93

Ventricular Fibrillation with Prominent Early Repolarization

Associated with a Rare Variant of KCNJ8/KATP Channel
MICHEL HAÏSSAGUERRE, M.D.,∗ STÉPHANIE CHATEL, M.S.,†,‡,§
FREDERIC SACHER, M.D.,∗ RUKSHEN WEERASOORIYA, M.D.,∗
VINCENT PROBST, M.D., Ph.D.,†,‡,§,¶ GILDAS LOUSSOUARN, Ph.D., M.D.,†,‡,§
MARC HORLITZ, M.D.,∗∗ RUEDIGE LIERSCH, M.D., Ph.D.,∗∗
ERIC SCHULZE-BAHR, M.D., Ph.D.,†† ARTHUR WILDE, M.D., Ph.D.,‡‡
STEFAN KÄÄB, M.D., Ph.D.,§§ JOSEPH KOSTER, Ph.D.,¶¶ YORAM RUDY, Ph.D.,¶¶
HERVÉ LE MAREC, M.D., Ph.D.,†,‡,§,¶ and JEAN JACQUES SCHOTT, Ph.D.,†,‡,§,¶
From the ∗ Université Bordeaux, Bordeaux–Pessac, France; †INSERM, UMR915, L’institut du Thorax, Nantes, France; ‡CNRS,
ERL3147, Nantes, France; §Université de Nantes, Nantes, France; ¶Service de Cardiologie, L’institut du Thorax, CHU de Nantes, Nantes,
France; ∗∗ Klinikum Wuppertal, Germany; ††Department of Cardiology and Angiology, Hospital of the University of Münster, Münster,
Germany; ‡‡Academic Medical Centre, Amsterdam, The Netherlands; §§Medizinische Klinik und Poliklinik I Marchioninistraße, Munich,
Germany; and ¶¶Washington University, Saint Louis, Missouri, USA

KCNJ8/K ATP Gene Variant and VF. Background: Early repolarization in the inferolateral leads
has been recently recognized as a frequent syndrome associated with idiopathic ventricular fibrillation
(VF). We report the case of a patient presenting dramatic changes in the ECG in association with recurrent
VF in whom a novel genetic variant has been identified.
Case Report: This young female (14 years) was resuscitated in 2001 following an episode of sudden death
due to VF. All examinations including coronary angiogram with ergonovine injection, MRI, and flecainide
or isoproterenol infusion were normal. The patient had multiple (>100) recurrences of VF unresponsive to
beta-blockers, lidocaine/mexiletine, verapamil, and amiodarone. Recurrences of VF were associated with
massive accentuation of the early repolarization pattern at times mimicking acute myocardial ischemia.
Coronary angiography during an episode with 1.2 mV J/ST elevation was normal. Isoproterenol infusion
acutely suppressed electrical storms, while quinidine eliminated all recurrences of VF and restored a normal
ECG over a follow-up of 65 months. Genomic DNA sequencing of K ATP channel genes showed missense
variant in exon 3 (NC_000012) of the KCNJ8 gene, a subunit of the K ATP channel, conferring predisposition
to dramatic repolarization changes and ventricular vulnerability. (J Cardiovasc Electrophysiol, Vol. 20,
pp. 93-98, January 2009)

early repolarization, sudden cardiac death, ventricular fibrillation, electrical storm, K ATP channel, genetic variant

Introduction tients13 with similar ECG pattern, nor provocative maneuvers

Sudden death occurs in the absence of structural heart dis-
ease in 6–14% of cases.1-4 Primary arrhythmic syndromes,
some associated with defects in the genes encoding cardiac
ion channels or their regulating proteins, have been described
to account for most of these deaths.5-11 A recent multicen-
ter study has shown that early repolarization in the infer-
olateral leads is associated with arrhythmic sudden cardiac
death, accounting for 31% of idiopathic ventricular fibril-
lation (IVF).12 So far, there is no characteristic to identify
high-risk patients within the broad population of normal pa-
Dr. Schulze-Bahr has received research support from the German Research
Foundation. Dr. Koster has received research support from an AHA Begin-
ning Grant-in-Aid.
Address for correspondence: Dr. Michel Haı̈ssaguerre, M.D., Hôpital Cardi-
ologique du Haut-Lévêque, 33604 Bordeaux–Pessac, Pessac, France. Fax:
33-5-57656509; E-mail: michel.haissaguerre@chu-bordeaux.fr
Manuscript received 11 July 2008; Revised manuscript received 5 August
2008; Accepted for publication 6 August 2008.
doi: 10.1111/j.1540-8167.2008.01326.x
to accentuate abnormal repolarization in vulnerable patients.
The present article reports a case of a young female pre-
senting with multiple episodes of IVF associated with very
dramatic changes in repolarization pattern and in whom a
rare variant in the KCNJ8 gene encoding the subunit Kir6.1
of K ATP channel was identified.
Case Report
An Idiopathic VF
A 14-year-old female presented on September 11, 2001, at
home with a sudden loss of consciousness while playing a video
game. Her father and a friend started resuscitation 2 minutes
later. Rescue services arrived, and she was found to be in ventric-
ular fibrillation (VF). Eight electrical shocks were performed to
restore sinus rhythm. During evaluation in the first clinic, the
ECG was interpreted as an incomplete left bundle branch block.
Myocardial infarction was eliminated by serial ECGs and car-
diac enzymes and normal echocardiogram; self-inflicted intox-
ication was also excluded.
New episodes of VF occurred, and she was transferred to the
regional general hospital. The diagnosis of idiopathic VF was
confirmed by the absence of structural heart disease at multiple
different examinations.1 Echocardiogram showed normal size
and function of the right and left ventricle. Cardiac catheter-
ization showed normal coronary angiogram (with negative
94 Journal of Cardiovascular Electrophysiology Vol. 20, No. 1, January 2009

ergonovine provocation), and the right ventricle angiogram and
MRI were normal; she also underwent right ventricular biopsy,
which was negative for any infiltration or inflammation. There
was no history of unexplained syncope before diagnosis and no
family history of sudden death.
The ECGs showed a QRS-ST junction (J point) deviated
from the baseline by >0.5 mV, either as a QRS slurring (smooth
transition from QRS to ST segment) or as notching (positive
J deflection). This early repolarization pattern was marked
and widespread, affecting the later part of QRS complex in 10
of 12 leads. This pattern was spontaneously and dramatically
varying at different times; particularly, it was accentuated at
the longer cycle lengths either during bradycardia or following
a postextrasystolic pause (Fig. 1). Parallel variations in ST seg-
ments were concomitantly observed, either positive or negative
(opposite to the J wave). A signal-averaged ECG revealed low-
amplitude late potentials at the same timing as the J wave seen
on the ECG (QRS duration 160 ms, RMS voltage in the termi-
nal 40 ms = 30 μV and the duration under 40 μV was 84 ms).
Two sodium channel blocker infusions were performed using
either ajmaline (1 mg/kg in 2 minutes) or flecainide (2 mg/kg
in 10 minutes) and they did not produce ST segment elevation
(>0.2 mV) in precordial leads V 1 –V 3 , excluding Brugada syn-
drome (Fig. 1).
A dual-chamber implantable cardiac defibrillator (ICD) was
implanted in October 2001. During the ensuing 15 months, fre-
quent episodes of VF recurred commonly during the night or
early morning and were successfully treated by internal shocks
from the implanted defibrillator. The following oral antiar-
rhythmic drugs were tried to prevent recurrent arrhythmia:
flecainide 100 mg morning and 50 mg evening, amiodarone
200–300 mg × 1/day, verapamil SR 240 mg × 1/day, mexiletine

Figure 1. Three-lead ECGs showing baseline ECG (QRS = 130 ms, QTc = 460 ms), during isoproterenol infusion normalizing the QRST pattern (QRS =
70 ms, QTc = 420 ms), and after flecainide challenge (QRS = 150 ms, QTc = 430 ms) showing no Brugada sign. The three-lead tracing (bottom) shows
nocturnal telemetry with major accentuation of early repolarization abnormality following long preceding cycle length.

150 mg × 2/day, and propafenone 300 mg × 2/day for a pa-
tient with body weight of 44 kg. Different beta-blockers (so-
talol 80 mg × 2/day, metoprolol 100 mg × 1/day) were tried;
however, this resulted in more recurrences of ventricular ar-
rhythmia. High-rate atrial pacing also failed to suppress the
arrhythmia. The ICD was replaced on October 2002 because
of generator depletion. The patient was transferred in January
2003 for consideration of catheter ablation of VF triggers.
Electrocardiographic Characteristics
ECGs recorded during an arrhythmic period showed fre-
quent short coupled ventricular ectopy, polymorphic ventricu-
lar tachycardia or VF, and a consistent increase in the ampli-
tude of early repolarization (Fig. 2). The ST elevation amplitude
ranged from 0.2 to 1 mV. Instantaneous changes in repolariza-
tion were documented, culminating in major ST elevation and
VF (Fig. 2). All documented ectopic morphologies had positive
QRS morphology in leads V 1 –V 2 , indicating an origin from the
left ventricle. The coupling interval of ectopy triggering VF was
337 ± 65 ms (range 260–420 ms).
Electrophysiological testing was performed using three mul-
tielectrode catheters introduced percutaneously through the
femoral vessels. The left ventricle was mapped by retrograde
aortic and transseptal catheterization. Mapping of the left ven-
tricle failed to demonstrate ventricular depolarization electro-
grams coincident with a wide terminal QRS abnormality, thus
confirming origin in repolarization. Because arterial hypoten-
sion developed at the beginning of anesthesia, 600 mg of calcium
gluconate was injected and 1 minute later it produced a 1.2-mV
elevation of J/ST segment and episodes of VF (Fig. 3). A coro-
nary angiogram was immediately performed to look for a spasm
and it demonstrated normal vessels. Later mapping demon-
strated at least nine ectopic morphologies, which were targeted
to the ventricular myocardium in seven and the Purkinje net-
Figure 2. Different patterns of early repolarization preceding initiation of polymorphic VT or VF. The bottom telemetric rhythm strip shows initiation of VF
after dramatic beat-to-beat increase (arrows) of early repolarization, culminating in major ischemia-like ST elevation.
Haı̈ssaguerre et al. KCNJ8/K ATP Gene Variant and VF 95
work in two. During the 7-hour duration of the procedure, the
patient presented 25 episodes of VF requiring electrical defib-
rillation. Two storms of immediately recurring episodes of VF
were treated by isoproterenol infusion at a rate of 0.02 mg/min,
which eliminated all arrhythmias when the sinus heart rate was
increased above 120 beats/min (bpm). Finally other VF triggers
morphologies were documented, including some displaying neg-
ative QRS morphology in leads V 1 –V 2 , and the procedure was
terminated with failure to eliminate all ectopy.
During the next days, other arrhythmic storms occurred,
requiring isoproterenol infusions; any attempt to reduce iso-
proterenol infusion and heart rate was associated with recur-
rence of multiple VF. In addition, isoproterenol infusion re-
duced the early repolarization pattern or restored a normal
ECG (Fig. 1). Isoproterenol was infused for a period of 5 days
during which amiodarone was administered at 1,200 mg/day.
We then again attempted to reduce the isoproterenol infusion
and recurrences of short coupled ectopy, and VF was again
observed for a total of 18 episodes of VF. Finally, based on
abnormality affecting the early phase of repolarization and ex-
perimental studies indicating the pivotal role of I TO channel in
arrythmogenesis in this condition, we decided to initiate treat-
ment with quinidine (blocker of I TO channel). A dose of 200 mg
of hydroquinidine was prescribed, and 2 hours later, a new
attempt to reduce isoproterenol was successful, with no recur-
rence of either isolated or repetitive ventricular arrythmias.
Quinidine was continued at 600 mg/day, and over a follow-up of
65 months, there was to date no recurrence of syncope, no detec-
tion of VF or polymorphic or monomorphic VT. There was also
a total elimination of short coupled ventricular ectopy on the
Holter recordings. It is to be noted that a single inappropriate
shock was delivered for atrial fibrillation, with rapid ventricu-
lar response 36 months later. The current baseline ECG shows a
nearly total abolition of early repolarization abnormality, with
a slightly prolonged QT interval (460 ms). Serial plasma levels
96 Journal of Cardiovascular Electrophysiology Vol. 20, No. 1, January 2009
of hydroquinidine ranged from 1.7 to 3.0 μg/mL (therapeutic
2–4.5 μg/mL).
Genetic Study
The patient underwent genetic evaluation, targeting cardiac
ion channels, particularly those implicated in the early phase of
repolarization. Genomic DNA was prepared from peripheral
blood lymphocytes using standard methods. Mutation anal-
ysis was conducted by direct sequencing of potassium chan-
nels, subunits and their transcriptional regulators (KCNQ1,
KCNE1, KCNH2, KCNE2, KCNJ2, KCNJ8, KCNJ11, ABCC9,
KCNJ5, KCNJ3, KCND3, IRX3, IRX5), sodium channels
(SCN5A, SCN1B), Na+ /Ca2+ exchanger (NCX1), calcium chan-
nels (CACNA1C, CACNB2), Ca2+ -binding proteins (CALR,
CASQ2), and gene encoding cytoskeletal protein interacting
with ion channels (ANK2).
Sequencing of KCNJ8 gene encoding the Kir6.1 subunit
of K ATP channel identified a missense variant in exon 3
(NC_000012). This heterozygous c.1265C → T transition caused
a p.S422L substitution of a highly conserved residue (Fig. 4A
and B). This variant was absent in 764 alleles from healthy con-
trols. The patient’s mother did not have the variant, whereas
the father did not consent to clinical and genetic testing. KCNJ8
gene was screened in a cohort of 156 additional patients pre-
senting with early repolarization pattern and a history of IVF
but the screening failed to identify this genetic variant.
Discussion
This report describes a patient with recurrences of IVF in
association with widespread early repolarization abnormality
in the electrocardiogram. The dramatic, and at times, instan-
taneous dynamic changes in repolarization coincident with
arrhythmia occurrence or recession appear to have a major
importance in the pathogenesis of the VF. In this specific case,
a mutation in gene encoding for K ATP channel was identified
Figure 3. ECGs showing major ST seg-
ment elevation 1 minute after injection of
600 mg of calcium gluconate, and 2 min-
utes later with initiation of VF. A coronary
angiogram was immediately performed to
look for a spasm and it demonstrated nor-
mal vessels.
that provides a likely explanation for both the electrocardio-
graphic alterations and the ventricular vulnerability.
Distinct Electrocardiographic Entity Associated with
Sudden Death
Different syndromes of arrhythmic sudden death have re-
cently been described, and most of them are associated with
defects in the genes encoding cardiac ion channels or their
regulating proteins.1-11 These syndromes may have over-
lapping phenotypes including conduction disturbances. The
ECG abnormalities in the present patient were widespread
in the inferior and left precordial leads and were both vari-
able and labile, as observed in the above repolarization syn-
dromes. That the dramatic alterations in early repolarization
were linked to arrhythmogenicity was supported by the dy-
namic changes affecting specifically this ECG marker, which
preceded and culminated in arrhythmia and receded with
their cessation. From our current registry including a total
of 142 patients with this condition, two aspects were unique
in the present case: the magnitude of J/ST changes mim-
icking severe acute myocardial ischemia, and the explosive
occurrence of the repolarization alterations (within the time
frame of 1–2 beats). A coronary disease or spasm was an un-
likely explanation as coronary artery patency was confirmed
at the peak of ECG changes, and the ECG was normalized
by drug therapy devoid of vascular action. However, myocar-
dial ischemia as the cause of J wave in the ECG has been
reported.14
Pathogenesis
There is mounting experimental evidence demonstrating
the arrhythmogenicity of a heterogeneity of action potentials
across the ventricular wall at the end of phase 1. Studies

Figure 4. (A) Sequencing traces of
KCNJ8 exon 3 (NC_000012) showing a
heterozygous C > T substitution resulting
in the missense S422L variant. (B) Par-
tial amino acid sequence of the Kir6.1
protein showing that the 422Ser residue
(red) is conserved across different species.
Correction made after online publication
October 13, 2008: the authors amended
the figure to correctly display data.
involving isolated canine ventricular epicardial and endo-
cardial tissues showed intrinsic cellular differences, particu-
larly with the presence of an I TO -mediated spike and dome
morphology in epicardial tissue responsible for differential
sensitivity to drugs or ischemic conditions.15-17 Any pertur-
bation in the balance of currents may amplify the epicardial
notch and disparity in voltage gradient, resulting in loss of
the epicardial potential plateau. Shortening of epicardial ac-
tion potentials is associated with ST segment elevation, and
coexisting short and normally repolarized cells can precipi-
tate phase 2 reentries and polymorphic VT. Experimentally,
sodium and calcium channel blockers, activation of I K−ATP ,
hypercalcemia, hypothermia, and bradycardia increase the
electrical gradient and are arrhythmogenic.15 Clinically, three
of the above conditions were encountered in our patient: an
underlying genetic abnormality in K ATP channel, calcium
injection as an exogenous precipitating factor, and the role
of long cycle lengths in amplifying early repolarization. In
contrast, the protective role of isoproterenol and quinidine in
our patient may be mediated through an activation of Ica-L
or blocking of I TO , respectively, resulting in reversal of the
electrical gradient.
Variant in the K ATP Channel
The cardiac K ATP channels are formed by association of
the Kir 6.1 (K inward rectifier) and SUR 2A (sulfonyl urea)
subunits. Their function is still not fully elucidated, but they
are thought to provide a link between cellular metabolism and
Haı̈ssaguerre et al. KCNJ8/K ATP Gene Variant and VF 97
membrane potential. K ATP channels are expressed in myocar-
dial cells with a very high density, in the same order as sodium
channels.18-21 As a consequence, it is sufficient to open a
small percentage of channels to generate sufficient current
that affects repolarization. Computer simulations show that
opening of 1.2% of channels is sufficient to shorten APD
by 50%,21 consistent with experimental estimates of 0.7–
1%.19,22 Also, channel sensitivity to ATP changes is greater
in the epicardium than in deeper regions of the ventricular
wall.17 This functional heterogeneity acts in synergy with
a transmural I TO gradient (largest at the epicardium) to sup-
press preferentially the epicardial action potential plateau and
shorten its duration more than in deeper myocardial layers.
The resulting potential gradient is reflected in ST segment el-
evation on the ECG.23 Despite their high density, K ATP chan-
nels are inactive in healthy ventricular myocardium and open
with decreasing levels of ATP. It is possible that the KCNJ8
mutation alters the channel kinetics and/or its ATP sensi-
tivity in such a way that it is activated even in the absence
of ischemic conditions.24,25 This hypothesis remains to be
tested in experimental preparations.
Another goal is to investigate the functional effects of
mutated ion channels and identify other arrhythmia suscep-
tibility genes or modifiers. The variant observed in Kir6.1
may have diverse functional impacts at the cellular level. It
may be an increase in K ATP channels trafficking, maybe due
to a defective endoplasmic retention region (RKR domain)
nearby the variant.26,27 It may be an increase in channel ac-
tivity, for instance, due to the removal of a serine potentially
98 Journal of Cardiovascular Electrophysiology Vol. 20, No. 1, January 2009
implicated in the PKC inhibition of the channel activity.28
Different approaches (Western blots, rubidium efflux, patch-
clamp, computational models, etc.) are needed to clarify
these hypotheses.
Clinical Implications
The information from the present study provides the first
genetic abnormality associated with IVF and inferolateral
early repolarization. Although this case is so far unique, it
indicates that genetic evaluation will probably improve the
recognition of individuals at risk of malignant arrhythmias
with this condition. In addition, the incidence of early re-
polarization abnormality as a potential cause of unexplained
death may be underestimated because of the fluctuation in the
ECG expression of J wave and impossibility to document VF
initiation and prodromal repolarization changes.12 It there-
fore is conceivable that this syndrome may be present but
phenotypically concealed on the ECG, but could be detected
by genetic testing or unmasked by drug challenge amplifying
intrinsic electrical heterogeneity. Finally, ECG patterns sim-
ulating myocardial ischemia and potential for the arrhythmia
to worsen with beta-blockers are of clinical relevance.
Conclusion
The present study reports a case of a young female pre-
senting with multiple episodes of IVF associated with very
dramatic changes in repolarization pattern and in whom a
variant in the gene encoding the subunit Kir6.1 (KCNJ8) of
K ATP channel was identified. Studies are required to inves-
tigate the electrophysiological consequences and establish a
pathogenetic link between phenotype and genotype.
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