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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
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
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
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
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
Ion channels: the basis of the ECG
Adapted from Gussak and Antzelevitch(Eds), Electrical Diseases of the Heart
Combined actions of multiple ion channelsgenerate the cardiac action potential
InwardDEpolarizing
Currents
OutwardREpolarizing
Currents
Gene
Syndromic conditions
Long QT Syndrome
Brugada Syndrome
Catecholaminergic Polymorphic Ventricular Tachycardia
Short QT Syndrome
Arrhythmogenic right ventricular dysplasia
Arrhythmia = Mutation affecting an ion channel
Long QT Syndrome
Long QT Syndrome is a “channelopathy”
LOD score = 26
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
Long QT Syndrome: channel dysfunction
LQT3
LQT1LQT2
InwardDEpolarizing
Currents
OutwardREpolarizing
Currents
Long QT Syndrome: channel dysfunction
LQT3
LQT1LQT2
InwardDEpolarizing
Currents
OutwardREpolarizing
Currents
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
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”
Genetic testing especially useful to identify at-risk family members
JACC 57, 51, 2011
10-fold increased risk
Brugada Syndrome: channel dysfunction
SCN5A mutations account for < 30% of BrS
Brugada Syndrome: channel regulator dysfunction
Circulation 116: 2260, 2007
LOD score > 4
Glycerol-3-phosphate dehydrogenase 1–like
LOD scores are low
New Brugada Syndrome loci?
6% of normal patients have “mutations”
Non-syndromic conditions
Family history of non-CAD SCD
Inheritability of QT interval
Abnormal ECG = Ion channel mutation
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
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)
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
Mutation affecting an ion channel
Abnormal ECG
=
Early repolarization and SCD
Acquired conditions
Drug-induced LQTS
Heart failure
“Multi-hit” hypothesis
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
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
Prolonged QTc in heart failure associated with decreased survival and sudden death
DIAMOND study of Dofetilide in heart failureCirculation 2003;107:1764
Not all patients with heart failure have a prolonged QTc: an acquired condition?
European Heart Journal (1986) 7, 14
Circ. Res. 2004;95;754
Heart failure, like drug-induced LQTS: A multi-hit hypothesis?
SCN5A S1103Y allele is associated with SCD from multiple triggers
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
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
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)
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
S524Y SNP – does not alter channel function:NOT predictive of ICD therapy
Albert Sun, Patrick Hranitzky
P = NS
VALIANTN Engl J Med 2005;352:2581
Rates of Sudden Death According to EF
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%
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?
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
FGF13 knockdown affects Na+ currents
Chuan Wang, Jessica Hennessey
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
Acknowledgements
Pitt LabJessica HennesseyAlbert SunChaojian WangChuan Wang
CollaboratorsRobert KirktonNenad BursacPat Hranitzky
Medtronic-Duke Strategic Alliance