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Endothelial Function and Hemodynamic Responses During Mental Stress

From the Duke University Medical Center, Durham, North Carolina, and University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Address reprint requests to: Andrew Sherwood, PhD, Box 3119, Duke University Medical Center, Durham, NC 27710. Email: sherw002{at}mc.duke.edu

	ABSTRACT

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OBJECTIVE: The hemodynamic basis of blood pressure responses during psychological stress shows striking individual differences that share an interesting similarity with risk for cardiovascular disease. Factors accounting for these individual differences are poorly understood. The present study examined the relationship of vascular endothelial function to stress-induced hemodynamic responses.

METHODS: Subjects were 40 healthy men and women, aged 25 to 44 years. Hemodynamic responses were assessed during exposure to a battery of four diverse laboratory stressors. Endothelium-dependent arterial dilation (EDAD) was measured by ultrasound imaging of the brachial artery in response to reactive hyperemia.

RESULTS: High EDAD response was associated with lower resting systolic (p < .01) and diastolic blood pressure (p < .05). EDAD response was unrelated to blood pressure responses during stress. However, systemic vascular resistance responses during laboratory stress were significantly greater (p < .02) for individuals with low EDAD responses.

CONCLUSIONS: Exaggerated systemic vascular resistance responses during stress may reflect endothelial dysfunction. This association may help explain the growing evidence of a relationship between stress hemodynamics and cardiovascular disease risk. The nature of this association is discussed in terms of a possible interplay between the sympathetic nervous system and the endothelium in regulation of vascular tone.

Key Words: endothelium • hemodynamics • stress • sympathetic nervous system • ultrasound

Abbreviations: CHD = coronary heart disease; SVR = systemic vascularresistance; HR = heart rate; SNS = sympathetic nervoussystem; EDAD = endothelium-dependent arterial dilation; SBP =systolic blood pressure; DBP = diastolic blood pressure; MAP= mean arterial pressure; CI = cardiac index; SVRI = systemicvascular resistance index

	INTRODUCTION

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Exaggerated blood pressure responses to stress have been associated with increased risk for the development of CHD and hypertension (1–4). More recently, the examination of hemodynamic factors has provided new insights into the potential mechanisms by which elevated blood pressure responses may contribute to this increased risk. For example, cardiovascular activation during stress has been described in terms of cardiac output and SVR alterations that give rise to pressor responses. The clinical significance of specific hemodynamic response patterns is suggested by growing evidence that individuals at increased risk for CHD exhibit characteristic hemodynamic responses. For example, African American men, who are at high risk for the development of CHD and hypertension, tend to exhibit greater contributions of SVR to blood pressure increases during exposure to laboratory stressors (5–7), whereas premenopausal women, who are at lower risk than men for CHD, exhibit a lower SVR contribution to blood pressure responses during stress (7). Recently, it was also shown that mental stress–induced myocardial ischemia is associated with a significant increase in SVR and relatively minor increases in HR and rate pressure product compared with ischemia induced by exercise (8).

Systemic vascular tone is regulated by a number of systems. Neuroendocrine regulation, particularly the SNS, seems to play a prominent role in regulating vascular tone during mental stress. Both SNS activation and the sensitivity of adrenergic receptors in the vasculature may contribute to changes in vasomotor tone and SVR during stress (5, 9, 10). Another fast-responding vascular regulatory system is the endothelial system. Among the substances released by the endothelium is nitric oxide, an endothelium-derived relaxing factor that is a fast-acting vasodilator of short duration, which is important in the regulation of arterial vasomotor tone and therefore SVR. Celermajer et al. (11) recently developed a noninvasive ultrasound methodology to examine endothelial function. This novel technique assesses the magnitude of EDAD elicited by reactive hyperemia. The magnitude of the EDAD response is used as a direct index of the functional status of the endothelium. Using this technique, it has been shown that compromised endothelial function is associated with advancing age and is also characteristic of patients with CHD, cigarette smokers, and children with a family history of hyperlipidemia (11).

To date, only one study has explored the association between EDAD and cardiovascular stress responses (12). The study measured the EDAD response in adolescents and found it to be directly related to cardiovascular fitness and inversely related to SBP reactivity to stress. However, the stressors used in that study were not of a psychological nature (eg, exercise, postural change, and cold pressor), and underlying hemodynamic measurements were not reported. Therefore, the purpose of our study was to examine, in a healthy sample of adult men and women, the relationship of endothelial function, assessed by EDAD, to hemodynamic responses during exposure to a diverse battery of laboratory stressors. It was hypothesized that individuals exhibiting relatively low EDAD responses would exhibit greater SVR during stress than individuals exhibiting relatively high EDAD responses.

	METHODS

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Subjects
Forty healthy men and women, aged 25 to 45 years, were recruited from the surrounding community. Subjects were recruited through fliers and advertisements placed in local newspapers. Exclusion criteria included known CHD, diabetes, cigarette smoking, resting blood pressure greater than 160/100 mm Hg and, for women, oral contraceptive use. Women were tested at random with regard to menstrual cycle phase. All eligible volunteers read and signed an informed consent form approved by the Duke Medical Center Institutional Review Board.

EDAD Assessment
The technique used to assess endothelial function followed procedures described by Celermajer et al. (11). Subjects were tested in a supine position. Under resting conditions (after 10 minutes of relaxation), ultrasound images of the brachial artery were obtained using an Acuson (Mountain View, CA) vascular imaging system (10-MHz linear array transducer and 128XP/10 system). Brachial artery flow velocity was also measured using the Acuson pulsed Doppler flow facility to assess flow at a 70° angle to the vessel, with the range gate adjusted to the center of the artery. Reactive hyperemia (increased brachial flow) was then induced by inflation to supra-SBP (approximately 200 mm Hg) of a pneumatic occlusion cuff, which was placed around the forearm. Lower arm occlusion was sustained for 5 minutes. A second ultrasound scan, obtained in exactly the same location as the baseline scan, was performed 30 seconds before through 90 seconds after cuff deflation, with repeated flow velocity measurement taken 15 seconds after deflation. All images were recorded on S-VHS video tape, and measurements were made by an ultrasound specialist (A.L.H.) blinded to test condition and patient identity. Brachial artery diameter measurements were made using electronic calipers at end diastole, incident with the electrocardiographic R wave. Measurements were made over four cardiac cycles and averaged. Changes in arterial diameter with reactive hyperemia were expressed as the percentage of change from resting baseline, providing an index of EDAD.

Laboratory Mental Stress Testing
Hemodynamic Measurements.
Blood pressure was measured noninvasively using a Suntech 4240 monitor (Suntech Medical Instruments, Raleigh, NC). During mental stress testing, blood pressure readings were taken once each minute. The Suntech 4240 uses the auscultatory method, facilitated by electrocardiographic R-wave gating, to determine SBP and DBP. SBP was recorded as the cuff pressure associated with the onset (phase 1) of Korotkoff sounds and DBP as that associated with their disappearance (phase V). MAP was computed as DBP plus one-third of pulse pressure.

Impedance cardiography was used to measure cardiac performance noninvasively (13). A Hutcheson impedance cardiograph (model HIC-1, UNC, Chapel Hill, NC) was used in conjunction with a tetrapolar band-electrode system. The inner two recording electrode bands were positioned around the base of the neck and around the thorax, over the xiphoid process. The outer two current electrode bands were positioned to encompass the neck and thorax, at least 3 cm from each of the recording electrodes. The electrocardiogram was recorded independently using disposable electrodes. Baseline thoracic impedance (Z₀), the first derivative of the pulsatile impedance (dZ/dt), and the electrocardiographic waveforms were processed using specialized ensemble-averaging software (COP, BIT Inc., Chapel Hill, NC), which was used to derive stroke volume using the Kubicek equation (14), HR, and cardiac output. Cardiac output was divided by body surface area to give the CI. SVRI was derived on the basis of the concurrently recorded blood pressure and cardiac output, using the following equation: SVRI (dyne-seconds/cm5/m2) = (MAP/CI) x 80.

Stress Test Protocol
Resting Baseline.
All test procedures were conducted in an electrically shielded, sound-attenuated, temperature-controlled (24°C) chamber. After instrumentation, subjects were seated in a comfortable chair and asked to relax for 20 minutes. Resting baseline hemodynamic measures were based on the average of three sets of readings taken during the last 3 minutes of this relaxation period.

Reaction Time/Shock Avoidance.
This simple reaction-time task has previously been described in detail (15). Briefly, the task lasted 3 minutes, with a loud audible tone presented at various unpredictable intervals (average = 23 seconds). Subjects were told to press a key as fast as possible on hearing each tone. Subjects were instructed that if, on any given trial, a reaction time was considered too slow, a "painful but harmless" electric shock would be delivered immediately by electrodes applied to the leg. In fact, shocks were never delivered.

Mirror Trace.
In this 3-minute task, subjects were required to trace the shape of a star using a metal stylus, but by viewing only their reflection in a mirror (Lafayette Instruments, Lafayette, IN). Instructions emphasized tracing the shape as many times as possible, but without making errors associated with deviating beyond the narrow boundaries of the star shape; errors elicited an aversive sound and were recorded with a digital counter.

Anger Interview.
Subjects were asked to focus on a recent incident from their lives that made them angry and that also involved interpersonal interaction associated with the incident. They were given 5 minutes of time alone to reflect on the incident with the knowledge that they would have to describe the incident to the experimenter for 5 minutes. Adapting a strategy proposed by Ewart and Kolodner (16), we instructed subjects to first describe the scenario, then their emotions and interpersonal interactions, and then to summarize the outcome and their level of satisfaction with their behavior in the situation.

Cold Pressor.
Subjects were required to immerse their left foot in a cooler containing a 4-inch-deep mixture of ice and water (0–4°C) for 90 seconds.

Task Order.
A 10-minute relaxation period separated tasks. The possibility of order effects associated with tasks was addressed by randomly assigning subjects to one of four possible task orders, as indicated by a William’s square design.

Data Reduction and Analyses
Subjects were categorized as exhibiting high or low EDAD responses on the basis of a median split. The median EDAD response was a 5.1% flow-mediated dilation of the brachial artery. Thus, two groups, each consisting of 20 subjects, were created to form an independent class variable, defined as high or low EDAD response. The dependent variables of interest were hemodynamic responses during the laboratory stressors. Response measures were SBP, DBP, CI, SVRI, and HR. Task responses for reaction time, mirror trace, and anger interview were defined as the mean of the three values recorded during the first 3 minutes of each task minus the resting baseline value. For the cold pressor task, the mean of two values recorded during the 90-second task were averaged and the baseline value subtracted.

The primary analytic strategy used was repeated-measures analysis of covariance, with EDAD group (high or low) as a between-subjects factor and the four tasks (reaction-time, mirror trace, anger interview, and cold pressor) forming a within-subjects repeated-measures dimension. Analyses of covariance were performed using the SAS general linear model procedure for each hemodynamic response measurement (SBP, DBP, CI, SVRI, and HR) using gender, resting baseline, and task order as covariates.

	RESULTS

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Characteristics of High vs.
Low EDAD Response Groups

Descriptive characteristics for the high and low EDAD groups are summarized in Table 1 . The two groups did not differ in terms of ethnicity, age, or body mass index. However, the high EDAD group was composed of a greater number of women than men, whereas the low EDAD group was composed of more men (2 = 8.12, p < .01). Subjects in the high EDAD group had significantly lower resting baseline blood pressures (SBP, F(1,38) = 8.08, p < 0.01; DBP, F(1,38) = 5.23, p < .05) but did not differ in other hemodynamic characteristics. As expected, flow-mediated EDAD response was much greater in the high than the low EDAD group (F(1,38) = 46.47, p < .0001). Importantly, the EDAD groups did not differ in the magnitude of increased blood flow elicited by reactive hyperemia (high = 712%; low = 688%), indicating that EDAD was not secondary to differential alteration of endothelial shear stress.

Hemodynamic Responses to Laboratory Stressors
SVRI responses were significantly greater (F(1,34) = 6.41, p < .02) for low EDAD than for high EDAD subjects. Table 2 summarizes mean hemodynamic responses aggregated across the four laboratory stressors. As illustrated in Figure 1 , EDAD group differences in SVRI responses were consistent across all four stressors. Subjects with larger EDAD responses, compared with subjects with lesser responses, exhibited either greater vasodilation (anger interview and reaction time tasks) or lesser vasoconstriction (cold pressor and mirror trace tasks), in accordance with the hemodynamic variations associated with tasks. There were no other EDAD group main or task interaction effects.

View larger version (23K): [in this window] [in a new window]   Fig. 1. Mean (±SE) SVRI responses to four laboratory stressors, anger interview (AI), reaction time (RT), cold pressor (CP), and mirror trace (MT), in subjects characterized by high (N = 20; cross-hatched bars) and low (N = 20; black bars) EDAD responses to reactive hyperemia.

	DISCUSSION

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Our findings suggest that when the cardiovascular system is activated during mental stress, the endothelial system plays a role in regulation of vascular tone. Endothelial function was unrelated to the magnitude of blood pressure responses during stress but was related to the underlying hemodynamic pattern giving rise to the pressor response. As hypothesized, individuals with relatively weak EDAD responses exhibited a greater contribution of SVR to their blood pressure responses. This observation is interpreted as reflecting a greater impact of endothelium-derived relaxing factor–mediated dilation of the systemic vasculature during stress in individuals characterized by a high EDAD response.

Psychological stress is associated with SNS activation, which elicits hemodynamic adjustments that are mediated by adrenergic receptors in the heart and vasculature (10). Activation of ß-adrenergic receptors results in chronotropic and inotropic effects on the heart, tending to increase cardiac output. Systemic vascular ß-adrenergic receptors mediate vasodilation and promote a reduction in SVR, whereas vascular -adrenergic receptor activation leads to vasoconstriction and increased SVR. The current findings suggest that the endothelial system may also contribute to the acute hemodynamic responses elicited during stress. A recent study indicates that vasodilation by vascular ß-adrenergic receptor activation, is dependent, at least in part, on endothelial vasodilator function. In 28 healthy young adult volunteers, forearm vasodilator responses to brachial artery infusion of the ß-adrenergic agonists isoproterenol and salbutamol were measured both with intact endothelial response capability and in the presence of N^G-monomethyl-L-arginine, a nitric oxide synthesis inhibitor (17). Vasodilation was inhibited by 50 to 60% in the presence of N^G-monomethyl-L-arginine, indicating that the ß-adrenergic vasodilator response is dependent on nitric oxide synthesis. The notion that endothelial vasodilator function may mediate the ß-adrenergic vasodilation response to SNS activation is consistent with our observation that endothelial function is related to SVR responses observed during psychological stress.

The current findings may be relevant to understanding the Psychophysiological Investigation of Myocardial Ischemia study findings that, in patients with CAD, myocardial ischemia during mental stress was best predicted by increased SVR (8). Anderson et al. (18) emphasized how the endothelial system is responsible for vasomotor control throughout the systemic vasculature. The systemic circulation includes the coronary circulation, and assessment of the EDAD response of the brachial artery has been found to be closely related to endothelial function in the coronary vessels (19). SVR increases during mental stress may therefore not only increase afterload on the heart, raising myocardial oxygen demand, but also be a marker of compromised myocardial blood supply associated with coronary endothelial dysfunction. The vasomotor response of coronary arteries to stress-induced SNS activation seems to depend on whether vessels are healthy or diseased. Although healthy coronary vessels dilate, facilitating myocardial perfusion, atherosclerotic vessels have been observed to constrict, leading to inadequate myocardial oxygen supply. In a study of patients with CAD, it was found that SNS activation of coronary vessel -adrenergic receptors can produce coronary vasoconstriction (20). However, in the presence of phentolamine, an -adrenergic receptor blocker, a vasodilatory response occurred. These observations further support the notion that vasomotor responses of the circulation during mental stress are a manifestation of both the SNS and the endothelial system.

One limitation of the present study is that we did not include an assessment of brachial artery responses to a nonendothelium-dependent vasodilatory stimulus. It is common, although not universal, for studies using the EDAD measure to include assessment of arterial dilation response to glyceryl trinitrate, which acts directly to relax arterial smooth muscle. The rationale for also studying the glyceryl trinitrate response is to demonstrate that it is independent of factors associated with the EDAD response, thereby supporting inferences regarding the role of the endothelium. For example, aging is thought to be associated with progressive endothelial dysfunction because it is related to reduced EDAD response but unrelated to the glyceryl trinitrate response (21). No studies to date have reported individual differences in EDAD responses that also express themselves as glyceryl trinitrate responses. The validity, as an index of endothelial function, of the EDAD response is further supported by a study that used N^G-monomethyl-L-arginine, a nitric oxide synthase inhibitor, and demonstrated nitric oxide to be essential for flow-mediated dilation of a large human conduit artery (22).

In summary, we made preliminary observations in healthy adults that show an association between a noninvasive index of endothelial function (EDAD) and SVR response during stress. In discussing these findings, we entertain the possibility that SVR responses may be a marker of endothelial dysfunction. Supporting this perspective is recent evidence that the endothelium is one pathway for SNS regulation of vascular tone. There is also compelling evidence that excessive cardiovascular reactivity associated with stress can promote damage to the endothelium and favor the development of atherosclerosis (23, 24). The health and functionality of the endothelium may therefore be both a cause and a consequence of cardiovascular responses elicited by stress. Additional study of the endothelial system is likely to be a fruitful avenue of investigation in behavioral cardiology. Its association with cardiovascular disease risk (11, 21, 25) suggests a pathway that should help refine our current concepts relating stress and cardiovascular disease.

	ACKNOWLEDGMENTS

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This study was supported by the National Institutes of Health (Grants HL49427 and HL53724) and the National Center for Research Resources, General Clinical Research Centers Program, National Institutes of Health (Grant M01-RR-30).

Received for publication October 23, 1998.

Revision received January 20, 1999.

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