Open access peer-reviewed chapter - ONLINE FIRST

Rat Electrocardiography and General Anesthesia

Written By

Pavol Svorc Jr and Pavol Svorc

Submitted: March 31st, 2022Reviewed: April 13th, 2022Published: May 7th, 2022

DOI: 10.5772/intechopen.104928

IntechOpen
Cardiovascular DiseasesEdited by David C. Gaze

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Cardiovascular Diseases [Working Title]

Dr. David C. Gaze

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Abstract

General anesthesia is an established and well-known factor with a significant impact on cardiac parameters, which can be a problem in the final evaluation of changes in the individual electrophysiological myocardial parameters after various interventions. The present chapter provides a composite review of published data on electrocardiographic parameters (heart rate, PR interval, P wave duration, P wave amplitude, QRS complex, QT and QTc interval duration, and R wave and T wave amplitude) for in vivo rat experiments under general anesthesia from 130 articles, which were retrieved from a search of the Web of Science database, for articles published mainly between 2000 and 2021. ECG parameters reported as baseline or control values were summarized, and averages with ranges were calculated. It is important to be cautious in interpreting the results of such studies and discussions addressing the mechanisms underlying a given type of arrhythmia, it is important to acknowledge that initial ECG parameters may already be affected to some extent by general anesthesia as well as by sex and the time of day the experiments are performed. Although it is not an original research work, researchers working with rats in the laboratory, who routinely perform anesthesia, can use this as a reference to look into while analyzing their data.

Keywords

  • ECG parameters
  • general anesthesia
  • sex
  • chronobiology
  • rat

1. Introduction

In vivoexperimental animal models are often used to elucidate or, at least clarify, specific mechanisms and/or to identify interrelationships between monitored functions that cannot be observed directly in humans. The results of such studies are often approximated to preclinical or clinical research and, can thus, have a significant scientific impact on a more detailed understanding of the monitored system.

A specific feature of in vivoexperimental animal models is the fact that experiments are usually performed with the animals under general anesthesia, in which homeostatic regulatory mechanisms are not removed and the animal responds to various interventions. Undoubtedly, this also applies to experiments in which changes in electrocardiographic (ECG) parameters are monitored after various interventions or after the administration of specific agents to assess the basis of the origin and development of heart rhythm disorders. However, different anesthetics may have varying impacts on myocardial electrophysiology. Thus, the extent to which ECG parameters are altered from normal after anesthetic administration can become a confounder—if not a problem—even before assessing the effects of the intervention itself.

The second problem is that many published methodologies do not describe the synchronization of the animals to the light-dark (LD) cycle, mainly in studies based on rat models. The LD cycle is the strongest synchronizer for this type of laboratory animal, and it is known that all measurable cardiovascular parameters oscillate depending on the LD cycle. Moreover, even when this synchronization is described, the time of day at which the experiments are performed is often not reported. In common practice, experiments are performed during regular work hours (i.e., during the day); therefore, after synchronization of rats, for example, to the LD cycle (12 h: 12 h), these experiments are essentially being performed on “sleeping” animals during their naturally inactive period. The question then becomes, what are the oscillations of ECG parameter values during a 24-h period (i.e., spanning the light [inactive] and dark [active] period) in healthy, sexually mature rats?

Another possible problem in the correct evaluation of changes in myocardial electrophysiology in rats may be sex. Sex is not typically considered in in vivocardiovascular and toxicological experiments involving rats, although this type of experimental model animal is commonly used to examine normal and pathological physiology. In the majority of experimental studies, only male rats are used; however, there is another sex (i.e., female) in which differences in the essence of functional systems and response(s) to the same interventions are different from males. The study of sex differences is also a driving force of development and, in many cases, the basis of health and medicine. However, there are opinions that the study of sex differences is ineffectual and does not merit extensive research [1]. One of the reasons why both sexes are not used in experiments is the simple fact that males and females are biologically different and these differences increase the range of variability. However, if sex differences are documented and accounted for in experimental studies, these must be respected. As such, future studies should address these questions and attempt to include females in experiments where possible.

This review aims to highlight the fact that there are differences in baseline or control values, which are, nevertheless, used as reference values in individual studies. However, they are impacted by the type of anesthesia used, and all the above-mentioned confounders/problems can significantly affect the correct interpretation of the results obtained.

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2. Evaluation of ECG parameters

The methodologies of studies that performed in vivorat cardiovascular or toxicological experiments were retrieved from a search of the Web of Science database for articles published mainly between 2000 and 2021; in total, 130 articles were retrieved. ECG parameters reported as baseline or control values were summarized and averages with ranges were calculated. Not all ECG parameters were described and evaluated in each study and, in some studies, two to three control values were reported. A relatively high number of studies described only changes in ECG parameters, in terms of lengthening and shortening, and these changes were directly indicated in graphs without reporting numerical baseline values.

Because each ECG parameter has diagnostic significance, we focused on commonly evaluated ECG parameters, including the following: heart rate (HR), atrial complex (PR interval, P wave duration, and P wave amplitude), and ventricular complexes (QRS complex, QT and QTc interval duration, and R wave and T wave amplitude).

Tables consider studies (although there were only one or two), which also suggest a possible sex difference with regard to the LD cycle on the monitored parameter. The figures show the ranges of the monitored parameter from at least three baseline or control values.

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3. Prognostic significance of changes in HR in arrhythmogenesis

HR is an easily measurable parameter of cardiac activity, and alterations in HR can have a direct effect on the cardiovascular system. Caetano and Alves [2] reported that increased resting HR is an independent predictor of cardiovascular and overall mortality in the general population. Thus, the occurrence of arrhythmias is often associated with baseline HR, which has prognostic significance. In a review article titled “Arrhythmias and heart rate: Mechanisms and significance of a relationship”, Zaza et al. [3] describe, in detail, the mechanisms influencing arrhythmogenesis according to HR, in which the authors focused on several factors related mainly to electrical stability of the myocardium. HR also reflects autonomic balance, which also affects myocardial stability. The prognostic significance of the relationship between arrhythmias and HR may vary depending on the substrate present in a specific case and should be considered. In rats, electrical stability of the heart has been shown to be greatest at increased HRs in the dark (i.e., active) part of the regimen day, when myocardial vulnerability to ventricular arrhythmias decreases [4].

It has been found that tachycardia may provide greater electrical stability to the myocardium; however, if an abnormal substrate is present, it may trigger arrhythmia [5]. Severe bradycardia, in contrast, can trigger life-threatening arrhythmias, thus reflecting its destabilizing effect on repolarization. Zaza et al. [3] remained cautious, arguing that, from a mechanistic perspective in assessing the relationship between HR and arrhythmias, the question should be “what is the appropriate sinus rate for autonomic balance?” and not “what is the high (or low) heart rate?” Thus, it can be assumed that baseline HR in in vivocardiovascular studies can significantly affect the results obtained during experimentation. The considerations mentioned above are also generally valid for rats. However, it is interesting that the effect of some interventions on HR is monitored and the impact of this change on myocardial electrophysiology is not further analyzed [6, 7, 8].

3.1 Telemetry and HR

To establish reference values for HR, as well as other ECG parameters, logically, the most suitable method is using telemetry studies, in which rats are not placed under general anesthesia and ECG can be recorded continuously throughout the day. Telemetry studies help to reveal very important information about fluctuations in myocardial electrophysiological parameters during the day. Currently, however, relatively few telemetry studies have analyzed ECG parameters in rats under in vivoconditions, and did not address circadian dependence and the dependence on sex.

Sex can also be a confounder. Nevertheless, several experimental rat studies [9] did not report any sex differences in heart repolarization, or that there is little clear evidence supporting sex differences in ventricular repolarizations per se, in which there is only a short estrous cycle lasting only 4 days [10]. Although no sex differences were found in the repolarization of isolated ventricular myocytes, they were associated with excitation and contraction [11]. Sex differences were not found in APD90 between isolated ventricular myocytes, in external K+ currents, Ipk and Isus, in internal rectification current IK1, or ICa [11, 12]. While less information is available from animal models, sex differences in the ionic basis of the effective refractory period in the atria and atrioventricular node may also contribute to sex differences in the incidence of atrial fibrillation and supraventricular tachycardias. Nevertheless, the physiological significance of sex differences has yet to be fully determined; as such, further studies are needed to clarify the basic mechanisms.

Baseline HR analysis from telemetry studies involving non-anesthetized rats, in which a chronobiological approach was applied, indicates that there is a circadian rhythm in HR among rats, with a higher HR during the active (i.e., dark) period of the regimen day and not only in males [13, 14, 15, 16, 17] but also in females [15, 18]. If HR exhibits circadian fluctuations, then when it is evaluated, it can be problematic.

The question is whether there are also sex differences in single-lighted periods. Telemetry studies have revealed that among females, HR values are lower in both light periods (Table 1). The averaged results of baseline HR values indicate that sex differences are exhibited in both the light and dark periods of the rat regimen day; however, more experimental studies are needed to confirm these data. In female rats, changes in HR depended on the LD cycle; however, LD differences were modified by the anesthetic used [19, 20]. Although the adaptation of animals to the LD cycle was described in the Methods sections, it is not clear from the methodologies whether the values of the presented HRs were average values from the entire 24-h period, or the current baseline value only from certain time intervals before the intervention itself when the measurements were performed or recorded.

AnesthesiaNot specifiedLight periodDark period
FemaleMaleFemaleMaleFemaleMale
Telemetry studies460
432–488
(n = 1)
346
310–362
(n = 16)
316
307–325
(n = 2)
349
340–357
(n = 5)
371
345–397
(n = 2)
390
382–398
(n = 5)
Pentobarbital374
359–389
(n = 22)
346
315–377
(n = 1)
369
328–410
(n = 1)
Thiopental349
332–366
(n = 13)
--
Phenobarbital368
340–396
(n = 1)
--
Nembutal
Ketamine/xylazine331
304–257
(n = 2)
288
239–293
(n = 18)
230
207–253
(n = 1)
276
247–305
(n = 1)
Ketamine/medetomidine-165
146–184
(n = 1)
--
Ketamine/diazepam-330
298–361
(n = 2)
--
Ketamine/midazolam-414
375–453
(n = 1)
--
Urethane378
352–403
(n = 14)
Isoflurane408
400–416
(n = 5)
Desflurane441
429–453
(n = 1)
Chloralose-418
404–431
(n = 2)
----
Tribromoethanol393
387–399
(n = 1)
Ether366
343–388
(n = 6)
Isolated heart368 ± 14
354–382
(n = 1)

Table 1.

Heart rate under individual types of anesthesia according to sex and light cycle (light [inactive]) versus dark [active]).

Data presented as average heart rate (beats/min) (range); (n, number of baseline or control values from which heart rate was evaluated). Not specified—the methodology did not specify the lighted period when the experiments were performed.

3.2 General anesthesia and HR

The question is what are the reference values for HR in the rat under normal circumstances? Based on the values reported in Table 1, is clear that HR varies depending on the type of general anesthesia, which can be problematic in evaluating changes in HR after an intervention. Other factors, in addition to general anesthesia, that may directly or indirectly affect the initial HR can be the methodology used to determine HR, the time of day (or part of the rat regimen day) at which the experiments are performed, or the fact that the majority of ECGs are evaluated only in male rats; as such, there is little-to-no information about HR in females.

Evaluation of HR in telemetry studies involving male rats [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31] reported a mean HR of 347 beats/min, with a range of 303 beats/min up to 362 beats/min without taking into account the evaluation methodologies and the time of day the experiments were performed.

If we consider that the average HR value with the range reported in telemetry studies involving male rats is our desired reference value, then a slightly increased average HR in pentobarbital (approximately 28 beats/min.) [32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51], and urethane anesthesia (approximately 32 beats/min) [52, 53, 54, 55, 56, 57, 58, 59, 60]. In female rats under pentobarbital anesthesia, baseline HR values were reported in only one study, depending on the LD cycle [20]. Even with pentobarbital anesthesia, although nonsignificant, there were LD differences. In female Wistar rats, pentobarbital probably only modifies circadian rhythms, but does not disturb them. Thiopental anesthesia [31, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71] did not alter HR from the mean HR reported in telemetry studies.

A significant tachycardic effect was found under isoflurane (approximately 62 beats/min) [72, 73, 74, 75], desflurane (approximately 95 beats/min) [72], and chloralose (approximately 72 beats/min) [76, 77] anesthesia in male rats.

Under ketamine/xylazine anesthesia [45, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92], HR was drastically reduced in males and reduced values were also recorded in females [93, 94]. In females have been preserved significant LD differences [19].

The effect of phenobarbital [95], ketamine/medetomidine [96], ketamine/midazolam [97], and ketamine/diazepam [96, 98] on anesthesia could not be assessed as valid because there was only one study.

Although ether is no longer used to induce general anesthesia, some works used this type of light anesthesia needed to perform ECG recordings [99, 100, 101, 102, 103, 104]. However, ether anesthesia had virtually no effect on HR. One study describing HR in isolated rat hearts did not reveal any significant deviation, in terms of tachycardia or bradycardia [105]. Interesting differences were also found between young and old rats under tribromoethanol anesthesia, where higher values prevailed in older rats (405 ± 11 beats/min vs. 381 ± 1 beats/min) [106]. Unfortunately, these comparisons are only from males and without a description of the adaptation of the animals to the LD cycle.

From Table 1 and Figure 1, it is evident that for different types of general anesthesia, baseline or control HR values can differ significantly compared to the mean baseline HR from telemetry studies, which can logically be considered as a reference value. There is very little information about HR in females and almost none of the studies took circadian fluctuations into account.

Figure 1.

Distribution of average values and ranges of heart rate (HR) from telemetry studies and under different types of general anesthesia in rat males without taking into account the light periods of the rat regimen day when the experiments were performed. Only HR ranges from at least three studies where HR has been evaluated are shown in the figure. Telemetry studies (n = 16), pentobarbital anesthesia (n = 22), thiopental anesthesia (n = 13), ketamine/xylazine anesthesia (n = 18), isoflurane anesthesia (n = 5), ether anesthesia (n = 6), urethane anesthesia (n = 14). (n—number of baseline or control values from which heart rate [HR] was evaluated).

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4. Prognostic significance of changes in the atrial complex in arrhythmogenesis

4.1 PR (PQ) interval

The PR (PQ) interval is measured from the beginning of the P wave to the beginning of the QRS complex. This interval reflects the time that the electrical impulse passes from the SA node through the AV node. The PR interval provides information about the time required for the transmission of the electrical impulse from the atria through the AV node, His bundle, Tawar’s branches, and Purkinje fibers to the start of ventricular muscle depolarization [107, 108, 109].

A prolonged PQ interval reflects a longer time of transmission of the impulse from the atrium to the ventricles in disorders of the conductive system of the AV node [110, 111]. A shortened PQ interval means that the impulse was transmitted to the ventricular conductive system earlier than normal; thus, it is likely that it passes around the AV node through abnormal connections of the conductive system [111, 112, 113]. The duration of the PR interval is a crucial marker in the diagnosis of atrioventricular blocks. However, it appears that the PR interval in rats also appears to be dependent on the type of anesthesia, and we have practically no information about sex differences and changes dependent on the LD cycle.

Although mean values of the duration of the PR (PQ) interval were comparable among the different types of anesthesia and did not exhibit significant differences (Table 2, Figure 2), the shortest duration was found with nembutal anesthesia [114]. With this type of anesthesia, there is a problem with the validity of this value because it is from only one study. The situation is similar with desflurane [72], ketamine/medetomidine [96], ketamine/diazepam [96], ketamine/midazolam, [97], anesthesia in isolated hearts [105, 115], and in tribromethal anesthesia [106, 116].

AnesthesiaNot specifiedLight periodDark period
FemaleMaleFemaleMaleFemaleMale
Telemetry Studies42.23 41.5–42.96
(n = 1)
49.26
47.51–50.88
(n = 10)
----
Pentobarbital47.53
45.35–49.71
(n = 18)
44.16 36.46–51.86 (n = 1)45.3
40.6–50
(n = 1)
Thiopental48.35
46.52–50.18
(n = 6)
--
Phenobarbital
Nembutal42
41–43
(n = 1)
Ketamine/Xylazine44
34–54
(n = 1)
44.77
41.02–45.42
(n = 13)
47
35.7–58.3
(n = 1)
36.5
30.7–42.3
(n = 1)
Ketamine/Medetomidine-67.5
66.3–68.7
(n = 1)
--
Ketamine/Diazepam-48.5
not reported
(n = 1)
--
Ketamine/Midazolam-47
44–50
(n = 1)
--
Urethane48.99
45.03–52.95
(n = 9)
Isoflurane48.05
46.52–49.63
(n = 6)
Desflurane41.6
40.08–43.12
(n = 1)
Chloralose
Tribromethanol52.6
50.4–54.8
(n = 2)
Ether49.7
44.7–54.7
(n = 4)
Isolated Heart44.5
41.8–47.2
(n = 2)
--

Table 2.

Duration of PR (PQ) interval duration under individual types of anesthesia according to sex and light cycle (light [inactive]) versus dark [active]).

Data are presented as the average value of PR (PQ) interval duration (ms) (range); (n, number of baseline or control values from which heart rate was evaluated). Not specified - the methodology did not specify the lighted period when the experiments were performed.

Figure 2.

Distribution of average values and ranges of PR (PQ) interval duration 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 PR (PQ) interval ranges from at least three studies where PR (PQ) interval was evaluated and is shown in the figure. Telemetry studies (n = 10), pentobarbital anesthesia (n = 18), thiopental anesthesia (n = 6), ketamine/xylazine anesthesia (n = 13), isoflurane anesthesia (n = 6), ether anesthesia (n = 4), urethane anesthesia (n = 9). n, number of baseline or control values from which duration of PR (PQ) interval was evaluated.

Duration of the PR (PQ) interval from telemetry studies [21, 23, 24, 25, 30, 117, 118, 119], inhalation (isoflurane) [72, 74, 75, 120, 121] pentobarbital [32, 34, 36, 37, 40, 43, 44, 45, 46, 47, 49, 122, 123, 124, 125, 126], thiopental [63, 64, 65, 68, 71], urethane [52, 53, 45, 56, 128, 60], and ether anesthesia [99, 100, 101, 104] did not differ significantly from one another. The shortened duration of the PR (PQ) interval was under ketamine/xylazine anesthesia [45, 78, 79, 84, 85, 89, 91, 92, 127, 128, 129]. The duration of the PQ (PR) interval in isolated hearts [105, 115] did not differ significantly from the duration with other types of anesthesia. For a given ECG parameter, it was difficult to determine sex differences, as well as differences dependent on the LD cycle because there was only one study (Table 2).

The P wave represents the depolarization of the atria. Atrial depolarization spreads from the SA node toward the AV node, and the right to the left atrium. In humans, but also in rats, the physiological sinus rhythm is characterized by the same P wave orientation as the R wave and its occurrence before each QRS complex in all cardiac cycles. P wave duration has been evaluated in Wistar rats, for which prolongation after myocardial infarction may be associated with increased sensitivity to supraventricular arrhythmias [130].

Other parameters of atrial complex evaluation include amplitude and polarity (either negative or positive, although it can also be so flat that it is indistinguishable from the isoelectric line). If the P wave is unusually high, it may reflect enlargement of the atria. Typically, an enlarged right atrium exhibits a high, spiked P wave, while an enlarged left atrium is reflected by a bifidic P wave on ECG. The absence of a P wave or its altered shape is present in various cardiac arrhythmias, the most common of which is atrial [131, 132]. Although the analysis of P wave duration and shape in humans provides clinically important information, there is a lack of experimental data from rats to draw definitive conclusions about sex-related changes and circadian rhythm in P wave amplitude and duration [45].

4.2 P wave duration and amplitude

The duration and amplitude of the P wave, despite their important prognostic significance, have only been sporadically evaluated in in vivoexperiments involving rats. The average amplitudes of the P wave were essentially the same at all types of anesthesia (i.e., in studies where the given parameter was evaluated). Only one telemetry study [118] evaluated P wave duration, and if it is considered as a reference value, only in males, prolonged duration was under ketamine/xylazine anesthesia [84, 89] and ketamine/medetomidine [96]. Shorter durations were under pentobarbital [46, 126] and thiopental [64] anesthesia. Approximately the same duration of the P wave was under the other types of anesthesia (Table 3). The amplitude of the P wave was the smallest in all combinations with ketamine (ketamine/xylazine) [82, 84, 89], ketamine/medetomidine [96], ketamine/diazepam [96, 98], ketamine/midazolam [97] and urethane [133], and isolated hearts [115].

AnesthesiaP wave amplitude (mV)P wave duration (ms)
Telemetry studies21.51 (19.84–23.18) n = 1
Pentobarbital0.39 (0.34–0.44) n = 216.15 (15.65–16.65) n = 2
Thiopental14 (12.8–15.2) n = 1
Phenobarbital
Nembutal0.29 (0.27–0.32) n = 1
Ketamine/xylazine0.05 (0.03–0.07) n = 426.25 (24.25–28.25) n = 2
Ketamine/medetomidine0.08 (0.05–0.11) n = 132 (31–33) n = 1
Ketamine/diazepan0.09 (0.06–0.13) n = 2
Ketamine/midazolam0.04 (0.013–0.067) n = 115 (13.5–16.5) n = 1
Isoflurane0.19 (0.17–0.21) n = 124.1 (23.1–25.1) n = 1
Desflurane23.5 (22.6–24.4) n = 1
Chloralose
Tribromethanol
Ether19.5 (17–22) n = 1
Urethane0.077 (0.074–0.080) n = 122.1 (18.7–25.5) n = 2
Isolated heart0.001 (0.00084–0.00116) n = 119.0 ± 0 n = 1

Table 3.

P wave amplitude and duration, regardless of synchronization of the male rats to the light and dark cycle under individual types of anesthesia.

Data presented as average (range); (n, number of baseline or control values in which the amplitude and duration of the P wave were evaluated).

The extent to which these values are valid cannot yet be assessed because there are an insufficient number of studies; this problem also affects sex and the LD effect on the amplitude and duration of the P wave. There is an indication, however, that there may be sex differences in the duration of the P wave under ketamine/xylazine anesthesia (21.99 ms [range 17.38 ms–26.62 ms]) for females and 20.37 ms (range 18.84 ms–26.49 ms) in males [19]. However, to date, this is not statistically demonstrable for other types of anesthesia.

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5. Prognostic significance of changes in the ventricular complex in arrhythmogenesis

Evaluation of the parameters of the ventricular complex (QT interval, QTc interval, QRS complex, R, and T wave amplitudes) is undoubtedly important because it provides information about the course of depolarization and repolarization of the ventricles. The distance from the beginning of the QRS complex to the end of the T wave is measured, with the total length corresponding to the duration of depolarization and repolarization of the ventricular muscle.

5.1 QT interval

In rats, the determination of the QT interval is more complicated because the T wave is not clearly separated from the QRS complex. Therefore, it is necessary to develop a method for analyzing repolarization time in nonanesthetized rats. However, the importance of QT interval dispersion is a complex matter involving at least two different phenomena—namely, prolongation of the average action potential duration and myocardial heterogeneity [26]. Based on the evaluation of the QT, as well as the QTc interval in rat experimental models, cardioprotection was also assessed after stimulation of vitamin D receptors and the effect of isoprenaline [42], the effect of doxorubicin [134] and L-glutamine in diabetic rats [135], saffron on atrial and ventricular conduction velocity [64], or the effect of preconditioning at different doses of noradrenaline on ischemia-induced ventricular arrhythmias.

The mentioned examples confirm the informative value of changes in the duration of the QT interval in the evaluation of the severity of disorders in the dispersion of ventricular refractory periods and their impact on the onset and development of ventricular arrhythmias. If we consider the values from telemetry studies, in terms of reference value and range [21, 26, 117, 118], QT interval prolongation was measured with virtually every type of barbiturate anesthesia; as such, under pentobarbital [32, 34, 37, 38, 40, 41, 43, 44, 45, 47, 48, 49, 50, 122, 124, 125, 126], thiopental [61, 62, 63, 64, 66, 67, 69], and Nembutal anesthesia [114]. Ketamine/xylazine [45, 78, 85, 87, 89, 90, 91, 92, 129, 136], ketamine/medetomidine [96], ketamine/diazepam [96, 98], and ketamine/ midazolam [97], anesthesia had the greatest effect on QT interval prolongation. A moderate prolongation was also found under chloralose anesthesia [77] and similar prolongations under ether anesthesia [99, 100, 101, 103, 104]. The shorter QT interval duration was under urethane [45, 52, 55, 56, 60, 135, 137, 138] and tribromoethanol [106] anesthesia compared with telemetry studies. Isoflurane [72, 74, 75, 120, 121] and desflurane anesthesia [72] did not affect QT interval duration. There were virtually no significant changes in QT interval duration in working with isolated hearts [105, 115, 139, 140]. All experiments were performed on males without specifying the adaptation of the animals to the LD cycle and there were no studies investigating 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 4, Figure 3).

Anesthesia.Not specifiedLight periodDark period
FemaleMaleFemaleMaleFemaleMale
Telemetry studies58.02
51.7–64.34
(n = 4)
----
Pentobarbital68.85 65.56–69.26
(n = 19)
73.5
58.1–88.9 (n = 1)
76.02
66.36–85.68 (n = 1)
Thiopental64.75
54.03–67.52
(n = 8)
--
Phenobarbital
Nembutal-62
60–63
(n = 1)
--
Ketamine/xylazine87
79–95
(n = 1)
74.97
70.88–79.23
(n = 11)
89.9
73–106.8
(n = 1)
91.7
82–101.4 (n = 1)
Ketamine/medetomidine-65
63.1–66.9
(n = 1)
--
Ketamine/Diazepam-101.25
84.15–116.7
(n = 2)
--
Ketamine/midazolam-78
69–87
(n = 1)
--
Isoflurane58.32
43.68–61.48
(n = 6)
Desflurane-69.0
67.72–0.28
(n = 1)
Chloralose-60.20
53.51–6.89
(n = 1)
Tribromethanol-36
33.5–38.5
(n = 1)
Ether69.86
66.4–73.4
(n = 5)
Urethane53.05
48.74–57.35
(n = 9)
Isolated heart72.75
68,8–76.7
(n = 4)

Table 4.

QT interval duration (ms) under individual types of anesthesia with regard to sex and the cycle of light (inactive) and dark (active).

Data presented as average (range); (n, number of baseline or control values from which QT interval was evaluated). Not specified—in the methodology does not specify the lighted period when the experiments were performed.

Figure 3.

Distribution of ranges of QT intervals 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 QT interval ranges from at least three studies in which QT interval was evaluated are shown in the figure.Telemetry studies (n = 4), pentobarbital anesthesia (n = 19), thiopental anesthesia (n = 8), ketamine/xylazine anesthesia (n = 11), isoflurane anesthesia (n = 6), ether anesthesia (n = 5), urethane anesthesia (n = 9), isolated heart (n = 4). n, number of baseline or control values from which duration of the QT interval was evaluated.

5.2 QTc interval

In human cardiology, QTc interval assessment enables the comparison of QT values overtime at different HRs and improves the identification of patients at increased risk for arrhythmias. Prolonged QTc is caused by premature action potentials during the late phases of depolarization. This increases the risk for ventricular arrhythmias, including fatal ventricular fibrillation [141]. These changes make it difficult to compare QT intervals measured at different HRs. To account for this and, thus, improve the reliability of QT measurements, the QT interval can be corrected for HR (QTc) using various mathematical formulae, a process that modern ECG recorders often perform automatically. The duration of the QTc interval is a key and critical factor in assessing changes in repolarization with regard to drug safety and cardiac disorders. There was only one study that reported changes in the duration of the QTc interval depending on commonly used drugs, especially when used in combination with other substances that affect their metabolism [142, 143]. Possible changes in QTc interval depending on sex and age have also been described in humans. Higher rates of prolonged QTc are observed in women, older patients, with high systolic blood pressure or HR, and low body height [144]. It was found that the rate of QT/RR hysteresis decreases with increasing age, while the duration of the individually corrected QTc interval increases with increasing age. In contrast to longer QTc intervals, the rate of QT/RR hysteresis was faster in women [145]. There are many causes of prolonged QT intervals, and acquired causes are more common than genetic causes [146].

Changes in the QTc interval have also been described in rats, where, for example, induction of ischemia shortened the QTc interval and led to ventricular arrhythmias. Administration of low doses of noradrenaline prevented shortening of the QTc interval during ischemia but could not significantly reduce the severity and incidence of arrhythmias [38]. However, in the experimental field, determination of QTc interval is somewhat more complicated because HR values are extremely variable among different species [147]. In rats, there is a lack of a validated approach to QT interval correction [143] and, despite some efforts [148, 149], there is no validated and widely used method for such QTc interval adjustment. Thus, most researchers in experimental cardiology, pharmacology, and toxicology must use formulas designed for other species, without commenting on their accuracy in rats [26, 150, 151], and its use should be considered carefully in case of very low HR [143] . This fact is reflected in the data reported in Table 5 and Figure 4 of the average values of the QTc interval, where relatively large deviations under different types of anesthesia are evident.

AnesthesiaQTc interval (ms)QRS complex (ms)R wave amplitude (mV)T wave amplitude (mV)
Telemetry studies87.02
(81.79–92.31)
n = 5
26.08
(25.68–29.52)
n = 5
0.139
(0.118–0.16)
n = 1
Pentobarbital203.77
(196.2–211.5)
n = 7
25.4
(23.68–27.13)
n = 19
0.56
(0.54–0.58)
n = 4
0.08
(0.07–0.9)
n = 2
Thiopental110.23
(100.5–120)
n = 7
22.76
(21.12–24.47)
n = 8
1.8
(1.76–1.84)
n = 1
Phenobarbital71.6
(69.36–73.84)
n = 1
55
(45–65)
n = 1
-
Nembutal-20
(19–21
n = 1
1.06
(0.99–1.12)
n = 1
0.37
(0.34–0.41)
n = 1
Ketamine/xylazine143.76
(138.97–148.55)
n = 8
23.9
(22.16–25.64)
n = 12
0.49
(0.41–0.57)
n = 5
0.09
(0.06–0.11)
n = 5
Ketamine/medetomidine-27.5
(22.5–32.5)
n = 1
-
Ketamine/diazepam-18.5
(13.25–23.75)
n = 2
-
Ketamine/midazolam-18
(16.8–19.2)
n = 1
-0.07
(0.034–0.106)
n = 1
Isoflurane58.32
(43.68–61.48)
n = 4
18.3
(16.75–19.85)
n = 4
1.7
1.5–1.9
n = 1
0.11
(0.09–0.13)
n = 1
Desflurane184.7
(181.32–188.08)
n = 1
28.8
(25.22–32.38)
n = 1
Chloralose-66
(55.7–76.3)
n = 1
Tribromethanol90.5
(85.5–95.5)
n = 1
26.2
(25.3–27.1)
n = 2
Ether153
(151–155)
n = 1
22.15
(18.8–25.5)
n = 2
Urethane165.5
(158.6–180.5)
n = 3
18.41
(17.39–20.5)
n = 15
0.65
(0.64–0.66)
n = 2
0.337
(0.335–0.337)
n = 1
Isolated heart83.43
(52.65–114.2)
n = 2
32.5
(31.4–33.6)
n = 2
1.61
(not specified)
n = 2
1.42
(0.95–1.89)
n = 1

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.

Data presented as average (range) n, number of experimental studies in which ventricular parameters were evaluated.

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.

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, 42, 43, 47, 51] ketamine/xylazine [87, 90, 91, 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].

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 ± 34.8 ms vs. dark 202.1 ms) [19], unlike pentobarbital anesthesia, where there were no significant differences (light 197.7 ± 40.9 ms vs. dark 190.7 ± 26.6 ms) [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 et al. [106], where the duration of the QTc interval was two times longer in older rats (117 ± 4 ms vs. 64 ± 6 ms) than in young rats at relatively the same HR (young, 381 ± 1 beats/min. vs. old, 405 ± 11 beats/min).

5.3 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, 118, 119] to barbiturate anesthesia—under pentobarbital [32, 34, 37, 40, 42, 44, 45, 46, 47, 48, 49, 51, 122, 124, 125, 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, 56, 57, 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 5). 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 5, Figure 5).

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.

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6. Conclusions

In the discussion sections of many published in vivostudies, 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 vivoexperiments, 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 24 h 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 vivorat 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 variations 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 the experiments or measurements are performed. Although rat ECG parameters are only analyzed in this study, these can be of basis to further researches and studies that may involve humans in the future.

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Acknowledgments

This work was supported by a VEGA grant: 1/0008/20.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

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Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Written By

Pavol Svorc Jr and Pavol Svorc

Submitted: March 31st, 2022Reviewed: April 13th, 2022Published: May 7th, 2022