Prolonged QTc Interval eJKI Vol. 6, No.

3, Desember 2018

RESEARCH ARTICLE

Prolonged QTc Interval in Rat after Long-term High-Intensity Interval Training

and Detraining

Dewi I.S. Santoso1*, Prasetyo S. Redjeki2, Nuryati C. Siregar3,

Jeanne J. Pawitan4

Department of Medical Physiology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia

1

2
Department of Oral Biology, Faculty of Dentistry Universitas Indonesia, Jakarta, Indonesia
3
Department of Pathological Anatomy, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
4
Department of Histology Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
*Corresponding author: dewi.irawati.1307@gmail.com
Accepted: 22 November 2018
DOI: 10.23886/ejki.6.9904.
Abstract
Long-term exercise induces cardiac remodelling known as exercise-induced ventricle hypertrophy
and accompanied by electrical remodelling that can be recorded by ECG. This study aimed at recognizing
electrocardiographic changes in rats undergoing long-term high-intensity interval exercise followed by a period of
detraining. This study conducted at the Laboratory of the Biochemistry and Molecular Biology Department, FMUI from
November 2014-January 2015. Four groups of young adults male wistar rats (100-200gBW) were randomly selected.
Group 1 and 2 were assigned as control group for ECG recording on week (4 and 8) and (12 and 16) respectively.
Group 3 was given 4 weeks of intensive training, followed by 4 weeks of detraining, while group 4 was given 12 weeks
of intensive training followed by 4 weeks of detraining. ECG examination was performed at the end of each period of
training or detraining and compared to control group of the same period of age. P wave in the exercising group was
significantly increased (p<0.05), PR interval was decreased in group 4 after detraining (p<0.05). QRS amplitude was
increased although not significantly different compared to control group. However, a significant persistent prolonged
QTc interval was observed in the exercising group (62.76+4.03 ms and 64.24+3.78 ms) compared to control group
(48.88+2.15 ms and 47.33+3.43 ms). Detraining did not restore QTc interval (57.81+1.96 ms and 61.16+5.02 ms) vs
(48.93+2.40 ms and 48.13+1.66 ms). In conclusion, cardiac remodelling after long-term high intensity interval training
causes ventricular hypertrophy with persistent repolarization disturbances after a period of detraining, indicated by an
increase in QRS amplitude and a significant prolonged QTc interval.
Key words: Long-term exercise; QTc interval

Pemanjangan Interval QTc pada Tikus setelah Latihan Intensitas Tinggi

dengan Interval Jangka Panjang dan Henti Latih

Abstrak
Latihan fisik intensif jangka panjang menyebabkan remodelling jantung yang disebut exercise-induced
hipertrofi ventrikel yang disertai perubahan listrik jantung yang dapat direkam melalui EKG. Penelitian ini bertujuan
mengamati perubahan pola EKG tikus yang diberi latihan intensitas tinggi dengan interval jangka panjang.
Penelitian dilakukan di Laboratorium Departemen Biokimia dan Biologi Molekuler FKUI, sejak November 2014
sampai Januari 2015. Tikus wistar jantan dewasa muda (BB 100-200 gram) dibagi 4 kelompok. Kelompok 1 dan
2 sebagai kelompok kontrol EKG (4 dan 8 minggu) serta (12 dan 16 minggu). Kelompok 3 diberi latihan intensif
4 minggu diikuti henti latih 4 minggu. Kelompok 4 diberi latihan intensif 12 minggu diikuti henti latih 4 minggu.
Rekaman EKG dilakukan pada akhir masa latihan dan masa henti latih kemudian dibandingkan dengan kelompok
kontrol sesuai usia. Didapatkan peningkatan voltase gelombang P yang bermakna (p<0,05) pada kelompok
latihan. Interval PR memendek pada kelompok 4 setelah henti latih (p<0,05). Amplitudo QRS meningkat meskipun
tidak berbeda bermakna dibandingkan kontrol. Didapatkan perpanjangan bermakna pada interval QTc kelompok
latih yang menetap (62,76+4,03 ms dan 64,24+3,78 ms) dibandingkan kelompok kontrol (48,88+2,15 ms dan
47,33+3,43 ms). Henti latih tidak memulihkan interval QTc (57,81+1,96 ms dan 61,16+5,02 ms) dibandingkan
(48,93+2,40 ms dan 48,13+1,66 ms). Remodelling jantung akibat latihan intensitas tinggi dengan interval jangka
panjang menyebabkan hipertrofi ventrikel disertai gangguan repolarisasi menetap meskipun telah dilakukan henti
latih, ditandai peningkatan amplitude QRS dan pemanjangan interval QTc yang bermakna.
Kata kunci: latihan fisik intensif; QTc interval.

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Introduction in the athletes were associated with abnormal

It is well established that regular exercise may cardiac structure. This study concluded that ECG
reduce the risk for cardiovascular disease and is could reveal abnormal patterns without indication
recommended for improving and maintaining health. of abnormal cardiac structure. Benito et al9 on
Despite the knowledge, ‘lack of time’ seems to be the other hand, showed that long-term intensive
the common cited obstacle in conducting regular exercise in rats caused changes in ventricle
exercise, so that sedentary lifestyle has become an functions and increased tendency to develop
expanding problem in modern society. Furthermore, arrhythmia. Basavarajaiah et al10 found prolonged
the exact dosage and type of exercise needed to QTc interval in 0.4% of the elite athletes with a
increase physical fitness is still very much debatable.1,2 tendency for developing long QT syndrome.
Increasing evidence demonstrates that high-intensity Long-QT syndrome (LQTS) have been thought
interval training (HIIT) may serve as a substitute to to be the underlying reason for polymorphic
endurance training.1 Moreover, it is perceived to be ventricular tachycardia (VT) during heavy physical
more enjoyable than moderate continues training.3 activity due to increased adrenergic stimulation.9,12
HIIT is also an effective training method in various VTs have long been associated with exercise related
endurance and sprint/power sports.4 sudden death in young athletes. Therefore, this
Long-term exercise induces cardiovascular study aimed at recognizing electrocardiographic
remodelling known as exercise-induced ventricle changes, specifically QTc interval changes, in
hypertrophy, which include enlargement of the left rats undergoing long-term high-intensity interval
ventricle cavity dimension, wall thickness and mass. training and whether a period of detraining would
Cardiac remodelling is considered as an important restore any disturbances in the ECG findings.
compensatory mechanism in response to volume or
pressure overload. Depending on the type and intensity Methods
of the exercise, two types of ventricular hypertrophy High Intensity Interval Training and ECG recording
may develop concentric and eccentric hypertrophy. were conducted at the Laboratory of the Biochemistry
Concentric hypertrophy is associated and Molecular Biology Department, FMUI from
with pressure overload, and is characterized by November 2014-January 2015. This is an in vivo
enlargement in the width of the cardiomyocyte, experimental study on young male adults wistar rats
while eccentric hypertrophy is the result from outbred strain albino Rattus norvegicus, aged 8-10
volume overload, characterized by longitudinal weeks with body weight of 100-200 g. The animals
growth of cardiomyocyte. Cardiac hypertrophy were housed in cages at a room temperature of 23+1°C
due to exercise is associated with an increase in and 12-hours cycle of light and dark. Food and drinks
systolic and diastolic function.5-7 Although, without were provided ad libitum. Acclimatization was done on
doubt, regular exercise is beneficial in enhancing an animal treadmill for 1 week with increasing duration
physical fitness in general and in prevention of and speed. The longest duration was for 12 minutes
cardiovascular diseases, extreme intense exercise with a maximal speed of 25 m/minute. Intensive
as done by elite athletes puts them in greater risk exercise was done on an animal treadmill with a speed
of developing cardiac arrhythmia.6 of 35m/minute for 15 minutes with a resting interval of
Changes in cardiomyocyte structure due 90 seconds every 5 minutes of exercise. The exercise
to high intensity training are accompanied by regimens were held 5 times/week and conducted for
electrical remodelling, which are reflected on the 4 weeks and 12 weeks. The exercise protocol used in
surface 12 ECG lead recording.8,7 This recording this experiment was according to previous study.11
is a simple non-invasive test that can help to Rats were randomly divided into 4 groups.
detect disturbances in cardiac rhythm and help Two groups were selected as controls to minimize
to diagnose other cardiac abnormalities such as the effects of repeated anaesthesia. Group 1 was
hypertrophy, ischemia, or infarction. assigned control group for ECG recordings on week-
A few observational studies have shown that 4 and 8 of the duration of the experiment. Group 2
intensive heavy exercise is associated with an was also control group for ECG recordings on week-
increase of developing arrhythmia, which may lead 12 and 16. Group 3 was given intensive exercise
to sudden death. Pellicia et al8 studied abnormal (training) for 4 weeks followed by cessation of exercise
ECG in a population of athletes and found that (detraining) for 4 weeks. Group 4 was given training
60% out of 12% abnormal ECG recordings were for 12 weeks followed by detraining of 4 weeks.
associated with “athlete’s heart”. Most of these ECG recordings were done on Fukuda M.E.
athletes with abnormal ECG were young of age. Cardisuny D300 using filter at 100 Hz, paper speed
Only 5% of these abnormal ECG recordings 50 mm/s and sensitivity of 1 mV = 20 mm. The rats

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were anaesthetized with ketamine 75 mg/kg BW distribution of sampling (p>0.05). Data were analysed
and xylazin 5 mg/kg BW. Amplitude and duration using ANOVA followed by post hoc: LSD test to
of amplitude ECG recordings were analysed by determine difference between groups (p<0.05)
scanner with enlargement of 100x and calculated
using paint program. All readings were done on lead Results
II. No rats were sacrificed during this experiment. Table 1 and Table 2 display ECG analysis
Collected data were expressed as mean + results of the control group and exercise group,
SD. Shapiro-Wilk test was used to ensure normal respectively.

Table 1. Mean ECG Values of the Control Group

Control Group
Parameters
4 weeks 8 weeks 12 weeks 16 weeks
Heart rate/min 294+5.99 296+9.23 286+18.35 280+14.88
P wave amplitude (mV) 0.05+0.01 0.06+0.01 0.07+0.01 0.07+0.01
P wave duration (ms) 17.51+0.75 16.92+0.01 15.11+2.25 16.24+1.30
PR interval (ms) 49.86+1.74 50.7+1.28 49.71+0.94 51.69+1.14
R wave amplitude (mV) 0.64+0.04 0.65+0.04 0.63+0.05 0.72+0.06
S wave amplitude (mV) 0.03+0.02 0.06+0.04 0.04+0.01 0.03+0.02
QRS interval (ms) 9.18+0.71 8.48+0.01 9.18+0.71 10.45+1.02
QTc interval (ms) 48.88+2.15 48.93+2.40 47.33+3.43 48.13+1.66
T wave amplitude (mV) 0.10+0.01 0.08+0.01 0.10+0.01 0.11+0.01

Four weeks of exercise did not appear to affect the in group 4 re-established the P wave to near the control
heart rate of the rats. The effect was more noticeable or normal values. Although there was an increase in the
after 12 weeks of exercise, with a slight and not amplitude of P wave, exercise of 4 weeks, 12 weeks,
significant reduction in heart rate compared to control and the respective detraining periods did not affect the
of the same age. Four weeks of detraining was not P wave duration indicating a normal conduction spread
found to increase heart rate. Analysis of the P wave through the atria.
showed a significant increase in the amplitude of the P Four weeks of exercise did not significantly
wave after 4 weeks and 12 weeks of exercise, which prolong the PR interval when compared to control and
might indicate the development of atrial enlargement. 4 weeks of detraining restored the PR interval values.
Detraining period in group 3 reduced the amplitude of Twelve weeks of exercise slightly increased the PR
the P wave, although the amplitude was still significantly interval duration, which was not significantly different
higher than control of the same age. Detraining period than control. On the other hand, detraining significantly
reduced the PR interval duration compared to control.

Table 2. Mean ECG Values of The Exercise Group and Detrained

Exercise Group
Parameters 4 wk + 12 wk +
4 wk 12 wk
detraining detraining
Heart Rate/min 294+10.21 300+8.09 273+20.80 270+19.3
P wave amplitude (mV) 0.1+0.01* 0.09+0.02* 0.09+0.01* 0.06+0.01
P wave duration (ms) 17.65+1.23 15.39+1.69 19.06+3.75 14.97+1.32
PR interval (ms) 54.94+1.82 50.98+2.46 51.27+2.22 45.76+1.38*
R wave amplitude (mV) 0.92+0.04* 0.85+0.05* 0.83+0.06* 0.87+0.08
S wave amplitude (mV) 0.13+0.05* 0.11+0.04 0.09+0.04 0.09+0.04
QRS interval (ms) 8.75+0.28 8.33+0.46 8.47+0.22 10.45+1.11
QTc interval (ms) 62.76+4.03* 57.81+1.96 64.24+3.78* 61.16+5.02*
T wave amplitude (mV) 0.16+0.02* 0.10+0.01 φ
0.10+0.01 0.12+0.02
*significant difference compared to control group (p<0.05), φsignificant difference compared to the
exercising group (p<0.05).

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Four weeks of exercise and its subsequent exercise and detraining group when compared to
detraining period as well as 12 weeks of exercise the control group.
significantly increased the amplitude of R wave The most noticeable change on the ECG
compared to their respective controls. A significant patterns caused by intensive training was the
increase in S wave amplitude was only found after change in QTc interval. Four weeks training as well
four weeks of exercise. Twelve weeks of exercise as 12 weeks training showed significant prolonged
and detraining also showed an increase, although QTc interval compared to their controls. Although
not significant when compared to control. Training four weeks of detraining reduced the QTc interval,
of 4 weeks, 12 weeks, as well as detraining did not it was still higher than normal. Even after 4 weeks
affect the duration of the QRS interval. of detraining following 12 weeks of exercise,
The T wave amplitude was significantly there was still a significant prolonged QTc interval
increased in the 4 weeks exercise, although during compared to its control group.
the subsequent detraining period, a T wave was Exercise protocol applied in this study induces
significantly reduced compared to its exercise ventricle hypertrophy as shown in an increase in
group. No difference was found in the 12 weeks QRS voltage (Figure 1).

Figure 1. Changes in QRS Amplitude after 4 Weeks, 12 Weeks and Its

Subsequent Detraining Periods in Rats. *Significant Difference
Compared to Its Control Group Respectively (p<0.05).

As mentioned before, the most noticeable prolonged QTc interval in the exercising group and
change in the ECG pattern is the persistent after its detraining period (Figure 2).

Figure 2. Changes In Qtc Interval after 4 Weeks, 12 Weeks and

Its Subsequent Detraining Periods in Rats. *Significant
Difference Compared to Its Control Group Respectively
(P<0.05).

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Discussion enlargement of cavity dimension, wall thickness,

This study describes the resting ECG changes in as well as increase in cardiomyocyte length and
a rat model after completing 4 weeks and 12 weeks width.9,18 Mechanical stress induced by increased
of high-intensity interval training with subsequent haemodynamic load to the heart during intense
detraining period of 4 weeks. The protocol used in exercise are translated into pro-hypertrophic
this study was proven to have reached an anaerobic intracellular signals. However, the exact
state with blood lactate of >4.1 mmol/dl.12 mechanisms of how these biomechanical stresses
Although no decrease in heart rate (HR) was are perceived by the cardiomyocyte are still
observed after 4 weeks of exercise, detraining unknown.15,19 The QRS duration in all four groups
raises the resting heart rate, which might indicate are similar indicating that no ventricular conduction
the recovery of increased vagal activities during disturbances were present.
exercise. The decrease in HR after 12 weeks of The QTc interval in this study was calculated
exercise supports the altered vagal activity towards using Bazett’s formula, which is commonly used in
the increased parasympathetic tone. The result evaluating patients with long QT syndrome (LQTS).20
of this study is similar to VanHoose et al13 which What the significance of an isolated prolonged QTc
assed the effect of aerobic exercise training on might indicate has never been studied before.12 In
diabetic fatty rats. However, while in this study we most forms of underlying structural heart disease
observed a decrease in HR of the control group with associated with sudden death in young athletes,
increasing age, all the groups in VanHoose et al13 arrhythmia is induced by exercise. A prolonged QT
experiment showed an increase in HR. Dor-Haim interval indicates repolarization abnormalities, which
et al14 observed a significant decrease in normal during intensive exercise, has a high risk of torsades
rat HR undergoing exercise for 8 weeks. The de points that can degenerate into ventricular
difference in results with this experiment might be fibrillation. LQTS is a heterogeneous genetic disorder
due to the difference in the exercise protocol. Dor- that affects ionic channels of myocardial cells. This
Haim et al14 used a treadmill with inclination and study was conducted on normal rats and no reports
the final duration of exercise lasted for 60 minutes. have been found indicating rats having possible gene
In this study we observed a significant increase disorders causing LQTS. So, the question is whether
in P wave amplitude after 4 weeks as well as 12 prolonged QT interval in this study was caused by
weeks of exercise. Four weeks of detraining in long intensive exercise, or is there another underlying
Group 4 showed a normal P wave amplitude. basis that needs to be looked upon.
Multiple studies have noted that P wave amplitude
is greater in athletes than in an aged-matched Conclusions
non-athlete population. The exact basis for this The result of this study showed that cardiac
finding is still unknown but it may be due to atrial remodelling after long-term high-intensity interval
enlargement.15 A study by Król et al16 concluded that training causes atrial and ventricular hypertrophy
left atrial enlargement was a common condition in with persistent repolarization disturbances after a
young, healthy rowers. The most often postulated period of detraining, indicated by an increase in P
mechanism of physiological LA dilatation in athletes wave amplitude, QRS amplitude and a significant
is due to an increase volume load. However, prolonged QTc interval.
according to a study conducted by Konopka et al17
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