Transcript channelopathies

CARDIAC CHANNELOPATHIES
Dr Binjo J Vazhappilly
SR Cardiology
Calicut Medical College
• Cardiac channelopathies refers to genetic disorders characterized
by altered cardiac excitability, in the absence of structural cardiac
involvement.
• Also known as inherited arrhythmogenic diseases (IADs).
• Disorders due to genetic mutation affecting the genes that control
the excitability of myocardial cells.
Major cardiac channelopathies include
Long QT Syndrome
Brugada syndrome
CPVT
Short QT syndrome
Webster and Berul circulation 2013;127:126-140
Long QT Syndrome
• LQTS is an IAD characterized by abnormally prolonged QT interval.
• 13 genes are found to be linked to LQTS till now.
• Mutations in 3 genes KCNQ1 (LQT1), KCNH2 (LQT2) and SCN5A
(LQT3) accounts for approximately 75% of cases with a strong
clinical phenotype.
Prevalence
 Assumed to be 1/2500 live births .
 In an Italian study ,where ECG was performed in 44,596 infants ,
0.07% had a QTc >470 ms and 0.47% had QTc between 451 and 470
ms
 Molecular screening showed
disease-causing mutation in
43% of neonates with
QTc >470 ms & 29% of
those with QTc b/w
461 and 470 ms
Schwartz etal Circulation. 2009;120:1761-1767
CHANNELOPATHY
GENE
PROTEIN
LQT 1
KCNQ1
α-subunit of Iks
LQT 2
KCNH2
α-subunit of Ikr
LQT 3
SCN5A
Sodium channel, α-subunit
LQT 4
ANK2
Cellular structural protein
LQT 5
KCNE1
β-subunit of Iks
LQT 6
KCNE2
β-subunit of Ikr
LQT 7
KCNJ2
α-subunit of Ik1
CHANNELOPATHY
GENE
PROTEIN
LQT 8
CACNA1C
l-type Ca + channel, α-subunit
LQT 9
CAV3
Plasma membrane structural protein
LQT 10
SCN4B
Sodium channel, β-subunit
LQT 11
AKAP9
Kinase anchoring protein (Yotaio)
LQT 12
SNTA1
Syntrophin α1 (affects sodium
current)
LQT 13
KCNJ5
Inwardly rectifying potassium
channel, α-subunit
Potassium Channel LQTS
• Potassium channel derangements account for majority of LQTS
cases : Long QT 1, 2, 5, 6, 7 and 13.
• IKs : slowly activating delayed rectifier cardiac potassium channel
 subunit is encoded by KCNQ1
β subunit is encoded by KCNE1
Loss of function mutation result in LQT 1 and LQT 5
• Ikr : rapid delayed rectifier potassium channel
 subunit encoded by KCNH2
β subunit encoded by KCNE2
Loss of function mutation result in LQT 2 and LQT 6.
• IKI : another inwardly rectifying K+ channel
encoded by gene KCNJ2
Loss of function mutation result in LQT 7 (Tawil-Anderson syn)
• KCNJ5 mutation which is a loss-of-function mutation in an inwardly
rectifying potassium channel result in LQT 13
Sodium channel LQTS
•  subunit of sodium channel is encoded by SCN5A and β subunit
encoded by SCN4B.
• Gain of function mutations in SCN5A produce LQT3.
• Mutations in SCN4B produce LQT10.
Molecular basis for long QT syndrome
Topol EJ, Califf RM et al
Pathophysiology of LQTS
• Prolonged repolarization results fm net reduction in outward
current, due to ↑ in inward Na + or Ca + current, ↓ in outward
K+ current or both resulting in long QT interval.
 Fast heart rate preceding TdP in LQT1 postulate delayed
afterdepolarizations (DADs) as its arrthymogenic mechanism.
• Increased Ca+ loading in parallel with QT prolongation, facilitate
DADs and DAD-dependent TdP.
 Pause-dependent TdP is triggered by early afterdepolarizations
(EADs).
• Pause leads to enhanced Ca+ release from intracellular stores and
activate Ca+ dependent transmembrane currents.
Initiation of arrhythmia in LQTS
 Non-pause dependent
torsade de pointes
 Mainly in LQT1
 Pause dependent
torsade de pointes
 Mainly in LQT2
Clinical features
• May be asymptomatic
• Symptomatic pts present with palpitations, presyncope, syncope or
cardiac arrest.
• Neuronal deafness is associated with Jervell and Lange-Nielsen
syndrome
• In a study on 287 pts , 61% were symptomatic : 9% presented with
a cardiac arrest, 26% with syncope ,10% with seizures , 6% had
presyncore or palpitation
• 67% had symptoms related to exercise, 18% had symptoms during
exercise and with emotion, 7% with emotion alone, 3% with loud
noise and exercise and 2% with anesthesia.
A Garson, M Dick et al Circulation. 1993;87:1866-1872
Triggers of arrhythmia
• Triggers include exercise, noise, emotion, sudden wakening from
sleep by noise , swimming or diving.
• Swimming and exertion-induced cardiac events are strongly
associated with LQT1.
• Auditory triggers and events
during postpartum period
occur in pts with LQT2.
• Events occurring during periods of
sleep or rest are most common in
LQT3.
Triggers of LQTS
Schwartz et al
Jervell and Lange-Nielsen syndrome
• Autosomal recessive variant of long QT syndrome.
• Due to homozygous or compound heterozygous mutations on
either the KCNQ1 or KCNE1 genes.
• Pts also suffer from congenital deafness.
• Most severe of major variants of LQTS.
• 90% have cardiac events, 50% become symptomatic by
age of 3 yrs and their average QTc is markedly prolonged (557± 65
ms)
Event-free survival comparing Jervell and LangeNielsen syndrome pts with other long-QTS
Timothy syndrome / LQT8
• Mutations in CACNA1C, encoding voltage-gated calcium channel
results in Timothy syndrome or LQT8.
• Rare and extremely malignant variant.
• Pts had marked QT prolongation and associated syndactyly .
• Presents with 2:1 atrioventricular block and macroscopic T-wave
alternans.
• Among 17 children reported by Splawski et al, 10 (59%) died at a
mean age of 2.5 yrs.
ECG in LQTS
• QTc values exceeding 440 ms (in males) and 460 ms (in females) are
considered abnormal .
• LQT1 is associated with a broad-based T wave.
• LQT2 with low-amplitude notched or
biphasic T wave.
• LQT3 with long isoelectric segment followed
by a narrow-based T wave.
LQTS : Diagnostic Criteria
Score
≤1 point: low probability
1.5–3 points: intermediate probability
≥3.5 points: high probability.
Schwartz et al
Circ Arrhythm Electrophysiol. 2012;
Keating Criteria
Asymptomatic with QTc > 470 ms or
Typical symptoms with QTc ≥ 450 ms
Sensitivity and specificity of
QTc duration alone ,
Schwartz score and
Keating criteria
Nynke Hofman, Arthur A.M. Wilde et al
EHJ
Risk stratification
Risk of a 1st cardiac event in pts younger than 40 years of age in the absence
of any LQTS active treatment
Treatment
• All LQTS pts with h/o syncope and asymptomatic individuals with
definite QT prolongation should be treated withβ-blockers
• Drugs used are Propranolol ( 2-4 mg/kg/d),
Nadolol (1-2.5 mg/kg/d)
Metoprolol (2-4 mg/kg/d)
• Dose titration done with a target of 25% to 35% reduction of
maximal heart rate attained on therapy.
• Left Cardiac Sympathetic Denervation may be considered in
symptomatic patients even after betablocker therapy.
Treatment
• ICD implantation along with β -blockers is recommended for LQTS
patients with previous cardiac arrest or who are experiencing
syncope and/or VT while receiving beta blockers.
• Permanent pacing is indicated for sustained pause-dependent VT,
with or without QT prolongation.
• Avoid competitive sports, QT-prolonging drugs and lowered K+
levels .
β-blocker therapy in LQTS
• β-blocker therapy results in 42% to 78% reduction of aborted
cardiac arrest or sudden cardiac death.
• Pts on β-blockers still have risk of sudden death.
• In a study , no. of cardiac events before initiation of β-blocker
therapy was 0.97 events /pt/yr which decreased to 0.31 after
initiation of therapy .
• β-blocker is most efficacious in LQT1 and less effective in LQT3.
• In LQT3, combination of mexiletine with a noncardioselective βblocker (propranolol ) is used .
Brugada Syndrome
• Characterized by peculiar ECG pattern of ST-segment elevation in
leads V1 to V3 and incomplete or complete RBBB in the absence of
signs of acute MI.
• Autosomal dominant disorder with variable expression
• More common in men than in women.
• Usually diagnosed in adulthood ( Avg age at diagnosis is 41 yrs).
Genes Involved in Brugada
CHANNELOPATHY
GENE
CHANNEL/PROTEIN
Effect
BrS 1
SCN5A
Cardiac sodium channel 
subunit
↓ Na+ current
BrS 2
GPD1L
Glycerol-6-phosphate
dehydrogenase
↓ Na+ current
BrS 3
CACNA1C
L-type calcium channel 
subunit
↓ Ca2+ current
BrS 4
CACNB2
L-type calcium channel β
subunit
↓ Ca2+ current
BrS 5
SCN1B
Cardiac sodium channel β1
subunit
↓ Na+ current
BrS 6
KCNE3
Transient outward current
β subunit
↑ K+ Ito current
BrS 7
SCN3B
Cardiac sodium channel β3
subunit
↓ Na+ current
ECG patterns
Type-1
≥ 2-mm J-point elevation, coved type ST-T segment elevation and
inverted T-wave in leads V1 and V2.
Type-2
≥ 2-mm J-point elevation, ≥ 1-mm St segment elevation, saddleback
ST-T segment and a positive or biphasic T-wave.
Type-3
Same as type 2, except that the ST-segment elevation is <1 mm.
Placement of precordial
leads in higher intercostal spaces
can unmask the
Brugada ECG pattern
Pathophysiology
• Debate is still going on whether pathophysiology is due to
repolarization or depolarization disorder.
Repolarization hypothesis by Yan and Antzelevitch
 Transmembrane voltage gradient b/w RV epicardium and
endocardium due to heterogenous loss of AP dome in epicardium
and not in endocardium.
 Heterogeneity of transmembrane voltage potentials result in phase
2 reentry and triggered VF.
Pathophysiology
Yan and Antzelevitch- Faulty repolarization
Cardiovascular Research 67 (2005) 367 – 378
Depolarization hypothesis
• In BS pts RVOT endocardium shows activation slowing and is the
last to depolarize.
• Delay in AP of RVOT causes an electrical gradient from more
positive RV to RVOT, leading to ST-elevation in right precordial
leads.
• When RVOT depolarizes later (during repolarization of RV), this
gradient is reversed and net current flows towards RV, resulting in a
negative T-wave in right precordial leads.
Depolarization Hypothesis
conduction delay in RVOT
Cardiovascular Research 67 (2005) 367 – 378
Clinical Presentation
• Clinical spectrum ranges from asymptomatic to SCD.
• Patients may present with late onset of VF, despite having
abnormal ECG pattern for decades.
• Syncope or seizures may occur due to self-terminating VF episodes.
• Agonal respiration and difficulty in arousal at night also may be
due to self-terminating VF episodes.
• Majority of BS pts are young, b/w 20 and 40 yrs of age at
presentation.
Brugada : Diagnostic criteria
Appearance of type 1 ST segment elevation (coved type) in > 1 rt
precordial lead (V1 - V3) in the presence or absence of a sodium
channel blocker, plus at least one of the following:
 Documented ventricular fibrillation.
 Polymorphic ventricular tachycardia (VT).
 Family h/o sudden cardiac death at less than 45 years of age.
 Family h/o of type 1 Brugada pattern ECG changes.
 Inducible VT during electrophysiology study.
 Unexplained syncope.
 Nocturnal agonal respiration .
Type 2 and type 3 ECG are not diagnostic of Brugada syndrome
Second Consensus Conference : Europeon Heart Rhythm Society
• Brugada pattern : Pts with typical ECG features who are
asymptomatic and not having other clinical criteria.
• Brugada syndrome : Pts with typical ECG features and clinical
criteria (who have experienced sudden cardiac death or a sustained
ventricular tachyarrhythmia or who have one or more of the other
associated clinical criteria )
Drug challenge
• Done in pts with resting ECG type 2 or 3 Brugada pattern and having
family h/o sudden cardiac death at < 45 yrs and/or a family h/o type
1 Brugada pattern ECG
• Drugs used
Flecainide
: 2 mg/kg over 10 min iv or 400 mg PO
Procainamide : 10 mg/kg over 10 min iv
Ajmaline
: 1 mg/kg over five minutes iv
Pilsicainide
: 1 mg/kg over 10 minutes iv
Drug challenge
Indications for termination of the drug challenge include:
 Development of a diagnostic type 1 Brugada pattern
 ≥2 mm increase in ST segment elevation in pts with type 2 Brugada
ECG pattern
 Development of ventricular premature beats or other arrhythmias
 Widening of the QRS ≥30 percent above baseline
Risk stratification
Treatment
• ICD is the only effective treatment to reduce mortality in BrS
• ICD indication
Class 1
BrS pts with previous cardiac arrest.
Class IIa
BrS pts with spontaneous pattern with h/o syncope.
BrS pts with documented VT that has not resulted in cardiac arrest.
Drugs : Quinidine or amiodarone may be used for pts not willing for
ICD / reduced life expectancy.
Electrical storm: Isoprotenol or Quinidine may be used.
Short QT Syndrome
• Rare condition with short-QT interval (<320 ms).
• Presents symptomatically with recurrent syncope, sudden cardiac
death and atrial fibrillation.
• Mutations in 6 different genes (3 gain of function and 3 loss of
function) are identified .
Genes in SQTS
CHANNELOPATHY
GENE
CHANNEL /PROTEIN
SQT 1
KCNH2
IKr
SQT 2
KCNQ1
IKs
SQT3
KCNJ2
IK1
SQT4
CACNA1C
l-type ca+ channel, α-subunit
SQT5
CACNB2
l-type ca+ channel, β-subunit
SQT 6
CACNA2D1
l-type calcium channel subunit
Basis of Arrhythmogenesis
• Abbreviation of action potential in SQTS is heterogeneous with
preferential abbreviation of either epicardial or endocardial cells as
compared with sub-endocardial M cells, resulting in dispersion of
repolarization .
• Dispersion of repolarization serves as substrate for initiation and
maintenance of reentry.
• In a case series1 of 29 pts
62 % (18 out of 29) were symptomatic
Cardiac arrest – 34 %(initial symptom in 28%)
Palpitations
– 31 %
Syncope
– 24 %
Atrial fibrillation – 17 %
• Electrocardiographic findings
Abnormally short QT interval
Absence of ST segment
Tall and peaked T waves
Prolonged Tpeak-Tend interval and Tpeak-Tend/QT ratio.
1.Carla Giustetto, Fernando Di Monte etal EHJ(2006) 27, 2440–2447
Proposed Diagnostic Criteria: SQTS
Michael H. Gollob, MD, Calum J. Redpath et al JACC Vol. 57, No. 7, 2011
Management
• ICD implantation recommended for both primary and secondary
prevention of SCD in pts with SQTS.
• Pharmacological therapy with QT prolonging drugs.
• Quinidine is recommended in SQT1 syndrome.
• Disopyramide and amiodarone are also shown to prolong QT in
SQTS pts.
Catecholaminergic polymorphic ventricular
tachycardia (CPVT)
• CPVT is a disorder of intracellular calcium handling causing
adrenergic-dependent arrhythmias and sudden death.
• Pts have normal resting ECG and develop ventricular ectopy
progressing to bidirectional or polymorphic VT during exercise or
catecholamine infusion .
• Pts present with life-threatening VT or VF occurring during
emotional or physical stress.
• Affected patients may have a family h/o juvenile sudden death or
stress-induced syncope .
• CPVT can also present sporadically following a de novo mutation.
Genetic basis
• Mutations in 2 genes are identified : ryanodine receptor gene
(RyR2) and calsequestrin 2 gene (CASQ2).
• RyR2 mediates release of Ca+ from SR which is is required for
myocardial contraction.
• RyR2 mutation result in Autosomal Dominant form of CPVT
• Calsequestrin 2 protein is a protein in sarcoplasmic reticulum which
binds large amounts of calcium.
• CASQ2 mutation result in Autosomal Recessive form of CPVT.
Mechanism for Arrhythmogenesis
• Delayed after depolarization (DAD) dependent triggered activity.
• Mutant ryanodine receptor is leaky and it releases excess of
calcium during diastole.
• This activates sodium-calcium exchanger that extrudes calcium
ions out from the cell.
• This generates a net inward current results in DAD.
• When large enough, DADs trigger extrasystolic action potential.
Mechanism for Arrhythmogenesis
Treatment
• Avoiding competitive sports
• Beta blockers for all pts with spontaneous or documented stressinduced ventricular arrhythmias.
• For survivors of cardiac arrest or pts with syncope or sustained VT
or VF despite therapy with beta blockers, ICD is recommend.
• Flecainide or verapamil may be given for pts who are symptomatic
with ICD and beta blockers .
• Left sympathetic denervation for pts who remain symptomatic after
maximal medical therapy.
Other Channelopathies
Arrhythmogenic Right Ventricular Cardiomyopathy ( ARVC )
 Subset of ARVC is caused by defects in cardiac ryanodine receptor
(RyR2)
 May represent a variant of CPVT rather than a subset of CPVT .
 Majority are caused by defects in desmosomal proteins
PKP2 encoding plakophilin 2 : most common
DSP encodes desmoplakin
DSG2 encodes desmoglein 2
 Hallmark of ARVC is fibrofatty replacement of the myocardium
 Arrhythmias may precede histological evidence of disease
Familial AF
 Familial clustering may occur in AF
 Account for a minority of pts with lone AF
KCNH2
IKr
↑ outward K+ current
KCNQ1
IKs
↑ outward K+ current
KCNJ2
IK1
↑ outward K+ current
GJA5
Gap-junction protein connexin 40
Impared conduction
Sinus Node Dysfunction and Conduction Defects
 Mutations of HCN4 gene which codes for cardiac pacemaker
current (If) results in sinus node dysfunction.
 Other mutation which are associated with conduction defects are
SCN5A , NKX2.5 and GATA 5
Summary
• Cardiac channelopathies represent a group of disorders with
inherited arrhythmogenic potential and structurally normal heart.
• Majority are due to mutations in genes encoding Na+ , K+ , Ca +
channels of heart.
• In LQTS arrhythmia is triggered by exercise , emotion or noice.
• Brugada syndrome is diagnosed by type 1 Ecg and documented
event.
• Beta blockers are useful in LQT1 and CPVT.
• ICD is indicated in survived cardiac arrest pts and in high risk
patients.
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