Genetics of Sudden Cardiac Death - European Society of...

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

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


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)

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?


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

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