SHA24/022003

SHA24-GHA1​0 Joint Scientific Conference

Riyadh, Kingdom of Saudi Arabia, February 13-16, 2013

Identify Inherited Arrhythmia for the Prevention of Sudden Cardiac Death  Recognizing the Gene-Specific ECG Patterns Li Zhang, MD Associate Professor, Jefferson Medical College Director, Cardiovascular Outcomes Research Lankenau Medical Center Lankenau Institute for Medical Research Philadelphia, Pennsylvania USA Conflict of interest: no relationships to disclose LDS Hospital Intermountain Healthcare

Sudden Cardiac Death ♥ Sudden cardiac death (SCD)  natural & unexpected death due to cardiac causes occurring in a short time period (generally ≤ 1 h of symptom onset) in a person with known/unknown cardiac disease. ♥Most SCDs are related to cardiac arrhythmias. ♥Approximately half of all cardiac deaths can be classified as SCDs. ♥SCD represents the first expression of cardiac disease in many individuals who experience outof-hospital cardiac arrest.

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Sudden Cardiac Death ♥ Although SCD rarely occurs at youth, when it does, it is a devastating event for both the family and local community. ♥ Can SCD be prevented? ♥ Yes, it sure can. If diagnosed early, treated properly and educate patients to avoid/eliminate the risk factors that can trigger life-threatening arrhythmias, most of SCDs could have been prevented.

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How ??? ♥ Knowing the causes ♥ Recognizing the characteristics of SCD-causing diseases is essential for making the correct diagnosis. ♥ Following the guidelines for risk assessment and treatment

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Cardiac Channelopathies ♥Approximately 50% Unexplained SCDs are caused by cardiac channelopathies & cardiomyopathies Behr ER, et al. Eur Heart J. 2008;29:1670-1680.

♥Cardiac channelopathies are a group of clinical syndromes that affect cardiac K+, Na+ & Ca2+ ion channels. ♥When the ion channel protein does not function properly, either due to gene mutation or acquired malfunction, the electrical properties of the patient’s heart will be altered, changing the surface ECG and/or predisposing them to lifethreatening, pro-arrhythmic events.

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Increased Risks of SCD Channelopathies Channelopathies •• Long LongQT QTSyndrome Syndrome(LQTS) (LQTS) •• Short ShortQT QTSyndrome Syndrome(SQTS) (SQTS) •• Brugada BrugadaSyndrome Syndrome(BrS) (BrS) •• Catecholaminergic CatecholaminergicPolymorphic PolymorphicVentricular VentricularTachycardia Tachycardia(CPVT) (CPVT) •• Familial Familialconduction conductiondisorders disorders •• Idiopathic IdiopathicVF VF •• Prescription Prescriptionor orrecreational recreationaldrug-related drug-relatedfatal fatalarrhythmias arrhythmiasdue dueto to genetic predisposition genetic predisposition Cardiomyopathies Cardiomyopathies •• Arrhythmogenic Arrhythmogenicright/left right/leftventricular ventricularcardiomyopathies cardiomyopathies(ARVC/ALVC) (ARVC/ALVC) •• Hypertrophic Hypertrophiccardiomyopathy cardiomyopathy(HCM) (HCM) •• Dilated Dilatedcardiomyopathy cardiomyopathy(DCM) (DCM) •• Non-compaction Non-compactionmyocardium myocardium(NCM) (NCM)

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Long QT Syndrome ♼ Caused by mutations of genes encoding cardiac potassium, sodium or calcium ion channels or channel regulatory properties, resulting in delayed repolarization, prolonged QT interval and increased risks of torsade de pointes (TdP), ventricular fibrillation (VF) and SCD.

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Table 1: Genetic basis of 14 subtypes of inherited LQTS Prevalence Type (among genotyped)

Chromosome / Gene

Protein

Protein function

Mutation effect

Romano-Ward syndrome (autosomal dominant inheritance) LQT1 LQT2 LQT3

40-45% (333)* 45-50% (433) 5-8% (189)

11p15.5 / KCNQ1

Kv7.1

α-subunit of IKs channel

IKs ↓

7q35-36 / KCNH2

Kv11.1

α-subunit of IKr channel

IKr ↓

3p21-24 / SCN5A

Nav1.5

α-subunit of Na+ channel

INa,L↑

LQT4

<1% (7)

4q25-27 / ANK2

Ankyrin B

Anchoring protein

multiple ion channels &

LQT5

<2% (16)

21q22.1 / KCNE1

minK

β-subunit of IKs channel

IKs ↓

LQT6

<2% (13)

21a22.1 / KCNE2

MiRP1

β-subunit of IKr channel

IKr ↓

LQT7

<5% (45)

17q23 / KCNJ2

Kir2.1

α-subunit of IK1 channel

IK1 ↓

LQT8

<1% (6)

12p13 / CACNA1C

Cav1.2

α-subunit of Ca2+ channel

ICa,L↑

LQT9

<1% (6)

3p25 / CAV3

Caveolin-3

INaL↑

LQT10

<0.1% (1)

11q23.3 / SCN4B

β-4

co-localizes with Nav1.5 at sarcolemma β-subunit of Na+ channel

LQT11

<0.1% (1)

7q21-22 / AKAP9

Yotiao

IKs ↓

LQT12

<0.2% (1)

20q11.2/ SNTA1

α1-syntrophin

Mediate IKs channel phosphorylation Regulates Na+ channel function

INaL↑

LQT13

<0.1% (1)

11q24 / KCNJ5

Kir2x, Kir3x

Inward rectifier K channels

IKirX ↓?

LQT14?

<2% (16)

1q43/ RyR2

Cav

Affects Ca2+ channel function

Cytosolic Ca2+ ↑

transporters ↓

INaL↑

Jervell, Lange-Nielsen syndrome (autosomal recessive inheritance) JLN1

<0.5%

11p15.5 / KCNQ1

Kv7.1

α-subunit of IKs channel

IKs ↓

JLN2

<0.5%

21q22.1 / KCNE1

minK

β-subunit of IKs channel

IKs ↓

♥ Among channelopathies, LQTS is the most well-studied LDS Hospital with 14 disease-causing genes identified.

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Gene-Specific Gene-Specific ECG ECG Patterns Patterns in in LQT1-3 LQT1-3

LQT3

LQT2

LQT1

Moss, et al, Circulation 1995;92:2929-34 LDS Hospital Intermountain Healthcare

Genotype-Specific ECG Patterns in LQT1-3 â&#x2122;Ľ Subsequently 10 ECG patterns in LQT1-3, including 4 in LQT1, 4 in LQT2 and 2 in LQT3 were identified and have been proven very helpful in LQTS clinical Dx and genotype prediction.

Zhang, et al, Circulation, 2000;102:2849-2855

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ECG Patterns

LQT1

(Zhang, et al Circulation 2000);102:2849-55 LDS Hospital

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Typical LQT1 ECG patterns 1. Infantile ST-T wave

2. Broad-based T wave 1 mV

1000 msec

3. Normal appearing T wave

4. Late onset of normal appearing T wave

Lead II LDS Hospital Intermountain Healthcare

ECG Patterns

LQT2

(Zhang, et al Circulation 2000);102:2849-55 LDS Hospital

Intermountain Healthcare

Typical LQT2 ECG patterns

Bifid T waves Type 2

Type 1 1 mV

1000 msec Type 4

Type 3

Lead II LDS Hospital Intermountain Healthcare

ECG Patterns

LQT3

(Zhang, et al Circulation 2000);102:2849-55 LDS Hospital

Intermountain Healthcare

Typical LQT3 ECG patterns 1. Late onset of narrow peaked T wave 1 mV

1000 msec

2. Asymmetrical peaked T wave

Lead II LDS Hospital Intermountain Healthcare

TdP

â&#x2122;Ľ Whether it is congenital or acquired, TdP is mostly a Long QT-associated polymorphic ventricular arrhythmia that comes in burst with QRS morphology changes beat to beat and axis twisting around isoelectric baseline once every few beats and in the rate ranging 150-250 bpm.

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Genotype-Specific Onset of TdP in LQT1 and LQT2

TdP in LQT1 is not pausedependent in most cases

Tan, et al Circulation, 2006;114:2096-13

TdP in LQT2: Pause-dependent in most cases LDS Hospital Intermountain Healthcare

Case 1.

•A 34 y.o. Caucasian female developed cardiac arrest on a sandy beach while on vacation. She had a Hx of recurrent syncope since age 14.

Family Hx of SCD (-).

QTc 660 ms with broad-based T waves •Paramedics found her in VF. Luckily, she was resuscitated successfully.

•Routine cardio work-up (-).

QTc= QT/√R-R •She had a markedly slow heart rate (<45 bpm) and was intolerable to beta- (Bazett’s formula) QT 660 ms blockers. Thus an implantable cardioverter defibrillator (ICD) was implanted .

Three years later she experienced one inappropriate ICD discharge during a thunderstorm. On the fifth year of wearing an ICD she collapsed in the middle of skiing. Her ICD revealed following rhythm which was converted into sinus rhythm by an appropriate treatment.

Non-pause dependent TdP degenerated into VF immediately LDS Hospital Intermountain Healthcare

Case 1 Quiz This is clearly a LQTS. What is your predicted genotype?

A. LQT3 B. LQT2

QTc 660 ms with broad-based T waves

QTc= QT/â&#x2C6;&#x161;R-R QT 660 ms

C. LQT1

Non-pause dependent TdP degenerated into VF immediately

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Answer for Case 1: C LQT1 Based on the ECG patterns and the nature of cardiac events, this patient was predicted as a possible LQT1 gene mutation carrier. A KCNQ1 mutation was identified a few years later from her. Family screening identified 5 more affected members.

QTc 660 ms with broad-based T waves

QTc= QT/â&#x2C6;&#x161;R-R QT 660 ms

0.49 s Proband BB Syncope /CA 0.62 s 0.49 s 0.47 s ICD BB 0.51 s BB

0.41 s

0.48 s BB

Non-pause dependent TdP degenerated into VF immediately LDS Hospital Intermountain Healthcare

Case 2 A 14 y.o. girl had “seizure-like spells”. EEG (-) Family Hx: Paternal grandmother died suddenly in her early 40s due to“grand mal seizures”

Correct answer B. LQT2

R-R

QT 620 ms

QTc 550 ms

A. LQT3 B. LQT2

Quiz:

a. What is your Dx? b. And your predicted genotype?

C. LQT1 LDS Hospital Intermountain Healthcare

Case 3 •A 32 y.o. Caucasian female was admitted to ER for recurrent syncope.

•She regained sinus rhythm after DC shocks.

•Hx: She had syncope/ seizures attacks triggered by loud noise or emotional stress.

•Both cardiac (serial ECGs, Holter, tilt table test and echo) and neurologic evaluation (EEG with sleep deprivation testing and head CT) had negative findings •

A ECG monitory

B C

QTc 520 ms measure from baseline ECG

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Case 3 Quiz

A ECG monitory

What is your Dx for And what is your predicted genotype?

B C

Correct answer LQT2

Baseline ECG: QTc 520 ms

Hint: subtle bifid T waves

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Case 3 10 y.o. son, asymptomatic, borderline QTc at rest Family screening Her son has a borderline QT prolongation at rest and it shortened dramatically during exercise (QTc 380 ms). T waves became peaked at 1-min recovery.

Quiz 3b Is he affected?

A.Yes B.No

QTc 459 ms

QTc shortened 1 min after exercise

QTc 380 ms

Answer: A. Yes, he is.

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Case 4

12 y.o. boy, asymptomatic, father had recurrent syncope

QTc 480 ms; normal appearing T wave Answer: A. LQT1

Case 4 Quiz What is your Dx, and your predicted genotype?

A. LQT1;

B. LQT3 C;

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Answer to Case 4 Quiz: LQT1 â&#x2122;Ľ Long QT + normal appearing T wave is the most common ECG pattern in LQT1 !

Pedigree analysis and mutation identification

Using ECG patterns we performed family phenotyping. Typical LQT1 ECG patterns were present in 87% of 31 family members who were genetically confirmed as KCNQ1Zhang, et al BMC Med Genet. 2008; 9: 87 L187P mutation carriers subsequently.

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Case 5 The oldest daughter 8 y.o, asymptomatic

Dx?

The 2nd oldest daughter 6 y.o., asymptomatic

Grandpa had SCD at age 57 and uncle had aborted SCD at age 16, a family with four children came for screening

QTc 500 ms

Quiz: ECG Dx and Predicted Genotype?

QTc 503 ms Dx? LDS Hospital Intermountain Healthcare

Case 5 Quiz: ECG Dx and Predicted Genotype?

The 3rd daughter 6 y.o., asymptomatic

QTc 490 ms Dx?

The youngest daughter 3 y.o., asymptomatic

Dx?

QTc 450 ms

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Answer to Case 5: LQT3 â&#x2122;Ľ Pedigree analysis revealed a total of 8 affected members. â&#x2122;Ľ Genetic testing identified a SCN5A-Delta KPQ deletion mutation that result in a gain-offunction of late sodium channels.

0.49 s died at age 81 0.49 s SD age 57

0.49 s

0.50 s BB

0.50 s BB

0.49 s BB

Proband CA ICD

QTc 0.51 s

0.45 s BB

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Summary ♥ Gene-specific ECG patterns are present in LQT1-3, the most common genotypes of LQTS. ♥ Recognizing gene-specific ECG patterns can help increase diagnostic accuracy, facilitate targeted gene search and appropriate therapy for the prevention of SCD. ♥ ECG and pedigree analysis are very helpful in family search to identify obligated gene-carriers. ♥ ECG patterns in inherited arrhythmias are easy to learn and can be better utilized in clinical practice. If ever encountered such a case, please feel free to contact me at ldlzhang@gmail.com, I’m only a click away, and willing to help you 24X7.

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SHA24-GHA10 Joint Scientific Conference

Riyadh, Kingdom of Saudi Arabia, February 13-16, 2013

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