Journal of Gerontology: BIOLOGICAL SCIENCES 2002, Vol. 57A, No. 7, B279–B284
Copyright 2002 by The Gerontological Society of America
Mental Stress Response, Arterial Stiffness, and Baroreflex Sensitivity in Healthy Aging Ruth D. Lipman,1 Paul Grossman,1 Sarah E. Bridges,1 J.W. Hamner,1 and J. Andrew Taylor1,2 1Laboratory
for Cardiovascular Research, Hebrew Rehabilitation Center for Aged, Boston, Massachusetts. 2Division on Aging, Harvard Medical School, Boston, Massachusetts.
This study examined the relationship of pressor responses during mental stress to arterial stiffness and baroreflex sensitivity. Hemodynamic responses of 24 healthy individuals (51–86 years old) to two mental stress tasks (math and speech) were compared with common carotid artery mechanical stiffness and autonomic nervous system regulation of blood pressure as measured by using the modified Oxford technique. At the ages studied, no effect of age on stress task responsiveness, carotid stiffness, or baroreflex sensitivity was observed. Carotid stiffness and baroreflex sensitivity demonstrated a strong inverse relation. Change in heart rate during the speech task was correlated with arterial stiffness, and the increase in mean arterial pressure was associated with carotid stiffness and was inversely correlated to baroreflex sensitivity. These associations suggest that acute hemodynamic reactions to mental stress among healthy adults are determined, in part, by structural properties of arterial vessels and sensitivity of arterial baroreflex. These observations may provide a mechanistic link between the physiology of cardiovascular reactivity to stress and risk of cardiovascular events in middle-aged and older individuals.
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ENTAL stress responses in healthy individuals include cardiovascular reactivity such as increases in heart rate, blood pressure, and brachial artery dilation (1), as well as increased sympathetic outflow (2), and circulating levels of epinephrine, adrenocorticotropic hormone, and cortisol levels (3). Cardiovascular reactivity to mental stress correlates with an increased risk of cardiovascular events. Although genetic and environmental factors modulate the extent to which mental stress responsiveness in young people predicts subsequent development of high blood pressure (4), increases in blood pressure in response to mental stress are still hypothesized to contribute to the development of hypertension (5). Among individuals with coronary artery disease, subsequent cardiac events are related to blood pressure and heart rate responses to mental stress (6). Specifically, the magnitude of blood pressure increase in response to mental stress is prognostic for the severity of myocardial ischemia (7) and may be as potent a trigger of ischemia as physical activity (8). Even in asymptomatic middle-aged and older individuals, exaggerated increases in blood pressure during mental stress are associated with occult myocardial ischemia during exercise (9), and reactivity to mental stress as assessed by change in heart rate significantly predicts 3-year follow-up of blood pressure (10). Healthy individuals with no known coronary risk factors have been reported to show age-associated increases in mental stress pressor responses (2). This likely reflects age-related functional deficits in cardiovascular control. Although these studies find an association between augmented pressor response to mental stress and cardiovascular risk, a link between mental stress responses and cardiovascular function
was recently not found when a population of young men was examined (11). An inability to measure this association may have resulted from the age group in which it was examined or from the indirect method utilized for assessment of baroreflex sensitivity. Psychological stress reactivity is modulated by many factors, among which cardiovascular structure and function undoubtedly factor significantly. With cardiovascular decline, reactivity to mental stress may be markedly affected. Pressure is regulated on a beat-by-beat basis by stretch-sensitive baroreceptive endings in the carotid sinus and aortic arch (12). Carotid and aortic stiffness are therefore integral to pressure control (13), and increased stiffness likely blunts baroreflex sensitivity (14). If the baroreflex is a primary regulator of the hemodynamic reactivity to psychological stress, there may be an association among arterial stiffness, baroreflex sensitivity, and mental stress pressor responses that may be most apparent in and most relevant to older individuals. The aim of this study was to examine the relationships among stiffness, baroreflex sensitivity, and cardiovascular responses to acute mental stress within the age range at greatest risk for coronary artery disease by using the modified Oxford technique (15) for baroreflex sensitivity assessment. METHODS Participants Subjects were screened and informed of potential risks, and each subject provided written consent prior to participation. All subjects (N 24), aged 51 to 86 years (63.0 8.0; B279
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six Caucasian men, two African American men, nine Caucasian women, and seven African American women), were negative for the following: current coronary artery disease, hypertension (blood pressure 140/90), diabetes, or body mass index 30. In addition, each subject’s response to a Bruce graded exercise test to volitional fatigue was within normal limits, and carotid ultrasound examination demonstrated no evidence of disease. The protocol was approved by the Clinical Investigations Committee at the Hebrew Rehabilitation Center for Aged, Boston, MA.
the task was provided to the subjects as an auditory signal differentiating correct and incorrect answers, and their current score was given as a visual cue. Prior to the task, subjects were given a 4-minute preparation period to review on the computer screen the instructions that had been presented orally. At least 15 minutes of recovery was allowed between the speech and math tasks. Task order varied such that 13 of 24 subjects performed the speech task first. Cardiovascular Assessment
Protocol Subjects were requested not to engage in vigorous exercise or to consume either alcohol- or caffeine-containing beverages for 12 hours before the study. The subjects were studied under standardized conditions in a semisupine position, in a quiet room at a comfortable temperature. A standard three-lead electrocardiogram was used to collect data from which the R-R interval (interval between consecutive R waves) was calculated. Arterial pressure was measured on a beat-by-beat basis from a cuff on the middle phalanx of the middle finger on the left hand, using a photoplethysmograph (Finapres, Model 2300, Ohmeda, Louisville, CO) (16,17); drift was minimized by incorporating the recommendations of Ristuccia and colleagues (18). A semiautomatic oscillometric pressure recording system (Dinamap, Critikon, Tampa, FL) was used to provide a standard measure of brachial arterial pressure to compare with the photoplethysmographic pressures. The electrocardiogram and arterial pressure waveforms were digitized throughout each task at 500 Hz for later analysis with signal-processing software (CODAS, Dataq Instruments, Inc., Akron, OH); brachial oscillometric pressure readings were only obtained at specific time points throughout the study, including both immediately before and after each task. Mental Stress Speech task.—Subjects were asked to give a 4-minute speech detailing their viewpoint on assisted suicide. They were told that their speech would be recorded on videotape for later assessment of the quality of their presentation and that they were required to speak for the entire 4 minutes. Subjects were then given 4 minutes for speech preparation and a sheet listing 6 points to cover during their speech. During this preparation period, a video camera was set up to record their presentation. Math task.—Subjects were asked to perform a 4-minute computerized math task of simple addition equations presented on a computer screen. They were instructed to add two numbers and enter the correct answer on a number keypad. Task difficulty was standardized across individuals by automatically adjusting for accuracy in two ways: by altering the complexity of the addition problems by increasing or decreasing the number of digits involved in computation, and by modifying the time allotted for processing. These adjustments ensured that the number of correct answers remained below that which was represented to the subjects as average for most participants. Performance feedback during
Carotid stiffness.—Images of the carotid artery, approximately 1 cm below the carotid bulb, were obtained by using a high resolution linear array transducer (Hewlett-Packard Company, Andover, MA). The longitudinal B-mode 30-Hz images were triggered from the R wave of the electrocardiogram (PCI DT3152 Frame Grabber, Data Translation, Inc., Marlboro, MA). Vessel diameters were calculated by using a previously validated algorithm (19) in the commercially available CVI acquisition software (Information Integrity, Maynard, MA). The images were collected for 2.5 minutes at a rate of 15 images per trigger. Baroreflex assessment.—Baroreflex function was assessed pharmacologically by using the modified Oxford technique (15). Briefly, a venous antecubital catheter was inserted to administer a 5-ml bolus of physiologic saline containing 100 g of the vasodilator sodium nitroprusside, followed in 1 minute by a 3.75-ml bolus containing 150 g of the vasoconstrictor phenylephrine HCl. This drug sequence, with the nitroprusside (which lowers pressure) being followed by phenylephrine (which raises pressure), moves arterial pressure through the threshold, linear, and saturation regions of baroreflex sensitivity (Figure 1). Three trials of this infusion sequence were performed in each subject; each trial was separated by at least 15 minutes of recovery. Data Analysis Commercially available software (Windaq, Dataq Instruments, and Matlab, Mathworks, Inc., Natick, MA) was used for artifact detection, signal conditioning, and data analysis. Electrocardiogram R waves and arterial pressure peaks and valleys were identified to provide beat-by-beat R-R intervals, heart rate (HR), systolic blood pressure (SBP), and diastolic blood pressure (DBP). Mean arterial pressure (MAP) was calculated as MAP 1/3[(SBP – DBP) DBP]. Responses to the stress tasks were derived from the means of beat-by-beat data over 30-second epochs (Figure 2). During the stress tasks, MAP was utilized as the measure of pressure response and HR as an assessment of tachycardia. The changes in MAP and HR during each mental stress task were calculated as the difference between averages of all 30-second epochs during task and baseline. Pulsatile stiffness of the carotid artery was calculated by using the B-mode ultrasonographic images of the vessel acquired simultaneously with the beat-by-beat photoplethysmographic measures of blood pressure as {[log (SBP/ DBP)]/[(systolic carotid diameter – diastolic carotid diame-
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Figure 2. Mean arterial pressure (MAP) and heart rate (HR) during mental stress: 30-second averages for MAP and HR ( SEM) are presented at baseline, and during preparation for, execution of, and recovery from math and speech tasks.
Figure 1. Representative baroreflex data: data from one subject showing beat-by-beat arterial pressure, R-R intervals, and their relation. The bottom graph depicts data averaged over 3-mm Hg increments during the rise in blood pressure occurring after administration of phenylephrine HCl following sodium nitroprusside. The R-R interval is the time between consecutive R-waves. Data defining the linear portion (r2 .95) of the sigmoid relation between R-R interval and systolic blood pressure. Data points included in defining the sigmoid relation only.
ter)]/(carotid diameter during diastole)} (20). An average value for carotid stiffness was calculated for each subject from beat-by-beat values after values of more than 2 standard deviations from the mean were excluded. Arterial baroreflex assessment related beat-by-beat systolic pressures and R-R intervals from the period of increasing blood pressure and lengthening R-R interval during the modified Oxford assessment. An example of the data collected during a typical assessment of the baroreflex is presented in Figure 1. The figure’s bottom panel is aligned with the data used to calculate baroreflex sensitivity from the relation of R-R interval to SBP. Beat-by-beat values were averaged over 3-mm Hg pressure increments to account for variation caused by respiration. A sigmoid fit was applied to the averaged data to identify the linear portion of the baroreflex curve (Figure 1, bottom panel). Data below threshold and above saturation were excluded to calculate linear gain (average r2 .92). For each subject, the gains for all three trials were averaged to provide a single value for baroreflex sensitivity.
Normality of the data was examined by using the Kolmogrov–Smirnov goodness-of-fit test (SigmaStat, Jandel Scientific, San Rafael, CA). Two-sample t tests using summary statistics (21) with a Bonferroni correction were used to compare values at baseline and during the mental stress tasks. Bland–Altman analysis was used to determine whether the changes in hemodynamic parameters during the two mental stress tasks were comparable (22). Correlations among HR responses, MAP response during speech, carotid stiffness, baroreflex sensitivity, and age were performed with Pearson’s product moment for analysis of normally distributed data. Spearman rank order correlation was used for analyses of MAP during the math task because these data were not normally distributed. Analysis of variance was used to assess various multiple linear models for the associations observed (S-PLUS 2000, MathSoft Inc., Seattle, WA). Correlations among parameters as well as differences between MAP and HR during baseline and after the math and speech tasks were considered statistically significant at p .05. Data are presented as mean standard error of the mean (SEM). RESULTS Stress task responsiveness did not demonstrate significant gender-based differences, which is consistent with reports from several larger-scale studies (23,24). As anticipated (25), there were no differences on the basis of race for stress task responsiveness. Therefore, for the purposes of this study, data from all participants were combined for analysis. Both the speech and math tasks induced significant increases in blood pressure and HR as shown in Figure 2 (MAP and HR vs baseline, p .004). Although the responses to the speech and math tasks were qualitatively similar within individuals, as previously reported (26) the responses were generally greatest during speech. The average increase in MAP during speech (25.31 2.81) was greater than that during math (15.65 2.01; p .004), and
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the average increase in HR during the speech task (13.42 1.77) was significantly greater than that observed during the math task (9.32 1.26; p .004). The greater cardiovascular reactivity during the speech task may reflect, in part, the increased physical demands of speaking. The effects of speech and math on MAP and HR were not reliable estimates one for the other in this population, as the correspondence in response between the two tasks, as assessed by Bland–Altman, yielded intraclass correlations of .05 for MAP and .51 for HR. Carotid stiffness ranged from 7.5 to 30.2 and baroreflex sensitivity ranged from 1.2 to 11.1 ms/mm Hg. Although these two parameters demonstrated a strong inverse relation (r .55; p .006), neither parameter correlated with subject age. The baseline MAP and HR were related significantly to baroreflex sensitivity (Table 1). In addition, baseline MAP tended to be associated with carotid stiffness. These baseline values, however, were not associated with the respective increases observed during stress tasks (r .2; p .5). The changes in MAP and HR during the math task did not demonstrate any significant association with age, carotid stiffness, or baroreflex sensitivity (Table 1). However, the increase in HR with the speech task correlated with carotid stiffness, whereas the increase in MAP during the speech task correlated with both carotid stiffness and baroreflex sensitivity (Table 1). Applying a multivariate analysis of variance model to the data to account for the effect of carotid stiffness did not significantly improve the association between baroreflex sensitivity and the increase in MAP during speech shown in Figure 3. DISCUSSION Baroreflex sensitivity is, in part, defined by vascular stiffness. Stiffness of the vascular tree increases with age (13, 14,27) and decreases the engagement of the stretch-sensitive baroreceptors (28). The association we observed between carotid stiffness and baroreflex sensitivity was therefore not surprising and is consistent with previous reports
Table 1. Correlations With Age, Carotid Stiffness, and Baroreflex Sensitivity for HR and MAP to Math and Speech Tasks Task Math Baseline HR MAP Response ( ) HR MAP Speech Baseline HR MAP Response ( ) HR MAP
Age
.30 .002
Carotid Stiff.
Baroreflex Sens.
.32 .45*
.47* .70*
.16 .05
.08 .18
.23 .19
.28 .36**
.43* .56*
.30 .20
.40* .41*
.04 .46*
.16 .43*
Notes: HR heart rate; MAP mean arterial pressure; response ( ) average value during task average value during baseline. Correlation coefficients for all cells in the table are shown. *p .05; **p .10.
Figure 3. Relation of the change in mean arterial pressure (MAP) during the speech task to baroreflex sensitivity: The linear correlation between average change in MAP during the speech task from baseline and baroreflex sensitivity was statistically significant.
(13,20,29). Although age, within the restricted range examined, was not observed to relate to stiffness or baroreflex sensitivity, these data demonstrate that even in healthy middle-aged individuals, a relation between increased carotid stiffness and decreased baroreflex sensitivity is observed. Interestingly, an animal model of aging that manifests neither hypertension nor atherosclerosis also fails to demonstrate age-related impairment in baroreflex function (30). If true for humans, it suggests that vascular stiffening, rather than age per se, is responsible for the declines in baroreflex sensitivity. Studies with inbred populations of rodents clearly show increased variability in the pathologies present with advancing age (31,32). Individual differences among people with age will be even greater as a result of genetic and environmental heterogeneity. Thus, it may be reasonable to suppose that baroreflex sensitivity is a more meaningful biomarker (33) of human cardiovascular aging than mere chronological age. Our data demonstrate that greater arterial pressure responses to mental stress modestly relate to greater carotid stiffness and lower arterial baroreflex sensitivity in middleaged and older individuals. Considering the strong association between carotid stiffness and baroreflex sensitivity, an augmented pressor response may be one manifestation of reduced baroreflex function caused by vascular stiffness. Both augmented pressor responses and low baroreflex sensitivity more than double the relative risk of subsequent cardiac events in patients (34,35). The present findings may represent a mechanism underlying the association of cardiovascular hyperreactivity to stress with morbid cardiovascular events. This is of especial significance in the age group studied, as the risk of mortality caused by cardiovascular disease increases logarithmically after age 50 (36). The inverse correlation between the rise in pressure during speech and baroreflex sensitivity suggests a commonality in the neural regulation of responses. Both tachycardiac responses to mental stress (37) and bradycardiac responses
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to increasing pressure (38) are at least partially under vagal control. Therefore, a vagal deficit might result in alterations to both. Surprisingly, we did not find any relation between tachycardiac responses to stress and baroreflex sensitivity. However, the baroreflex is reset to higher heart rates in response to acute or chronic increases in arterial pressure (39), and the magnitude of resetting may not be proportional to basal sensitivity. The relation between basal sensitivity and blood pressure responses might be explained by the decrease in sensitivity attendant to mental stress (40). A reduction in an already low sensitivity would further diminish buffering capacity, and it would result in greater arterial pressure rises during stress. A previous study by Fauvel and colleagues reported no association between a pressor response induced by mental stress and baroreflex sensitivity in a population of males 18–55 years of age (11). The lack of association between stress-induced pressor response and baroreflex sensitivity within this younger cohort does not conflict with our observations in middle-aged and older subjects, because the association between baroreflex sensitivity and blood pressure modulation may become more appreciable with increasing age (41). Moreover, their examination of baroreflex sensitivity was within a relatively constrained pressure range as compared with the modified Oxford method, a technique that calculates sensitivity over a broad range of pressures and therefore is a better measure of baroreflex function. The assessment by Fauvel and colleagues was limited to crossspectral analysis of blood pressure and assessment of HR by the sequence method. The sequence measure, unlike the modified Oxford, relies on extrapolated values obtained from data generated for short time intervals; a comparable analysis of data from our subjects at rest failed to correlate with the pharmacologically generated baroreflex sensitivity (r .17; p .56). Our failure to find comparable results by using an indirect assessment and a direct engagement of the baroreflex reflex is consistent with previously reported inconsistency between these methodologies (42). Thus the question of whether associations between baroreflex sensitivity and hemodynamic response to mental stress exist in younger individuals should be revisited. The observed associations between pressor response to a speech task and both carotid stiffness and baroreflex sensitivity suggest that acute hemodynamic reactions to mental stress among healthy middle-aged and older individuals are determined, in part, by the structural properties of arterial vessels and the sensitivity of the arterial baroreflex. This association may have a causal role in the augmented pressure response to mental stress observed in individuals with carotid atherosclerosis. Moreover, this may provide a mechanistic link for the association between cardiovascular reactivity to stress and coronary artery disease. It may be of interest to determine the effect of disease on the relations among pressor responses, carotid stiffness, and baroreflex sensitivity. Acknowledgments This research was supported by Grant HL59332 from the National Heart, Lung and Blood Institute (to J. A. Taylor).
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The authors thank Allison MacDonald and Ingrid Frey for their tireless efforts in recruiting and working with the subjects in this project; Dr. Daniel Forman for help with subject screening; Drs. Brian Hunt and William Farquhar for their technical assistance; and our subjects for their participation. Address correspondence to J. Andrew Taylor, PhD, Laboratory for Cardiovascular Research, Research and Training Institute, Hebrew Rehabilitation Center for Aged, 1200 Centre Street, Boston, MA 02131. E-mail:
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Received December 10, 2001 Accepted April 1, 2002 Decision Editor: John A. Faulkner, PhD
