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(Circulation. 1996;94:1471-1474.)
© 1996 American Heart Association, Inc.

Articles

Sex Hormones Prolong the QT Interval and Downregulate Potassium Channel Expression in the Rabbit Heart

Milou D. Drici, MD, PhD; Thomas R. Burklow, MD; Vedanandam Haridasse, DVM; Robert I. Glazer, PhD; Raymond L. Woosley, MD, PhD

the Department of Pharmacology, Georgetown University Medical Center, Washington, DC (M.D.D., V.H., R.I.G., R.L.W.), and Children's National Medical Center, Department of Cardiology, Washington, DC (T.R.B.).

Correspondence to Dr R.L. Woosley, Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Rd NW, Washington, DC 20007. E-mail WoosleyR@gunet.georgetown.edu.

	Abstract

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Background Sex hormones are known to exert direct and indirect effects on cardiovascular function, but their effects on cardiac repolarization have not been elucidated. The repolarization phase of the cardiac action potential or QT interval of the ECG is regulated largely by potassium channels such as the delayed rectifier currents HK2 and I_sK.

Methods and Results The effects of ovariectomy (OVX) and estradiol (E2) or dihydrotestosterone (DHT) treatment were evaluated on HK2, HERG, and I_sK mRNA levels, QT duration, and quinidine-induced changes in QT interval in isolated rabbit hearts. HK2 and 0.7-kilobase I_sK mRNA were downregulated in cardiac ventricular tissue from OVX rabbits treated with either E2 or DHT. The QT interval was prolonged in E2- and DHT-treated animals (OVX+vehicle, 223±6 ms; OVX+DHT, 236±10 ms; and OVX+DHT, 245±6 ms; P<.05).

Conclusions The association between hormone-induced changes in baseline QT interval and the mRNA level for these channels suggests that sex hormones may play a critical role in regulating cardiac repolarization. However, the changes in baseline QT and potassium channel mRNA after hormone treatment were not concordant with the changes in QT interval after the infusion of quinidine, after which E2-treated animals responded similarly to controls (18.4±4.6% and 19.3±4.6% increase in QT interval, respectively) and DHT-treated animals exhibited less QT prolongation (11.4±3.8% increase; P<.03).

Key Words: potassium • hormones • sex • electrophysiology

	Introduction

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Although sex hormones are known to exert direct and indirect effects on cardiovascular function,¹ their effects on cardiac repolarization have not been elucidated. The repolarization phase of the cardiac action potential or QT interval of the ECG is regulated largely by potassium currents.² Among them, two distinct classes of potassium channels, HK2^{3 4} and I_sK,⁵ produce delayed rectifier currents that influence the duration of repolarization. HK2 is a member of the Shaker gene family, elicits a rapidly activating and slowly inactivating voltage-dependent outward potassium current,^{3 4} and is inhibited by terfenadine.⁶ I_sK is structurally unrelated to HK2 and produces a slowly activating, voltage-dependent outward current when expressed in Xenopus oocytes that is similar to the cardiac delayed rectifier current I_Ks.⁴ Estrogens^{7 8} and pregnancy^{9 10} modulate I_sK expression in the rat and mouse uterus, but its hormonal regulation in the heart has not been investigated. There are no studies of the sex hormone regulation of HK2.

Female sex has been associated with a slower rate of cardiac repolarization, ie, a longer ECG QT interval.^{11 12} The fact that the QT interval is longer in females than in males has been known for >75 years,¹³ but some investigators¹⁴ have recently found that the difference is due to shortening of the QT interval that develops in men between puberty and approximately age 55. Therefore, it has been suggested that differences between the actions of androgens and estrogens may account for the sex differences observed in QT duration. These differences are possibly responsible for the greater risk for women to develop the torsade de pointes form of ventricular tachycardia when treated with antiarrhythmic agents such as quinidine.¹⁵

The present study was undertaken to address three important questions: First, what effect, if any, does OVX and subsequent treatment with E2 or DHT have on mRNA for potassium channel proteins HK2, I_sK, and HERG in rabbit hearts? Second, if a hormone-dependent effect exists, is it related to a change in cardiac repolarization? Finally, do changes in potassium channel mRNA level predict sex differences in QT duration or response to quinidine infusion?

	Methods

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Isolated Heart Preparation
A total of 24 5-month-old albino New Zealand White rabbits (HRP Inc, Denver, Pa) were studied. Sixteen female rabbits were subjected to OVX and implanted with two sustained release pellets (Innovative Research of America) of vehicle, 200 mg of DHT, or 150 mg of E2. Eight untreated rabbits of the same strain (4 males and 4 females) served as controls. DHT was chosen as the androgenic hormone because it is not metabolized to E2 by cytochrome P-450 aromatase.¹⁶ Hormones were administered as sustained release pellets designed to maintain concentrations in the physiological range. After 20 days, animals were anesthetized and the hearts excised and perfused by the nonrecirculating Langendorff technique¹⁷ with a modified oxygenated Tyrode's solution (95% O₂, 5% CO₂), pH 7.4, containing NaCl 115 mmol/L, KCl 4.7 mmol/L, CaCl₂ 2 mmol/L, MgCl₂ 0.7 mmol/L, NaHPO₄ 1 mmol/L, NaHCO₃ 27.9 mmol/L, glucose 20 mmol/L, and 40 mg purified bovine serum albumin per liter. The perfusate was maintained at 37°C and was delivered through the aortic inflow cannula at a constant rate by a Masterflex pump. The cannulated and perfused heart was then mounted on a modified Langendorff apparatus and immersed in a tissue bath filled with warmed (37°C) Tyrode's solution. The AV node was destroyed to reduce the intrinsic heart rate. The isolated heart was paced at a fixed cycle length of 400 ms and twice diastolic threshold intensity. Six Ag-AgCl electrodes were positioned in a simulated Einthoven cardiac lead configuration with the reference and foot electrodes fixed beneath the heart on the walls of the tissue bath, which approximated the diameter of a rabbit thorax.¹⁸ Electrophysiological signals were amplified by an ECG amplifier (Colbourn Instruments) that allowed for the simultaneous recording of three signals termed X, Y, and Z. Four beats from each set of recordings were chosen for analysis and averaged for QT measurement. The end of the T wave was defined as the point of maximal change in the slope of the T wave as it merged with the electric baseline (paper speed, 100 mm/s).

Study Protocol for OVX Rabbits
After the paced hearts were perfused for an equilibration period and baseline measurements were obtained, hearts were perfused for 40 minutes with 400 mL of Tyrode's solution containing 3 µmol/L quinidine, followed by a 50-minute washout period with Tyrode's solution. Six animals were studied in each of the DHT- and E2-treated groups and 4 animals in the vehicle-treated group. Untreated normal animals served as a control and were used to examine sex differences in QT interval.

Northern Blotting
Approximately 2 g of left ventricular tissue was processed after completion of the Langendorff experiments. RNA was prepared by the one-step guanidine isothiocyanate procedure (Tri-Reagent, Molecular Research Center), and poly(A)RNA was purified by affinity chromatography on oligo(dT) cellulose (Molecular Research Center). Approximately 10 µg of ventricle poly(A)RNA was separated by electrophoresis in a 1% agarose-formaldehyde gel, and RNA was transferred to a nylon membrane (Qiagen Inc) by capillary transfer overnight with 5x SSC buffer (0.75 mol/L NaCl, 0.075 mol/L Na citrate, pH 7). Hybridization was performed with either a 400-bp HindIII/EcoRI fragment of human I_sK, a 1.7-kb HK2 cDNA, a 2.6-kb partial cDNA for HERG, or a 0.43-kb partial cDNA to human GAPDH (American Type Culture Collection). After hybridization for 16 hours at 42°C, the membrane was washed twice with 1x SSC/0.1% SDS at room temperature and twice with 0.5x SSC/0.1% SDS at 38°C. Autoradiography was performed with Kodak Biomax film for 4 days, and blots were measured by use of a Molecular Dynamics PhosphorImager. Blots were stripped and reprobed in succession with each of the probes, and autoradiography was used to ensure that each stripping completely removed the previous radioactive probe.

Statistical Analysis
Baseline values were analyzed by Kruskal-Wallis ANOVA to determine whether there was a main effect by group, a main effect by time, or a time-by-group interaction. If the global test showed a significant effect or interaction, post hoc contrast groups at various time points were examined with Dunnett's test for multiple comparisons. Continuous variables, such as the time course of the increase in QT, were analyzed by one-way ANOVA for repeated measures. A probability value of P<.05 was considered significant.

	Results

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Influence of OVX and Hormonal Pretreatment on Hormone Circulating Levels and Potassium Channel mRNAs
In the hormone-treated groups, the serum levels of DHT and E2 were 3.5±0.5 ng/mL and 302±58 pg/mL (mean±SEM), respectively, 20 days after pellet implantation. Vehicle-treated OVX rabbits were devoid of detectable DHT or E2. After completion of the quinidine perfusion, cardiac ventricular tissue from rabbits was analyzed for HK2, HERG, and I_sK mRNA levels. Levels of mRNA were normalized to GAPDH mRNA levels. Two I_sK transcripts of 3.4 and 0.7 kb were found in vehicle-treated cardiac tissue from OVX rabbits. However, the 0.7-kb I_sK mRNA was absent in E2- and DHT-treated OVX rabbits. The 5-kb HK2 mRNA also was reduced markedly in hormone-treated animals, but the levels of HERG mRNA remained unchanged (Fig 1).

View larger version (76K): [in this window] [in a new window]   Figure 1. Northern blot analysis of delayed rectifier potassium channel mRNAs in cardiac ventricular tissue. The bar graph displays the relative level of mRNA, denoted by the arrowheads in the Northern blots, normalized to GAPDH levels. The 0.7-kb IsK and HK2 mRNA transcripts were reduced in E2- and DHT-treated OVX rabbit cardiac ventricular tissue, whereas HERG remained unchanged. C and Ctl indicate control.

Influence of Sex Hormone Pretreatment on Hormone Levels and Baseline QT Duration in OVX Rabbits
All hearts were infused with Tyrode's solution; the stability of the electrophysiological variables over 3 hours in our experimental conditions has been validated previously in a group of three rabbits. The baseline QT interval of the hearts from the OVX rabbits treated with vehicle was 223±6 ms, whereas the QT interval in DHT- and E2-treated groups was 236±10 and 245±6 ms, respectively (each treated group versus control, P<.05) (Fig 2).

View larger version (85K): [in this window] [in a new window]   Figure 2. Orthogonal in vitro ECG recording from an OVX female rabbit heart 40 minutes after the beginning of the quinidine infusion. Paced cycle length is 400 ms.

Evidence of a Sex Difference Expressed Both at Baseline and in Response to Infusion of Quinidine
Comparison of untreated male and female rabbits indicated that male animals had a shorter QT interval than female animals (males, 225±3 ms; females, 244±6 ms; P=.01). A 40-minute infusion of 3 µmol/L quinidine to OVX rabbits resulted in a significant increase in the QT interval in all experiments (P<.001) that reached a plateau within 25 minutes in the vehicle and DHT groups but not in the E2 group. There was also a significant difference in the extent of the quinidine-induced increase in QT prolongation between the vehicle or E2 groups and the DHT group. The maximal effect for the vehicle- and E2-treated animals was a 19.3±4.6% and 18.4±4.6% increase from baseline, respectively, whereas in DHT-treated animals, an 11.4±3.8% increase was observed (P<.03) (Fig 3). The rate of increase of the QT interval during the quinidine infusion was greater in vehicle-treated OVX rabbits (2.2±0.4 ms/min) than in DHT-treated (1.7±0.7 ms/min) and E2-treated animals (1.3±0.3 ms/min) (P<.02). However, the magnitude of the response to quinidine was not predicted by the changing levels of HK2, I_sK, or HERG mRNA.

View larger version (93K): [in this window] [in a new window]   Figure 3. Changes in QT interval in isolated rabbit heart from OVX rabbits during perfusion with quinidine. A, QT interval durations before quinidine infusion. E2- and DHT-treated rabbits showed a significantly longer baseline QT interval (P<.01) than control (Ctl) OVX rabbits. B, Changes in QT interval after quinidine infusion. Quinidine increased the QT interval further in all groups (P<.02), with control>E2-treated>DHT-treated rabbits.

	Discussion

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In this report, we show that HK2 and 0.7-kb I_sK mRNA are downregulated in cardiac ventricular tissue from OVX rabbits treated with E2 or DHT. Two I_sK transcripts of 3.4 and 0.7 kb were found in control cardiac tissue and are believed to reflect alternative splicing and/or alternate transcriptional start sites.^{19 20} Although the physiological significance of the different transcripts is unknown, the 0.7-kb transcript is found mainly in rabbit cardiac ventricular tissue and is also the predominant I_sK mRNA in human heart (T.R.B., MD, et al, unpublished data, 1996).

I_sK has been shown previously to be induced in rat and mouse uterus by estrogens^{7 8} and to be expressed maximally in fetal and neonatal rat and mouse heart. As rats age, the cardiac action potential shortens²¹ and the level of expression of I_sK declines progressively.^{8 10} These changes in mRNA may reflect transcriptional regulation of this gene through cAMP- or estrogen-responsive elements^{22 23} or mRNA stabilization. Although there are no previous studies of the regulation of HK2 by sex hormones, glucocorticoids have been shown to induce HK2 expression in rat ventricular tissue after adrenalectomy.²⁴ HK2 mRNA levels also were reduced markedly in hypertrophied cardiac tissue, which demonstrates prolongation of the plateau phase of the cardiac action potential.²⁵ HERG is a cardiac potassium channel for which mutations have been associated with the familial long-QT syndrome.^{26 27}

For many years, it has been recognized that the QT interval is longer in women than in men.^{13 14 15} Recent studies have shown that this is because the QT interval shortens in men beginning at puberty and lasting until approximately age 55.¹⁴ We have found that OVX produces a shorter QT interval and that both male and female hormones can lengthen it. We also found that hormone-induced lengthening of the QT interval was associated with a downregulation of expression of mRNA for I_sK and HK2. These data suggest that the hormonal milieu of cardiac tissue may be an important regulatory process for the expression of these two delayed rectifier potassium channels and the QT interval.

It is now well recognized that women are more prone than men to the occurrence of torsade de pointes and QT lengthening after treatment with drugs such as quinidine, sotalol, and terfenadine.²⁸ When rabbit hearts pretreated with E2 or DHT were perfused with quinidine, an agent known to cause QT prolongation and torsade de pointes,^{15 29 30} quinidine elicited QT prolongation in vehicle and in both hormone-treated groups. Importantly, the extent of QT lengthening due to quinidine was least in the DHT-treated group but did not correlate with the changes in mRNA levels of I_sK, HERG, and HK2. Even though E2 treatment downregulated expression of mRNA for I_sK and HK2, the vehicle-treated group showed the same degree of quinidine response as the E2-treated group. These data suggest that DHT produces some change that limits the tissue responsiveness to quinidine. This also suggests that this experimental system may be a reasonable model for understanding potential causes for the increased risk of torsade de pointes seen in women. Because the magnitude of the response to quinidine did not correlate with the levels of HK2 and I_sK mRNA, the increased incidence of adverse reactions to quinidine in women is unlikely to be related to the level of expression of these channels.

Further studies delineating the mechanism of sex hormone effects on the transcriptional or posttranscriptional regulation of these ion channels should provide a better understanding of the hormonal effects on potassium channel expression in the heart. Studies of the effects of sex hormones on the expression of additional potassium channels are needed to understand the resistance of androgen-treated tissues to response to quinidine.

	Selected Abbreviations and Acronyms

 

bp = base pair DHT = dihydrotestosterone E2 = 17-ß estradiol kb = kilobase OVX = ovariectomy, ovariectomized

	Acknowledgments

 
Dr Drici is a recipient of a Merck International Fellowship in clinical pharmacology. Dr Burklow is the recipient of a military fellowship. We thank Drs Richard Swanson (Merck Inc), Arthur M. Brown (Baylor College of Medicine), and Yi Li (Human Genome Sciences, Inc) for generously providing the cDNA for I_sK, HK2, and HERG, respectively.

	Footnotes

 
The opinions and assertions in this article are those of the authors and do not necessarily represent those of the Department of the Army or Department of Defense.

Drs Drici and Burklow contributed equally to this article.

Received December 4, 1995; revision received March 13, 1996; accepted April 7, 1996.

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				T. V. Pham, E. A. Sosunov, E. P. Anyukhovsky, P. Danilo Jr, and M. R. Rosen Testosterone Diminishes the Proarrhythmic Effects of Dofetilide in Normal Female Rabbits Circulation, October 15, 2002; 106(16): 2132 - 2136. [Abstract] [Full Text] [PDF]

				R. A. DeFazio and S. M. Moenter Estradiol Feedback Alters Potassium Currents and Firing Properties of Gonadotropin-Releasing Hormone Neurons Mol. Endocrinol., October 1, 2002; 16(10): 2255 - 2265. [Abstract] [Full Text] [PDF]

				M.-D. Drici, L. Baker, P. Plan, J. Barhanin, G. Romey, and G. Salama Mice Display Sex Differences in Halothane-Induced Polymorphic Ventricular Tachycardia Circulation, July 23, 2002; 106(4): 497 - 503. [Abstract] [Full Text] [PDF]

				M Malik, P Farbom, V Batchvarov, K Hnatkova, and A J Camm Relation between QT and RR intervals is highly individual among healthy subjects: implications for heart rate correction of the QT interval Heart, March 1, 2002; 87(3): 220 - 228. [Abstract] [Full Text] [PDF]

				T. V. Pham and M. R. Rosen Sex, hormones, and repolarization Cardiovasc Res, February 15, 2002; 53(3): 740 - 751. [Abstract] [Full Text] [PDF]

				T. V Pham, R. B Robinson, P. Danilo Jr, and M. R Rosen Effects of gonadal steroids on gender-related differences in transmural dispersion of L-type calcium current Cardiovasc Res, February 15, 2002; 53(3): 752 - 762. [Abstract] [Full Text] [PDF]

				Y. Wu and M. E Anderson Reduced repolarization reserve in ventricular myocytes from female mice Cardiovasc Res, February 15, 2002; 53(3): 763 - 769. [Abstract] [Full Text] [PDF]

				C. E Conrath, A. A.M Wilde, R. J.E Jongbloed, M. Alders, I. M van Langen, J Peter van Tintelen, P. A Doevendans, and T. Opthof Gender differences in the long QT syndrome: effects of {beta}-adrenoceptor blockade Cardiovasc Res, February 15, 2002; 53(3): 770 - 776. [Abstract] [Full Text] [PDF]

				B Huang, D Qin, and N El-Sherif Spatial alterations of Kv channels expression and K+ currents in post-MI remodeled rat heart Cardiovasc Res, November 1, 2001; 52(2): 246 - 254. [Abstract] [Full Text] [PDF]

				M. Johansson and L. Carlsson Female Gender Does Not Influence the Magnitude of Ibutilide-Induced Repolarization Delay and Incidence of Torsades de Pointes in an In Vivo Rabbit Model of the Acquired Long QT Syndrome Journal of Cardiovascular Pharmacology and Therapeutics, September 1, 2001; 6(3): 247 - 254. [Abstract] [PDF]

				M.-D. Drici Influence of gender on drug-acquired long QT syndrome Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K41 - K47. [Abstract] [PDF]

				M.R. Rosen Isolated tissue models and proarrhythmia Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K64 - K69. [Abstract] [PDF]

				B. London Taking the Gender Gap to Heart Circ. Res., August 31, 2001; 89(5): 378 - 379. [Full Text] [PDF]