606
Increased Response to Physical and Mental
Stress in Men With Hypertensive Parents
Bengt R. Widgren, John Wikstrand, Goran Berglund, and Ove K. Andersson
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Blood pressure and heart rate responses to isometric handgrip exercise were studied at age 31 and after
5 years in young nonhypertensive men with positive family histories of hypertension (n=13) and in those
with negative family histories of hypertension (n=13) for two generations to test whether subjects with
positive family histories established a pattern of increased blood pressure and heart rate responses during
the 5-year follow-up period. At follow-up the response to mental stress (Stroop's color word test) was also
studied. Baseline blood pressure and heart rate at rest did not differ, initially or at follow-up, between the
groups. At the initial examination, absolute blood pressure levels were significantly higher during
isometric handgrip exercise just before exhaustion in subjects with positive family histories. At follow-up
the absolute blood pressure level (/»<0.001) and the blood pressure responses (/?<0.01-0.001) were found
to be significantly increased during handgrip exercise in subjects with positive family histories compared
with subjects with negative family histories. In subjects with positive family histories the diastolic blood
pressure response was significantly higher (/><0.01) at follow-up than initially and was significantly
related (r=0.70, p<0.01) to changes in baseline diastolic blood pressure during the follow-up period. In
subjects with negative family histories the systolic blood pressure response was somewhat lower at
follow-up than initially. During the mental stress test, the blood pressure response was significantly
greater in subjects with positive than with negative family histories. We conclude that nonhypertensive
men with positive family histories of hypertension were characterized by increased blood pressure
responses under both physical and mental stress compared with subjects with negative family histories.
Such increased responsiveness to different stressors could be related to subsequent development of high
blood pressure in subjects predisposed to primary hypertension. (Hypertension 1992;2(h6O6-611)
KEY WORDS • family characteristics • stress • hypertension, genetic
D
espite varying opinions concerning the etiology
of primary hypertension, most investigators
agree on the importance of genetic factors.1-2
Page's mosaic theory3 implies that the hereditary factors underlying primary hypertension consist of a spectrum of variants more or less randomly mixed in the
genetic coding of human reproduction. Epidemiological
studies have demonstrated that hypertension is also
related to genetic and environmental conditions such as
body weight and weight gain.4-9 The mechanisms
through which the interaction of genetic and environmental factors operate, thus directing the development
of increased arterial blood pressure, has yet to be
established.
Almost 50 years ago it was proposed that a period of
vascular hyperreactivity precedes the development of
sustained hypertension.10 Previous studies have shown
that the offspring of hypertensive humans differ from
those of normotensive persons in that they exhibit enhanced blood pressure responses to laboratory stresFrom the Department of Medicine, Division of Angiology,
Hypertension Unit and the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska Hospital, University of GOteborg,
GOteborg, Sweden.
Address for correspondence: Bengt R. Widgren, Department of
Medicine, Section of Angiology, Hypertension Unit, Sahlgrenska
Hospital, S-413 45 Goteborg, Sweden.
Received December 27,1991; accepted in revised form June 26,
1992.
sors.11"14 This reactivity pattern has also been observed
in patients with established hypertension.15 In spontaneously hypertensive rats (SHR), the animal model for
primary hypertension, increased sympathetic activity
that closely agrees with that of the defense reaction has
been found.16-17 During such increased stressor response
in SHR, increased sympathetic activity in renal nerves
and decreased sodium excretion have also been found.18
It has been suggested that this is mediated by £-adrenergic receptors in the central nervous system.19 In subjects with positive family histories of hypertension, an
increased pressor response to various pressor stimuli has
recently been found,20-21 and this has also been found in
animal models of primary hypertension.18-22
The aim of the present investigation was to study
whether subjects with positive family histories of hypertension were characterized by increased blood pressure
and heart rate responses to physical and mental stress.
Methods
The present study was approved by the Ethics Committee of the Medical Faculty, University of Goteborg,
and informed consent was obtained from the subjects
before the investigations. All subjects attended the
research laboratory at the Department of Clinical Physiology, Sahlgrenska Hospital. All subjects were instructed to avoid changes in their daily life habits and to
avoid heavy exertion during the days before the experimental procedure. On both occasions the subjects were
Widgrtn et al History of Hypertension and Stress Reactivity
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investigated between 9 and 11 AM in a soundproof room
with a temperature of 22-24°C.
All subjects included in the present study were
healthy sons of normotensive or hypertensive fathers
who had participated in the Primary Preventive Trial in
Goteborg, Sweden, in which a random third (n=9,996)
of the male population 47-54 years of age was examined
for cardiovascular risk factors.23 All men (n=686) with
two consecutive recordings of blood pressure above 175
mm Hg systolic or 115 mm Hg diastolic or being treated
for hypertension were referred to the Hypertension
Unit. Both parents of 49 of these hypertensive men had
been treated for hypertension or stroke before the age
of 65 years. These 49 men were asked if they had a son
living near Goteborg, and a total of 24 sons with positive
family histories of primary hypertension for two generations were contacted and invited to participate. All
mothers of the sons with positive family histories of
hypertension were also contacted by telephone at the
initial examination and asked about current medication.
Four mothers of the sons with hypertensive fathers were
taking antihypertensive medication. Sixteen subjects
(31 ±6 years of age) with positive family histories of
hypertension were initially examined. Of the remaining
eight individuals, one was excluded because of current
medication for hypertension, one because of alcoholism,
two because they were traveling salesmen, and one
because he was in military service and could not participate. Three subjects declined to participate. At
follow-up, all 16 subjects with positive family histories
were reexamined. However, in the present study three
subjects with positive family histories of hypertension
dropped out, two because of technical difficulties in the
blood pressure measurements during the stress tests
and one because he declined to participate in this part
of the follow-up.
Subjects in the control group were recruited from the
sons of 50 normotensive randomly selected men (blood
pressure below 130 mm Hg systolic, 90 mm Hg diastolic)
from the same screening examination.23 These normotensive men had negative family histories of hypertension or stroke. These 50 normotensive men had 26
sons. All mothers of the subjects in the control group
were also contacted by telephone about their current
medication and state of health and whether they were
also normotensive according to recent medical investigation. Because the group with positive family histories
of hypertension turned out to be heavier than the
normotensive control group, slight overweight emerged
as an important selection criterion for the group with
negative family histories. On this basis, 15 of these 26
men were matched for age and body weight with the
men from the group with positive family histories of
hypertension. The mothers of those 15 subjects had no
hypertension. Thirteen of the 15 subjects with negative
family histories of hypertension were reexamined at
follow-up, but two were unwilling to participate. Subjects with positive and negative family histories of
hypertension who did not participate in the follow-up
did not differ in blood pressure response compared with
the group mean.
Follow-up blood pressure data9 and pathophysiological mechanisms in these subjects have previously been
reported.20-21
607
Blood Pressure, Heart Rate, and Stress Tests
Baseline blood pressure was measured phonographically24 after 45 minutes of rest in the supine position and
during isometric handgrip exercise, which was performed in the supine position. At follow-up, measurements were also made in a sitting position during the
mental stress test. A 12x35-cm standard cuff, automatically inflated and deflated, was used. A microphone
(EMT25C, Siemens-Elema, Stockholm, Sweden) was
placed over the brachial artery, and signals indicating
the Korotkoff sounds were registerated on a mingograph (Siemens-Elema). Signals indicating cuff pressure
were also registered simultaneously on the same mingograph. Diastolic blood pressure was recorded when
the Korotkoff sounds disappeared (phase V). Mean
arterial blood pressure is used in the figures to show
changes during isometric exercise and was calculated as
one third of the pulse pressure plus the diastolic blood
pressure. This method of noninvasive blood pressure
measurement has been evaluated during simultaneous
intra-arterial blood pressure measurements (n=32) and
has been found to be reliable, with a mean±SD difference in systolic blood pressure between the two methods of 0.7±4.68 (confidence interval -2.6 to 1.16)
mm Hg (r=0.95) and in diastolic blood pressure of
1.0±3.1 (confidence interval -0.21 to 2.29) mm Hg
(r=0.86).
Baseline blood pressure before the stress tests is
presented as the mean of three recordings taken at
5-minute intervals during the last 15 minutes before the
tests were started. During isometric handgrip exercise,
blood pressure was registered at 1 minute, 3 minutes,
and just before exhaustion, whereas during the mental
stress test blood pressure was registered at 2, 4, 6, 8,12,
16, and 20 minutes.
Isometric handgrip exercise was performed with the
right hand on a strain gauge dynamometer at 30% of the
maximum developed force determined before exercise,
using an electromechanical device. The mental stress
test consisted of exposure to Stroop's color word conflict
test in a modified version lasting for 20 minutes.25 The
test consists of color words written in incongruent
colors, and the subjects are asked to state the color they
see and to ignore the written word as well as the color
word given by a disturbing voice.
Statistics
Mean values, standard deviations (SD), and confidence intervals were calculated using standard methods. Student's t test was used for comparisons of means
between the two groups and regarding changes within
the groups. Only two-tailed tests were used, and/7<0.05
was regarded as statistically significant. Two-way analysis of variance was used to test the hypothesis of no
difference in means between the two groups in repeated
measurements. When this analysis yielded significant
differences, the / test was used for comparisons of
means between the two groups. The relation between
variables was analyzed using linear regression coefficients. All statistics were handled using the STATVIEW
512+ package (Abacus Concepts, Inc., Calabasas, Calif.)
implemented on an Apple Macintosh personal computer (Cupertino, Calif.).
608
Hypertension
Vol 20, No 5 November 1992
TABLE 1. Absolute Blood Pressure and Heart Rate Levels During Isometric Handgrip Test at Initial and Folkrw-Up Examinations in
Subjects With Positive and Negative Family Histories of Hypertension
Measurement
Initial examination
Baseline (prestress)
1 min
3 min
Maximal blood pressure
Follow-up examination
Baseline (prestress)
1 min
3 min
Maximal blood pressure
Positive family history (" = 13)
Blood pressure
(mm Hg)
Heart rate
Systolic
Diastolic
(beats per min)
Negative family history (" = 13)
Blood |pressure
(mmHg)
Heart rate
(beats per min)
Diastolic
Systolic
125±11
145 + 19
160+14
164±13*
69±8
79±15
90±15
93±7'
62±9
75 ±7
88±12
91±12
122±10
141±11
151±12
154±12
68±4
75±8
80±12
86±10
63+5
75 ±10
80±9
83±10
129+19
149±25
161±21t
170±l&t
74±11
87±14
97±16t
107±10t
61±7
73±8
79±8
85±5t
126±13
137+14
143+14
152±18
72+11
79±12
82±14
90±13
6O±5
68±6
74±6
79±5
Values are mean±SD.
V<0.05, tp<0.01,3p<0.001 different from negative family history.
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Results
Baseline Blood Pressure and Heart Rate
At the initial examination, systolic and diastolic blood
pressures and heart rate at supine rest did not differ
between subjects with positive family histories of hypertension and control subjects. Heart rate was also similar
between the two groups (Table 1).
At follow-up 5 years later, neither systolic nor diastolic blood pressure differed between groups at supine
rest (Table 1) or sitting rest (126±14/75±8 versus
126± 11/76+11 mm Hg, respectively, for positive versus
negative family history groups). Heart rate also did not
differ between groups at supine rest (Table 1) or sitting
rest (data not shown). Furthermore, there were no
significant changes in blood pressure or heart rate
within the groups between testing sessions (Table 1).
Blood Pressure and Heart Rate Responses to
Handgrip Exercise
Absolute blood pressure levels during isometric
handgrip exercise at the initial examination are shown
in Table 1. At 30% of maximum developed force,
absolute blood pressure levels were significantly higher
(p<0.05) just before exhaustion in subjects with positive family histories of hypertension (Figure 1). However, the blood pressure and heart rate responses (i.e.,
relative changes from baseline level) to isometric handgrip exercise did not differ between groups at the initial
examination (Table 2).
At the follow-up examination 5 years later, absolute
systolic and diastolic blood pressure levels were significantly higher at 3 minutes (p<0.01, Table 1), as was the
maximum blood pressure at 30% of maximum developed force (/xO.001, Figure 2), in subjects with positive
family histories of hypertension compared with control
subjects. Maximum heart rate was also significantly
higher (p<0.01) in subjects with positive family histories during isometric handgrip exercise (Table 1). Moreover, blood pressure and heart rate responses to isometric handgrip exercise at the follow-up examination were
significantly greater at 1 minute (p<0.05 and p<0.01,
respectively), at 3 minutes (p<0.001 and NS, respec-
tively), and at maximum (p<0.01 and/7<0.01, respectively) in subjects with positive family histories than in
the control group (Table 2).
In subjects with positive family histories of hypertension, the relative change in diastolic blood pressure to
handgrip exercise at follow-up was significantly greater
(p<0.01, Table 2) than at the initial examination.
Systolic blood pressure and heart rate responses did not
differ between examinations in subjects with positive
family histories. In control subjects, blood pressure and
heart rate responses were somewhat, but not significantly, lower at follow-up than at the initial examination. There was also a significant (r=0.70, p<0.01)
relation between changes in baseline diastolic blood
pressure level and reactivity (i.e., relative changes in the
diastolic blood pressure response, Table 2) to handgrip
exercise during the 5-year follow-up in subjects with
positive family histories, while in subjects with negative
family histories no such relation was found (r=0.18, not
significant).
130
IX)
no
100
to
•PFH-
-NFH-
FIGURE 1. Plots of baseline and maximal attained mean
arterial blood pressure during handgrip exercise at initial
examination in subjects with positive family histories of hypertension (PFH) and subjects with negative family histories
of hypertension (NFH). Squares and bars indicate mean ±SD.
*p<0.05.
Widgren et al
History of Hypertension and Stress Reactivity
609
TABLE 2. Blood Pressure and Heart Rate Responses to Physical Stress of Initial and FoUow-Up Examinations and to Mental Stress at
FoUow-Up Examination in Subjects With Positive and Negative Family Histories of Hypertension
Positive family history i(« = » )
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Measurement
Isometric handgrip
Initial examination
1 min
3 min
Maximum response
Follow-up examination
1 min
3 min
Maximum response
Mental stress test
2 min
4 min
6 min
8 min
12 min
16 min
20 min
Blood pressure
(mmHg)
Diastolic
Systolic
Heart rate
(beats per min)
Negative family history (n = 13)
Blood pressure
(mm Hg)
Heart rate
Systolic
Diastolic
(beats per min)
24±15
36±12
39±11
11±9
21±13
24±6
15±8
25±13
28±14
21 ±9
31±10
35±10
12±14
18±11
20±12'
32±9t
41±12$
13±7*
12±5t
7±3
18±7
24±6t
11±6
18±10
27±14
8±6
23±12t
33±llt§
11±7
18±11
14±4
18±6
14±6*
16±6*
10±8*
15±5t
16±5t
17±7t
20±13
13±10
18±9
19±8
18±8
14±9
13±7
12±7
10±8
10±8
10±8
11±9
10±7
10±8
8±9
8±7
7±8
2±8
0±9
3±8
15±10
16±7
15±8
14±8
13±9
13±7
6±11
22±13*
21 ±12*
19±3*
16±11
15±11
14±12
5±11
7±8
8±8
9±7
13±8
19±8
22±9
Values are mean±SD change from baseline.
*/7<0.05, tp<0.001, 4p<0.01 different from negative family history.
§p<0.01 different from initial examination.
Blood Pressure and Heart Rate Responses to Mental
Stress Test
During the mental stress test, blood pressure and
heart rate increased significantly in both groups. The
systolic blood pressure response was significantly higher
during the first 6 minutes, whereas the diastolic blood
pressure response was significantly higher throughout
the test, in subjects with positive family histories of
hypertension than in control subjects (Table 2). The
heart rate response was somewhat higher in subjects
with positive family histories but did not differ significantly between groups during the mental stress test
(Table 2).
Discussion
Increased blood pressure and heart rate responsiveness (both absolute levels and relative changes from
baseline) were observed during isometric handgrip exercise and the mental stress test in subjects with positive
140
family histories of hypertension. This supports the hypothesis of increased central and peripheral cardiovas130
cular responsiveness to different stressors in nonhyper120
tensive subjects predisposed to development of primary
hypertension. We also found a significant relation beno
tween changes in baseline diastolic blood pressure level
and changes in diastolic blood pressure response (i.e.,
100
relative change) to handgrip exercise during the 5-year
follow-up. This means that those subjects with a positive
90
family history of hypertension whose baseline diastolic
blood pressure increased during follow-up also had
n
increased their diastolic blood pressure response to
70
isometric handgrip exercise during the 5-year follow-up.
At the initial examination, the absolute blood pressure level during isometric handgrip exercise at 30% of
maximum developed force was increased just before
exhaustion in subjects with positive family histories of
FIGURE 2. Plots of baseline and maximal attained mean
hypertension compared with control subjects. After the
arterial blood pressure during handgrip exercise at follow-up 5 years of follow-up, still without significant differences
examination in subjects with positive family histories of hyor changes in baseline blood pressure, the diastolic
pertension (PFH) and subjects with negative family histories blood pressure response during isometric handgrip exof hypertension (NFH). Squares and bars indicate mean ±SD. ercise was even more markedly increased in subjects
***p<0.001.
with positive family histories. However, it must be
610
Hypertension
Vol 20, No 5 November 1992
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indicated that the diastolic blood pressure response was
somewhat lower in the control group at follow-up than
at the initial investigation. A lower response to repeated
stress stimuli, such as during handgrip exercise in subjects with negative family histories of hypertension,
could be due to habituation to the examination procedure. However, the difference in blood pressure response between the two groups was repeated during the
mental stress test.
Cardiovascular responses to stress are often assessed
by the application of either physical or emotional stimuli
in a laboratory environment. We used both physical and
emotional stressors to induce blood pressure and heart
rate responses in subjects selected by a procedure
suggested by others2 to study plausible pathophysiological factors in subjects with positive family histories of
primary hypertension.
Previously, longitudinal studies have supported the
notion that enhanced blood pressure and heart rate
responses to mental stress are an important marker of
future primary hypertension.11-26-27 In patients with borderline or established primary hypertension, an increased blood pressure and sympathoadrenal response
to the color word test has been reported.28 Such enhanced responsiveness has also been observed in
SHR.16-17 In SHR, the animal model for primary hypertension, such a cardiovascular pattern also occurs during the development of high blood pressure.29-30 In
studies by Julius and Esler,31 convincing evidence has
been presented that a hyperkinetic circulatory pattern
characterizes early primary hypertension, and follow-up
studies in young persons with borderline hypertension32-33 also contribute to the hypothesis of an initial
defense reaction-like hyperkinetic state, gradually
transferred into established primary hypertension.
In the present study baseline blood pressure and
heart rate did not differ between the two groups.
Furthermore, in a previous report, no signs of difference
in the sympathetic nervous system activity measured as
24-hour urinary catecholamine excretion or venous
plasma concentrations of norepinephrine and epinephrine have been observed.9 However, measurements of
circulating venous plasma levels of catecholamines have
been said to give poor information about the prevailing
sympathetic nervous system activity.34
The mechanisms involved in the increased blood
pressure and heart rate responses in subjects with
positive family histories of hypertension are not completely understood. Whether the increases are due to an
increase in peripheral resistance, cardiac output, or
both has not been clarified in the present study. However, at follow-up the absolute diastolic blood pressure
level was significantly higher than at the initial examination, even with the heart rate response somewhat
lower than initially. One might speculate if this may
indicate increased peripheral vascular resistance in relation to different kinds of stress stimuli in subjects with
positive family histories of hypertension, which is further supported by the higher diastolic blood pressure
throughout the mental stress test. In previous studies,
an enhanced systemic and renal vascular sensitivity to
angiotensin II20 has been reported in subjects with
positive family histories of hypertension. However, the
cardiovascular response to a-adrenergic receptor agonist stimuli did not differ between subjects with positive
family histories of hypertension and control subjects.35
In the same study35 calf and forearm hemodynamics
were found to be similar in normotensive subjects with
and without positive family histories of hypertension.
The defense reaction involved in the cardiovascular
adjustments to different kinds of stimuli is a composed
neurohormonal pattern involving both bulbar and peripheral reflexes as well as changes in cardiovascular
hormones.36 In an interesting study by Koepke and
DiBona,19 increased renal sympathetic nerve activity
and decreased sodium excretion owing to a stressful
environment related to 0-adrenergic receptors in the
central nervous system were found in SHR. Interestingly, in a study by Webb et al37 increased systemic and
renal sensitivity to angiotensin was observed in "psychosocial mice," in which hypertension developed under environmental stress.
In a physiological-psychological study, young persons
with borderline hypertension revealed significantly
higher irritability than normotensive control subjects,38
which may reflect a mild accentuation of the average
level of mental arousal. Other studies have shown that
subjects with borderline hypertension had blood pressure
responses similar to those of normotensive subjects.39
Such differences have been demonstrated as an effect of
information about blood pressure levels40 and may also
be attributable to different degrees of habituation to the
investigative procedures used. In the present study it
must be remembered that both groups have been examined several but equally many times and followed up for
5 years and that the baseline blood pressure and heart
rate did not differ between subjects with and without
positive family histories of hypertension.
One might speculate as to whether a mild defense
reaction and slightly increased renal sympathetic nerve
activity were involved in previous findings of blunted
sodium excretion during saline loading and increased
sensitivity to angiotensin II among subjects with positive
family histories of hypertension.20-21 Previously, sodium
intake has been shown to be similar in the two groups.9
However, this does not exclude the possibility that
sodium intake and the sympathetic nervous system are
concurrent factors involved in the cardiovascular response to different stress stimuli. An altered renal
response that contributes to the differences in cardiovascular reactivity in subjects with positive family histories of hypertension has previously been demonstrated.41 A psychological, stress-induced sodium and fluid
retention has been reported in subjects at high risk for
primary hypertension.14
In an epidemiological study by Julius et al,39 hyperreactivity to stress was not found to be a predictor of
future hypertension. Another study focusing on the
importance of stress and the sympathetic nervous system in the development of hypertension and atherosclerosis has recently been reviewed.42
One of the most interesting findings in the present
study was that the increased response to two different
kinds of stress stimuli was present in nonhypertensive
subjects with positive family histories of hypertension
with apparently similar levels of blood pressure at
baseline as in control subjects with negative family
histories of hypertension. Another is that subjects with
increasing diastolic blood pressure during follow-up
also had increased their diastolic blood pressure re-
Widgren et al
sponse to handgrip exercise at follow-up. The present
study does not clarify whether this enhanced diastolic
blood pressure responsiveness is a marker of future
hypertension.
In conclusion, we found that nonhypertensive men
with positive family histories of hypertension for two
generations were characterized by increased blood pressure and heart rate responsiveness to different stressor
stimuli without significant differences in baseline blood
pressure. Furthermore, we also found a relation between changes in baseline diastolic blood pressure and
changes in the diastolic blood pressure response to
handgrip exercise over the 5-year follow-up. Such an
increased response to different stress stimuli could be
an early marker for subsequent development of primary
hypertension.
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Hypertension. 1992;20:606-611
doi: 10.1161/01.HYP.20.5.606
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