Ventricular hypertrophy amplifies transmural dispersion of repolarization by preferentially increasing the late sodium current in endocardium.

BACKGROUND: The late sodium current (INa-L) contributes importantly to rate-dependent change in action potential duration (APD) and transmural dispersion of repolarization (TDR). However, little is known about the mechanisms of increased APD rate-dependence and amplified TDR in left ventricular hypertrophy (LVH) and failure. The purpose of this study was to investigate the role of INa-L in rate-adaptation of transmural APD heterogeneity. METHODS: APD, its rate-dependence and INa-L current were examined in myocytes isolated from the endocardium and epicardium of the control and LVH rabbits. AP was recorded using the standard microelectrode technique, and INa-L was recorded using the whole-cell patch clamp technique. RESULTS: Early afterdepolarizations (EADs) were frequently recorded in the isolated myocytes of the LVH rabbits but not in those of controls. LVH prolonged APD more significantly in the endocardial myocytes than in the epicardium (31.7±3.4 vs. 21.6±1.5% n=6, p<0.05), leading to a marked increase in TDR. LVH endocardial myocytes exhibited a greater rate-dependent change in APD compared to the epicardial myocytes. INa-L densities were significantly increased in both LVH endocardium and epicardium. However, LVH increased the INa-L density preferentially in the endocardial myocytes compared to the epicardial myocytes (54.5±4.8% vs. 39.2±3.3%, n=6, p<0.05). CONCLUSIONS: Our results demonstrate that LVH increased the INa-L preferentially in the endocardium over the epicardium, which contributes importantly to the stronger rate-dependent change in repolarization and longer APD in the endocardium. This results in an amplified TDR capable of initiating EAD and ventricular arrhythmias.

Wenxin Keli suppresses ventricular triggered arrhythmias via selective inhibition of late sodium current.

BACKGROUND: Wenxin Keli is a popular Chinese herb extract that approximately five million Asians are currently taking for the treatment of a variety of ventricular arrhythmias. However, its electrophysiological mechanisms remain poorly understood. METHODS AND RESULTS: The concentration-dependent electrophysiological effects of Wenxin Keli were evaluated in the isolated rabbit left ventricular myocytes and wedge preparation. Wenxin Keli selectively inhibited late sodium current (INa) with an IC50 of 3.8 ± 0.4 mg/mL, which was significantly lower than the IC50 of 10.6 ± 0.9 mg/mL (n = 6, P < 0.05) for the fast INa. Wenxin Keli produced a small but statistically significant QT prolongation at 0.3 mg/mL, but shortened the QT and Tp-e interval at concentrations ≥ 1 mg/mL. Wenxin Keli increased QRS duration by 10.1% from 34.8 ± 1.0 ms to 38.3 ± 1.1 ms (n = 6, P < 0.01) at 3 mg/mL at a basic cycle length of 2,000 ms. However, its effect on the QRS duration exhibited weak use-dependency, that is, QRS remained less changed at increased pacing rates than other classic sodium channel blockers, such as flecainide, quinidine, and lidocaine. On the other hand, Wenxin Keli at 1-3 mg/mL markedly reduced dofetilide-induced QT and Tp-e prolongation by attenuation of its reverse use-dependence and abolished dofetilide-induced early afterdepolarization (EAD) in four of four left ventricular wedge preparations. It also suppressed digoxin-induced delayed after depolarization (DAD) and ventricular tachycardias without changing the positive staircase pattern in contractility at 1-3 mg/mL in a separate experimental series (four of four). CONCLUSIONS: Wenxin Keli suppressed EADs, DADs, and triggered ventricular arrhythmias via selective inhibition of late INa.

Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes.

HBI-3000 (sulcardine sulfate) has been shown to suppress various ventricular arrhythmias in animal models. The electrophysiological properties of HBI-3000 were investigated using standard microelectrode and patch-clamp techniques in single human ventricular myocytes. HBI-3000 led to concentration-dependent suppression of dofetilide-induced early afterdepolarizations in single nonfailing human ventricular myocytes and early afterdepolarizations seen in failing ventricular myocytes. The concentration-dependent prolongation of action potential duration (APD) by HBI-3000 was bell shaped with maximum response occurring around 10 µM. Interestingly, HBI-3000 at the concentration of 10 µM modestly prolonged the APD at all 3 basic cycle lengths. The slope of APD-cycle length curve of HBI-3000 was only slightly steeper than that of control (88.8 ± 7.7 ms/s vs. 78.9 ± 5.2 ms/s in control, n = 8, P > 0.05). HBI-3000 only showed a minimal use-dependent prolongation of the APD in human ventricular myocytes. HBI-3000 inhibited fast sodium current (INa-F), late sodium channel (INa-L), L-type calcium current (ICa-L), and rapidly activating delayed rectifier K current (IKr) in single human ventricular myocytes. The estimated half-maximal inhibitory concentration values of INa-F, INa-L, ICa-L, and IKr were 48.3 ± 3.8, 16.5 ± 1.4, 32.2 ± 2.9, and 22.7 ± 2.5 µM, respectively. The ion channel profile and electrophysiological properties of HBI-3000 are similar to those of ranolazine and chronic amiodarone (reduced INa-F, INa-L, ICa-L, and IKr). HBI-3000 may be a promising antiarrhythmic agent with low proarrhythmic risk.

Utility of Normalized TdP Score System in Drug Proarrhythmic Potential Assessment: A Blinded in vitro Study of CiPA Drugs.

Drugs that prolong QT may cause torsade de pointes (TdP). However, translation of nonclinical assessment of QT prolongation or hERG channel, targeted by QT-prolonging drugs, into clinical TdP risk has been insufficient to date. In this blinded study, we confirmed the utility of a Normalized TdP Score System in predicting drug-induced TdP risks among 34 drugs, including 28 with low, intermediate, and high TdP risks under the Comprehensive In Vitro Proarrhythmia Assay (CiPA) initiative plus six compounds with names blinded to the investigators, using the rabbit ventricular wedge assay. Concentration-dependent TdP scores were determined by drug-induced changes in QT, Tp-e , and proarrhythmias. Disclosure of the names and testing concentrations was made after completion of the experiments and report to the sponsors. Drugs' normalized TdP scores were calculated thereafter based on their respective free clinical maximum concentration (Cmax ). Drugs' normalized TdP scores were calculated and ranked for 33 drugs, excluding 1 investigational drug, and the TdP risks of the 28 CiPA drugs were correctly distinguished according to their respective categories of low, intermediate, and high TdP risks under the CiPA initiative. Accordingly, we are able to propose the cutoff values of the normalized TdP scores at 1 × Cmax : ≤ 0, > 0 to < 0.65 and ≥ 0.65, respectively, for low, intermediate, and high risk. This blinded study supports utility of our Normalized TdP Score System in predicting drug-induced TdP risks in 33 drugs, including 28 used for characterization of other assays under the CiPA initiative. However, these results need to be replicated in other laboratories.

[Effects of chronic amiodarone therapy on L-type calcium current recovery and action potential duration of rabbit ventricular myocytes].

OBJECTIVE: To investigate the effects of chronic amiodarone therapy on L-type calcium current recovery and action potential duration of rabbit ventricular myocytes. METHODS: Healthy rabbits (1.6-1.8 kg) were treated with amiodarone (80 mg x kg(-1) x d(-1)) for four weeks. Action potential duration (APD) was recorded under isolated arterially perfused left ventricular wedge preparation, then single myocytes were isolated using enzyme digestion. L-type calcium current recovery (time constant, tau) were determined by fitting data with monoexponential. Tau/APD90 were compared in cells treated with saline, amiodarone and sotalol (3 x 10(-5) mmol/L). RESULTS: In chronic amiodarone treated myocytes, tau [(164 +/- 8) ms vs. (98 +/- 8) ms, P<0.05], APD90 [(321 +/- 12) ms vs. (220 +/- 10) ms, P<0.05] and tau/APD90 (0.51 +/- 0.03 vs. 0.44 +/- 0.03, P<0.05) were significantly increased than those in control myocytes. Sotalol significantly increased tau [(128 +/- 7) ms vs. (98 +/- 8) ms, P<0.05] and ADP90 [(405 +/- 13) ms vs. (220 +/- 10) ms, P<0.05] while reduced the tau/APD90 (0.32 +/- 0.05 vs. 0.44 +/- 0.03, P<0.05) compared to control myocytes. CONCLUSION: The differential effect of amiodarone and sotalol on ventricular myocytes tau/APD90 ratio might be responsible for the safety profile of these two drugs.

L-type calcium current recovery versus ventricular repolarization: preserved membrane-stabilizing mechanism for different QT intervals across species.

BACKGROUND: Long QT syndrome is associated with early after-depolarization (EAD) that may result in torsade de pointes (TdP). Interestingly, the corrected QT interval seems to be proportional to body mass across species under physiologic conditions. OBJECTIVE: The purpose of this study was to test whether recovery of L-type calcium current (I(Ca,L)), the primary charge carrier for EADs, from its inactivated state matches ventricular repolarization time and whether impairment of this relationship leads to development of EAD and TdP. METHODS: Transmembrane action potentials from the epicardium, endocardium, or subendocardium were recorded simultaneously with a transmural ECG in arterially perfused left ventricular wedges isolated from cow, dog, rabbit, and guinea pig hearts. I(Ca,L) recovery was examined using action potential stimulation in isolated left ventricular myocytes. RESULTS: The ventricular repolarization time (action potential duration at 90% repolarization [APD(90)]), ranging from 194.7 +/- 1.8 ms in guinea pig to 370.2 +/- 9.9 ms in cows, was linearly related to the thickness of the left ventricular wall among the species studied. The time constants (tau) of I(Ca,L) recovery were proportional to APD(90), making the ratios of tau to APD(90) fall into a relatively narrow range among these species despite markedly different ventricular repolarization time. Drugs with risk for TdP in humans were shown to impair this intrinsic balance by either prolongation of the repolarization time and/or acceleration of I(Ca,L) recovery, leading to the appearance of EADs capable of initiating TdP. CONCLUSION: An adequate balance between I(Ca,L) recovery and ventricular repolarization serves as a "physiologic stabilizer" of ventricular action potentials in repolarization phases.

L-type calcium current reactivation contributes to arrhythmogenesis associated with action potential triangulation.

INTRODUCTION: The morphology of the mammalian cardiac action potential (AP) is an important factor in the susceptibility to drug-induced early afterdepolarizations (EADs) that may initiate torsade de pointes (TdP). AP triangulation has been shown to be an important predictor of drug-induced TdP. METHODS AND RESULTS: APs from guinea pig and rabbit left ventricular single myocytes were recorded using a microelectrode-recording technique. I(Ca-L) currents were recorded in ventricular myocytes of guinea pig and rabbit using patch-clamping technique. At a stimulus frequency of 0.5 Hz, guinea pig ventricular myocytes displayed a square-like AP, whereas rabbit ventricular myocytes exhibited a triangle-like AP. Dofetilide-induced EADs were observed only in rabbit ventricular myocytes. Under the guinea pig AP clamping condition, the normalized I(Ca-L) instant reactivation currents in guinea pig and rabbit myocytes at voltages of -40 mV were 0.13 +/- 0.01 and 0.14 +/- 0.01, respectively. However, when rabbit AP served as the first clamping voltage, the normalized I(Ca-L) reactivation currents at -40 mV in guinea pig and rabbit myocytes were 0.20 +/- 0.01, 0.21 +/- 0.01, respectively, indicating that the I(Ca-L) recovery from inactivation in the rabbit triangular AP condition was significantly faster than in the guinea pig square AP condition. Comparison of the voltage clamp using the triangular waveform with the square waveform further confirmed that triangulation accelerates I(Ca-L) recovery from inactivation. CONCLUSIONS: In rabbit ventricular myocardium, AP triangulation accelerates I(Ca-L) channel recovery from inactivation, leading to instability of the cell membrane potential during repolarization, which is capable of initiating TdP.

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias.

BACKGROUND: The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP. METHODS AND RESULTS: Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max). CONCLUSIONS: Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.

How to determine cardiac ion channels targeted by drugs using the isolated rabbit ventricular wedge model.

INTRODUCTION: The rabbit left ventricular wedge (RLVW) has been demonstrated as a highly sensitive and specific preclinical model in assessing drug-induced QT prolongation and proarrhythmias. However, there is a need to determine drugs' cardiac ion channel profiles beyond QT measurement. In this study, we present an approach to determine cardiac ion channels targeted by drugs with analyzing a few key ECG parameters plus a contractility parameter obtained from the RLVW. METHODS: The RLVW assay was used for testing 18 drugs with well-known ion channel profiles. A transmural ECG and isometric contractility were recorded. Five parameters including QRS, QT, Tp-e/QT ratio, QT-BCL slope and the positive staircase response of contractility were analyzed. RESULTS: There were distinguished drug-induced ECG and contractility changes from which targeted cardiac ion channels by drugs could be determined. Inhibition of sodium channel resulted in rate-dependent QRS widening, QT and Tp-e shortening and a reduced QT-BCL slope. Although both IKr and IKs blockers prolonged QT interval, IKr blockers but not IKs increased Tp-e/QT ratio. Both potassium channel openers and calcium channel blockers markedly shortened QT and Tp-e intervals, but only calcium channel blockers could reverse the positive staircase response of contractility. DISCUSSION: The results in the present study are correlated closely to the drugs' well-known clinical profiles. This indicates that the RLVW assay with an adequate experimental protocol plus analysis of 5 key parameters is highly valuable in preclinical assessment of drug candidates for their detailed ion channel activities, proarrhythmic risks and other adverse effects. The limitations of the RLVW assay are also addressed.

Differentiating electrophysiological effects and cardiac safety of drugs based on the electrocardiogram: a blinded validation.

BACKGROUND: The ventricular components (QRS and QT) on the electrocardiogram (ECG) depend on the properties of ventricular action potentials that can be modulated by drugs via specific ion channels. However, the correlation of ECG ventricular waveforms with underlying ion actions is not well established and has been extensively debated. OBJECTIVE: To conduct a blinded in vitro assessment of the ionic mechanisms for drug-induced ECG changes. METHODS AND RESULTS: Fourteen cardiac and noncardiac drugs with known effects on cardiac ion channels were selected by the study sponsor, and were tested in the rabbit left ventricular wedge preparation with recording of the ECG and contractility. The investigators who performed the experiments and analyzed the data were blinded to names, concentrations, and molecular weights of the drugs. The compounds were prepared by the sponsor and sent to the investigators as 56 stock solutions. The effects of I(Kr), I(Ks), I(Ca,L), I(Na) blocker, and I(KATP) opener on QRS, QT, and T(p-e), were evaluated. Disclosure of the names and concentrations after completion of the study revealed that there were highly correlated ECG changes with underlying ionic mechanisms and proarrhythmic potential of drugs that, respectively, target I(Kr), I(Ks), I(Ca,L), I(Na), and I(KATP). Among ECG parameters, T(p-e) was more useful in differentiating drugs' actions. CONCLUSIONS: Specific electrophysiological action and the consequent proarrhythmic potential of a drug can be accurately determined by analysis of drug-induced changes in ECG in the rabbit left ventricular wedge preparation. Change in T(p-e) provides the most relevant information.

Contribution of late sodium current (I(Na-L)) to rate adaptation of ventricular repolarization and reverse use-dependence of QT-prolonging agents.

BACKGROUND: Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization. OBJECTIVE: The purpose of this study was to examine the role of the late sodium current (I(Na-L)) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents. METHODS: The effects of I(Na-L) blockade, I(Na-L) enhancement, I(Kr) blockade, and changes in extracellular potassium concentration ([K(+)](o)) on rate adaptation of the QT interval and action potential duration (APD) were examined in isolated rabbit ventricular wedges and single myocytes. Rate dependence of I(Na-L), delayed rectifier potassium current (I(K)), and L-type calcium current (I(Ca)) was determined using a whole-cell, voltage clamp technique. RESULTS: At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when [K(+)](o) remained constant. The rate dependence of APD was significantly enhanced by reduction of [K(+)](o) from 4 to 1 mM or by I(Na-L) enhancement but was markedly blunted by the selective sodium channel blocker tetrodotoxin. The I(Kr) blocker dofetilide (3 nM) amplified the QT to basic cycle length slope (71.2 ± 13.1 ms/s vs 35.1 ± 8.8 ms/s in control, n = 4, P <.05). This reverse use-dependence was abolished by tetrodotoxin at 5 µM (11.4 ± 4.3 ms/s, n = 4, P <.01). There were no significant differences in I(Ca) or I(K) over the range of basic cycle lengths from 2,000 to 500 ms. However, I(Na-L) exhibited a significant rate-dependent reduction. CONCLUSION: I(Na-L) is sensitive to rate change due to its slow inactivation and recovery kinetics and plays a central role in the rate dependence of APD/QT and in the reverse use-dependence of select APD/QT-prolonging agents.

Calcium-activated chloride current contributes to action potential alternations in left ventricular hypertrophy rabbit.

T-wave alternans, characterized by a beat-to-beat change in T-wave morphology, amplitude, and/or polarity on the ECG, often heralds the development of lethal ventricular arrhythmias in patients with left ventricular hypertrophy (LVH). The aim of our study was to examine the ionic basis for a beat-to-beat change in ventricular repolarization in the setting of LVH. Transmembrane action potentials (APs) from epicardium and endocardium were recorded simultaneously, together with transmural ECG and contraction force, in arterially perfused rabbit left ventricular wedge preparation. APs and Ca(2+)-activated chloride current (I(Cl,Ca)) were recorded from left ventricular myocytes isolated from normal rabbits and those with renovascular LVH using the standard microelectrode and whole cell patch-clamping techniques, respectively. In the LVH rabbits, a significant beat-to-beat change in endocardial AP duration (APD) created beat-to-beat alteration in transmural voltage gradient that manifested as T-wave alternans on the ECG. Interestingly, contraction force alternated in an opposite phase ("out of phase") with APD. In the single myocytes of LVH rabbits, a significant beat-to-beat change in APD was also observed in both left ventricular endocardial and epicardial myocytes at various pacing rates. APD alternans was suppressed by adding 1 microM ryanodine, 100 microM 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), and 100 microM 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid (SITS). The density of the Ca(2+)-activated chloride currents (I(Cl,Ca)) in left ventricular myocytes was significantly greater in the LVH rabbits than in the normal group. Our data indicate that abnormal intracellular Ca(2+) fluctuation may exert a strong feedback on the membrane I(Cl,Ca), leading to a beat-to-beat change in the net repolarizing current that manifests as T-wave alternans on the ECG.

Assessment of the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide in experimental models of torsades de pointes.

BACKGROUND: This study examined the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide. METHODS AND RESULTS: The electrophysiological and proarrhythmic effects of AZD7009 and dofetilide were assessed in the arterially perfused canine and rabbit left ventricular wedge preparation. The proarrhythmic potential of AZD7009, dofetilide, and azimilide was further assessed in the methoxamine-sensitized rabbit model of torsades de pointes (TdP) in vivo. AZD7009 lengthened the action potential duration (APD) and the QT interval in a bell-shaped manner (15.9 +/- 1.3% in canine wedge and 46.1 +/- 2.9% in rabbit wedge) occurring at 3 and 1 microM. In contrast, dofetilide did not show the bell-shaped concentration response and the QT interval was lengthened more extensively (27.7 +/- 1.6% and 100.8 +/- 10.0%). Furthermore, whereas dofetilide prolonged the midmyocardial and endocardial APD predominantly, resulting in an increased transmural dispersion of repolarization (TDR), AZD7009 prolonged the APD more homogenously in all cell layers. At 1 microM, AZD7009 produced phase 2 early afterdepolarizations (EADs) in 1/4 rabbit preparations but without ventricular R-on-T extrasystoles or TdP. In contrast, starting at 0.03 microM, dofetilide-induced EADs, R-on-T extrasystoles and TdP in 6/6, 5/6, and 4/6 preparations. Following intravenous infusion of AZD7009 (210 nmol/kg/minute), dofetilide (2 nmol/kg/minute) or azimilide (3.33 micromol/kg/minute), TdP was induced in 0/8, 5/8, and 5/8 rabbits (P = 0.026 vs AZD7009), respectively. In 5/5 rabbits, AZD7009 promptly suppressed TdP induced by dofetilide. CONCLUSIONS: In animal models of TdP, AZD7009 delays ventricular repolarization in a self-limited way associated with a low risk of repolarization-related proarrhythmia.

Electrophysiologic effects of SB-237376: a new antiarrhythmic compound with dual potassium and calcium channel blocking action.

Combined potassium and calcium channel blocking activities are suggested to be the basis for antiarrhythmic efficacy with low proarrhythmic risk. The electrophysiologic effects of SB-237376 were investigated in single myocytes and arterially perfused wedge preparations of canine or rabbit left ventricles. The concentration-dependent prolongation of action potential duration (APD) and QT interval by SB-237376 was bell-shaped and the maximum response occurred at 1-3 microM SB-237376 inhibited rapidly activating delayed rectifier K current (I(Kr) ) with an IC50 of 0.42 microM and use-dependently blocked L-type Ca current (I (Ca,L) ) at high concentrations. The SB-237376 (3 microM) induced phase-2 early afterdepolarizations (EADs) in five of six rabbit wedge preparations but none of six canine wedge preparations. This is probably due to larger increases of APD, QT interval, and transmural dispersion of repolarization (TDR) in rabbits than dogs. Based on the drug effects on QT interval, TDR, and EAD in rabbit ventricular wedge preparations, a scoring system predicted lower proarrhythmic risk for SB-237376 than for dl-sotalol, a specific I blocker. In conclusion, SB-237376 increases APD, QT interval, and TDR mainly by I (Kr) inhibition. These effects are self-limited due to SB-237376-induced I(Ca,L) blockade at high concentrations, which may explain its lower proarrhythmic risk than dl-sotalol.

Increasing I(Ks) corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy.

Excessive action potential (AP) prolongation and early afterdepolarizations (EAD) are triggers of malignant ventricular arrhythmias. A slowly activating delayed rectifier K+ current (I(Ks)) is important for repolarization of ventricular AP. We examined the effects of I(Ks) activation by a new benzodiazepine (L3) on the AP of control, dofetilide-treated, and hypertrophied rabbit ventricular myocytes. In both control and hypertrophied myocytes, L3 activated I(Ks) via a negative shift in the voltage dependence of activation and a slowing of deactivation. L3 had no effect on L-type Ca(2+) current or other cardiac K+ currents tested. L3 shortened AP of control, dofetilide-treated, and hypertrophied myocytes more at 0.5 than 2 Hz. Selective activation of I(Ks) by L3 attenuates prolonged AP and eliminated EAD induced by rapidly activating delayed rectifier K+ current inhibition in control myocytes at 0.5 Hz and spontaneous EAD in hypertrophied myocytes at 0.2 Hz. Pharmacological activation of I(Ks) is a promising new strategy to suppress arrhythmias resulting from excessive AP prolongation in patients with certain forms of long QT syndrome or cardiac hypertrophy and failure.