genotype- and phenotype-guided management of congenital long qt [복구됨] [자동 저장]
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Genotype- and Phenotype-Guided Management of
Congenital Long QT Syndrome
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Sudden Cardiac Death
Those Who Suffer from Frequent and Strong Faintness without a
manifest cause Die Suddenly.
Hippocrates (460~375 BC)
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History of LQTS 1856: Friedrich Ludwig Meissner in Germany reports probably the first case of LQTS. He describes a deaf g
who collapses and dies while being publicly admonished at school. When the parents are informed, they indicate
that two brothers of the girls have already died suddenly after a violent fright or rage.
1957: Anton Jervell and Fred Lange-Nielsen provide the first complete description of LQTS. The disease
called "Jervell, Lange-Nieslen syndrome".
1963/64: Romano and O. Connor Ward report independently patients with a cardiac disorder almost
identical to that described by Jervell and Lange-Nielsen but without deafness. It is soon appreciated that the entity
that many are already calling "Romano-Ward syndrome" was not much more frequently encountered than the
"Jervell-Lange-Nielsen syndrome" but also that it involves a different genetic transmission, presumably autosomal
dominant.
1979: Crampton, Moss and Schwartz initiate the International Registry for LQTSwith the objective of
enrolling a large number of patients in a prospective study which is expected to last 25 years.
1991: Keating demonstrates tightlinkage of LQTS to the Harvey ras-1 gene locus on the short arm of chromosom
11in one large family. This is considered the most significant breakthrough.
1995-1996:The identification of three LQTS genestakes place within 9 months, between March 1995 and Januar1996.
http://www.qtsyndrome.ch/bio.htmlhttp://www.qtsyndrome.ch/bio.htmlhttp://www.qtsyndrome.ch/bio.htmlhttp://www.qtsyndrome.ch/bio.htmlhttp://www.qtsyndrome.ch/bio.htmlhttp://www.qtsyndrome.ch/bio.htmlhttp://www.qtsyndrome.ch/bio.htmlhttp://www.qtsyndrome.ch/bio.html -
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First Formal Description
Am He
QT 0.50 QT
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Genetic and ElectrophysiologicalBasis of LQTS
Giudicessi & Ackerman. Curr Probl Cardiol 2013;38:417 Giudicessi & Ackerma
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Genetic and ElectrophysiologicalBasis of LQTS
Antzelevitch. Am J Physiol Heart Circ Physiol 2007;293:H2024
Yan & Antzelevitch. C
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Torsades de Pointes
EPI
M
ENDO
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Long QT Syndrome Genes
Schwartz et al. Circ Arrhythm E
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Current-centric Classification of LQTS
susceptibility Genes
Giudicessi & Ackerman
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Major LQTS-Susceptibility Genes KCNQ1
Kv7.1 pore-forming -subunit - Iks(slowly activating component of delayed rectifier K curre
maintaining the physiological QT shortening (increased sympathetic tone or heart rates), epotassium cycling
Heterozygous loss-of function mutations : AD type I LQTS (physical & emotional stress)
Dominant negative effect (50%) : coassemble to wild type
KCNH2
Kv11.1 (hERG1) : Ikr(rapidly activating component of delayed rectifier K current)
Haploinsufficiency (50%)
acquired or drug induced LQTS (36% - underlying genetic mutation)
SCN5A
Nav1.5 cardiac sodium channel
Shortens at higher heart rates, But tends to prolong excessively at slower heart rates
Cardiac event at rest, particularly during sleep (diurnal variation in cardiac repolarization)
Genetic and Electrophysiological Basis of LQTS
i i i i f
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Minor LQTS-Susceptibility Genes
The 7 minor genes that present with a pure LQTS phenotype
Other minor genes that present with QT prolongation in the settingof prominent extracardiac manifestations
Genetic and Electrophysiological Basis of LQTS
Giudicessi & Ackerman. Curr Probl C
G ti d El t h i l i l B i f LQTS
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Genetics of Multisystem LQTS: Ankyrin-B,Anderson-Tawil, Timothy, and RecurrentInfantile Cardiac Arrest Syndromes
Ankyrin-B syndrome : QT prolongation, sinus node dysfunction, episodic
fibrillation
Andersen-Tawil syndrome : Dysmorphic physical features (low-set ears,
and clinodactyly), periodic paralysis, nonsustained ventricular arrhythm
Timothy syndrome : autism spectrum disorder, syndactyly, severe cardi
arrhythmias
Sudden infant death syndrome : severe LQTS, neurodevelopmental de
recurrent cardiac arrest
Genetic and Electrophysiological Basis of LQTS
G ti d El t h i l i l B i f LQTS
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Genetic Modifiers of LQTS DiseaseSeverity
Incomplete penetrance & Variable
expressivity
Complex combination of genetic and
environmental factors
: Symptom onset, degree of QTc prolongation,
risk of cardiac events
Single nucleotide polymorphisms (SNP)
: Enhance or diminish the expression of either
wild-type or mutant alleles
Genetic and Electrophysiological Basis of LQTS
Giudicessi & Ackerman. Curr Pro
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Lethal cardiac events according totriggers and genotype
Ikscurrent (essential for QT shorincreases in heart rate)
LQT1 : during exercise or stress LQT2 : emotional stress such as
(sudden noises, telephone ringrest)
LQT3 : asleep or at rest
Schwartz et al. Circula
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Corrected QT
The corrected QT interval estimates the QT interval at a heart rate of 60 bpm This allows comparison of QT values over time at different heart rates and imp
of patients at increased risk of arrhythmias.
Bazettsformula : QTc = QT /
Fredericiasformula : QTc = QT/RR1/3
Framingham formula : QTc = QT + 0.154 (1-RR)
Hodges formula : QTc = QT + 1.75 (Heart rate60)
Bazettsformula is the most commonly used due to its simplicity. It over-correcrates > 100 bpm and under-corrects at heart rates < 60 bpm, but provides ancorrection for heart rates ranging from 60100 bpm.
At heart rates outside of the 60100 bpm range, the Fredericia or Framinghaare more accurate and should be used instead.
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Clinical Presentation and Diagnosis of LQTS
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Standard Diagnostic Approaches
Meticulous personal and family history
syncope, seizure, aborted sudden cardiac arrest sudden unexplained deaths or accidents or drownings, long standing dia
seizure disorder (first, second, and third degree relatives)
Borderline LQT : reflex vasovagal symptoms
AHA-ACC-HRS : QTc 450ms in men, 460ms in women (95 percentile
QTc 470ms in men, 480ms in women : improve PPV for LQTS
Schwartz score (1985): ECG, personal history, family history : 3.5 (high
Further assessment (provocation test, stress test, genetic test)
Clinical Presentation and Diagnosis of LQTS
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1993-2011 LQTS Diagnostic Criteria
Schwartz et al. Ci
Clinical Presentation and Diagnosis of LQTS
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Provocation or Stress Tests andGenetic Testing
g
Assessing the risk of SCD, selecting appropriate therapeutic interventidentifying potentially at-risk relatives
Catecholamine provocation & exercise stress tests : confined to unmLQT1 genotype
Paradoxical QTc prolongation during the recovery phase (>470ms at 2-4recovery)
Paradoxical lengthening of the absolute QT interval by > 30ms following epinephrine administration (0.1mcg/kg/min)
Increases the pretest probability of LQT1
Not equal a diagnosis of LQT1 or LQTS
Can not rule out other types of LQTS in the presence of normal QTc short
Clinical Presentation and Diagnosis of LQTS
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Provocation or Stress Tests andGenetic Testing
g
Clinical Presentation and Diagnosis of LQTS
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Provocation or Stress Tests andGenetic Testing
Clinical Presentation and Diagnosis of LQTS
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Provocation or Stress Tests andGenetic Testing
HRS-EHRA (2011)
1) Any individual with a strong clinical suspicion of LQTS based on clinicaland electrocardiographic phenotype
2) Any asymptomatic individual with unexplained QTc prolongation (>48puberty and >500ms after puberty)
3) Appropriate relatives when a LQTS causative mutation has been identcase
Approximately 4% of healthy whit
Amino acid-altering genetic variathree major LQTS-susceptability ge
Signal-to-Noise ratio
How the presence of a VUS in a msusceptibility gene should be inter
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LQTS2009LQTS8
5LQT1 (+)family study 1
2PhenotypeLQTS (+),
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ICD for LQTS(18) at AMC1996.4 ~ 2013.10.31 ICD354
16958731 M 1974 199622928324 F 1958 1999
29682294 M 1987 2004
18143720 F 1951 2004
31240578 M 1978 2005
27999787 F 1975 2005
11378866 F 1944 2006
11852890 F 1958 2007
20436285 F 1973 2007
33840602 F 1956 2009
39195146 M 1957 2009
23461071 F 1955 2010
40859673 F 1974 2010
41434604 M 1945 2012
22613228 F 1998 2012
44749583 F 1996 2013
45182455 F 1976 2013
37476685 F 1975 2013
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SCD : Epidemiology
General population 0.1%/yr 100/10/
Young gen population 0.0034%/yr 3.4/10/
Asymptomatic WPW 0.2%/yr 200/10/
Long QT Syndrome 0.3%/yr 300/10/
Brugada Syndrome 0.5%/yr 500/10/
Early Repolarization 0.01%/yr 10/10/
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Sudden Cardiac Death in LQTS
0.3-0.6% per year
Priori et al. NEJM 2003;348:1866
Annual Sudden Death in US Only a small minority : LQTS
heritable arrhythmia syndro
Potentially life-threatening,treatable genetic disorder
Prototype or paradigm thabroadly applicable to the sinherited and acquired for
predisposing CV disorders
Genotype- and Phenotype-Guided Risk Stratification and Management o
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Genotype- and Phenotype-DrivenRisk Stratification
Schwartz et al. C
Cumulative rates of cardia93%
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Priori e
Mullally et al. Heart Rhythm 2013;10:378
Sauer et al. JACC 2007;49:329
Genotype- and Phenotype-Guided Risk Stratification and Management o
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Genotype- and Phenotype-DrivenRisk Stratification
Higher risk ( 50%) for experiencing an LQTS-associated cardiac event(s)before the age of 40 years
non-JLNS patients with LQTS-causative mutations on > 1 major LQTS-susceptibility allele (eg, compound heterozygosity or digenic heterozygo
QTc 550 ms, regardless of LQTS genotype
2 but
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Genotype- and Phenotype-DrivenRisk Stratification
Intermediate risk(30-49%) for experiencing an LQTS-associated caevent(s) before the age of 40 years
QTc between 500 and 549 ms, regardless of genotype
< 2 cardiac events before the age of 18 years
Females with major genotype-positive LQTS (QTc < 500 ms in LQT2
QTc 500 ms in LQT3) Male LQT3 patients with a QTc < 500 ms
some form of treatment, typically -adrenergic blockers
G t d Ph t D i
Genotype- and Phenotype-Guided Risk Stratification and Management o
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Genotype- and Phenotype-DrivenRisk Stratification
Lower risk
All other patients with LQTS (eg, asymptomatic patients with a
< 500 ms aside from certain high-risk gender or genotype
combinations such as postpubertal females with LQT2)
The selection of appropriate therapy is performed on an
individualized basis
G t d Ph t D i
Genotype- and Phenotype-Guided Risk Stratification and Management o
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Genotype- and Phenotype-DrivenRisk Stratification
Genotype- and phenotype-guided Based on probability of experiencing a f
cardiac event (syncope, seizure, sudden
sudden cardiac death) before 40 years
appropriate therapeutic interventions
Purple : Genotype-guidedOrange : Phenotype-guidedBlack : Genotype and phenotype-guided
Giudicessi & Ackerman. Curr P
M di l S i l d D iGenotype- and Phenotype-Guided Risk Stratification and Management o
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Medical, Surgical, and Device-Related Management
Should avoid QT-prolonging medications Maintain adequate hydration and thereby normal electrolyte levels,
especially in the setting of emesis, diarrhea, or other medical conditionsknown to cause hypokalemia.
Sudden cardiac arrest or death can be the sentinel event, appropriatetailored therapeutic interventions should be initiated in most patients withLQTS.
Currently, LQTS therapy targets the following 2 distinct strategies:
1) reduction in sympathetic or adrenergic tone, and therefore arrhythmia risk, via
the use of -adrenergic receptor antagonists and or LCSD
2) correction or cessation of life-threatening arrhythmias via the timely delivery of
electrical impulses by an ICD
d i t t i tGenotype- and Phenotype-Guided Risk Stratification and Management o
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-adrenergic receptor antagonists
Moss et al. Circulation 2000;101:106
Moss et al. Circu
Schwartz et al. Circ
d i t t i tGenotype- and Phenotype-Guided Risk Stratification and Management o
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-adrenergic receptor antagonists
Propranolol
(2-4mg/kg/day; hahours)
Nadolol (1-2mg/kg/day; ha
hours)
L ft C di S th ti
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Left Cardiac SympatheticDenervation
Raise the threshold for ventr
Collura et al. Heart Rhythm 2009;6:752
Implantable Cardioverter DefibrillaGenotype- and Phenotype-Guided Risk Stratification and Management o
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Implantable Cardioverter-Defibrilla
Survived a cardiac arrest despite adequate beta blockade or LCSD
Survived a cardiac arrest off therapy, except when a reversible or
preventable cause such as QT prolonging medications or electrolyte
abnormalities are identified
Recurrent LQTS-triggered syncope despite adequate beta blockad
LCSD is not a viable option
In rare extenuating circumstances, such as asymptomatic patients w
QTc550 ms with overt signs of electrical instability (e.g., T wave altern
ECG or additional objective evidence of being high risk (e.g., postpub
women with LQT2) despite adequate beta blockade and LCSD, or bo
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Implantable Cardioverter-Defibrilla
Reynolds et al. JACC 2006;47:2493
The long term comp
associated with Early
Not experienced a c
failed beta blocker??
Defensive medicin
31% of LQTSat lea
Schwartz et al. Circulation 2010;122:1272
Horner et al. He
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Implantable Cardioverter-Defibrilla
Schwartz et al. Circ
Based on M-FACT criteria & single center study indicates that most patients with LQtreated effectively without an ICD
Horner et al. Heart Rhyth
Genotype Guided ManagementGenotype- and Phenotype-Guided Risk Stratification and Management o
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LQT1 : Antiadrenergic interventions (beta blockers, LCSD)
Noncompliance or concomitant use of QT prolonging medications
Most of the life-threatening breakthrough cardiac events
Strenuous exercise, particularly swimming
Strictly ban the competitive sports participation
The low rate of LQTS-triggered cardiac events during sports & rising
obesity rates in USpatient or family centered approach
Genotype-Guided Management
Genotype Guided ManagementGenotype- and Phenotype-Guided Risk Stratification and Management o
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LQT2 :
When serum potassium levels fall
When aroused from sleep or rest by sudden noises such as alarm clocks,telephones, or crying babies (during the postpartum period)
Careful maintenance of serum potassium levels with a combination of diet, oralpotassium supplementation, and if necessary, use of potassium-sparing diuretics
Blunting or removal of causes of sudden noise from the bedroom and educationof family members and other individuals sharing the home to avoid yelling orotherwise startling the patient
Counseling women with LQT2 and their partners on the necessity of beta blockecompliance, adequate rest, and avoidance of QT-prolonging medications durinthe postpartum period.
Life threatening breakthrough cardiac events (6-7%)high risk patients withLQTS2 require LCSD or, if clinically indicated, an ICD.
Genotype-Guided Management
Wilde et al. J
Genotype Guided ManagementGenotype- and Phenotype-Guided Risk Stratification and Management o
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LQT3 : highest rate of breakthrough cardiac events on beta blocker (10-1
SCN5A gain-of-function : adjuvant sodium channel blocker (mexiletine or ra
Unwanted type 1 Brugada syndrome-like ECG pattern (pleiotropic nature of smutations)drug challenge test
LSCD or ICD implantation
Mere presence of LQT3-causative mutation - ICD??
Minor LQTS subtypes : no specific genotype-phenotype correlations exist
evidence-based guidelines for management
Managed as the corresponding major LQTS subtype
More malignant or multisystem forms of LQTS (JLNS, TS) : BB, AAD, LCSD, IC
Genotype-Guided Management
Management of Concealed orGenotype- and Phenotype-Guided Risk Stratification and Management o
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Management of Concealed orLow-Risk LQTS
Roughly 25% of patients with genotype-positive LQTS fail to manifesany overt clinical hallmark of the disease
Concealed LQTS : markedly reduced risk of SCD or ACA (4% vs 15%
Might need prophylactic beta-blocker therapy??
Goldenberg et al. JACC 2011-57
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.