Hypertension. 2000;36:622-628
(Hypertension. 2000;36:622.)
© 2000 American Heart Association, Inc.
Lacidipine and Blood Pressure Variability in Diabetic Hypertensive Patients
Alessandra Frattola;
Gianfranco Parati;
Paolo Castiglioni;
Felice Paleari;
Luisa Ulian;
Giovanni Rovaris;
Gabriele Mauri;
Marco Di Rienzo;
Giuseppe Mancia
From Clinica Medica (F.P., G.R., G. Mauri, G. Mancia), University of
Milano-Bicocca and Ospedale S. Gerardo, Monza; Istituto Scientifico Ospedale
S. Luca (A.F., G.P., L.U.), IRCCS Istituto Auxologico Italiano, Milano; and
Laboratorio di Ricerche Cardiovascolai (P.C., M.D.R.), Centro di
Bioingegneria, IRCCS Fondazione Don C. Gnocchi, Milano, Italy.
Correspondence to Giuseppe Mancia, MD, Clinica Medica, Università di Milano-Bicocca, Ospedale S. Gerardo, Via Donizetti 106, 20052 Monza, Italy. E-mail mancia.g{at}mailserver.unimi.it
 |
Abstract
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Abstract—The aim of our study was
to assess the effects
of lacidipine, a long-acting calcium
antagonist, on 24-hour
average blood pressure, blood
pressure variability, and baroreflex
sensitivity. In 10 mildly to
moderately hypertensive patients
with type II diabetes mellitus (aged
18 to 65 years), 24-hour
ambulatory blood pressure was continuously
monitored noninvasively
(Portapres device) after a 3-week pretreatment
with placebo
and a subsequent 4-week once daily lacidipine (4 mg) or
placebo
treatment (double-blind crossover design). Systolic
blood pressure,
diastolic blood pressure, and heart rate
means were computed
each hour for 24 hours (day and night) at the end
of each treatment
period. Similar assessments were also made for blood
pressure
and heart rate variability (standard deviation and variation
coefficient) and for 24-hour baroreflex sensitivity, which
was
quantified (1) in the time domain by the slope of the spontaneous
sequences characterized by progressive increases or reductions
of
systolic blood pressure and RR interval and (2) in the
frequency
domain by the squared ratio of RR interval and
systolic blood
pressure spectral power
0.1 and 0.3 Hz over
the 24 hours. Compared
with placebo, lacidipine reduced the 24-hour,
daytime, and
nighttime systolic and diastolic blood
pressure (
P<0.05)
with no significant change in heart
rate. It also reduced 24-hour,
daytime, and nighttime standard
deviation (-19.6%, -14.4%,
and -24.0%, respectively;
P<0.05) and their variation coefficient.
The 24-hour
average slope of all sequences (7.7±1.7
ms/mm Hg) seen during placebo
was significantly increased by
lacidipine (8.7±1.8 ms/mm Hg,
P<0.01), with a significant
increase being obtained
also for the 24-hour average
coefficient
at 0.1 Hz (from 5.7±1.5
to 6.4±1.3 ms/mm Hg,
P<0.01). Thus, in diabetic
hypertensive patients, lacidipine
reduced not only 24-hour blood
pressure means but also blood
pressure variability. This reduction was
accompanied by an
improvement of baroreflex sensitivity. Computer
analysis of
beat-to-beat 24-hour noninvasive blood pressure
monitoring
may offer valuable information about the effects of
antihypertensive
drugs on hemodynamic and autonomic
parameters in daily life.
Key Words: blood pressure monitoring, ambulatory • calcium antagonists • hypertension, essential • diabetes mellitus • baroreflex
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Introduction
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Several studies have shown that the organ damage of
hypertension
is more closely associated with 24-hour average blood
pressure
(BP) than with the BP obtained in the clinical
environment.
1 2 They have also shown that in addition to
24-hour average
BP, organ damage bears a significant association with
24-hour
BP standard deviation (SD), ie, with BP variability
(BPV).
2 3 4 This implies that antihypertensive treatment
should aim
at reducing not only ambulatory mean BP values but also
ambulatory
BP fluctuations. However, these fluctuations cannot be
easily
measured in an accurate fashion by available noninvasive
techniques,
because the intermittent BP sampling, which characterizes
commonly
used 24-hour automatic ambulatory BP monitoring devices,
misses
most fast BP changes, thereby providing data of limited accuracy
and significance in assessing BPV.
5 The above problem can
be overcome by beat-to-beat monitoring, which until recently
was
possible only through intra-arterial recording of
BP.
However, this approach is difficult to apply in clinical practice
because of its invasiveness, particularly when, as requested
by studies
on antihypertensive treatment, BP recordings have
to be
performed not just once but both before and during treatment.
An alternative noninvasive approach to continuous BP monitoring has
been recently made available (Portapres device).6 We used
the Portapres technique to determine the ability of lacidipine,
a long-acting dihydropyridine calcium
antagonist,7 to reduce 24-hour mean BP and its
BPV. We studied diabetic hypertensive patients, because in these
patients autonomic dysfunction is a frequent complication, which may
contribute to an increased BPV. Despite the evidence that a pronounced
BP reduction by treatment is particularly beneficial in hypertensives
with diabetes,8 the information on the possibility of also
reducing BPV is limited. We estimated baroreflex function throughout
the day and night because BRS is an important determinant of the
magnitude of BP fluctuations in daily life.9
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Methods
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Subjects
The present study was performed in 10 mildly to moderately
hypertensive
outpatients (7 men and 3 women) with type II diabetes
mellitus.
Although the duration of diabetes and hypertension is always
difficult to assess precisely, both conditions had been present
in
these patients for at least a few years. The selection criteria
were
(1) grade 1 to 2 essential hypertension (diastolic BP
[DBP]
90 and
110 mm Hg, systolic BP [SBP]
160
and
200 mm Hg
without complications), (2) age
18 and
65
years, (3) type II
diabetes mellitus, and (4) body mass index
30
kg/m
2 for men
and
20
kg/m
2 for women. Patients were excluded from the
study
if they had any major disease besides diabetes and/or clinical
manifestations of cardiac or vascular disease.
Microalbuminuria
was present in 50% of the patients,
who had, on the other hand,
no significant retinopathy
(grade III and IV of the Keith-Wagener
classification) or
neuropathy. All patients had received oral
antidiabetic and
antihypertensive drugs, but antihypertensive
treatment was withdrawn 3
weeks before the administration of
lacidipine or placebo (see below).
The demographic and blood
chemistry data of the patients recruited for
the present study
are shown in Table 1
. Fasting plasma glucose levels were, on
average, within normal limits, whereas glycated hemoglobin
was slightly
abnormal in most patients. All subjects gave their
informed consent to
the study. The study protocol was approved
by the local ethics
committee.
Ambulatory BP and Heart Rate Monitoring
Beat-to-beat BP was monitored noninvasively through the
Portapres model 2 device (TNO-TPD, Biomedical
Instrumentation),6 which is based on the
arterial volume clamp method of Pèñaz
(Wesseling et al10 ). It measures BP through 2 small cuffs
wrapped around the middle and ring fingers of one hand; the fingers are
used alternatively at 30-minute intervals to avoid the discomfort
associated with prolonged measurements from one finger only. The
Portapres device also includes a system capable of automatically
correcting for changes (with a 2-second time constant) in finger BP
induced by modifications in the hydrostatic height difference between
the heart and the instrumented finger that are due to hand
displacements during the activities of daily life. These changes are
further minimized by instructing the subjects to refrain from
unnecessary movements of the equipped arm and hand. The
height-corrected finger BP and the hydrostatic height signal are all
stored on a flash memory card. The microprocessor, the electronic pump,
the memory card, and the battery package are all included in a soft
belt bound to the patient’s waist. Although analysis of finger
BP tracings leads to some overestimation of SBP variability, compared
with data obtained invasively from more proximal arteries, such an
overestimation is constant with time and at different BP levels, and it
does not affect comparisons between recordings performed at
different periods with or without antihypertensive
treatment.6
Protocol
The present study was performed in a single center and had a
double-blind, placebo-controlled, randomized crossover design. All
patients were subjected to a careful clinical history and physical
examination. The eligible patients first entered a single-blind 3-week
run-in period with placebo, followed by either lacidipine (4 mg) or
placebo once daily for 4 weeks. The treatment was then switched for
another 4 weeks. BP was measured in the sitting position with a mercury
sphygmomanometer, and heart rate (HR) was measured from the radial
pulse for 30 seconds. Each patient was given an appropriate number of
placebo tablets to cover the whole run-in period (21±2 days) and
thereafter was visited a second time to obtain a blood sample (for
measurement of fasting serum glucose plus collection of routine
biochemical and hematological data) and a urine sample (for
urinalysis). Patients were hospitalized in the morning and instrumented
with the Portapres device (see below), which began its
recording around noon, after the administration of lacidipine
or placebo. This procedure was repeated at the end of the run-in period
and at the end of the first and second 4-week treatment periods. During
the 24-hour Portapres recordings, patients were free to move
within the hospital area, attending to their usual activities. Some
activities were standardized more strictly; eg, the patients were asked
to be in bed for the medical visit, the afternoon siesta, and at night
(from 10:00 PM to 7:00 AM) and to have meals at
the regular hospital times.
Data Analysis
The 24-hour Portapres recording was analyzed
offline, with the analog signals sampled at 168-Hz real time and
analog-to-digital conversion carried out with a 0.25 mm Hg
resolution by dedicated software (FAST package, TNO-TPD, Biomedical
Instrumentation). SBP and DBP values were derived from each single
pulse wave. HR was computed from consecutive pulse waves. BP and HR
data were visually scanned and edited for artifacts by an interactive
procedure. Editing included the recorded segments containing the
automatic calibration signal,6 which were removed from the
tracings. In each subject, mean±SD values for SBP, DBP, and HR were
computed for each half hour of the recording and then averaged
over the entire 24 hours, daily (from 7:00 AM to 10:00
PM), and nightly (from 10:00 PM to 7:00
AM) and for each hourly subperiod. The SD and the variation
coefficient (VC) of the mean values (SD divided by the mean multiplied
by 100) were taken, respectively, as measures of absolute and
normalized short-term variability of the signals.
BRS was assessed by time-domain and frequency-domain methods for the
evaluation of spontaneous baroreflex control of HR; these methods have
been validated and described in detail previously.9 11 12
Both these methods are based on the computerized analysis of
spontaneous fluctuations in SBP and of the associated reflex
fluctuations in pulse interval (PI, the reciprocal of HR), with no need
of any external intervention on the patient. Briefly, the time-domain
method consisted of computer scanning of the SBP tracing to identify
sequences of 4 consecutive beats characterized by (1) a progressive
increase in SBP and a linearly related increase in PI (+PI/+SBP)
(correlation coefficient, r0.85) or (2) a progressive
reduction in SBP and linearly related decrease in PI (-PI/-SBP)
(r0.85). The combined number of the +PI/+SBP and
-PI/-SBP sequences was calculated for the entire 24 hours, the day
and night subperiods, and each hour of the recording. The slope
of the regression line between PI and SBP values within each sequence
was taken as an index of BRS and averaged over the 24 hours, the day
and night subperiods, and each recording hour.
The frequency domain measure of BRS was obtained from stationary SBP
and PI signal segments of 512 beats characterized by a
coherence13 value >0.5 between SBP and PI spectral powers
in the frequency ranges from 0.04 to 0.15 Hz (midfrequency [MF]) and
from 0.16 to 0.5 Hz (high frequency [HF]), by calculating for these
segments the squared ratios between PI and SBP powers. These were
called the MF and HF coefficients and taken as indices of BRS in
the frequency domain. As with the sequence method, for each subject,
average values for the MF and HF coefficients were computed for the
whole 24-hour period, daily, and nightly and for each recording
hour.
Statistical Analysis
From individual averages, we obtained means for the group that
were statistically analyzed in 3 different ways: (1) by
comparing the 2 placebo periods to determine whether there was any
effect of time per se on BP and HR; (2) after the evidence that this
was not the case (see Results), by comparing the average of the 2
placebo periods with the treatment period; and (3) by comparing the
treatment period separately with either placebo period, with special
emphasis on the second period (ie, after randomization) to eliminate
from the treatment effect whatever small and insignificant
time-treatment interaction might have occurred. Comparison between
placebo and lacidipine data were made by both the Student t
test for paired observations and by ANOVA for repeated measurements.
Given the nonnormal distribution of SD values, the statistical
significance of data obtained for lacidipine and placebo was assessed
by the Wilcoxon signed rank test. A value of P<0.05
was taken as the level of statistical significance. The ±SEM values in
the Figures refer to the between-subject standard error of the
mean.14
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Results
|
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The 24-hour averages of the SBP, DBP, and HR values obtained
for
the 10 diabetic hypertensive patients in the present study
were not
significantly different for the 2 placebo periods,
ie, the one before
and the one after randomization. As shown
in Figure 1
, the 24-hour BP profiles (average of
the 2 placebo
periods) shared a marked between-hour variability in
daytime
SBP and DBP, with some BP reduction at night with respect to
daytime values. SBP and DBP for lacidipine displayed a similar
24-hour
profile, but values were in most instances lower than
those seen during
the placebo period. Twenty-four hour, daytime,
and nighttime SBP and
DBP values were all significantly less
for lacidipine than for placebo
(Figure 2
). HR also showed
some reduction
for nighttime compared with daytime values,
but these values were not
significantly and consistently different
for placebo and
lacidipine (Figures 1
and 2
). Figure 3
shows
the variability data. For placebo
(average of 2 placebo periods),
the SD was greater for SBP than for
DBP. For 24-hour, daytime,
and nighttime placebo data, the SD values
for SBP were similar,
and the SD values for DBP were similar. This was
also the case
for lacidipine, which was characterized, however, by
significantly
lower SD values for SBP, although not for DBP,
throughout.
The VC for SBP was also always slightly lower for
lacidipine
than for placebo. On the other hand, SD and VC values for HR
were similar for the 2 conditions, with the exception of the
nighttime
values, for which both were significantly greater
for lacidipine than
for placebo. The lower ambulatory BP mean
values and variability for
lacidipine than for placebo were
also apparent when comparisons were
made between the active
treatment and the second placebo period (ie,
the placebo period
after randomization) (Table 2
). Figure 4
shows the baroreflex
data obtained by
the time-domain and frequency-domain analysis
of the 24-hour
SBP and PI signals. The number of PI/SBP sequences
identified over the
24 hours was significantly greater for
lacidipine than for placebo
(average of 2 periods) and so was
the average 24-hour regression
coefficient (or slope) of the
sequences (Figure 4
, top panels).
The number of segments showing
a high coherence between PI and SBP
powers was similar for
the 2 conditions, both in the MF and in the HF
band. The
coefficient
of the HF band was similar for placebo and
lacidipine, whereas
the
coefficient of the MF band was greater for
lacidipine
than for placebo. The increases in the slope of the PI/SBP
sequences
and in the
coefficient of the MF band for lacidipine were
more
evident during the nighttime (Figure 5
).
View larger version (20K):
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Figure 1. Twenty-four–hour profiles of SBP (top), DBP
(middle), and HR (bottom) for 10 hypertensive diabetic patients. Data
are shown as mean±SEM hourly values.  indicates placebo data; •,
lacidipine data.
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[in a new window]
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Figure 2. Twenty-four–hour, daytime, and nighttime
mean±SEM values for SBP (left), DBP (middle), and HR (right) in the 10
hypertensive subjects of Figure 1. Open bars indicate placebo
data; solid bars, lacidipine data. *P<0.05 for
differences between placebo and lacidipine.
|
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View larger version (21K):
[in this window]
[in a new window]
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Figure 3. SD (top) and VC (SDx100/mean value) (bottom
panels) for SBP (left), DBP (middle), and HR (right).
Twenty-four–hour, daytime, and nighttime data are separately shown as
mean±SEM values for the 10 hypertensive diabetic subjects of Figure 1. Open bars indicate placebo data; solid bars, lacidipine data.
*P<0.05 for differences between placebo and lacidipine
data.
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Discussion
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In the present study, the ability of lacidipine at the
once-a-day
dose of 4 mg to lower 24-hour BP in hypertensive patients
with
type II diabetes was investigated by means of a technique that
allows beat-to-beat noninvasive ambulatory BP monitoring to
be
obtained.
6 The results show that (1) SBP and DBP values
were significantly less for lacidipine than for placebo throughout
the
24 hours, (2) the BP reduction was accompanied by a reduction
in
24-hour SBP SD and VC, and (3) the above 2 effects were
associated with
no tachycardia. Thus, we can conclude that
in hypertensive
patients with diabetes, once-a-day lacidipine
effectively lowers
daytime and nighttime BP. We can also conclude
that this reduction is
not accompanied by an increase in HR,
as is sometimes seen with a
vasodilator,
15 also belonging
to the
dihydropyridine class. We can finally conclude that
SBP variability in diabetic hypertensive individuals is also
reduced by
this drug. Given the association between BP variability
and
hypertension-related organ damage,
2 3 4 this reduction
may
be regarded as an additional potential benefit of this
type of
treatment.
The present study was not designed for and therefore cannot explain
the mechanisms responsible for the reduction in BP variability induced
by lacidipine in diabetic hypertensive patients. However, it is
tempting to relate this effect to the increase in BRS induced by the
drug, because previous studies have shown that the magnitude of hourly
BP fluctuations is inversely related to the hourly
BRS.9 16 We can speculate that the enhancing effect of
lacidipine on BRS takes place because this drug (because of its high
lipophilicity7 ) acts on the structures that centrally
integrate the baroreflex arch, as has been suggested in relation to the
enhancing effect on the baroreflex of agents with a more clearly
documented central influence, such as ß-blockers and
rilmenidine.17 18 However, it is also possible that
lacidipine increases large-artery distensibility through the relaxation
of contracted (and thus stiffer) vascular muscles,19
thereby increasing the baroreceptor responsiveness to sudden BP
changes. Finally, it is possible that to some extent the increased
arterial distensibility is brought about by the reduction
in BP per se, because large-artery distensibility is related to BP in
an inverse curvilinear fashion.19
In previous studies, 24-hour ambulatory BP profiles of untreated and
treated patients with diabetic hypertension were obtained through
automatic devices that sample BP only intermittently. However,
intermittent sampling does not reliably record BP variations, which
can be particularly pronounced in diabetics. In this context, our
beat-to-beat ambulatory BP results provide 2 sets of novel data of some
interest: (1) Patients with diabetic hypertension can indeed be
characterized by increased values of hourly BP SDs and between-hour
average BP differences, ie, by an increase in 24-hour BP variability
that, compared with the SD found in patients with essential
hypertension on beat-to beat BP monitoring,20 may amount
to >50% (+66.6% and +50.1% SD for SBP and DBP, respectively). (2)
In patients with diabetic hypertension with no clinical evidence of
autonomic dysfunction (see inclusion criteria) compared with patients
with essential hypertension, the magnitude of nocturnal hypotension may
already be somewhat blunted. In particular, there may be a clear-cut
blunting of the marked reductions in BPV and HRV that normally occur at
night (50%) but occurred to a much lesser extent in our patients.
This supports previous evidence that alterations in autonomic
cardiovascular modulation can occur before disclosure
by traditional laboratory tests.21 That diabetic
patients may have an autonomic impairment earlier than is commonly
believed is further supported by the observation that in our patients
the number and the slope of events in which HR was modulated by the
baroreflex were, over the 24 hours, less than those observed in healthy
subjects,11 indicating an early dysfunction of spontaneous
reflex cardiac control.
Because no other studies have been performed on the effects of
antihypertensive treatment on the beat-to-beat ambulatory BP of
diabetic patients, the effects of lacidipine shown in the present
study cannot be compared with those of other agents. However, this will
be made possible in the future if the important advantages of the
Portapres technique over both automatic BP (ie, beat-to-beat
recording) and intra-arterial monitoring (ie, lack
of invasiveness) make this approach more widely used in clinical
pharmacological studies and in studies addressing the effect of
antihypertensive drugs on the mechanisms involved in
cardiovascular regulation.
Received February 14, 2000;
first decision March 6, 2000;
accepted April 24, 2000.
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Top
Abstract
Introduction
