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Deep Inside

Long QTS
FM Leonelli MD
Hereditary Arrhythmias
• Heart rhythm requires AP and propagation of
electrical impulse
• Change in expression or function of ion
channels or structural proteins can lead to
“primary cardiac arrhythmias”
LQT and other syndromes affecting repolarization
Brugada Syndrome
Cathecolaminergic Polymorphic VT
Familial SVT and conduction system disease
Short QTS
Genetics of LQTS
• Hereditary LQTS genetic disorder with
variable penetrance characterized by delayed
repolarization in the absence of structural
cardiac abnormalities
• Presentation: silent, syncope, TdP, SCD
• Phenotypic manifestations include organ
deficiencies and malformations
• Familial vs sporadic (high variability :
50% Brugada, 0% caveolin, 100% JLN)
Genetics of LQTS

• Prevalence of manifest LQTS 1:5,000

• Subclinical disorders much higher (modifier
genes, affecting penetrance)
• 40-50 % LQTS genotype negative
• Repolarization reserve
Disease of repolarization
• Prolonged QT on ECG due to reduction in
net repolarizing currents:
Decrease IKs,IKr IK1
Increase of ICa or late INa
Disease of repolarization

• Inherited arrhythmogenic diseases can be

grouped as disease of:
V-dependent ion channels
Intracellular handling proteins
Anchoring proteins

Na * K
* Ca²
Caveolin β
* * RyR2
Ca² Ca²
** RyR2

* Na/Ca² Na/H



* Loss of function
*Gain of function
♀ ♂


Variation: polymorphism or



Homologous: identical chromosome in organization and genes carried

Alleles: alternative form of genes at specific locus carried by homologous chromosome
Locus: position of gene on a chromosome
Genetics of LQTS
• Genes encoding ion channels are substrate
for many arrhythmogenic syndromes
• Ten genes with different penetrance linked to
genetic arrhythmias with over 300 genetic
mutations (>90% LQT1,2,3)
Dysfunctional channel reduction in current
Loss of function
p15.5 KCNQ1 11
KCNE1 21 β

KCNE2 21 β


Dysfunctional channel failing to close

Gain of function
Disease Disease Disease Locus Gene Protein Protein
Cluster Type Subtype Function


LQT5* KCNE1 MinK IKs β
IKs IKs α
LQT-JLN1° 11p15.5 KCNQ1 KVLQT1
LQT1-LJN° 21q22.1 KCNE1 MinK IKs β

V gated
Channels LQT2* 7q35 KCNH2 HERG IKr β
IKr LQT6* IKr α
21q22.1 KCNE2 MiRP1

INa Br-S 3p21 SCN5A Nav 1.5 INa α

Anchoring Ankryn
Proteins LQT4* 4q25 ANK2 Ankryn B Ankryn
Disease Disease Disease Locus Gene Protein Protein
Cluster Type Subtype Function

Scaffolding Caveolae LQT9* CAV3 Caveolin3


Auxiliary Navβ LQT10* SCN4B Navβ4 INaβ


CACNA1C α1C subunit Cav1.2 L type

V gated
IK1 And-S1LQT7* 17q23 SCNJ2 Kir2.1 IK1

CASQ2 CASQ2 Calcequestrin

Intrac. Ca Calsequestrin CPTV2* 1p11
Handling Ryanodin dis CPTV1* 1q42 RyR2 RyR2 Ryanodine recep
Determined from 3-5 cardiac cycles (SR)
Leads II V5 or V6 and the longest value used
Exclude: AMI, CMP,hypo-Mg-Ca-K, vagal, hypothermia, drugs
HR correction: QTc=QT/√HR in sec
1-15 yrs Adult Male Adult Female
Normal ms <440 < 430 < 450
Borderline 440-460 430-450 450-470
Prolonged >460 > 450 > 470
Genetics of LQTS
• Ion channels different time/V characteristics
resulting in possible gene specific clinical
ST-T pattern
QT during exercise or other triggers
Clinical course
• Possible for only three genes (LQT1,2,3)
• Helps directing genetic screening
T wave morphology:
LQT1: broad based (88%)
LQT2: bifid or notched (88%)
LQT3: late, peaked/biphasic (65%)
Genotype-Phenotype Correlations

IKs block IKr block Slow late INa inactivation

M cells: weaker repolarizing currents (less IKs more late Na) causing longer APD
prolonging more than epicardium or endocardium in response to slower HR
Isoproterenol increases IKs, hypoK decreases IKr
ATX-II increases late INa
JACC 200;35:778
LQT1,2,3 models

JACC 200;35:778 IKs block IKr block Slow inactivation Na current

LQT3 and Brugada
INa Disease
• LQT3 disrupts fast inactivation: Na channel
reopens inducing small persistent INa
throughout AP (gain of function)
• Brugada syndrome induces either failure to
express INa, slow recovery or accelerated
inactivation (loss of function)

ECG in Brugada syndrome
ECG and re-entry in Brugada syndrome

Ito shortens APD. Present in the Epicardium (RV) but not in the Endocardium
normally determines the J-wave followed by isoelectric ST segment
Reduction of INa shortens APD more markedly in RV Epicardium
Variable ventricular K channels expression:
Heterogeneous Repolarization

High density of Itof , IKur , IKr

High density of Itof

+ density of Itof

* Low IKs, ++ density of Ito

++ late INa, +++ INa-Ca
+++ density of Itof , IKr

EAD underlies the premature beat initiating TdP

Phase 2 EAD Ca dependent phase 3 Na dependent

TDR creates a vulnerable window for re-entry

Intrinsic heterogeneity amplified by drugs, electrolytes, ischemia, β agonists etc
Mechanism of Arrhythmia in LQT 1,2,3
Intrinsic heterogeneity

Net repolarizing current

Net depolarizing current
LQT1 LQT2,3 LQT1,2,3

Prolongation of APD Prolongation of APD EAD induced

(Homogeneous) Preferentially M cells trigger beats
(Purkinje or M cells)

Long QT interval Long QT interval

No dispersion of refractoriness Dispersion of refractoriness


J Electrocardiol 1999;32;158
Clinical Presentation
• Wide spectrum of clinical phenotypes :
Symptoms (palpitations, syncope, SD) and
abnormal ECG
Family member of proband
Asymptomatic with abnormal ECG
Symptomatic or asymptomatic with borderline
or normal ECG (provocative tests)
Diagnostic Criteria Score

QTC ms
≥480 3
460-470 2
450 (males) 2
Torsade de pointes* 1
T-wave alternans 0.5
Notched T w in 3 leads
Low HR for age (below 2nd perc for age)

Clinical History: 2
Syncope*: 1
With stress
Without stress

Congenital Deafness
Family History 0.5
Member with definitive LQTS*
Risk stratification
• LQTS genotype
• Sex
• Age at onset
• Syncope
• QT duration
Risk stratification
QTc duration

• Baseline QTc ≥ 500 ms associated

with high risk of cardiac events
• Max QTc duration measured at any
time predicts events (500-549 msec
3.3 fold increase and ≥ 550 msec 6.6
fold in adults)
Risk stratification
• Syncope most powerful predictor of
subsequent SCD and ACA
• In adolescents (age 10-20 yrs):

– Two or more recent (within 2 yrs) syncope

events increased 18 fold risk of SCD or ACA
– One recent syncopal event increase 12 fold
– Distant syncope (2 to 10 yrs) increase 3 fold
Risk stratification

• In adults (age 18-40 yrs):

– Syncope after age 18 increased 5 fold risk of

– Syncope before age 18 no significant risk
Risk stratification
Time dependent gender effect:
• Male sex 85% increases chance of
cardiac event before 15 yrs of age
• After 14 yrs of age female probands 87%
increase of events
• LQT1 boys have a 71% increase risk of
cardiac event compared to girls
• Risk increases 3fold after age 16 in girls
with LQT1 and LQT2
JACC 2008;51:2291
Risk stratification
• Possibly due to androgens shorten QT
while estrogen seem to modify expression
of IK and have dose dependent blocking
effect on IKs
• Pregnancy decreases while post partum
increases risk in LQT2
Risk stratification
LQTS Genotype
• LQT1 cardiac events associated with
vigorous physical activities (swimming)
• LQT2 triggers sudden loud noise
• LQT3 rest or arousal from sleep
• Higher risk in LQT1 and LQT2 than LQT3
• Lethality events higher in LQT3
• Other suggest penetrance i.e. phenotypic
evidence more important
5yrs Kaplan-Meier rates of SCD or ACA

14% Very High Risk

Secondary Prevention
Post CPR Manifest TdP

Primary Prevention High Risk

3% QTc > 500msec
Prior Syncope

QTc < 500msec

0.5% Low Risk
No Syncope

JACC 2008;51:2291
JACC 2008;51:2291
Therapeutic Implications
• No prospective randomized trials
• Beta-blockers first line therapy in high risk,
intermediate, and on individual basis low
risk patients
• LQT1 and LQT2 benefit most
• In symptomatic, treated patients, risk of
SCD, ACA remains 10% in LQT1, 23% in
LQT2, 32% in LQT3
Therapeutic Implications
• Flecanide possibly beneficial in LQT3 (late
Na current blocker)
• Family members stratified according to risk
factors (age, gender, QTc, duration, history
of syncope) and treated accordingly
• ICD indicated in high risk secondary
prevention and high risk primary prevention
patient still symptomatic despite β bl
Therapeutic Implications
• ICD indicated in Jervell and Lang-Nielsen
• Family history of SCD not independent risk
factor for lethal event
• Risk to remaining family members depends
on their risk factor profile
Therapeutic Implications
• Left Cervico-thoracic sympathetic
denervation considered in patients on beta-
blockers experiencing ICD storms
• Residual risk post surgery is high (54% in a
study of 147 pts)
• Gene specific therapies (Na channel
blocker, K channel activator, alpha
adrenergic blocker, atropine, protein-kinase
inhibitor) probably useful in future
Risk Stratification in LQTS
Risk of SD by age 40

QTc ≥ 500msec
≥ 50% LQT1
Male LQT3

QTc ≥ 500msec QTc < 500msec

Female LQT3 Female LQT3
< 50% Female LQT2
Male LQT3

QTc < 500 msec

< 30% Male LQT2
Structure affected : channel itself, nearby
subunits mediating cell adhesion signal
transduction gating and channel
expression at the plasma membrane (Tw
altrn bradycardia block SCN5A and
RyR2 excessive response to caffeine,
excessive release of
Ca leading to triggered arrhythmias
Caveolins facilitate efficient rapid transfer
of signals as simpathetic stimulus or
inhibiting signals In this case increase the
late Na component
Timothy s affects Ca channnel with de
novo missense mutation impairing channel
deactivation Ankyrin pathways are
necessary for proper localization of Na
channels (Ank 1), Na/K, Na/Ca leading to
excessive Ca accumulation especially
during adrenergic stimulation
Therapeutic Implications
• ICD highly effective reducing SCD from
16% to 1.3% (J Cardiov Electr 2003;14:337)
• Annual ICD shock rate in high risk patients
is 4%
• ICD indicated in secondary prevention and
primary prevention in high risk patients
symptomatic despite beta blocker therapy
• ICD indicated as initial therapy in high risk
Jervell Lange-Nielsen patients
• Sex:
Incidence of SD reduced in LQT1(QTc≥500 msec
regardless of sex 30% asymptomatic)
LQT2 female sex carries highest risk (QTc<500 msec
fourfold higher risk than male)
Increased dispersion of repolarization

• QT adaptation:
Reduced in LQT1 (IKs)
Increased dispersion of repolarization
• Response to epinephrine infusion*:
Increase QTc in LQT1

• Triggers of arrhythmias:
Increased sympathetic activity, swimming in LQT1
Emotions, auditory stimuli, rest LQT2
Rest or sleep LQT3

Zipes fig pg 654/ circ 2003 107 838 Own case

Effects of Propranolol on APD and QT interval

Effects of Mexiletine on APD and QT interval

LQT3 and Brugada
• Mutations of a single genes can induce opposing
or compensating effects
• Gating changes can be observed in the mutations
of Na channel which can induce loss of function
and gain of function sometime associated
(stronger depolarization needed to open channel
but also a parallel shift in V dependency of on
activation) leading to different manifestations (ie in
this case loss of function was balanced so it was
not severe enough to cause Brugada symptoms
but only conduction problems)
An important property of ventricular myocardium is spatial
variability of ion channels expression leading to heterogeneity

High density of Itof , IKur , IKr

Low density IKs

High density of Itof , IKr

Na channel Gating
pg 77
• Family history independent risk factor on
multiple large studies
Arrhythmia in Ryanodine, Calsequestrin disease

Leak of Ca from SR and intracellular overload leading to Na/Ca exchange in forward

mode and activation of inward depolarizing current (DAD)
Circulation 2005;112:2517
K Channel Assembly
Cardiac Heterogeneity
V-gated K channel
• Different regional expression of Kv channels
• Dispersion of epicardial repolarization
between LV apex (shorter APD) and base
• RV highest density of Ito with shortest APD
and more marked phase 1
• Marked transmural gradients of
depolarization in isolated cells and intact
Electrical heterogeneity of Ventricular myocardium

Prominent Ito current in epicardial and M cells more marked in the LV than RV. M cells APD prolongs disproportionately in response to
Slow HR and othe APD prolonging agents due to a smaller IKs, larger late Ina and larger INa-Ca exchange. Ica, iKr and IK1 are simila
in three cell type. M cells are a hybrid between Purkinije and ventricular cells. M cells prolong APD and EAD after IKs, IKr block,
Ca loading,
Europace 2007 9(Supplement 4):iv4-
T wave inscription

V difference on either side of M cells

Arrhythmia mechanism in Brugada Syndrome

Increased Ito in epicardial cells, especially RV, shortens the APD in

Brugada syndrome creating a V gradient inducing ST elevation,
TDR and local re-excitation (phase 2 re-entry)
Drug Induced TdP

Sotalol Dofetilide Eryhromycin IKr blockers

Quinidine Cisapride block inwardand outward currents in a biphasic fashion
Chromanol, Na Pentobarbitol and Amiodarone block IKr,IKs and late INa
Cellular basis for ECG in LQT1

Transmembrane APs and transmural

ECG in control, during IKs block
and during block and Isoproterenol
Tpeak-Tend as measure of transmural
dispersion of repolarization (TDT)
TdP during IKs block and Isoproterenol.
Spontaneous and S2 induced arrhythmia
originating from deep subendocardium
Circulation 1998;98:2314
• LQTS risk is a continuum time dependent
and is determined by age, location of
mutation, sex, genetic polymorphism,
• Age of SCD family member not risk factor
• LQT1 reduces IKs current which is
sympathetic driven and remains opened
longer at faster HR (ex, sympathetic act)
• Symptoms correlate to the QTC
• Symptoms correlate to the location of the
mutation (pore mutation vs assembly
mutation determine degree of functional
ECG and re-entry in Brugada syndrome

Ito shortens APD. Present in the Epicardium (RV) but not in the Endocardium
normally determines the J-wave followed by isoelectric ST segment
Reduction of INa shortens APD more markedly in RV Epicardium