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Sudden death and ion channel disease: Pathophysiology and implications for
management

Article  in  Heart (British Cardiac Society) · June 2011

DOI: 10.1136/hrt.2011.223883 · Source: PubMed

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Department of Cardiovascular
Sciences, St George’s University
of London, London, UK
Correspondence to
Elijah R Behr, St George’s
University of London, Division of
Cardiovascular Sciences,
Cranmer Terrace, London SW17
0RE, UK; ebehr@sgul.ac.uk
Accepted 23 May 2011
Published Online First
16 June 2011
Heart 2011;97:1365e1372. doi:10.1136/hrt.2011.223883
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Sudden death and ion channel disease:
pathophysiology and implications for
management
Rachel Bastiaenen, Elijah R Behr
ABSTRACT
The underlying aetiology of sudden arrhythmic death
syndrome is predominantly inherited cardiac disease, and
‘channelopathies’ (cardiac ion channel disease) are the
most common detectable cause of death. This
heterogeneous group includes Brugada syndrome, long
QT syndrome and catecholaminergic polymorphic
ventricular tachycardia. Common features include
variable penetrance, sudden death due to ventricular
arrhythmias, and the absence of structural heart disease.
The understanding of cardiac ion channel disease has
been revolutionised by genetics. At present, genotype
contributes to risk stratification in Brugada syndrome,
long QT syndrome and catecholaminergic polymorphic
ventricular tachycardia, and the future promises
management tailored to the genetic diagnosis.
SUDDEN ARRHYTHMIC DEATH SYNDROME AND
ION CHANNEL DISEASE
In the UK, sudden cardiac death (SCD) claims
400e800 young lives each year.1 A proportion of
these deaths remain unexplained despite a careful
and expert post mortem and toxicological analysis.
This is known as the sudden arrhythmic death
syndrome (SADS).2 3 Most cases are young men,
who die during sleep or at rest, with only
a minority reporting prior syncope. The underlying
aetiology is predominantly inherited cardiac
disease, and a history of other premature sudden
deaths can be elicited in up to 30% of victims’
families.3e5 Comprehensive cardiological evalua-
tion can identify a diagnosis in up to half of SADS
families, most commonly cardiac ion channel
disease, also known as ‘channelopathies’.3 4 6 7 This
heterogeneous group includes Brugada syndrome
(BrS), long QT syndrome (LQTS) and catechol-
aminergic polymorphic ventricular tachycardia
(CPVT). Other channelopathies outside the scope
of this article are short QT syndrome, progressive
cardiac conduction defect and inherited atrial
fibrillation. Ion channel disease has also been
implicated in the aetiology of sudden infant death
syndrome, in w10% of cases.8
Channelopathies have features in common:
a genetic basis; a structurally normal heart; and
predisposition to life-threatening cardiac arrhyth-
mias. There is genetic heterogeneity, meaning that
many different genes may be causative (genotype).
As a result of variable penetrance, members of
a family group with the same genetic mutation
may demonstrate different severity of clinical signs
(phenotype), and it is possible for a mutation
Review
carrier to appear entirely unaffected. The basis for
this genotypeephenotype discordance may be
other genetic modifiers, but this has not yet been
fully explained.9 Each member of a family group
must therefore be assessed individually to deter-
mine their risk.
Genetic testing is predominantly used to confirm
diagnosis by identifying a causative mutation in
a patient with overt clinical phenotype. The chance
of a positive result varies from 60e70% expected
success rate in LQTS and CPVT to 20% in BrS.10 11
A negative result therefore does not rule out the
condition. A positive genetic test can be used for
cascade screening of asymptomatic family
members. Less commonly, it may clarify diagnosis
in a borderline case or form part of the molecular
autopsy in SADS screening.4
ION CHANNELS AND THE VENTRICULAR MYOCYTE
ACTION POTENTIAL
Ion channel disease is associated with mutations in
genes encoding proteins that form or interact with
the specialised channels that conduct sodium,
potassium and/or calcium ions.12 These are pore-
forming proteins, first proposed by Hodgkin and
Huxley in their 1952 Nobel Prize theory of the
nerve impulse and later confirmed by Neher and
Sakmann using the patch clamp technique.13
Ion channel flux is essential for normal cardiac
action potential initiation, propagation and repo-
larisation. The electrical impulse initiates in sinus
node pacemaker cells and propagates via the
specialised cardiac conduction system. This is
possible because the cell membrane has an elec-
trochemical gradient and myocytes are electrically
coupled at their endplates by gap junctions. In the
ventricular myocyte, the electrical potential at rest
(phase 4) is negative ( 90 mV) inside the cell with
respect to the outside. The electrical gradient is
maintained by the sodium calcium exchanger and
inward rectifier currents (IK1 and IK2p).
During depolarisation (phase 0), the membrane
becomes permeable to sodium ions via voltage-
gated sodium channels (INa). These sodium chan-
nels are responsible for the amplitude and upstroke
velocity of the action potential, important deter-
minants for impulse propagation and conduction
velocity.14 There is rapid inwards flux of sodium,
and the electrochemical gradient reverses
(+40 mV). Partial repolarisation begins when the
Ito current is initiated (phase 1) and the membrane
becomes permeable to potassium ions via potas-
sium channels. These potassium channels control
resting potentials, action potential waveforms,
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Figure 1 Ventricular myocyte action potential. The action potential of
atrial and ventricular myocytes consists of five phases: depolarisation
(phase 0), partial repolarisation (phase 1), plateau (phase 2),
repolarisation (phase 3) and resting (phase 4). The long plateau phase
and stable resting phase are characteristic of myocyte action potential.
Specific ion flows contribute sequentially. The corresponding electrical
activity as seen on the ECG is also displayed.
automaticity and refractory periods.14 During the plateau phase
(phase 2), calcium ions enter the cell through voltage-gated
L-type calcium channels (ICa). This triggers release of calcium
from the sarcoplasmic reticulum via the ryanodine receptor
voltage-gated ion channel (hRyR2), and activation of sarcomeric
and myocardial contraction. Subsequently, there is increasingly
rapid efflux of potassium via slow and rapid rectifier currents (IKs
and IKr, respectively) with contributions from IKur, IKATP and
Figure 2 ECG demonstrating the
type1 Brugada pattern. There is
characteristic coved ST segment
elevation followed by T wave inversion
in leads V1 and V2 (type 1 Brugada
pattern) and ‘saddleback’ ST segment
elevation in lead V3 (type 2 Brugada
pattern).
1366
IKACh. IKr is predominantly responsible for repolarisation (phase
3), which results in restoration of the negative electrochemical
gradient. Simultaneously there is uptake of calcium ions by the
sarcoplasmic reticulum, removal by the sodium calcium
exchanger and cardiac relaxation (figure 1).
Disturbance of the balance of depolarisation and repolarisa-
tion is arrhythmogenic, and two main mechanisms are respon-
sible for the generation of tachyarrhythmias in ion channel
disease: triggered activity and re-entrant excitation. Triggered
activity arises from afterdepolarisations which may be early or
delayed. These are premature depolarisations that result from
oscillations in intracellular calcium. If large enough, they can
result in sufficient activation of voltage-gated sodium channels
to cause sodium influx and a subsequent premature action
potential that may result in an ectopic beat. In re-entrant exci-
tation, there is spatial and temporal dispersion of refractoriness
allowing re-entry and propagation of an action potential.
Resultant ventricular tachycardia (VT) is usually polymorphic
and can degenerate into ventricular fibrillation (VF).14
BRUGADA SYNDROME
The BrS is associated with right ventricular conduction delay
and ST elevation in the right precordial ECG leads, syncope and
sudden death due to VF.15 A type 1 Brugada ECG pattern
describes coved ST segment and J point elevation $0.2 mV
followed by a negative T wave (figure 2). BrS is diagnosed when
the type 1 ECG is observed in two or more right precordial leads
(V1eV3) in conjunction with other clinical features (table 1).
The ECG abnormality may be concealed, dynamic and/or
induced by sodium channel blocking agents, such as ajmaline
and flecainide, which can be used to aid diagnosis.15 Placing right
precordial leads in the second and third intercostal spaces
increases sensitivity for detection of the type 1 pattern.15 16
GENETICS
BrS is inherited as an autosomal dominant trait with incomplete
penetrance. It has been associated with more than 250 muta-
tions in seven different genes (table 2). Mutations in the SCN5A
gene, encoding the a subunit of the Nan1.5 sodium channel, are
identified in 21% of index cases (probands).10 In one series, loss-
of-function mutations in genes CACNA1C, CACNB2 and
CACNA2D1, encoding the L-type calcium ion channel,
accounted for a further 12% of Brugada cases, some of which
also exhibited a short QT interval.17 Mutations in the GPD1L
channel interacting protein (ChIP), and SCN1B and SCN3B
b subunits, have been identified in a few cases and result in loss
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Table 1 Diagnostic criteria for Brugada syndrome
One of the following must also be
Diagnostic ECG criteria present
Type 1 BrS pattern in $2 Documented VF
ECG leads (V1eV3)*
Documented polymorphic VT
Family history of SCD <40 years old
Type 1 BrS ECG patterns in family
members
Inducible VT with programmed electrical
stimulation
Syncope
Nocturnal agonal respiration
*In the presence or absence of a sodium channel blocking agent.
BrS, Brugada syndrome; SCD, sudden cardiac death; VF, ventricular fibrillation; VT,
ventricular tachycardia.
of function with impaired INa. There is one example of a gain-of-
function mutation in KCNE3, the putative b subunit for Ito.
Recent evidence suggests that, in some families, the SCN5A
variant represents a genetic modifier rather than a causative
mutation.18
PATHOPHYSIOLOGY
Studies in expression systems have demonstrated that loss-of-
function mutations due to failure of channel expression (traf-
ficking) or changes in functional properties (gating) result in
reduced inwards depolarising sodium current INa.10 There are
two competing hypotheses for the mechanism of ventricular
arrhythmias. The repolarisation theory suggests that unopposed
action of the Ito current in right ventricular epicardium leads to
loss of the action potential dome. Dispersion of repolarisation
allows re-entry during phase 2 of the action potential, providing
the substrate for initiation of VT/VF. The depolarisation theory
suggests that delayed conduction in the right ventricular
outflow tract (RVOT) facilitates re-entry and subsequent
arrhythmia.18
The majority of BrS remains genetically undefined, and there
appears to be overlap with short QT syndrome and early repo-
larisation syndrome (see below). In addition, there is evidence
that structural changes in the RVOT can result in the BrS
phenotype. Therefore the concept of BrS as a single disease
entity caused by reduced INa has been challenged. It is possible
that, in different patients, the type 1 ECG pattern relates to
different underlying mechanisms.18
RISK STRATIFICATION AND MANAGEMENT
Arrhythmias usually occur at rest, particularly at night, and may
be induced by febrile illness and sodium channel blocking agents.
Management involves avoidance of drugs known to exacerbate
the condition (see http://www.brugadadrugs.org) and use of
paracetamol or ibuprofen to reduce fever. At present, the only
reliable treatment to prevent SCD is the implantable cardi-
overter defibrillator (ICD). Isoproterenol is effective at
suppressing VF in patients with BrS who present with electrical
storm.19 Quinidine, a class Ia antiarrhythmic agent with Ito
blocking effects, appears to suppress ventricular arrhythmias in
high-risk patients.20 As yet there are insufficient prospective
studies to consider quinidine first-line treatment, and a registry
has been set up to address this. It can be used as adjunct therapy
in patients with an ICD and recurrent appropriate shocks.20
Epicardial ablation of the RVOT has recently been shown to
normalise the type 1 ECG pattern and prevent VT/VF recurrence
in BrS.21 Catheter ablation may therefore prove to be an alter-
native strategy in patients with recurrent symptoms.
Risk stratification is controversial. There is general agreement
that patients with aborted SCD or syncope are at high risk and
should receive an ICD.15 However, the majority of sudden death
victims have no recorded premorbid symptoms, and in asymp-
tomatic patients with BrS the event rate appears to be lower
than initially expected.22e25 Asymptomatic patients with
spontaneous type 1 ECG patterns appear to be at higher risk.15
Although electrophysiological testing to induce sustained poly-
morphic VT/VF has been used to aid risk stratification, meta-
analyses have failed to find an association between inducibility
and risk. Programmed electrical stimulation in asymptomatic
patients may, however, have a useful negative predictive value.26
Additional high-risk features in BrS include male gender and
South East Asian ethnicity.15 Late potentials on signal-averaged
ECG are more common in symptomatic patients but not an
independent risk factor. QRS fragmentation appears to predict
patients at risk of syncope due to VF.27
While patients with multiple SCN5A mutations present at
a younger age than those with a single mutation, positive
genotype alone is not an independent risk factor for SCD.10
One recent study has, however, suggested earlier and frequent
recurrence of VF in symptomatic BrS patients with SCN5A
mutations compared with those without.28 The severity of
the biophysical consequence in INa resulting from an SCN5A
mutation does appear to influence phenotype and possibly risk,
with increased syncope and longer PR and QRS durations in
patients with mutations leading to protein truncation compared
with missense mutations.29 The functional impact of mutations
may therefore support novel risk stratification strategies.
EARLY REPOLARISATION SYNDROME
Early repolarisation (ER) was long considered a benign ECG
variant, but in recent years has remerged as a marker of SCD.
ER, particularly in the inferior and inferolateral leads, is associ-
ated with idiopathic VF. ER syndrome (ER with idiopathic VF)
in one patient has been associated with a mutation in KCNJ8,

Table 2 Genetic mutations associated with Brugada syndrome

BrS subtype Gene Protein Ion channel Effect of mutation Frequency
BrS1 SCN5A Nav1.5 a subunit INa Loss of function 21%10
BrS2 GPD1L G3PD1L Interacts with a subunit INa Loss of function e
BrS3 CACNA1C Cav1.2 a subunit ICa Loss of function 5.5%16
BrS4 CACNB2 Cavß2 ß subunit ICa Loss of function 4.9%16
BrS5 SCN1B Navß ß subunit INa Loss of function e
BrS6 KCNE3 MiRP2 ß subunit IKs/Ito Gain of function e
BrS7 SCN3B Navß3 ß subunit INa Loss of function e
BrS8 CACNA2D1 Cava2d1 a2d subunit ICa Loss of function 1.8%16
ICa, depolarising inward L-type calcium current (slow); IKs, repolarising outward slow rectifying potassium current; INa, depolarising inward sodium current (fast); Ito, transient outward
potassium current.

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Table 3 Diagnostic criteria for long QT syndrome (the Schwartz score) GENETICS
Diagnostic criteria Points The LQTS has both autosomal recessive (Jervell Lange-Neilsen)
ECG findings QTc calculated by Bazett’s $480 ms 3
and dominant (Romano Ward) modes of inheritance but may
formula* also be polygenic. Although 12 different culpable genes have
460e470 2 been identified (table 4), three subtypes account for 70e75% of
ms definite congenital LQTS cases11: LQT1 results from loss-of-
450 ms 1 function mutations in KCNQ1 (encoding the a subunit of IKs),
(males)
LQT2 from loss-of-function mutations in KCNH2 (encoding the
Torsades de pointesy 2
a subunit of IKr), and LQT3 from gain-of-function mutations in
T wave alternans 1
SCN5A (encoding the a subunit of INa). The remaining nine
Notched T wave in three 1
leads genes include other loss-of-function mutations in potassium
Resting heart rate below 0.5 channels, gain-of-function mutations in calcium channels,
second centile for age and mutations in ChIPs such as ankyrin B and caveolin 3.
Clinical history Syncopey With 2 AndersoneTawil syndrome (LQT7) is a multi-system disorder
stress associated with loss-of-function mutations in KCNJ2, encoding
Without 1 the IK1 current, expressed in both skeletal and cardiac muscle.
stress
Congenital deafness 0.5
The resulting phenotype consists of dysmorphology, hypo-
Family historyz Family members with definite 1
kalaemic periodic paralysis and QT prolongation. Timothy
LQTS by Schwartz score syndrome (LQT8) is another multi-system disorder with gain-
Immediate family members 0.5 of-function mutations identified in CACNA1C encoding the
with SCD <30 years old a subunit of the L-type calcium current. The syndrome
Score #1, low probability of LQTS; 2e3, intermediate probability of LQTS; $4, high comprises QT prolongation with syndactyly, cognitive abnor-
probability of LQTS. malities, immune deficiency and intermittent hypoglycaemia.
*In the absence of drugs or disorders known to affect QTc.
yMutually exclusive. Compound or digenic disease occurs in w5% of cases.11
zThe same family member cannot be counted in both family history categories.
LQTS, long QT syndrome; QTc, corrected QT interval; SCD, sudden cardiac death.
PATHOPHYSIOLOGY
Different mutations affect ion channel function by different
molecular mechanisms, but in all cases TdP results from trig-
and, in one series, mutations in CACNA1C, CACNB2 and
gered activity due to early afterdepolarisations.33 In LQT1,
CACNA2D1 were demonstrated in 16% of probands (as well as
trafficking defects tend to result in a milder clinical phenotype
in 12% of BrS probands).17 There are similarities between ER and
(haploinsuffiency), but formation of dysfunctional ion channels
BrS, including response to heart rate and drugs. This has led to
from mutant and wild-type subunits causes more severe clinical
the suggestion that both form part of the same spectrum of
disease (dominant negative effect).34 Trafficking defects are more
disease, the ‘J wave syndromes’.30 However, important differ-
common in LQT2, while LQT3 mutations result in late re-
ences exist: ER changes are not provoked by sodium channel
activation of sodium channels and increased late sodium current.
blocker administration and in ER syndrome the signal-averaged
ECG rarely shows abnormal late potentials. Patients with ER
and resuscitated SCD warrant ICD implantation and may RISK STRATIFICATION AND MANAGEMENT: ROLE FOR
benefit from quinidine therapy.31 At present, there are no risk GENETICS
stratifiers for asymptomatic subjects with ER. Management of LQTS includes avoidance of QT-prolonging
drugs (see http://www.azcert.org) and high-intensity sport.
Medical therapy with b-blockers is first-line prophylaxis.
THE LONG QT SYNDROME Patients with aborted SCD or syncope and/or TdP despite
The LQTS is associated with QT prolongation, syncope and b-blocker therapy should be considered for ICD implantation.35
sudden death due to torsades de pointes (TdP) and VF.32 Diag- Left cardiac sympathetic denervation is effective at reducing
nosis is made according to the Schwartz score (table 3).32 ventricular arrhythmias in patients intolerant of b-blockers, in

Table 4 Genetic mutations associated with congenital long QT syndrome

LQTS subtype Gene Protein Ion channel Effect of mutation Frequency
LQT1 KCNQ1 KV7.1a IKs Loss of function 30e35%
LQT2 KCNH2 KV11.1a IKr Loss of function 25e30%
LQT3 SCN5A NaV1.5a INa Gain of function 5e10%
LQT4 ANK2 Ankyrin-B INa,K, INCX Loss of function 1e2%
LQT5 KCNE1 minKß IKs Loss of function 1%
LQT6 KCNE2 MiRP1ß IKr Loss of function Rare
LQT7* KCNJ2 Kir2.1a IK1 Loss of function Rare
LQT8y CACNA1C CaV1.2a1c ICa,L Gain of function Rare
LQT9 CAV3 Caveolin-3 INa Gain of function Rare
LQT10 SCN4B NaV1.5ß4 INa Gain of function Rare
LQT11 AKAP9 Yotiao IKs Loss of function Rare
LQT12 SNTA1 A1-syntrophin INa Gain of function Rare
ICa, depolarising inward calcium current (slow); IK1, Kir2.1 inward rectifying current; IKr, repolarising outward rapid rectifying potassium current; IKs, repolarising outward slow rectifying
potassium current; INa, depolarising inward sodium current (fast).
*AnderseneTawil syndrome.
yTimothy syndrome.

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children in whom an ICD may be avoided, and as an adjunct in

those with recurrent ICD therapies.36 Permanent pacing with
rate-smoothing algorithms can reduce bradycardia and pause
dependent TdP, but does not reduce sudden death in high-risk
patients, and therefore utilising the pacing function of an ICD is
considered a safer alternative.
Risk assessment is predominantly based on clinical pheno-
type, the majority of data coming from the International LQTS
Registry. The best predictors of events have been female
adulthood, corrected QT interval (QTc) $500 ms, and previous
syncope or aborted sudden death.37 A single episode of syncope
has been associated with a sixfold increase in the risk of
subsequent SCD.38 It has been proposed that patients
presenting with aborted sudden death and spontaneous TdP be
considered high risk, those with QTc $500 ms and previous
syncope intermediate risk, and those with QTc #500 ms and no
syncope low risk. Clinical risk assessment should be continuous,
as there are age- and gender-specific differences. The risk of
cardiac events is higher in males during childhood and females
during adulthood, with gender risk reversal in the mid-teens.39
Arrhythmic episodes also appear to be associated with stressful
life events.40
Genotypeephenotype studies have provided insights into
ECG characteristics, clinical course and risk of cardiac events
including sudden death (figure 3).41 Patients with LQT1 tend
to have broad-based T waves and syncope or sudden death
during exercise, particularly swimming. LQT2 patients have
low-amplitude or notched T waves and syncope or sudden
death with sudden auditory stimulidfor example, the
morning alarm clock. Patients with LQT3 have long, flat ST
segments, a tendency towards bradycardia and sudden death
during sleep.
b-blocker therapy is most effective in LQT1 and LQT2. In
LQT1, atenolol has been associated with 77% reduction in
the risk of cardiac events in high-risk patients. In LQT2,
nadolol was associated with 87% risk reduction.42 b-blocker
therapy is least effective in LQT3.37 Sodium channel blockers,
such as flecainide, have been shown experimentally to reduce
the QT interval in some LQT3 patients, but may unmask
or exacerbate ST elevation in those with Brugada overlap
syndromes.43
The role of genotype in risk prediction is uncertain at present.
A recent study of genetic carriers with a normal resting QTc
showed a 10-fold increased risk of events compared with
mutation negative relatives.44 In clearly affected individuals, it
was thought initially that LQT1 and LQT2 patients were at
higher risk of cardiac events, but events were more lethal in
LQT3.45 Subsequent studies found a lower event rate in LQT1
and no significant difference between genotypes after adjust-
ment for clinical risk factors.46 47 Exceptions are male children
with LQT1 and female adults with LQT2, who appear to have
elevated risk.38 For female adult LQT2 carriers, this risk appears Figure 3 ECG characteristics in long QT syndrome subtypes. LQT1
greatest in the first year post partum.48 Transmembrane-located tend to have broad-based T waves. LQT2 have low-amplitude or notched
mutations and those with dominant negative effect are associ- T waves. LQT3 patients often have long flat ST segments.
ated with increased risk independent of traditional risk factors in
LQT1, and ion channel pore-forming mutations carry greater
risk in LQT2.34 Future risk prediction may therefore be possible more severe disease.49 In addition, incompletely penetrant LQTS
based on biophysical properties of mutated channels. In subjects may be more clearly expressed and individuals therefore more
with digenic or compound mutations, the QTc may be more symptomatic when co-segregation of deleterious common
prolonged than in monogenic carriers, and risk of cardiac events polymorphisms occurs.50 These examples of oligogenic and
is higher. Common genetic variation also appears to act as an polymorphic effects in LQTS demonstrate the concept of
important genetic modifier. Single-nucleotide polymorphisms in impaired ‘repolarisation reserve’, a reduction in the capacity of
NOS1AP, known to modulate the QT interval in the general the heart to repolarise that may become more evident clinically
population, have been associated with longer QTc intervals and when additional ‘hits’ to this reserve are present.

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CATECHOLAMINERGIC POLYMORPHIC VENTRICULAR
TACHYCARDIA
CPVT was first described in children with syncope, sudden
death, bidirectional or polymorphic VT and VF after a rapid
increase in sympathetic tone, usually secondary to physical or
emotional stress.51 Bidirectional VT shows an alternating QRS
axis with 1808 rotation on a beat-to-beat basis (figure 4).
GENETICS
CPVT displays both autosomal dominant and autosomal recessive
modes of inheritance with high penetrance. Approximately
55e65% of probands carry a mutation in the RYR2 gene, encoding
the cardiac ryanodine receptor, which accounts for autosomal
dominant disease.52 Mutations in the CASQ2 gene, encoding
calsequestrin, a calcium-buffering protein, account for a small
number of autosomal recessive cases. KCNJ2 mutations associated
with Anderson syndrome may underlie a minority of cases.
PATHOPHYSIOLOGY
Both the ryanodine receptor and calsequestrin are involved in
intracellular calcium homoeostasis and excitationecontraction
coupling. Calcium leakage from the sarcoplasmic reticulum is
exacerbated during adrenergic stimulation, causing calcium
overload and delayed afterdepolarisations. The mechanism of
bidirectional VT is therefore triggered activity possibly arising
from Purkinje tissue.53
RISK STRATIFICATION AND MANAGEMENT
Patients should avoid competitive and high-intensity sports,
stimulant drugs and digoxin. b-Blocker therapy is recommended,
and the dose should be titrated against response using exercise
testing to achieve optimal control of arrhythmias. Although
early data suggested almost complete protection except in
non-compliant patients, other studies observed recurrence of
cardiac events even on maximal tolerated doses.51 54 ICD
implantation is indicated after aborted SCD and for patients
who have recurrence of syncope or VT despite b-blocker therapy.
Figure 4 ECG from an exercise
tolerance test in a patient with
catecholaminergic polymorphic
ventricular tachycardia. Arrowed are
multiple ventricular ectopics with
bidirectional couplets. Note the
alternating QRS axis with 1808 rotation
on a beat-to-beat basis.
1370
As in LQTS, left cardiac sympathetic denervation can be
a helpful adjunct if symptoms persist.55 Blockade of L-type
calcium channels by verapamil and of RyR2 channels by flecai-
nide or propafenone appears to reduce intracellular calcium
and in turn arrhythmia recurrence. Given in combination with
b-blockers, these represent an alternative additional therapy.56
While evidence suggests that CPVT is a highly malignant
condition, current data are limited and this view may change
with accumulation of information from asymptomatic carriers.
RYR2 mutations are, however, associated with earlier symptom
onset, and male carriers have a fourfold higher risk of cardiac
events.54 b-Blocker therapy is therefore recommended even in
asymptomatic RYR2 mutation carriers.
FUTURE DIRECTIONS
Improved risk stratification in the channelopathies is vital,
particularly as ICD implantation is not without complication
and our ability to discriminate those individuals likely to benefit
is limited. Inappropriate therapy for sinus tachycardia and atrial
arrhythmias is problematic and relevant in cardiac ion channel
disease because patients tend to be young and physically active
and SCN5A and RYR2 mutation carriers are prone to atrial
arrhythmias.57 Long-term endovascular lead placement in young
patients is also associated with inappropriate therapy secondary
to lead failure requiring lead extraction, although this compli-
cation may be reduced in future by new ICD technologies with
subcutaneous leads (S-ICD).57
Genotyping may be increasingly useful for risk stratification
of patients. Rapid advances in sequencing technologies, together
with cost reductions, have already brought genetic testing out of
the research laboratory and into mainstream clinical practice.
The number of known causative mutations increases steadily
along with our understanding of the molecular mechanisms of
arrhythmia initiation and modifiers of these events. This may
fuel the development of ‘gene-specific’ therapy to directly
counteract the functional consequences of mutations and
improve management of affected individuals and their families.
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Translational collaboration between basic scientists and clinicians
will be important to facilitate further advancement in this area.
CONCLUSIONS
Ion channel disease offers a paradigm for the understanding of
a molecular lesion in the patient and its translation to pheno-
type and eventually management decisions. Nonetheless there
are many gaps in our understanding, particularly of incomplete
penetrance, risk stratification and the underlying pathophysi-
ology of some of the conditions. Progress is rapid, and patients
and their families will continue to benefit as our knowledge
improves.
Funding Funds for research received from Biotronik and Boston Scientific.
Competing interests None.
Provenance and peer review Commissioned; externally peer reviewed.
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1372 Heart 2011;97:1365e1372. doi:10.1136/hrt.2011.223883

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Sudden death and ion channel disease:

pathophysiology and implications for
management
Rachel Bastiaenen and Elijah R Behr

Heart 2011 97: 1365-1372 originally published online June 16, 2011
doi: 10.1136/hrt.2011.223883

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