Sex-specific I_KAS activation in rabbit ventricles with drug-induced QT prolongation

Abstract

Background

Female sex is a known risk factor for drug-induced long QT syndrome (diLQTS). We recently demonstrated a sex difference in apamin-sensitive small-conductance Ca²⁺-activated K⁺ (SK) current (I_KAS) activation during β-adrenergic stimulation.

Objective

To test the hypothesis that there is a sex difference of I_KAS in the rabbit models of diLQTS.

Methods

We evaluated the sex differences in ventricular repolarization from 15 male and 22 female Langendorff-perfused rabbit hearts with optical mapping techniques during atrial pacing. HMR1556 (I_Ks blocker), E4031 (I_Kr blocker) and sea anemone toxin (ATX-II, I_NaL activator) were used to simulate types 1-3 LQTS, respectively. Apamin, an I_KAS blocker was then added to determine the magnitude of further QT prolongation.

Results

HMR1556, E4031 and ATX-II led to APD₈₀ prolongation in both male and female ventricles at pacing cycle lengths (PCLs) of 300-400 ms. Apamin further lengthened APD₈₀ (in PCL350 ms) from 187.8±4.3 to 206.9±7.1 (p=0.014) in HMR1556 treated, from 209.9±7.8 to 224.9±7.8 (p=0.003) in E4031 treated, and from 174.3±3.3 to 188.1±3.0 (p=0.0002) in ATX-II treated female hearts. In contrast, apamin did not further lengthen the APD₈₀ in male hearts. Compared with the baseline, the Ca_i transient duration (Ca_iTD) was significantly increased in diLQTS but without sex differences. There were no significant effects of apamin on Ca_iTD.

Conclusion

We conclude that I_KAS is abundantly increased in female but not in male ventricles with diLQTS. Increased I_KAS helps preserve the repolarization reserve in female ventricles treated with I_Ks and I_Kr blockers or I_NaL activators.

Introduction

Drug-induced long QT syndrome (diLQTS) is the most common reason that prevents a drug from reaching the market.¹ The most common type of diLQTS is due to the inhibition of the rapid component of the delayed rectifier potassium current (I_Kr).² Cardiac repolarization is controlled by the balance between outward and inward ionic conductances during the plateau phase of the action potential.³ Mutations of KCNQ1 (I_Ks), KCNH2 (I_Kr) and SCN5A (I_NaL) genes cause long QT syndrome (LQTS) types 1-3, respectively.⁴ However, family members with the same genetic mutations may have vastly different QT intervals,^{5, 6} indicating that other factors may potentially play a role in determining the QT interval in patients with congenital LQTS.^6-8 Apamin-sensitive small-conductance Ca²⁺-activated K⁺ channel (SK) current (I_KAS) is present but not active or only minimally active in the normal ventricles.^{9, 10} However, I_KAS is abundantly present in heart failure, myocardial infarction and hypokalemia when repolarization reserve is reduced.^11-13 We recently documented that β-adrenergic stimulation activates ventricular I_KAS in females to a much greater extent than in males.¹⁴ We hypothesize that (1) I_KAS is activated in rabbit ventricles in diLQTS, and (2) the magnitude of I_KAS activation during diLQTS is greater in female than in male ventricles. We performed an optical mapping study in Langendorff-perfused normal rabbit ventricles to test these hypotheses.

Methods

The study protocol was approved by the Institutional Animal Care and Use Committee of Indiana University School of Medicine and the Methodist Research Institute and conform to the Guide for the Care and Use of Laboratory Animals.

Surgical preparations

Adult New Zealand White rabbits (N=37, 2.7-3.5 Kg) were euthanized by intravenous sodium pentobarbital overdose (160 mg/kg, i.v.). Hearts were harvested and Langendorff perfused with 37°C Tyrode solution (in mmol/L: NaCl 128.3, KCl 4.7, NaHCO₃ 20.2, NaH₂PO₄ 0.4, CaCl₂ 1.8, MgSO₄ 1.2, glucose 11.1 and bovine serum albumin 40 mg/L) bubbled with 95% O₂/5% CO₂ to maintain a pH of 7.4. All chemicals were purchased from Sigma-Aldrich (St. Louis, MO). Pseudo-electrocardiogram (pECG) was simultaneously recorded by placing widely spaced electrodes close to the right atrium (RA) and the apex of the left ventricle (LV), respectively, to determine the QT interval and ventricular rhythm. The signals were band-pass filtered between 0.5 Hz to 150 Hz with a sampling rate of 1000 Hz. The pECG traces and methods of QT measurements are shown in Figure 1.

Figure 1.

Sinus bradycardia of diLQT1, diLQT2 and diLQT3 in ex vivo female rabbit hearts. A, representative pseudo ECG traces of diLQT1 (HMR1556, 100 nmol/L), diLQT2 (E4031, 50 nmol/L), and diLQT 3 (ATX-II, 20 nmol/L). Apamin (100 nmol/L) was then given during continued drug infusion. B, magnified figures showing the typical ECG traces from the box in (A), schematic illustration of the tangent method to define the T-wave end. The gray bars indicate the QT interval. C, Linkage graphs show the alterations of the RR and QT intervals in different types of diLQTS. There are significant (p<0.05) differences between baseline and diLQTS (*) as well as between diLQTS and post-apamin (**).

Optical mapping

Simultaneous optical mapping of intracellular calcium (Ca_i) and membrane potential (V_m) was performed using previously reported techniques.¹⁴ The hearts were stained with Rhod-2 AM (1.4 μmol/L, from Invitrogen, Grand Island, NY) for Ca_i mapping and RH237 (10 μmol/L, from Invitrogen, Grand Island, NY) for V_m mapping. Blebbistatin (15~20 μmol/L, from Tocris Bioscience, Minneapolis, MN) was used to inhibit contraction. The epicardial surfaces of the right and left ventricles were excited with a laser (Verdi G5, Coherent Inc., Santa Clara, CA) at a wavelength 532 nm, and the emitted fluorescence was filtered with a 715 nm long pass filter. The fluorescence was recorded with 100 x 100 pixels for a spatial resolution of 0.35 x 0.35 mm² per pixel at a 2-ms/frame sampling rate. Optical signals were processed with both spatial and temporal filtering. A dynamic atrial pacing protocol was performed and the optical signals were recorded at different pacing cycle lengths (PCLs).¹⁵ When comparing action potential duration (APD) among baseline and after each treatment, we paced the right atrial at fixed PCL (S1S1) to avoid rate-dependent APD changes. The slowest pacing rate is limited by the competing sinus or escape rates of the Langendorff perfused hearts. We were unable to consistently pace with PCL longer than the sinus cycle length (250-400 ms). We started to acquire optical mapping signals after at least 30 paced beats at the same PCL. The PCLs were progressively shortened (400, 350, 300, 250, 200, and 170 ms) until the loss of 1:1 capture. APD at 80% repolarization (APD₈₀) were used for data analyses. We did not use programmed stimulation to induce arrhythmias. In all protocols, the drugs were sequentially added and recirculated in the perfusate.

Protocol-I (diLQT1):

Epicardial optical signals were mapped sequentially at baseline, after adding HMR1556 (I_Ks blocker) to simulate type 1 LQTS, after adding apamin in the continued presence of HRM1556 and after washout. This study was performed in a total 5 male and 8 female rabbit hearts. The optical voltage signals were obtained from the anterior surface of the heart including both right ventricle (RV) and left ventricle (LV). The annotated RV/LV locations and image data acquisition procedures are shown in Online Supplement Figure 1. After baseline recording, HMR1556 (100 nmol/L) was added to the perfusate. APD measurement was performed 15 min after HMR1556 infusion. Apamin (100 nmol/L) was subsequently added in the continued presence of HMR1556. All drugs were washed out 15 min after apamin infusion. The APDs were measured at least twice in pharmacological steady-state. All experiments were completed within 1.5 hr to minimize phototoxicity induced by long-term laser exposure in these ex vivo ventricles.

Protocol-II (diLQT2):

Epicardial mapping of both the RV and the LV was conducted at baseline, after adding E4031 (I_Kr blocker, 50 nmol/L), after adding apamin (100 nmol/L) in the continued presence of E4031 and after washout. This protocol was performed in 6 male and 7 female hearts.

Protocol-III (diLQT3):

Epicardial mapping of both the RV and the LV was conducted at baseline, after adding sea anemone venom (ATX-II, 20 nmol/L), after adding apamin (100 nmol/L) in the continued presence of ATX-II and after washout. ATX-II is a specific late sodium channel (I_NaL) enhancer.¹⁶ This protocol was done in 4 males and 7 females.

Statistical analysis

APD₈₀ was optically measured at the level of 80% repolarization. Calcium transient duration at the level of 80% (Ca_iTD₈₀) were used as the index of total Ca_i duration. We averaged the APD in the region of interests and presented them in summary data. Continuous variables were expressed as mean ± SEM. Paired t-tests were used to compare two different treatments in the same rabbit ventricle. One-way repeated measures ANOVA with post-hoc tests were used to compare the means among three or more different variables. We used the correlation of variance generated from the optically imaged region to quantify APD heterogeneity.¹⁷ A two-sided P value of <0.05 was considered as statistically significant.

Results

diLQTS is associated with I_KAS activation in female ventricles

We were unable to measure heart rate-controlled QT intervals at a fixed pacing cycle lengths (PCLs) because of the superimposition of the atrial pacing artifacts with the terminal portion of the preceding T wave. Representative examples of pECG recordings and QT interval measured during sinus rhythm are shown in Figure 1A and Figure 1B, respectively. HMR1556, E4031 and ATX-II all significantly prolonged RR interval (reduced sinus heart rate) in these female hearts. Figure 1C shows that all 3 drugs significantly increased the average RR intervals and the sinus QT intervals. T-wave end was determined by tangent method as shown in Figure 1B.¹⁸ Apamin further prolonged sinus QT intervals, indicating the diLQT 1-3 were associated with the increased I_KAS. However, apamin failed to prolong QT intervals in male hearts (Online Supplement Figure 2). The other sinus rhythm parameters (P, PR, and QRS) were not changed by drug treatments. Figure 2 shows the changes (delta) of RR and QT intervals from baseline in female hearts, showing significant increments after drugs and further increase after apamin. Table 1A shows the actual QT intervals of male and female hearts measured during sinus rhythm. We have removed 2 (1 male and 1 female) hearts with diLQT1, 2 (both female) from diLQT2 and 2 (both male) from diLQT3 groups due to third degree AV block. The data from those hearts were excluded from analyses. Figure 3A shows that the APD₈₀ was increased by HMR1556 (100 nmol/L) at all PCLs. However, the increases were more apparent at longer PCL (350 ms) than at shorter PCLs (300 and 250 ms). The APD₈₀ was further increased by apamin (100 nmol/L) (Figure 3B and 3C). Table 1B shows HMR1556 prolonged the APD₈₀ in female ventricles. These results indicated that I_KAS is functionally elevated during the diLQT1 at longer PCLs. Similar results were demonstrated in the diLQT2 model as shown in Figure 4. E4031 (50 nmol/L), the I_Kr blocker, significantly prolonged APD₈₀. While female ventricles had greater prolongation than male ventricles, the difference was statistically insignificant (Table 1B). Subsequent addition of apamin further increased the APD₈₀. The numeric results are displayed in Table 1B. Figure 4C shows that APD₈₀ was significantly lengthened by E4031 at PCLs longer than 250 ms.

Figure 2.

Effects of drugs and apamin on RR and QT intervals in female hearts. A, differences (delta) in RR intervals between treatments and baseline. The delta between RR interval and baseline was statistically significant both after drug and after apamin. B, the delta QT interval at different stages of the experiment. The delta QT interval was increased by the drugs and by apamin. The RR and QT intervals were only partially reduced after attempted washout (WO). Asterisks (*diLQTS compared with baseline; **diLQTS compared with post-apamin) represent significant differences (p<0.05, each n=7-8).

Table 1.

Effects of apamin on repolarization and calcium transients

A. ECG QT intervals during sinus rhythm
Type	Sex	Sinus QT	QT (diLQTS)	QT (apamin)	n
IKs (HMR1556)	Male	229.8 ± 11.6	295.4 ± 17.1 *	303.4 ± 18.9	5
	Female	220.8 ± 7.8	284.5 ± 14.9 *	304.6 ± 18.1 **	8
IKr (E4031)	Male	235.7 ± 8.6	319.2 ± 12.3 *	325.8 ± 11.7	6
	Female	228.0 ± 11.7	320.0 ± 9.4 *	344.6 ± 14.2 **	7
INa,L (ATX-II)	Male	221.3 ± 11.3	287.3 ± 8.4 *	293.5 ± 6.6	4
	Female	234.4 ± 6.3	302.1 ± 13.8 *	328.7 ± 8.1 **	7
*p<0.05 compared with baseline; **p<0.05 compared with diLQTS; time scale: ms.
B. Optical mapping APD during atrial pacing with cycle length of 350 ms
Type	Sex	Baseline APD80	ΔAPD80 (diLQTS)	ΔAPD80 (apamin)	n
IKs (HMR1556)	Male	162.0 ± 3.6	23.8 ± 3.0 *	−0.2 ± 1.8	5
	Female	163.9 ± 3.9	23.9 ± 1.9 *	19.1 ± 5.9 **	8
IKr (E4031)	Male	166.3 ± 4.8	37.0 ± 6.0 *	−2.3 ± 2.8	6
	Female	160.7 ± 4.3	49.1 ± 8.0 *	14.7 ± 2.9 **	7
INa,L (ATX-II)	Male	161.8 ± 5.5	22.3 ± 3.9 *	−0.8 ± 1.5	4
	Female	158.0 ± 3.5	21.3 ± 2.9 *	13.9 ± 1.6 **	7
*p<0.05 compared with baseline; **<0.05 compared with males; time scale: ms.
C. Optical mapping CaiTD during atrial pacing with cycle length of 350 ms
Type	Sex	Baseline CaiTD80	ΔCaiTD80 (diLQTS)	ΔCaiTD80 (apamin)	n
IKs (HMR1556)	Male	185.0 ± 1.6	29.4 ± 3.3 *	−0.6 ± 4.1	5
	Female	184.5 ± 2.6	26.5 ± 1.8 *	1.6 ± 3.4	8
IKr (E4031)	Male	185.3 ± 2.6	41.0 ± 4.1 *	−0.2 ± 2.9	6
	Female	182.7 ± 1.7	48.4 ± 4.1 *	3.3 ± 3.1	7
INa,L (ATX-II)	Male	181.5 ± 3.6	35.5 ± 5.5 *	−1.5 ± 1.8	4
	Female	181.3 ± 2.1	33.7 ± 3.0 *	2.6 ± 3.2	7
*p<0.05 compared with baseline; time scale: ms.

Figure 3.

Changes in APD₈₀ in female ventricles treated with HMR1556 followed by apamin and washout in a female heart. A, the color maps show epicardial APD distribution at different pacing cycle lengths (PCLs). HMR1556 (100 nmol/L) increased APD₈₀. Apamin (100 nmol/L) further increased the APD₈₀, and after washout (Protocol I, diLQT1). B, HMR1556 prolonged APD₈₀. Addition of apamin further increased the APD₈₀. APD₈₀ is persistently prolonged after washout (WO). C, summary of these studies at different PCLs. The magnitude of APD prolongation by HMR1556 was more prominent at long PCLs than at short PCLs. The apamin further prolonged APD₈₀ at multiple PCLs. Data presented as mean ± SEM. Asterisks (*diLQTS compared with baseline; **diLQTS compared with post-apamin) represent significant differences (p<0.05, n=8).

Figure 4.

Changes in APD₈₀ in female ventricles treated with E4031 followed by apamin and washout. A, representative membrane potential traces and APD₈₀ maps at baseline and in the presence of E4031 (50 nmol/L), after apamin (100 nmol/L), and after washout (Protocol II, diLQT2). B, at 350 ms PCL, E4031 (50 nmol/L) significantly prolonged APD₈₀ and apamin further increased the APD₈₀. APD₈₀ is persistently prolonged after washout (WO). C, summary of apamin effects on APD₈₀ at different PCLs. Significant effects of apamin were observed at all but 250 ms PCLs. Asterisks (*diLQTS compared with baseline; **diLQTS compared with post-apamin) represent significant differences (p<0.05, n=7).

Figure 5A shows a representative example of optical mapping and APD traces at baseline, after infusion of ATX-II (20 nmol/L), after apamin and after washout. At PCL 350 ms, ATX-II significantly prolonged APD and subsequent addition of apamin (100 nmol/L) in the continued presence of ATX-II in the perfusate further lengthened APD₈₀ at the long, but not short, PCLs (Figure 5B and 5C).

Figure 5.

Changes in APD₈₀ in female ventricles treated with ATX-II followed by apamin and washout. A, representative membrane potential traces and APD₈₀ maps at baseline and in the presence of ATX-II (20 nmol/L), after apamin (100 nmol/L), and after washout (Protocol III, diLQT3). B, at 350 ms PCL, ATX-II significantly prolonged APD₈₀ and apamin then further increased the APD₈₀. APD₈₀ is persistently prolonged after washout (WO). C, summary of apamin effects on APD₈₀ at different PCLs in normal rabbit ventricles. The apamin effects were observed at multiple PCLs but not in 250 ms PCL. Asterisks (*diLQTS compared with baseline; **diLQTS compared with post-apamin) represent significant differences (p<0.05, n=7).

I_KAS was not significantly activated in male diLQTS hearts

We applied the same protocol in male hearts but failed to observe APD prolongation after apamin administration in diLQTS (PCL 350 ms). No apamin effects were observed in the diLQT1, diLQT2, and diLQT3 models of male rabbit hearts (Figure 6). Table 1A shows the numeric values of the QT interval changes. Online Supplement Figures 3-5 show typical examples of experiments in male rabbit hearts. They showed that while all 3 drugs prolonged APD₈₀ especially at longer PCLs, addition of apamin failed to further prolong APD₈₀. The numeric values are summarized in Table 1B. These results indicated that I_KAS is magnified in female but not in male ventricles of diLQTS. Apamin did not induce further changes of the APD heterogeneity in female diLQTS ventricles (PCL350 ms) (Online supplement Figure 6).

Figure 6.

Apamin did not prolong APD₈₀ in male ventricles with diLQT1 (A), diLQT2 (B) and diLQT3 (C). There were significant APD₈₀ prolongations after drug administration, especially at longer PCLs. However, no further prolongation was observed after apamin, indicating absence of I_KAS activation in male diLQTS model. Asterisks indicate significant differences (p<0.05, each n=4-6).

Apamin had little effects on intracellular calcium transient duration (Ca_iTD)

Ca_i mapping was simultaneously performed and analyzed (Figure 7). Compared with baseline, HMR1556 (100 nmol/L), E4031 (50 nmol/L) and ATX-II (20 nmol/L) markedly prolonged Ca_i transient duration. The numeric values are summarized in Table 1C. These findings indicate that Ca_iTD was significantly prolonged in diLQT1, diLQT2 and diLQT3. The E4031 prolonged CaiTD to a greater extent in female than in male ventricles, but the difference was statistically insignificant. Apamin (100 nmol/L) had a minimal further effect on Ca_iTD prolongation. The sex differences of I_KAS activation could not be explained by the differential prolongation of Ca_iTD in male and female ventricles.

Figure 7.

Effects of I_KAS blockade on Ca_iTD in diLQTS models. A, representative Ca_i (blue) and V_m (black) traces at baseline, during E4031, and after apamin (Protocol-II) at 350 ms PCL in a female heart. Compared with baseline, E4031 (50 nmol/L) markedly prolonged Ca_iTD₈₀. Apamin (100 nmol/L) only slightly prolonged Ca_iTD, but the prolongation was statistically insignificant. B, representative Ca_iTD distribution maps of diLQT1 (top), diLQT2 (middle) and diLQT3 (bottom) with female hearts treated with HMR1556 (100 nmol/L), E4031 (50 nmol/L) or ATX-II (20 nmol/L), respectively, at 350 ms PCL. Addition of apamin (100 nmol/L) did not further prolong the Ca_iTD. C, linkage graphs show the alterations of the Ca_iTD₈₀ in different types of diLQTS, neither male nor female ventricles showed Ca_iTD₈₀ prolongation after adding apamin at 350 ms PCL. Asterisks indicate significant differences (p<0.05, each n=4-8).

Discussion

We found that I_KAS is abundantly increased in female but not in male rabbit ventricles with diLQTS. I_KAS activation helps preserve the repolarization reserve in female ventricles treated with I_Ks and I_Kr blockers or I_NaL activators. A clinical implication is that I_KAS blockers may be proarrhythmic in female ventricles.

Significance of I_KAS activation in female diLQTS

As compared with men, women have longer rate-corrected QT intervals and are more prone to QT interval prolongation and Torsade de Pointes (TdP) ventricular arrhythmias after treatment with drugs that inhibit K⁺ channels.^19-21 A detailed understanding of proarrhythmic potential of ionic channel blockade is an important step towards the development of better antiarrhythmic strategy in female patients. The diLQTS is the single most common cause for withdrawal or restriction of the use of drugs already marketed.¹ Common mechanisms of diLQTS include I_Ks and/or I_Kr blockade ^{2, 3} as well as I_NaL activation,²² although many other mechanisms also play a role.⁷ In rabbit models of diLQT2, adult females had significantly lower I_Kr and, perhaps, inward rectifying K⁺ current, which contributed to their longer QT interval and greater arrhythmia vulnerability compared with male rabbit counterpart.²³ The present consensus is that normal female hearts express fewer functional K⁺ channels, resulting in longer APD.²⁴ When treated with agents that inhibit I_Kr, adult females have a greater vulnerability to early afterdepolarizations (EAD) and TdP. More recent studies showed that rare variations in genes responsible for congenital arrhythmia syndromes are frequently found in diLQTS.^{7, 8} In addition to genetic variations, disease states such as heart failure are also a prominent risk factor of diLQTS.¹

I_KAS blockade and QT prolongation

Heart failure is a disease condition associated with significant SK channel upregulation. While I_KAS is inactive or only minimally active in normal ventricles,^{9, 25} it is increased in heart failure.^{12, 26, 27} Failing ventricles have decreased K⁺ currents, increased I_NaL, reduced repolarization reserve and increased QT interval.²⁸ In the meantime, it activates I_KAS to preserve the repolarization reserve. Sex-specific I_KAS activation in the female ventricle helps to preserve repolarization reserve when other K⁺ channels are suppressed or I_NaL is activated by drugs. Therefore, drugs that block I_KAS may be more proarrhythmic in women than in men. One of the known cardiac I_KAS blocker is ondansetron.²⁹ Consistent with the importance of I_KAS in female ventricles, female sex is a major risk factor for QT prolongation induced by ondansetron in patients with cardiovascular diseases.³⁰

Ca_i prolongation accompanied with diLQTS as a factor for I_KAS activation

Cardiac repolarization alternans often precedes life-threatening ventricular arrhythmias. In alternans, Ca_i and V_m are coupled either positively (large Ca_i transient prolongs APD of the same beat) or negatively (large Ca_i transient shortens APD of the same beat).³¹ V_m and Ca_i are coupled via calcium sensitive currents, such as I_CaL, I_NCX, I_Ks and I_KAS.^{31, 32} The results of our study showed positive Ca_i-V_m coupling in diLQTS. The increased APD resulted in increased Ca_iTD, which in turn may contribute to the activation of calcium sensitive potassium currents, such as I_Ks and I_KAS. In diLQT1 when I_Ks is inhibited, the I_KAS may help maintain the repolarization reserve. However, Ca_iTD prolongation occurred both in male and female ventricles and the magnitudes of prolongation were not different between sexes. These findings indicate that sex-specific I_KAS elevation is not secondary to differential prolongation of Ca_iTD.

I_KAS blockade enhanced sinus bradycardias in diLQTS

Apamin is known to slow diastolic depolarization and reduce pacemaker rate in isolated sinoatrial node cells and intact tissue.³³ We found that apamin amplified the diLQT-induced heart rate slowing. The effects of apamin on APD₈₀ was greater in slower heart rates than in faster heart rates. The rate-dependent increase of I_KAS suggests that I_KAS is particularly important during bradycardia to maintain repolarization reserve. I_KAS blockade might increase the arrhythmic risk in women with bradycardia.

Study limitations

Our findings imply that I_KAS is activated in female but not in male ventricles during diLQTS. A possible contributing factor is that the subtype-2 SK channel protein expression was significantly higher in female than male rabbit ventricles.¹⁴ Furthermore, I_Ca,L is approximately 30% higher in female than male rabbit ventricles.²⁴ The increased I_Ca,L could facilitate the activation of the I_KAS.³⁴ A limitation of the present study is that we did not directly measure the I_Ca,L in males and females to test the latter hypothesis. Apamin does not block any known major cardiac potassium currents.³⁵ However, because of molecular diversity of potassium channel genes in the myocardium,³⁶ the specificity of apamin cannot be determined until all cardiac potassium channel genes are completely characterized.

Conclusions

We conclude that I_KAS is abundantly increased in female but not in male ventricles with diLQTS. Increased I_KAS helps preserve the repolarization reserve in female ventricles treated with I_Ks and I_Kr blockers or I_NaL activators.