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. LDS Hospital Intermountain Healthcare
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. LDS Hospital Intermountain Healthcare
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. Intermountain Healthcare
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
Intermountain Healthcare
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
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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. LDS Hospital Intermountain Healthcare
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. LDS Hospital Intermountain Healthcare
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;
LDS Hospital C. LQT2 Intermountain Healthcare
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. LDS Hospital Intermountain Healthcare
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. LDS Hospital Intermountain Healthcare
SHA24-GHA10 Joint Scientific Conference
Riyadh, Kingdom of Saudi Arabia, February 13-16, 2013
LDS Hospital Intermountain Healthcare