International Journal of Cardiology 99 (2005) 373 – 379 www.elsevier.


Long term effects of hormone replacement therapy on heart rate variability, QT interval, QT dispersion and frequencies of arrhytmia
¨ rem a, Mustafa Go ¨ kc ¸ e a,*, Burhan Karahan a, Remzi Yilmaz a, Cihan O ¨ zdemir b Cevdet Erdo ¨ l a, S ßafak O
b a Department of Cardiology, Karadeniz Technical University, Trabzon 61080, Turkey Department of Obstetrics/Gynecology, Karadeniz Technical University, Trabzon, Turkey

Received 31 July 2002; received in revised form 7 January 2003; accepted 11 March 2003

Abstract Background: The aim of the study was to investigate the effects of a long term (1 year) hormone replacement therapy (HRT) on QT interval, QT dispersion (QTd) frequencies of arrhythmia and heart rate variability (HRV) parameters. Methods: Forty-six healthy postmenopausal women (mean age; 55.34 F 4.21) as a hormone replacement therapy group and 25 healthy premenopausal women (mean age; 35.36 F 6.06) as a control group were prospectively enrolled to the study. Hormone replacement therapy group was divided into two groups; estrogen replacement therapy (ERT) group (n = 23) and progestin – estrogen replacement therapy (PERT) group (n = 23). Standard 12 lead electrocardiograms and 24-h ambulatory Holter recording were obtained to evaluate the effects of one year of ERT and PERT on QT intervals, QTd, frequencies of arrhytmias and HRV parameters. Results: Long term use of ERT increases QT interval, QTd, in the frequencies of arrhytmia and HRV indexes of parasympathetic activity; however, the increase in frequencies of arrhythmia was not statistically significant ( p > 0.05). Long term use of PERT did not effected QT interval, QTd, frequencies of ventricular arrhythmia and HRV parameters ( p>0.05).Frequency of supraventricular tachycardia increased in post-treatment PERT group was compared with pre-treatment PERT group. Conclusion: These findings supported the hypothesis that estrogen may directly modulate ventricular repolarization. But progestin do not effect the ventricular repolarization. However, these findings must be supported with a large-scale study. D 2003 Elsevier Ireland Ltd. All rights reserved.
Keywords: Hormone replacement therapy; QT dispersion and heart rate variability

Some experimental and clinical studies demonstrated that hormone replacement therapy (HRT) reduces coronary artery disease risk and the rates of cardiovascular and total mortality in postmenopausal women [1,2]. The beneficial effects of HRT have been attributed to the favorable effects on plasma lipids, hemostatic and vascular factors [3]. But some studies indicated that HRT did not reduce the overall rate of coronary heart disease (CHD) events in postmenopausal women with established coronary disease. However, the effects of HRT on myocardial repolarization and autonomic tone cannot be excluded [4,5]. QT interval dispersion (QTd) is a non-invasive method of measuring regional inhomogenities in ventricular recovery times [6,7]. High levels of interlead dispersion have been

* Corresponding author. Tel.: +90 4623 775594; fax: +90 4623 250518. E-mail address: (M. Go ¨ kc ¸ e). 0167-5273/$ - see front matter D 2003 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.03.030

correlated with an increased incidence of ventricular arrhytmias [8,9]. QTd has been demonstrated to increase during myocardial ischaemia [10], and to decrease reversal of the ischemic state following thrombolytics [11] or angioplasty [12] QTd has also been demonstrated to decrease in menopausal patients with syndrome X who received estrogen. In normal adult population, QT and corrected QT (QTc) intervals are longer in women than in men. In addition, women are more likely to develop torsades de pointes when they receive QT lengthening drugs such as antiarrythmics and probucol when compared to men. These suggest that cardiac repolarization has a slower rate in women and female sex may be more prone to QT prolongation induced by various conditions inherited long QT, bradycardia and QT lengthening drugs [13]. In this context of increased arrhytmic risk in females, it is of interest that estrogens and tamoxifen, the classical estrogen receptor antagonist have been shown to modulate the electrophysiological properties of myocytes [14 – 16]. However, estrogen replacement ther-

QT analysis 1. ECG monitoring was made during their minimal daily activities with their normal sleep –wake rhythms. QT intervals were measured manually from the onset of QRS to and of T wave.625 mg/day CEE along (Premarin. JT intervals were measured manually from the end of QRS to onset of the T wave. HRV has been shown to be increased by 17 Boestradiol in an uncontrolled. Corrected QT intervals. the study was performed between 11 a.20]. and no differences in QT interval length have been reported during HRT [18].374 M. QT interval analysis was done on a standard 12-lead electrocardiogram (Hewlett Packard Model M1771 A).m. Women were excluded from the study if they had a known cardiac disease. QT interval was measured to the nadir of the curve between the T and U waves. clinical study. receiving oral contraceptives. The postmenopausal state was defined as the presence amenorrhea z 1 year and a serum FSH level of 45 IU/L. diabetes mellitus. / International Journal of Cardiology 99 (2005) 373–379 ¨ kc apy (ERT) in postmenopausal women for one month did not change the myocardial repolarization determined by analysis of QT interval length and QT dispersion [17]. we investigated the long term effects of HRT on the myocardial repolarization time. Women with postmenopausal state were divided into two groups. USA) or 0.5. Patients with abnormal baseline ECG (also contain undetected T wave) or positive stress tests on standard Bruce protocol were excluded. None of the women hadn’t taken any medication known to affect QT interval or autonomic tone (beta-blocker. All subjects underwent routine physical examinations. Hormone regimens were continuously 0. All participant women were normotensive (less than 140/90). Reduced HRV is thought to be an independent marker for an increased risk of cardiovascular mortality after myocardial infarction [19. Wheyt Ayerst Lab). In this study. etc. and a reduced HRV could indicate an increased risk of cardiovascular mortality [21]. allergy to estrogen.06 years.). QT intervals were calculated using Bazett’s formula (QTc = QT/square root of RR interval). All patients had a rest 12-lead ECG recorded at 25 and 50 mm/s paper speed with amplitude of 1 and 2 mV after 20 min rest in supine position. Systemic blood pressures were measured from the patients in the supine position with a mercury sphygmomanometer by the same physician . Heart rate variability (HRV) is a statistical measure of the cyclic beat-to-beat variation of heart rate. calcium antagonists. range: 45 to 62 years). history of breast cancer or estrogen depended neoplasia and untreated thyroid disease. All patients regularly took HRT during 1 year. maximum QT and minimum QT were measured and QT dispersion was calculated as the difference between maximal and minimal values of QT. Methods 2. Their recordings were taken before and after HRT 1 year later. PA. – 3 p. In contrast to the other study of HRT attenuate HRV in healthy postmenopausal women. If U waves were present. Four patients (9%) used to smoke cigarettes in the study group. The data files were edited to find and correct any errors in QRS labeling. Philadelphia. severe migraine or stroke. From these cycles. dispersion and autonomic tone in healthy postmenopausal women. defined as a return to the T –P baseline.21 years. which correlates with the individual autonomic tone. Control group The control group was comprised of 25 healthy women (mean age 35. 1. The ECG recordings were taken before and after HRT 1 year later. The Holter recordings of the patients started at 09:00 pm.34 F 4. range 26– 47 years) . progestin. Wheyt-Ayerst Lab.5 mg/day medroxyprogesterone asetate (MPA) (Premelle 2. Beat information was . a history of deep venous thrombosis. None of the women had ever used HRT and none did not take any medication known to affect QT interval or autonomic tone (beta-blocker.1. 1. calcium antagonists. women with the history of hysterectomy received only the CEE regimen (estrogen replacement therapy group (ERTG)). digitalis.2. To prevent the diumal changes of QT intervals and QT dispersion [22].and the average of the measurement taken at three consecutive outpatient clinic visits was obtained from all the subjects who also underwent a treadmill exercise test before inclusion into the study. admitted to the Department of Obstetrics and Gynecology at our institution from April 1999 to May 2000. 3.625 mg/day conjugated equine estrogen (CEE) plus 2. Go ¸e et al. Replay for QRS defection was performed by a Series Century 3000 Holter management system. or iodine. while other women with uterus had MPA added to the estrogen to prevent endometrial hypeplasia and carcinoma (progestin – estrogen replacement therapy group (PERTG)).36 F 6. Two patients (8%) used to smoke cigarettes in the study group.). Four consecutive cycles in each of the 12 leads evaluated. All women with menopausal state had a normal mammogram during the past year. All participant women were normotensive (less than 140/90). Heart rate variability measurement Ambulatory electrocardiographic recording was obtained using Kardiosis DL 700 Digital three-channel recorder in all subjects.m. digitalis etc. Patients group The patients group was comprised of 46 women with postmenopausal state (mean age: 55.

. PNN50. The ratio of LF to HF power was also calculated.6 F 9. The power spectral density was estimated by using an autoregressive (AR) model.8 F 8.9 166. IVb and V arrhythmias were considered to have a complex ventricular arrhytmias.05) (Table 1). Supraventricular tachycardias were defined as narrow QRS rhythm which had >3 consecutive supraventricular beats and rate over 120/per min.8 127. The LF and HF components of the RR interval spectrum were evaluated in normalized units (nu). The 24-h RR interval file was divided into consecutive 512 interval segments. Mc Nemar and Fisher’s exact tests were used for paired proportions. QTd and HRV values between the control group and the HRT (ERTG + PERTG) group after 1 year (post-treatment) were shown in Table 3.05) (Table 2).34 F 4.68 126. Only cycles in which beats had normal morphological characteristics were used for analysis.65 F 8. LF.04 – 0.18 p P < 0. All measurements were made by two blinded experienced cardiologists. 5. Relations between variables were analysed using Pearson correlation analysis. JT.4 F 21 43. DBP: Diastolic blood pressure.3 128. HF (nu). A p value of less than 0. For statistical analyses between-pre-ERT and post-ERT. hormone replacement therapy group in pre-treatments and post-treatment were shown in Table 3. The frequency axis was scaled by considering the intervals to be spaced at distances equal to the mean interval length over the segment. pre- BMI: Body mass index.02 for QT dispersion.05 was considered statistically significant. SDNNN. The QT intervals.04 F 11.28 HRT Group (n = 46) 55. QTd and HRV values between the pre-treatment HRT group and the posttreatment HRT group were shown in Table 3. JTc. it showed that PR .04 F 1. PR and QT interval.1 74. The QT intervals. HRV parameters and frequency of arrhythmias among control group. The QT intervals.7 44.36 F 6.4 73. In this comparison.06 2/25(8%) 23. and the measurement of individual leads and 0. / International Journal of Cardiology 99 (2005) 373–379 ¨ kc 375 transferred into a personal computer for the measurement of RR intervals. In this comparison. There is both significant depression of vagal tone indicators and the decreased QT interval in women with postmenopausal state.15 – 0. SDNN.M.01 for QT intervals. In such instances.52 F 6. To evaluate the changes of QT parameters. SBP: Systolic blood pressure. There were no significant differences in baseline clinical characteristics between the ERTG and PERTG ( p>0. The spectral power of the HF and LF could be valid in RR intervals segments of 512 beats. normal and ectopic beats inaccurately measured because of the artifact were excluded from the analysis. standard deviation of all 5 min mean normal RR intervals(SDANN).93 F 9. percent of difference between adjacent normal RR intervals that were greater than 50 ms (PNN50). Go ¸e et al. Ventricular arrhytmias were quantified by 24-h Holter ECG recording and classified according to the Lown classification system [23].1 73. NS: Not significant. Power spectra was quantified by measuring the power in two frequency bands: low frequency (LF) power (0. standard deviation of normal RR intervals (SDNN). Statistical analysis All descriptive data are reported as the mean F SD. Results There were no significant differences in baseline clinical characteristics between the control group and the hormone replacement therapy group except age ( p>0.21 4/46(9%) 24. HF values in the post-treatment HRT group were higher and LF/HF ratio was lower than those of the pre-treatment HRT group. JTc.97 F 13 171.05). Intervals between ectopic beats. HF. Normalization was obtained by expressing the power of each component as the percentage of the total oscillatory power minus DC power. Only those patients with a class IVa. In the HRT group with pre-treatment state. QTd was determined by blinded repeats of the measurement in 18 random patients. Heart rate variability was assessed in two ways. whereas frequency domain analysis decomposes RR intervals into their frequency components and calculates the power spectral density.52 F 27. HF/LF. Intra-observer correlation coefficient was 0. Each beat record consisted of time of occurrence and a classification code. pre-PERT and post-PERT group differences were performed with the use of Student’s paired t-test . Time domain analysis is a statistical analysis of the fluctuations in RR intervals. it showed that JT. mean RR interval. time domain analysis [1] and frequency domain analysis [2]. The QT intervals. Variability in the intra-observer measurement of QT interval JT interval.99 128.8 F 7.6A 10. Five time domain measures of HRV were considered. and the square root of the mean of the sum of the squares of differences between adjacent normal RR intervals (r-MSSD).92 F 1. rMSSD. PNN50.48 F 6. QTc. QTd and HRV values between the pretreatment ERT group and the post-treatment ERT group Table 1 Clinical characteristic of control groups and hormon replacement therapy group Control group (n = 25) Age (years) Smoking BMI (kg/m2) SBP (mm Hg) DBP (mm Hg) Heart rate (beats/min) Triglyceride (mg/dl) Total Cholesterol (mg/dl) HDL Cholesterol (mg/dl) 35. one-way factorial analysis of variance (ANOVA) were used. the next interval analysed was three beats after the last non-sinus beat.5 75.40 HZ). rMSSD.15 Hz) and high frequency (HF) power (0. HRT and post-HRT group. LF (nu) significantly lower than those of the control group ( p < 0. LF values in the post-treatment HRT group were lower than those of the control group. HF. QT dispersion and HRV values among the control group.05 NS NS NS NS NS NS NS NS 4.

7 p NS NS NS P < 0.1 76 F 12.05 P < 0. Pre-treatment 159 F 16.2 F 4.25 F 0.2 F 0.2 25 F 2. Frequencies of complex ventricular ectopy increased with ERT (4% in pre-treatment group and 22% in post-treatment group).3 58 F 3.5 F 77. ERT increased QT interval parameters.05 P < 0.05 vs. In comparison to QT intervals.5** 125 F 12.1 50 F 5.9 3.1 38 F 6.6 388 F 26.05 P < 0.Otherwise. SBP: Systolic blood pressure.5* 45 F 7.05 NS NS NS NS NS NS: not significant. HF (nu).1 F 7. QTd and HRV parameters in among control group.9 20 F 8.7 386 F 11. Consequently.42 F 0.05 NS NS NS P < 0.05 P < 0.46 48 F 5 127.9 2.8 395 F 14.1* 373 F 96.8**& 384 F 97.5** 388 F 19. control group.2 F 4.5 F 8.2 170.7 F 0.6 777 F 42. control group.05 NS Table 2 Clinical characteristic of ERTG and PERTG ERTG Patient number (n) Age (year) Age at menopause (year) SBP (mm Hg) DBP (mm Hg) Smoking Triglyceride (mg/dl) Total Cholesterol (mg/dl) HDL Cholesterol (mg/dl) BMI (kg/m2) Heart rate(beats/min) 23 55.5 75. QTd and HRV values between the pre-treatment with PERT and the post-treatment with PERT after 1 year were shown in Table 5. In comparison to QT interval. .1 32 F 4.5 F 12.2 Post-treatment 159 F 17.8 F 1. JTc.05).5 45. ** p < 0.376 M.1 274 F 24.3 43.1 6.2 F 5.2 77 F 11. rMSSD.8 123 F 4. The frequency of supraventricular tachycardia in the post-PERT group increased in comparison with the pre-PERT group (0% in the pre-PERT group vs.3 F 42.4* 390 F 11.75 19.5 182 F 92.9 224 F 156.7 393 F 22.67 33.3 376 F 106.2 53 F 5.3 F 86. there were no differences between the pre-ERT and the post-ERT group.4 173 F 22. indexes of sympathetic activity decreased.92* 32 F 5.03 768 F 56.1* 3.4 391A 18.8 46 F 5. QT interval and QTd at pre-treatment ERT group and posttreatment ERT group Variable PR (msn) QRS (msn) RR (msn) QT (msn) QTc (msn) QTd (msn) JT (msn) JTc (msn) SDANN (msn) SDNN (msn) PNN 50 (%) RMSSD (msn) HF (ms2) LF (ms2) LF/HF HF (nu) LF (nu) Pre-treatment 158 F 14.5* 125 F 51.2**& 278 F 23.5& 156 F 75.17 F 4.3 75.05). HRT pretreatment group and post-treatment group Control group (n = 25) PR (msn) QRS (msn) RR (msn) QT (msn) QTc (msn) QTd (msn) JT (msn) JTc (msn) SDANN (msn) SDNN (msn) PNN 50(%) RMSSD (msn) HF (ms2) LF (ms2) LF/HF HF (nu) LF (nu) 158.8 525.7 BMI: Body mass index. the post-HRT and the control group. DBP: Diastolic blood pressure.4 51 F 8.03 51.4 79 F 11.6 5.6 39 F 5.3 386 F 11.9 39 F 7. HF.7 394 F 10.6 2/23(9%) 128.2 268 F 17.3 283 F 27.8 385 F 20.8 398 F 17 47 F 7.3 129 F 8. QTd. JT.3 79 F 9.8 F 7.7 F 32 369.96 F 2 30 F 11.8 that only this value may be meaningless .7 384 F 115.5 54.6 80 F 10.6 31 F 9.3* 382 F 12.2 131.3 116 F 8.4 F 210.05 P < 0.3 132 F 23. * p < 0.4 F 6. there were no significant differences between the two groups except rMSSD value.4 Post-treatment 158 F 17. QT.9 399 F 13. But this increase was not significantly ( p>0.05 vs.4 F 17. HRT pre-treatment group. additional HRV values would be present.5** 2.1 F 0.5 F 10. There were also significant differences between Table 5 Indexes of HRV.8** 30 F 9.04 49 F 4 129.9 F 17.3 113 F 14. Go ¸e et al.8 11 F 3.5* 50 F 5.2 3.9 49 F 5.6 2.8 280 F 28.85& 36 F 7.7 273.7 771 F 55. QT interval and QTd at pre-treatment PERT group and post-treatment PERT group Variable PR (msn) QRS (msn) RR (msn) QT (msn) QTc (msn) QTd (msn) JT (msn) JTc (msn) SDANN (msn) SDNN (msn) PNN 50(%) RMSSD (msn) HF (ms2) LF (ms2) LF/HF HF (nu) LF (nu) NS: not significant. There were also no significant differences in the pre-treatment and the post-treatment group with PERT (4% in the pre-treatment group and 9% in the post-treatment group) ( p>0.7 78 F 10.5**& 115 F 24. QTc.5 798 F 33.3 54 F 5.05 P < 0.5 23 F 3.8A 14.5 115. LF/HF ratio significantly was lower in the posttreatment group than that of the pre-treatment group.1 2/23(9%) 126. after 1 year were shown in Table 4.6 383.6 F 4. On the point of supraventricular tachycardia. LF (nu) significantly increased much more in post-treatment group than the pre-treatment group.66 32.4 p N NS NS NS NS NS NS NS NS NS NS P < 0.7 118 F 21.5 F 5.4 772 F 54.5 F 7.8 250 F 17.72 F 19.4 F 1.8 255 F 20.4 379 F 12.1 71.8 49 F 8.1** 6 F 1.2 786 F 17.05).2 6. Meanwhile.69 30.7 HRT group (n = 46) (pre-treat) 158.5 773 F 55.5 F 1.8 F 1.2 264 F 21.9 257 F 11.3 F 6.2 73.4 PERTG 23 55.8 F 6.5 260 F 22.5 134 F 64. & p < vs.52 F 4.4 115 F 15.6 254 F 19.05 NS P < 0.4 F 11. 26% the post-PERT group) ( p < 0.4 78 F 8.8 F 15.3* 6 F 1. / International Journal of Cardiology 99 (2005) 373–379 ¨ kc Table 4 Indexes of HRV.6 6.9* 20 F 7.2* 127 F 14. The frequency of ventricular arrhythmias was shown in Table 6.7 F 14.4 143 F 11.7 125. QTd and HRV values between before PERT and after PERT.1 F 18.4 126 F 11.6 259 F 11.11 F 1.3* HRT Group (n = 46) (post-treat) 158.8 3. It is accepted Table 3 QT Intervals.4 259 F 20.1 119 F 13. QTd and while HRV indexes of parasympathetic activity increased.

Pre-PERT group. [27] demonstrated that acute administration of estradiol 17-h affects the electrical conduction within the right atrium and prolongs the absolute refractory period in this cardiac chamber. there are very limited studies which investigate the effects of HRT on QT interval and QT dispersion.04) (0. whereas both QT and QTc prolonged significantly in women with syndrome X [30]. QT interval.96) (0. the control group and the pre-HRT group (respectively. Sbarouni et al.78) (0. Accordingly. / International Journal of Cardiology 99 (2005) 373–379 ¨ kc Table 6 Frequencies of ventricular arhythmia in control and study groups Groups Complex ventricular arrhythmia 2/25 2/46 7/46 1/23 5/23 1/23 2/23 (0. Discussion The incidence of cardiovascular disease is lower in women before the menopause as compared to men. There is an experimental evidence that sex hormones can alter the cardiac repolarization. Yildirir et al. Go ¸e et al. Unopposed estrogen in conventional doses administered orally in a short term in women with known coronary artery disease had no effects on QT and QTc both at rest and on exercise in one study [17]. demonstrated that no significant differences between estrogen treated and placebo groups with respect to QT values.04) (0.17) (0) (0.M.96) (0. Acute estrogen effects that are referred to as ‘‘nongenomic’’ are not dependent on changes in gene expressions. in female rabbits. Although the estrogeninduced QT prolongation seems to be mediated mainly through the potassium channel blockade. ** p < 0. In this study .08) (0.15) (0. [16] measured the effect of dihydrotestostenore and estrogen treatment on cardiac depolarization in ovarrectomized rabbits via potassium channel mRNA levels. Haseroth et al. These observations confirm that estradiol 17-h has electrophysiologic properties in vivo too.91) Supraventricular tachycardia 3/25 0/46 8/46 0/23 2/23 0/23 6/23 (0. [32] investigated that the effects of a 6month treatment of two different hormone regimens on QT intervals and QT dispersion in women free from cardiac symptoms and negative exercise tests. indicated that HRT significantly decreased the QTd and QTcd in . Acute effects of sex hormones are mostly related to their non-genomic action and can be demonstrated after the intravenous administration.29]. Rosano et al. Two distinct classes of delayed rectifier channels were downregulated in cardiac ventricular tissues when treated with estradiol or dihydrotestosterone. 6. it has been suggested that sex differences observed in corrected QT intervals be longer in females. Both types of mechanisms may account for the observed effects on the cardiac repolarization [13]. A trend toward a prolongation of atrioventricular conduction was also observed.05). However.92) (0. This study also showed that androgen treated tissues were more resistant to quinidine-induced QT prolongation when compared with estrogen treated groups.24]. In addition. had no significant effects on heart rate.96) (0. These properties may play a relevant role in the transmission of the electrical signal within the cardiac chamber. while menopausal women have an incidence of coronary disease similar to that of men at the same age [24]. there are very limited studies which investigate the long term effects of HRT on QT interval and QT dispersion.09) Grade 0 – III ventricular arrhythmia 23/25 44/46 39/46 22/23 18/23 22/23 21/23 (0. control group. 0% in pre-HRT group) ( p < 0. and be related to the differences in the action of androgens and estrogens on myocardial repolarization. other mechanisms may also be involved. However. Drici et al. or corrected QT interval in post menopausal women without a structural heart disease. [18] demonstrated that estrogen. It can be expected that HRT could potentially prolong the QT interval. shortens the QT interval and both estradiol and testosterone can lengthen it.22) (0.12) (0)** (0.04) (0. Yildirir et al.26)* 377 Control group Pre-HRT (ERT + PERT) Post-HRT (ERT + PERT) Pre-ERT Post-ERT Pre-PERT Post-PERT * p < 0.05 vs. [17] investigated the effects of a conventional 4-week estrogen replacement therapy on rest and exercise QT intervals and QT dispersion in 10 patients with coronary artery disease. whereas effects that occur over a period of hours and days referred to as ‘‘genomic’’ are dependent on changes in gene expressions. HRT and arrhytmia Stumpf [26] showed the presence of nuclear and cytosolic receptor for sex hormones throughout the cells within the cardiovascular system and its neuroregulatory tissue. Based on these experimental studies and observations. Larsen et al. Ovariectomy. Likewise. Clinical studies have reported contradictory results. 12% in control group. Evidence from the experimental and the clinical data suggests that hormone replacement therapy may slow the progression of coronary artery disease and reduce the peripheral vascular resistance. [31] demonstrated that combined progestin – estrogen replacement therapy reduces the dispersion of ventricular repolarization in postmenopausal women compared to the control group and estrogen replacement therapy prolongs QT intervals.05 vs.85) (0. Sbarouni et al. the action potential duration is lengthened by estradiol but shortened by testosterone compared to placebo in oophorectomized rabbits [25]. estrogen deprivation state or estrogen/progestin imbalance may be of importance in facilitating arrhythmias in a variety of cardiac conditions [28. alone or in combination with progestins. this is due to the down regulation of potassium channels in cardiac tissue [16]. HRT could potentially prolong the QT interval.2.08) (0) (0. cardiovascular and total mortality in the postmenopausal women [1. which produced significantly prolonged QT intervals above the baseline. acute administration of supraphysiological doses of estrogen in healthy women produced no significant changes in QT and QTc intervals. but does not affect QT dispersion.

QTd was markedly increased in the post menopausal compared to the premenopausal women. Estrogen deficiency is unlikely to cause cardiac arrhytmias. except when HRT was used. Mercuro et al. Our study showed that the control group (without menopause) had supraventricular tachyardia more frequently than the pretreatment HRT group (with menopause). however. QTd and HRV indexes of parasympathetic activity. Postmenopausal women exhibited both a higher basal level of norepinephine and a greater increase in heart rate. References [1] Grodstein F. Previous observations reported how. Rosano et al. pre-PERT and post-PERT.32]. [35] indicated that a 3-month cycle of ERT returned spectral and non-spectral values of HRV in oophorectomized women to a level comparable to that recorded at baseline before. whereas progestin or other ovarian hormones play a marginal role. but because of these hormone opposes estrogens. although it may worsen the pre-existing rhythm disorders. These findings support the hypothesis that sex steroids may affect ventricular repolarization in vivo. a long-term use of PERT in postmenopausal healthy women did not effect both parasympathetic activity and sympathetic activity of HRV parameters. pre-HRT and control group for complex ventricular arrhytmia. The addition of a progestin compound. we investigated the effects of 1 year with different hormone regimens on the frequencies of arhythmia in women free from cardiac symptoms. In comparison with pre-ERT group. [33] described that increased inhomogeneity in ventricular repolarization during low estrogen states.37]. the long-term effects (1 year) of estrogen as well as estrogen plus progesterone therapy on QT dispersion. frequencies of arrhytmia in healthy postmenopausal women have not previously been reported. . This observation suggests that estrogen alone is involved in sympathovagal balance in fertile women through an inhibitory mechanism of the sympathetic tone. at a dose achieving plasma levels of the hormone similar to those observed with chronic estrogen replacement therapy. clinical study [38]. In this study. Little is known about the electrophysiologic effect of progesterone.HRV parameters but increased frequencies of supraventricular tachycardia. perse. Some studies showed that ERT did not affect QT dispersion [18. and decreased the HRV indexes of sympathetic activity. Estrogen also alters favourably the autonomic imbalance that occurs during the menopause as this reflects a higher baroreflex sensitivity and a heart rate variability [14].29]. the autononic nervous control of the cardiovascular system was modified [34. / International Journal of Cardiology 99 (2005) 373–379 ¨ kc postmenopausal women without coronary artery diseases. which suggested that QTd was increased by low estrogen states. QTd was decreased in some previously published studies with ERT [32. Estrogen seems to decrease the sympathetic drive in postmenopausal women and reduction in sympathetic tone. frequencies of complex ventricular arrhythmia . and were independent from the addition of MPA to the regimen. seems to exclude a role for gonadotropin in autonomic nervous regulation. The finding. There was no difference between pre-ERT and post-ERT. whereas the long-term use PERT in postmenopausal healthy women didn’t affect the QT interval. Prog Cardiovasc Dis 1995. HRV has been shown to have been increased by 17-h-estradiol in an uncontrolled. may outweigh this benefit [21]. In this study. had a significant electrophysiologic effect in menopausal women. Stampfer MJ. The epidemiology of coronary heart disease and estrogen replacement therapy in postmenopausal women. Saba et al. But this study did not use the frequencies of arrhytmia and it was a shorter-term one than our study.38:199 – 210. But this increase was not reached to statistically significant difference. [31] To the best of our knowledge. A direct correlation between episodes of arrhytmias and plasma progesterone levels have been shown in women with regular menstrual cycles [27. acute administration of estradiol 17-h. after natural menopause.31]. Frequency of supraventricular tachycardia in post-PERT group was higher than that of the pre-PERT group and this result was statistically a significant difference. On the other hand. Christ et al.378 M. [21] indicated that HRT may attenuate HRV in healthy postmenopausal women and this effect may appear to be restricted to HRT containing progestins. The discrepancy between the previous studies and the results of our study may explain that the previous published studies had possible inhomogeneous study groups. frequencies of ventricular arrhytmia slightly increased in post-ERT group. There is only one long-term (6 month) study in the literature [32]. Go ¸e et al. which is significantly reduced with chronic ERT. which progestin was able to blunt the estrogen effect on HRV. and norepinephrine excretion in response to psychological stressors than premenopausal women [36. Some studies also showed that PERT reduced QTd [31. QTd. The QT interval and QTd were not modified in postmenopausal women receiving a combine progestin –estrogen replacement therapy. the present study suggests that long-term use ERT in postmenopausal healthy women increases QT interval. systolic blood pressure. The present study shows that a long-term use of ERT in postmenopausal healthy women increased the HRV indexes of parasympathetic activity. it may exert a facilitatory effect on cardiac arrhytmias.33].36]. In this study. In conclusion. [38] demonstrated that healthy postmenopausal women have an increased sympathetic drive. One of the major findings of the present study is that a long-term (1 year) estrogen replacement therapy increased the QT interval and QTd in postmenopausal healthy women suggesting that long term estrogen replacement therapy increased inhomogeneity in ventricular repolarization.

editor. Sarrel PM. Am J Cardiol 1997. 347. Kremastinos DT. [17] Sbarouni E. [34] Mercuro G.82:993 – 5. Int J Cardiol 2000. [7] Han J. Kabakci MG. Colditz GA. Patrizi R.285:1068 – 72. Use of QT dispersion measured on treadmill exercise electrocardiograms for detecting restenosis after percutaneous transluminal coronary angioplasty. Circulation 1992. Tajino K. [23] Lown B.46:13 – 25. J Am Coll Cardiol 2002. Woosley RL. [16] Drici MD. Approaches to sudden death from coronary heart disease. [3] Barrett-Conner E. et al. Seyffart K. Effect of estrogen replacement therapy on heart rate variability and heart rate in healthy postmenopausal women. Circulation 1983. Circulation 1971. Circulation 1994. Lancet 1998. Seyffart K.. Principles of Medical Therapy in Pregnancy. Surawicz B. Munakata K. Effect of low estrogen states in healthy women on dispersion of ventricular repolarization. Lee YT. Katchman A. Campbell RWF. Attenuation of heart-rate variability in postmenopausal women on progestin-containing hormone replacement therapy. Akgul E. Ebert SN. Effects of gonadal steroids on ventricular repolarization on the response to E4031. [26] Stumpf WE. vol. [38] Rosano GM. Am J Cardiol 1999. 54(3):381 – 5. In: Gleicher N.85:787 – 9. Haridasse V. Kremastinos TD.94:1471 – 4. Ikr. The antiestrogen tamoxifen blocks the delayed rectifier potassium current. Campbell RW. Estrogen and coronary heart disease in women. Effects of hormone replacement therapy on QT interval.287:877 – 83. Go ¸e et al. Leonardo F. 710 – 25. Villanueva MT. Lancet 1996. [11] Moreno FL. Furniss SS. N Engl J Med 1997. 1988.75(2 – 3):161 – 5.6(3):193 – 7.22:103 – 6.353:1939 – 40.44:130 – 42. et al. Oestrogens and the heart. et al. Ouyang P.16. Am J Cardiol 2000. Longu G.280(7):605 – 13. Matthews KA. McDonald RH.87(3):354 – 6. Effects of progestinestrogen replacement therapy on QT-dispersion in postmenopausal women. 379 [21] Christ M. Br Heart J 1994. in rabbit ventricular myocytes. Yoshino H. Absence of effects of short-term estrogen replacement therapy on resting and exertional QT and QTc dispersion in postmenopausal women with coronary artery disease. Danilo PJ. [20] Bigger JT. Steroid hormones and the cardiovascular system: direct actions of estradiol. [31] Haseroth K. [37] Saab PG. Schwartz PJ.351:478 – 84. Aksoyek S. et al. Stoney CM.M. Am J Cardiol 1996. [30] Lee TM. New York: Plenum Medical Book Company. Anderson JL. Frequency domain measures of heart period variability and mortality after myocardial infarction. Sex hormones prolong the QT interval and downregulate potassium channel expression in the rabbit heart. QT dispersion. Podda A. Bigger JT. [10] Higham PD. Tung RH. [22] Batur MK. Mortara A. Homoud MK. [5] Schulman SP. Am Heart 1999.265:1861 – 7. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. progesterone. Psychophysiology 1989. Am J Cardiol 2001. 347:786 – 8. p. Leonardo F. [28] Rosano GMC. Grady D.137:692 – 7. / International Journal of Cardiology 99 (2005) 373–379 ¨ kc [2] Grodstein F. [18] Larsen JA. Evidence of a role of endogenous estrogen in the modulation of autonomic nervous system. Panina G. Rosen MR. Link MS. [12] Koide Y.73:32 – 6. Br Heart J 1995.39(2):231 – 7.129:749 – 55.90:94 – 100. Arch Intern Med 1972. Goldman ME. Circulation 1993. Baroreflex sensitivity and heart-rate variability in prediction total cardiac mortality after myocardial infarction.75:165 – 6. Cherchi A. Coronary artery disease/myocardial infarction: reduction in QT interval dispersion by successful thrombolytic therapy in acute myocardial infarction. Zheng W. Characteristics and possible mechanism of ventricular arrhythmia dependent on the dispersion of action potential durations. [35] Mercuro G. J Pharmacol Exp Ther 1998. Int J Card Imaging 2000. Duff HJ. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. et al.22:639 – 48. et al. Tsai CH. JAMA 1991. Zoncu S. Bush TL. Am J Card Imaging 1999.71: 508 – 10. Arrhythmias in pregnancy. Hormone replacement therapy and ventricular repolarization: the verdict is not out yet. Bukulmez O. Sadananda R. Increased precordial QTc dispersion predicts ventricular fibrillation during acute myocardial infarction. Dicandia C.21:2392 – 5. Aybar F.67:1356 – 67. gluco. Experientia 1990. Effect of estrogen on ventricular repolarization in menopausal patients with syndrome X and effects of nicorandil. et al.M.88:2794 – 802. Matthews KA. [4] Hulley S. Su SF. Cyclical variation in paroxysmal supraventricular tachycardia in women. Stampfer MJ. [8] Kuo CS. Ishikawa K. Circadian variation of QTc Dispersion: Is it a clue to morning increase of sudden cardiac death? Clin Cardiol 1999. et al. Pacing Clin Electrophysiol 1998. JAMA 1998. et al. Increased expression of the cardiac L-type calcium channel in estrogen receptodeficient mice. [24] Rosano GM. Woosley RL. J Pharmacol Exp Ther 1998. Wehling M. Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina. Hormone replacement therapy shortens QT dispersion in healthy postmenopausal women. 26:270 – 80.85:164 – 71. Bush T. Burklow TR. Goel BG. Kyriakides ZS. [15] Johnson BD. Impaired forearm blood flow and vasodilator reserve in healthy postmenopausal women. Fleiss JL.86:1385 – 7. [13] Sbarouni E. Wolf M. testosterone. Oto A. [6] Higham PD. Wehling M. . Leonardo F. Oto A. [36] Owens JF. et al.and mineralocorticoids and soltriol (Vitamin D) on central nervous regulatory and peripheral tissues. Stoney CM. Electrophysiologic precursors of ventricular tachyarrhythmias. Acute electrophysiologic effect of estradiol 17h in menopausal women. [29] Meller J. Postmenopausal hormone therapy and mortality. Pitzalis L. et al. [9] Yunus A.110:135 – 40. [25] Hara M. Steinman RC. Karagounis LA. Reddy CP. Premenopausal and postmenopausal women differ in their cardiovascular and neuroendocrine responses to behavioral stressors. Yarali H. J Gen Physiol 1997. Marcus FI. Am J Cardiol 1998. Korach KS. [27] Rosano GMC. [19] La Rovere MT. [14] Liu XK. Menopausal status influences ambulatory blood pressure levels and blood pressure changes during mental stress. et al. [32] Yildirir A. [33] Saba S. Gurgan T. et al. Zarvalis E. Tokgozoglu SL. Christ M.78:706 – 8. Yotsukura M. QT dispersion and components of the QT interval in ischemia and infarction. Circulation 1996. Glazer RI.80:815 – 7. Ann Noninvasive Electrocardiol 2001. Gillis A. Therapie 1999. Clin Cardiol 1999.336:1775 – 96. Lancet 1999.84:65 – 9. Thiemann DR.