Genotype- and PhenotypeGuided Management of Congenital Long QT Syndrome

Sudden Cardiac Death

Hippocrates (460~375 BC)

Those Who Suffer from Frequent and Strong Faintness without any manifest cause Die Suddenly.

History of LQTS

1856: Friedrich Ludwig Meissner in Germany reports probably the first case of LQTS. He describes a deaf girl
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

called "Jervell, Lange-Nieslen syndrome".

provide the first complete description of LQTS. The disease is

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 LQTS with the objective of

enrolling a large number of patients in a prospective study which is expected to last 25 years.

1991: Keating demonstrates tight linkage of LQTS to the Harvey ras-1 gene locus on the short arm of chromosome
11 in one large family. This is considered the most significant breakthrough.

1995-1996: The identification of three LQTS genes takes place within 9 months, between March 1995 and January
1996.

First Formal Description

QT 0.60

QT 0.50

Am Heart J 1957;54:59

Introduction

Genetically heterogeneous group of heritable disorders of myocardial repolarization linked by the shared clinical phenotype of QT prolongation on electrocardiogram and an increased risk of potentially life-threatening cardiac arrhythmias.
Classically, LQTS follows 2 distinct patterns of inheritance:

the autosomal dominant Romano-Ward syndrome, which affects between 1:2000 and 1:5000 individuals and presents with an isolated cardiac phenotype, the autosomal recessive Jervell and Lange-Nielsen syndrome (JLNS), which affects between 1:1,000,000 and 1:4,000,000 individuals and presents with bilateral sensorineural deafness in addition to a malignant LQTS cardiac phenotype.

In reality, LQTS represents a genetically and phenotypically heterogeneous group of disorders, which also includes rare multisystem disorders the genetic phenomena of incomplete penetrance and variable expressivity, whereby genotype-positive family members display a spectrum of clinical phenotypes ranging from a lifelong asymptomatic state to sudden death in infancy
The Complex Interplay between Genotype and Phenotype

Genetic and Electrophysiological Basis of LQTS

Giudicessi & Ackerman. Curr Probl Cardiol 2013;38:417

Giudicessi & Ackerman. Transl Res 2013;161:1

Genetic and Electrophysiological Basis of LQTS

Antzelevitch. Am J Physiol Heart Circ Physiol 2007;293:H2024 Yan & Antzelevitch. Circulation 1998;98:1928

Torsades de Pointes
EPI

ENDO

Long QT Syndrome Genes

Major

Schwartz et al. Circ Arrhythm Electrophysiol 2012;5:868

Current-centric Classification of LQTS susceptibility Genes

Giudicessi & Ackerman. Transl Res 2013;161:1

Genetic and Electrophysiological Basis of LQTS

Major LQTS-Susceptibility Genes

KCNQ1

Kv7.1 pore-forming -subunit - Iks (slowly activating component of delayed rectifier K current) maintaining the physiological QT shortening (increased sympathetic tone or heart rates), endocochlear potassium 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

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 setting of prominent extracardiac manifestations

Giudicessi & Ackerman. Curr Probl Cardiol 2013;38:417

Genetic and Electrophysiological Basis of LQTS

Genetics of Multisystem LQTS: Ankyrin-B, Anderson-Tawil, Timothy, and Recurrent Infantile Cardiac Arrest Syndromes

Ankyrin-B syndrome : QT prolongation, sinus node dysfunction, episodic atrial fibrillation

Andersen-Tawil syndrome : Dysmorphic physical features (low-set ears, micrognathia, and clinodactyly), periodic paralysis, nonsustained ventricular arrhythmia

Timothy syndrome : autism spectrum disorder, syndactyly, severe cardiac

arrhythmias

Sudden infant death syndrome : severe LQTS, neurodevelopmental delays, seizures, recurrent cardiac arrest

Genetic and Electrophysiological Basis of LQTS

Genetic Modifiers of LQTS Disease Severity

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 Probl Cardiol 2013;38:417

Demographic and exogenous modifiers of ECG phenotype and SCD risk

Giudicessi & Ackerman. Transl Res 2013;161:1

Clinical Presentation and Diagnosis of LQTS

Prevalence and Clinical Presentation

Expressed QTc clinical phenotype prevalence 1:2000 Pathogenic LQTS genotype 1:80 Incomplete penetrance and variable expressivity : discordance

QTc values beyond the 99th percentile

Not necessarily equal a diagnosis of LQTS

Normal QTc (10-40% gene (+), QTc WNL) normal QT interval LQTS or concealed LQTS

Lethal cardiac events according to triggers and genotype

Iks current (essential for QT shortening during increases in heart rate) LQT1 : during exercise or stress LQT2 : emotional stress such as auditory stimuli (sudden noises, telephone ringing, esp. while at rest) LQT3 : asleep or at rest

Schwartz et al. Circulation 2001;103:89

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 improves detection of patients at increased risk of arrhythmias.

Bazetts formula : QTc = QT /

Fredericias formula : QTc = QT/RR1/3 Framingham formula : QTc = QT + 0.154 (1-RR) Hodges formula : QTc = QT + 1.75 (Heart rate 60)

Bazetts formula is the most commonly used due to its simplicity. It over-corrects at heart rates > 100 bpm and under-corrects at heart rates < 60 bpm, but provides an adequate correction for heart rates ranging from 60 100 bpm.
At heart rates outside of the 60 100 bpm range, the Fredericia or Framingham corrections are more accurate and should be used instead.

How to measure QT if the QT segment is abnormal

T wave morphology
Often biphasic or notched in particularly precordial leads Notched T waves : more frequent in symptomatic patients (81% vs 19%) Subthreshold EADs Markedly more frequent after exercise (85% vs 3%) Gene specific ECG patterns LQT1 : smooth, broad-based T

LQT2 : low-amplitude and notched T

LQT3 : late onset of the T

LQT3

LQT2

LQT1

Moss et al. Circulation 1995;92:2929

Clinical Presentation and Diagnosis of LQTS

Standard Diagnostic Approaches

Meticulous personal and family history

syncope, seizure, aborted sudden cardiac arrest sudden unexplained deaths or accidents or drownings, long standing diagnosis of a 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 probability)

Further assessment (provocation test, stress test, genetic test)

1993-2011 LQTS Diagnostic Criteria

Schwartz et al. Circulation 2011-124-2181

Clinical Presentation and Diagnosis of LQTS

Provocation or Stress Tests and Genetic Testing

Assessing the risk of SCD, selecting appropriate therapeutic interventions, identifying potentially at-risk relatives Catecholamine provocation & exercise stress tests : confined to unmasking an LQT1 genotype

Paradoxical QTc prolongation during the recovery phase (>470ms at 2-4 minutes of recovery)
Paradoxical lengthening of the absolute QT interval by > 30ms following low-dose 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 shortening

Clinical Presentation and Diagnosis of LQTS

Provocation or Stress Tests and Genetic Testing

Clinical Presentation and Diagnosis of LQTS

Provocation or Stress Tests and Genetic Testing

Clinical Presentation and Diagnosis of LQTS

Provocation or Stress Tests and Genetic Testing

HRS-EHRA (2011)
1) 2) 3)

Any individual with a strong clinical suspicion of LQTS based on clinical or family history and electrocardiographic phenotype Any asymptomatic individual with unexplained QTc prolongation (>480ms before puberty and >500ms after puberty) Appropriate relatives when a LQTS causative mutation has been identified in the index case

Approximately 4% of healthy white

Amino acid-altering genetic variant in one of the three major LQTS-susceptability genes Signal-to-Noise ratio How the presence of a VUS in a major LQTSsusceptibility gene should be interpreted

Clinical Presentation and Diagnosis of LQTS

Mutation types and missense mutations localizing to particular topological structure-function domains
the probabilistic interpretation of an LQTS genetic result

Giudicessi and Ackerman. Curr Opin Cardiol 2013;28:63

LQTS

2009 LQTS : 8

5 LQT1 (+) family study 1 2 Phenotype LQTS (+), gene (-)

ICD for LQTS(18) at AMC 1996.4 ~ 2013.10.31 ICD 354

16958731 22928324 29682294 18143720 M F M F 1974 1958 1987 1951 1996 1999 2004 2004

31240578
27999787 11378866 11852890 20436285 33840602 39195146 23461071 40859673 41434604 22613228 44749583 45182455 37476685

M
F F F F F M F F M F F F F

1978
1975 1944 1958 1973 1956 1957 1955 1974 1945 1998 1996 1976 1975

2005
2005 2006 2007 2007 2009 2009 2010 2010 2012 2012 2013 2013 2013

SCD : Epidemiology

General population

0.1%/yr

100/10/
3.4/10/

Young gen population 0.0034%/yr

Asymptomatic WPW Long QT Syndrome

0.2%/yr 0.3%/yr

200/10/ 300/10/

Brugada Syndrome
Early Repolarization

0.5%/yr
0.01%/yr

500/10/
10/10/

Sudden Cardiac Death in LQTS

Annual Sudden Death in US : >250, 000 Only a small minority : LQTS and other heritable arrhythmia syndromes Potentially life-threatening, yet highly treatable genetic disorder

Prototype or paradigm that could be broadly applicable to the study of other inherited and acquired forms of SCDpredisposing CV disorders

0.3-0.6% per year Priori et al. NEJM 2003;348:1866

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype- and Phenotype-Driven Risk Stratification

Cumulative rates of cardiac events in JLNS: 93%

Schwartz et al. Circulation 2006;113:783

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype- and Phenotype-Driven Risk Stratification

TS (LQT8)

Sauer et al. JACC 2007;49:329

Splawski et al. Cell 2004;119:19

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype- and Phenotype-Driven Risk Stratification

Highest risk (80%) of having 1 or more LQTS-associated cardiac events before the age of 40 LQT1-causative mutations on >1 KCNQ1 allele (eg, JLNS & AR-LQT1)

Timothy syndrome (LQT8)

Experienced 10 cardiac events before the age of 18 years Aggressive clinical management (left cardiac sympathetic denervation and/or ICD)

Mullally et al. Heart Rhythm 2013;10:378

Sauer et al. JACC 2007;49:329

Priori et al. NEJM 2003;348:1866

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype- and Phenotype-Driven Risk 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 LQTSsusceptibility allele (eg, compound heterozygosity or digenic heterozygosity) QTc 550 ms, regardless of LQTS genotype 2 but <10 cardiac events before the age of 18 years QTc 500 ms with an LQT1, LQT2, or males with an LQT3 genotype

Combination of medical, surgical, or device-related management

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype- and Phenotype-Driven Risk Stratification

Intermediate risk(30-49%) for experiencing an LQTS-associated cardiac event(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 LQT2,3, QTc 500 ms in LQT3)
Male LQT3 patients with a QTc < 500 ms

some form of treatment, typically -adrenergic blockers

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype- and Phenotype-Driven Risk Stratification

Lower risk All other patients with LQTS (eg, asymptomatic patients with a QTc < 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

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype- and Phenotype-Driven Risk Stratification

Genotype- and phenotype-guided risk classification

Based on probability of experiencing a first or recurrent cardiac event (syncope, seizure, sudden cardiac arrest, or sudden cardiac death) before 40 years of age without appropriate therapeutic interventions
Purple : Genotype-guided Orange : Phenotype-guided Black : Genotype and phenotype-guided

Giudicessi & Ackerman. Curr Probl Cardiol 2013;38:417

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Medical, Surgical, and DeviceRelated Management

Should avoid QT-prolonging medications Maintain adequate hydration and thereby normal electrolyte levels, especially in the setting of emesis, diarrhea, or other medical conditions known to cause hypokalemia. Sudden cardiac arrest or death can be the sentinel event, appropriate tailored therapeutic interventions should be initiated in most patients with LQTS. 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 correction or cessation of life-threatening arrhythmias via the timely delivery of electrical impulses by an ICD

2)

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

-adrenergic receptor antagonists

Moss et al. Circulation 2000;101:106

Schwartz et al. Circulation 2001;103:89 Moss et al. Circulation 2000;101:106

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

-adrenergic receptor antagonists

Propranolol (2-4mg/kg/day; half life 4-5 hours) Nadolol (1-2mg/kg/day; half life 14-24 hours)

Left Cardiac Sympathetic Denervation Raise the threshold for ventricular fibrillation

Collura et al. Heart Rhythm 2009;6:752

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Implantable Cardioverter-Defibrillators
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 blockade when LCSD is not a viable option In rare extenuating circumstances, such as asymptomatic patients with a QTc550 ms with overt signs of electrical instability (e.g., T wave alternans) on ECG or additional objective evidence of being high risk (e.g., postpubertal women with LQT2) despite adequate beta blockade and LCSD, or both

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Implantable Cardioverter-Defibrillators
The long term complications & QOL
associated with Early ICD implantation Not experienced a cardiac arrest or not failed beta blocker?? Defensive medicine 31% of LQTS at least one adverse event
Horner et al. Heart Rhythm 2010;7:1616 Reynolds et al. JACC 2006;47:2493

Schwartz et al. Circulation 2010;122:1272

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Implantable Cardioverter-Defibrillators

Schwartz et al. Circulation 2010;122:1272

Based on M-FACT criteria & single center study indicates that most patients with LQTS can be treated effectively without an ICD
Horner et al. Heart Rhythm 2010;7:1616

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype-Guided Management

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 US patient or family centered approach

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype-Guided Management

LQT2 :

When serum potassium levels fall

Wilde et al. JACC 1999;33:327

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, oral potassium supplementation, and if necessary, use of potassium-sparing diuretics Blunting or removal of causes of sudden noise from the bedroom and education of family members and other individuals sharing the home to avoid yelling or otherwise startling the patient Counseling women with LQT2 and their partners on the necessity of beta blocker compliance, adequate rest, and avoidance of QT-prolonging medications during the postpartum period.

Life threatening breakthrough cardiac events (6-7%) high risk patients with LQTS2 require LCSD or, if clinically indicated, an ICD.

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Genotype-Guided Management

LQT3 : highest rate of breakthrough cardiac events on beta blocker (10-15%)

SCN5A gain-of-function : adjuvant sodium channel blocker (mexiletine or ranolazine) Unwanted type 1 Brugada syndrome-like ECG pattern (pleiotropic nature of some SCN5A mutations) drug challenge test LSCD or ICD implantation Mere presence of LQT3-causative mutation - ICD??

Minor LQTS subtypes : no specific genotype-phenotype correlations exist and no evidence-based guidelines for management Managed as the corresponding major LQTS subtype More malignant or multisystem forms of LQTS (JLNS, TS) : BB, AAD, LCSD, ICD therapy

Genotype- and Phenotype-Guided Risk Stratification and Management of LQTS

Management of Concealed or Low-Risk LQTS

Roughly 25% of patients with genotype-positive LQTS fail to manifest any overt clinical hallmark of the disease Concealed LQTS : markedly reduced risk of SCD or ACA (4% vs 15%)

Goldenberg et al. JACC 2011-57-51

Might need prophylactic beta-blocker therapy??