Hypertension. 1998;31:843-847
(Hypertension. 1998;31:843-847.)
© 1998 American Heart Association, Inc.
Circadian Blood Pressure Variation in Hypertensive Patients With Primary Hyperaldosteronism
George A. Mansoor;
; William B. White
From the Section of Hypertension and Vascular Diseases, University of
Connecticut School of Medicine (Farmington).
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Abstract
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Abstract—A less-than-normal decline
in nocturnal blood pressure (BP) has been associated with excessive
hypertensive complications. This is concerning because secondary
hypertension is often associated with this so-called nondipper BP
profile. A nondipping pattern is more frequently found in the presence
of pheochromocytoma, Cushing's syndrome, and sleep apnea syndrome, but
the prevalence is unclear in patients with primary hyperaldosteronism.
We therefore studied ambulatory BP profiles in 16 hypertensive patients
with primary hyperaldosteronism and an equal number of essential
hypertensive subjects. The awake-sleep BP difference of the
hyperaldosteronism patients was similar to that of essential
hypertensives (15/14±3/2 versus 14/9±3/2 mm Hg,
P=NS). The prevalence of dippers and nondippers
(according to two distinct criteria) in the two groups was similar.
Repeat ambulatory BP monitoring in 12 subjects with primary
hyperaldosteronism after specific intervention (3 after surgical
removal of an adrenal adenoma and 9 after commencement and titration of
spironolactone therapy) showed highly significant reductions in office
BP (22/10±6/4 mm Hg, P<.05) and awake and sleep
BP. However, the extent of nocturnal BP decline was unchanged between
the two studies (17/16±3/3 versus 16/12±2/2 mm Hg,
P=NS). There was no correlation between the awake-sleep
difference and serum or urinary aldosterone levels or the
aldosterone-to-renin ratio. In this study, we did not
detect any differences in the awake-sleep differences between a group
of hypertensives with primary hyperaldosteronism and a control group of
essential hypertensives.
Key Words: blood pressure, ambulatory • hyperaldosteronism • blood pressure variability • hypertension, secondary
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Introduction
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The circadian BP
profile is likely a result of the complex interaction of neurological
and hormonal circadian changes and the superimposed effects of physical
and mental activity and posture.1 2 As part of
this variation, there is a long-standing observation that BP decreases
in the majority of normotensive and hypertensive subjects during
sleep.3 Therefore, a terminology has come into
practice for subjects with normal sleep BP decline who are labeled
dippers and those with a less-than-expected decline are called
nondippers. These categories are not clearly defined, and the extent of
BP reduction during sleep is affected by several factors such as age,
sleep quality, and underlying comorbidity.3 4 5
For example, autonomic failure,6 Shy-Drager
syndromes,7 catecholamine excess
states,8 chronic renal
failure,9 Cushing's
syndrome,10 and diabetes
mellitus11 are all associated with an attenuation
of the nocturnal BP decline. However, there are conflicting
reports8 12 13 14 15 16 17 on whether patients with primary
hyperaldosteronism have a normal circadian BP profile.
The issue of whether the BP profile is altered in subjects with primary
hyperaldosteronism is a relevant one because the nondipper profile is
associated with excess hypertensive
complications.18 19 20 21 22 We therefore have
prospectively evaluated the circadian BP profiles of 16 subjects with
newly diagnosed primary hyperaldosteronism and compared them with the
profiles of 16 essential hypertensive control subjects. Furthermore,
the effects of specific therapy (ie, surgical excision of an adenoma
and aldosterone antagonists) on the circadian
BP profiles have also been studied.
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Methods
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Patients and Control Subjects
The study protocol was approved by the Institutional Review
Board and conducted according to its guidelines. The study patients and
control subjects were all evaluated at our referral center for
hypertension and vascular diseases. They were all referred by their
physicians for evaluation of their hypertensive disease process because
of its severity, the suspicion of secondary hypertension, or reports by
the patient of multiple side effects from antihypertensive medications.
Patients were evaluated for primary hyperaldosteronism if they
developed spontaneous hypokalemia (serum K+
<3.6 mmol/L) or marked diuretic-induced hypokalemia
(serum K+ 
3.0 mmol/L) or had refractory
hypertension. We studied 11 women and 5 men diagnosed with primary
hyperaldosteronism as well as 16 subjects with essential hypertension.
Five of these patients developed severe hypokalemia while taking
diuretics, whereas 10 developed spontaneous hypokalemia and 1
subject was evaluated primarily because of resistant
hypertension. Patients were diagnosed in a standard way with multiple
measurements of serum and urinary aldosterone, plasma renin
activity, and urinary potassium levels on a high sodium diet after
hypokalemia had been corrected. Those patients with elevated urinary
aldosterone levels, elevated serum aldosterone
levels, or elevated aldosterone-renin ratios underwent
computed axial tomography with sections at 2.5-mm intervals to exclude
an adenoma. In some subjects, adrenal vein sampling (4 patients) and
[131I]iodomethyl-19-norcholesterol
(NP-59) adrenocortical scintigraphy with
dexamethasone suppression (4 patients) were performed.
There were 4 subjects diagnosed with an adrenal adenoma and 12 had
bilateral adrenal hyperplasia.
Control subjects with essential hypertension were taken from our
ambulatory BP monitoring database. These control subjects had been
referred to us for similar reasons as the primary hyperaldosteronism
patients but were found to have essential hypertension. Matching
control subjects were within 5 years of age, of the same gender, and
had office BP readings within 5 mm Hg.
Repeat Ambulatory BP Study
We repeated the ambulatory BP study in 3 subjects with
aldosterone producing adenoma 3 months after surgery (on no
antihypertensive therapy) and in 9 subjects with adrenal hyperplasia
after 3 to 6 months of spironolactone therapy. Patients diagnosed as
bilateral adrenal hyperplasia were treated with spironolactone in
addition to the patients' current antihypertensive therapy and then
titrated upward to a minimum of 100 mg/d. If BP control was achieved,
then withdrawal of other antihypertensives was attempted.
BP Measurements
Office BP was measured in standard fashion with the patient
sitting for 
5 minutes. The SBP was taken as the first sound on
deflation of the cuff (Korotkoff phase I), and the DBP was taken as the
complete disappearance of Korotkoff sounds (Korotkoff phase V). At
least two readings were taken and averaged to give the office BP used
in this analysis.
Twenty-four–hour ambulatory BP monitoring was performed on 9 subjects
in each group using the QuietTrak recorder (Welch Allen, Tycos) and
on 7 subjects in each group with the Accutracker II monitor (Suntech
Medical Instruments). All patients were studied on a typical workday,
and none performed night shift work. The results of the BP monitor had
to agree with the mercury sphygmomanometer within 5 mm Hg before
the study was started. Readings were made every 15 minutes during the
daytime (8:00 AM to 9:59 PM) and at least every
30 minutes at night (10:00 PM to 7:59 AM). The
obtained data were manually entered into a computer and edited
according to previously described criteria.23 All
subjects kept a written diary of activities and actual sleep times, and
this was used to separate the 24-hour data into awake and sleep times
for data analysis. Summary averages and BP loads were then
calculated. Awake BP loads were calculated using a threshold of
140/90 mm Hg, and sleep BP loads were calculated using a
threshold of 120/80 mm Hg. The individual loads are the
percentage of elevated readings during each study period.
Nondipping was defined in two ways because there is no agreement on the
best method to categorize patients. First, a nondipper was defined
according to the criterion of Verdecchia (A) in which a decline in both
SBP and DBP of <10% was present.21 A second
criterion (B) in which the systolic and diastolic
night-to-day ratio (expressed as a percentage) equals 100% was used
because this is reported to be independent of office BP
levels.4
Statistical Analysis
All statistical analyses were performed using JMP (v3.0
statistical software for Macintosh (SAS Institute). Variables that
were not normally distributed were log transformed before
analyses. Data are shown as mean±SEM unless otherwise stated.
Descriptive statistics were calculated for the awake and sleep periods
as well as for the awake-sleep BP difference (expressed as a
percentage of awake BP and as an absolute value in mm Hg). The
awake-sleep BP averages were also expressed as a ratio
percentage.4 Demographic variables between
the study patients and control subjects were tested by
2 analysis or t tests as
appropriate. Correlation coefficients were calculated by the Pearson
method, and all values of P<.05 were considered
significant. Changes in the paired BP data were analyzed in a
standard way with paired t tests.
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Results
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Baseline Demographics
Demographic characteristics of the primary hyperaldosteronism
patients and their control subjects are shown in Table 1
. The two groups were matched for age,
body mass index, treatment status, and office BPs. Eleven patients in
the primary hyperaldosteronism group and 10 patients in the control
group were receiving pharmacological therapy. In the secondary
hypertension group, 2 patients were receiving three drugs, 4 patients
were receiving two drugs, and 5 patients were receiving one drug. In
the control group, 1 patient was receiving four drugs, 2 patients were
receiving three drugs, and 7 patients were receiving one drug. One
subject in each group had adult-onset diabetes mellitus at the time of
the ambulatory BP study. No subject in either group had congestive
heart failure, renal insufficiency (serum creatinine
133 µmol/L), or orthostatic hypotension and no
patient in either group was receiving corticosteroids.
The mean duration of hypertension before the diagnosis of primary
hyperaldosteronism was 13±3 years (range, 1 to 40 years; median, 11
years). The hyperaldosteronism group, as expected, had low serum
potassium levels of 2.9±0.1 mmol/L (normal, 3.6 to 4.8
mmol/L), elevated serum aldosterone of 655±99 pmol/L
(normal, 56 to 250 pmol/L), elevated urinary aldosterone of
75±11 nmol/d (normal, <39 nmol/d), and elevated serum
aldosterone-to-renin ratio of 130±30
(aldosterone expressed in ng/dL and renin expressed in
ng/mL per hour). There were 10 other patients who were diagnosed with
primary hyperaldosteronism (5 with adenomas) during this time but did
not undergo ambulatory BP monitoring. Because of the small number of
patients with adenomas, the two subgroups were combined for
analysis.
Clinic and Ambulatory BPs
The two groups were moderately hypertensive (stage 2) with >50%
SBP loads but had similar clinic, 24-hour, awake, and asleep BP
averages (Table 1
). The awake-sleep differences in the
hyperaldosteronism group and the essential hypertension group were also
similar in the two groups (Table 2),
whether expressed as an absolute value in mm Hg (15/14±3/2
versus 14/9±3/2 mm Hg) or as a sleep-to-awake ratio percentage
(90/85±2/3% versus 90/90±2/3%). The mean percentage decline in
sleep BP (awake-sleep BP difference/awake BP) was 13±2% in the study
group and 10±2% in the control group (P=NS). There were 11
dippers in the study group and 8 dippers in the control group according
to criterion A but 15 and 13, respectively, according to the criterion
B. There were no differences between dippers and nondippers in regard
to serum and urinary aldosterone levels and
aldosterone-to-renin ratio (data not shown). There also
were no differences in the nocturnal BP decline in patients with
adenoma and those with bilateral adrenal hyperplasia (data not
shown).
In the 12 patients in whom repeat ambulatory BP studies were performed,
there was a highly significant decline in office and ambulatory BPs
(Table 3), but the awake-sleep BP
difference remained unchanged. The BP load declined significantly for
both awake (70/50±9/9% versus 30/16±10/3%, P.05) and
sleep (68/40±10/10% versus 38/14%, P<.05) BP. The three
patients with adenomas who had a repeat ambulatory BP study were all
normotensive at the repeat study (24-hour BP, <135/85 mm Hg),
and of the remaining 9 with bilateral adrenal hyperplasia, only 3
subjects had an average 24-hour BP of >135/85 mm Hg. No patient
had 24-hour SBP of >160 mm Hg or 24-hour DBP of >90
mm Hg. The number of dippers at the first and second studies was 8 and
9, respectively, according to criterion A, and 11 and 11, respectively,
according to criterion B.
Relationship of BP to Biochemical Values
There were no significant correlations between office or
ambulatory BP and serum aldosterone, urinary
aldosterone, or the aldosterone-to-renin ratio.
There also were no relationships between the awake-sleep differences
and these biochemical parameters.
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Discussion
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The main finding of this study was that the circadian BP variation
in subjects with primary hyperaldosteronism is preserved compared with
that of essential hypertensives. Of note, the hyperaldosteronism
patients studied here composed a group mainly with bilateral adrenal
hyperplasia and stage 2 hypertension and were otherwise clinically
uncomplicated. Our study examined the nocturnal decline as an absolute
number in mm Hg relative to the awake pressure, as a percentage
of awake BP, as a ratio of sleep to awake BP, and categorically as
dipper and nondipper according to two definitions. When 12 patients
underwent ambulatory BP monitoring 3 to 6 months after specific
intervention for primary hyperaldosteronism, there was a highly
significant reduction in office and ambulatory BP averages and BP loads
but no change in the awake-sleep BP differences according to any
definition.
The reduction in mean arterial pressure of 13% and 10% in
the primary hyperaldosteronism and essential hypertension groups,
respectively, is well within the values described in large studies that
examined the BP decline during sleep. For example, in their study of
1042 subjects with untreated essential hypertension, Schillaci et
al5 showed that individuals in the age group of
50 to 59 years have an 11.2/14.4±7/8% decline in systolic and
DBP. Similarly, the calculated sleep-to-awake ratios in a large group
of subjects with essential hypertension4 are
similar to our findings.
It is problematic to researchers that different definitions
and methods are used to express the circadian BP variation. Therefore,
in our study we were careful to use more than one method so
deficiencies in a particular method would not jeopardize our results.
For the categorization of dippers and nondippers, we used two
definitions that have been studied in a large number of subjects. The
first criterion (A) was taken from a prognostic study done in
Italy,21 in which a nondipping profile was found
to have a deleterious effect on cardiovascular events
in women. The second4 criterion (B) is from the
large international database of >7000 patients, which is the most
comprehensive analysis of nocturnal BP to date.
Our results are consistent with previous results that in
general show the circadian BP variation is preserved in patients with
primary hyperaldosteronism (Table 4). Not
included in this table are the results of two other
studies16 17 from which the absolute awake-sleep
drop in BP could not be calculated. A review of publications in this
area shows considerable differences in methodology used by authors to
examine the circadian BP profile. The cosinor
method16 has been used by a few authors but is
very rigid and imposes unrealistic limitations on the
data.24 Also, there is variability in the
definition of awake and sleep periods and in the methods. We used
patient diaries to separate the ambulatory BP data and then calculate
the BP difference; this method has been shown to avoid
misclassification of the dipping status.25
Our study also illustrates that specific therapy for primary
hyperaldosteronism of surgical removal of an adrenal adenoma or
administration of spironolactone significantly reduces office, awake,
and sleep BPs as well as BP loads but does not affect the awake-sleep
difference. Such effects of specific therapy on sleep BP have not been
reported previously. Almost all patients with bilateral adrenal
hyperplasia achieved good BP control with the addition of
spironolactone to their regimen.
The possible ways that secondary hypertension may affect the circadian
BP include sympathetic nervous system activation, fluid retention, and
increases in peripheral vascular resistance. A reduction in
the activity of the sympathetic nervous system during sleep is thought
to be a major factor contributing to the normal decline in sleep
BP.26 Many causes of secondary hypertension, such
as pheochromocytoma,6
hyperthyroidism,6 and sleep
apnea,27 28 but not primary
hyperaldosteronism,29 30 do indeed appear to
elevate sleep BP, primarily through activation of the sympathetic
nervous system.
Our inability to detect a relationship between either office or
ambulatory BP levels and serum or urine aldosterone levels
are similar to the findings of Blumenfeld et
al,31 who found a relationship between mean
arterial pressure and urinary aldosterone in
subjects with adenomas but not in patients with bilateral adrenal
hyperplasia.
Our study has several limitations. Our data were obtained in a small
sample size but indicated that the essential hypertensive control
subjects tended to have smaller awake-sleep BP declines. A larger
study would help confirm our findings. Our conclusions cannot be
assumed to apply to patients with more severe levels of hypertension
due to primary hyperaldosteronism or to subjects with only
aldosterone-producing adenomas. Furthermore, it is not
possible to be sure whether differences in drug therapy and levels of
physical activity affected our results.
In conclusion, primary hyperaldosteronism is associated with a normal
circadian BP variability, and the specific treatment of primary
hyperaldosteronism leads to a highly significant decline in all BP
parameters but does not alter the extent of the nocturnal
BP variation. Additional studies of larger number of subjects with both
aldosterone-producing adenoma and adrenal hyperplasia are
warranted to exclude a small blunting in sleep BP.
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Selected Abbreviations and Acronyms
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| BMI |
= |
body mass index |
| BP |
= |
blood pressure |
| DBP |
= |
diastolic BP |
| HR |
= |
heart rate |
| SBP |
= |
systolic BP |
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Acknowledgments
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This work was supported in part by General Clinical Research
Center Grant MO1-RR-06192 at the University of Connecticut Health
Center.
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Footnotes
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Presented in part at the 12th American Society of Hypertension Meeting, San Francisco, May 29, 1997.
Requests for reprints to George A. Mansoor, MD, Section of Hypertension and Vascular Diseases, Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT 06030-3940.
Received July 22, 1997;
first decision September 10, 1997;
accepted October 24, 1997.
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Top
Abstract
Introduction