genotype- and phenotype-guided management of congenital long qt [복구됨] [자동 저장]

8/13/2019 Genotype- and Phenotype-Guided Management of Congenital Long QT [ ] [ ]

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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


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


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


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)



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1993-2011 LQTS Diagnostic Criteria

Schwartz et al. Ci



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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



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g



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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



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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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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



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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



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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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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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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



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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.


Wilde et al. J



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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


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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genotype- and phenotype-guided management of congenital long qt [복구됨] [자동 저장]

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