Basic Science for the Clinical Electrophysiologist

Management of Ventricular Arrhythmias

in Suspected Channelopathies
Manoj N. Obeyesekere, MBBS; Charles Antzelevitch, PhD; Andrew D. Krahn, MD

A lthough structural heart disease remains the predominant

substrate for ventricular arrhythmia, channelopathies
including long QT syndrome (LQTS), short QT syndrome
(SQTS), Brugada syndrome (BrS), catecholaminergic polymor-
phic ventricular tachycardia (CPVT), and early repolarization
syndrome (ERS) are less common but important contributing
entities. These etiologies require specific therapies potentially
contrary to empirical management of arrhythmias associated
with structural heart disease. Conventional therapy including
antiarrhythmic drug therapy may not only fail to resolve unsta-
ble arrhythmias but worsen them. Additionally, channelopathy
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Although numerous variables have been reported to increase
the risk of TdP in patients with LQTS, the degree of QTc pro-
longation remains foundational.2 SCD in patients with con-
genital LQTS and a normal QTc (<440 ms) is low (4% at 40
years and 10% at 70 years).3 This is significantly lower com-
pared with patients with LQTS with prolonged QTc (>440 ms,
15% at 40 years and 24% at 70 years).3 However, the risk of
death in patients with LQTS and a normal QTc is still 10-fold
compared with unaffected family members (0.4% at 40 years
and 1% at 70 years).3 Risk of TdP is directly related to QTc
with QTc values >500 ms requiring prompt attention even in

patients with implantable cardioverter defibrillators (ICD) and
arrhythmic storms represent a major challenge, and the acute
care team needs to be cognizant of unique circumstances that
require specific acute therapies beyond empirical advanced life
support algorithm recommendations.1
Successful and considered acute management of ventricular
arrhythmias is contingent on a number of variables, including
knowledge of the cardiac substrate or potential substrate; form,
mechanism, and precipitants of ventricular arrhythmias; and
acute effect of potential therapies. In the longer term, an under-
standing of the natural history of the channelopathy along with
the efficacy of long-term therapy will lead to superior outcomes.
This review will present the risk of ventricular arrhythmias asso-
ciated with these uncommon entities, the evolving understand-
ing of the mechanism of arrhythmia, and the mechanistic basis
of therapies along with a clinical approach to summarize the evi-
dence pertaining to acute and long-term management.
Long QT Syndrome
Patients with a prolonged QT interval are at risk of sudden
cardiac death (SCD) due to Torsade de Pointes (TdP; Fig-
ure 1). Most patients with congenital LQTS are asymptomatic
and diagnosed incidentally on electrocardiogram screening or
following family screening. However, syncope, aborted SCD,
or SCD may be the first presentation. Most arrhythmic events
in congenital LQT1 occur during physical or emotional stress,
at rest or in association with sudden auditory stimulation in
LQT2, and during sleep or rest in LQT3 patients.2 Although
typical presentations can assist in raising the suspicion of
LQTS, the history alone remains insufficient to diagnose the
genotype and guide management.
the absence of arrhythmias.
Mechanism of Arrhythmia
QT prolongation can be due to common genetic variants or
acquired, commonly due to QT-prolonging medications.
Decreased outward potassium current mediated by loss-
of-function mutations in IKs (slowly activating delayed recti-
fier potassium current) channels leads to LQT1 (Figure 2).
Decreased outward potassium current, mediated by loss-of-
function mutations in IKr (rapidly activating delayed rectifier
current) channels, leads to LQT2. Increased inward sodium
current, mediated by gain-of-function mutations in the cardiac
sodium channel, causes slowed or incomplete channel inacti-
vation leading to LQT3.
The dysfunction of the ion channels results in prolonged
repolarization and can lead to development of early after
depolarizations due to an inward shift in the balance of current
flowing during phases 2 and 3 of the cardiac action potential
(AP). When the early after depolarizations reach the thresh-
old for activation of the inward calcium current, they gener-
ate triggered extrasystoles. Differences in the degree of AP
prolongation among the 3 cell types that comprise the ven-
tricular wall lead to development of transmural dispersion
of repolarization (TDR), thus creating a vulnerable window
across the ventricular wall and other regions of the ventricu-
lar myocardium, which can lead to development of reentrant
arrhythmias. When an early after depolarization–induced trig-
gered response falls within this vulnerable window, the result
is an atypical polymorphic ventricular tachycardia (PMVT),
known as TdP.4 To date, mutations in 15 different genes have
been identified in patients clinically diagnosed with LQTS

Received September 14, 2014; accepted December 24, 2014.

From the Department of Cardiology, Northern Healthcare Group, Epping, Victoria, Australia (M.N.O.); Masonic Medical Research Laboratory, Utica,
NY (C.A.); and Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada (A.D.K.).
Correspondence to Manoj N. Obeyesekere, MBBS, The Northern Healthcare Group, 185 Copper Street, Epping 3076, Victoria, Australia. E-mail
Manoj.Obeyesekere@nh.org.au
(Circ Arrhythm Electrophysiol. 2015;8:221-231. DOI: 10.1161/CIRCEP.114.002321.)
© 2015 American Heart Association, Inc.
Circ Arrhythm Electrophysiol is available at http://circep.ahajournals.org DOI: 10.1161/CIRCEP.114.002321

221
 222  Circ Arrhythm Electrophysiol  February 2015
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(Table 1). LQT1 to LQT3 account for an estimated 85% to
95% of genotype-positive LQTS cases.2
Medications that prolong the QT interval are the best-
characterized risk factors for acquired LQT, which is far
more common than congenital LQTS. The vast majority of
QT-prolonging drugs act by blocking IKr (Figure 2). Some
IKr blockers can augment late INa via inhibition of the phos-
phoinositide 3-kinase pathway. Thus, the torsadogenic
actions of these IKr blockers are mediated by both a reduc-
tion in outward current and an increase in inward current.5
An up-to-date list of drugs associated with QTc prolonga-
tion and cardiac arrhythmias can be found at www.qtdrugs.
org. Pharmacodynamic and pharmacokinetic drug–drug
interactions may also lead to QTc prolongation.
Acquired LQTS is commonly associated with multi-
ple risk factors. In 1 series of 11 patients with acquired
LQT (9/11 with TdP), there were ≥2 risk factors for the
development of LQT, which always included ≥1 known
QT-prolonging medication and ≥1 electrolyte disturbance
(hypokalemia, hypocalcemia, and hypomagnesaemia).6
Patients were taking an average of 2.8±0.3 QT-prolonging
medications in this series. Average QTc interval at presen-
tation was 633.8±29.2 ms. A QTc >500 to 550 ms should
prompt clinicians to assess the risk/benefit ratio of con-
tinuing QT-prolonging pharmacotherapy, depending on
contributing arrhythmic variables and competing clinical
indications for QT-prolonging pharmacotherapy.
Therapeutic Strategies
The management principles hinge on pharmacological and
nonpharmacological attempts to produce an outward shift in
the balance of currents to overcome the abnormally prolonged
repolarization and suppress triggers. Acutely, correction of
electrolyte abnormalities, such as hypokalemia and hypomag-
nesemia, is essential in both acquired and congenital LQTS.
Studies have reported the safety and utility of intravenous
magnesium sulfate for the treatment of TdP associated with
acquired and congenital LQTS.7
Figure 1. Long QT syndrome with resultant Torsade
de Pointes (TdP) (top, exercise-induced TdP; bot-
tom, bradycardia-induced TdP).
β-blockers are considered first-line therapy for patients
with LQT1 and LQT2, but remain controversial in LQT3.
Metoprolol seems to be less effective than propranolol and
nadolol.8 The longer half-life of nadolol also allows twice-
a-day administration and is preferable. Similarly sustained
release propranolol should be preferred. Limited data suggest
that atenolol may be less effective compared with propranolol.9
Endo
Epi
25 mV
50 ms
INa
ICaL
Ito
IKr
IKs
IKI, IKATP , IKACh
INa/Ca
ECG
Figure 2. The ionic currents of the action potential (AP). Epicar-
dial (Epi) AP and current are shown by dotted lines and endo-
cardial (Endo) by solid lines. Depolarizing inward currents are
depicted downward and repolarizing outward currents upward.
The Epi AP has a characteristic notch caused by larger phase 1
Ito compared with Endo. ECG indicates electrocardiogram; ICaL,
inward calcium currents; IK1, inward rectifier current; IKACh, acetyl-
choline-activated current; IKATP, adenosine triphosphate–sensitive
current; IKr, rapid delayed rectifier current; IKs, slow delayed recti-
fier current; INa, inward sodium current; INa/Ca, sodium calcium
exchange; and Ito, transient outward current.
 Obeyesekere et al   Management of Arrhythmia in Channelopathies   223

Table 1.  Gene Defects Responsible for Long QT Syndrome potent blocker of the open sodium channel, in low dose con-
sistently shortened the QTc interval (565±60 ms to 461±23
Chromosome Gene Ion Channel
ms; P<0.04) and normalized QTc in patients with LQT3 (n=5)
LQT1 11 KCNQ1, ↓ IKs 30%–35% with a DKPQ mutation.15 Class 1b and 1c agents may also be
KvLQT1
tried acutely intravenously in patients with TdP due to LQT3,
LQT2 7 KCNH2, HERG ↓ IKr 20%–25% although no study has reported safety or efficacy.
LQT3 3 SCN5A, Nav1.5 ↑ Late INa  5%–10% The late INa blocker ranolazine is effective in abbreviating
LQT4 4 Ankyrin-B, ↑ Cai, ↑ Late INa 1%–2% QT interval and suppressing TdP in experimental models of
ANK2 LQT317 and in significantly abbreviating QTc in patients with
LQT5 21 KCNE1, MinK ↓ IKs 1% LQT3.20 In patients with DKPQ-mediated LQT3, ranolazine
LQT6 21 KCNE2, MiRP1 ↓ IKr Rare has been shown to cause a dose-dependent abbreviation of the
LQT7* 17 KCNJ2, Kir 2.1 ↓ IK1 Rare QTc interval with no change in PR or QRS intervals.20 The
LQT8† 6 CACNA1C, ↑ ICa Rare
lack of effect of ranolazine on PR interval and QRS duration
Cav1.2 is consistent with the finding that ranolazine does not signifi-
LQT9 3 CAV3, ↑ Late INa Rare
cantly inhibit peak INa in the ventricle at therapeutic concentra-
Caveolin-3 tions.20 Clinical trials of ranolazine in LQT1 and LQT2 are not
LQT10 11 SCN4B, NavB4 ↑ Late INa Rare
as yet available.
Adrenergic stimulation may be of benefit in the case of
LQT11 7 AKAP9, Yatiao ↓ IKs Rare
acquired LQTS associated with bradycardia and long pauses.
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LQT12 20 SNTA1, a1 ↑ Late INa
Syntrophin
LQT13 11 KCNJ5, Kir 3.4 ↓ IKACh
LQT14 14 CALM1,
Calmodulin
LQT15 2 CALM2,
Calmodulin
*Andersen–Tawill syndrome.
†Timothy syndrome.
Additional data suggest that in LQT1, the risk reduction is
similar among atenolol, metoprolol, propranolol, and nadolol,
but in LQT2, nadolol provided the only significant risk reduc-
tion.10 Currently evidence is lacking to recommend cardiose-
lective over noncardioselective β-blockers.
Experimental data indicate β-blockade (propranolol) to be
effective in preventing ventricular tachycardia (VT)/ventricu-
lar fibrillation (VF) in a validated LQT3 model.11 However,
other experimental data suggest β-blockade may facilitate
TdP in LQT3.12 The apparent lack of clinical efficacy in
small populations of patients with LQT3 on β-blockers has
been suggested to be due to analysis including patients with
LQT3 who had suffered a cardiac arrest in the first year of life
who remained at high risk compare with patients who did not
have events early in life who appeared to remain protected
by β-blockers.13 The largest clinical series from 9 registries
worldwide (published in conference abstract form) included
403 patients with LQT3 and concluded β-blocker therapy to
be effective in significantly reducing the risk of aborted car-
diac arrest or SCD.14
Preliminary data suggest that patients with LQT3 could
benefit more from Na+ channel blockers, such as mexi-
letine, flecainide, and ranolazine, although long-term data
are not available as yet.15–17 Experimental data have shown
that mexiletine reduces TDR and prevents TdP in LQT3, as
well as LQT1 and LQT2, suggesting that agents that block
late sodium current may be effective in all forms of LQTS.18
In rare cases, cautious use of mexiletine has been advocated
due to reported prolongation of the QT interval by facilitat-
ing trafficking of mutant proteins in LQT3.19 Flecainide, a
Rare Isoproterenol or epinephrine may exacerbate arrhythmias
in patients with acquired LQT with a concurrent congenital
Rare defect but may be beneficial in patients with acquired LQT
Rare with no concurrent gene mutation by recruiting functional
IKs channels and accelerating heart rate21 (Table 1; Figure 3).
Rare β-adrenergic stimulation induces TdP by increasing TDR in
canine models of LQT1 and 2 but suppresses TdP by reduc-
ing dispersion in the LQT3 canine model.12 Thus acutely,
β-adrenergic stimulation can be beneficial in LQT3 and
β-blockers in LQT1 and LQT2. Acute temporary pacing can
minimize pause-dependent TdP in both acquired and congeni-
tal LQT patients.22
The implantation of an ICD is pivotal secondary prevention
in LQTS and a reasonable primary prevention approach in
select cases.2 Thoughtful ICD programming to prevent inap-
propriate shocks is important and usually requires a VF-only
zone (detect rate, >220–240 beats per minute).
Left cardiac sympathetic denervation (LCSD) is generally
limited to the treatment of patients with LQT1 or LQT2 with
recurrent syncope despite β-blocker therapy, in patients who
experience arrhythmic events with an ICD, and considered in
patients intolerant to β-blocker therapy.2 LCSD has been per-
formed both as primary and secondary prevention in LQTS
with excellent outcomes in select patients.23 Marked reduction
in number of cardiac events is usually seen following LCSD.
However, nearly 50% of patients with high-risk LQTS con-
tinue to experience breakthrough events. Thus, LCSD should
not be viewed as curative or as an alternative to ICDs for high-
risk patients. Furthermore, in appropriate patients, LCSD is
initially favored, with subsequent right cardiac sympathetic
denervation if there is arrhythmia recurrence.24
Short QT Syndrome
The SQTS is characterized by an abbreviated QTc interval
(<330 ms), with J-point to T-wave peak <120 ms (measured
in the precordial leads with the T-wave of greatest amplitude),
with a relatively large amplitude peaked T-wave with a steep
downward slope, ventricular and atrial arrhythmias (due to
short atrial and ventricular effective refractory periods), and
SCD/syncope.2 The majority of affected individuals typically
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Figure 3. An algorithm for acute pharmacological treatment of arrhythmias in suspected channelopathies. CPVT indicates catecholamin-
ergic polymorphic ventricular tachycardia; LQT, long QT; LQTS, long QT syndrome; PMVT, polymorphic ventricular tachycardia; and VF,
ventricular fibrillation.
have a personal or family history of syncope or autopsy-nega-
tive SCD in a first- or second-degree young relative.25 SQTS is
relatively rare with <60 cases reported in a recent expert con-
sensus statement.2 There are no validated diagnostic criteria,
although a scoring system for diagnosis has been proposed.26
It is likely that the severity of QT abbreviation is related to
prognosis, although this has not been validated.
In contrast to the mutations that underlie LQTS, SQT1 is
caused by mutations that cause a gain of function of outward
currents or loss of function of inward currents. The increased
net outward current accelerates repolarization of the AP, thus
abbreviating the QT interval. Gain-of-function mutations in
the KCNH2 (IKr), KCNQ1 (IKs), and KCNJ2 (IK1) genes account
for SQT1, 2, and 3, respectively. Loss-of-function mutations
in the CACNA1C, CACNB2, and CACNA2D1 genes encoding
for the a1, b, and a2δ subunits of the cardiac L-type calcium
channel account for SQT4, 5, and 6, respectively (Figure 2).27
Mechanism of Arrhythmia in SQTS
Abbreviation of the AP in SQTS is heterogeneous, most com-
monly displaying preferential abbreviation in epicardium,
thus giving rise to an increase in TDR. Augmented TDR as the
basis for arrhythmogenesis in SQTS has been demonstrated
in experimental models in which repolarization is abbrevi-
ated using the IKr agonist, PD-118057,28 thus mimicking the
cellular conditions created by the genetic defect associated
with SQT1. Dispersion of repolarization and refractoriness
serve as substrates for reentry by promoting unidirectional
block. Marked abbreviation of wavelength (product of refrac-
tory period and conduction velocity) is an additional factor
promoting the maintenance of reentry. Tpeak–Tend interval and
Tpeak–Tend/QT ratio, an electrocardiographic index of spatial
dispersion of repolarization, including TDR, are significantly
augmented in cases of SQTS.29,30 This ratio is greater in symp-
tomatic patients.31
Therapeutic Strategies
Isoproterenol has been reported to suppress VF due to
SQTS32 in 1 case report. This beneficial action was secondary
to a reduction of Tpeak–Tend, suggesting a reduction in TDR.
However, this observation is in contrast to some experimen-
tal models of SQTS, which have shown a significant further
abbreviation of QT interval and increase in TDR with isopro-
terenol, leading to more inducible PMVTs.33 Thus, strong evi-
dence is lacking regarding isoproterenol in SQTS.
Fifty-three patients from the European Short QT Registry
were followed up for 64 months and found to have an incidence
of arrhythmic events of 5% per year in patients without pharma-
cological prophylaxis compared with no arrhythmic events in
those administered hydroquinidine,25 suggesting patients with
SQTS should be considered for pharmacological prophylaxis
at the least. Quinidine can normalize the QT interval but has
not been evaluated in large long-term or comparative studies.
Flecainide, sotalol, ibutilide, and quinidine were studied in 6
patients with SQTS. Only quinidine was associated with sig-
nificant QT prolongation (263±12 ms to 362±25 ms), resulting
in a longer ventricular effective refractory period and noninduc-
ibility of VF during provocative testing.34
There are no data to support implantation of ICDs in
asymptomatic patients. An ICD may be considered in patients
with a genotype or phenotype diagnosis of SQTS and a fam-
ily history of SCD with evidence of a short QTc in relative/s
with SCD (class IIb).2 Appropriate programming is needed to
prevent inappropriate shocks from T-wave over sensing.
Brugada Syndrome
The majority of patients with a Brugada electrocardiogram
pattern are asymptomatic, diagnosed incidentally, and may
remain asymptomatic for life. Others may present with VF
or SCD (particularly at night), nocturnal agonal breathing,
syncope, and palpitations. Patients with a Brugada type-1
 Obeyesekere et al   Management of Arrhythmia in Channelopathies   225

electrocardiogram (Figure 4) have an approximate cardiac Table 2.  Gene Defects Responsible for Brugada Syndrome
event-rate per year of 7.7% in patients with aborted SCD, Locus Gene Ion Channel
1.9% in patients with syncope, and 0.5% in asymptomatic
BrS1 3p21 SCN5A, Nav1.5 ↓ INa 11%–28%
patients.35
BrS2 3p24 GPD1L ↓ INa Rare
Mechanism of Arrhythmia BrS3 12p13.3 CACNA1C, ↓ ICa 6.6%
Cav1.2
Mutations in 19 genes have been associated with the Bru-
gada electrocardiogram, and in each, a decrease in the inward BrS4 10p12.33 CACNB2b, ↓ ICa 4.8%
Cavß2b
sodium or calcium current or an increase in an outward potas-
BrS5 19q13.1 SCN1B, Navß1 ↓ INa 1.1%
sium current has been demonstrated, resulting in an outward
shift in the balance of current during the early phases of the BrS6 11q13-14 KCNE3, MiRP2 ↑ Ito Rare
AP (Table 2). The reduction in INa allows the transient outward BrS7 11q23.3 SCN3B, Navß3 ↓ INa Rare
(Ito) current to repolarize the cell during phase 1 beyond the BrS8 12p11.23 KCNJ8, Kir6.1 ↑ IKATP 2%
voltage range at which L-type Ca+2 channels activate. Failure BrS9 7q21.11 CACNA2D1, ↓ ICa 1.8%
of the Ca+2 channels to activate results in loss of the AP pla- Cavα2δ
teau, predominantly in the subepicardial cells where Ito is most BrS10 1p13.2 KCND3, Kv4.3 ↑ Ito Rare
prominent. Conduction of the AP dome from epicardial sites BrS11 17p13.1 RANGRF, MOG1 ↓ INa Rare
at which it is maintained to sites at which it is lost results in BrS12 3p21.2-p14.3 SLMAP ↓ INa Rare
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the development of phase 2 reentry, giving rise to a closely BrS13 12p12.1 ABCC9, SUR2A ↑ IKATP Rare
coupled extrasystole. BrS14 11q23 SCN2B, Navß2 ↓ INa Rare
Interestingly, these repolarization abnormalities give BrS15 12p11 PKP2, ↓ INa Rare
rise to low-voltage fractionated electrogram activity and Plakophillin-2
high-frequency late potentials when a bipolar electrogram BrS16 3q28 FGF12, FHAF1 ↓ INa Rare
is recorded in the epicardial region of the right ventricular BrS17 3p22.2 SCN10A, ↓ INa 16.7%
outflow tract (RVOT) in an experimental model.36 The low- Nav1.8
voltage fractionated electrogram activity, initially thought BrS18 6q HEY2 ↑ INa Rare
to be due to delayed conduction in the RVOT,37 has more (transcriptional
recently been shown in an experimental model to be due to factor)
dyssynchrony in the appearance of the epicardial AP dome BrS19 7p12.1 SEMA3A, ↑ Ito Rare
secondary to accentuation of the AP notch, and the high-fre- Semaphorin
quency late potentials are due to concealed phase 2 reentry,
both the result of repolarization abnormalities in the RVOT
Therapeutic Strategies
epicardium.36
Fever should be treated promptly with antipyretics, and drugs
that unmask or aggravate BrS (www.brugadadrugs.org) should
be avoided. A number of precipitants for ventricular arrhyth-
mias have been reported (Figure 4) and should be addressed
acutely. Isoproterenol has been used successfully to control
VF storm.38 The occurrence of spontaneous VF in patients
with BrS is often related to increases in vagal tone, and cor-
respondingly, electrical storm is sometimes treatable by the
increase of sympathetic tone via isoproterenol administration
(Figure 3).
Quinidine may have a role in asymptomatic patients; how-
ever, this has not been evaluated in large double-blinded
clinical trials.39 Quinidine is effective as adjunctive therapy
in symptomatic patients, with recurrent arrhythmias and fre-
quent ICD discharges.40 Effectiveness of quinidine or hydro-
quinidine in doses ≤600 mg/d is 85% (median follow-up of
Figure 4. Brugada electrocardiogram types and precipitants of 4 years).41 A prospective registry of empirical quinidine for
ventricular arrhythmia in Brugada syndrome. Type 1 is character- asymptomatic BrS has been established (http://clinicaltrials.
ized by a coved-type ST-segment elevation of ≥2 mm in the right gov/ct2/show/NCT00789165?term_brugada&rank_2). Doses
precordial leads (V1–V3) followed by a negative T-wave. In type 2,
ST-segment elevation has a saddleback appearance with a high
between 600 and 900 mg are recommended by the study, if
takeoff ST-segment elevation of >2 mm, a trough displaying >1- tolerated.39
mm ST-elevation followed by a positive or biphasic T-wave. Type The relatively low annual rate of arrhythmic events in asymp-
3 has an ST-segment morphology that is either saddleback or tomatic patients (0.5% versus 7.7%–10.2% in patients with
coved with an ST-segment elevation of <1 mm. PMVT indicates
polymorphic ventricular tachycardia; PVC, premature ventricular VF and 0.6%–1.2% in patients with syncope) warrants careful
contraction; and VF, ventricular fibrillation. consideration for ICDs in asymptomatic patients.42 In the recent
 226  Circ Arrhythm Electrophysiol  February 2015
HRS/EHRA/APHRS (Heart Rhythm Society/European Heart
Rhythm Association/Asia Pacific Heart Rhythm Society) guide-
lines, ICDs are not recommended in asymptomatic patients.2
However, the ICD is first-line therapy for BrS patients with a
history of VT/VF or arrhythmic syncope. Long detect durations
and high detect rates along with careful programming of dis-
criminators may minimize inappropriate ICD therapy.
In 9 patients with VF storm due to BrS, electroanatomic
mapping has demonstrated abnormally low, prolonged volt-
ages and fractionated late potentials clustering exclusively
in the anterior aspect of the RVOT epicardium.43 Ablation at
these sites rendered VT/VF noninducible and normalized the
Brugada electrocardiogram pattern in the majority. Long-term
outcomes (20±6 months) were excellent, with no recurrent
VT/VF with only 1 patient on medical therapy with amioda-
rone.43 One recent study (10 patients) reports late activation
in the endocardium of the RVOT as a potential VF substrate
in BrS patients with VF episodes.44 Radiofrequency ablation
within the RVOT endocardium normalized the electrocardio-
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gram, suppressed VF storm, and reduced VF recurrence.
Early Repolarization Syndrome
Although early repolarization (ER; Figure 5) was histori-
cally considered benign, this perception changed in 2000
when experimental data in wedge models of ER were shown
to be capable of generating rapid PMVT.45 Validation of this
hypothesis came with the landmark study of Haïssaguerre et
al46 and coworkers demonstrating a high prevalence of ER in
patients with idiopathic VF. Numerous studies have shown a
clear increased representation of the ER pattern in patients
with idiopathic VF, with augmentation of the amplitude of ER
preceding the development of ventricular arrhythmias.47
The early repolarization pattern should be viewed as
largely benign.47 In some, ER is a modifier of risk of underly-
ing cardiac conditions, and rarely ER represents as a primary
arrhythmogenic disorder (ie, the ERS when other etiologies
have been systematically excluded and when ER is associ-
ated with otherwise unexplained VF). The risk of arrhythmia
is reported to depend on the location, pattern, and magnitude
of ER. A relatively high risk is associated with ER in the infe-
rior limb leads with a high amplitude J-point/wave (>0.2 mV)
and a horizontal or descending ST segment after the J-point
(compared with rapidly ascending/upsloping ST segments).48
These high-risk features are observed in <0.3% of the popula-
tion.48 In the general population, ER is associated with a 1.3-
to 6-fold increased relative risk of death.48 The highest risk is
associated with global ER, in which ER is apparent in inferior,
lateral, and anterior (right precordial) leads. Despite the high
overall prevalence of ER in the general population (6%–13%)
and the even higher prevalence of ER in patients with idio-
pathic VF (>20%–30%, ≤50%–60%), VF itself is rare (ER is
estimated to increase VF risk from 3.4 per 100 000 to 11 per
100 000).49 The ideal method to accurately identifying individ-
uals with ER with an increased risk of death or VF compared
with the benign ER observed in a substantial proportion of the
population remains elusive.
Mechanism of Arrhythmia
ER is reported to be due to steep transmural AP gradients that
predispose to arrhythmogenesis.47 The normal epicardial AP
differs from the endocardial in having a prominent phase 1
notch or spike-and-dome morphology (Figure 2). The differ-
ence is due primarily to a larger Ito in the epicardium, which
results in greater net repolarizing (outward) current flow
Figure 5. A, Early repolarization pattern
in the inferior and lateral leads. Isoproter-
enol-mediated attenuation of inferolateral
early repolarization; early repolarization is
apparent at a heart rate of 54 beats per
minute (B) with gradual attenuation as
heart rate increases (C and D).
 Obeyesekere et al   Management of Arrhythmia in Channelopathies   227
during phase 1. In ER, a further enhancement in epicardial net
outward current results in an enhancement of the endocardial-
to-epicardial AP differences that manifests as J-waves, which
reflects current flow resulting from transmural voltage gradi-
ents generated by the presence of a prominent AP notch in
epicardium but not endocardium.50
Recent studies have provided insight into how the repolar-
ization gradients in ER translate into arrhythmogenesis.51 The
study by Koncz et al51 suggest that the AP dome of cells within
LV epicardium become accentuated giving rise to phase 2
reentry and PMVT. This study showed that repolarization
defects can be accentuated by acetylcholine, explaining the
deleterious influence of elevated vagal tone, and that relatively
high intrinsic levels of Ito account for the greater sensitivity of
the inferior LV wall to development of VT/VF. Quinidine and
isoproterenol were shown to ameliorate effects by reversing
the repolarization abnormalities. The mechanism underlying
development of arrhythmias in these models of ERS has been
shown to be nearly identical to those of BrS.52
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Therapeutic Strategies
Because of their similar pathophysiological mechanism, it is
not surprising that the approach to therapy of ERS is similar
to that of BrS. β-adrenergic activation with isoproterenol is
effective in suppressing ER arrhythmias by enhancing inward
calcium current (Figures 2 and 5).53 Quinidine via its effects
to inhibit Ito is effective as well.53 A multicenter observational
cohort study has demonstrated that isoproterenol in acute
cases and quinidine in chronic cases is effective for suppres-
sion of VF related to ERS.54 In this study (n=122; 90 male
patients; mean age, 37±12 years), patients with ER in the
inferolateral leads with >3 episodes of idiopathic VF (includ-
ing those with electrical storms) had empirical antiarrhythmic
drug therapy prescribed by the treating physicians. Follow-up
data were obtained for all patients using an ICD. Isoproterenol
infusion immediately suppressed electrical storms in 7 of 7
patients. Quinidine decreased recurrent VF from an average
of 33 episodes to none over >2 years of follow-up. In addition,
quinidine restored a normal electrocardiogram. Although this
was a case series with empirical drug therapy, there was no
suggestion of benefit from a number of antiarrhythmic drugs
(ie, β-blockers, verapamil, mexiletine, amiodarone, and class
1C agents). In 7 patients with J-wave syndromes (5 patients
with BrS and 2 patients with ERS) who experienced ICD
shocks due to recurrent VF after ICD implantation, combina-
tion therapy of cilostazol and bepridil has been effective in
suppressing VF recurrence.55
An ICD is indicated following cardiac arrest or docu-
mented VT/VF. There is no current risk stratification strategy
for asymptomatic patients with ER in the general population
and within families with ER. Syncope attributed to ER seems
clinically uncommon and warrants an aggressive attempt to
verify that syncope is related to arrhythmia.
Catecholaminergic PMVT
Affected patients typically present with life-threatening (poly-
morphic or bidirectional VT or VF) associated with adrenergic
stress (physical or emotional; Figure 6). CPVT is rare (estimated
at 1/10 000), with SCD as the first presentation in ≤30% of
cases.56 Mortality is high when untreated, reaching 30% to 50%
by age 30.56 CPVT-related symptoms occur early in life and are
reported to occur in ≈35% and 72% by the age of 10 and 20,
respectively. The mean age at presentation is between 7 and 9
years. An atypical form of CPVT (typically gene negative) may
be observed in older patients and seems to be more sporadic.56
Mechanism of Arrhythmia
CPVT is caused by mutations in genes involved in the intracellu-
lar calcium homeostasis of cardiac cells. Excitation contraction
coupling is mediated by calcium-induced calcium release at the
time of cardiac depolarization. A gain-of-function mutation of
the (ryanodine receptor-2) RyR2 receptor leads to a premature
release of calcium.57 With cellular depolarization, a small influx
of calcium into the cytosol binds the RyR2 channel on the sar-
coplasmic reticulum and opens the channel, leading to a larger
release of calcium from the sarcoplasmic reticulum. This calcium
binds to contractile proteins within the cardiac cell with resultant
muscle contraction. Mutations in (calsequestrin-2) CASQ2, a
regulatory protein, also contributes to abnormal calcium regula-
tion.58 Thus, an increase in diastolic calcium is thought to cause
delayed afterdepolarizations and the subsequent arrhythmia by
activating a calcium-dependent inward current.59
Mutations in 2 other genes (KCNJ2 and ANKB) may cause
catecholamine-induced ventricular arrhythmia (including
bidirectional VT) and may resemble CPVT.
Figure 6. Exercise-induced bidirectional
ventricular tachycardia in catecholaminer-
gic polymorphic ventricular tachycardia.
 228  Circ Arrhythm Electrophysiol  February 2015
Therapeutic Strategies
Treatments for CPVT include medical and surgical efforts to
suppress the release and effects of epinephrine at the myocar-
dial level or modulate calcium regulation by inhibiting RYR2
function. ICDs seek to treat the ventricular arrhythmia when
the aforementioned measures fail.
β-blockers are considered first-line therapy and should be
prescribed in every patient with CPVT. Urgent management
of unstable patients typically involves bolus or continuous
infusion of intravenous β-blockers. Conscious sedation and
even general anesthetic may reduce the adrenergic state that
occurs in unstable CPVT patients, particularly with flurries of
ICD shocks, although this approach is unproven. Arrhythmic
event rates on β-blockers remain significant. In a review
combining 11 studies (mean follow-up range, 20 months to
8 years), totaling 403 patients with 88% on a β-blocker, the
estimated 8-year arrhythmic event-rate was 37.2% (95% CI,
16.6%–57.7%), with a near-fatal event-rate of 15.3% (95%
CI, 7.4%–23.3%) and a fatal event-rate of 6.4% (95% CI,
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3.2%–9.6%).60 This review demonstrated that suppression
of exercise-induced ventricular arrhythmias with β-blockers
does not necessarily translate into long-term effectiveness of
therapy. Studies have also demonstrated the occurrence of
SCD despite a negative exercise stress test in asymptomatic
gene-positive CPVT patients in the absence of β-blockers.60
Flecainide may offer clinical benefit as a first-line therapy
and has been demonstrated efficacious in combination with
β-blocker therapy as a second-line agent in genotype-positive
and genotype-negative patients.61,62 Flecainide directly targets
the molecular defect in CPVT by inhibiting RYR2 channels
and preventing arrhythmogenic calcium waves.63 In the afore-
mentioned recent multicentre international study,61 prior to
flecainide therapy, all genotype-positive patients had persis-
tent physical or emotional stress-induced ventricular arrhyth-
mias while taking β-blockers. Twenty-two of 33 patients
had either partial (n=8, 28%) or complete (n=14, 48%) sup-
pression of exercise-induced ventricular arrhythmias with
flecainide (P<0.001). In the subset of patients already on opti-
mal β-blocker therapy (n=15), flecainide further significantly
suppressed ventricular arrhythmias compared with β-blocker
therapy alone (P<0.003). Patients without suppression of
exercise-induced ventricular arrhythmias (24%, n=7) received
a significantly lower dose of flecainide compared with patients
with ventricular arrhythmia suppression. During follow-up
(median, 20 months), VT recurred in a single patient who
experienced several ICD shocks for PMVT after 8 months
of flecainide treatment. The serum flecainide level was low,
suggesting noncompliance. The optimal dose of flecainide
was reported to be 150 to 200 mg/d (range, 100–300 mg/d).
Daily doses <100 mg were associated with a lack of therapeu-
tic response. These findings suggested that flecainide should
be considered for CPVT patients with refractory ventricular
arrhythmias on β-blocker therapy, and the combination could
even be considered a first-line therapy. Patients with CPVT
treated with flecainide were limited to patients with predomi-
nantly RyR2 (RyR2, n=32; CASQ2, n=1) mutations.
The efficacy of flecainide in patients with genotype-neg-
ative CPVT was also recently reported.62 Twelve patients
with genotype-negative CPVT were treated with flecainide.
Flecainide was initiated because of significant ventricular
arrhythmias (n=8), syncope (n=3), or cardiac arrest (n=1),
despite conventional therapy. At the baseline exercise test
before flecainide, 6 patients had ventricular tachycardia and 5
patients had bigeminal or frequent ventricular premature beats.
Flecainide reduced ventricular arrhythmias at the exercise test
in 8 patients compared with conventional therapy, similar to
that in patients with genotype-positive CPVT. During a fol-
low-up of 48±94 months, arrhythmic events (SCD and aborted
cardiac arrest) associated with noncompliance occurred in 2
patients. Flecainide was not discontinued owing to side effects
in any of the patients.
LCSD interrupts the major source of norepinephrine
released to the heart and is an effective and safe therapeu-
tic option when symptoms persist despite pharmacologi-
cal therapy. However, it requires at least minimally invasive
endoscopic surgery, is not universally available, and has only
been tested in small cohorts.23,64 The procedure increases the
threshold for VF and increases ventricular refractoriness.64
LCSD has been reported as a primary prevention strategy in
a single patient with CPVT65 and patients with LQTS.23 Most
Figure 7. A short-coupled (200 ms) premature ven-
tricular contraction initiating ventricular fibrillation
in the absence of electrocardiogram features of
early repolarization, long QT, short QT, or Brugada
pattern.
 Obeyesekere et al   Management of Arrhythmia in Channelopathies   229
patients have a significant improvement in symptoms post
LCSD, which should likely be considered early in the course
of therapy in high-risk patients.66
ICD therapy has been studied in a multicenter, retrospective
review of young patients with CPVT (n=24).67 Freedom from
appropriate shock at 1 year was 75%. Of appropriate shocks,
only 57% demonstrated successful primary (or immediate) ter-
mination (all for VF). No episodes of PMVT or bidirectional
VT demonstrated successful primary termination. There were
no deaths in this study. Forty-six percent of patients received
65 inappropriate shocks at 1 year. Despite the role for ICDs,
ICD shocks may also be proarrhythmic in patients with CPVT
because they induce an adrenergic state in the patient.68 The
ICD should be programmed with long delays before shock
delivery and high cutoff rates.
All symptomatic CPVT patients should avoid intensive
sports and exercise. Asymptomatic patients may undertake
low-intensity exercise. Exercise restriction can be guided by
response observed during exercise stress testing. However,
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suppression of exercise-induced ventricular arrhythmias with
β-blocker therapy does not necessarily translate into long-
term effectiveness of therapy.69
Idiopathic VF
PMVT is usually initiated by a short-coupled relatively narrow
complex premature ventricular contraction (PVC) (often from
the Purkinje network; Figure 7) in the absence of an identifiable
arrhythmic substrate including the aforementioned channelo-
pathies.70 PMVT/VF can also be triggered from RVOT PVCs.70
The distinction from benign RVOT ectopy seems to relate to a
shorter coupling interval that initiates ventricular arrhythmias.71
Mechanism of Arrhythmia
The underlying mechanism for sustained VF that follows an
initiating short-coupled PVC remains unknown.72
Therapeutic Strategies
Isoproterenol has been shown to be effective in suppressing
VF, and quinidine has also been reported for acute suppres-
sion and for long-term prophylaxis.54,73 Verapamil has been
reported to be acutely effective in patients with idiopathic
Purkinje-related VF but does not prevent SCD with long-term
use.74 Although the efficacy of quinidine has been attributed
to its ability to inhibit Ito, and suppression of arrhythmias in
J-wave syndromes by minimizing transmural electric inho-
mogeneity, in patients with idiopathic VF, the mechanism of
efficacy is unknown.73
Catheter ablation of the triggering PVC has been reported and
has demonstrated a cure rate as high as 89%.70 Reported long-
term outcomes are also relatively favorable with an 18% rate of
recurrent VF postablation. Recurrences may be caused by a dif-
ferent PVC trigger highlighting the underlying arrhythmic sub-
strate.75 An ICD is recommended for secondary prevention.
Conclusions
Knowledge of the pathophysiology of ion channel defects is
essential to understand the acute and chronic suppression of
ventricular arrhythmias. In contrast to conventional triggers
and substrate for ventricular arrhythmias, defect-specific ther-
apy is often crucial in the acute setting to prevent fatal out-
comes, coupled to long-term effective prevention strategies.
A careful history and electrocardiogram recognition of both
repolarization patters and onset patterns is crucial to directing
tailored arrhythmia suppression.
Sources of Funding
This work was supported by grants HL47678 from the National
Heart, Lung, and Blood Institute, National Institutes of Health (Dr
Antzelevitch), C026424 from the NYSTEM (New York State Stem Cell
Science; Dr Antzelevitch), and the Masons of New York State, Florida,
Massachusetts, Connecticut, Maryland, Rhode Island, and Wisconsin.
Disclosures
None.
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Key Words: Brugada syndrome ◼ long QT syndrome ◼ short QT syndrome
 Management of Ventricular Arrhythmias in Suspected Channelopathies
Manoj N. Obeyesekere, Charles Antzelevitch and Andrew D. Krahn

Circ Arrhythm Electrophysiol. 2015;8:221-231

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