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 Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 3  |  Issue : 3  |  Page : 154-158

Comparative study of heart rate, QT and QTc intervals during the different phases of the menstrual cycle


1 Department of Physiology, JSS Medical College, JSS University, Mysore, India
2 Department of Physiology, Basaveshwara Medical College, Chitradurga, Karnataka, India

Date of Web Publication13-Aug-2014

Correspondence Address:
Rajeshwari Lokeshwaraiah
Department of Physiology, JSS Medical College, Mysore 570 015, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2278-344X.138589

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  Abstract 

Background and Objectives: The menstrual cycle is much more than a cycle of periods. Gonadal hormones influence the cardiovascular system both directly and indirectly. Ventricular arrhythmias are more common in women and seem to exhibit variation in accordance with the menstrual cycle. There are contradictory hypotheses regarding the influence of the menstrual cycle on the QT and QT c intervals of electrocardiogram (ECG). This study is an attempt to evaluate the effect of different phases of the menstrual cycle on the QT and QT c intervals of ECG. Materials and Methods: A total of 30 healthy female students, who were aged 18-22 years and had regular menstrual cycles over past 6 months, were included in the study. All the subjects were monitored on three separate occasions during two consecutive menstrual cycles. ECG was recorded for 5 min in Lead-II using ADInstruments PowerLab, once during every phase. The computerized recordings of heart rate (HR), QT and QT c intervals thus obtained were analyzed statistically using repeated measures ANOVA, at P < 0.05 to assess if any significant difference existed in these parameters during the different phases of the menstrual cycle. Results: This study showed the HR was highest in the luteal phase when compared with the follicular and menstrual phases, while the QT and QT c intervals were prolonged in the follicular phase of the cycle in comparison to the other two phases. The differences in both QT and QT c intervals between the phases were statistically significant. Conclusion: This study showed prolonged QT and QT c intervals during the follicular phase, which maybe aggravated in individuals on concurrent treatment with drugs that may further increase the QT c interval. This would increase the predisposition of developing potentially fatal arrhythmia in such women. Hence, such drugs must be prescribed with caution.

Keywords: Gonadal hormones, QT and QT c intervals, ventricular arrhythmia


How to cite this article:
Lokeshwaraiah R, Ganashree CP, Chandran A, Gorkal AR. Comparative study of heart rate, QT and QTc intervals during the different phases of the menstrual cycle. Int J Health Allied Sci 2014;3:154-8

How to cite this URL:
Lokeshwaraiah R, Ganashree CP, Chandran A, Gorkal AR. Comparative study of heart rate, QT and QTc intervals during the different phases of the menstrual cycle. Int J Health Allied Sci [serial online] 2014 [cited 2023 Feb 9];3:154-8. Available from: https://www.ijhas.in/text.asp?2014/3/3/154/138589


  Introduction Top


The female reproductive system shows cyclical changes brought about by complex interactions between gonadotrophic hormones and ovarian hormones, for example, the increase in estradiol (E 2 ) levels during the luteal phase. Menstruation is just one manifestation of the ovarian cycle, which by itself is associated with more than 200 physical, psychological and behavioral changes. These hormones are known to influence other organ systems such as the cardiovascular system (CVS), substrate metabolism (especially in bones), thermoregulation etc., Among these influences, the effects on the CVS are of immense clinical significance. Higher incidence of ischemic heart disease observed in the menopausal and postmenopausal age groups suggest a close association between ovarian hormone levels and the CVS. Emerging data regarding variation in plasma volume, cardiovascular homeostasis and sympathetic regulation have also increased the interest regarding the overall influence of female gonadal hormones.

The QT interval is a measure of the time period between the beginning of the Q wave and the end of the T wave in the electrical cycle of the heart. QT c interval is QT interval corrected for the heart rate (HR). In general, the QT interval represents electrical depolarization and repolarization of both ventricles. A prolonged QT interval is a biomarker for ventricular tachyarrhythmias like torsades de pointes (Tdp) and thereby, a risk factor for sudden death. QT c longer than 0.44 s is conventionally considered abnormal even though physiologically, some females may have QT c up to 0.46 s.

QT interval results from the net effect of multiple ion channels and transporters. The combined activities of two delayed rectifier currents - rapid delayed rectifier potassium channel and slow delayed potassium channel - accounts for the major portion of Phase III repolarization of the ventricles. Several mutations in genes regulating these channels are responsible for the more common forms of inherited long-QT (LQT) syndrome.

Women are at higher risk than men, of developing a dangerous drug-induced cardiac arrhythmia that can be fatal. This risk may be heightened during menstruation and ovulation. [1]

Ventricular arrhythmias are more common in women and its incidence exhibits cyclical variation with the menstrual cycle, which suggests the strong influence exerted by sex hormones on the CVS. Many studies have suggested that sex steroids play a role in altering cardiac repolarization. [1],[2],[3] Some researchers have found no difference in QT c interval duration in women evaluated during the three different phases of the menstrual cycle, [1],[4] while others have reported that the QT c interval is prolonged during the luteal phase. [5] Yet others have observed that QT c interval was prolonged in menstrual phase. [6],[7] However, animal studies have suggested that estrogen is the main facilitator in prolongation of ventricular depolarization and repolarization. Hence, our hypothesis is that this prolongation must be highest in the follicular phase of the cycle in humans. However, the literature regarding as to during which phase of the menstrual cycle are women most vulnerable to arrhythmias (i.e. when is there more prolonged QT, QT c intervals) is not only controversial, but scanty, especially in South Indian population. In view of all the above, this study was undertaken to evaluate the cyclical variation of the HR, QT and QT c intervals during different phases of the menstrual cycle in the given population.


  Materials and methods Top


This study was conducted in the Department of Physiology, JSS Medical College, Mysore, Karnataka, India. Female undergraduate medical students in the age group of 18-22 years, who volunteered to participate in the study, were screened through a detailed clinical history and general physical examination. Among them, 30 healthy students with history of regular menstrual cycles (between 28 and 30 days) over a minimum time period of past 6 months were selected at random for this study. After the purpose of the study and the procedure to be followed were clearly explained and understood by the participants, written informed consent was obtained from them. The study was approved by the Institutional Ethics Committee of JSS Medical College and Hospital, Mysore, Karnataka, India.

Fertility thermometer and ADInstruments computer-based PowerLab data acquisition systems with bioamplifier and AD Instruments LabChart 7 Pro software application for Windows - Version 7.3.7 for windows were used to collect the required data. ADInstruments PowerLab was used to record the electrocardiogram (ECG) from the limb leads. The digitalized ECG signals were stored on removable hard disks for off-line verification and analysis. The HR, QT intervals and QT c intervals were noted after analysis of the data.

The study was carried out over a time period of 3 months. Throughout these 90 days, the subjects were asked to record and note down their basal body temperature every morning, (immediately on waking up) in order to find out the time of ovulation during each menstrual cycle. Then, they were asked to report on specified days, in the evenings between 4 and 6 p.m. Recording of the basal HR, QT interval and QT c interval was done via ECG for 5 min in Lead-II using ADInstruments PowerLab instrument. This was carried out in a well-ventilated quiet room with the subject in the supine position after she rested for 20 min.

The ECG of all the 30 subjects were recorded on three separate occasions during each menstrual cycle-once during the menstrual phase (from 1 st to 5 th day after the onset of menstruation), once during the follicular phase (from 8 th to 12 th day of the menstrual cycle) and once during the luteal phase (20 th and 21 st day of the menstrual cycle). The procedure was repeated for all the subjects during their successive menstrual cycle also. This means that ECG was recorded on six different occasions for each subject. The mean of the two readings (recorded during the same phase of consecutive menstrual cycles) was noted for each of the parameters.

The data collected were entered in MS Excel 2010 and analyzed using SPSS Inc. Released 2009. PASW Statistics for Windows, Version 18.0. Chicago: SPSS Inc. Descriptive statistical measures of mean and standard deviation were applied. Repeated measures ANOVA was applied to test the difference between mean HR, QT interval and QT c intervals across menstrual, follicular and luteal phases. The differences were interpreted to be statistically significant at P < 0.05.


  Results Top


The mean HR among subjects was the highest during the luteal phase and the lowest during the follicular phase as compared with that during the remaining two phases but this difference was not statistically significant [Table 1] and [Table 2].
Table 1: Mean values HR, QT & QTc intervals observed during the three phases of menstrual cycle

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Table 2: Comparison of HR (bpm) between the different phases of menstrual cycle

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Mean duration of QT interval was the lowest (0.28 ± 0.049) in the luteal phase when compared to the other two phases, whereas it was most prolonged during the follicular phase [Table 1]. This difference in QT interval across the phases was statistically significant (P = 0.034) [Table 3].
Table 3: Comparison of QT interval (in seconds) between the different phases of menstrual cycle

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Similarly, mean duration of QT c interval was the lowest (0.35 ± 0.057) in the luteal phase and was most prolonged during the follicular phase in comparison to the other two phases and this difference also, was found to be statistically significant (P = 0.03) [Table 1] and [Table 4].

Post-hoc test (Bonferroni test) revealed that both the QT and QT c intervals in the luteal phase stood out as significantly different from the rest of the two phases.
Table 4: Comparison of QTc interval (in seconds) between the different phases of menstrual cycle

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  Discussion Top


The ovarian hormones influence the CVS either directly by affecting repolarization or indirectly through the autonomic nervous system. [8],[9] The direct effects are mediated by alterations in potassium channel expression, potassium ion conductance, repolarization in the cardiac smooth muscle cells and response of QT interval to drugs. [10],[11] These hormones influence the CVS indirectly by modulating the autonomic tone. [12]

Estrogen down-regulates messenger RNA levels for both the rapid delayed and slow delayed rectifier potassium current channels, thereby prolonging the QT interval. [13] Both estrogen and progesterone play an important role in the regulating the levels of calcium in the sarcoplasmic reticulum of cardiac muscle as proved by animal studies. [14] Thus normal physiological changes in the circulating levels of estrogen and progesterone could influence baseline cardiac repolarization and momentarily predispose to greater QT and QT c intervals, especially when the patient is on certain drugs like antipsychotics. [15] In general, women are at higher risk than men for developing dangerous and potentially fatal drug-induced arrhythmias. This risk is more during menstruation and ovulation. [1]

In an ECG, QT interval is said to be prolonged when time interval between the beginning of Q wave and end of T wave is unusually increased. This indicates that recharging of the heart between consecutive beats is too slow. Prolonged QT interval is dangerous as it can cause potentially fatal arrhythmia known as TdP, a French phrase, which literally means "twisting of the points" that refers to the characteristic appearance of the ECG during such an abnormality of rhythm.

The female gender has been considered to be an independent risk factor for some types of LQT dependent cardiac arrhythmias for quite a while now. [13],[16],[17] Some researchers have not found any difference in QT c interval duration in women evaluated during the three different phases of the menstrual cycle. [1],[4] Others have reported prolongation of QT c interval during the luteal phase. [5] Yet others have noted prolonged QT c interval during the menstrual phase. [6],[7] However, the observation of this study is that QT c interval is prolonged during the follicular phase. [18],[19] Such prolongation is likely to produce arrhythmias if those individuals are exposed to agents that further increase the refractory period, for example, antipsychotic drugs. This warrants more research in larger populations.

The complexity of the cardiac system has ensured that, determining just how much of a role physiological concentration of circulating sex steroid hormones play in gender linked arrhythmia susceptibility is very difficult. [20] That E 2 and progesterone have opposite effects on cardiac repolarization - estrogen prolongs and progesterone reduces QT interval - has been proved but whether normal hormonal fluctuations are sufficient to account for the variability in QT interval during the menstrual cycle in still not known. [18],[20],[21] The effect of physiological concentrations of hormones on arrhythmia susceptibility is also not understood well. One experimental study has utilized hormone concentrations in the micromolar range that is of higher order of magnitude than the normal physiological circulating estrogen level (which is in nanomoles). [22] Micromolar concentrations of estrogen are apparently cardioprotective via their effect on L-type calcium channels. High hormonal concentrations may be relevant during physiological conditions like pregnancy. Another study has shown that estrogen at one nanomolar concentration did not have a significant effect, either on the slow delayed potassium channels or on the L-type calcium channels. [18]

Some studies have predicted that effects of testosterone and progesterone on ion channels hasten repolarization, thereby protecting from drug-induced arrhythmias. [21] Fluctuations of QT intervals during the menstrual cycle suggest that progesterone may reverse effects of estrogen-induced QT prolongation. [23] Chronic exposure to sex hormones may alter the response of tissues to acute application of sex hormones, [24] alter the expression of L-type calcium channels and may cause structural remodeling of the myocardium. [25] The findings from computational model simulations suggest the potential utility of progesterone as a therapeutic agent for inherited and acquired forms of LQT syndrome and that progestin-only contraceptives should be given special consideration for their potential amelioration of LQT risk among premenopausal women. The link between estrogen containing hormone replacement therapy among postmenopausal women and increased incidence of adverse cardiac events needs to be investigated in the context of acute hormone effects on ion channels.

It has been well established by research studies carried out at the tissue level (by local application of sex steroid hormones) and in lower animals like rats, that estrogen causes prolongation of the QT, QT c intervals of the ECG. Many scientists have been working on establishing the same as a fact in humans also, by trying to show that even in physiological concentrations, there is prolongation of these time intervals during the follicular phase when concentration of estrogen reaches its maximum in the menstrual cycle. Yet conflicting results as per the various studies have ensured that this issue remains controversial. The results of this study, showing prolonged QT and QT c intervals in the follicular phase of the menstrual cycle show that estrogen has an effect on ventricular action potentials, even within the range of fluctuations seen physiologically in healthy young adults.


  Limitations Top


The small sample size may be the reason for the statistically not significant findings of the other parameters of our study. Hence, this study must be extended in order to cover larger populations.


  Acknowledgments Top


The authors would like to thank the Principal, JSS Medical College and Hospital, Mysore, Karnataka, India for encouraging us and providing the facilities to carry out this research work. We also thank sincerely the students who have participated as subjects in the present study.

 
  References Top

1.Rodriguez I, Kilborn MJ, Liu XK, Pezzullo JC, Woosley RL. Drug-induced QT prolongation in women during the menstrual cycle. JAMA 2001;285:1322-6.  Back to cited text no. 1
    
2.Drici MD, Burklow TR, Haridasse V, Glazer RI, Woosley RL. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. Circulation 1996;94:1471-4.  Back to cited text no. 2
    
3.Liu XK, Katchman A, Drici MD, Ebert SN, Ducic I, Morad M, et al. Gender difference in the cycle length-dependent QT and potassium currents in rabbits. J Pharmacol Exp Ther 1998;285:672-9.  Back to cited text no. 3
    
4.Burke JH, Ehlert FA, Kruse JT, Parker MA, Goldberger JJ, Kadish AH. Gender-specific differences in the QT interval and the effect of autonomic tone and menstrual cycle in healthy adults. Am J Cardiol 1997;79:178-81.  Back to cited text no. 4
    
5.Rosano GM, Leonardo F, Sarrel PM, Beale CM, De Luca F, Collins P. Cyclical variation in paroxysmal supraventricular tachycardia in women. Lancet 1996;347:786-8.  Back to cited text no. 5
    
6.Varshney VP, Bedi M, Bhandari B, Bhatnagar J. Effect of handgrip exercise on QT c interval during different phases of menstrual cycle. Vasc Dis Prev 2006;3:83-6.  Back to cited text no. 6
    
7.Hosakatti D, Hosakatti S. Variation in QT c interval with menstrual cycle in young healthy individuals. Biomed 2011;31:550-4.  Back to cited text no. 7
    
8.Katsube Y, Yokoshiki H, Nguyen L, Yamamoto M, Sperelakis N. L-type Ca 2+ currents in ventricular myocytes from neonatal and adult rats. Can J Physiol Pharmacol 1998;76:873-81.  Back to cited text no. 8
    
9.Trépanier-Boulay V, St-Michel C, Tremblay A, Fiset C. Gender-based differences in cardiac repolarization in mouse ventricle. Circ Res 2001;89:437-44.  Back to cited text no. 9
    
10.Saba S, Zhu W, Aronovitz MJ, Estes NA 3 rd , Wang PJ, Mendelsohn ME, et al. Effects of estrogen on cardiac electrophysiology in female mice. J Cardiovasc Electrophysiol 2002;13:276-80.  Back to cited text no. 10
    
11.Korte T, Fuchs M, Arkudas A, Geertz S, Meyer R, Gardiwal A, et al. Female mice lacking estrogen receptor beta display prolonged ventricular repolarization and reduced ventricular automaticity after myocardial infarction. Circulation 2005;111:2282-90.  Back to cited text no. 11
    
12.Dart AM, Du XJ, Kingwell BA. Gender, sex hormones and autonomic nervous control of the cardiovascular system. Cardiovasc Res 2002;53:678-87.  Back to cited text no. 12
    
13.Pham TV, Rosen MR. Sex, hormones, and repolarization. Cardiovasc Res 2002;53:740-51.  Back to cited text no. 13
    
14.Jiang C, Poole-Wilson PA, Sarrel PM, Mochizuki S, Collins P, MacLeod KT. Effect of 17 beta-oestradiol on contraction, Ca 2+ current and intracellular free Ca 2+ in guinea-pig isolated cardiac myocytes. Br J Pharmacol 1992;106:739-45.  Back to cited text no. 14
    
15.Hulot JS, Démolis JL, Rivière R, Strabach S, Christin-Maitre S, Funck-Brentano C. Influence of endogenous oestrogens on QT interval duration. Eur Heart J 2003;24:1663-7.  Back to cited text no. 15
    
16.Abi-Gerges N, Philp K, Pollard C, Wakefield I, Hammond TG, Valentin JP. Sex differences in ventricular repolarization: From cardiac electrophysiology to Torsades de Pointes. Fundam Clin Pharmacol 2004;18:139-51.  Back to cited text no. 16
    
17.James AF, Choisy SC, Hancox JC. Recent advances in understanding sex differences in cardiac repolarization. Prog Biophys Mol Biol 2007;94:265-319.  Back to cited text no. 17
    
18.Kurokawa J, Tamagawa M, Harada N, Honda S, Bai CX, Nakaya H, et al. Acute effects of oestrogen on the guinea pig and human IKr channels and drug-induced prolongation of cardiac repolarization. J Physiol 2008;586:2961-73.  Back to cited text no. 18
    
19.Kurokawa J, Furukawa T. Non-genomic action of sex steroid hormones and cardiac repolarization. Biol Pharm Bull 2013;36:8-12.  Back to cited text no. 19
    
20.Yang PC, Kurokawa J, Furukawa T, Clancy CE. Acute effects of sex steroid hormones on susceptibility to cardiac arrhythmias: A simulation study. PLoS Comput Biol 2010;6:e1000658.  Back to cited text no. 20
    
21.Nakamura H, Kurokawa J, Bai CX, Asada K, Xu J, Oren RV, et al. Progesterone regulates cardiac repolarization through a nongenomic pathway: An in vitro patch-clamp and computational modeling study. Circulation 2007;116:2913-22.  Back to cited text no. 21
    
22.Kadish AH, Greenland P, Limacher MC, Frishman WH, Daugherty SA, Schwartz JB. Estrogen and progestin use and the QT interval in postmenopausal women. Ann Noninvasive Electrocardiol 2004;9:366-74.  Back to cited text no. 22
    
23.Philp KL, Hussain M, Byrne NF, Diver MJ, Hart G, Coker SJ. Greater antiarrhythmic activity of acute 17beta-estradiol in female than male anaesthetized rats: Correlation with Ca2 channel blockade. Br J Pharmacol 2006;149:233-42.  Back to cited text no. 23
    
24.Nakagawa M, Ooie T, Takahashi N, Taniguchi Y, Anan F, Yonemochi H, et al. Influence of menstrual cycle on QT interval dynamics. Pacing Clin Electrophysiol 2006;29:607-13.  Back to cited text no. 24
    
25.Patterson E, Ma L, Szabo B, Robinson CP, Thadani U. Ovariectomy and estrogen-induced alterations in myocardial contractility in female rabbits: Role of the L-type calcium channel. J Pharmacol Exp Ther 1998;284:586-91.  Back to cited text no. 25
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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