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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
Na * K
**
Ca²
*
* Ca²
Caveolin β
* * RyR2
*
Ca² Ca²
** RyR2
* Na/Ca² Na/H
*
Ankyrin
Myofibrils
* Loss of function
*Gain of function
♀ ♂
ACGGTTG TACCGCTC
ACCGTTG TTCCGATC
*
Variation: polymorphism or
disease
LOCUS
LOCUS
KCNH2 7
α
IKr
KCNE2 21 β
SCN5A 3
Na
V gated
Channels LQT2* 7q35 KCNH2 HERG IKr β
IKr LQT6* IKr α
21q22.1 KCNE2 MiRP1
LQT3*
INa Br-S 3p21 SCN5A Nav 1.5 INa α
Lenegre
Anchoring Ankryn
Proteins LQT4* 4q25 ANK2 Ankryn B Ankryn
dis
Disease Disease Disease Locus Gene Protein Protein
Cluster Type Subtype Function
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
*
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
β-adrenergic
TORSADE de POINTS
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
Findings
ECG:
QTC ms
≥480 3
460-470 2
1
450 (males) 2
1
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
0.5
Congenital Deafness
1
Family History 0.5
Member with definitive LQTS*
Risk stratification
LQTS
• LQTS genotype
• Sex
• Age at onset
• Syncope
• QT duration
Risk stratification
QTc duration
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
patients
• 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
LQT2
Male LQT3
• Triggers of arrhythmias:
Increased sympathetic activity, swimming in LQT1
Emotions, auditory stimuli, rest LQT2
Rest or sleep LQT3
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
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