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1 Cardiovascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania 15213; and 2 Department of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka 812-8582, Japan
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Transgenic mice are widely used
to study cardiac function, but strain-dependent differences in
autonomic nervous system activity (ANSA) have not been explored. We
compared 1) short-term pharmacological responses of cardiac
rhythm in FVB vs. C57Black6/SV129 wild-type mice and 2)
long-term physiological dynamics of cardiac rhythm and survival in
tumor necrosis factor (TNF)-
transgenic mice with heart failure
(TNF- mice) on defined backgrounds. Ambulatory telemetry
electrocardiographic recordings and response to saline, adrenergic, and
cholinergic agents were examined in FVB and C57Black6/SV129 mice. In
FVB mice, baseline heart rate (HR) was higher and did not change after
injection of isoproterenol or atropine but decreased with propranolol.
In C57Black6/SV129 mice, HR did not change with propranolol but
increased with isoproterenol or atropine. Mean HR, but not indexes of
HR variability, was an excellent predictor of response to autonomic
agents. The proportion of surviving animals was higher in TNF- mice
on an FVB background than on a mixed FVB/C57Black6 background. The
homeostatic states of ANSA are strain specific, which can explain the
interstrain differences in mean HR, pharmacological responses, and
survival of animals with congestive heart failure. Strain-specific
differences should be considered in selecting the strains of mice used
for transgenic and gene targeting experiments.
electrophysiology; transgenic models; heart rate
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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RECENT
ADVANCES in genetic engineering have provided the tools
for reproducing cardiac pathology in biological models. For example,
mouse models have been developed to investigate the pathogenesis of
heart failure by overexpressing the pleiotropic peptide tumor necrosis
factor (TNF)- (TNF- mice) (19). Although these mouse models provide robust platforms for elucidating the pathology of heart
muscle disease, the unique physiology of the mouse heart may abrogate
the ability to apply measures that are standard in larger animals
(17). Furthermore, little attention has been given to
strain-specific physiological differences that might underlie or modify
any phenotypic changes in electrophysiological characteristics elicited
by transgenic overexpression or gene targeting.
An example of this conundrum is seen when attempting to assess autonomic nervous system activity (ANSA) in mice. Although of critical importance in the pathology of heart muscle disease, ANSA is difficult to monitor effectively in experimental animals because of 1) the complex relationships between cardiac rhythm dynamics and ANSA, 2) the varied effects of hormone status, respiratory rate, body temperature, and activity level on ANSA, 3) the inability of a controlled environment to reproduce the natural pattern of ANSA during regular daily activities, and 4) the presence of largely random variations in external and internal modifiers of ANSA (1, 8, 26, 29). Indeed, attempts to measure ANSA in mouse models have resulted in markedly different findings both in baseline heart rate (HR) and in responses to autonomic agents (7, 12, 14, 16, 17, 21, 30, 31).
We hypothesized that a significant portion of the differences between
various wild-type and transgenic mouse models might be attributable to
intrinsic variability in autonomic activity in different mouse strains.
To test this hypothesis, we measured HR variability and
pharmacological responses in three different experimental settings:
1) wild-type FVB mice, a common strain used in transgenic
overexpressors; 2) C57Black6/SV129 mice, the most common
strain found in gene-targeted mice; and 3) TNF- mice (on
a FVB background) that develop a dilated cardiomyopathy by 12 wk of
age. We found that the homeostatic states of ANSA are strain specific
and that this can explain the interstrain differences in mean HR, the
responses to pharmacological agents, and the blunted HR response in the
TNF- mouse. It may also lead to the marked strain-dependent
differences in mortality.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Ambulatory telemetry recordings were examined in 10 FVB
mice (age 3-9 mo; 3 female, 7 male), 9 C57Black6/SV129 mice (age
3-15 mo; 5 female, 4 male), and 13 TNF- transgenic mice
engineered on an FVB background (age 3-9 mo; 6 female, 7 male).
FVB mice were used because they are the most common strain used for
overexpression transgenics, whereas C57Black6/SV129 hybrids were used
because most gene-targeted (knockout) mice are engineered in SV129 stem cells and backcrossed into C57Black6. In this study, C57Black6/SV129 mice were the results of three to five backcrosses of 50%
C57Black6/50% SV129 mice into C57Black6 mice and were thus 
90%
C57Black6. Radiotelemetry devices (DATA Sciences) were implanted
subcutaneously on the backs of the mice. Twenty-four-hour recordings
were performed 6 days later with the MacLab recording system, and
animals were monitored for the duration of the drug study (2 wk). A
subset of mice was monitored for up to 5 mo.
Electrocardiographic data were digitized at 400 Hz and 16-bit resolution and interpolated to 1,600 Hz with cubic spline to enhance the time resolution. QRS complexes were classified with custom software and verified by an experienced Holter technician. The RR intervals between normal QRS complexes were extracted, and a regularly spaced time series was sampled at 16 Hz with a boxcar low-pass filter (3). Gaps in the time series resulting from noise or ectopic beats were filled in with linear splines, which can cause a small reduction in high-frequency power but do not affect other components of the power spectrum (2).
We found that the mean HR in control mice [645 ± 48 beats/min (bpm)] was approximately eight times higher than in humans, assuming an average HR in healthy humans of 80 ± 7 bpm (23). Therefore, the time intervals and time- and frequency-domain variables were adjusted for these high HRs. Time- and frequency-domain analysis of RR intervals was performed over the entire 24-h period. The time course of changes in RR intervals during pharmacological tests was analyzed in 37.5-s intervals and averaged for each consecutive 7.5-min interval. To estimate the pharmacological effects, four consecutive 7.5-min windows before and four consecutive 7.5-min windows after the injection were included in the nonparametric ANOVA. The mean values represent averages over 30 min before and after the injections. The duration of the time intervals for analysis was obtained by dividing the 300- and 3,600-s intervals, respectively, traditionally used in humans by 8.
Time domain analysis. Mean HR, standard deviation of normal RR intervals (SDNN), the square root of the mean of the squared differences between adjacent normal RR intervals (r-MSSD), and the percentage of those differences between adjacent normal RR intervals >6 ms (pNN6) were estimated such that pNN6 was analogous to the percentage of the differences between adjacent normal RR intervals that are >50 ms (pNN50) in humans (4).
Frequency domain analysis.
After the mean was subtracted from the time series, power spectral
analysis was performed with fast Fourier transform and a Hanning
window. Zero padding was applied to increase the outcome frequency
resolution, and the resulting power spectrum was corrected for the
filtering and windowing (22). The frequency ranges were obtained from the values used for the analysis of human data by multiplying by 8, which is similar to the computations used in previous
investigations (Fig. 1; Refs.
12 and 30). Power was integrated in high (HFP;
1.2-3.2 Hz), low (LFP; 0.32-1.2 Hz), and very low (VLFP;
0.0264-0.32 Hz) frequency ranges, and the ratio of low- to
high-frequency power (LFP/HFP) was also calculated. We did not use the
normalized LFP and HFP, because they provide essentially the same
information as the ratio LFP/HFP (8). The
ultra-low-frequency component (ULFP; 0-0.0264 Hz) and the 24-h
total power (TP; 0-3.2 Hz) were determined over the entire recording for comparison between different strains.
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Pharmacological tests. Tests were performed at the same time of day and in the same room; only one test was performed on each given day. The pharmacological tests were performed in the following order: saline, isoproterenol (1 µg), propranolol (4 mg/kg), atropine (1 mg/kg), carbamyl choline (carbachol; 0.5 mg/kg), methoxamine (6 mg/kg), prazosin (1 mg/kg), and saline. Serial changes in cardiac rhythm were examined during 30 min before and after each intraperitoneal injection. Methoxamine was dissolved in 0.1% DMSO. Injection with 0.1% DMSO alone had effects similar to those of saline (data not shown).
Strain-dependent survival.
Male TNF- mice (X-linked transgene) were mated with FVB or
C57Black6 females. Survival of female TNF- transgene offspring was
compared on the FVB vs. 50% FVB/50% C57Black6 background with the
Kaplan-Meier cumulative survival curve and Gehan's Wilcoxon test.
Statistical analysis. Comparisons between strains were performed with nonparametric Mann-Whitney U-test. Changes in the variables during pharmacological tests were estimated with nonparametric Friedman ANOVA for repeated measurements. Nonparametric Spearman correlations were used to assess the relationship between mean HR and its reaction to pharmacological tests. Results are presented as means ± SD unless otherwise indicated. Statistical significance was accepted at the level of P < 0.05.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Twenty-four-hour differences in strain patterns of cardiac
rhythm.
FVB mice had faster 24-h mean HRs than C57Black6/SV129 mice
(Table 1). SDNN and TP, gross measures of
HR variability, and pNN6, a measure of short-term rhythm irregularity,
were significantly lower in FVB mice than in C57Black6/SV129 mice.
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Short-term pharmacological responses to autonomically active agents
in FVB and C57Black6/SV129 strains.
Injection of saline caused a stress response manifested by an increase
in HR and a decrease in SDNN (Figs. 2 and
3A) that peaked at 8-15 min (second 7.5-min window) and
lasted ~50 min (Table 2). The peak
response to other agents injected intraperitoneally was similarly
delayed. To control for the changes in the stress response over time,
injections of saline were given at the beginning and at the end of the
protocol. The differences between the two responses were not
statistically significant.
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-adrenergic receptors with isoproterenol did not
cause any changes in HR or SDNN in FVB mice (Figs. 2 and 3). However,
r-MSSD, an index of short-term HR variations, increased in this group
compared with saline (Fig. 3). In
C57Black6/SV129 mice, which had lower baseline HRs and higher HR
variability, isoproterenol caused an increase in HR, a decrease in
SDNN, and no change in r-MSSD.
The effect of parasympathetic blockage with atropine was similar to
that of isoproterenol. Atropine did not change HR or SDNN in FVB mice
but increased HR and decreased SDNN in C57Black6/SV129 mice. In both
groups, atropine reduced the spectral indexes of HR variability, HFP
and LFP, and decreased the ratio LFP/HFP. Of note, changes in the
short-term indexes of HR variability in C57Black6/SV129 were
incoherent: r-MSSD increased, whereas pNN6 declined.
In response to propranolol, HR decreased in FVB mice but did not change
in C57Black6/SV129 mice. However, propranolol did prevent the increase
in HR in the latter group seen with the injection of saline. In FVB
mice, the HR variability did not change, contrasting the pronounced
reaction of HR. Although the HRs were unchanged in C57Black6/SV129
mice, SDNN and LFP declined.
Responses to the modifications of -adrenergic activity were similar
in both groups. Stimulation of 1-adrenergic receptors with methoxamine decreased HR and increased its total variability, reflected in SDNN. The short-term variability (r-MSSD, pNN6, and HFP)
also increased, but the upsurge in LFP was greater, causing a rise in
LFP/HFP. The effects of 1-adrenergic blockage with prazosin were small and did not reach statistical significance (data
not shown).
Long-term physiological dynamics of cardiac rhythm in FVB and
TNF- strains.
Four TNF- mice had continuous atrial arrhythmias and were excluded
from HR variability analysis. Mean HRs were somewhat slower in TNF-
mice in sinus rhythm compared with FVB control mice (Table 1).
mice compared with FVBs (Table 1). Serial
ambulatory telemetry recordings from three TNF- mice showed progressive decrease in HR, whereas the frequency of ventricular ectopy
and its complexity increased in two of the three animals (Table
3). Ventricular runs occurred two times
more often after the age of 3 mo than at a younger age. All time (SD,
r-MSSD, and pNN6)- and most frequency (TP, VLFP, and LFP)-domain
indexes and the ratio LFP/HFP also increased with time in TNF- mice.
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Survival in TNF- mice with congestive heart failure on different
genetic backgrounds.
The proportion of surviving animals with heart failure was
significantly higher in female TNF- mice on an FVB background than
in female TNF- mice on an FVB/C57Black6 background. (Fig. 4).
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Relationship to prior murine studies of cardiac rhythm.
Our data suggested that the response to autonomic agents is strain
dependent and correlates with baseline HR. We compared our data with
that of nine prior studies (Table 4). In
those studies that monitored HR for >1 h, wild-type strains with
higher average HRs had greater propranolol-induced HR deceleration
(r = 
0.94, P = 0.005;
n = 6) and smaller atropine-induced HR acceleration (r = 0.75, P = 0.05;
n = 7). Mean HR in unrestrained wild-type mice was an
excellent identifier of the strain response to -adrenergic blockage
[r = 1.0; n = 5, excluding the data
by Uechi et al. (30)].
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Main results and comparison with previous studies.
A strong relationship was identified between mean HR in the long-term
ambulatory recordings and strain-specific pharmacological responses.
Mice of the FVB strain had a high mean HR, large -blocker-induced HR
deceleration, and small atropine-induced acceleration of HR. Mice of
the C57Black6/SV129 strain had lower mean HR, small HR response to
-blocker, and large atropine-induced HR increase. This suggests that
FVB mice have higher basal sympathetic and lower parasympathetic
activity than C57Black6/SV129 mice and that mean HR is an excellent
indicator of the strain-specific homeostatic state of ANSA.
Short-term HR responses to pharmacological tests. The injection of saline induced a stress response that is likely due to endogenous catecholamines, and the duration of this effect was similar to that of isoproterenol injected intraperitoneally (Table 2). Therefore, appropriate controls are required to distinguish pharmacological effects.
The highest baseline and pharmacologically modified HRs were similar in this and previous studies, which may reflect the existence of an upper limit of sinus node automaticity in the mouse (Table 4). Reaching the upper limit may explain blunted HR responses to-adrenergic
stimulation in FVB mice, whose HRs were initially high.
In our study, the responses to -adrenergic stimulation and
parasympathetic blockage were similar (Fig. 2). Both isoproterenol and
atropine increased the HRs in C57Black6/SV129 mice but had no effect in
FVB mice. Thus the homeostatic state of ANSA could be shifted in a
similar way by modifying either sympathetic or parasympathetic
activity, which does not support the traditional point of view of
negligible parasympathetic effects in all mice (17). Our
results are not inconsistent with data previously reported by other
groups (8, 14, 30).
Specificity of cardiac rhythm indexes for analysis of changes in ANSA. Several fundamental features of the HR variability analysis may affect its representation of ANSA. First, the association between the HR variability indexes and specific changes in ANSA is not strong even in the controlled experiments (8, 13). Second, in ambulatory conditions, this association is further diminished by varying respiration and other physiological and external transients (26). Third, HR variability responses depend on individual baseline values, leading to divergent effects of the same stimulus in different subjects (18). They also depend on the intensity of the stimulation and could have different dose-response curves for different pharmacological agents (13, 27).
We sought to determine the indexes of HR variability whose changes during ANSA modifications demonstrated concordant trends in both FVB and C57Black6/SV129 mice and did not depend on baseline values. Most previous studies observed a weak correspondence between the changes in HR variability and specific ANSA modifications (14, 15, 17, 30). We also found that the association between the indexes of HR variability and modifications of-adrenergic and parasympathetic
activity was weak and affected by the corresponding baseline values. In
FVB mice with high baseline HR and low HR variability, the effects of
atropine and propranolol on total HR variability were small, whereas in
C57Black6/SV129 mice with lower baseline HR and greater HR variability,
the effects of these agents were more pronounced (Fig. 3A).
Thus caution is required for interpretation of HR variability in terms
of specific changes in ANSA. An approximate adaptation of the frequency
ranges derived for larger mammals to those in mice is possible
(17). However, in uncontrolled ambulatory conditions,
gross measures of HR variability and individually tailored pattern
recognition techniques may provide more reliable indication of changes
in ANSA than spectral methods (16, 26).
The oscillatory nature of the HR variability characteristics requires
HR to be stable during the investigated period. Because the peak
pharmacological effect of HR usually occurs 8-15 min after
intraperitoneal injection, the HR variability changes are further
delayed (Table 2).
Modifications of -adrenergic tone elicited concordant changes in FVB
and C57Black6/SV129 mice. In particular, stimulation of -adrenergic
receptors caused predominant increase in the low-frequency oscillations
manifested by an increase in the ratio LFP/HFP. This confirms previous
observations that -adrenergic control of vasomotor oscillations in
mice is confined to frequencies below 1 Hz (15, 17).
Long-term dynamics of cardiac rhythm and survival in transgenic
mice with heart failure.
Recordings from conscious, unrestrained FVB mice showed fast HRs and
pronounced -blocker responses, which suggests that intrinsic sympathetic activity is high. HR in young TNF- mice was similar to
that in FVB controls but tended to decrease with age. The lack of
increased HR despite the presence of heart failure in TNF- mice may
depend in part on the baseline high sympathetic activity in the FVB
background. Thus the choice of FVB as a background strain for studying
the ANSA phenotype and changes in cardiac rhythm during the development
of heart failure might not be optimal.
mice might indicate sinus node dysfunction and the
development of supraventricular arrhythmias. This is consistent with
our findings of atrial flutter with variable block in many of these
animals with optical mapping (data not shown; Ref. 20). In
human studies, atrial arrhythmias, blunted responses of HR to
pharmacological and physiological sympathetic stimulation, and enhanced
short-term HR irregularity have been found in patients with advanced
heart failure and poor prognosis (5, 6, 24).
A transgenic mouse model that overexpressed Gs
in the
heart was engineered in a wild-type strain with lower mean HR and, presumably, lower sympathetic activity (30). Here, the
heart failure syndrome was associated with an increase in HR
(30). Differences in the background strains might be
responsible for the divergence of HR dynamics between this and the
TNF- model of heart failure. In addition, the Gs
model directly manipulates sympathetic response and may not be
generalizable to other mouse models. In both TNF- and
Gs mice, LFP/HFP was decreased because of an increased
proportion of the high-frequency elements in the cardiac rhythm
dynamics. This pattern differed from the predominant increase in the
low-frequency components and LFP/HFP in response to -adrenergic
stimulation (Fig. 3). The increased proportion of the high-frequency
components in heart failure could be explained by reduction of LFP and
increased contribution of nonneural mechanisms to HFP, similar to what
has been observed in humans (9, 25).
The proportion of surviving animals was significantly greater in
TNF- mice with heart failure on an FVB background than in mice on an
FVB/C57Black6 background. Although higher vagal activity is generally
viewed as cardioprotective, in heart failure, the shift of ANSA toward
increased sympathetic tone is important for providing inotropic support
to the failing myocardium and maintaining adequate pressure and
perfusion to peripheral tissues (10, 11). Thus it is
possible that the TNF- mice with heart failure on an FVB/C57Black6
background, who presumably had a lower sympathetic and a higher
parasympathetic activity, lacked the compensatory effects of heightened
sympathetic tone. Although other explanations may exist, it is possible
that the higher intrinsic sympathetic activity in TNF- mice on the
FVB background might be associated with beneficial compensatory effects
in animals with impaired cardiac function.
Limitations. In our study, the dose-response curves were not examined for the pharmacological modifications of ANSA. Different strains could have distinctive dose-response curves that would amplify but not eliminate the strain differences in cardiac cycle dynamics. Thus the main conclusions of this study regarding the strain-specific homeostatic states of ANSA would not be affected.
We compared mean HR and response to pharmacological agents in FVB mice vs. C57Black6/SV129 mice. Because of the back crossing, >90% of the genes in the mixed C57Black6/SV129 mice should have been derived from the C57Black6 strain. However, we cannot exclude a contribution of SV129 genes to the lower sympathetic activity in the mixed strain. A direct comparison of pharmacological effects on the TNF- and FVB
mice was not conducted in the unrestrained conscious state. In
anesthetized animals with pronounced bradycardia, isoproterenol increases HR to a similar extent in TNF- and FVB mice
(19). Serial changes in pharmacological responses that
accompany development of the heart failure in the TNF- mice require
further study. Comparison of HR and pharmacological responses in
TNF- mice on an FVB background and on an FVB/C57Black6 background
might provide more evidence regarding the differences in ANSA in the
two strains.
The small sample size of the examined strains could have affected the
results of statistical comparisons. To minimize the effects of the
sample size and the distribution differences, nonparametric tests were
used for statistical analysis.
The strain differences in blood pressure and in intrinsic HR after
combined blockage of -adrenergic and muscarinic receptors were not
examined in this study. These experiments, although not crucially
important for the goal of this investigation, could provide additional
information about homeostatic states of ANSA in each strain. The data
regarding HR and pharmacological responses in TNF- mice on an
FVB/C57Black6 background was unavailable at the time of this study,
precluding direct comparison of ANSA in TNF- mice on an
FVB/C57Black6 and on a pure FVB background.
In conclusion, interstrain differences in ANSA are important when
studying transgenic models. The homeostatic states of ANSA are
strain specific, leading to differences in HR, responses to pharmacological agents, and pathophysiological changes in disease models. Strain-specific differences should be considered in selecting the strains of mice used for transgenic and gene targeting experiments. Genetic mouse models in different backgrounds might be useful for
understanding genetic determinants of cardiac rhythm and ANSA in humans
(28).
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ACKNOWLEDGEMENTS |
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We thank Toshiaki Kadokami, Alexandre F. R. Stewart, and Charles F. McTiernan for technical assistance.
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FOOTNOTES |
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This study was supported by a Scientist Development Grant 0030248N (V. Shusterman) and a Grant-in-Aid (B. London) from the American Heart Association, National Heart, Lung, and Blood Institute (NHLBI) Specialized Center of Research Grant P50-HL-52338 (V. Shusterman), NHLBI R01-HL-58030 and R01-HL-66096 (B. London), NHLBI R01-HL-60032 (A. M. Feldman), and a grant from Guidant Corporation of St. Paul, MN (V. Shusterman).
Address for reprint requests and other correspondence: V. Shusterman, Univ. of Pittsburgh, 200 Lothrop St., Rm. B535, Pittsburgh, PA 15213 (E-mail: shustermanv{at}msx.upmc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published February 14, 2002;10.1152/ajpheart.00917.2001
Received 22 October 2001; accepted in final form 6 February 2002.
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TOP
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METHODS
RESULTS
DISCUSSION
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) are indicated. Error bars indicate corresponding
SE.
5).