Physiol. Res. 65: 717-725, 2016 https://doi.org/10.33549/physiolres.

933270

REVIEW

Electrocardiography in Rats: a Comparison to Human

P. KONOPELSKI1, M. UFNAL1
1
Department of Experimental Physiology and Pathophysiology, Laboratory of Centre for Preclinical
Research, Medical University of Warsaw, Warsaw, Poland

Received December 3, 2015

Accepted March 18, 2016
On-line July 15, 2016

Summary of ECG recordings have been thoroughly described in

Electrocardiography (ECG) in rats is a widely applied multiple handbooks and research papers (Hall et al. 2011,
experimental method in basic cardiovascular research. The Wagner et al. 2009).
technique of ECG recordings is simple; however, the Despite some differences, such as the lack of Q
interpretation of electrocardiographic parameters is challenging. wave in most leads (Driscoll 1981, Farraj et al. 2011),
This is because the analysis may be biased by experimental there are essential similarities between rat and human
settings, such as the type of anesthesia, the strain or age of ECG (Sambhi and White 1960), (Fig. 1). Therefore, ECG
animals. Here, we aimed to review electrocardiographic in rats has been exploited in basic cardiovascular research
parameters in rats, their normal range, as well as the effect of dealing with the heart’s performance under physiological
experimental settings on the parameters variation. Furthermore, conditions and in animal models of cardiovascular
differences and similarities between rat and human ECG are diseases.
discussed in the context of translational cardiovascular research. Although the technique of ECG recordings is
rather simple, the interpretation of the acquired data is
Key words challenging. First, in contrast to humans, the criteria of
Rats • Cardiovascular system • Cardiac electrophysiology • QT • reference ECG parameters in rats have not been
Interval • QRS established. Second, there are significant differences in
ECG parameters between the experimental studies in rats.
Corresponding author The latter seems to result from different experimental
M. Ufnal, Department of Experimental Physiology and settings, such as the age and strain of animals and the
Pathophysiology, Medical University of Warsaw, Banacha 1B, type of anesthesia used (Table 1, 2).
02-097 Warsaw, Poland. Phone/Fax: +48 221 166 195. E-mail: Here, we aimed to review electrocardiographic
mufnal@wum.edu.pl parameters in rats, their range, as well as the effect of
experimental settings on the parameters variation. The
Introduction review is confined to Sprague Dawley (SD) and Wistar
rats, as these are the two strains most commonly used in
Electrocardiography (ECG) in humans was cardiovascular experiments.
introduced in 1903 by Willem Einthoven. Since then, it
has become one of the most widespread diagnostic tools Major ECG techniques
in clinical medicine. ECG recording reflects the electrical
activity of the heart and may provide important insights There are several invasive and non-invasive
into functional and structural characteristics of the techniques that allow 1 to 12 channel ECG recordings in
myocardium. The physiological and pathological criteria laboratory animals. Most studies use a limb lead II that is

PHYSIOLOGICAL RESEARCH • ISSN 0862-8408 (print) • ISSN 1802-9973 (online)

 2016 Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic
Fax +420 241 062 164, e-mail: physres@biomed.cas.cz, www.biomed.cas.cz/physiolres
718 Konopelski and Ufnal Vol. 65

Table 1. Comparison of ECG parameters between Sprague-Dawley and Wistar rats.

HR (bpm) PR (ms) QRS (ms) QT (ms) QTc (ms) ST (ms)

Sprague-Dawley 239-508 38-70 12-22 50-75.9 119-1411 12.3-18.1

Wistar 242-452 39-78 14-28 57-95 133-1732 9.5 -14.8

1
Heart rate in beats per minute (bpm), other parameters in milliseconds (ms). – QTc calculated by Fridericia formula,
2
– QTc calculated by Bazett’s formula.

Table 2. The effect of anesthetics on ECG parameters in Sprague-Dawley and Wistar rats.

Strain/anesthetics HR (bpm) PR (ms) QRS (ms) QT (ms)

Sprague-Dawley
Light ether 340-508 48-70 11.3-16.1 50-70
Ketamine and xylazine 239-272 56-66 12-15.7 -
Urethane 417-451 48-56 18.5-21.5 60.6-62.5
Pentobarbital 387-446 38-44 20-22 63-74

Wistar
Light ether 290-378 52-78 18-28 57-75
Ketamine and xylazine 242-336 39-57 17-25 75-95
Urethane 357-452 49-58 14-16 -
Pentobarbital 334-349 - 18-19.6 69-76

Heart rate in beats per minute (bpm), other parameters in milliseconds (ms).

sufficient for the general analysis of ECG parameters in mediastinum. Data from transmitters are gathered
rodents (Farraj et al. 2011, Buschmann et al. 1980), wirelessly by a receiver positioned outside the rat cage
whereas precordial leads are used to localize pathological (Sgoifo et al. 1998). This enables measurements in freely
processes such as myocardial ischemia (Krenek et al. moving rats for several weeks. The method provides data
2009). that are free of anesthesia and stress-induced artefacts
(Braga et al. 2011). However, the quality of the
Invasive methods recordings may be compromised by movement of
Surface ECG recording is the most commonly animals, displacement of the electrodes or inflammation
used technique in anesthetised rats. To obtain a limb at the site of electrode implantation.
leads recording, the electrodes are placed under the skin An in vitro method for recording the electric
of left and right forepaws and the tail. Additionally, activity from the isolated heart is the method introduced
unipolar leads can be positioned anteriorly at the by the Langendorff in 1898. The heart is extracted form
midsternum (Normann et al. 1961). Advantages of this terminally anesthetized rat and placed into a perfusion
method include its simplicity, high quality of collected apparatus. The heart is perfused with a perfusion fluid
data and repeatability, while its main drawback is that under physiological pressures, keeping the
measurements may be confounded by anesthetics. electromechanical work of the myocardium, functions of
An ECG recording technique that escapes the the valves and coronary blood flow. Advantages of this
effect of anesthesia is telemetry. Telemetry transmitters technique include a precise recording of the origin and
are implanted subcutaneously in the interscapular region amplitude of electrical events as well as possibility of
or in the abdominal cavity, whereas electrodes connected concomitant evaluation of the coronary blood flow and
to the transmitters are placed subcutaneously on the contractility of the myocardium. The advantages,
dorsal surface of the xiphoid process and anterior however, are limited by the fact that the isolated heart is
2016 ECG in Rats 719

separated from physiological effects of humoral and and Purkinje fibres, finally reaching ventricular
nervous control (Skrzypiec-Spring 2007, Döring 1989). cardiomyocytes. A typical ECG tracing mirrors the
repeating cycle of three major electrical events, including
The effect of anesthesia on ECG atrial depolarization (P wave), ventricular depolarization
The choice of anesthesia may significantly affect (QRS complex) and ventricular repolarization (T wave),
the results of experiments, as anesthetics differ in their (Fig. 1).
effects on cardiomyocytes and conducting system of the
heart. For example, it has been found that inhalation Heart rate and RR interval
anesthetics may have an arrhythmogenic potential. Heart rate (HR) represents the number of heart
Halotane, isoflurane, and enflurane have been shown to contractions over a specific period of time, most
block Ca2+ channels and Na+/Ca2+ exchange in commonly 1 min (beats per minute, bpm). RR interval is
cardiomyocytes (Mayo and Jamali 1999). Cardiotoxic the time between the consecutive R wave peaks. Under
effects have also been reported after parenteral physiological conditions, HR can be calculated from RR
anesthesia. Urethane anesthetised rats show a significant interval according to the following formula: HR=60/(R-R
depression of HR, whereas the effect is not observed in interval in seconds). In humans HR can also be calculated
rats treated with pentobarbital and thiopental. by measuring the time between the consecutive Q waves,
Pentobarbital, however, was found to evoke ventricular while in rats HR is calculated using RR intervals only.
arrhythmias. In contrast, thiopental was found to possess This is because rat ECG lacks the Q wave in most leads
antiarrhythmic activity (Zorniak et al. 2010). Ketamine, and/or the Q wave may be difficult to locate, especially in
another commonly used anesthetic drug, apart from its noisy and low amplitude ECG.
anti-NMDA activity, interacts with cardiac voltage- Mammals have a wide distribution of resting RR
sensitive Ca2+ channels that may also significantly affect interval. For an adult human, resting RR interval ranges
the electrical activity of cardiomyocytes (Hirota and from 0.6-1 s (HR≈60-100 bpm) (Hall et al. 2011),
Lambert 1996, Baum and Tecson 1991), (Table 2). whereas for matured rats RR interval is 118-251 ms
(HR≈239-508), (Table 1). In rats HR depends on age, and
Non-invasive systems it has been found to increase during the first 4 weeks after
An example of a non-invasive method of ECG the birth (Malfatto et al. 1990, Dickhout and Lee 1998).
recordings is dressing rats in a cotton jacket with two In newborn restrained Wistar rats, HR is 298-306 bpm
electrodes attached to its inner surface. Before wearing and then reaches steady values of 429-473 bpm just
the coat, rats’ skin must be shaved in anterior thoracic before puberty (Malfatto et al. 1990). Therefore, in
region. Measurements are performed in conscious rats contrast to humans, there seems to be no clear negative
placed in plastic restrainers (Pereira-Junior et al. 2010). correlation between HR and aging before puberty in rats.
Advantages of this technique include non-invasiveness, On the other hand, a decrease in HR with aging was
measurements in conscious animals and a significantly found in postpubertal Wistar rats using chronic telemetry
lower cost in comparison to telemetry. Nevertheless, recording (Sgoifo et al. 1998).
restraint-stress and difficulties with placing the electrodes HR seems to be strongly affected by the type of
in the same position in different rats are significant anesthesia used. In SD rats anesthetised with ketamine
limitations of the method. and xylazine mixture, light ether, urethane and
Another method is a non-invasive ECG pentobarbital heart rate was found to be 239-272 bpm
recording in conscious rats placed in a restrainer also (Regan et al. 2005, Regan et al. 2007), 340-508 bpm
referred as a tunnel. In this technique paws of the rat are (Normann et al. 1961), 417-451 bpm (Lin et al. 1997),
placed on ECG sensors embedded in the tunnel floor. and 387-446 bpm (Sugiyama et al. 2005), respectively.
After short adaptation period up to 6 lead ECG, lasting HR in Wistar rats was reported as 242-336 bpm under
30-60 min, can be obtained (Mongue-Din et al. 2007). ketamine and xylazine anesthesia (Miranda et al. 2007),
290-378 bpm under light ether anesthesia (Fraser et al.
Electrocardiographic parameters 1967), 357-452 bpm under urethane anesthesia
An action potential in the heart is generated in (Buschmann et al. 1980), and 334-349 bpm in rats
sinoatrial node and subsequently conducted through anesthetised with pentobarbital (Ahmad et al. 2015).
atrioventricular node, His bundle, His bundle branches
720 Konopelski and Ufnal Vol. 65

The P wave QRS complex

In ECG recording, the P wave reflects QRS complex is located between Q and
depolarization of the atria. In both humans and rats, S waves. Its duration shows the time of propagation of
physiological sinus rhythm is characterized by a positive depolarization through the ventricles. The analysis of the
deflection of the P wave in limb lead II, a negative length of QRS complexes provides important data on
deflection of the P wave in lead aVR, and the presence of electrical activity of the heart. QRS narrowing can be
QRS complex after every P wave. The lack of the P wave seen in supraventricular arrhythmias, whereas wide QRS
or its altered shape is present in various cardiac complexes reflect ventricular rhythms as well as
arrhythmias, the most common of which is atrial disturbances of intraventricular conduction that can be
fibrillation. seen in right and left bundle branch blocks, heart failure
Similarly to humans, atrial fibrillation in rats is and myocardial ischemia. Wide QRS complexes were
characterized by the lack of the P wave (Haugan et al. found after treating rats with several drugs, for example
2004, Nattel et al. 2005). Although in humans the doxorubicin (Kelishomi et al. 2008), disopyramide (Król
analysis of the length and shape of the P wave brings et al. 2015), and azithromycin (Atli et al. 2015).
clinically important insights, in rats there is not enough Since Q wave is usually not detectable in rats,
experimental data to conclude form alterations in the RS or Rs complexes are evaluated in rat ECG. Duration
P wave shape and length. However, Milliez and of RS complexes in SD rats under a light ether anesthesia
collaborators reported that the prolongation of the P wave is 11.3-16.1 ms (Kelishomi et al. 2008), 12-15.7 ms in
may be associated with increased susceptibility to rats anesthetized with ketamine and xylazine (Regan et
supraventricular arrhythmias in Wistar rats after al. 2005), 20-22 ms in rats undergoing pentobarbital
myocardial infarction (Milliez et al. 2005). anesthesia (Sugiyama et al. 2005), and 18.5-21.5 in rats
under urethane anesthesia (Badole et al. 2014).
PR interval QRS length in Wistar rats was found to be
The PR interval, also referred to as the 14-16 ms (Buschmann et al.1980), 17-25 ms (Miranda et
PQ interval Q wave is not always present, reflects the al. 2007), 18-19.6 ms (Ahmad et al. 2015), and 18-28 ms
propagation of depolarization from atria to the heart (Fraser et al. 1967) in rats anesthetized with urethane,
ventricles (Hoffman et al. 1960, Beinfield and Lehr 1968). ketamine combined with xylazine, pentobarbital and
The PR interval is determined by measuring the time from ether, respectively.
the beginning of the P wave until the beginning of the QRS
or RS complex. The analysis of the length of PR interval is ST segment
crucial in the diagnosis of atrioventricular blocks. ST segment represents the time when the
The PR interval in SD rats ranges from 38 to ventricles are depolarized and is defined as the time from
70 ms and its length seems to be significantly affected by the end of QRS complex to the beginning of T wave. It is
the type of anesthesia. Namely, the PR interval was isoelectric and lasts approximately 80 to 120 ms in
reported to be 38-44 ms in pentobarbital anesthesia humans. The evaluation of the parameter is essential in
(Sugiyama et al. 2005), 48-70 ms in light ether anesthesia the diagnosis of myocardial ischemia and myocardial
(Normann et al. 1961), 48-56 ms in urethane anesthesia infarction. Therefore, in humans the criteria of significant
(Lin et al. 1997), 56-66 ms in ketamine combined with changes, i.e. a depression or elevation of ST segment,
xylazine anesthesia (Regan et al. 2005, Regan et al. have been thoroughly described (Wagner et al. 2009).
2007), and 52-60 ms in isoflurane anesthesia (Hamdy and Alteration of ST segment may also occur in other
Brocks 2009). conditions such as channelopathies e.g. Brugada
In Wistar rats, PR interval was found to be 39 to syndrome, intraventricular conduction blocks, water-
78 ms, and its length also varied dependent on the type of electrolyte balance disturbances and others.
anesthesia. Rats anesthetized with a mixture of ketamine Studies in rats showed significant changes in
and xylazine had the shortest duration of the parameter ST segment in myocardial infarction (Chrastina et al.
(39-57 ms) (Miranda et al. 2007). A longer PR interval 2014) and in myocardial ischemia (Speechly-Dick et al.
was reported in rats under urethane (49-58 ms) 1994), however, clear criteria of significant changes in
(Buschmann et al. 1980) and ether anesthesia (52-78 ms) ST segment have not been established. Some researchers
(Fraser et al. 1967). evaluated the duration of ST in rats. In SD rats
2016 ECG in Rats 721

undergoing light ether anesthesia the duration of T wave may result from myocardial infarction and
ST segment was reported to be 12.3-18.1 ms (Kelishomi pulmonary embolism.
et al. 2008), while in Wistar rats anesthetized with ether it Rat ECG shows the upright T wave in limb
was 9.58-14.8 ms (Dragojevic-Simic et al. 2004). lead II. Inversion of the parameter in rat ECG was
However, the length of ST segment is of limited reported after injection of isoproterenol and myocardial
importance for ECG analysis. First, it is difficult to detect infarction (Hill et al. 1960). Hypokalaemia in rats was
ST segment in rat ECG as the T wave often rises in found to produce prolongation and decrease in voltage of
continuity with the S wave (Sambhi and White 1960, T wave (Akita et al. 1998).
Jensen et al. 1984) (Fig. 1). Second, the prolongation of
ST segment lengthens QT (RT) intervals. Therefore, it is QT interval
more convenient to analyse the two latter parameters QT interval describes the time from the Q wave
rather than ST segment. to the end of the T wave. In rats, this parameter
is usually measured from the onset of Rs complex to the
end of T wave, due to difficulties with detecting Q waves.
QT interval represents the time of depolarization and
repolarization of ventricular cardiomyocytes.
Pathological duration of this parameter indicates
disturbances in electrical activity of the heart due to
an intrinsic heart disease or toxic effects of exogenous
compounds. For example, QT interval may be prolonged
by hypokalaemia, ischemia, myocardial infarction,
channelopathies, including Long QT syndrome. Finally,
multiple drugs may produce prolongation of QT interval
leading to ventricular tachyarrhythmia, including torsade
de pointes. Therefore, the prolonged QT interval is
considered to be a useful indicator of drug cardiotoxicity
(Hanada et al. 1999, Roden et al. 2004). Interestingly,
sex-related differences have been observed in
susceptibility to drug-induced arrhythmias in both
humans and laboratory animals (Makkar et al. 1993, Liu
et al. 1999).
A number of studies have shown that cardiotoxic
drugs prolong QT interval in rodents, and ECG recording
in rats has been used as a screening tool in cardiotoxicity
studies (Hanada et al. 1999, Ohtani et al. 1996, Król et al.
2016). However, it needs to be stressed that the
Fig. 1. Original recording of human (a) and Wistar rat (b) ECG,
II limb lead. RR interval in humans in seconds, in rats in
translation of the results of those studies to humans has
milliseconds. Q waves and ST segments in rats are difficult to limitations. This is because rats’ hearts do not express the
detect. human Ether-à-go-go-Related Gene (hERG), whereas
drugs cardiotoxicity is strongly associated with blocking
T wave of hERG-related potassium channels (De Bruin et al.
T wave reflects repolarization of the ventricles. 2005). However, the rats’ hearts express a variant of
The T wave has a positive deflection in the majority of Ether-à-go-go-Related Gene (rat ERG, also known as
leads including limb lead II. In humans, high Kcnh2) (Matus et al. 2015), which may play a role in
voltage/peaking of T wave may be found in drug induced cardiotoxicity, but further research is
hyperkalaemia, in early phases of acute myocardial needed to support this notion.
infarction and in patients with Long QT Syndrome. A prolonged QT interval in rats has also been
A decreased amplitude of the T wave may be present in found in hypokalaemia (Akita et al. 1998) and
hypokalaemia, whereas a negative deflection of the myocardial infarction (Mackiewicz et al. 2014).
722 Konopelski and Ufnal Vol. 65

Furthermore, as with other ECG parameters, QT length (Baillard et al. 2000).

seems to be affected by the type of anesthesia. In SD rats Another method for calculating the QTc is
it was found to be 50-70 ms (mean 53.6 ms) under light Fridericia’s formula, which is as follows: QT interval
ether anesthesia (Normann et al. 1961), 60.6-62.5 ms divided by cube-root of RR-interval,
under urethane anesthesia (Hanada et al. 1999), 63-74 ms
𝑄𝑄𝑄𝑄
under pentobarbital (Sugiyama et al. 2005), and ( )
∛𝑅𝑅𝑅𝑅
64.1-75.9 ms under isoflurane anesthesia (Hamdy and
Brocks 2009). Some researchers suggest that this equation may
In conscious Wistar rats QT length in telemetric be the preferable way of correcting the QT (Schwartz and
recording was reported to be 69-71 ms (Baillard et al. Wolf 1978). QTc interval calculated by Fridericia’s
2000), 57-75 ms in rats under ether anesthesia (Fraser et formula in isoflurane anesthetized Sprague-Dawley rats
al. 1967), 69-76 ms in rats under pentobarbital anesthesia was found to be 119-141 ms (Funck-Brentano and Jaillon
(Ahmad et al. 2015), and 75-95 ms in rats under ketamine 1993).
and xylazine anesthesia (Miranda et al. 2007). The profound analysis of correlation between
QTc and QT, dependent on HR, was performed by
Corrected QT interval Kmecova and Klimas (2010). Their research suggest that
It is well-established that the length of QTc interval should be calculated according to adjusted
QT interval in humans depends on HR. In general, Bazett’s formula, namely
an increase in HR shortens QT as the ratio of the lengths
of systole and diastole increases. Therefore, a corrected QTc =
𝑄𝑄𝑄𝑄
,
𝑅𝑅𝑅𝑅
QT interval (QTc) that takes into account changes in HR � 𝑓𝑓

is often used as a more objective parameter of

depolarization and repolarization of ventricles (Funck- where f is the normalization factor according to the basal
Brentano and Jaillon 1993, Ahnve 1985). RR duration in rats, that is 150 ms (Kmecova and Klimas
Although in rats HR is about 5-6 times higher 2010).
than in humans, there is no consensus on whether there is
a need to adjust QT to HR (Hayes et al. 1994, Kmecova Conflict of Interest
and Klimas 2010). The majority of rat studies use one of There is no conflict of interest.
several formulas to calculate QTc (Hamdy and Brocks
2009, Baillard et al. 2000). Conclusions
One of the adjustments of QT to HR is the Rat electrocardiography is an important
Bazett’s formula, which was presented in 1920 after the investigational tool in experimental cardiology. However,
analysis of ECG changes associated with exercises. The the interpretation of electrocardiographic parameters is
formula is based on dividing QT interval by the square problematic. In contrast to human studies, the criteria to
root of RR-interval, distinguish significant from insignificant changes in ECG
parameters in rats have not been established. This is due
𝑄𝑄𝑄𝑄
(√𝑅𝑅𝑅𝑅 ), (Bazett 1920). to a relatively small number of experimental studies, as
well as significant variations in electrocardiographic
Due to its simplicity, it is a very useful tool in parameters between the studies. The latter is likely caused
both at the bedside and experimental research. However, by differences in rat strains and anesthetics used.
it seems inappropriate for HR exceeding 100 bpm Therefore, there is a need for more studies, preferably
(Molnar et al. 1996). In Wistar rats, QTc calculated employing measurements in conscious rats. In the
according to Bazett’s formula was reported to be meanwhile, the interpretation of ECG in rats should
133-173 ms in ether-anesthetized rats (Fraser et al. 1967), always take into account the effect of experimental
and 152-156 ms in telemetry recordings in conscious rats settings, especially anesthesia and the strain of rats.
2016 ECG in Rats 723

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