Effects of mental stress on brachial artery flow-mediated vasodilation in healthy normal individuals

Effects of mental stress on brachial artery flow-mediated vasodilation in healthy normal individuals Charles W. Harris, MD,a Jennifer L. Edwards, MD,a Amy Baruch, MD,= Ward A. Riley, PhD,b Benjamin BA,a Walter J. Rejeski, PhD,= and David M. Herrington, MD, MHS, FACG Winston-S&m, NC

Background increases

in endogenous

assessment

and age

rate

mental

23.5

tal hyperemia

and

increased

in a 64% mental

years).

was

a transient

similar

2-to

men

Mental

stress

normal

Similar

studies

of mental

stress

in the development

ultrasound

and

resulted increase blood

in flow-mediated

Conclusions individuals.

3-fold

and

women.

can

have

artery effect

pressure

marked

of cardiovascular

to measure cuff

occlusion

blood

fl ow

on cuff

Mental stress is associated with an increased risk for cardiovascular events, including myocardial ischemia and sudden deathI-3 possibly caused by catecholamineinduced increases in heart rate (HR) and blood pressure (BP) that result in enhanced myocardial oxygen demand.” However, the effect of mental stress on vasomotor tone and the implications for cardiovascular risk are less well understood. Zeiher et al5 showed that an intact endothelium is necessary for a normal vasodilator response to sympathetic stimulation in human coronary arteries. More recently, Yeung et al6 demonstrated significant coronary vasoconstriction with mental stress in patients with coronary atherosclerosis and presumed endothelial dysfunction. Thus mental stress also could intluence the risk for cardiovascular events through an

From the Deportments 01 %ternol Medicme/Cordlology ond bNeurology, Woke Forest Unwersity School of Medicme; and cthe Department 01 Health and Exercise Science, Woke Forest Un,versity Supported I” port by the General Research Center of Woke Forest University 8op hst Medico1 Center, Winston-Sole,,,, NC (grant MO I-RR07 122, Notion01 lnst~tuter 01 Heofth) Submitted March 3, 1999; accepted July 28, I999 Reprint requests. Dowd M. Herrrngton, MD, MHS, Deportment 01 Internal Medicme/Cordlology, Wake Forest University School of Medrone, Medical Center Blvd. Winston-Salem, NC 27 I57.1045. E-mail: [email protected] Copyright 0 2000 by Mosby, Inc. 0002.8703/2000/$12.00 +0 4/1/101784

by 17.9%.

on endotheliumdependent,

events.

(Am

HeartJ

used

for

noninvasive

in sympathetic

flow-mediated

2000;139:405-1

blood

During

The

further

vasodilation men,

1 1 women;

flow,

causing

mental

sympathetic vasodilator

flow-mediated may

(10

forearm

release.

(P < .OO 1). Th e enhanced

function

of acute

changes

individuals

of distal

on average

endothelial

been

artery

1 healthy

response

impaired

because

unknown. brachial

in 2

has

its associated

increased

effects with

and remains

challenge) artery

possibly

vasodilation

stress

in vivo

used

a 3-minute

vasodilator

in individuals

tone was

in brachial

events,

flow-mediated

arithmetic from

cardiovascular

of mental

vasomotor

by a standard

stimulus

by 29.6% for

The

Two-d’ rmensional fl ow

risk for

brachial

function.

(provoked

The

increase

increased

endothelium-dependent

stress

on average

average stress

artery

with

Recently,

endothelial

and Results after

is associated

catecholamines.

on brachial

Methods average

stress

of macrovascular

activation

before

Mental

E. Pusser,

our

stress,

disheart

stimulus

resulted

response

during

vasodilation understanding

in healthy, of the

role

1.)

adverse effect on coronary vasomotor tone and myocardial oxygen supply in individuals with impaired endothelial function. To further characterize the normal relation between mental stress and endotheliumdependent vasomotor tone, we used 2-D ultrasound to measure brachial artery flow-mediated vasodilation in 21 healthy individuals without risk factors for coronary artery disease before and during mental stress provoked by a standard arithmetic challenge.

Methods Study

participants

We studied 21 healthy medical student volunteers (10 men, 11 women) (average age 23.5 years). None of the participants had any signs, symptoms, or risk factors for coronary artery disease, including smoking and hypertension. The study protocol was approved by the institutional clinical research practice committee, and written informed consent was obtained from each participant.

Ultrasound

protocol

Participants were studied under identical conditions by a single sonographer between 8 and 11 AM after an overnight fast, with the use of methods that have been described previ0us1y.~ Each participant rested in the supine position for several minutes in a temperature-controlled room before testing. An automated sphygmomanometer was placed on the left arm for simultaneous BP and HR measurements at 5minute intervals throughout the test, and resting baseline BP and HR were

American

406

Harris

et 01

Figure

Hear1 Journal March 2000

1

Di-

(mm)

5.143

Grid line

Time to Max

Time (Seconds) Representative

plot

of brachial

recorded. A pediatric cuff was placed on the right arm 2 inches below the right antecubital fossa to transiently prevent forearm blood flow. The brachial artery was identified approximately 7 cm proximal to the bra&al bifurcation with the use of a lO-MHz Biosound Phase 2 ultrasound system (Biosound Esgote, Indianapolis, Ind). Baseline images of the artery in the mid-sagittal plane were obtained for 2 minutes. After baseline imaging, the right arm cuff was inflated to >50 mm Hg above systolic BP (SBP) for 3 minutes. After 3 minutes, the cuff was deflated, and the ischemia-induced distal hyperemia produced a transient increase in bra&al artery blood flow. The brachial artery was continuously imaged during cuff occlusion and for 3 minutes after deflation. Images were captured on S-VHS tape. The same protocol was repeated during mental stress testing as described below.

Mental

stress testing

Ten minutes after completion of the first brachial artery study, the entire procedure was repeated. During the second test, a mental stressor was initiated 30 seconds before baseline diameter measurements were made and was continued throughout the vasodilation phase for a total of approximately 7 to 8 minutes. The mental stressor used was a standard mental arithmetic challenge. Each participant was given a 3-digit number and asked to take the sum of the 3 digits and then add this sum to the 3digit number. For example, if the number /I 111” is given, the sum of the 3 digits is 3; this sum added to 111 is 114. The sum of the digits 114 is 6. The sum of 6 and 114 is 120, and so on. The participants were instructed to add as quickly and as accurately as possible. Every 15 seconds, the participants were intentionally frustrated by being prompted to increase speed and accuracy and by being frequently corrected. The total number of calculations attempted and the number of correct calculations were recorded. To enhance the psyche logic stress of the standard arithmetic challenge, an attempt was

artery

diameter

(mm)

calculated

vs time.

made fo “personalize“ the stress by prefacing the instructions with the following contrived information: “Recent literature has linked level of intelligence with disease. Several studies have suggested that the ability to assimilate and manipulate data correlate with the reactivity of several physiologic qstems. This study has been designed to use mathematic ability as an indicator of intelligence. Both the percentage of correct answers as well as the number of problems completed in 3 minutes are important in estimating your level of intelligence.” At the end of the brachial artery examination, the participants were asked to rate the experience as “very stressful,” “stressful,” or “mildly stressful” and “very challenging,” “challenging,” or “mildly challenging.”

Image

analysis

Ultrasound image analysis was performed in the Wakr Forest University Cardiology Image Processing Laboratory. The baseLine images were automatically digitized every 333 ms for 10 seconds (30 frames) and stored on an image analysis computer (Sun Microsystems, Palo Alto, Calif). An automated boundary detection algorithm developed at our institution was used fo identify the boundaries of interest for all 30 baseline frames.s The average medial-adventitial diameter in each frame was automatically determined, and the baseline diameter was identified as the mean of the diameter from the 30 baseline frames. A similar procedure was used to automatically determine the arterial diameter during the 3 minutes after cuff release. For images after the cuff release, video frames were digitized every 333 ms for 3 minutes. beginning with the first useable frame after cuff release. The same automated boundary detection methods were used to measure the diameter in the 360 frames after cuff release. A sliding weighted average was used to determine the estimate of diameter at any time after cuff release, and the resulting diameter estimates were plotted

Amer~con tieorl ~ournai

Volume 139, Number

Table

3

Harris

I. Hemodynamic

responses

with

and

without

mental

stress

Mental

stress

Without Heart rate (beats/min) Baseline Maximum % Change SBP (mm Hg) Baseline Maximum % Change DBP (mm Hg) Baseline Maximum % Change RPP (x 100) Baseline Maximum % Change

et al 407

With

70.0 91.0 29.6

(10.3) (16.9) (10.9)

107.0 127.0 17.9

(9.6) (14.5) (6.1)

109.0 (12.0) 110.0(11.9) 1 .O (5.6)

NS coo 1 q.001

62.1 75.7 17.7

(6.0) (6.9) (7.1)

62.0 (7.3) 62.5 (6.6) 1.3 (9.3)

NS c.00 1 coo 1

77.7 1 15.9 53.7

72.0 70.0 -2.9

(16.5) (26.5) (32.3)

(10.9) (10.7) (12.01)

P value

78.8 75.04 -1.3

(15.8) (13.6) (11.0)

NS coo 1 c.00 1

NS <.oo 1 coo 1

NS, Not significant.

Table

II. Brachial

artery

vasodiiator

response

with

and

without

mental

Mental

stress

stress

Without Baseline diameter (mm) Maximum diameter (mm) Change in diameter % Dilation

(mm)

4.16 4.37 0.21 5.05

(0.63) (0.64) (0.11) (2.20)

versus time for review (Figure 1). The primary measure of analysis was relative change in mean arterial diameter calculated as % Dilation = ([Maximum diameter - Baseline diameter]/Baseline diameter) x 100, where maximum diameter was the maximum mean diameter observed during the 3 minutes after cuff release. This method has been demonstrated previously to be highly reproducible, with a coefficient of variation for maximum/baseline of 2.10%. comparable to previously published reproducibility data.9,‘” HR, BP, brachial artery diameters, vasodilator responses, and mental stress test scores were entered into a personal computer and compared with the use of a paired, 2-sided t test.

Results Hemodynamic responses with and without mental stress Table I shows the hemodynarnic responses during the first bra&al artery study with no mental stress and during the second study, when participants were performing the arithmetic challenge. There were no significant changes in HR, BP, or rate pressure product (RPP) during the initial study, confllg the absence of any significant sympathetic activation as a result of the

With 4.03 4.38 0.35 8.68

(0.57) (0.67) (0.26) (3.00)

P value .05

.BB -coo0 <.ooo

1 1

ultrasound procedure itself. In contrast, during the mental arithmetic, HR, SBP, diastolic BP (DBP), and RPP increased 29.6%, 17.9%, 17.7%, and 53.7%, respectively (P < .OOl for each). A majority of participants rated the mental stress test as “stressful” or “very challenging.” OveraIl, 6 (29%) of 21 considered it “very stressful,” 12 (57%) of 21 participants considered the test “stressful,” and 3 (14%) of 21 considered it “mildIy stressful.” Ten (48%) of 21 participants reported that the test was “very challenging,” 8 (38%) of 2 1 considered it “chaIIenging,” and only 2 (10%) of 21 participants considered the test “miIdly challenging.” The study participants attempted an average of 55 +Z20 arithmetic calculations and got an average of 69% f 19% correct. There was no significant correlation (+ = -0.02) between the percentage of correct calculations and the hemodynamic responses. Brachial flow-mediated vasodilator responses Table II shows brachial artery vasodilator responses with and those without mental stress. During the initial ultrasound protocol (without mental stress), the base-

American

408

Harris

et al

Heart Journal March Zoo0

Figure 2

WITHOUT

Comparison

of vasodilator

diameter

without

compared

with

stress 8.68%

responses and

DURING STRESS

STRESS

during

f 3.00%,

for mental

a 71.9%

each

study

stress. increase

participant

Mean

(n = 2 1) measured

vasodilator

response

without

as percent stress

was

change

in vessel

5.05%

+ 2.20%

(P < .OOl).

line brachial artery diameter was 4.16 f 0.63 mm, and the mean brachial artery diameter increased by 0.21 f 0.11 mm, which corresponded to a flow-mediated vasodilator response of 5.05% f 2.20% (P c .OOl). However, during mental stress, the baseline brachial artery diameter was 4.03 f 0.57 mm, and the mean brachial artery diameter increased by 0.35 f 0.26 mm (8.68% f 3.00%) (P < .OOl>.Although the mean baseline brachial artery diameter during mental stress was smaller (P c .05), the absolute change in brachial artery diameter during mental stress represented a 71.9% increase in the vasodilator response compared with the response without mental stress (P c .OOl>(Figure 2). There was a negative correlation (r = -0.44) between the initial vessel diameter and the vasodilator response, but there was no significant correlation between the vasodilator response and SBP(r= O.lS), HR (I= 0.06), or RPP(r= 0.10). Men versus women There was no significant difference between men and women in their hemodynamic response to mental stress. HR in the men increased 20.40% i 9.53% versus 23.49% f 12.22% for women (P = .52). SBPin men increased 16.58% f 5.86% compared with 13.06% f 6.18% for women (P = .20). The baseline brachial artery diameter was kger in men (4.46 * 0.20 mm) than in women (3.63

0.51 mm) (P = .0002). However, there was no significant difference in the vasodilator response between men (7.5% f 2.42%) and women (7.8% f 3.50%) (P = .80). f

Discussion Our study showed that we could invoke acute mental stress with the use of a standard arithmetic challenge and thus cause sympathetic activation, evidenced by significant increases in HR, BP, and RPP.We also showed that mental stress signScantly enhanced the difference between baseline and maximum bra&al diameter after a flow stimulus in individuals without atherosclerosis or risk factors for coronary artery disease and that there was no difference between men and women in their hemodynamic or vasodilator responses to mental stress. The mean baseline brachial artery diameter during mental stresswas smaller than the mean baseline diameter witbout mental stress. This can be attributed to the vasoconstrictor effect of catecholamines evoked by the mental stress test that began just before the baseline diameter measurements. However, the absolute change in the vessel diameter after cuff release was significantly larger during mental stress, which suggests greater synthesis, release, or delivery of nitric oxide to the vascular smooth muscle or possibly greater responsiveness to the effects of nitric oxide.

American Heart Journal Volume 139, Number 3

Since the initial 1980 discovery by Furchgott and Zawadtkilt of the obligatory role of the endothelium in modulating vascular tone, many studies have examined endothelial function in both health and disease states.tz-1s Experimental and clinical studies have shown that increased shear stress(resulting from increases in blood flow) causes an endotheliumdependent vasodilator responsel3~16~t7that largely is caused by the stimulation of vascular mechanoreceptors and the subsequent release of nitric oxide, a powerful vasodilator.ts Some studies have used invasive approaches to evaluate flowmediated vasodilation of the coronary arteries as a measure of endothelial function.16~19~20Recently, endotheliumdependent vasodilation of the bra&al artery has been assessed noninvasively with the use of high-resolution ultrasound.10.14.‘5,21,22This technique has been shown to be reproducible23 and to correlate with invasive testing of coronary endothelial function.23 Mental or psychologic stress has been associated for decades with cardiac events (eg, sudden cardiac death, acute myocardial infarction, malignant arrhythmias, silent myocardial ischemia, angina pectoris).3.2*29 In fact, anxiety,30931hostility,32 depression33 and anger34335 all have been linked to an increased incidence of adverse cardiovascular events. Jiang et all suggested that the relation between psychologic stressand adverse cardiac events may be mediated by the occurrence of ischemia, and numerous laboratory studies have demonstrated that mental stress can evoke myocardial ischemia.2.3.36.37However, the mechanism by which mental stress causes ischemia is not well understood. It has been postulated that the sympathetic activation elicited by mental stress causes increased HR and BP, leading to increased myocardial oxygen demand, which can cause ischemia.3wl It also has been suggested that mental stress and its subsequent neurohumotal and/or hemodynamic effects may cause ischemia by increasing platelet aggregability. Several studies4tA4 have shown that emotional stress can cause platelet secretion and increased aggregation, and Haft and Fani showed that emotional stress caused microcirculatory occlusive platelet aggregation in an animal model. Mittleman et al46 reported that aspirin appeared to mitigate the effects of anger on coronary heart disease risk: Regular aspirin users were at approximately half the risk of nonusers. The authors speculated that the protective effect of aspirin was a result of the prevention of platelet aggregation and subsequent thrombus formation. Another possible mechanism for mental stress associated cardiac ischemia is through catecholamine-mediated modulation of vasomotor tone or response to other vaso motor stimuli. Studies with positron emission tomography have shown that mental stress testing can produce an absolute decrease in regional coronary blood flow in patients with coronary artery disease.47Yeung et al6

Harris

et al 409

reported direct angiographic visualization of coronary vasoconstriction at sites with atherosclerotic plaque during mental stress, supporting the concept of reduced coronary flow as a significant pathophysiologic mechanism of mental stress-induced ischemia. Similarly, other investigatorssV48have shown that atherosclerotic coronary arteries vasoconstrict in response to sympathetic stimulation by use of the cold pressor test. Atherosclerosis and other risk factors for coronary artery disease are associated with endothelial dysfunction,l0~t4~*9 and it is a widely held hypothesis that an impaired vascular endothelium may predispose blood vesselsto spasm.50 Catecholamines are known to be powerful vasoconstrictors because of their direct effect on vascular smooth muscle. However, in vitro studies have shown that catecholamines (ie, norepinephrine) also can cause vasodilation in porcine and canine coronary arteries.51 This patadoxic vasodUion of normal arteries in response to sympathetic stimulation is thought to be mediated by the endothelium.52 Several studiesst~s*sshave suggested that catecholamine stimulation of endothelial cell a,,adrenergic receptors may enhance the release of nitric oxide from the endothelium, which may counteract the direct vascular smooth muscle vasoconstrictor effect of catecholamines. Our study extends this concept by suggesting that sympathetic activation, elicited by mental stress, does indeed increase resting vasomotor tone but that it may also enhance endothelium-mediated vasodilation in vivo that occurs in response to other endotheliumdirected vasodilator stimuli. In individuals with an intact endothelium, endogenous catecholamines released during mental stress may enhance the bioavailability or augment the release of nitric oxide from endothelial cells and override the direct vasoconstrictor effect of the catecholamines. However, in individuals without this offsetting endotheliumdependent vasodilation, mental stressand its associated sympathetic stimulation may be harmful.35356

Limitations

of the study

There was no measurement of change in bra&al artery blood flow after cuff release in our study participants. However, other investigators have documented a greater than 3-fold increase in blood flow immediately after lower-arm cuff occlusions of 5 minutes’ duration.57 We did not measure plasma catecholamine levels in our study; however, we were able to show significant increases in SBPand DBP, HR, and RPP.A standard arithmetic challenge (similar to the one we used) has been shown to raise plasma levels of both epinephrine and norepinephrine.ss$s9 Most investigators characterize bra&al flow-mediated vasodilation by measuring the end-diastolic diameters in 1 frame or a few frames at baseline and at a prespecified time after cuff release. We quantified the vasodilator response by continuously measuring the mean arter-

Amencon 410

Harris

Heart Journal March 2000

et al

ial diameter at baseline and after the flow st&mlus. This strategy allows us to average large numbers of observations, thereby improving the signal-to-noise ratio and precision, and ensures that we detect the maximal diameter that occurs during the response phase. However, vasodilator responses measured in this way may not be exactly comparable to results obtained in other studies based on more limited evaluation of changes in brachial diameter. In summary, sympathetic activation caused by mental stress has complex and competing effects on conduit artery vasomotor tone, including direct vasoconstrictor effects on vascular smooth muscle and vasodilator effects mediated through endothelial nitric oxide. This study suggests that sympathetic activation also may potentiate the effects of other endotheliumdirected vasodilator stimuli, such as increases in shear stress from transient increases in blood flow. In the setting of impaired endothelial function, direct effects on vasoconstriction probably would dominate, resulting in potentially signitkant reductions in blood flow. Thus endothelial injury could transform relatively benign, everyday stressful experiences into life-threatening episodes of myocardial ischemia. Additional research is needed on the effects of mental stress on regulation of vasomotor tone in the setting of established coronary disease to clarify the role of psychosocial stress in the pathogenesis of acute ischemic syndromes.

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