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Am J Physiol Heart Circ Physiol 296: H1907–H1913, 2009.
First published April 24, 2009; doi:10.1152/ajpheart.00681.2008.
Genetic influence on electrocardiogram time intervals and heart rate in aging
mice
Shuqin Xing, Shirng-Wreng Tsaih, Rong Yuan, Karen L. Svenson, Linda M. Jorgenson, Milly So,
Beverly J. Paigen, and Ron Korstanje
The Jackson Laboratory, Bar Harbor, Maine
Submitted 30 June 2008; accepted in final form 18 April 2009
genetic influences on cardiac conduction, cardiac arrhythmia, and
especially aging-related cardiac electrophysiological changes in
the general population. Studies using inbred mice may reveal
these influences, as inbred mice have been used to dissect the
genetic factors underlying many human diseases (31).
The ECG is a diagnostic and research tool that measures and
records the electrical activity of the cardiac conduction system.
Various ECG measurements, such as the P-R interval, QRS
complex duration, QT, and QTc interval, have been used to
diagnose and predict some cardiac arrhythmias and other
cardiac diseases. Forty years ago, Goldbarg et al. (18) noted
ECG differences between anesthetized mice of two strains.
Since then, ECG characteristics of different mouse strains have
been reported, but the inconsistent techniques used make it
impossible to compare them. To conduct meaningful research
on the cardiac conduction system, accurate and comparable
ECG data from a large number of inbred strains, using conscious mice, are needed. Modern ECG technology has made
collecting this data possible (6). To that end, we characterized
ECG time intervals in 6-, 12-, and 18-mo-old mice from 28
inbred mouse strains. The resulting data will greatly facilitate
discovering the genetic factors that regulate the cardiac conduction system and susceptibility to cardiac arrhythmias.
cardiac arrhythmia; broad-sense heritability
MATERIALS AND METHODS
initiates electrical impulses
and controls the route of the impulses through the myocardium.
Abnormalities in the system may cause cardiac arrhythmias,
the major causes of mortality and morbidity in developed
countries. More than 2.2 million Americans, particularly the
elderly, suffer from atrial fibrillation (AF), the most common
type of cardiac arrhythmia (33). As the percentage of elderly in
the population is rising, so is the incidence of AF (17). About
479,700 Americans died of cardiac arrhythmias in 2002–more
than died from stroke, lung cancer, breast cancer, and acquired
immunodefiency syndrome combined (36). Of these, 185,000
died of sudden arrhythmic death, the most dangerous and
difficult to prevent form of arrhythmia (7).
If new therapeutic targets for cardiac arrhythmias are to be
developed, the genetic influences on cardiac electrophysiology
must be identified and understood (2). Yet, the mechanisms of
arrythmogenesis are complex and largely unknown (24). Although several rare inherited lethal cardiac arrhythmias are caused
by mutations in genes encoding ion channels or other membrane
components (11, 26), very few studies have sought to identify the
THE CARDIAC CONDUCTION SYSTEM
Address for reprint requests and other correspondence: R. Korstanje, The
Jackson Laboratory, 600 Main St., Bar Harbor, ME 04609 (e-mail: ron.korstanje
@jax.org).
http://www.ajpheart.org
Mice. We recorded ECG characteristics of the following 28 inbred
mouse strains: 129S1/SvImJ (129S1), A/J, AKR/J (AKR), BALB/
cByJ (BALB), BTBR-T⫹tf/J, BUB/BnJ (BUB), C3H/HeJ (C3H),
C57BL/10J, C57BL/6J (B6), C57BLKS/J (BLKS), C57BR/cdJ
(C57BR), C57L/J (C57L), CBA/J, DBA/2J (D2), FVB/NJ (FVB),
KK/HIJ, LP/J, MRL/MpJ, NOD.B10Sn-H2/J (NOD), NON/ShiLtJ
(NON), NZO/H1LtJ (NZO), NZW/LacJ, P/J, PL/J, RIIIS/J (R3),
SJL/J (SJL), SM/J (SM), and SWR/J. Mice were born, raised, and
maintained at The Jackson Laboratory. At the ages of 6 – 8 wk, they
were transferred from breeding rooms to a specific pathogen-free
room, where they remained until ECGs were recorded. Same-sex mice
were housed as 4 mice/pen in duplex polycarbonate cages (31 ⫻ 31 ⫻
214 cm) equipped with pressurized individually ventilated mouse
racks (Thoren Caging Systems) with a high efficiency particulate
air-filtered supply and exhaust. Water and food pellets containing 6%
fat (Lab Diet 5K52, PMI Nutritional, Bentwood, MO) were provided
ad libitum. Mouse rooms were maintained at an ambient temperature
of 21–23°C and a 12:12-h light-dark cycle. Colonies were regularly
monitored for 15 viruses, 17 bacterial species (including Helicobacter
spp., Pasteurella pneumotropica, and two Mycoplasma spp.), ectoand endoparasites, and the microsporidium Encephalitozoon cuniculi.
All animal protocols were approved by The Jackson Laboratory
Animal Care and Use Committee. Mouse handling and care complied
with Public Health Service animal welfare policies.
ECG recording. ECGs (1,244 total) of 8 males and 8 females from
each of the 28 inbred strains were recorded at 6, 12, and 18 mo of age.
One hundred mice died before they reached the age for ECG analysis.
0363-6135/09 $8.00 Copyright © 2009 the American Physiological Society
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Xing S, Tsaih S, Yuan R, Svenson KL, Jorgenson LM, So M,
Paigen BJ, Korstanje R. Genetic influence on electrocardiogram
time intervals and heart rate in aging mice. Am J Physiol Heart Circ
Physiol 296: H1907–H1913, 2009. First published April 24, 2009;
doi:10.1152/ajpheart.00681.2008.—Understanding the genetic influence on ECG time intervals and heart rate (HR) is important for
identifying the genes underlying susceptibility to cardiac arrhythmias.
The objective of this study was to determine the genetic influence on
ECG parameters and their age-related changes in mice. ECGs were
recorded in lead I on 8 males and 8 females from each of 28 inbred
strains at the ages of 6, 12, and 18 mo. Significant interstrain
differences in the P-R interval, QRS complex duration, and HR were
found. Age-related changes in the P-R interval, QRS complex duration, and HR differed among strains. The P-R interval increased with
age in 129S1/SvlmJ females. The QRS complex duration decreased
with age in C57BR/J males and DBA2/J females but increased in
NON/ShiLtJ females. HR decreased in C57L/J females and SM/J and
P/J males but increased in BALB/cByJ males. Differences between
males and females were found for HR in SJL/J mice and in the P-R
interval in 129S1/SvlmJ mice. Broad-sense heritability estimates of
ECG time intervals and HR ranged from 0.31 for the QRS complex
duration to 0.52 for the P-R interval. Heritability estimates decreased
with age for the P-R interval. Our study revealed that genetic factors
play a significant role on cardiac conduction activity and age-related
changes in ECG time intervals and HR.
H1908
GENETIC INFLUENCE ON MOUSE ELECTROCARDIOGRAM
the ECG parameters measured across three time points, we conducted multivariate regression analysis. If the interaction effect of
strain by age was revealed, the Tukey-Krammer HSD test was used
to analyze the difference of means of each strain between groups.
P ⬍ 0.05 was considered as statistically significant. All statistical
analyses were performed using JMP statistical analysis software
(SAS Institute).
Heritability of ECG phenotypes was calculated by estimating
broad-sense heritability. Interclass correlations (r1) and coefficients of
genetic determination (g2), both measures of broad-sense heritability,
were calculated using methods as outlined by Festing (13). r1 was
defined as the proportion of the total variation that is accounted for by
differences between strains and was estimated by the following
formula:
r 1 ⫽ 共MS B ⫺ MSW兲/关MSB ⫹ 共n ⫺ 1兲MSW兴
where MSB is the mean square of the between-strain comparison,
MSW is the mean square of the within-strain comparison, and n is
number of mice tested per strain with appropriate corrections for
differences in mouse numbers per strain; n ⫽ 16 for our calculation.
A modification of this formula gives g2, which takes into account the
doubling of the additive genetic variance with inbreeding. It was
calculated as follows:
g 2 ⫽ 共MS B ⫺ MSW兲/关MSB ⫹ 共2n ⫺ 1兲MSW兴
Fig. 1. ECG (lead I) from 10 strains representing the variety of ECGs in the survey.
AJP-Heart Circ Physiol • VOL
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To eliminate circadian influences, ECGs were recorded between 8:30
and 11:00 AM. Mice were gently removed from their cages and
carefully positioned on the ECG recording platform (Mouse Specifics,
Boston, MA). The size and arrangement of the electrodes were
configured to contact three paws, providing an ECG signal equivalent
to Eithenoven lead I. To minimize stress, mice were accustomed to the
platform by placing them on it for 10 min before ECGs were recorded.
ECG signals were digitized at a sampling rate of 2,500 samples/s (Fig. 1).
Only data from continuous recordings of 20 –30 signals were used in
the analysis. Each signal was analyzed using e-MOUSE (Mouse
Specifics) (6). The QRS duration, P-R interval, and heart rate (HR)
were measured and reported automatically. One of the authors (S.
Xing) visually examined each trace for clear P, Q, R, and S peaks
before accepting the automatic calculations. All raw data have been
deposited in the Mouse Phenome Database (www.jax.org/phenome)
and is available for download.
Statistical analysis. ECGs of 1,244 mice were evaluated, and data
from 1,194 mice with a regular sinus rhythm were analyzed. Data
from 50 mice were excluded because of irregular rhythms and/or bad
signals. Data are presented as means ⫾ SD. One-way ANOVA was
performed to test the main effect of strain and sex, and the interaction
effect of strain by sex on the ECG parameters was measured at 6, 12,
and 18 mo of age. If the test of interaction was significant (P ⬍ 0.001),
then a t-test was applied to identify the sex effect within strain, and the
post hoc pairwise multiple-comparison procedure of Tukey-Krammer
honestly significant difference (HSD) test was used to analyze the
difference between strain means. To test the overall effect of age on
H1909
GENETIC INFLUENCE ON MOUSE ELECTROCARDIOGRAM
Table 1. HRs and ECG time intervals in females for 28 inbred mouse strains at 6 mo of age
HR, beats/min
Strain
8
8
8
7
6
7
8
7
8
8
7
8
7
8
8
8
6
6
6
8
8
8
5
10
8
8
8
8
Means ⫾ SD
b,c,d,e
710⫾44
723⫾73a,b,c,d,e
782⫾15a,b,c
697⫾24c,d,e
722⫾29a,b,c,d,e
791⫾25a,b
744⫾72a,b,c,d,e
711⫾63a,b,c,d,e
735⫾11a,b,c,d,e
678⫾47e
729⫾23a,b,c,d,e
739⫾21a,b,c,d,e
745⫾44a,b,c,d,e
712⫾16a,b,c,d,e
771⫾33a,b,c,d
728⫾17a,b,c,d,e
726⫾51a,b,c,d,e
726⫾27a,b,c,d,e
801⫾33a
714⫾19a,b,c,d,e
737⫾42a,b,c,d,e
688⫾72d,e
751⫾19a,b,c,d,e
744⫾37a,b,c,d,e
672⫾98e
699⫾44c,d,e
744⫾27a,b,c,d,e
743⫾40a,b,c,d,e
n
8
7
8
7
5
7
8
7
8
8
7
8
7
8
8
8
5
6
5
8
8
8
5
0
8
8
8
7
QRS Complex Duration, ms
Means ⫾ SD
a,b,c,d,e
26.5⫾4.3
29.6⫾1.3a,b,c
22.3⫾5.1d,e,f
27.7⫾1.6a,b,c,d,e
31.5⫾1.8a
16.0⫾3.1f
20.7⫾3.8e,f
30.1⫾4.5a,b
29.4⫾4.5a,b,c,d
30.2⫾2.3a
31.9⫾1.3a
30.7⫾2.3a
26.0⫾5.0a,b,c,d,e
25.9⫾7.1a,b,c,d,e
23.5⫾3.5b,c,d,e
29.5⫾1.9a,b,c
29.4⫾1.6a,b,c,d
32.0⫾1.0a
29.5⫾1.0a,b,c,d
23.2⫾4.7b,c,d,e
32.2⫾1.4a
31.6⫾2.2a
20.3⫾2.9e,f
28.5⫾4.5a,b,c,d
28.8⫾5.3a,b,c,d
28.4⫾1.4a,b,c,d
23.2⫾3.7c,d,e
29.9⫾1.2a,b,c
n
Means ⫾ SD
8
8
8
7
6
7
8
7
8
8
7
7
7
8
7
8
6
6
6
8
8
8
5
0
8
8
8
8
10.8⫾1.1a,b,c
10.0⫾1.3b,c
10.7⫾0.9a,b,c
12.2⫾1.5a
9.5⫾0.3c
11.1⫾1.5a,b,c
9.6⫾0.9c
11.3⫾1.7a,b,c
10.3⫾0.7a,b,c
11.2⫾1.0a,b,c
11.2⫾0.4a,b,c
10.4⫾0.2a,b,c
10.3⫾1.5a,b,c
11.2⫾1.7a,b,c
10.1⫾0.3a,b,c
11.3⫾1.6a,b,c
10.5⫾0.9a,b,c
10.9⫾0.6a,b,c
10.6⫾0.9a,b,c
10.1⫾1.2a,b,c
11.9⫾0.9a,b
11.1⫾1.0a,b,c
10.1⫾0.8a,b,c
11.8⫾0.9a,b
10.5⫾1.7a,b,c
11.7⫾0.7a,b
9.9⫾0.7b,c
10.9⫾0.6a,b,c
n, no. of mice/group. HR, heart rate. One-way ANOVA analysis was significantly different for ECG parameters among strains (P ⬍ 0.001). The
Tukey-Krammer honestly significant difference (HSD) post hoc test was used for all pair comparison. a–fParameter levels not connected by the same letter are
significantly different (P ⬍ 0.05).
Whereas MSW was determined separately for each strain at each
age, MSB was determined from ANOVA between stains at different
ages for the estimation of broad-sense heritability.
RESULTS
Strain differences in ECG characteristics. We calculated
strain differences in ECG characteristics of 6-, 12-, and 18mo-old males and females. We collected data as part of another
larger study that included three wild-derived strains: PWD/PhJ,
WSB/EiJ, and CAST/EiJ. Due to their nervous behaviors, we
could not record the ECGs of conscious mice from these
strains. Hence, we excluded them from our study. ECG characteristics measured included HR, the P-R interval, and the
QRS complex duration. Because HR is a reciprocal of the R-R
interval, and more commonly used than the R-R interval, we
reported HR instead of the R-R interval. Before ECGs were
recorded, all mice were weighed. No correlations between
body weight and any ECG parameters were found (data not
shown).
Data from 6-mo-old mice are shown in Table 1 for females
and Table 2 for males. Data from 12- and 18-mo-old mice are
shown in Supplemental Tables 1 and 2.1
Sex differences in ECG time intervals and HR. Because sex
plays an important role in the development of cardiovascular
disease, we analyzed its influence on cardiac conduction func1
Supplemental material for this article is available online at the American
Journal of Physiology-Heart and Circulatory Physiology website.
AJP-Heart Circ Physiol • VOL
tion. Overall, males had higher HRs than females. However,
when tested for individual strains at the different time points,
only SJL males at 6 mo of age had significantly higher HRs
than females (778 ⫾ 17 vs. 699 ⫾ 44 beats/min, nominal P ⫽
0.001; Fig. 2A). For the intervals, we only found a difference
for the P-R interval at 12 mo in one strain: 129S1 females had
longer P-R intervals than males (31.4 ⫾ 0.3 vs. 22.4 ⫾ 3.2 ms,
nominal P ⬍ 0.001; Fig. 2B).
Age-related changes in HR and ECG time intervals. To
analyze the effect of age on cardiac conduction function, we
compared ECG time intervals and HRs among 6-, 12-, and
18-mo-old mice (except for AKR and SJL mice, which died
before 18 mo of age). HRs significantly decreased with age in
female C57L (Fig. 3A) and male SM and P/J mice but increased in male BALB mice (Fig. 3A). NZO and R3 mice
showed, respectively, a decrease and an increase at 12 mo
compared with 6 mo but then were at similar levels again at 18
mo of age. The P-R interval only significantly increased with
age in 129S1 female mice (Fig. 3B). The QRS complex
duration significantly decreased over time in C57BR males
(Fig. 3C) and D2 females but increased in NON females.
Heritability estimates. r1 is defined as the proportion of the
total variation accounted for by interstrain differences. g2 is a
modification of r1 that controls the additive genetic variance
occurring with inbreeding. Because g2 results in more conservative heritability estimates, it has been considered as a better
indicator of broad-sense heritability (13). However, because it
is rarely reported, we report both estimates for ECG time
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129S1/SvImJ
A/J
AKR/J
BALB/cByJ
BTBR-T⫹tf/J
BUB/BnJ
C3H/HeJ
C57BL/10J
C57BL/6J
C57BLKS/J
C57BR/cdJ
C57L/J
CBA/J
DBA/2J
FVB/NJ
KK/HIJ
LP/J
MRL/MpJ
NOD.B10Sn-H2⬍b⬎/J
NON/ShiLtJ
NZO/H1LtJ
NZW/LacJ
P/J
PL/J
RIIIS/J
SJL/J
SM/J
SWR/J
n
P-R Interval, ms
H1910
GENETIC INFLUENCE ON MOUSE ELECTROCARDIOGRAM
Table 2. HRs and ECG time intervals in males for 27 inbred mouse strains at 6 mo of age
HR, beats/min
Strain
n
Means ⫾ SD
7
8
7
8
7
7
8
8
7
7
8
8
8
7
8
8
8
4
8
7
7
7
5
7
8
8
8
a,b,c,d
753⫾54
703⫾86d,e,f
766⫾20a,b,c,d
673⫾21e,f
787⫾20a,b
808⫾26a
760⫾18a,b,c,d
754⫾16a,b,c,d
720⫾36b,c,d,e,f
746⫾23a,b,c,d
734⫾27b,c,d,e
768⫾19a,b,c,d
733⫾35b,c,d,e
781⫾21a,b,c
747⫾28a,b,c,d
777⫾49a,b,c
757⫾26a,b,c,d
785⫾25a,b,c
707⫾30d,e,f
761⫾22a,b,c,d
709⫾78c,d,e,f
770⫾17a,b,c,d
742⫾37a,b,c,d,e
657⫾60f
778⫾17a,b,c
764⫾13a,b,c,d
722⫾51b,c,d,e,f
QRS Complex Duration, ms
Means ⫾ SD
n
a,b,c
7
8
7
8
7
7
8
8
7
6
8
8
8
7
8
7
8
4
8
7
6
7
5
7
7
8
7
28.4⫾5.7
28.0⫾4.0a,b,c
21.5⫾4.4c,d,e,f
25.9⫾1.8a,b,c,d,e
18.1⫾6.1e,f
16.9⫾1.1f
26.3⫾3.5a,b,c,d
30.0⫾2.6a,b
29.3⫾3.1a,b,c
31.8⫾0.8a
31.3⫾1.1a
26.6⫾5.1a,b,c
25.2⫾8.3a,b,c,d,e
27.1⫾1.2a,b,c
27.8⫾2.4a,b,c
29.4⫾0.9a,b
28.2⫾5.4a,b,c
27.8⫾1.8a,b,c
25.7⫾6.5a,b,c,d,e
30.2⫾2.0a,b
32.1⫾1.2a
19.1⫾2.0d,e,f
80.8⫾2.5a,b
29.3⫾4.4a,b,c
28.1⫾0.9a,b,c
23.8⫾5.7b,c,d,e,f
32.4⫾1.2a
n
Means ⫾ SD
7
8
7
8
7
7
8
8
7
6
8
8
8
7
8
8
8
4
8
7
7
7
5
7
7
8
8
10.2⫾1.1b,c
10.9⫾1.6a,b
11.3⫾1.1a,b
12.9⫾1.2a
10.5⫾1.3b,c
8.7⫾0.6c
10.9⫾0.5a,b
10.3⫾0.4b,c
11.0⫾1.0a,b
11.0⫾0.2a,b
10.3⫾0.3b,c
10.2⫾1.0b,c
10.4⫾1.6b,c
10.4⫾0.5b,c
10.5⫾1.1b,c
10.4⫾0.6b,c
10.8⫾0.7b,c
10.3⫾0.9b,c
11.3⫾2.0a,b
11.7⫾0.8a,b
11.4⫾1.7a,b
10.9⫾1.3a,b
10.9⫾1.4a,b
10.0⫾1.3b,c
11.2⫾0.4a,b
10.4⫾0.9b,c
11.3⫾1.1a,b
n, no. of mice/group. One-way ANOVA analysis was significantly different for ECG parameters among strains (P ⬍ 0.001). The Tukey-Krammer HSD post
hoc test was used for all pair comparison. a–fParameter levels not connected by the same letter are significantly different (P ⬍ 0.05).
intervals and HRs (Table 3). Heritability estimates were different for different time intervals and HRs. Regardless of sex,
P-R interval broad-sense heritability decreased significantly
from 0.52 [95% confidence interval (CI): 0.48 – 0.60] at 6 mo
to 0.22 (95% CI: 0.17– 0.27) at 18 mo for r1 and from 0.37
(95% CI: 0.29 – 0.45) at 6 mo to 0.13 (95% CI: 0.09 – 0.17) at
18 mo for g2 (Table 3). Broad-sense heritability estimates were
stable for the QRS complex duration (0.20 for g2 and 0.3 for r1)
and HR (0.25 for g2 and 0.40 for r1) in different age groups,
indicating that age did not influence heritability (variance data
for these estimates and sex-specific heritability estimates are
shown in Supplemental Tables 3, 4, and 5).
Fig. 2. Sex differences in heart rates [in beats/min (bpm)] between 6-mo-old
male (M) and female (F) SJL/J mice (A) and in P-R intervals between
12-mo-old male and female 129S1/SvImJ (129S1) mice (B). Graphs show
means ⫾ SD.
AJP-Heart Circ Physiol • VOL
DISCUSSION
Both genetic and environmental factors influence HR,
which may consequently affect ECG measurements (35). To
obtain comparable and reliable data, we controlled possible
extraneous variables by the following strategies: 1) the
environment (light, temperature, noise, etc.) was carefully
controlled; 2) ECGs of obviously sick mice were not used;
3) to eliminate circadian influences, ECGs were measured at
fixed times; and 4) ECGs were recorded in conscious mice
acclimated to the instrument.
HRs, P-R intervals, and QRS complex durations differed
significantly among inbred strains (Tables 1 and 2), indicating
that the genetic background influenced cardiac conduction. Our
study showed that BLKS mice had lower HRs and NOD mice
had higher HRs, which is similar to a report by Howden et al.
(22). However, they reported a generally lower HR than ours.
The difference of the mean value of HR may be due to the
difference of age of tested mice or the difference in animal
arousal levels. Chu et al. (6) reported that HR differs among
three mouse strains: 129S1, B6, and FVB. Desai et al. (12)
reported that HRs of anesthetized mice differ among six
strains. The HRs reported in those strains are lower than those
we recorded for the same six strains, a discrepancy that may be
caused by the influence of anesthetic agents on HR. Goldbarg
et al. (18) reported that HR is not significantly different among
anesthetized mice from strains C57BL/10, SEC/J, and their F1
progeny. Anesthetic agents can significantly affect cardiovascular parameters and may have masked important physiological phenotypes in that study.
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129S1/SvImJ
A/J
AKR/J
BALB/cByJ
BUB/BnJ
C3H/HeJ
C57BL/10J
C57BL/6J
C57BLKS/J
C57BR/cdJ
C57L/J
CBA/J
DBA/2J
FVB/NJ
KK/HIJ
LP/J
MRL/MpJ
NOD.B10Sn-H2⬍b⬎/J
NON/ShiLtJ
NZO/H1LtJ
NZW/LacJ
P/J
PL/J
RIIIS/J
SJL/J
SM/J
SWR/J
P-R Interval, ms
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GENETIC INFLUENCE ON MOUSE ELECTROCARDIOGRAM
The P-R interval represents the time from the onset of atrial
depolarization to the onset of ventricular depolarization. In
6-mo-old female mice, NZO mice had the longest P-R interval,
double that of the shortest interval in BUB mice (32.2 vs. 16.0
ms). Humans and dogs display a wide range of P-R intervals
(3, 20), although an optimal P-R interval has been demonstrated for both species (3). It has been suggested that the P-R
interval increases linearly with heart length (28), a relationship
that could have been responsible for the interstrain P-R interval
differences we observed. Unfortunately, no data for mouse
heart length were available for us to explore this relationship.
Our study revealed that the QRS complex duration differed
significantly among strains. The QRS complex duration represents ventricle excitation time and marks the time required to
depolarize the entire contractile myocardium. QRS durations
ranged from 8.7 ms for C3H males to 12.9 ms for BALB
males, a 48% difference. Another study (6) has reported
interstrain differences in the QRS complex duration. Studies
(23, 30) have suggested that the distribution pattern of the
Purkinje fiber network in the myocardium and ventricular wall
thickness play an important role in ventricle excitation time.
Interstrain differences in the QRS complex duration may reflect interstrain differences in ventricular wall thickness.
Influence of sex on ECG time intervals and HR. Overall,
males had higher HRs than females. However, when strains
were tested individually, only 6-mo-old SJL males had higher
HRs. Twelve-month-old 129S1 females had a significantly
higher P-R intervals than 129S1 males. Intersex differences in
ECG time intervals were not found in other strains. These
observations agree with a previous report by Mitchell et al.
(29). However, Chu et al. (6) reported that 2-mo-old males in
three strains have higher ECG time intervals than same-age
AJP-Heart Circ Physiol • VOL
Table 3. Estimates of broad-sense heritability
HR, beats/min
6 mo
12 mo
18 mo
P–R interval, ms
6 mo
12 mo
18 mo
QRS complex duration, ms
6 mo
12 mo
18 mo
g2 (95% CI)
r1 (95% CI)
0.27 (0.20–0.34)
0.21 (0.16–0.26)
0.24 (0.19–0.29)
0.40 (0.31–0.49)
0.34 (0.27–0.41)
0.37 (0.30–0.44)
0.37 (0.29–0.45)
0.33 (0.26–0.40)
0.13 (0.09–0.17)
0.52 (0.48–0.60)
0.47 (0.40–0.54)
0.22 (0.17–0.27)
0.20 (0.13–0.27)
0.18 (0.12–0.24)
0.16 (0.11–0.21)
0.31 (0.23–0.39)
0.29 (0.22–0.36)
0.27 (0.21–0.33)
g2, coefficient of genetic determination; r1, interclass correlation; CI, confidence interval.
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Fig. 3. Examples of age differences in heart rates for C57L/J (C57L) females
and BALB/cByJ (BALB) males (A), differences in P-R intervals in 129S1
females (B), and differences in QRS intervals in C57BR/cdJ (C57BR) males
(C). Graphs show means ⫾ SD.
females: P-R intervals are higher in 129S1 and FVB males and
QRS durations are higher in 129S1 and B6 males. Chu et al.’s
results may reflect the age of the mice studied: intersex HR
differences are present in humans (37) and rats (5); in humans,
it disappears with age (37).
Age-related changes of HR and ECG time intervals. The
mouse is currently the principal mammalian model for studying biological processes, particularly those related to cardiac
pathophysiology (4). However, changes of cardiac electrical
activity with age in different mouse strains were previously
unknown. We found that the QRS complex duration increased
with age in NON females and decreased in C57BR males and
D2 females and that the P-R interval increased with age in
129S1 females. HR decreased with age in SM and P/J males
and C57L females. These findings support that aging slows
cardiac conduction. However, in BALB males, we found an
increase of HR as they get older. Although the mechanisms are
not understood, slowed conduction may be one of the strongest
triggers for AF (1). In humans, increased P-R intervals with
aging has been observed consistently (9, 15). QRS complex
duration changes in humans have not been reported. Increased
ECG time intervals with age might be explained by concomitant anatomic and electrophysiological changes. The main
causes of slowed conductions are decreases in cell excitability
(10), intercellular coupling (8, 32), and changes in the cellular
architecture of cardiac tissue(16). In rats, electrophysiological
and contractile properties of the heart change significantly with
aging. For example, the action potential duration increases in
senescent rat hearts (40). Increased ventricular action potential
duration is an indication of the QRS duration. Furthermore, the
number of sinoatrial nodal cells decreases dramatically with
age (25), and interventricular septal and ventricular thickness
due to cardiac myocyte enlargement with aging may slow
cardiac conduction.
We observed age-related ECG changes in only a few strains,
suggesting that the genetic background plays a crucial role in
the cardiac aging process and/or aging velocity. The aging rate
of the cardiac conduction system may vary among different
strains. For some strains, these changes might happen after 18
mo of age, which is out of the time window of our study. Our
study showed that the QRS duration increased relatively late in
A/J mice, whereas it increased relatively early (at an age equal
to 61.7% of their life span) in 129S1 mice (unpublished
observations from our aging study).
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GENETIC INFLUENCE ON MOUSE ELECTROCARDIOGRAM
AJP-Heart Circ Physiol • VOL
related changes in these indexes differed among strains. Our
study provides the information necessary for investigators to
choose the appropriate mouse strains to cross to identify the
genes that regulate HR, ECG time intervals, and aging-related
cardiac conduction changes.
ACKNOWLEDGMENTS
The authors are grateful to Maarten van den Berg for critical review of the
manuscript and Jesse Hammer and Thomas G. Hampton for assistance with the
graphics.
GRANTS
This work was funded by National Institute of Aging Nathan Shock Center
Grant AG-25707 and by grants from the Ellison Medical Foundation (to B. J.
Paigen).
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Genetic contribution to the variation of HR and ECG time
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