was 2.9). In contrast with the findings of Matthews et al. (19), we found that total cortisol exposure was associated with measures of atherosclerosis and that diurnal cortisol decline was not. Although, our results confirm the hypothesis that total cortisol exposure might be an independent risk for atherosclerosis, the effect estimates were relatively small: persons with AUC values in the highest tertile had a mean increase of 0.3 plaques. We did not expect diurnal cortisol decline not to be related to plaque score. In our study we found that higher age was associated with flatter slopes. Possibly, in the elderly the effects of cortisol levels are more important in the development of atherosclerosis than diurnal cortisol decline.

Other studies performed in patient groups and healthy volunteers are also in agreement with the notion that cortisol might play a role in the development of atherosclerosis. Eller et al. (25, 26) found that the level of salivary cortisol 1 h after awakening and the reactivity in cortisol the first hour after awakening were associated with higher intima media thickness (IMT) of the common carotid arteries in a group of 84 women. Furthermore, they found that the awakening cortisol response was related to progression in IMT in women but not in men (26). Troxler et al. (27) studied 71 male outpatients who underwent coronary angiography because of medical reasons, as part of their medical evaluation as a U.S. Air Force aircrew member. They found significant correlations between elevated morning plasma cortisol levels and moderate to severe coronary atherosclerosis. Alevizaki et al. (28) showed in a group of 46 subjects undergoing coronary angiography for suspected coronary artery disease that high morning anticipatory stress cortisol levels predict severity of coronary artery disease. In addition, Peppa-Patrikiou et al. (29) showed that the IMT of the carotid arteries of insulin-dependent diabetes mellitus patients is already increased in adolescence. The higher level was positively related to urinary free cortisol.

Several biological mechanisms might explain the association between HPA axis functioning and atherosclerosis. Cortisol increases glucose levels and is an important factor in the development of diabetes mellitus (18). Indeed, in our study we found a strong association between total cortisol exposure and diabetes mellitus. However, adjustment for diabetes mellitus only marginally changed our results. Furthermore, previous studies found that dysregulation of the HPA axis is associated with hypertension (16, 17), increased heart rate (30), and total and low-density lipoprotein cholesterol (18). In the present study, total cortisol exposure was associated with systolic blood pressure. We corrected for systolic blood pressure, total cholesterol, and HDL cholesterol in our analyses, and found that these factors did not explain the association between total cortisol exposure and number of plaques. Evidence is accumulating that the influence of glucocorticoids on cardiovascular outcome is not mediated exclusively by known cardiovascular risk factors but may also be the result of direct effects in the blood vessel wall. Inflammation plays a pivotal role in the development of atherosclerosis, and cortisol is implicated in the regulation of the immune system (31, 32). Increased local cortisol levels in the blood vessels may promote perivascular inflammation (33). Furthermore, antiinflammatory treatment with glucocorticoids may enhance calcification within arteriosclerotic lesions (34). However, we cannot exclude that higher cortisol levels are a marker of other pathological processes, which in themselves promote the development of atherosclerotic lesions.

In summary, we showed that in an elderly population, higher total cortisol exposure while awake was associated with the number of atherosclerotic plaques of the carotid arteries. This association was independent of cardiovascular risk factors and sociodemographical factors. Our results confirm the hypothesis that total cortisol exposure may be an independent risk factor in the development of atherosclerosis. Prospective studies are needed to confirm the associations.

	Acknowledgments

 
We thank all participants, general practitioners, and pharmacies of the Ommoord district for their contributions to the Rotterdam Study.

	Footnotes

 
The Rotterdam Study is supported by the Erasmus Medical Center and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research, The Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission (DG X11), and the Municipality of Rotterdam. Additional funding for the work on cortisol in aging and age-related diseases was provided by Research Institute of the Diseases in the Elderly Grant 948-00-008.

Disclosure Statement: The authors have nothing to disclose.

First Published Online August 5, 2008

Abbreviations: AUC, Area under the curve; BMI, body mass index; CES-D, Center for Epidemiologic Studies Depression Scale; CI, confidence interval; Cort_aw, salivary cortisol directly after awakening; Cort_aw+30, salivary cortisol 30 min later; Cort_1700h, salivary cortisol at 1700 h; Cort_bed, salivary cortisol at bedtime; CVD, cardiovascular disease; HDL, high-density lipid; HPA, hypothalamic-pituitary-adrenal; IMT, intima media thickness; SES, socioeconomic status.

Received March 3, 2008.

Accepted July 25, 2008.

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