genetics of sudden cardiac death - european society of...
TRANSCRIPT
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Genetics of Sudden Cardiac Death
Geoffrey Pitt
Ion Channel Research Unit
Duke University
DukeU VN I E R S YI T
Disclosures: Grant funding from Medtronic
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Sudden Cardiac Death
• High incidence
– 50-100 per 100 000 in Europe and US
– 250 000 to 300 000 deaths annually in US
– More deaths in US than stroke, lung cancer, breast cancer, and HIV AIDS combined
• Poor survival
– Overall survival rate 4.6%
• Often presents without warning or recognized trigger
– Mean age is in the mid 60s
Prediction and Prevention Remain a Challenge
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SCD prevention and prediction challenges
• Limited information about specific triggers 30-40% events are unwitnessed; 95% of victims do not survive
• Unheralded by symptoms in 40-50% 80% with high-grade CAD at autopsy, but <5% with known prior CAD
Prog Cardiovasc Dis. 2008; 51:213
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Adapted from N Engl J Med 2001;345:1473
All are substrates for SCD, but SCD only occurs in a minority of subjects
SCD prevention and prediction challenges
Inherited rhythm abnormalities, acquired rhythm abnormalities, arrhythmogenic disorders, congenital heart disease, other causes
Non-CAD SCD
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Types of non-CAD sudden cardiac death
• SyndromicInherited arrhythmias (e.g., congenital Long QT Syndrome
or Brugada Syndromes)
(Arrhythmogenic right ventricular dysplasia)
• Non-syndromicPopulation-based QTc changes and risk of SCD
• Acquired(Drug-induced Long QT Syndrome) and heart failure
Arrhythmia = Mutation affecting an ion channel
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Ion channels: the basis of the ECG
Adapted from Gussak and Antzelevitch(Eds), Electrical Diseases of the Heart
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Combined actions of multiple ion channelsgenerate the cardiac action potential
InwardDEpolarizing
Currents
OutwardREpolarizing
Currents
Gene
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Syndromic conditions
Long QT Syndrome
Brugada Syndrome
Catecholaminergic Polymorphic Ventricular Tachycardia
Short QT Syndrome
Arrhythmogenic right ventricular dysplasia
Arrhythmia = Mutation affecting an ion channel
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Long QT Syndrome
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Long QT Syndrome is a “channelopathy”
LOD score = 26
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Long QT Syndrome is a “channelopathy” Type Mutation %
LQT1 alpha subunit of the slow delayed rectifier potassium channel (KvLQT1 or KCNQ1) 30-35
LQT2 alpha subunit of the rapid delayed rectifier potassium channel (HERG + MiRP1) 25-30
LQT3 alpha subunit of the sodium channel (SCN5A) 5-10
LQT4 channel anchor protein Ankyrin B <1
LQT5 beta subunit MinK (or KCNE1) which coassembles with KvLQT1 ~1
LQT6 beta subunit MiRP1 (or KCNE2) which coassembles with HERG <1
LQT7 potassium channel KCNJ2 (or Kir2.1) <1
LQT8 alpha subunit of the calcium channel Cav1.2 encoded by the gene CACNA1c <1
LQT9 channel organizing protein caveolin 3 ~1
LQT10 beta subunit SCN4B which coassembles with Nav1.5 (SCN5A) <1
LQT11 channel anchor protein AKAP9 ~1
LQT12 sodium channel regulator SNTA1 ~1
LQT13 alpha subunit of the G protein-activated potassium channel 4 (GIRK4) <1
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Long QT Syndrome: channel dysfunction
LQT3
LQT1LQT2
InwardDEpolarizing
Currents
OutwardREpolarizing
Currents
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Long QT Syndrome: channel dysfunction
LQT3
LQT1LQT2
InwardDEpolarizing
Currents
OutwardREpolarizing
Currents
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HERGLQT2
Evolution of LQTS diagnosisSpectrum of reported mutations - 2009
KCNQ1LQT1 SCN5A
LQT3
36% yield overall75% yield among high
probability patients
Heart Rhythm 2009;6:1297
missense mutations
non-missense mutations
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Not all variants are mutations
Circulation. 2009;120:1752
HERGLQT2
KCNQ1LQT1 SCN5A
LQT3
cases
rare variants in controls
polymorphisms
6% of normal patients have “mutations”
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Genetic testing especially useful to identify at-risk family members
JACC 57, 51, 2011
10-fold increased risk
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Brugada Syndrome: channel dysfunction
SCN5A mutations account for < 30% of BrS
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Brugada Syndrome: channel regulator dysfunction
Circulation 116: 2260, 2007
LOD score > 4
Glycerol-3-phosphate dehydrogenase 1–like
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LOD scores are low
New Brugada Syndrome loci?
6% of normal patients have “mutations”
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Non-syndromic conditions
Family history of non-CAD SCD
Inheritability of QT interval
Abnormal ECG = Ion channel mutation
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Familial risk of SCD in menThe Paris Prospective Study I
Events in Subjects
SCD[n=118]
Fatal MI[n=192]
Controls[n=6,762] p
ParentalHistory of SCD
22[18.6%]
19[9.9%]
716[10.6%]
0.02
Relative Risk1 affected parent
1.95[p=.005]
0.97[p=NS]
Relative Risk2 affectedParents
9.44[p=.01]
Circulation. 1999;99:1978
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Many common variants affect QT interval
• Ion ChannelsKCNQ1, KCNH2, KCNE1, KCNJ2, SCN5A, SCN10A
• Ion Channel RegulatorsNOS1AP, ATP1B1, CASQ2, PLN
• OthersTranscription factors, kinases, and others
NOS1AP
Nat Genetics 41,399 (2009)Nat Genetics 41,407 (2009)Nat Genetics 42,1068 (2010)
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Many common variants affect QT interval
• Ion ChannelsKCNQ1, KCNH2, KCNE1, KCNJ2, SCN5A, SCN10A
• Ion Channel RegulatorsNOS1AP, ATP1B1, CASQ2, PLN
• OthersTranscription factors, kinases, and others
NOS1AP
PNAS 105 4477, 2008
NOS1AP
Nat Genetics 41,399 (2009)Nat Genetics 41,407 (2009)Nat Genetics 42,1068 (2010)
NOS1AP-1 Hz
Loss of
Function
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Mutation affecting an ion channel
Abnormal ECG
=
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Early repolarization and SCD
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Acquired conditions
Drug-induced LQTS
Heart failure
“Multi-hit” hypothesis
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Drug induced LQTS: an acquired condition with genetic susceptibility
Circ Arrhythmia Electrophysiol. 2009;2:511
QT prolonging
drug%
pa
tie
nts
with
c L
QT
S lo
cu
s m
uta
tio
n
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Elevated risk of SCD in heart failure
MADIT II SCD-HEFT
N Engl J Med 2002; 346:877 N Engl J Med 2005; 352:225
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Prolonged QTc in heart failure associated with decreased survival and sudden death
DIAMOND study of Dofetilide in heart failureCirculation 2003;107:1764
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Not all patients with heart failure have a prolonged QTc: an acquired condition?
European Heart Journal (1986) 7, 14
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Circ. Res. 2004;95;754
Heart failure, like drug-induced LQTS: A multi-hit hypothesis?
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SCN5A S1103Y allele is associated with SCD from multiple triggers
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Primary Prevention ICDs
Appropriate
ICD Rx
Allele Status at 1103
None / Inappropriate ICD Rx
Allele Status at 1103
Duke EPGEN case-control studyIs SCN5A S1103Y associated with appropriate ICD therapy?
112
8923
Sun et al., Circ: Genetics, in press
Ischemic or non-ischemic cardiomyopathy, EF < 35%
Shock and/orAnti-tachycardia pacing
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Baseline Characteristics Stratified by ICD Therapy
Characteristic
Entire Cohort(n=112)
Appropriate ICD Therapy(n=23)
No Appropriate ICD Therapy(n=89)
Age, Mean (SD), y 63 (12) 64 (9) 63 (13)Male, No. (%) 74 (66) 18 (78) 56 (63)Medical HistoryNon-Ischemic Cardiomyopathy, No. (%) + 60 (54) 17 (74) 43 (48)
Diabetes, No. (%) 57 (51) 11 (46) 46 (52)Tobacco Use, No. (%) 59 (53) 12 (52) 47 (53)Hypertension, No. (%) 101 (90) 22 (96) 79 (89)Hyperlipidemia, No. (%) 81 (72) 18 (78) 63 (71)Atrial Fibrillation, No. (%) 51 (46) 9 (39) 42 (47)NYHA Class, Mean (SD) 2.4 (0.6) 2.3 (0.7) 2.4 (0.6)Ejection Fraction, Mean (SD), % 25 (6) 24 (7) 25 (6)
QTc, Mean (SD), ms 464 (41) 463 (45) 465 (40)Serum K+ at Enrollment, Mean (SD), mmol/L 4.2 (0.5) 4.1 (0.4) 4.2 (0.5)QT Interval corrected using Bazett’s Formula (QTc=QT/√RR)+ P=0.03
Sun et al., Circ: Genetics, in press
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S1103Y SNP predicts ICD therapy in African Americans with Reduced LVEF
Sun et al., Circ: Genetics, in press
Adjusted Hazard Ratio= 4.33(95% CI 1.60-11.73, p=<0.01)
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S1103Y SNP predicts ICD therapy in African Americans with Reduced LVEF
Adjusted Hazard Ratio= 4.33(95% CI 1.60-11.73, p=<0.01)
Transient Hypokalemia?
Sun et al., Circ: Genetics, in press
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S524Y SNP – does not alter channel function:NOT predictive of ICD therapy
Albert Sun, Patrick Hranitzky
P = NS
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VALIANTN Engl J Med 2005;352:2581
Rates of Sudden Death According to EF
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Will S1103Y be prognostic fro ICD therapy in African Americans with LVEF >35% ?
Incidence of SCD Number of SCD Events
Low EF
High EF
35%
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SUMMARY
• Syndromic conditionsMany discovered mutations; not all are pathogenic:
effect upon channel function should be validated
Several disease gene loci (channel modulators) not yet discovered
• Non-syndromic/Acquired conditionsManifestations of a genetic predisposition
Proof of principle: arrhythmias in heart failure may have a genetic basis → Future biomarkers?
What are methods for discovery of new loci/biomarkers
and subsequent validation?
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Fibroblast Growth Factor Homologous Factors (FHFs)
• FGF11-14
• Not secreted
• Do not bind FGF-Rs
• Bind to Na+ channels
– Modulate Na+ channel function
• Regulate neuronal excitability
– FGF14: locus for spinocerebellar ataxia 27 (SCA27)
– FGF14-/- mice are ataxic
Function of FHFs in heart - unexplored
FHFs
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FGF13 knockdown affects Na+ currents
Chuan Wang, Jessica Hennessey
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FGF13: a cardiac Na+ channel modulator
• Increases Na+ channel availability
• Accelerates conduction velocity• Candidate for an arrhythmogenic locus
– Loss of function mutations: BrS
• Molecular, cellular, and animal models useful for analyses of new candidate loci
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Acknowledgements
Pitt LabJessica HennesseyAlbert SunChaojian WangChuan Wang
CollaboratorsRobert KirktonNenad BursacPat Hranitzky
Medtronic-Duke Strategic Alliance