Diurnal variation of the QT interval in rhesus monkeys

M. Hassimoto¹^{, 2}, M. Kuwahara¹, T. Harada², N. Kaga²
M. Obata², H. Mochizuki², H. Tsubone¹
¹Department of Comparative Pathophysiology, Graduate School of Agricultural and Life Sciences
The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, JAPAN
²Toxicology Laboratory, Research Center, Mochida Pharmaceutical Co. Ltd.
342 Gensuke, Fujieda-city, Shizuoka, JAPAN

Abstract: QT prolongation and the proarrhythmic risk of drugs has been widely discussed. These fatal side effects should be detected during pre-clinical study. However, little information on the basic characteristics of the QT profile is available in primates, the species nearest to humans. In this study, therefore, we subjected 3 male and female rhesus monkeys to 24-h ECG monitoring for evaluating the physiological QT interval. There was no significant difference in 24-h-averaged heart rate, RR interval, QRS, PR, or QT interval between male and female rhesus monkeys. However, male rhesus monkeys showed that their nighttime QT was significantly longer than the daytime one over the entire RR range, whereas females showed this to be the case only at the longest RR interval. These results may indicate that parasympathetic effects on ventricular repolarization are different between male and female rhesus monkeys. In conclusion, QT interval become longer during nighttime, and in its profile male and female may differ. We must take into account this information when using rhesus monkeys in cardiovascular studies.

INTRODUCTION

Many of the non-arrhythmetic drugs are known to induce QT prolongation [1] . These fatal side effects should be detected during pre-clinical study. For evaluation of these side effects in a pre-clinical study, the electrocardiogram (ECG) in experimental animals is quite important. However, little information on the basic characteristics of the QT profile in experimental animals has been reported, especially with respect to primates. Moreover, the QT interval is always changing, as it is under neural or humoral control that is greatly dependent on the RR interval. In this study, we evaluated the physiological QT interval in rhesus monkeys by use of the Holter ECG, focusing on the dependence on the RR interval and on diurnal variation.

METHODS

Male and female rhesus monkeys (N=3 each sex) were obtained at 4 years of age. As the ECG profile is quite affected by the adaptation of test animals to experimental environmental and physical conditions, the animals were carefully accustomed to body touching and hand-to-hand feeding every day for 6 months, with the ECG and blood checked monthly. Before Holter ECG recording, the animals wore a monkey-vest for holding the Holter recorder for 2 weeks for acclimation to the Holter attachment. After 24-h recording of the ECG, we extracted ECG data every 5 minutes, for a total of 288 datum points per animal. RR interval and QT interval were analyzed for all data. From these points, pairs of QT-RR with RR intervals at 400, 500, or 600 msec were selected to avoid any effect of the QT dependence on heart rate (HR). In these 3 groups, daytime and nighttime QT’s were compared.

Fig. 1-a

Fig. 1-b

Figure 1. QT-RR correlation in male (a, N=3) and female (b, N=3) rhesus monkeys.
: a pair of QT-RR in daytime, : a pair of QT-RR in nighttime

RESULTS

ECG observations

The 24-h-averaged ECG parameters are shown in Table 1. There was no significant difference in HR, RR interval, PR, QRS, or QT interval between males and females.

Day to night change in QT interval

Correlations of QT-RR are shown in Fig 1. QT interval becomes longer as the RR interval increased. In addition, nighttime QT interval seemed to be longer than the daytime ones. In RR-restricted analysis (Fig. 2), the nighttime QT in male rhesus monkeys was significantly longer than the daytime one in all RR groups. However, for the females, the nighttime QT was significantly longer than the daytime one only at the RR interval of approx. 600 msec.

TABLE 1
ECG observations (24-h-averaged values) on male and female rhesus monkeys.
The results for each parameter were expressed as the mean ± SD

	Male	Female
N	3	3
HR	120±18	117±24
RR interval	516±78	545±104
PR	86±3	78±6
QRS	49±3	45±1
QT interval	253±8	261±34

DISCUSSION

Among experimental animals, rhesus monkeys are one of the species nearest to humans that are often used in pharmacological or toxicological studies. However, the physiological characteristics of their ECG are almost unknown. In this study, we could show the diurnal variation in the QT interval in unrestrained rhesus monkeys by use of the Holter ECG method.

Some clinical studies reported women to have a longer QT interval than men [2] , and it is thus thought that some sexual hormone may induce QT prolongation in women. In this study, however, no difference between male and female could be detected in rhesus monkeys. This result may account for the shorter QT interval in rhesus monkeys than in humans. Another possibility is an irregular hormonal balance in female rhesus monkeys in the current study, because primates often show unstable reproductive cycles in an experimental environment.

QT interval were longer at nighttime even when the HR was taken into account in male rhesus monkeys, whereas QT prolongation at nighttime in female rhesus monkeys was detected only with the longest RR interval evaluated. One explanation for these results may be that parasympathetic effects on ventricular repolarization are different between male and female rhesus monkeys. Another possibility is some sexual hormone effect such as an estrogen effect on the QT profile in female rhesus monkeys without the induction of QT prolongation. Further studies are needed to elucidate the reason for this difference in QT profile between male and female rhesus monkeys.

Study limitations in current study are the following: First, we analyzed the 24-h-recorded ECG for only 1 day. Though these rhesus monkeys are maintained daily under the same conditions, their physiological circadian rhythms may slightly change every day. Second, an unstable reproductive cycle may effect on the ECG profiles in female rhesus monkeys, as mentioned above. Thus, the present observations should be confirmed in future studies with a greater number of animals.

In conclusion, obvious diurnal variation existed in HR and QT interval, but the character of ventricular repolarization was different between male and female rhesus monkeys. We must take into account this information when using rhesus monkeys in cardiovascular studies.

Figure 2. Comparison of daytime QT and nighttime one in RR-restricted groups. : daytime QT, : nighttime QT. **p<0.01 by student’s t-test

REFERENCES

[1] F. De Ponti, E. Poluzzi, and N. Montanaro, “Organising evidence on QT prolongation and occurrence of Torsades de Pointes with non-antiarrhythmic drugs: a call for consensus”. Eur J Clin Pharmacol, 57(3): pp. 185-209, 2001.

[2] M.D. Drici and N. Clement, “Is gender a risk factor for adverse drug reactions? The example of drug-induced long QT syndrome”. Drug Saf, 24(8): pp. 575-585, 2001.