© 1998 American Heart Association, Inc.
Original Contributions |
Depressed Heart Rate Variability and Arterial Baroreflex in Conscious Transgenic Mice With Overexpression of Cardiac Gs
From the Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences (M.U., K.A., A.S., N.S., Y.I., D.E.V., R.P.S., S.F.V.), Pittsburgh, Pa; the Department of Molecular and Cellular Biology, The Edison Institute, Ohio University (T.E.W.), Athens, Ohio; the First Department of Internal Medicine, Nippon Medical School (M.O., H.H.), Tokyo, Japan; and COR Therapeutics (C.J.H.), South San Francisco, Calif.
Correspondence to Stephen F. Vatner, MD, George J. Magovern Chair and Director, Cardiovascular and Pulmonary Research Institute, Allegheny University of the Health Sciences, 320 East North Ave, Pittsburgh, PA 15212.
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Abstract |
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Abstract—Recently, we developed a transgenic mouse with cardiac-specific Gs
overexpression (TG mouse), which exhibits enhanced postsynaptic
ß-adrenergic receptor signaling, ultimately developing a
cardiomyopathy. The goal of the present study
was to determine whether cardiac Gs
overexpression alters autonomic cardiovascular control,
which could shed light on the mechanism responsible for the later
development of cardiomyopathy. Mean
arterial pressure was increased (P<.05) in
conscious, chronically instrumented TG mice (123±1 mm Hg)
compared with age-matched wild-type (WT) control mice (103±1
mm Hg). Respiratory frequency was increased (P<.05) in
TG mice (269±26/min) compared with WT mice (210±20/min). By use of
telemetric techniques, baseline heart rate (HR) was elevated
(P<.05) in conscious, untethered TG mice (696±13 bpm)
compared with WT mice (568±28 bpm). Intrinsic HR, after
propranolol and atropine or after ganglionic blockade with
hexamethonium, was not different between TG and WT
mice. Both the normal minute-to-minute and circadian variations of HR
observed in WT mice were markedly blunted in TG mice. HR variability
was assessed by the time-domain and frequency-domain methods. At
baseline, time-domain analysis indices were reduced
(P<.05) in TG mice compared with WT mice. Although the
low frequency (LF) component was higher (P<.05) than
the high frequency (HF) component in WT mice, the LF component was less
(P<.05) than the HF component in TG mice. In addition,
arterial baroreflex regulation of HR was markedly blunted
in TG mice in response to both nitroglycerin-induced
hypotension and phenylephrine-induced hypertension. The
reduced LF/HF ratio in TG mice was surprising in view of enhanced
ß-adrenergic signaling and may be due to reduced neural tone
secondary to the elevated arterial pressure or alterations
in arterial baroreflex control. Dobutamine
infusion in WT mice also resulted in depressed HR variability. The
combination of elevated baseline HR, arterial pressure, and
respiratory frequency suggests that enhanced ß-adrenergic signaling
in TG mice results in reduced HR variability, in terms of both
minute-to-minute variability and the lack of circadian variations in
HR. The lack of normal HR variability in general and the failure of HR
to decline, even during sleep, may actually be critical mechanisms
contributing to the ultimate development of
cardiomyopathy in these animals.
Key Words: spectral analysis • sympathetic nervous system • ß-adrenergic receptor • circadian rhythm • arterial baroreflex
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The stimulatory GTP-binding protein (Gs) plays an important role in ß-adrenergic signal transduction and, consequently, control of heart rate.1 Gs is activated by catecholamines binding to ß-adrenergic receptors, and subsequently, its
subunit
(Gs) stimulates the intracellular
cAMP pathway. This leads, in turn, to phosphorylation
of L-type Ca2+ channels by cAMP-dependent protein
kinase A. Additionally, Gs may stimulate cardiac
Ca2+ channels directly. Anesthetized
transgenic mice with cardiac-specific
Gs overexpression (TG mice) exhibit
enhanced heart rate and left ventricular contractile
responses to exogenous
catecholamines.2 In view of this, it
is likely that these TG mice with overexpressed cardiac
Gs exhibit altered autonomic control,
which could be important in understanding the mechanisms contributing
to the later development of cardiomyopathy in that
model.3
Accordingly, the goal of the present investigation was to determine
whether cardiac Gs overexpression
alters autonomic cardiovascular control of heart rate
in chronically instrumented conscious mice. To accomplish this goal,
heart rate and its variability were assessed in conscious mice using
both time- and frequency-domain
analyses.4 5 Studying these mice in the
conscious state was particularly important, because
anesthesia influences heart rate control in
general6 7 and heart rate variability in
particular.7 8 This was verified in the
present study by examining heart rate variability before and after
general anesthesia. Studies were also conducted using
tele- metric techniques to avoid the effects of restraints and
tethers on autonomic control. To further understand heart rate control,
additional experiments measuring arterial pressure and its
effect on heart rate were conducted in conscious, chronically
instrumented TG mice and age-matched controls, since
arterial baroreflexes are critical to heart rate control.
Additional studies on respiratory control were also conducted in the TG
mice and wild-type (WT) controls. The effects of sympathetic and
parasympathetic blockade with propranolol and atropine as
well as ganglionic blockade with hexamethonium were
also examined. Finally, we wished to determine whether administration
of a sympathomimetic amine, dobutamine, to WT controls
would result in a picture of heart rate variability mimicking that in
TG mice.
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Materials and Methods |
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Animals
Twenty-four male TG mice (5.2 months old) and 26 male WT littermates (5.3 months old) from the same genetic background were studied. Briefly, the transgene consists of a rat
-myosin heavy
chain promoter linked to a Gs DNA
coding for the short isoform of
Gs.9 Animals
used in the present study were maintained in accordance with the
Guide for Care and Use of Laboratory Animals (Department of
Health and Human Services publication No. [NIH] 83–23, revised
1985).
Effects of Autonomic Blockade on Heart Rate
The mice were anesthetized with ketamine (0.065
mg/g), acepromazine (0.002 mg/g), and xylazine (0.013 mg/g) injected
intraperitoneally.2 In seven
TG mice and nine WT controls, three electrodes were placed
subcutaneously, two on either side of the thorax and one on the
midback, and a PE-10 catheter was inserted into the right jugular vein.
The catheters and electrodes were tunneled subcutaneously to the back,
externalized, and secured in a plastic cap. All mice were treated with
30 mg of cephalothin subcutaneously for 3 days after surgery.
Experiments were initiated 3 to 6 days after recovery from surgical
instrumentation. In the interim, the mice were trained daily for 1 to 3
hours to rest quietly in a mouse holder (Kent Scientific Co). On the
day of the study, each mouse was placed in the mouse holder, the
jugular venous catheter was accessed and connected to a microliter
syringe (Hamilton Co), and the three electrodes were connected to an
ECG amplifier (Gould). All experiments were recorded with animals
in the conscious state between 10:00 AM and 3:00
PM on a multichannel tape recorder (Honeywell). After a
30- to 120-minute control period, when a stable heart rate was
achieved, the baseline ECG was recorded for 30 to 40 minutes.
Atropine (1 mg/kg) was then administered intravenously
using an infusion pump (Harvard Apparatus, Inc), and the
ECG recording was repeated. On a separate day, after a baseline
recording as described above, propranolol (1 mg/kg)
was administered intravenously, the ECG recording
was again repeated, and then another ECG recording was taken
after atropine (1 mg/kg) was administered
intravenously.
We tested the effects of hexamethonium on heart rate and heart rate variability in five TG mice and six WT controls. Hexamethonium (30 mg/kg) was slowly administered intravenously over a 10-minute period.
Telemetric ECG Recording in Mice
Five TG mice and six WT controls, similar in age to the other
mice, were anesthetized as above, and a telemetric transmitter
(TA20E, Data Science Co Ltd) was implanted in the peritoneal cavity
with paired wire electrodes placed subcutaneously over the thorax
(chest bipolar ECG lead). Experiments were initiated 3 to 6 days after
recovery from surgical instrumentation. Mice with implanted telemetric
devices were housed in individual cages with free access to food and
water and were exposed to 12-hour light/dark cycles (light, 6:00
AM to 6:00 PM; dark, 6:00 PM to
6:00 AM) in a thermostatically controlled (24°C to
26°C) room. ECGs were recorded from the untethered conscious mice
for 48 hours by using a tape recorder (Metrum) (Fig 1
).
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Effects of ß-Adrenergic Stimulation on Heart Rate in WT
Controls
In five WT controls, surgical instrumentation was performed as
described for autonomic blockade. After baseline recording,
dobutamine (20 to 30 µg ·
kg-1 · min-1) was
administered intravenously. After the heart rate response
stabilized during dobutamine infusion, another ECG
recording was taken, which was subjected to analysis of
time and frequency domains.
Effects of Anesthesia on Heart Rate in WT
Controls
Six WT controls were anesthetized as described above and
positioned on a warming pad (Deltaphase isothermal pad) to keep
temperature constant at 37°C. ECG leads were attached to each limb
using needle electrodes (Grass Instruments). After the administration
of anesthesia, the ECG was recorded when the heart rate
stabilized.
Arterial Pressure Measurement
Six TG mice and six WT controls were anesthetized, and
ECG electrodes and a jugular venous catheter were implanted as
described. In addition, a mechanically stretched PE-10 catheter was
inserted into the femoral artery. The catheters and electrodes were
tunneled subcutaneously to the back, externalized, and secured in a
plastic cap. Experiments were initiated 2 to 3 days after recovery from
surgical instrumentation. Each mouse was placed in the mouse holder,
and the femoral artery catheter was connected to a 1.8F
micromanometer catheter (Millar Instruments) via a
25-gauge needle. The jugular venous catheter was connected to a
microliter syringe. After the mouse was allowed to rest in the mouse
holder for 30 to 120 minutes and a stable heart rate was achieved,
baseline ECG and arterial blood pressure were recorded
for 20 minutes. After baseline recording, arterial
baroreflex sensitivity was also assessed by pharmacologically
manipulating arterial pressure. Hypotension was induced by
nitroprusside (5 to 40 µg/kg), and hypertension was induced by
phenylephrine (5 to 40 µg/kg). All experiments were
recorded in the conscious mice between the hours of 9:00
AM and 12:00 noon on a multichannel tape recorder
(Honeywell).
Respiratory Rate and Frequency Measurement
In nine TG mice and nine WT controls, piezoelectric ultrasonic
dimension crystals were implanted on opposing left and right surfaces
of the chest wall to measure respiratory rate and frequency. All
experiments were performed with animals in the conscious restrained
state. Respiratory rate was recorded after the mouse had relaxed
and a stable heart rate was achieved.
Quantification of Atrial Gs
Protein
The procedures for quantifying atrial
Gs protein were similar to those used
previously in the ventricle in this model.9 Mouse
atria (n=5 Gs atrial samples and n=5
WT control atrial samples) were placed in cold Tris buffer (50
mmol/L Tris-HCl, 5 mmol/L EDTA, and 1 mmol/L
MgCl2, pH 7.4) and homogenized with a
Polytron (Brinkmann) at half speed three times for 5 seconds each.
Samples were centrifuged at 14 000g for 30 minutes,
and the pellet was resuspended in Tris buffer plus 250 mmol/L
NaCl. The suspension was homogenized for 15 seconds and
then placed on ice for 20 minutes. Samples were centrifuged at
14 000g for 30 minutes. The pellet was resuspended in Tris
buffer, and protein was quantified. Tissue extracts were then lysed in
Laemmli's buffer (62.5 mmol/L Tris-HCl, 2% SDS, 1%
ß-mercaptoethanol, 10% glycerol, and 0.0025% bromophenol blue) for
Gs immunoblotting.
The lysate was boiled for 5 minutes, and 20 µg was subjected to 10%
SDS-PAGE. The gels were transferred to Immobilon-P membranes (Millipore
Corp) by use of a semidry apparatus (Emprotech). The
membranes were blocked with 2.5% BSA (fraction V, Sigma Chemical Co)
and 2.5% nonfat dry milk in TBST (50 mmol/L Tris-HCl, pH 8.0,
100 mmol/L NaCl, and 0.5 mL/L Tween 20) for 1 hour at room
temperature. Blots were probed with
Gs-specific antisera (Santa Cruz
Biotech) for 1 hour at room temperature. Unbound antibodies were
eliminated by three 5-minute washes in TBST followed by incubation with
anti-rabbit F(ab')2 coupled to horseradish
peroxidase (Amersham Corp) for 20 minutes at room temperature. Unbound
antibodies were washed as described above with an enhanced
chemiluminescence detection kit (DuPont-NEN). The blots were exposed to
x-ray film, and the bands were quantified by densitometry.
Data Analysis and Statistics
The ECG and respiratory signals were analyzed off-line
on a PC computer (Hewlett Packard Vectra 133v). After antialias
filtering at a cut-off frequency of 1 kHz with eight-pole Butterworth
filters, all the signals were sampled at 2 kHz. R waves were detected
from the ECG, and a 30-Hz heart rate tachogram was
constructed.10 Maximum inspiration was used to
detect respiratory cycle, and a 30-Hz respiration rate tachogram was
constructed. The power spectra of the heart, as
(beats/min)2 , and respiration rate, as
(breaths/min)2 , were analyzed for a
30-second segment by autoregressive spectral analysis. The
degree of the autoregressive model was determined by optimizing
Akaike's theoretic information criterion.11 We
defined the low frequency (LF) and high frequency (HF) bands as 0.1 to
1.75 Hz and 1.75 to 5.0 Hz, respectively. To normalize the power
spectra, LF and HF energy levels, which represent the spectral
components of the LF band and HF band, respectively, were divided by
the total power, defined as the amplitude of the spectral component
between 0.03 and 7.5 Hz.
All data were reported as mean±SE. Comparisons between TG mice and WT controls were made by using Student's t test for group data. The responses to autonomic blockades were analyzed by one-way ANOVA for repeated measurements. If the ANOVA demonstrated significant overall differences, individual comparisons between baseline and the response to each drug were made by contrast analysis. A value of P<.05 was taken as the minimal level of significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Baseline Heart Rate in Conscious State
The resting heart rates of restrained, conscious TG mice (736±15 bpm, n=12) were higher (P<.05) than those of WT controls (580±18 bpm, n=13) (Table 1
). In
conscious, unrestrained mice, average heart rates derived using
telemetry over 48 hours were also elevated (P<.05) in TG
mice (696±13 bpm, n=5) compared with WT controls (568±28 bpm, n=6).
Interestingly, in conscious mice, heart rates were not different in
conscious restrained versus unrestrained WT controls (580±18 versus
568±28 bpm) but were significantly higher (P<.05) in the
conscious restrained overexpressed Gs
mice compared with conscious unrestrained TG mice (736±15 versus
696±13 bpm). These differences may be due to the postsynaptic
amplification of sympathetic effects in the TG mice, associated with
restraint.
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Circadian Variation of Heart Rate in Unrestrained Mice
Heart rates were elevated during both daytime and nighttime in TG
mice compared with the WT controls. However, the variance of the
24-hour heart rate recordings was reduced (P<.05)
in TG mice (1335±757 bpm2 ) compared with WT
controls (4776±2099 bpm2 ). Furthermore, the
normal circadian variation observed in WT controls, ie, a significantly
higher heart rate during nighttime than during daytime, was markedly
blunted in TG mice (Figs 2 and 3).
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Time-Domain and Frequency-Domain Indices of Variation in Restrained
and Unrestrained Mice
The time-domain indices of variation, the standard deviation of
the R-R interval, and the coefficient of variation of the R-R interval
were reduced (P<.05) in TG compared with WT restrained
(Table 1
) and unrestrained (data not shown) mice. The frequency-domain
indices, both in restrained (Table 2) and
unrestrained (Figs 3 and 4) mice, ie, the
LF component, HF component, and total power, were also decreased
(P<.05) in TG mice compared with WT controls. In WT
controls, the normalized LF component (P<.05) was higher
than the HF component. Conversely, in TG mice, the normalized LF
component was lower (P<.05) than the HF component. This
difference, expressed as the LF/HF ratio, was reduced
(P<.05) in TG mice compared with WT controls.
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Effects of Autonomic Blockade
Effects of Propranolol and Atropine
Propranolol administration decreased heart rate to a
greater degree (P<.05) in TG mice (-142±10 bpm, n=6) than
in WT controls (-85±10 bpm, n=9). Atropine administration increased
(P<.05) heart rate less (P<.05), by 18±7 bpm,
in TG mice (n=7) than in WT controls (94±21 bpm, n=7). Intrinsic heart
rate following combined autonomic blockade with propranolol
and atropine was not different between TG mice (588±34 bpm, n=6) and
WT controls (532±14 bpm, n=8) (Fig 5).
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Effects of Ganglionic Blockade
After ganglionic blockade with hexamethonium, the
baroreflex heart rate response to sodium nitroprusside was blocked by
90% in WT controls and 88% in TG mice, whereas the baroreflex heart
rate response to phenylephrine was blocked by 82% in WT
controls and 86% in TG mice. Hexamethonium increased
heart rate in WT controls (557±25 to 632±32 bpm). In contrast,
hexamethonium decreased heart rate in TG mice (from
749±12 to 656±37 bpm). After hexamethonium, just like
after combined propranolol and atropine, intrinsic heart
rates were no longer different in TG mice compared with WT controls
(Fig 5).
In WT controls, both the LF and HF components were significantly
(P<.05) decreased after autonomic blockade with atropine
and propranolol (LF, from 98±29 to 1±1; HF, from 29±8 to
4±2; n=5), and the values were not different from the baseline values
of TG mice. On the other hand, in TG mice, these components were also
decreased after autonomic blockade with atropine and
propranolol but were not statistically different (LF, from
4.1±1.6 to 0.4±0.1; HF, from 6.0±2.3 to 1.3±0.3; n=5),
because fluctuations in heart rate mediated by sympathetic and
parasympathetic inputs were already markedly depressed at baseline.
Similar changes were also observed after administration of
hexamethonium (Table 3).
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Baroreflex Sensitivity
Baseline mean arterial pressure was elevated
(P<.05) in TG mice (123±1 mm Hg, n=6) compared with
WT controls (103±1 mm Hg, n=6). Arterial baroreflex
sensitivity (Fig 6) was assessed by
pharmacologically manipulating arterial
pressure. Nitroprusside-induced hypotension resulted in less
(P<.05) of an increase in heart rate in TG mice (+33±9
bpm) than in WT controls (+148±19 bpm), despite a greater decrease in
mean arterial pressure in TG mice (-39±4 mm Hg)
than in WT controls (-16±3 mm Hg).
Phenylephrine-induced hypertension also elicited less
bradycardia in TG (-83±17 bpm) than in WT controls (-186±20 bpm),
although increases in mean arterial pressure were similar
in TG mice (+28±4 mm Hg) and WT controls (+24±3
mm Hg).
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Effects of Dobutamine
In WT controls, dobutamine increased heart rate (from
548±28 to 697±15 bpm) and decreased markedly the power spectra (Fig 7). Indeed, the power spectra in WT
controls in the presence of dobutamine were
indistinguishable from those in TG mice under baseline conditions (Fig 7).
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Effects of Anesthesia
In WT controls, anesthesia decreased heart rate
(248±34 bpm) and also decreased the power spectra (Fig 7).
Respiratory Frequency
Respiratory rate was higher (P<.05) in TG mice
(269±26 breaths/min) than in WT controls (210±20 breaths/min) (Fig 8). The power spectra of respiratory
variability are compared with heart rate variability in Fig 8. The
power spectra of respiration was coupled closely with the HF component
of the ECG power spectra.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have developed a TG mouse model with overexpression of cardiac Gs
.2 3 9 This
mouse heart, in vitro, is characterized by enhanced
Gs protein and by increased numbers
of ß-adrenergic receptors binding agonists with high
affinity.9 Importantly, the G protein is also
overexpressed in the atria, ie, by 523±79% (Fig 9). In vivo, the TG mice are
characterized by augmented responses of heart rate and myocardial
contractility to ß-adrenergic receptor stimulation as
well as by elevated baseline heart rate.2 3 Our
hypothesis is that the ß-adrenergic receptor stimulatory gain is
enhanced in the TG mice. Thus, for any given amount of receptor
occupancy the effects on cardiac inotropy and
contractility are amplified.
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The first goal of the present investigation was to determine whether heart rate measured using telemetric techniques in unrestrained, conscious TG mice was also elevated and whether the alterations in ß-adrenergic signal transduction affected circadian rhythm and heart rate variability. The unrestrained TG mice had a significantly higher heart rate than did their WT littermates. Heart rates were higher in both restrained and unrestrained conscious TG mice. Interestingly, a comparison of restrained versus unrestrained heart rate measurements revealed no difference in WT controls but a significant increase in heart rate in restrained TG compared with unrestrained TG mice. This is most likely due to amplification of the consequences of restraint on sympathetic activity; ie, for any given increase in synaptic norepinephrine, a greater postsynaptic ß-adrenergic receptor gain is observed in the TG mice. Enhanced respiratory activity was also observed in TG mice that was consistent with a state of augmented sympathetic activity. The increased baseline heart rate was most likely due to enhanced sympathetic activity, since after combined sympathetic and parasympathetic blockade or after hexamethonium, the resultant intrinsic heart rate was no longer enhanced in TG mice. Interestingly, hexamethonium elicited opposite effects on heart rates in WT and TG mice, ie, increasing the heart rate as expected in WT controls and actually decreasing heart rate in TG mice. An increase in heart rate would be predicted for normal conscious animals. The fall in heart rate in TG mice after ganglionic blockade supports the argument that the increased baseline heart rate in these animals is due to enhanced sympathetic activity. It could be, however, that sympathetic tone is similar and that the increased heart rate was directly due to augmented postsynaptic ß-adrenergic receptor gain.
Surprisingly, both the normal fluctuations in heart rate that occur
during daily life and circadian variability were attenuated in TG mice
(Fig 2). In most mammalian species, heart rate is higher during the
day.12 13 However, in mice the reverse is
observed, most likely because these animals sleep during daylight
hours. In the present study, both groups of animals demonstrated
heart rates that were significantly higher during nighttime. These day
and night differences were markedly blunted in the TG mice.
To examine further these attenuated heart rate fluctuations, we used the technique of heart rate variability analysis developed by Akserlod et al,4 which provided insight into the autonomic control of heart rate. The frequency components of the heart rate spectra have been shown to be affected by both the sympathetic and parasympathetic nervous systems.4 Two major components can be identified in the heart rate spectrum: an HF component, which is associated with respiratory fluctuations,4 14 and an LF component, which is associated with baroreceptor regulation of arterial blood pressure fluctuations and includes some part of the HF component.15 16 17 Time-domain analyses of heart rate variability have been used traditionally as indices of parasympathetic tone.18
These techniques have been used extensively in larger mammals,
including humans.5 14 15 19 Less data are
available in mice,20 21 particularly conscious
mice, because of the technical limitations associated with their high
cardiac frequency. Accordingly, one important feature of the
present study was the development of techniques required to assess
heart rate variability in conscious mice. By using this method, a lack
of heart rate variability in TG mice was observed; ie, standard
deviation of heart rate and total power frequency were diminished
(Tables 1 and 2).
We also used heart rate variability analysis to evaluate autonomic regulation of the heart in the TG mice. In the present study, we observed in the mouse an LF peak in the frequency range 0.1 to 1.75 Hz and an HF peak in the frequency range 1.75 to 5.0 Hz. These results are consistent with those of other studies in mice.20 21 In addition, the frequency range of the respiratory power spectra corresponded to the HF components of ECG power spectra in WT controls and TG mice.
Naively, one might expect that the TG mice would demonstrate an
elevated LF component, corresponding to enhanced ß-adrenergic
signaling, compared with WT controls. However, the reverse was
observed. The LF component was markedly reduced in the TG mice compared
with the WT controls. The LF/HF ratio, which is commonly used as a
measure of sympathetic/parasympathetic balance, was also reduced in TG
compared with WT mice. There are several potential explanations that
could reconcile these surprising results. It is possible that because
they are acting above their normal operating point
(arterial pressure is elevated above normal) in the TG
mice, autonomically mediated reflex mechanisms (such as the
baroreceptor) are unresponsive or reset and thus generate reduced
variability in the levels of parasympathetic and sympathetic inputs to
the heart. In support of this concept, the arterial
baroreflex regulation of heart rate was found to be markedly impaired.
Reflex changes in heart rate in response to both baroreflex
hypertension and hypotension were severely blunted in TG mice (Fig 6).
Potentially, as a result, both the HF and LF peaks in the heart rate
power spectrum and measures of total heart rate variability are
markedly diminished in the TG mice. Interestingly, patients with
chronic hypertension exhibit a pattern of heart rate variability
similar to that of the TG mice, reduced HF and LF heart rate
variability.12 Another possibility relates to the
elevated respiratory rate. The respiratory frequency peaks coincided
with the HF heart rate peak. This action could also tend to reverse the
LF/HF ratio in the TG mice.
The elevated arterial and cardiac pressures in the conscious TG mice are most likely the result of enhanced postsynaptic ß-adrenergic signal transduction. These hemodynamic factors, in combination with increased cardiac output, could trigger autonomic reflexes (eg, the baroreflex) to reduce sympathetic tone and enhance parasympathetic tone. Thus, there could be a dichotomy between depressed resting neural tone and enhanced postsynaptic cellular signal transduction that is not detectable by spectral analysis techniques. It is important to keep in mind that because of amplification of ß-adrenergic signaling for the same sympathetic neural input (ie, for the same receptor occupancy), the TG mice will respond with increased cardiac activity. Conceivably, with reduced neural input, the enhanced postsynaptic signal transduction could still result in increased heart rate. This reasoning could also explain why propranolol might reduce heart rate more in TG mice than in WT controls, despite potentially reduced neural activity. Nonetheless, the higher heart rates in TG mice were indeed autonomically mediated, since intrinsic heart rates were similar in TG mice and WT controls.
The heart rate variability data after autonomic blockade in WT controls
as well as variability in response to a sympathomimetic amine or
dobutamine and also in response to anesthesia
provided clues to why heart rate power spectra were so depressed in TG
mice. Since autonomic blockade and anesthesia impair
autonomic control, both these interventions resulted in marked
reductions in heart rate power spectra in WT controls, as expected.
However, increasing postsynaptic sympathetic activity with
dobutamine also resulted in marked reductions in heart rate
power spectra in WT controls, such that their spectra were similar to
those in TG mice at baseline. These data indicate that in mice either
increasing sympathetic activity of the heart or abolishing autonomic
tone reduces heart rate variability, a condition that is observed under
baseline conditions in TG mice with overexpressed
Gs.
A final note of caution is that there is not always a direct
correlation between increased sympathetic activity on the one hand and
an increased LF component on the other. Several studies have shown that
interventions that increase sympathetic tone reflexly (eg,
nitroglycerin or postural hypotension alone) increase
the LF component.14 22 Recently Pagani et
al14 demonstrated a predominance of the LF
component in normal human subjects under conditions in which
sympathetic tone increased. Conversely, other studies, with either
direct electrical nerve stimulation or
physiological stimulation of the sympathetic system
(eg, during exercise), failed to detect an increase in the LF
component.23 24 25 26 Therefore, as noted above, it is
not possible to correlate mean levels of autonomic tone and spectral
analysis. This is important to keep in mind for clinical
studies, in which spectral analysis of heart rate variability
is often used. In this connection, a recent study in patients with
heart failure demonstrated absent LF variability despite increased
heart rate and neural sympathetic nerve
activity.19 This is particularly relevant to the
overexpressed Gs animal model, in
which reduced LF is observed in an animal model that ultimately
developed cardiomyopathy.
In summary, the overexpression of cardiac
Gs results in enhanced postsynaptic
ß-adrenergic signal transduction. This leads to chronic elevation in
ambient levels of ß-adrenergic signaling, chronic elevations in heart
rate, but depressed minute-to-minute and circadian variability and
variability in frequency spectra. This was associated with concomitant
elevations in arterial pressure and respiratory frequency.
It is possible that the chronically elevated arterial
pressure results in depressed sympathetic neural activity and
arterial baroreflex control, as shown in Fig 6, or that the
enhanced postsynaptic ß-adrenergic receptor signaling resulted in
depressed heart rate variability, as occurs with administration of a
sympathomimetic amine. In either case, the unexpected findings of
spectral frequency analysis highlight the limitations using
this technique to predict levels of sympathetic activity. The
combination of the enhanced ß-adrenergic receptor signaling with
chronically elevated heart rate and associated lack of normal
variability and circadian rhythm and impaired arterial
baroreflex control over the life of the TG mice may be important
mechanisms mediating the subsequent development of
cardiomyopathy in these
animals.2 3 This latter point may be crucial; ie,
the inability to reduce the frequency and force of cardiac contraction
even during sleep may prevent the replenishment of energy stores and
exacerbate the discrepancy between energy supply and demand, resulting
in the development of cardiomyopathy over the life
of the animals.
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Acknowledgments |
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This study was supported in part by US Public Health Service grants HL-59139, HL-33107, and HL-37404. This study was also supported in part by an educational grant from Merck Research Laboratories. We are grateful to Professor Massimo Pagani, Milano, Italy, for providing the inspiration for the utilization of the heart rate variability technique.
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Footnotes |
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1 Both authors contributed equally to this study.
This manuscript was sent to Dr François M. Abboud, Consulting Editor, for review by expert referees, editorial decision, and final disposition.
Received March 14, 1997; accepted December 10, 1997.
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References |
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1. Yatani A, Okabe K, Codina J, Birnbaumer L, Brown AM. Heart rate regulation by G proteins acting on the cardiac pacemaker channel. Science. 1990;249:1163–1166.
2.
Iwase M, Bishop SP, Uechi M, Vatner DE, Shannon RP,
Kudej RK, Wight DC, Wagner TE, Ishikawa Y, Homcy CJ, Vatner SF. Adverse
effects of chronic endogenous sympathetic drive induced by
cardiac Gs overexpression. Circ
Res. 1996;78:517–524.
3.
Iwase M, Uechi M, Vatner DE, Asai K, Shannon RP, Kudej
RK, Wagner TE, Wight DC, Patrick TA, Ishikawa Y, Homcy CJ, Vatner SF.
Cardiomyopathy induced by cardiac
Gs overexpression. Am J
Physiol. 1997;272:H585–H589.
4.
Akserlod S, Gordon D, Ubel FA, Shannon DC, Bager AC,
Cohen RJ. Power spectrum analysis of heart rate fluctuations: a
quantitative probe of beat-to-beat cardiovascular
control. Science. 1981;213:220–222.
5.
Hayano J, Sakakibara Y, Yamada M, Kamiya T, Fujinami
T, Yokoyama K, Watanabe Y, Takata K. Diurnal variations in vagal and
sympathetic cardiac control. Am J Physiol. 1990;258:H642–H646.
6. Vatner SF, Braunwald E. Cardiovascular control mechanisms in the conscious state. N Engl J Med. 1975;293:970–976.[Medline] [Order article via Infotrieve]
7. Latson TW, Ashmore TH, Reinhart DJ, Klein KW, Giesecke AH. Autonomic reflex dysfunction in patients presenting for elective surgery is associated with hypotension after anesthesia induction. Anesthesiology. 1994;80:326–337.[Medline] [Order article via Infotrieve]
8. Johnson ES, Colley PS. Effects of nitrous oxide and fentanyl anesthesia on fetal heart-rate variability intra- and postoperatively. Anesthesiology. 1980;52:429–430.[Medline] [Order article via Infotrieve]
9.
Gaudin C, Ishikawa Y, Wight DC, Mahdavi V,
Nadal-Ginard B, Wagner TE, Vatner DE, Homcy CJ. Overexpression of
Gs protein in the hearts of
transgenic mice. J Clin Invest. 1995;95:1676–1683.
10. Berger RD, Akselrod S, Gordon D, Cohen RJ. An efficient algorithm for spectral analysis of heart rate variability. IEEE Trans Biomed Eng. 1986;33:900–904.[Medline] [Order article via Infotrieve]
11. Akaike H. Statistical predictor identification. Am Int Stat Math. 1970;22:203–217.
12. Chakko S, Mulingtapang RF, Huikuri HV, Kessler KM, Materson BJ, Myerburg RJ. Alterations in heart rate variability and its circadian rhythm in hypertensive patients with left ventricular hypertrophy free of coronary artery disease. Am Heart J. 1993;126:1364–1372.[Medline] [Order article via Infotrieve]
13. Ashkar E. Twenty-four-hour pattern of circulation by radiotelemetry in the unrestrained dog. Am J Physiol. 1979;236:R231–R236.
14.
Pagani M, Montano N, Porta A, Malliani A, Abboud FM,
Birkett C, Somers VK. Relationship between spectral components of
cardiovascular variabilities and direct measures of
muscle sympathetic nerve activity in humans. Circulation. 1997;95:1441–1448.
15. Sleight P, La Rovere MT, Mortara A, Pinna G, Maestri R, Leuzzi S, Bianchini B, Tavazzi L, Bernardi L. Physiology and pathophysiology of heart rate and blood pressure variability in humans: is power spectral analysis largely an index of baroreflex gain? Clin Sci. 1995;88:103–109.[Medline] [Order article via Infotrieve]
16. Bernardi L, Leuzzi S, Radaelli A, Passino C, Johnston JA, Sleight P. Low-frequency spontaneous fluctuations of R-R interval and blood pressure in conscious humans: a baroreceptor or central phenomenon? Clin Sci. 1994;87:649–654.[Medline] [Order article via Infotrieve]
17.
Madwed JB, Albrecht P, Mark RG, Cohen RJ. Low-frequency
oscillations in arterial pressure and heart
rate: a simple computer model. Am J Physiol. 1989;256:H1573–H1579.
18. Kleiger RE, Stein PK, Bosner MD, Rottman JN. Time domain measurements of heart rate variability. Cardiol Clin. 1992;10:487–498.[Medline] [Order article via Infotrieve]
19.
van de Borne P, Montano N, Pagani M, Oren R, Somers VK.
Absence of low-frequency variability of sympathetic nerve activity in
severe heart failure. Circulation. 1997;95:1449–1454.
20.
Ishii K, Kuwahara M, Tsubone H, Sugano S. Autonomic
nervous function in mice and voles (Microtus arvalis):
investigation by power spectral analysis of heart rate
variability. Lab Anim. 1996;30:359–364.
21.
Mansier P, Medigue C, Charlotte N, Vermeiren C,
Coraboeuf E, Deroubai E, Ratner E, Chevalier B, Clairambault J, Carre
F, Dahkli T, Bertin B, Briand P, Strosberg D, Swynghedauw B. Decreased
heart rate variability in transgenic mice overexpressing atrial
ß1-adrenoreceptors.
Am J Physiol. 1996;271:H1465–H1472.
22.
Rimoldi O, Pierini S, Ferrari A, Cerutti S, Pagani M,
Malliani A. Analysis of short-term oscillations of
R-R and arterial pressure in conscious dogs. Am
J Physiol. 1990;258:H967–H976.
23. Ahmed MW, Kadish AH, Parker MA, Goldberger JJ. Effects of physiologic and pharmacologic adrenergic stimulation on heart rate variability. J Am Coll Cardiol. 1994;24:1082–1090.[Abstract]
24.
Bailey JR, Fitzgerald DM, Applegate RJ. Effects of
constant cardiac autonomic nerve stimulation on heart rate variability.
Am J Physiol. 1996;270:H2081–H2087.
25. Piepoli M, Adamopoulos S, Bernardi L, Sleight P, Coats AJS. Sympathetic stimulations by exercise-stress testing and by dobutamine infusion induce similar changes in heart rate variability in patients with chronic heart failure. Clin Sci. 1995;89:155–164.[Medline] [Order article via Infotrieve]
26.
Bernardi L, Salvucci F, Suardi R, Solda PL, Calciati A,
Perlini S, Falcone C, Ricciardi L. Evidence for an intrinsic mechanism
regulating heart rate variability in the transplanted and the intact
heart during submaximal dynamic exercise? Cardiovasc Res. 1990;24:969–981.
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|
|
|
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|
|
|
|
|
|
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|
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|
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|
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|
|
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