Downregulation of Delayed Rectifier K+ Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes
Background—Acquired QT prolongation enhances the susceptibility to torsades de pointes (TdP). Clinical and experimental studies indicate ventricular action potential prolongation, increased regional dispersion of repolarization, and early afterdepolarizations as underlying factors. We examined whether K+-current alterations contribute to these proarrhythmic responses in an animal model of TdP: the dog with chronic complete atrioventricular block (AVB) and biventricular hypertrophy.
Methods and Results—The whole-cell K+ currents ITO1, IK1, IKr, and IKs were recorded in left (LV) and right (RV) ventricular midmyocardial cells from dogs with 9±1 weeks of AVB and controls with sinus rhythm. ITO1 density and kinetics and IK1 outward current were not different between chronic AVB and control cells. IKr had a similar voltage dependence of activation and time course of deactivation in chronic AVB and control. IKr density was similar in LV myocytes but smaller in RV myocytes (−45%) of chronic AVB versus control. For IKs, voltage-dependence of activation and time course of deactivation were similar in chronic AVB and control. However, IKs densities of LV (−50%) and RV (−55%) cells were significantly lower in chronic AVB than control.
Conclusions—Significant downregulation of delayed rectifier K+ current occurs in both ventricles of the dog with chronic AVB. Acquired TdP in this animal model with biventricular hypertrophy is thus related to intrinsic repolarization defects.
Acquired QT prolongation is a common ECG finding in heart disease, but it can also be present as a primary derangement in the absence of structural abnormalities or drugs.1 It is regarded as 1 of the risk factors of ventricular arrhythmias and sudden cardiac death.1 Clinical studies on the acquired long-QT syndromes indicate an enhanced susceptibility to polymorphic ventricular tachycardias, notably torsades de pointes (TdP).2 Unlike for the congenital long-QT syndromes, in which distinctive defects of ion-channel function in myocardial cells cause delayed repolarization,3 the ionic basis of acquired QT prolongation not related to drugs is poorly understood.
In recent years, we have used the dog with chronic complete atrioventricular block (AVB) as a model for the study of TdP.4 QT intervals and ventricular endocardial monophasic action potential durations (APDs) are much longer than expected on the basis of the bradycardia alone and point toward a disturbed ventricular repolarization,5 corresponding to clinical findings on acquired AVB.6 Anesthetized dogs show an enhanced susceptibility to acquired TdP after several weeks of AVB duration, which is associated with the development of increased interventricular dispersion of repolarization and early afterdepolarizations.5 Electrical remodeling is accompanied by the development of biventricular hypertrophy.5 7 Approximately 15% of the chronic-AVB dog population dies suddenly, often during circumstances of excitement (eg, during feeding or ambulation). Transmembrane action potential recordings in isolated myocytes indicate that the prolonged ventricular repolarization of chronic AVB is an intrinsic abnormality, which is amplified by class III antiarrhythmic drugs.7 In addition, action potential prolongation is more pronounced in left (LV) than right (RV) ventricular myocytes, supporting the in vivo finding of increased regional dispersion of repolarization.
In our search for the ionic mechanisms of electrical remodeling and proarrhythmia in dogs with chronic AVB, we investigated the possible contribution of K+-current alterations to ventricular action potential prolongation and increased regional dispersion of repolarization. To this end, we measured whole-cell K+ currents in midmyocardial cells of animals with documented TdP and directly compared LV and RV myocytes in the same hearts.
Animal handling was in accordance with the Dutch Law on Animal Experimentation and the European Directive for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes (86/609/EU). The experiments were approved by the Committee for Experiments on Animals of our university.
In Vivo Studies
Twenty-four adult mongrel dogs of either sex and weighing between 22 and 37 kg were used for the experiments. For a complete description of the creation of AVB (ndogs=15), the perioperative care, and the definition of TdP, we refer to a previous publication.5 Anesthesia was induced by sodium pentobarbital 20 mg/kg IV; subsequently, the dogs were ventilated with a mixture of oxygen, nitrous oxide, and halothane (vapor concentration 0.5% to 1.0%). To test the induction of TdP, the class III agent almokalant (0.12 mg · kg−1 · 10 min−1 IV) was used.8 These experiments were performed during anesthesia ≥1 week before the dogs were euthanized for cell isolation.
Anesthetized chronic-AVB (9±1 weeks) and control dogs (with sinus rhythm; ndogs=9) received intravenous heparin on thoracotomy. The hearts were quickly excised and washed in cold cardioplegic solution. Heart weights of chronic-AVB dogs were significantly greater than those of control dogs: 306±12 versus 220±8 g, respectively (P<0.05). When corrected for body weight, this difference remained significant: 11.6±0.3 versus 8.6±0.3 g/kg (P<0.05).
To isolate single LV and RV midmyocardial cells simultaneously, the left anterior descending and right coronary arteries were cannulated. The isolation procedure was the same as recently described.9 Whole-cell currents were measured with patch pipettes (borosilicate glass) with resistances of 1.0 to 3.0 MΩ when filled with internal solution. Experiments were performed at 37±0.5°C. Cell capacitance was measured by hyperpolarizing steps from a holding potential of −60 mV. In the LV myocytes, average values were 216±9 pF (nChronic AVB=35) versus 227±11 pF (nControl=27; P=NS). In RV myocytes, capacitances were 221±12 pF (nChronic AVB=28) versus 228±11 pF (nControl=29; P=NS). Length times width of these myocytes was, on average, LVChronic AVB=186×36 μm versus LVControl=193×33 μm (P=NS); RVChronic AVB=204×35 μm versus RVControl=192×36 μm (P=NS). Compared with a large population study indicating hypertrophy of the individual myocytes in chronic AVB,7 the cells used in this study represent the larger bin size.
For the measurements of ITO1, we used a holding potential of −70 mV. Na+ current was inactivated by a 10-ms prepulse to −40 mV. L-type Ca2+ current was inhibited with nifedipine 5 μmol/L. ITO1 amplitudes were measured as peak amplitudes minus steady-state values at the end of depolarizations. For the measurements of IK1, IKr, and IKs, the holding potential was set at −50 mV. IKr and IKs were measured as the peak tail currents on repolarization. For IKr, we used the tail current sensitive to 2 μmol/L almokalant (specific IKr blocker) on repolarization to the holding potential of −50 mV. For IKs, almokalant-resistant tail currents were used.
The standard buffer solution used for the experiments contained (in mmol/L) NaCl 145, KCl 4.0, CaCl2 1.8, MgCl2 1.0, NaH2PO4 1.0, glucose 11, and HEPES 10; pH was adjusted to 7.4 with NaOH at 37°C. The patch-pipette solution contained (in mmol/L) potassium aspartate 125, KCl 20, MgCl2 1.0, MgATP 5, HEPES 5, and EGTA 10; pH was adjusted to 7.2 with KOH.
The data are expressed as mean±SEM. Intergroup comparisons were made with ANOVA (for multiple comparisons) and with Student’s t test for unpaired and paired data groups, after testing for the normality of distribution. Differences were considered significant if P<0.05.
Acquired QT Prolongation and Susceptibility to TdP in the Study Group
In vivo electrophysiological recordings revealed significant QT prolongations in all chronic-AVB dogs. On average, the QT time (measured in ECG lead II) increased from 241±9 ms at sinus rhythm to 316±14 ms on creation of AVB (P<0.05) and to 374±15 ms in the chronic phase at 9±1 weeks thereafter (P<0.05 versus acute AVB). Corresponding RR intervals measured 488±24, 1479±142 (P<0.05), and 1381±80 ms, respectively (P=NS versus acute AVB). An example of these 3 states in the same animal is shown in Figure 1⇓. From acute to chronic AVB, QRS widths did not change significantly (see Figure 1⇓). However, broad-based T waves developed early after the QRS complex. In 13 of the 15 animals with chronic AVB, LV and RV endocardial monophasic action potentials were recorded at the idioventricular cycle length. In all 13, the LV APD was longer than the RV APD, on average 419±25 versus 354±19 ms (P<0.05), yielding an interventricular difference of 65±12 ms (in line with previous results).5 8 In 6 of 7 animals tested with almokalant, TdP occurred.
In the sinus rhythm control group used for comparisons in the cellular investigations, the RR interval was 421±22 ms, with a QT time of 231±6 ms (both P=NS versus preoperative sinus rhythm in the chronic-AVB group).
ITO1 Is Not Altered in Chronic AVB
The activation of ITO1 was tested during steps of −40 to +70 mV. In all 4 cell types, the current activated at a test voltage (Vtest) ≥ −20 mV (Figure 2⇓). There was no difference in ITO1 density between chronic AVB and control in either ventricle, and the normal interventricular difference9 was maintained. ITO1 was nearly completely inhibited by 5 mmol/L 4-aminopyridine in all 4 cell types. ITO1 inactivation during the 300-ms Vtest was best fitted with a single exponential function yielding similar time constants (range, 7 to 14 ms) in chronic AVB and control. As illustrated in Figures 3A⇓ and 3B⇓, voltage dependence of steady-state inactivation and time-dependent recovery from inactivation were not different between the cell types.
Properties of IK1
Figure 4⇓ shows typical recordings of IK1 in chronic-AVB and control myocytes, as well as current density-voltage relations at the end of Vtest of −140 to −20 mV in both LV and RV. The current was fully inhibited in K+-free superfusate (0 [K+]o; not shown). IK1 outward currents at Vtest positive to the K+ reversal potential were similar in chronic AVB and control. Only at very hyperpolarizing pulses in RV cells were current densities less negative in chronic AVB. There were no interventricular differences between chronic AVB and control.
Downregulation of IKs and IKr
To dissect the 2 components of the delayed rectifier K+ current at baseline, we applied a protocol in which, after a depolarization to +30 mV, repolarization was divided into 2 steps: to 0 mV for 4.5 seconds and then back to −50 mV (Figure 5⇓).10 Tail currents at the first repolarization step (to 0 mV) were insensitive to the IKr blocker almokalant (Figure 5⇓, left arrow in both panels), indicating that they were largely composed of deactivating IKs and largely devoid of IKr. Tail currents at the second repolarization step (to −50 mV) decreased significantly on almokalant administration, indicating the opposite: namely, that they were composed largely of deactivating IKr with a much smaller contribution of IKs than at 0 mV (Figure 5⇓, right arrow in both panels). From these data, it appeared that IKs was smaller in chronic-AVB than control myocytes: for LV, 0.19±0.02 versus 0.40±0.09 pA/pF, and for RV, 0.21±0.03 versus 0.51±0.08 pA/pF, respectively (both P<0.05). For the same comparison, IKr was similar in LV, 0.34±0.03 versus 0.42±0.05 pA/pF (P=NS), but smaller in RV myocytes, 0.34±0.02 versus 0.48±0.02 pA/pF, in chronic AVB versus control, respectively (P<0.05). To elaborate further on the contribution of IKs to total delayed rectifier K+ current, we performed envelope-of-tails tests at baseline and in the presence of almokalant. These experiments revealed that IKs made up a significant portion of the total current, even for depolarizations as short as 300 ms. However, contributions were much smaller in chronic-AVB than control cells (data not shown).
Voltage-dependent activation of IKs was evaluated from tail currents on repolarization to −25 mV in 0 [K+]o in the presence of almokalant. Examples of families of current traces and pooled data are given in Figure 6⇓. There was no saturation of tail-current amplitudes. Voltage-dependence of IKs activation was similar in the 4 cell types. However, IKs density was significantly smaller in chronic AVB than in control. Overall, tail currents were reduced by 50% in LV and by 55% in RV myocytes (ie, average percentage of tail-current differences for the conditioning voltages indicated by asterisks [P<0.05] in Figure 6⇓). Whereas interventricular differences of IKs exist in normal canine hearts (Figure 6⇓),9 because of the small current amplitudes in chronic AVB, no differences could be discerned. Voltage dependence of IKs deactivation was not different between chronic AVB and control. Likewise, the time course of deactivation proved similarly fast in all 4 cell types.
IKr was quantified as the almokalant-sensitive tail-current portion measured by digital subtraction on single-step repolarizations to −50 mV in 4.0 mmol/L [K+]o (Figure 7⇓). Activation occurred after depolarizations ≥ −10 mV and showed saturation at conditioning voltages (Vcond) > +20 mV. Boltzmann fits to the data revealed half points of 0.3±1.1 and −1.1±3.1 mV in LV and of −2.5±2.1 and 1.1±1.7 mV in RV for chronic AVB and control, respectively (both P=NS). Corresponding slope factors were 5.8±1.0 and 5.7±2.8 mV in LV and 5.5±1.7 and 5.5±1.5 mV in RV (both P=NS). IKr density was similar in LV myocytes but smaller in RV myocytes of chronic AVB versus control (reduction of 45%; Figure 7⇓). There were no interventricular differences. In both ventricles, voltage dependence and time course of IKr deactivation were similar for chronic AVB and control.
We have demonstrated that acquired QT prolongation in dogs with chronic AVB and documented TdP is associated with significant reductions of IKs in the LV and RV. In the RV of these animals, IKr is also downregulated. Of the other K+ currents, ITO1 is unaltered, and so is IK1 in the physiological range of voltages.
Reproducible Induction of TdP in Chronic AVB
The dog with chronic AVB is a very suitable large-animal model for the study of TdP. In vivo experiments indicate the critical importance of regional dispersion of repolarization, early afterdepolarizations, and multiple ectopic beats for the initiation of TdP.8 Interventricular dispersion during arrhythmogenesis probably reflects the existence of significant repolarization gradients in closely adjacent areas, possibly the septum.11 Our most recent results demonstrate that electrical remodeling of the myocardium is the substrate for the enhanced susceptibility to TdP.5 7 The in vivo part of the present study confirmed that the dogs used for cellular experiments were a representative population with significant QT prolongation and a low threshold for TdP.
Contribution of Reduced IKs and IKr to Action Potential Prolongation
In a previous study, at serial testing in vivo, it was found that chronic (versus acute) AVB leads to increases of endocardial monophasic APDs of ≈ +30% in the LV and +20% in the RV.5 On the basis of our recent microelectrode study,7 the relative increase of the APD in chronic-AVB myocytes is 10% to 30% in the LV (depending on the pacing cycle length) and maximally 10% in the RV under baseline conditions. In these cells, the class III agents almokalant and d-sotalol cause marked action potential prolongation and the occurrence of early afterdepolarizations, which uncovers the importance of IKr for ventricular repolarization in chronic AVB. Whether a 50% to 55% reduction of IKs can account for the action potential characteristics in LV and RV can only be answered indirectly. In a recent study on canine LV midmyocardial tissue, the IKs blocker chromanol 293B at 30 μmol/L increases the APD from 284±13 to 357±25 ms at a pacing cycle length of 2000 ms (+25%).12 This concentration reduces IKs by ≈80% in guinea pig myocytes.13 In a theoretical model of the normal human ventricular action potential,14 adapted from the Luo-Rudy model,15 50% inhibition of IKs increases the APD from 374 to ≈425 ms (+15%; Figure⇑ 12 of Reference 14 ). Thus, at rough approximation, the 50% to 55% decrease of IKs observed in our present study could account for a 10% to 30% action potential prolongation, at least in the LV. The RV exhibits only minor action potential alterations under baseline conditions, despite its additional downregulation of IKr (−45%). To explain why the alterations are less pronounced in the RV than the LV, we have to consider that the basic determinants of repolarization are different between the 2 ventricles. In the normal canine heart, ITO1 and IKs are much larger in the RV, indicating a larger repolarization reserve.9 In chronic AVB, the difference in ITO1 is maintained, and it is likely that other membrane currents and/or their remodeling are also responsible for the amplification of interventricular action potential inhomogeneities. We are currently investigating 2 candidates: the L-type Ca2+ current and Na+-Ca2+ exchange.16
Ionic Remodeling in Chronic AVB
Cardiac function of dogs with AVB of 9 weeks’ duration is unimpaired, which is confirmed at the myocyte level.5 16 Most animals have an enhanced contractile performance at the imposed bradycardia and lack signs of heart failure. Significant growth responses (only of cell length) are observed in both RV (+23%) and LV (+13%) myocytes,7 whereas autopsy findings reveal increased RV and LV tissue weights.5 These data strongly support the contention that dogs with long-standing (weeks to months) AVB have a compensated form of biventricular hypertrophy.17
In many other animal models and in humans with cardiac hypertrophy or failure, downregulation of K+ currents has been implicated in (inhomogeneous) ventricular action potential prolongation18 and the increased risk of ventricular arrhythmias and sudden cardiac death.19 Reduction of ITO1 is probably most often observed in the spectrum of early compensated hypertrophy to terminal heart failure20 and has been linked to action potential prolongation.21 22 However, it has been questioned whether downregulation of this current alone can cause increased APDs in large mammals, including humans.14 ITO1 downregulation as the basis for action potential prolongation was also challenged by Antzelevitch and coworkers (eg, see Reference 23 ). Reduction of ITO1 is clearly absent in dogs with chronic AVB, which corresponds to the finding of marked notch amplitudes in midmyocardial action potentials (RV > LV).7 There have been only a few reports on the downregulation of delayed rectifier K+ current in cardiac hypertrophy induced by pressure overload in cats,24 25 but these investigations did not discriminate between IKr and IKs. Our data do make this distinction for the hypertrophied cells of dogs with chronic AVB and indicate that changes of these relatively small currents can have major impact on the course of repolarization, as noted before.26
The importance of IKr and IKs for normal human cardiac repolarization has been established in cellular electrophysiological studies,27 28 and the characteristics of both components resemble those found in the dog. Differential downregulation of RV and LV delayed rectifier K+ currents could possibly contribute to repolarization abnormalities and arrhythmogenesis in patients with (this or other forms of) cardiac hypertrophy or failure, which is also indicated in a recent modeling of the human ventricular action potential.14 Experimental data on the possible changes of IKr and IKs in human ventricular hypertrophy or failure are not yet available, but the importance of these currents can be underscored by the congenital long-QT syndromes.
The combined findings of an enhanced susceptibility to acquired TdP, the (supposed) adrenergic dependence of TdP, the typical T-wave patterns during prolonged QT intervals, and the reduction of IKs in the dog with chronic AVB closely resemble the clinical characteristics of the LQT1 or LQT5 form of the human congenital long-QT syndrome. Approaches to a basic electrophysiological and molecular understanding of QT prolongation and T-wave abnormalities in chronic AVB could be derived from information currently obtained in the long-QT syndrome.
Limitations of the Study
We found a differential baseline contribution and hypertrophy-related remodeling of K+ currents in the 2 ventricles of the chronic-AVB dog. Similar current alterations could affect the transmural layers of the LV free wall and/or the septum and thus increase local dispersion of repolarization, which would facilitate the induction of TdP. However, this was not investigated.
The studies on IKs were performed with the Ca2+ buffer EGTA in the pipette solution, and thus, Ca2+-modulated IKs was not recorded. In addition, the response of IKs to stimulation of protein kinase A was not evaluated. The important questions of Ca2+-dependent and protein kinase A–mediated (dys)function of IKs in chronic AVB are currently being addressed in ongoing studies.
Significant downregulation of delayed rectifier K+ current contributes to the repolarization abnormalities in the LV and RV of dogs with chronic AVB. The low functional expressions of IKs and IKr, in combination with the maintained interventricular difference in ITO1 and possibly other membrane currents, are responsible for the amplification of interventricular action potential inhomogeneities at control. The resultant increased regional dispersion of repolarization constitutes the substrate for an enhanced susceptibility to acquired TdP.
Dr Volders is supported by the Wynand M. Pon Foundation, Leusden, Netherlands. Dr Sipido is supported by the National Fund for Scientific Research, Belgium. The authors wish to thank Jérôme G.M. Jungschleger, MD, and Ferenc F. van der Hulst, BS, for helpful assistance.
- Received January 25, 1999.
- Revision received July 15, 1999.
- Accepted July 15, 1999.
- Copyright © 1999 by American Heart Association
Zipes DP, Wellens HJJ. Sudden cardiac death. Circulation.. 1998;98:2334–2351.
Roden DM, Lazzara R, Rosen M, Schwartz PJ, Towbin J, Vincent GM, the SADS Foundation Task Force on LQTS. Multiple mechanisms in the long-QT syndrome: current knowledge, gaps, and future directions. Circulation.. 1996;94:1996–2012.
Vos MA, Verduyn SC, Gorgels APM, Lipcsei GC, Wellens HJJ. Reproducible induction of early afterdepolarizations and torsade de pointes arrhythmias by d-sotalol and pacing in dogs with chronic atrioventricular block. Circulation.. 1995;91:864–872.
Vos MA, de Groot SHM, Verduyn SC, van der Zande J, Leunissen HDM, Cleutjens JPM, van Bilsen M, Daemen MJAP, Schreuder JJ, Allessie MA, Wellens HJJ. Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation.. 1998;98:1125–1135.
Volders PGA, Sipido KR, Vos MA, Kulcsár A, Verduyn SC, Wellens HJJ. Cellular basis of biventricular hypertrophy and arrhythmogenesis in dogs with chronic complete atrioventricular block and acquired torsade de pointes. Circulation.. 1998;98:1136–1147.
Verduyn SC, Vos MA, van der Zande J, Kulcsàr A, Wellens HJJ. Further observations to elucidate the role of interventricular dispersion of repolarization and early afterdepolarizations in the genesis of acquired torsade de pointes arrhythmias: a comparison between almokalant and d-sotalol using the dog as its own control. J Am Coll Cardiol.. 1997;30:1575–1584.
Volders PGA, Sipido KR, Carmeliet E, Spätjens RLHMG, Wellens HJJ, Vos MA. Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation.. 1999;99:206–210.
Carmeliet E. Voltage- and time-dependent block of the delayed K+ current in cardiac myocytes by dofetilide. J Pharmacol Exp Ther.. 1992;262:809–817.
van der Hulst FF, Vos MA, Leunissen HDM, Wellens HJJ. Transseptal dispersion in the dog with chronic complete atrioventricular block: distribution and frequency dependence. Eur Heart J. 1998;19(suppl):72. Abstract.
Shimizu W, Antzelevitch C. Cellular basis for the ECG features of the LQT1 form of the long-QT syndrome: effects of β-adrenergic agonists and antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation.. 1998;98:2314–2322.
Bosch RF, Gaspo R, Busch AE, Lang HJ, Li GR, Nattel S. Effects of the chromanol 293B, a selective blocker of the slow component of the delayed rectifier K+ current, on repolarization in human and guinea pig ventricular myocytes. Cardiovasc Res.. 1998;38:441–450.
Priebe L, Beuckelmann DJ. Simulation study of cellular electric properties in heart failure. Circ Res.. 1998;82:1206–1223.
Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential, I: simulations of ionic currents and concentration changes. Circ Res.. 1994;74:1071–1096.
Sipido KR, Volders PGA, de Groot SHMA, Vos MA. Enhanced cardiac contractile performance and sarcoplasmic reticulum Ca2+ release in dogs with chronic complete atrioventricular block. Circulation. 1998;98(suppl I):I-141–I-142. Abstract.
Tomaselli GF, Beuckelmann DJ, Calkins HG, Berger RD, Kessler PD, Lawrence JH, Kass D, Feldman AM, Marban E. Sudden cardiac death in heart failure: the role of abnormal repolarization. Circulation.. 1994;90:2534–2539.
Beuckelmann DJ, Näbauer M, Erdmann E. Alterations of K+ currents in isolated human ventricular myocytes from patients with terminal heart failure. Circ Res.. 1993;73:379–385.
Kääb S, Nuss HB, Chiamvimonvat N, O’Rourke B, Pak PH, Kass DA, Marban E, Tomaselli GF. Ionic mechanism of action potential prolongation in ventricular myocytes from dogs with pacing-induced heart failure. Circ Res.. 1996;78:262–273.
Litovsky SH, Antzelevitch C. Transient outward current prominent in canine ventricular epicardium but not endocardium. Circ Res.. 1988;62:116–126.
Kleiman RB, Houser SR. Outward currents in normal and hypertrophied feline ventricular myocytes. Am J Physiol.. 1989;256:H1450–H1461.
Furukawa T, Myerburg RJ, Furukawa N, Kimura S, Bassett AL. Metabolic inhibition of ICa,L and IK differs in feline left ventricular hypertrophy. Am J Physiol.. 1994;266:H1121–H1131.
Kass RS. Genetically induced reduction in small currents has major impact. Circulation.. 1997;96:1720–1721.
Li GR, Feng J, Yue L, Carrier M, Nattel S. Evidence for two components of delayed rectifier K+ current in human ventricular myocytes. Circ Res.. 1996;78:689–696.
Iost N, Virág L, Opincariu M, Szécsi J, Varró A, Papp JG. Fast and slow delayed rectifier potassium currents in undiseased human ventricular myocytes. Pacing Clin Electrophysiol. 1999;22(pt II):762. Abstract.