(Circulation. 1999;100:2455.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Downregulation of Delayed Rectifier K+ Currents in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsades de Pointes
From the Department of Cardiology (P.G.A.V., M.A.V., R.L.H.M.G.S., J.D.M.L., H.J.J.W.), Cardiovascular Research Institute Maastricht (E.C.), Maastricht University, the Netherlands, and the Laboratory of Experimental Cardiology, University of Leuven, Belgium (K.R.S.).
Correspondence to Paul G.A. Volders, MD, PhD, Department of Cardiology, Cardiovascular Research Institute Maastricht, Academic Hospital Maastricht, PO Box 5800, 6202 AZ, Maastricht, Netherlands. E-mail p.volders{at}cardio.azm.nl
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Abstract |
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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.
Key Words: electrophysiology • ventricles • torsades de pointes • myocytes • ions
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Introduction |
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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.
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Methods |
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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.
Cellular Experiments
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 M
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=186x36 µm versus
LVControl=193x33 µm (P=NS);
RVChronic AVB=204x35 µm versus
RVControl=192x36 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.
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Results |
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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.
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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.
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t) of 5 to 50 ms (5-ms increments),
60 to 180 ms (20-ms increments), and 2000 ms in a chronic-AVB LV
myocyte. Middle, Voltage-clamp protocol indicates prepulse to +60 mV
followed by Vtest to +60 mV at increasing
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.
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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).
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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.
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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.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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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
Clinical Perspectives
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.
Conclusions
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.
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Acknowledgments |
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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.
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  X. Qi, Y.-H. Yeh, D. Chartier, L. Xiao, Y. Tsuji, B. J.J.M. Brundel, I. Kodama, and S. Nattel The Calcium/Calmodulin/Kinase System and Arrhythmogenic Afterdepolarizations in Bradycardia-Related Acquired Long-QT Syndrome Circ Arrhythm Electrophysiol, June 1, 2009; 2(3): 295 - 304. [Abstract] [Full Text] [PDF]
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F. Suto, W. Zhu, A. Chan, and G. J. Gross IKr and IKs remodeling differentially affects QT interval prolongation and dynamic adaptation to heart rate acceleration in bradycardic rabbits Am J Physiol Heart Circ Physiol, April 1, 2007; 292(4): H1782 - H1788. [Abstract] [Full Text] [PDF]
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E. Schulze-Bahr Arrhythmia Predisposition: Between Rare Disease Paradigms and Common Ion Channel Gene Variants J. Am. Coll. Cardiol., October 27, 2006; 48(9_Suppl_A): A67 - A78. [Abstract] [Full Text] [PDF]
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M. Stengl, C. Ramakers, D. W. Donker, A. Nabar, A. V. Rybin, R. L.H.M.G. Spatjens, T. van der Nagel, W. K.W.H. Wodzig, K. R. Sipido, G. Antoons, et al. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted {beta}-adrenergic activation Cardiovasc Res, October 1, 2006; 72(1): 90 - 100. [Abstract] [Full Text] [PDF]
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Y. Tsuji, S. Zicha, X.-Y. Qi, I. Kodama, and S. Nattel Potassium Channel Subunit Remodeling in Rabbits Exposed to Long-Term Bradycardia or Tachycardia: Discrete Arrhythmogenic Consequences Related to Differential Delayed-Rectifier Changes Circulation, January 24, 2006; 113(3): 345 - 355. [Abstract] [Full Text] [PDF]
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N. Jost, L. Virag, M. Bitay, J. Takacs, C. Lengyel, P. Biliczki, Z. Nagy, G. Bogats, D. A. Lathrop, J. G. Papp, et al. Restricting Excessive Cardiac Action Potential and QT Prolongation: A Vital Role for IKs in Human Ventricular Muscle Circulation, September 6, 2005; 112(10): 1392 - 1399. [Abstract] [Full Text] [PDF]
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W. Dun and P. A. Boyden Diverse phenotypes of outward currents in cells that have survived in the 5-day-infarcted heart Am J Physiol Heart Circ Physiol, August 1, 2005; 289(2): H667 - H673. [Abstract] [Full Text] [PDF]
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J. Rose, A. A. Armoundas, Y. Tian, D. DiSilvestre, M. Burysek, V. Halperin, B. O'Rourke, D. A. Kass, E. Marban, and G. F. Tomaselli Molecular correlates of altered expression of potassium currents in failing rabbit myocardium Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2077 - H2087. [Abstract] [Full Text] [PDF]
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T. Aiba, W. Shimizu, M. Inagaki, T. Noda, S. Miyoshi, W.-G. Ding, D. P. Zankov, F. Toyoda, H. Matsuura, M. Horie, et al. Cellular and ionic mechanism for drug-induced long QT syndrome and effectiveness of verapamil J. Am. Coll. Cardiol., January 18, 2005; 45(2): 300 - 307. [Abstract] [Full Text] [PDF]
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C. Antzelevitch Cardiac repolarization. The long and short of it Europace, January 1, 2005; 7(s2): S3 - S9. [Abstract] [Full Text] [PDF]
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K. D. Schreiner, K. Kelemen, J. Zehelein, R. Becker, J. C. Senges, A. Bauer, F. Voss, P. Kraft, H. A. Katus, and W. Schoels Biventricular hypertrophy in dogs with chronic AV block: effects of cyclosporin A on morphology and electrophysiology Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2891 - H2898. [Abstract] [Full Text] [PDF]
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Y. Fukuda, S. Miyoshi, K. Tanimoto, K. Oota, K. Fujikura, M. Iwata, A. Baba, Y. Hagiwara, T. Yoshikawa, H. Mitamura, et al. Autoimmunity against the second extracellular loop of beta1-adrenergic receptors induces early afterdepolarization and decreases in K-channel density in rabbits J. Am. Coll. Cardiol., March 17, 2004; 43(6): 1090 - 1100. [Abstract] [Full Text] [PDF]
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W. Dun, P. Chandra, P. Danilo Jr., M. R. Rosen, and P. A. Boyden Chronic atrial fibrillation does not further decrease outward currents. It increases them. Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1378 - H1384. [Abstract] [Full Text] [PDF]
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M. Stengl, P. G A Volders, M. B Thomsen, R. L H M G Spatjens, K. R Sipido, and M. A Vos Accumulation of slowly activating delayed rectifier potassium current (IKs) in canine ventricular myocytes J. Physiol., September 15, 2003; 551(3): 777 - 786. [Abstract] [Full Text] [PDF]
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M. Schoenmakers, C. Ramakers, J. M. van Opstal, J. D.M. Leunissen, C. Londono, and M. A. Vos Asynchronous development of electrical remodeling and cardiac hypertrophy in the complete AV block dog Cardiovasc Res, August 1, 2003; 59(2): 351 - 359. [Abstract] [Full Text] [PDF]
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P. G.A. Volders, M. Stengl, J. M. van Opstal, U. Gerlach, R. L.H.M.G. Spatjens, J. D.M. Beekman, K. R. Sipido, and M. A. Vos Probing the Contribution of IKs to Canine Ventricular Repolarization: Key Role for {beta}-Adrenergic Receptor Stimulation Circulation, June 3, 2003; 107(21): 2753 - 2760. [Abstract] [Full Text] [PDF]
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M. Peschar, K. Vernooy, W. Y.R Vanagt, R. S Reneman, M. A Vos, and F. W Prinzen Absence of reverse electrical remodeling during regression of volume overload hypertrophy in canine ventricles Cardiovasc Res, June 1, 2003; 58(3): 510 - 517. [Abstract] [Full Text] [PDF]
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S. M Pogwizd, K. R Sipido, F. Verdonck, and D. M Bers Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis Cardiovasc Res, March 15, 2003; 57(4): 887 - 896. [Full Text] [PDF]
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F. Verdonck, P. G.A Volders, M. A Vos, and K. R Sipido Increased Na+ concentration and altered Na/K pump activity in hypertrophied canine ventricular cells Cardiovasc Res, March 15, 2003; 57(4): 1035 - 1043. [Abstract] [Full Text] [PDF]
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C Ramakers, M.A Vos, P.A Doevendans, M Schoenmakers, Y.S Wu, S Scicchitano, A Iodice, G.P Thomas, C Antzelevitch, and R Dumaine Coordinated down-regulation of KCNQ1 and KCNE1 expression contributes to reduction of IKs in canine hypertrophied hearts Cardiovasc Res, February 1, 2003; 57(2): 486 - 496. [Abstract] [Full Text] [PDF]
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Y. Tsuji, T. Opthof, K. Yasui, Y. Inden, H. Takemura, N. Niwa, Z. Lu, J.-K. Lee, H. Honjo, K. Kamiya, et al. Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block Circulation, October 8, 2002; 106(15): 2012 - 2018. [Abstract] [Full Text] [PDF]
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X. Xu, J. J. Salata, J. Wang, Y. Wu, G.-X. Yan, T. Liu, R. A. Marinchak, and P. R. Kowey Increasing IKs corrects abnormal repolarization in rabbit models of acquired LQT2 and ventricular hypertrophy Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H664 - H670. [Abstract] [Full Text] [PDF]
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K. R Sipido, P. G.A Volders, M. A Vos, and F. Verdonck Altered Na/Ca exchange activity in cardiac hypertrophy and heart failure: a new target for therapy? Cardiovasc Res, March 1, 2002; 53(4): 782 - 805. [Abstract] [Full Text] [PDF]
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S. Kaab and M. Nabauer Diversity of ion channel expression in health and disease Eur. Heart J. Suppl., September 1, 2001; 3(suppl_K): K31 - K40. [Abstract] [PDF]
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S. C. Verduyn, C. Ramakers, G. Snoep, J. D. M. Leunissen, H. J. J. Wellens, and M. A. Vos Time course of structural adaptations in chronic AV block dogs: evidence for differential ventricular remodeling Am J Physiol Heart Circ Physiol, June 1, 2001; 280(6): H2882 - H2890. [Abstract] [Full Text] [PDF]
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P. B. Adamson and E. Vanoli Early autonomic and repolarization abnormalities contribute to lethal arrhythmias in chronic ischemic heart failure: Characteristics of a novel heart failure model in dogs with postmyocardial infarction left ventricular dysfunction J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1741 - 1748. [Abstract] [Full Text] [PDF]
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J.M van Opstal, S.C Verduyn, H.D.M Leunissen, S.H.M de Groot, H.J.J Wellens, and M.A Vos Electrophysiological parameters indicative of sudden cardiac death in the dog with chronic complete AV-block Cardiovasc Res, May 1, 2001; 50(2): 354 - 361. [Abstract] [Full Text] [PDF]
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P. Chevalier, C. Rodriguez, L. Bontemps, M. Miquel, G. Kirkorian, R. Rousson, F. Potet, J.-J. Schott, I. Baro, and P. Touboul Non-invasive testing of acquired long QT syndrome: Evidence for multiple arrhythmogenic substrates Cardiovasc Res, May 1, 2001; 50(2): 386 - 398. [Abstract] [Full Text] [PDF]
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P.-S. Chen, L. S Chen, J.-M. Cao, B. Sharifi, H. S Karagueuzian, and M. C Fishbein Sympathetic nerve sprouting, electrical remodeling and the mechanisms of sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 409 - 416. [Abstract] [Full Text] [PDF]
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X. Xu, S. J. Rials, Y. Wu, J. J. Salata, T. Liu, D. B. Bharucha, R. A. Marinchak, and P. R. Kowey Left Ventricular Hypertrophy Decreases Slowly but Not Rapidly Activating Delayed Rectifier Potassium Currents of Epicardial and Endocardial Myocytes in Rabbits Circulation, March 20, 2001; 103(11): 1585 - 1590. [Abstract] [Full Text] [PDF]
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S. C. Verduyn, J. M. v. Opstal, J. D. Leunissen, and M. A. Vos Assessment of the Pro-Arrhythmic Potential of Anti-Arrhythmic Drugs: An Experimental Approach Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2001; 6(1): 89 - 97. [PDF]
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M. A. Vos, B. Gorenek, S.C. Verduyn, F. F. van der Hulst, J. D. Leunissen, L. Dohmen, and H. J. Wellens Observations on the onset of Torsade de Pointes arrhythmias in the acquired long QT syndrome Cardiovasc Res, December 1, 2000; 48(3): 421 - 429. [Abstract] [Full Text] [PDF]
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S. Nattel Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders Cardiovasc Res, November 1, 2000; 48(2): 188 - 190. [Full Text] [PDF]
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Y. Tsuji, T. Opthof, K. Kamiya, K. Yasui, W. Liu, Z. Lu, and I. Kodama Pacing-induced heart failure causes a reduction of delayed rectifier potassium currents along with decreases in calcium and transient outward currents in rabbit ventricle Cardiovasc Res, November 1, 2000; 48(2): 300 - 309. [Abstract] [Full Text] [PDF]
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K. R. Sipido, P. G. A. Volders, S. H. M. de Groot, F. Verdonck, F. Van de Werf, H. J. J. Wellens, and M. A. Vos Enhanced Ca2+ Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular Myocytes : Potential Link Between Contractile Adaptation and Arrhythmogenesis Circulation, October 24, 2000; 102(17): 2137 - 2144. [Abstract] [Full Text] [PDF]
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S. H. M. de Groot, M. Schoenmakers, M. M. C. Molenschot, J. D. M. Leunissen, H. J. J. Wellens, and M. A. Vos Contractile Adaptations Preserving Cardiac Output Predispose the Hypertrophied Canine Heart to Delayed Afterdepolarization-Dependent Ventricular Arrhythmias Circulation, October 24, 2000; 102(17): 2145 - 2151. [Abstract] [Full Text] [PDF]
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P. G.A. Volders, M. A. Vos, B. Szabo, K. R. Sipido, S.H.M. de Groot, A. P.M. Gorgels, H. J.J. Wellens, and R. Lazzara Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts Cardiovasc Res, June 1, 2000; 46(3): 376 - 392. [Full Text] [PDF]
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L. Jordaens How to make sure complications are avoided after an otherwise safe procedure Europace, January 1, 2000; 2(3): 191 - 192. [PDF]
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