1st Worldwide Internet Symposium on Drug1st Worldwide Internet Symposium on Drug--Induced QT Induced QT y p gy p g QQProlongation, October 2007Prolongation, October 2007

Drug induced LQT Syndrome: Sotalol ExperienceDrug-induced LQT-Syndrome: Sotalol-Experience, Heart failure, Susceptibility to drug induced LQT

Stefan KääbLudwig-Maximilians Universität München

Klinikum Grosshadern, Med. Klinik IStefan.Kaab@med.uni-muenchen.de

LMU

no conflicts of interest to disclose

Objective and Outline• review data on Sotalol as an examplary agent of drug-induced LQT

syndrome

• introduce the multifactorial nature of drug-induced LQT syndrome,

highlighting hypertrophy and heart failure as important co-factors for

TdP in the conte t of dr gs ith QT prolonging potential (i ETdP in the context of drugs with QT-prolonging potential (i.E.

Sotalol)

Sotalol as a tool to study altered repolarization and susceptibility to• Sotalol as a tool to study altered repolarization and susceptibility to

TdP in the context of QT prolonging drugs

common genetic variants modulate myocardial repolarization and• common genetic variants modulate myocardial repolarization and

define intrinsic individual susceptibility to drug-induced LQT

syndromesyndrome

Sotalol induced changes in myocardial l i ti i h lth l trepolarization in healthy volunteers

(n=39)

Couderc JP et al. J Electrocardiol 2003; 36:115-120

QTc and area-based repolarization parameters are affected by sotaloli di ti d i d d h i T h lindicating drug induced changes in T-wave morphology

Sotalol induced changes in QTcSotalol induced changes in QTc--Interval Interval i t i l d t i l h th i ti ti t i l d t i l h th i ti tin atrial and ventricular arrhythmia patients in atrial and ventricular arrhythmia patients

(n=209) (n=209)

160 mg b.i.dDischarge 80 mg b.i.d.Discharge

Baseline

QTc (ms)

Kim RJ, et al., Pace 2006; 29:1219-1225

Yield of in-hospital monitoring for initiation of sotalol in atrial arrhythmia patientsof sotalol in atrial arrhythmia patients

(n=120)

• new or increased ventricular arrhythmias in n=7 (5.8%) (TdP in n=2)

• significant bradycardia in n=20 (16.7 %)

• excessively prolonged QTc interval in n=8 (6.7 %)

Ch MK t l J A C ll C di l 1998 32 169 176Chung MK, et al., J Am Coll Cardiol 1998;32:169-176

Proarrhythmia with sotalol• pooled analysis of n=1.288 patients enrolled in premarketing trials

showed new or increased ventricular arrhythmia occurred in 4.3% (1.9% classified as torsades de pointes)1( p )

• the survival with oral d-sotalol (SWORD) trial demonstrated increased mortality in remote myocardial infarction group with LVEF between

230-40% (RR=7.9) with increased risk in women2

• in general proarrhythmia is reported with a range of 1% to 8% for sotalolsotalol

• sotalol causes a concentration dependent lengthening of the QT interval, increasing action potential duration and refractory periods predominantly by blocking the delayed rectifier potassium current (IKr)

1Soyka LF et al., Am J Cardiol 1990; 65:74A-81A2Pratt CM, et al., Am J Cardiol 1998; 81:869-876

Increased short-term variability of repolarization rather than QT prolongation predicts d-sotalol induced

t d d i t i d ith h i AV bl ktorsades de pointes in dogs with chronic AV block induced LV-hypertrophy

Thomsen MB, et al., Circulation 2004; 110:2453-2459

LV-Hypertrophy and congestive heart failure b d d f f i d LQTcan be regarded as forms of acquired LQT

syndrome and thus are specific risk factors f d i d d LQT dfor drug induced LQT syndrome

Heart Heart FailureFailure

neurohumoral neurohumoral pump failurepump failure electrical failureelectrical failure

DepolarizationDepolarization RepolarizationRepolarization

activationactivationstretchstretch

ImbalanceImbalance

(substrate)(substrate)

hemodynamic hemodynamic

short termshort termlong long termterm (trigger)(trigger)

EADEAD InhomogeneityInhomogeneity( ti( ti t l)t l)compensationcompensation (spatio(spatio--temporal)temporal)

altered gene expressionaltered gene expression

Torsades de Pointes TachycardiaTorsades de Pointes Tachycardiapolymorphic VTpolymorphic VTdd di d thdd di d thsudden cardiac deathsudden cardiac death

modified from: Marban E, J Cardiovasc Electrophysiol, 1999;10:1425-8

Prolongation of APD due to reduced IProlongation of APD due to reduced Ito1to1in isolated human cardiomyocytes in congestive heart failurein isolated human cardiomyocytes in congestive heart failurey y gy y g

12

pF] NonFailing

Failing

6

8

10

nsity

Ito

[pA/

p Failing

0

2

4Den

Center0

Density Ito Human Ventricle

Beuckelmann DJ, Näbauer M, Erdmann E. Circ Res 73:379 (1993) Beuckelmann DJ, Näbauer M, Erdmann E. Circ Res 73:379 (1993)

Transmural Dispersion of Repolarization in Heart Failure

Tachycaria induced HF modelTachycaria induced HF model

canine LV wedge preparationscanine LV wedge preparations

APD contour maps

APD recordingsg

F. Akar and D. Rosenbaum, Circ. Res. 2003; 93:638-645

Excessive AP-Prolongation by K+ channel block (CsCl) in congestive heart failure – evidence for reduced g

repolarization reserve

700

800

(ms)

Control + CsCl

400

500

600

APD

90

(

100

200

300

Control Myocytes Failing Myocytes0

Pak P, et al., JACC (1997)Pak P, et al., JACC (1997)dog ventricular myocytes

Hypertrophy and Congestive Heart Failure in Humans: an Acquired Form of Long-QT-Syndrome

Congestive Heart FailureLV-Hypertrophy

6006001/2 ]

600

400

500

600

400

500

600

tion

[mse

c1

400

500

600

440 ms

200

300

400

200

300

400

QTc

- D

ura

200

300

400

0

100

200

0

100

200

0

100

200

Singh JP, et al. , Choy AM et al.,

Choy Roden

0Singh

0QTc-Duration

0 Survivers (2-4 years)

Other Cardiac Death SCD, VT

g , ,JACC 29: 778 (1997) Fu G-S, et al. , Eur Heart J 18:281 (1997)

y ,Circulation 96:2149 (1997)

Heart Heart FailureFailure

Genetics of acquired LQT Syndrome ?Genetics of acquired LQT Syndrome ?

neurohumoral neurohumoral pump failurepump failure electrical failureelectrical failure

DepolarizationDepolarization RepolarizationRepolarization

Genetics of acquired LQT Syndrome ?Genetics of acquired LQT Syndrome ?

activationactivationstretchstretch

ImbalanceImbalance

(substrate)(substrate)

hemodynamic hemodynamic

short termshort termlong long termterm (trigger)(trigger)

EADEAD InhomogeneityInhomogeneity( ti( ti t l)t l)Search for genetics of heart failureSearch for genetics of heart failurecompensationcompensation (spatio(spatio--temporal)temporal)Search for genetics of heart failureSearch for genetics of heart failure

Search for genetics of altered repolarizationSearch for genetics of altered repolarizationaltered gene expressionaltered gene expression

Torsades de Pointes TachycardiaTorsades de Pointes Tachycardiapolymorphic VTpolymorphic VTdd di d thdd di d thsudden cardiac deathsudden cardiac death

modified from: Marban E, J Cardiovasc Electrophysiol, 1999;10:1425-8

Case Report

• 25 y, female patient

• ARDS, Sepsis

• Cardiomyopathy

• repetitive polymorphic VTrepetitive polymorphic VT

• TdP CPR• TdP, CPR Hinterseer et al., Br J Anaesth 2006

A tibi ti ThA tibi ti ThAntibiotic Therapy:Antibiotic Therapy:CefotiamCefotiamGentamycineGentamycine

16.04.16.04.

GentamycineGentamycineErythromycineErythromycine

TEE from April 17th. : LVEDD 60 ms, FS<10%

April 17th : Torsades de Pointes ArrhythmiaApril 17th : Torsades de Pointes Arrhythmia

QTc=510 msQTc=510 msQTc 510 msQTc 510 ms

•• polymorphic ventricular tachycardiapolymorphic ventricular tachycardia•• changing amplitude and QRSchanging amplitude and QRS axisaxis•• changing amplitude and QRSchanging amplitude and QRS--axisaxis•• prolonged QT inervalprolonged QT inerval•• initial shortinitial short--longlong--shortshort--sequencesequence•• initial shortinitial short--longlong--shortshort--sequencesequence

Cardiological Evaluation(5 weeks past acute illness)(5 weeks past acute illness)

• ECG :

regular SR, HR 80/min, left axis deviation,QTc 423 ms

• cardiac catheterization & EP study:

no structural heart diseaseno sustained arrhythmia induceabley

• echocardiography:

within normal limits

Testing Myocardial Repolarisation Reserve by i.v. Sotalol

pre Sotalol post SotalolG.F. (25 y)

by i.v. Sotalol

IIQTc 420ms QTc 510ms

V2

Control:

II

Control:

QT 450

V2QTc 410 ms QTc 450ms

according to protocol in Kaab et al, Eur Heart J. 2003; 24: 649-657

Sotalol testing unmasks reduced repolarization reserve in patients with history of drug induced LQT syndrome

600

650

600

650Study GroupControl Group

550

600

550

600

450

500

450

500 QTc [ms]

400 400

300

350

300

350

postprepostpreSotalol

postpreSotalol

postpre

Kääb et al., Eur Heart J, 2003;24:649-657

Repolarization ReserveRepolarization Reserve

n n

Electrolyte Electrolyte disturbancedisturbance

Genetic Disposition Genetic Disposition female genderfemale gendergenetic variants ?genetic variants ?

ispe

rsio

nis

pers

ion

on

on ↑↑

gg

f QTc

f QTc↑↑,

d, dpo

lariz

atio

pola

rizat

io&

SC

D&

SC

D

DrugsDrugsCardiac DiseaseCardiac Disease

number of risk factorsnumber of risk factors

risk

oris

k o

of re

pof

rep

TdP

&Td

P &

CNS diCNS di S t d f tiS t d f ti P hi t i DiP hi t i DiCNS diseaseCNS disease System dysfunctionSystem dysfunction Psychiatric DiseasePsychiatric Disease

KCNH2: alphaKCNH2: alpha--subunit of Isubunit of IKrKr

new mutation KCNH2 (Arg328Cys)new mutation KCNH2 (Arg328Cys)

Family

?

mutation KCNH2 (Arg328Cys)mutation KCNH2 (Arg328Cys)

? QTc 395QTc 395

QTc 423QTc 423 ???? QTc 420QTc 420

QTc 463QTc 463 QTc 416QTc 416QTc 430QTc 430QTc 428QTc 428QTc 439QTc 439

Questions

• Is genetic susceptibility to acquired LQTIs genetic susceptibility to acquired LQT syndrome relevant?

• What is the substrate of genetic susceptibility to acquired LQT syndrome?susceptibility to acquired LQT syndrome?

Monogenic and Complex Genetic Diseases

relative risk attributed to genetic variant Human Genetics

M i “

Continuous distributionof genetic variants

RR 1000RR 1000 Arrhythmogenic RightArrhythmogenic Right--Ventricular DysplasiaVentricular Dysplasia

„Mutations“gshaped by

mutation and selection

RR 100RR 100

RR 10RR 10

LongLong--QT SyndromeQT SyndromeHypertrophic CardiomyopathyHypertrophic Cardiomyopathy

Genetic Epidemiology„Polymorphisms“

RR 5RR 5

RR 2RR 2

F V LeidenF V LeidenQT prolonging QT prolonging SNPsSNPs

50 %50 %10 %10 %0,001 %0,001 % 0,01 %0,01 % 0,1 %0,1 % 1 %1 %RR 1RR 1

Prevalence in populationPrevalence in population

monogenicpolygenic

adapted from : N.E. Morton et al.

QTc Associated with Risk of SCD in the General Population (Rotterdam Study, n=4.344)

Log Survival FunctionLog Survival Function QTc normal m: ≤ 430f

QTc normalQTc normal

f: ≤ 450QTc borderline m: 431- 450

f: 451- 470QTc abnormal m: > 450

f: > 470 QTc borderlineQTc borderline

QTc abnormalQTc abnormal

QTc and Risk for SCD(< Median age 55-68 y)

borderline 1 6 (0 9 3 1)borderline(n=1.109 / 514)

1.6 (0.9-3.1)3.7 (1.1-14.0)

abnormal 2.5 (1.3-4.7)

FollowFollow--up (days)up (days)(6.7 (6.7 ±± 2.3 years)2.3 years)

(n=681 / 212) 8.0 (2.1-31.3)

Straus et al., JACC 2006;47:362-7

Genetic Variants and Risk for ArrhythmiasGenetic Variants and Risk for Arrhythmias

Common Disease Common Variant (?)Common Disease Common Variant (?)Common Disease Common Variant (?)Common Disease Common Variant (?)

•• From Rare to Common DiseasesFrom Rare to Common Diseases

•• From Rare to Common Gene VariantsFrom Rare to Common Gene Variants

Genetic susceptibility to Arrhythmias in the context of drugsmay follow the common disease common variant hypothesisy yp

LDLD--mapping in 4 LQT disease genesmapping in 4 LQT disease genes

chr11:2,450,000 | chr11:2,850,000 |chr11:2,550,000 | chr11:2,650,000 | chr11:2,750,000 |

KCNQ1 (11p15.5-p15.4)450 kb

• • • • •

16 Exons

81 SNPs

5‘

1 2 34

5 6 7 8 9 10 11 12

rs757092rs23017000.04480.2780

rs7396770.01600.2570

rs7570920.01290.0007

+1.67 ms

rs4639240.04050.8865

rs25191840.00180.4870

rs757092+1.67 ms/allele0.5% variance

p=2.3*10-5

n=3,966

chr7:150,000,000 | chr7:150,090,000 |

KCNH2 (7q36)

120 kb

5‘

chr21:34,700,000 | chr21:34,800,000 |

KCNE2 (21q22.11-q22.12) KCNE1

173 kb

5‘ 5‘

,

•• • • •

15 Exons

59 SNPs

5‘

1

2

3 45

6 7

• ••

2+3 Exons

34 SNPs

5‘ 5‘

1 2 3 4 5 6 7 89

rs8856840.01080.1665

rs9566420.02730.9998

rs18051230.02230.0017

-1.83 ms

rs38007790.04600.7194

rs17999830.03480.8917

rs28344560.00790.4451

rs28344880.01710.4825

rs7279570.00810.0498

+1.49 ms

Pfeufer et al., Circ Res. 2005K897T

Common variants (SNPs) in LQT disease genes modulate QT interval in the general population

Combined effect of 3 SNPs (6 alleles) on QT-interval

QT l i ll l QT RAS SDQT-prolonging allele QTc_RAS ± SD n

0 412.3 ± 13.8 70

1 415.8 ± 17.1 432

2 416.7 ± 16.4 905

3 417.7 ± 17.3 955

4 420.3 ± 17.7 561

5 420.4 ± 19.7 162

6 426.6 ± 18.2 19Analysis of 174 LD based SNPs in 4 LQT-disease genes shows positive

association in 3 loci and explains 15 ms of QT-interval variancePfeufer et al. Circ Res 2005

Hypotheses on genetic disposition to acquired LQTSHypotheses on genetic disposition to acquired LQTS

common gene variants in LQT disease genes and

genes modulating cardiac repolarization or cardiac

electrical properties are associated with risk for

arrhythmia in acquired LQT syndrome

(e.g. in the context of QT prolonging drugs)(e.g. in the context of QT prolonging drugs)

Searching for novel genesSearching for novel genes involved in QT regulation as the surrogate

marker for cardiac repolarizationmarker for cardiac repolarization

w/ hypothesis -> disease genes

w/o hypothesis -> genome wideyp g

GWA of QT interval in the General Population (KORA) using 100 K SNP Chip

Stage 1• n=103/103 from each extreme

(top and bottom 7.5th %tile)

Stage 2• n=300/300 from each extreme

• relaxed exclusion criteria

Stage 3• n=3,966, KORA S4 survey• relaxed exclusion criteria

Three stage design:

( p )• strict exclusion criteria

• females only• Genomewide genotyping

(s AF,pacer, pregnancy)• females only

• SNPs that passed stage 1

(s AF,pacer, pregnancy)• both genders

• SNPs that passed stage 2

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QTc_RAS QTc_RAS QTc_RAS

NOS1AP (C ) d l t QT i t l b 5 10 (1 5% )NOS1AP (Capon) modulates QT interval by 5-10 ms (1,5% var.)An hypothesis free genome wide association study was useful to identify a novel gene variant that modulates QT in the general population and may be a risk factor for drug induced LQT syndrome

Arking, Pfeufer et al., Nat. Genet 2006;38:644-651

risk factor for drug induced LQT syndrome

Summaryt l l t ti d d t l th i f th QT i t l i i• sotalol causes a concentration dependent lengthening of the QT interval, increasing

action potential duration and refractory periods predominantly by blocking the delayed

rectifier potassium current (IKr)

• for sotalol proarrhythmia is reported with a range of 1% to 8%

• hypertrophy and heart failure are acquired states with reduced repolarization reserve

due to downregulation of repolarizing currents and thus are important co factors fordue to downregulation of repolarizing currents and thus are important co-factors for

TdP in the context of drugs with QT-prolonging potential (i.E. Sotalol)

• Sotalol as a predominantly IKr blocking agent is a valid tool to study altered

repolarization and susceptibility to TdP in the context of QT prolonging drugs

• common genetic variants modulate myocardial repolarization, define intrinsic

individual repolarization stability and are likely to define intrinsic individualindividual repolarization stability and are likely to define intrinsic individual

susceptibility to drug-induced LQT syndrome

• Combinations of multiple extrinsic and intrinsic factors (multiple allels) are defining the

overall individual risk for drug induced LQT syndrome

CollaborationsVanderbilt UniversityDan Roden

Amsterdam University

LMU München GroßhadernMed. Klinik IMoritz Sinner

Johns Hopkins University& McKusick-Nathan InstituteDan E. ArkingWendy PostAmsterdam University

Arthur WildeConnie Beccina

University Münster

Martin HinterseerBritt-Maria Beckmann

TU München IHG, & GSF

Wendy PostW.H. Linda KaoAravinda Chakravarti

U i it M di l C tUniversity MünsterEric Schulze-Bahr

Nantes, INSERMJean-Jaques Schott

Arne PfeuferShapour JalilzadehMahmut AkyolThomas Meitinger

University Medical Center UtrechtMarc VosMorten ThomsenJean Jaques Schott

Denis Escande (†)

Johns Hopkins UniversityCardiology

Thomas Meitinger

GSF, EPI & IMEI Siegfried Perz Th Illi

University of RochesterJean-Philippe CoudercWojciech ZarebaCardiology

Peter M. SpoonerGordon TomaselliEduardo Marbán

Thomas IlligH.-Erich Wichmann

Wojciech ZarebaArthur Moss

University MiamiRobert MyerburgNanette Bishopric

Grant Support

German National Genome Research Network

http://www.allianceagainstscd.org/