J S Floras, M O Hassan, J V Jones, B A Osikowska, P S Sever and P Sleight

Factors influencing blood pressure and heart rate variability in hypertensive humans.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
Copyright 1988 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Hypertension
doi: 10.1161/01.HYP.11.3.273
1988;11:273-281 Hypertension.
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Factors Influencing Blood Pressure and Heart
Rate Variability in Hypertensive Humans
JOHN S. FLORAS, M. OSMAN HASSAN, JOHN VANN JONES, BARBARA A. OSIKOWSKA,
PETER S. SEVER, AND PETER SLEIGHT
SUMMARY We examined the influence of baroreceptor reflex sensitivity (the increase in pulse
interval in response to a phenylephrine-induced increase in blood pressure), age, blood pressure, and
/3-adrenergic receptor blockade on the variability of blood pressure and heart rate in essential
hypertension. Fifty-six subjects were studied before treatment; intra-arterial blood pressure was
recorded outside the hospital for 24 hours. Variability was defined (from all beats occurring while
subjects were awake) as the standard deviation about the average waking value for mean arterial
pressure (MAP) or pulse interval. The correlation (r) between baroreceptor reflex sensitivity and
blood pressure variability was -0. 47 (p<0.0002). Baroreceptor reflex sensitivity was the only
independent determinant of blood pressure variability on multiple regression analysis. Thirty subjects
were restudied after 5 months of /3-adrenergic receptor blockade. Ambulatory blood pressure was
lower during treatment, whereas pulse interval, its variability, and baroreceptor reflex sensitivity
were higher. Blood pressure variability was unchanged. The variability of MAP was inversely corre-
lated with baroreceptor reflex sensitivity before (r = -0. 42, p<0.02) and during ( r = - 0. 45,
p < 0.02) treatment, but it was unrelated to the average ambulatory MAP or to the variability of pulse
interval either before or during /3-blockade. Sixteen subjects whose average waking ambulatory blood
pressure was 140/90 mm Hg or less were not treated. This group of borderline hypertensive subjects
had less variable MAP than did the remaining 40 subjects (12.4 2.3 [SD] vs 14.5 2.5 mm Hg;
p<0.01). We conclude that 1) the decline in baroreceptor reflex sensitivity is the principal determi-
nant of increased blood pressure variability in hypertension, 2) MAP and its variability are regulated
independently, 3) heart rate variability is not influenced by baroreceptor reflex sensitivity and is
unrelated to blood pressure variability, and 4) the blood pressure of subjects with borderline hyper-
tension is not excessively labile. (Hypertension 11: 273-281, 1988)
KEY WORDS ambulatory blood pressure baroreceptor reflex sensitivity /3-adrenergic
receptor blockade borderline hypertension labile hypertension age
I
NTRA-ARTERIAL ambulatory blood pressure
recordings demonstrate graphically the great
beat-to-beat variability of blood pressure present
From the Department of Cardiovascular Medicine, University of
Oxford, John Radclifife Hospital, Headington, Oxford, and the De-
partment of Clinical Pharmacology, St. Mary's Hospital, Norfolk
Place, London, United Kingdom.
Supported in part by a grant from the British Heart Foundation.
Dr. Floras was supported by a Rhodes Scholarship and currently
holds a Career Scientist Award from the Ministry of Health of the
Province of Ontario. Dr. Hassan was in receipt of a Research
Fellowship from the Medical Research Council (UK).
Dr. Hassan's present address: Department of Medicine, King
Abdul Aziz University Hospital, Jeddah, Kingdom of Saudi Ara-
bia. Dr. Jones's present address: Department of Cardiology, Bristol
Royal Infirmary, Bristol, Avon, United Kingdom.
Part of this work was presented at the Second Gent Workshop on
Blood Pressure Variability, Gent, Belgium, 1981.
Address for reprints: Dr. John S. Floras, Division of Cardiology,
Toronto General Hospital, 12 EN-234,200 Elizabeth Street, Toron-
to, Canada M5G 2C4.
Received June 25, 1987; accepted October 26, 1987.
in normal and hypertensive humans,
1
but factors that
might influence and regulate this variability remain
imperfectly understood. Considerable experimental
evidence supports the concept that the arterial barore-
ceptor reflex is intimately involved in the short-term
regulation of arterial blood pressure. Denervation of
the sinoaortic baroreceptors in rats and dogs consis-
tently increases the beat-to-beat variation of blood
pressure but has less dramatic and disputed effects on
its level.
2
"
5
Central interruption of the baroreceptor
reflex by lesioning nucleus tractus solitarii produces
hypertension, tachycardia, and increased blood pres-
sure variability in awake animals.
6
Selective removal
of the noradrenergic innervation of this nucleus does
not induce hypertension, but it does cause an increase
in blood pressure variability that is inversely related to
a decrease in the baroreceptor reflex control of heart
rate.
7
In hypertension, the threshold for baroreceptor fir-
ing is reset
8
and the receptors themselves are less sensi-
273
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274 HYPERTENSION
VOL 11, No 3, MARCH 1988
tive to further increases in arterial pressure.
9
One might
predict, as a consequence, that the reflex parasympa-
thetic and sympathetic responses to a similar pressor
stimulus would be attenuated. Indeed, the ability of the
arterial baroreceptor reflex to inhibit efferent sympa-
thetic activity is impaired in several experimental mod-
els of hypertension,
10
"
13
and the lability of blood pres-
sure is increased in rabbits whose baroreceptor afferent
discharge is reduced, whether due to renal hyperten-
sion, experimental atherosclerosis, or medial sclero-
TABLE 1. Subject Characteristics
SIS.
14-16
In humans, the arterial baroreceptor reflex control of
cardiac cycle length has been well studied using tech-
niques that quantify the reflex changes in heart rate in
response to stimuli that alter blood pressure. If phen-
ylephrine is administered, a linear relationship be-
tween the systolic blood pressure of each beat and the
subsequent pulse interval can be established over the
course of the pressure rise. The slope of this line has
been used as an index of baroreceptor reflex sensitivity
(BRS). This technique examines primarily the para-
sympathetic efferent limb of this reflex.
17
Persons with
more sensitive baroreceptor reflexes exhibit a greater
reflex bradycardia for a similar absolute increase in
blood pressure. Increasing age and mean arterial pres-
sure (MAP) act independently to lower the slope of this
response.
18
The aim of the present investigations was to deter-
mine the influence of factors such as age, blood pres-
sure, heart rate variability, and /3-adrenergic receptor
blockade on intra-arterial blood pressure variability in
awake, ambulatory subjects. Our hypotheses were that
1) the reduction in BRS in hypertension would be
associated with increased variability of ambulatory
blood pressure, 2) the variability of blood pressure
would be inversely related to the variability of heart
rate, 3) subjects with greater plasma norepinephrine
concentrations would also display increased blood
pressure variability, and 4) /3-adrenergic receptor
blocking drugs would increase BRS and reduce the
lability of blood pressure.
Subjects and Methods
Fifty-six subjects (41 men, 15 women) were re-
ferred for assessment of newly diagnosed, untreated
hypertension. They ranged in age from 16 to 69 years
(mean age, 46 11 [SD] years; Table 1).
Hypertension was diagnosed if supine cuff pres-
sures, obtained on three or more separate occasions
over 1 week apart were 140/90 mm Hg (Phase V dia-
stolic) or greater in subjects under 40 years of age and
160/95 mm Hg or greater in subjects over 40 years of
age. Readings below these values were recorded at
other times in some subjects. Their average clinic pres-
sure ranged from 137 to 216 mm Hg systolic (mean,
172 19 [SD] mm Hg) and from 80 to 137 mm Hg
diastolic (mean, 107 10 mm Hg).
No subject had fundal changes greater than Grade
2.
19
In 18, the chest radiograph or electrocardiogram
showed changes of left ventricular enlargement. None
were in heart failure. Secondary hypertension was ex-
Variable
Age (yr)
MAP (mm Hg)
VMAP (mm Hg)
PI (msec)
VPI (msec)
LBRS
PNE
At rest (pg/ml)
Exercise (biking; pg/ml)
% Change
All subjects
(n = 56)
4611
118.317.9
13.82.4
678 87
13234
0.78 0.30*

. Subjects in whom
PNE was measured
(n = 44)
4511
119.018.5
13.5 + 2.3
691 82
13O3O
0.800.30
651+228
1112448
81+81
Values are means SD. PNE = plasma norepinephrine;
V = variability; PI = pulse interval; LBRS = log baroreceptor re-
flex sensitivity.
*n = 55.
eluded by routine investigations in all patients but one,
who had renal artery stenosis. Two were taking medi-
cations concurrently: One was taking digoxin, 0.125
mg/day, for control of atrial fibrillation, and another,
sulfasalazine, 2 g/day, for Crohn's disease.
The purpose and nature of the protocol were ex-
plained during recruitment and again on the morning of
the first study, when informed written consent was
obtained. Consent was also obtained before the second
study day, when the protocol was repeated during
long-term /3-adrenergic receptor blockade. Permission
for these investigations was granted by the hospital
ethics committee.
Protocol
Subjects arrived at 0930 after a light breakfast at
home, avoiding tea, coffee, or cigarettes. There were
no other dietary restrictions.
Arterial pressure was recorded from a left brachial
catheter connected to a strain gauge transducer cali-
brated at all times at midchest level.
20
An adjacent
antecubital vein was cannulated for blood sampling or
phenylephrine injection. The electrocardiogram (Lead
II) and blood pressure were displayed on an oscillo-
scope and recorded continuously onto ultraviolet light-
sensitive paper, magnetic tape, and minicomputer
disk.
Plasma Norepinephrine
Venous blood was withdrawn from the antecubital
catheter in 44 of these subjects as they sat quietly for 15
minutes on a bicycle ergometer and again in the 10th
minute of upright bicycle exercise (5 minutes at 50 W,
then 5 minutes at 75 W). A 10-ml sample was obtained
and immediately centrifuged for 10 minutes at room
temperature (1000 g) and frozen and stored at - 40 C.
Norepinephrine concentration was measured by ra-
dioenzymatic assay.
21
Interassay and infra-assay coef-
ficients of variation were 9.6% and 8.7%, respec-
tively.
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VARIABILITY OF BLOOD PRESSURE AND HEART RATE/Floras et al. 275
Measurement of Baroreceptor Reflex Sensitivity
From 30 to 140 fig of phenylephrine hydrochloride
(Boots, Nottingham, UK), 100 ptg/ml, was adminis-
tered by bolus intravenous injection with 6 ml of dex-
trose over 5 seconds. Doses were adjusted to increase
systolic blood pressure by 20 to 30 mm Hg. Blood
pressure and heart rate usually returned to baseline
levels within a minute of the injection; 5 minutes was
allowed between injections, and between five and
eight injections were given to each subject.
Ambulatory Blood Pressure Monitoring
A portable blood pressure transducer unit
22
'
a
was
calibrated, then connected to the arterial cannula. Out-
put from this unit was recorded by analog cassette tape
recorder.
22
'
H
Lead II of the electrocardiogram and time
were recorded on additional channels. The transducer
unit and recorder were placed in a comfortable pouch
worn across the chest. Subjects were supplied a digital
watch and voice recorder to keep an accurate record of
their activities, paying particular attention to times of
sleeping and waking. Subjects then left the hospital to
resume their routine daily activity and returned in the
evening for about 15 minutes, at which time the trans-
ducer was recalibrated, the line flushed, and the sub-
ject's pulses and arm checked. The following after-
noon, the cannula was removed from the artery and a
pressure bandage applied. All of the procedures were
well tolerated and without incident.
Since the frequency response of the entire ambula-
tory recording and replay system falls off rapidly
above 10 Hz,
23
we used mean arterial blood pressure in
these calculations.
Calculation of Baroreceptor Reflex Sensitivity
Cardiac cycles from the beginning of the rise in
arterial pressure until the peak of the pressure rise were
used to calculate a regression line of pulse interval on
systolic pressure with its regression coefficient (or
slope), variance, and correlation coefficient for each
injection. All cardiac cycles during the pressure rise
were included in these calculations since respiration
does not alter this determination of BRS in subjects
with slopes less than 15 msec/mm Hg.
17
For each phenylephrine injection, regression equa-
tions were calculated with shifts, or delays, of from 0
to + 3 cardiac cycles interposed between the systolic
pressure and pulse interval regressed against it.
24
At
heart rates below 75 beats/min the correlation between
these two variables was usually best with a delay of 0
cycles. At faster rates, the correlation improved if a
delay of 1 to 3 cardiac cycles was used. Slopes could
not be obtained in one subject.
The delay that consistently gave slopes with the
highest correlation coefficients was determined for
each subject; regression coefficients and variances cor-
responding to this delay were used to compute weight-
ed mean BRS. A weighting factor, the inverse of the
variance, was applied to each slope. From the several
slopes obtained, all estimates of the "true" slope or
BRS of the subject, a weighted mean slope that took
these relative weightings into account was calculated
for each subject.
23
This method gives estimates of BRS
with less variance greater weight when determining the
mean slope.
Blood Pressure Variability
Analysis of the Ambulatory Blood Pressure Record
The 24-hour record was replayed at 25 times real
time. Raw blood pressure was sampled at a frequency
of 16 kHz and analyzed using a Fortran IV program
with display and interaction facilities to allow valida-
tion of the signal.
26
If more than a third of an hour's
pulses were edited because of damped waveforms or
artifacts, that hour was excluded from further analysis.
Each 24-hour record was divided into waking and
sleeping periods according to subjects' diaries. Fre-
quency histograms of waking MAP were computed
using all valid beats during this period. Hourly fre-
quency histograms were also calculated, and histo-
grams from selected hours were combined to cover
larger periods of the record. Data in these histograms
were normally distributed. The standard deviation of
these blood pressure measurements (i.e., the square
root of the variance), was used to describe blood pres-
sure variability.
Short-term and Medium-term Variability of Blood
Pressure in Individual Subjects
In eight subjects, ten 2-minute intervals from a 20-
minute segment of the tape, recorded at the time of
waking, were selected to study short-term variability
of blood pressure in individual subjects. This interval
was chosen because blood pressure and heart rate in-
crease markedly on waking.
27
We correlated the blood
pressure and pulse interval with their respective stan-
dard deviations within each 2-minute segment in each
subject. If blood pressure variability is dependent on
the absolute level of arterial pressure, one should find a
parallel increase in blood pressure and its variability at
this time.
All waking hours from eight subjects' records were
used to examine medium-term blood pressure variabil-
ity in individual subjects. The waking record was di-
vided into (14-17) hourly histograms. We correlated
MAP and pulse interval, with their standard devi-
ations, for each hour in each subject.
/3-Adrenergic Receptor Blockade
Although hypertension had been diagnosed clinical-
ly in all subjects, the ambulatory blood pressure of
many subjects was often well below 140/90 mm Hg.
Sixteen with mean waking ambulatory blood pressures
less than 140/90 mm Hg (12 men, 4 women; mean age,
43 9 years) were considered to have borderline hy-
pertension and were not treated.
Thirty of the hypertensive subjects (22 men, 8 wom-
en; mean age, 46 12 years) participated in the sec-
ond half of this study. They were randomized to a
regimen of one of four /3-adrenergic receptor blocking
drugs, each to be taken once daily in the morning. The
initial dose of each drug was atenolol, 100 mg (n = 7);
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276 HYPERTENSION VOL 11, No 3, MARCH 1988
metoprolol, 200 mg (n = 9); pindolol, 15 mg (n = 8);
propranolol, 160 mg (n = 1); and slow-release pro-
pranolol, 160 mg (n = 6). The manufacturers provided
white, unmarked formulations. The randomization
schedule was held in the hospital pharmacy until after
the second study.
Subjects were evaluated subsequently at monthly
intervals at the same time of day, and doses were
titrated as required.
20
After 3 to 8 months (mean time, 5
months), the protocol was repeated at the same time of
day as in the first (control) study with the assigned drug
taken as usual at 0800. Average doses were atenolol,
121 57 mg (meanSD); metoprolol, 300 107
mg; pindolol, 32 10 mg; and propranolol, 457 194
mg. The average clinic blood pressure of these subjects
was 175 25/107 11 mm Hg before the first (con-
trol) study and 146 24/93 15 mm Hg at the last
clinic visit before the second (treatment) study.
Rest and exercise samples of venous blood for plas-
ma norepinephrine concentrations were obtained on
both study days in 21 of these subjects.
Statistics
The Statistical Package for the Social Sciences Pro-
gram (SPSS) was used for paired comparisons (Stu-
dent's / test), stepwise multiple regression analysis,
and calculation of partial correlation coefficients.
28
The Bonferroni method
29
was used to calculate a modi-
fied t statistic when multiple comparisons were per-
formed. Partial correlation coefficients were also cal-
culated to determine the relationship between two
variables while excluding the confounding effect of
other variables. Results are reported as means SD
throughout.
Results
AH Subjects
Baroreceptor Reflex Sensitivity
Mean weighted baroreceptor reflex slopes (ex-
pressed as BRS) ranged from 1.6 to 38.1 msec/mm Hg
(mean, 8.0 7.8 msec/mm Hg; n = 55), and as de-
scribed by Gribbin et al. ,
18
they were inversely related
to age and MAP and displayed a skewed distribution.
A normal distribution and linear relationships between
BRS, age ( r = -0.62,p<0.0001), and systolic blood
pressure (r = - 0. 61, p< 0.0001), but not heart rate,
were established when these slopes were transformed
logarithmically (log
]0
BRS; LBRS). Therefore, LBRS
was used to represent BRS in subsequent calculations.
Correlation Between Short-term and Medium-term
Variability of Blood Pressure and Level of Pressure
Within Subjects
In no subject was the short-term variability of blood
pressure (2-minute intervals about the time of waking)
related to the absolute level of arterial pressure (Table
2). In three of the eight subjects studied, pulse interval
and its variability were positively correlated.
Over the medium term (1-hour segments), variabil-
TABLE 2. Correlation Between MAP and Systolic Blood Pressure
and Pulse Interval and Their Short-term (2 min) Variability in Eight
Subjects
VMAP vs MAP
0.10
0.07
0.50
-0.02
0.24
-0.31
-0. 27
0.21
VSBP vs SBP
0.22
0.21
0.25
-0. 08
0.39
-0. 42
-0. 06
0.37
VPI vs PI
0.65*
0.76*
0.36
-0. 30
0.01
0.54
0.95*
0.31
Values are correlation coefficients. PI = pulse interval (msec);
SBP = systolic blood pressure; V = variability.
*p<0.05.
ity of a subject's blood pressure was again unrelated to
the level of blood pressure in these eight subjects, and
the variability of pulse interval also was unrelated to its
absolute value (Table 3).
Variability of Ambulatory Blood Pressure
Between Subjects
The average waking ambulatory MAP ranged from
90 to 160 mm Hg (mean, 118.3 17.9 mm Hg;
n = 56). Its variability (VMAP) ranged from 8.5 to
20.5 mm Hg (mean, 13.8 2.4 mm Hg; see Table 1).
Variability of MAP increased with age (r = 0.32,
p<0.01) and MAP (r = 0.43, p<0.0005) and dis-
played an inverse correlation with LBRS (r = 0.47,
p<0.0002, n = 55). Variability of MAP was not
related to the variability of pulse interval (r = 0.12).
When multiple regression analysis was performed on
these data, only LBRS contributed (p<0.005) to the
regression equation: VMAP = 16.76 - (3.79 X
LBRS) with standard error of regression coefficient
0.98.
The partial correlation between LBRS and variabil-
ity of MAP (i.e., excluding the influence of age and
MAP) was -0. 27 (p<0.05).
The independent effect of BRS on blood pressure
variability may be seen in Figure 1, in which frequency
TABLE 3. Correlation Between MAP and Systolic Blood Pressure
and Pulse Interval and Their Medium-term (1 hr) Variability in
Eight Subjects
VMAP vs MAP
-0. 14
0.22
0.28
-0. 26
-0.38
0.36
0.46
0.28
VSBP vs SBP
0.20
-0. 12
0.21
-0. 06
-0. 47
0.52*
0.26
0.70*
VPI vs PI
-0. 29
-0. 15
0.23
0.23
0.11
-0. 07
-0. 34
0.05
Values are correlation coefficients. PI = pulse interval (msec);
SBP = systolic blood pressure; V = variability.
*p<0.05.
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VARIABILITY OF BLOOD PRESSURE AND HEART RATE/Floras et al. 277
3DCD
g. mo
i 10M
50 100 150 200
Man Arterial Prtssurt DUD Hg
FIGURE 1. Frequency histograms of ambulatory waking MAP
in two subjects: Subject 1 (age, 42 years; average MAP, 104
mm Hg; variability of MAP, 12 mm Hg; baroreceptor reflex
sensitivity, 10.6 msec/mm Hg; solid line) and Subject 2 (age, 42
years; average MAP, 105 mm Hg; variability of MAP, 18 mm
Hg; baroreceptor reflex sensitivity, 5.7 msec/mm Hg; dotted
line). Subject 1 had a more sensitive baroreceptor reflex re-
sponse and displayed less blood pressure variability than Sub-
ject 2 despite similar age and mean ambulatory blood pressure.
histograms of two subjects with similar mean ambula-
tory MAPs and age, but differing BRS values, are
superimposed.
With cycling, plasma norepinephrine increased
from 645 228 to 1151 462 pg/ml (p<0.001; see
Table 3). Subjects with greater variability of MAP also
showed greater relative (i.e., percent) increases in
plasma norepinephrine when bicycling (r = 0.35,
p<0.0l).
The 16 subjects with elevated clinic pressure but
average awake ambulatory blood pressures less than
140/90 mm Hg (borderline hypertensive) were similar
in age (43 9 vs 46 12 years) to the 40 others (hy-
pertensive) but had greater reflex bradycardia in re-
sponse to phenylephrine (LBRS: 0.9 0.3 borderline
vs 0.7 0. 3 hypertensive; p<0. 05) . Their waking
MAP was lower (99 5 vs 126 1 5 mm Hg;
p<0. 00001) and less labile (VMAP: 12.4 2.3 bor-
derline vs 14.5 2.5 mm Hg hypertensive; p< 0.01;
Figure 2).
BHT
Average
ambulatory
MAP mmHg
3 + 5 126+ IS
FIGURE 2. Blood pressure and its variability in 16 borderline
hypertensive subjects (BHT) and 40 hypertensive (HT) subjects.
Single (p<0.01) and double (p<0.00001) asterisks indicate
significant difference between groups.
Variability of Ambulatory Heart Rate Between Subjects
There was no relationship between BRS and the
variability of pulse interval (r = 0.22). For example,
the variability of pulse interval (or coefficient of vari-
ation) in the 20 subjects with the most sensitive
baroreceptor reflex responses was 144 32 msec
(0.20 0. 03%) and in the 10 subjects with the least
sensitive baroreceptor reflex responses was 143 40
msec (0.21 0.05%). The variability of pulse interval
was unrelated to subjects' age or ambulatory blood
pressure.
Influence of /9-Adrenergic Receptor Blockade
Patient Randomization
Subjects' ages and clinic blood pressures before ran-
domization (control study) were similar within each of
the four groups.
Exercise Heart Rate
In 26 subjects, /3-blockade reduced resting heart rate
from 81 14 to 61 9 beats/min. Maximum exercise
heart rate during cycling was reduced from 128 24 to
93 15 beats/min. The increase in heart rate with ex-
ercise was significantly attenuated by )3-blockade
0><0.001).
Plasma Norepinephrine Concentration
Cycling increased plasma norepinephrine concen-
trations from 648 223 to 1098 433 pg/ml
(p<0. 001) before and from 730 275 to 1330 444
pg/ml (p< 0.001) during treatment. /3-Blockade had
no significant effect on baseline plasma norepineph-
rine or on the increase in plasma norepinephrine with
exercise.
Baroreceptor Reflex Sensitivity
BRS increased from 6.6 5. 2 to 9.2 2. 6
msec/mm Hg ( p<0. 01) . LBRS increased from
0.7 0. 3 to 0.8 0. 3 (p = 0.02).
Ambulatory Blood Pressure and Its Variability
/3-Blockade reduced awake ambulatory MAP (from
126.4 14.7 to 105.8 16.1 mm Hg;/7<0.001) but
did not reduce its variability (14.6 2. 5 before vs
14.9 3.3 mm Hg during /3-blockade). Mean pulse
interval increased from 667 80 to 846 103 msec
(p<0.00001), and the variability of pulse interval in-
creased from 120 22 to 186 97 msec (p< 0.002),
leaving the coefficient of variation of pulse interval
unchanged (0.18 0.04% before and 0.21 0.09%
during /3-blockade).
The variability of MAP was inversely correlated
with BRS both before (r = - 0. 42, p<0.02) and dur-
ing (r = - 0. 45, p<0.02) /3-blockade (Figure 3), ac-
cording to the following regression equations:
control VMAP = 17.32-(3.68 x LBRS) and
0-blockade VMAP = 18.53 - (4.40 x LBRS).
Variability of MAP was unrelated to average wak-
ing MAP in this smaller group either before (r = 0.28)
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278 HYPERTENSION VOL 11, No 3, MARCH 1988
25
OP
fi
3
20
- n

15
.5 <
CO c
> co
CD
10
r = -0.42
n = 30
p<0.02
I I I
05 1 1.5
Log,
0
Baroreflex Sensitivity ms/mm Hg
25
C3J
fi
3
3
5 >
< CD
>.&
20
15
< 10
B
I I I
0.5 1 1.5
Log,
0
Baroreflex Sensitivity ms/mm Hg
FIGURE 3. The variability of MAP was inversely related to
baroreceptor reflex sensitivity both before (A) and after (B)
chronic fi-adrenergic receptor blockade.
or during (r = 0.18) /3-adrenergic receptor blockade.
Similarly, there was no relationship between blood
pressure variability and the variability of pulse interval
before or during treatment.
In contrast to the control state, the variability of
MAP was not related to the relative increase in plasma
norepinephrine with bicycle exercise during ^-block-
ade ( r = - 0 . 0 8 , n = 2l).
Discussion
The principal findings in this study were 1) de-
creased BRS in hypertension is associated with in-
creased variability of blood pressure; 2) the variability
of blood pressure is not always dependent on its abso-
lute level; 3) subjects with borderline hypertension do
not have more labile blood pressure than subjects with
mild or moderate hypertension; and 4) subjects with
evidence of greater sympathetic responsiveness to ex-
ercise also display greater blood pressure variability.
We were unable to demonstrate 1) a relationship be-
tween either the variability of blood pressure or BRS
and the variability of heart rate, either before or after
/3-adrenergic receptor blockade, or 2) an effect of -
adrenergic receptor blockade on blood pressure vari-
ability.
These results suggest that persons with impaired
baroreceptor reflex regulation of heart rate are less able
to buffer short-term fluctuations in blood pressure.
Such intermittent elevations in blood pressure might
lead to adaptive changes in the heart and resistance
vessels.
30
These data relate to the waking period of the 24-hour
record. The sleep portion of the record was specifically
excluded from the current analysis. Sleep, which low-
ers both blood pressure and heart rate by about 25%, '
becomes the greatest source of blood pressure variabil-
ity and heart rate variability when 24-hour ambulatory
records are analyzed uncritically. This sleep effect
would obscure any attempt to determine mechanisms
by which waking blood pressure is regulated using
ambulatory blood pressure recordings.
Other groups have used direct ambulatory blood
pressure monitoring to document relationships be-
tween BRS and arterial blood pressure variability.
31
"
33
However, Mancia et al.
33
analyzed fluctuations in
blood pressure over brief periods, rather than its beat-
to-beat variability, whereas Watson et al.
3
' confined
their patients to hospital and restricted them to a stan-
dard protocol of rest and exercise. Our study of ambu-
lant, unrestricted subjects confirms the presence of an
inverse relationship between BRS and the beat-to-beat
variability of blood pressure during conditions that
simulate, as near as possible, subjects' daily activities.
Despite the free-ranging activity permitted in this
study, which might be expected to limit our ability to
detect such an association, the variability of waking
MAP before treatment was more closely related to
BRS than to the average ambulatory MAP, or age, and
was unrelated to the level of MAP during /3-blockade.
Multiple regression analysis revealed BRS to be the
only independent predictor of blood pressure var-
iability.
Blood pressure variability appeared to provide a
useful index of sympathetic nervous activity, correlat-
ing well with the increase in plasma norepinephrine
during bicycle exercise in untreated subjects.
The independence of pressure and its variability in
individual subjects when measured over the short and
medium term indicates that it is not necessary to con-
vert this index of variability into a coefficient of vari-
ation (SD/mean). The similarity of blood pressure
variability despite the markedly different pressures be-
fore and after /3-blockade also suggests that MAP and
its variability are regulated independently. This con-
clusion is supported by data from experimental studies
that have demonstrated that selective interruption of
baroreceptor reflex pathways either centrally or pe-
ripherally can increase the variability of arterial pres-
sure independently of the blood pressure level.
33
'
7
Our measure of BRS reflects largely the vagal re-
sponse to an increase in arterial blood pressure.
17
Blood pressure variability can be attenuated in con-
scious dogs by atropine.
34
Therefore, one interpreta-
tion of our findings is that regulation of cardiac output
by the parasympathetic nervous system is the principal
determinant of blood pressure variability in normal and
uncomplicated hypertensive subjects. Our observa-
tions during /3-adrenergic receptor blockade support
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VARIABILITY OF BLOOD PRESSURE AND HEART RATEJFloras et al. 279
such an interpretation: The significant inverse correla-
tion between BRS and blood pressure variability was
preserved. Indeed, although ^-blockade may reduce
blood pressure variability during selected periods of
activity,
35
neither a-adrenergic nor /J-adrenergic re-
ceptor blockade appears to alter ambulatory blood
pressure variability overall.
36
Although arterial compliance is a major determinant
of BRS, the baroreceptor reflex can be altered indepen-
dently of changes in arterial compliance at the level of
the central nervous system, autonomic ganglia, or the
neuroeffector junction. Angiotensin, for example, de-
creases BRS in humans
37
through a central mechanism,
likely at the level of the area postrema, and facilitates
noradrenergic transmission through a prejunctional ac-
tion. In addition, there is considerable evidence that
modulation of these reflexes by ionic mechanisms,
endogenous peptides, and drugs can occur at the level
of sensory afferents; these changes can occur indepen-
dently of alterations in arterial compliance.
38
Our data
permit us to conclude that the baroreceptor reflex con-
trol of pulse interval, as assessed by the phenylephrine
technique, bears an inverse correlation with blood
pressure variability. Without an accurate measure of
arterial compliance, we are not able to determine
whether this is the major determinant of blood pressure
variability in hypertensive subjects or whether the ef-
fect of arterial compliance on the BRS of each of these
subjects may have been modulated by one or more of
these mechanisms.
We did not observe a significant relationship be-
tween blood pressure variability and heart rate vari-
ability, in contrast to others, or between blood pressure
and heart rate variability either before or after ^-block-
ade.
32
'
33
Differing patient populations or methods may
be responsible. We included all cardiac cycles in our
analysis of these data, whereas Mancia et al.
33
pro-
cessed their records to provide mean values for each 3-
second interval. The latter approach may have contrib-
uted to their finding by eliminating extremes of blood
pressure and heart rate (regression to the mean). Fur-
ther, we assessed the variability of pulse interval, rath-
er than heart rate itself. The use of pulse interval has
several advantages: The unit interval of time is used in
the calculation of BRS; the use of pulse interval per-
mits analysis of beat-to-beat variability of the cardiac
cycle length; and frequency histograms of pulse inter-
val over the waking period are normally distributed,
whereas those of heart rate, its. inverse, are skewed.
39
Nonetheless, the standard deviation may be too crude
an expression of heart rate or blood pressure variabil-
ity. More sophisticated techniques, such as spectral
analysis,
4041
may provide additional insight into the
relationship between these two variables.
Recent studies have suggested an important contri-
bution of heart rate to the buffering of acute changes in
blood pressure in humans, such that subjects with more
sensitive baroreceptor reflexes buffer these changes
(and hence reduce arterial pressure variability) by
greater variations in pulse interval.
42
However, our
results did not permit us to conclude that the variability
of cardiac cycle length is influenced by either BRS or
blood pressure variability. The variability of heart rate
may reflect emotional and physical factors that cannot
be controlled in studies of unrestricted subjects. This
possibility may explain our inability to identify a rela-
tionship between BRS and cardiac cycle variability.
The effect of such factors on the baroreceptor reflex
control of heart rate is well documented. Mental arith-
metic,
43
handgrip,
44
'
43
and dynamic exercise
46
attenu-
ate (probably centrally) the baroreceptor reflex regula-
tion of heart rate. The extent of this attenuation cannot
be predicted from heart rate responses to pressor doses
of phenylephrine given when subjects are resting
quietly.
In contrast to the regulation of heart rate, the carotid
arterial baroreceptor reflex regulation of blood pres-
sure, as tested by the neck collar technique, is not
suppressed by mental stress
47
or isometric exercise.
48
It
may be attenuated during supine (not upright) bicycle
exercise in humans.
49
This latter point remains contro-
versial; arterial baroreceptor reflexes of conscious
dogs appear to continue to operate effectively during
treadmill exercise.
50
"
52
The strong association we ob-
served between BRS and blood pressure variability
could be explained if the reflex regulation of blood
pressure was preserved during physical activity but
was less potent in hypertensive than in normal sub-
jects.
Intermittent, noninvasive ambulatory monitoring
53
and clinic blood pressure measurements
54
have been
used to investigate the variability of blood pressure in
borderline hypertension. Although such techniques
cannot evaluate beat-to-beat blood pressure variabil-
ity, our observations support the overall conclusion of
these studies, namely, that blood pressure is not exces-
sively labile in borderline hypertension. Blood pres-
sure variability in untreated subjects was directly relat-
ed to the level of arterial pressure and age; young
borderline hypertensive subjects had less variable
blood pressure than older, more hypertensive subjects
did, even though the latter may have been less active.
We conclude that 1) of the factors studied, the de-
cline in BRS that occurs in both borderline and estab-
lished hypertension diminishes the ability to buffer
changes in arterial pressure and becomes the principal
determinant of increased blood pressure variability in
essential hypertension; 2) MAP and its variability are
regulated independently; 3) blood pressure variability
is not affected by /3-adrenergic receptor blockade; 4)
heart rate variability is not influenced by BRS and is
unrelated to blood pressure variability; and 5) patients
with borderline hypertension do not have more labile
pressure than those with established hypertension. It is
not known how variability over the 24-hour period
relates to blood pressure variability in the same subject
over weeks, months, or years. Nor is it clear whether
an increase in variability of blood pressure leads, with
time, to more cardiovascular complications,
30
" or
whether the impairment of BRS may itself contribute
to the development and maintenance of essential
hypertension.
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280
HYPERTENSION VOL 11, No 3, MARCH 1988
Acknowledgment
The cost of plasma norepinephrine determinations was borne by
Astra Pharmaceuticals (UK) and the Wellcome and Rhodes Trusts.
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