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Novel Pathogenesis and Treatments for Cardiovascular Disease
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use should be considered carefully in case of very low HR [143] . This fact is reflected
in the data reported in Table and Figure of the average values of the QTc interval,
where relatively large deviations under different types of anesthesia are evident.
When comparing the duration of the QTc interval with the mean value from telemetry studies [26, 30, 31, 117, 118], significant prolongation occurred under pentobarbital
[32, 38, 41–43, 47, 51] ketamine/xylazine [87, 90–92, 129, 136, 152, 153], and urethane
[52, 57, 60] anesthesia, with moderate prolongation under thiopental [31, 62, 63, 66,
68, 71] anesthesia. The shortened QTc interval duration compared with the mean value
from telemetry studies was under isoflurane anesthesia [72, 74, 75, 121].
Anesthesia QTc interval
Telemetry studies 8 7.0 2
Pentobarbital 203.77
Thiopental 110.23
Phenobarbital 71.6
Nembutal - 20
Ketamine/xylazine 143.76
Ketamine/
medetomidine
Ketamine/diazepam - 18.5
Ketamine/
midazolam
Isoflurane 58.32
Desflurane 184.7
Chloralose - 66
(ms)
(81.79–92.31)
n=5
(196.2–211.5)
n=7
(100.5–120)
n=7
(69.36–73.84)
n=1
(138.97–
148.55)
n=8
- 27.5
- 18
(43.68–61.48)
n=4
(181.32–
188.08)
n=1
QRS complex
(ms)
26.08
(25.68–29.52)
n=5
25.4
(23.68–27.13)
n=19
22.76
(21.12–24.47)
n=8
55
(45–65)
n=1
(19–21
n=1
23.9
(22.16–25.64)
n=12
(22.5–32.5)
n=1
(13.25–23.75)
n=2
(16.8–19.2)
n=1
18.3
(16.75–19.85)
n=4
28.8
(25.22–32.38)
n=1
(55.7–76.3)
n=1
R wave amplitude
(mV)
— 0.139
0.56
(0.54–0.58)
n=4
1.8
(1.76–1.84)
n=1
- —
1.06
(0.99–1.12)
n=1
0.49
(0.41–0.57)
n=5
- —
- —
- 0.07
1.7
1.5–1.9
n=1
— —
— —
T wave amplitude
(mV)
(0.118–0.16)
n=1
0.08
(0.07–0.9)
n=2
—
0.37
(0.34–0.41)
n=1
0.09
(0.06–0.11)
n=5
(0.034–0.106)
n=1
0.11
(0.09–0.13)
n=1
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
Anesthesia QTc interval
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(ms)
Tribromethanol 90.5
(85.5–95.5)
n=1
Ether 153
(151–155)
n=1
Urethane 165.5
(158.6–180.5)
n=3
Isolated heart 83.43
(52.65–114.2)
n=2
Data presented as average (range) n, number of experimental studies in which ventricular parameters were evaluated.
Table 5.
QTc interval, QRS complex duration, R and T wave amplitude, regardless of the synchronization of the animals
to the light and dark cycle under individual types of anesthesia.
QRS complex
(ms)
26.2
(25.3–27.1)
n=2
22.15
(18.8–25.5)
n=2
18.41
(17.39–20.5)
n=15
32.5
(31.4–33.6)
n=2
R wave amplitude
(mV)
— —
— —
0.65
(0.64–0.66)
n=2
1.61
(not specified)
n=2
T wave amplitude
(mV)
0.337
(0.335–0.337)
n=1
1.42
(0.95–1.89)
n=1
Figure 4.
Distribution of ranges of QTc interval from telemetry studies and under different types of general anesthesia in
male rat males without taking into account the light periods of the rat regimen day when the experiments were
performed. Only QTc interval ranges from at least three studies where QTc interval has been evaluated are shown
in the figure. Telemetry studies (n=5), pentobarbital anesthesia (n=7), thiopental anesthesia (n=7), ketamine/
xylazine anesthesia (n=8), urethane anesthesia (n=3), isoflurane anesthesia (n=4). n, number of baseline or
control values from which duration of QTc interval was evaluated.
The problem is the comparison between the sexes and to evaluate the effect of
the LD cycle, for which insufficient experimental data are available. LD differences
were found in females under ketamine/xylazine anesthesia (light 174.5±34.8ms vs.
dark 202.1ms) [19], unlike pentobarbital anesthesia, where there were no significant
differences (light 197.7±40.9ms vs. dark 190.7±26.6ms) [20]. Unfortunately, this
dependence has not been tested with other types of general anesthesia. The age effect
of rats was demonstrated under rather unconventional tribromoethanol anesthesia
by da Silva etal. [106], where the duration of the QTc interval was two times longer
in older rats (117±4ms vs. 64±6ms) than in young rats at relatively the same HR
(young, 381±1 beats/min. vs. old, 405±11 beats/min).
Novel Pathogenesis and Treatments for Cardiovascular Disease
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. QRS complex
In some cases, it is also important to evaluate other parameters related to the
electrophysiology of the ventricles. For example, the QRS complex indicates depolarization of the right and left ventricles and the contraction of the large ventricular
muscles. Any conduction abnormality lasts longer and causes “extended” QRS complexes. The duration, amplitude, and morphology of the QRS complex are useful in
the diagnosis of cardiac arrhythmias, conduction abnormalities, ventricular hypertrophy, myocardial infarction, electrolyte disturbances, and other disease states.
High-frequency analysis of the QRS complex may be useful for detecting coronary
artery disease during a stress test. Evaluation of the amplitude of the R wave as well
as the P wave in experimental work on rats also proved to be important. They are
informative and changes can help to determine the tendency of the myocardium to
arrhythmias.
When comparing the average value of QRS complex duration from telemetry
studies [21, 31, 117–119] to barbiturate anesthesia—under pentobarbital [32, 34,
37, 40, 42, 44–49, 51, 122, 124–126, 154], thiopental [31, 61, 63, 64, 68, 69, 71], and
Nembutal [114] anesthesia—the average value of the QRS complex duration was
somewhat shorter and the ranges did not differ significantly.
Ketamine/xylazine [45, 78, 79, 84, 85, 89, 91, 92, 128, 129, 152], ketamine/diazepam
[96, 98], and ketamine/midazolam [97] as well as ether [100, 101] and urethane
anesthesia [45, 53, 55–58, 60, 135, 137, 138] shortened the duration of the QRS complex
compared to the value(s) from telemetry studies. The longer duration was under phenobarbital [95], ketamine/medetomidine [96], desflurane [72], chloralose [77] anesthesia, and in isolated hearts [105, 115] (Figure ). Of course, such comparisons can be
misleading because the values were reported in only one study. Similar to previously
described ECG parameters, all experiments were performed on males without specifying the adaptation of the animals to the LD cycle, and there was no study addressing
sex differences. Similarly, it was not possible to determine the circadian fluctuation in
the duration of the QT interval or the dependence on the LD cycle (Table , Figure ).
Figure 5.
Distribution of ranges of QRS complex from telemetry studies and under different types of general anesthesia
in male rats without taking into account the light periods of the rat regimen day when the experiments were
performed. Only QRS complex ranges from at least three studies where QRS complex has been evaluated are
shown in the figure. Telemetry studies (n=5), pentobarbital anesthesia (n=19), thiopental anesthesia (n=8),
ketamine/xylazine anesthesia (n=12), urethane anesthesia (n=15), isoflurane anesthesia (n=4). n, number of
baseline or control values from which duration of QT interval was evaluated.
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
. Conclusions
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In the discussion sections of many published
in vivo studies, the results obtained
are compared with previously published findings. Although changes in ECG parameters are often described, the type of anesthesia used in the experiments is not taken
into account. Moreover, in acute in vivo experiments, the time of day the experiments
are performed, and the adaptation of the animals to the LD cycle, and/or sex, are not
taken into account whatsoever. This approach is self-evident and logical because the
experiments are mostly performed only on males and during the workday, often without regard for chronobiological principles.
However, if changes in ECG parameters are considered to be important indicators
of arrhythmogenesis, such comparisons may be misleading and must not be immediately regarded to indicate a difference in myocardial electrical stability. We should
be more careful in interpreting results and, in discussing the mechanisms underlying
a given type of arrhythmia, acknowledge that initial ECG parameters may already be
affected to some extent by the anesthesia used and by regular daytime experimentation. The data presented in the tables clearly demonstrate the differences in baseline
or control values with different types of anesthesia and whether the baseline or control value is “normal” or already altered by anesthesia should be taken into account.
For example, a change in the evaluated ECG parameter after an intervention may not
necessarily indicate a possible electrophysiological substrate for the development of
an arrhythmia, it can only be “adjusted to a normal value” because we do not know
the reference value.
Similarly, sex and time of day the experiments are performed can be a problem
because it is not possible to determine sex differences as well as changes during the
active and nonactive period of rat regimen day because there are no studies that have
directly addressed this aspect. Telemetry studies that would reveal changes in ECG
parameters in circadian dependence, to describe reference values and, possibly, sex
differences, could help to facilitate interpretation of the results obtained. However, it is
highly speculative to consider the values from the cited telemetry studies as reference
values (although the ECG is measured from nonanesthetized rats) because the methodologies do not report whether the indicated baseline value is the 24h average (mesor)
or is the current value measured immediately before the intervention. Most likely, they
are baseline values before the experimental intervention and this only applies to male
rats, whereas the lighted (light or dark) period when the experiment is performed is not
reported, although an adaptation of animals to the LD cycle is described.
Thus, the question “Which anesthetic is the most suitable anesthetic in
in vivo
rat cardiological experiments so that the initial electrophysiology of the heart is not
significantly affected” is relatively difficult to address for several reasons. First, we
do not currently have specified sex-related reference values for rats. Second, because
there are circadian variations in the measurable parameters of the cardiovascular
system, there are also changes in individual ECG parameters, depending on the light
cycle (inactive period) and dark (active period). Finally, the effects of anesthetics at
the level of ion channels are not described in detail because the entire electrophysiology of the myocardium depends on ionic currents and the overall metabolism of
minerals.
As such, when evaluating changes in ECG parameters in rats, these possible varia-
tions should also be taken into account. The correct assessment of changes, in turn,
depends on knowledge of the reference values according to sex and on the time of day
Novel Pathogenesis and Treatments for Cardiovascular Disease
the experiments or measurements are performed. Although rat ECG parameters are
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only analyzed in this study, these can be of basis to further researches and studies that
may involve humans in the future.
Acknowledgements
This work was supported by a VEGA grant: 1/0008/20.
Rat Electrocardiography and General Anesthesia
DOI: http://dx.doi.org/10.5772/.104928
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