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California Heart Rhythm SymposiumSan Francisco, CASeptember 8, 2012

“ J Wave Syndromes. Mechanisms”

Charles AntzelevitchMasonic Medical Research Laboratory

Utica, NY 13501

Gilead Sciences - Research Support and ConsultantshipAstraZeneca - Research Support and ConsultantshipCardiome - Research SupportMerck - Research SupportPopulation Council - Research Support Buchang Group - Research Support

NIH - Research SupportNYSTEM - Research SupportAHA - Research SupportNew York State &Florida Masons - Research Support

Disclosures & Acknowledgments

Action Potential StudiesSilvio LitovskyAnton LukasS. Krishnan


Voltage Clamp StudiesAndrew ZygmuntJonathan CordeiroHelen Diana (Dan Hu)Hector Barajas-MartinezJanire UrrutiaYoshiyasu Aizawa


Perfused Wedge StudiesGan-Xin YanSerge SicouriWataru ShimizuJose Di DiegoA. BurashnikovJeffrey FishGi-Byoung NamTetsuro EmoriMasahiko KondoMasato TsuboiFabrice ExtramianaChinmay PatelEyal NofYoshino MinouraIstván Koncz


In Vivo and Modeling StudiesVladislav V. Nesterenko


Stem Cell & Molecular BiologyXavier Michael JesudossBobby Cherian KallukalamYuesheng WuMayurika DesaiJackie Treat


CollaboratorsSami Viskin, Michel Haissaguerre, Mel Scheinman, Minoru Horie , Yoshifusa Aizawa, Arthur Wilde, Andras Varro, Michael Glickson, Michael Eldar, Liron Miler, Michael Ackerman, Jon

Steinberg, Pedro, Josep & Ramon Brugada, Wee Nademanee, Fiorenzo Gaita, Carla Giustetto, Martin Borggrefe,, Peter Schwartz, Lia Crotti, Michael Sanguinetti, Mike Ackerman, Christian Wolpert, Rainer Schimpf, Christian Veltmann, Lior Gepstein

CollaboratorsSami Viskin, Michel Haissaguerre, Mel Scheinman, Minoru Horie , Yoshifusa Aizawa, Arthur Wilde, Andras Varro, Michael Glickson, Michael Eldar, Liron Miler, Michael Ackerman, Jon

Steinberg, Pedro, Josep & Ramon Brugada, Wee Nademanee, Fiorenzo Gaita, Carla Giustetto, Martin Borggrefe,, Peter Schwartz, Lia Crotti, Michael Sanguinetti, Mike Ackerman, Christian Wolpert, Rainer Schimpf, Christian Veltmann, Lior Gepstein

Molecular GeneticsGuido PollevickAlejandra GuerchicoffRyan PfeifferElena BurashnikovGabriel CaceresColleen Puleo


Characteristics of the J Wave

•Also referred to as an Osborn wave•A distinct J wave is commonly

observed in the baseline ECG of some animal species, including baboons and dogs.

•A distinct J wave is rarely observed in humans under normal conditions, although an elevated J point is commonly encountered

•In humans and animals, the appearance of a prominent J wave in the ECG is considered pathognomonic of hypothermia, hypercalcemia, the Brugada syndrome, early repolarization pattern or other arrhythmogenic syndromes

2

Lead II ECG (dog)Hypothermia (24.5 C)

Yan and Antzelevitch. Circulation 93:372-379, 1996

3

Restitution of J wave parallels that of action potential notch


Cellular Basis for the J Wave

Transmural distribution of the Ito-mediated action potential notch is responsible for the inscription of the electrocardiographic J wave


Early Repolarization Patterns

Modified from Antzelevitch et al, JACC, 2011

4

Antzelevitch C.. J Cardiovasc Electrophys 12:268, 2001

Type 1

Brugada Syndrome

V1

V2

V3 V6

V5

V4

Ventricular Arrhythmias in Brugada Syndrome

BrS1 3p21 INa SCN5A, Nav1.5 11-28%

BrS2 3p24 INa GPD1L Rare

BrS3 12p13.3 ICa CACNA1C, Cav1.2 6.6%

BrS4 10p12.33 ICa CACNB2b, Cavβ2b 4.8%

BrS5 19q13.1 INa SCN1B, Navβ1 1.1%

BrS6 11q13-14 Ito KCNE3, MiRP2 Rare

BrS7 11q23.3 INa SCN3B, Navβ3 Rare

BrS8 12p11.23 IK-ATP KCNJ8, Kir6.1 2%

BrS9 7q21.11 ICa CACNA2D1, Cavα2δ 1.8%

BrS10 1p13.2 Ito KCND3, Kv4.3 Rare

BrS11 17p13.1 INa MOG1 Rare

Genetic Basis for Brugada SyndromeCausative Genes

Locus Ion Channel Gene/Protein % of Probands

5

15q24-q25 If HCN4

7q35 IKr KCNH2, HERG

Xq22.3 Ito KCNE5 (KCNE1-like)

Genetic Basis for Brugada SyndromeModulatory Genes

Locus Ion Channel Gene/Protein

I. Antiarrhythmic drugs Na+ channel blockers

Class IC drugs (Flecainide, Pilsicainide, Propafenone)Class IA drugs (Ajmaline, Procainamide, Disopyramide, Cibenzoline)

Ca2+ channel blockers (Verapamil) Beta Blockers (Propranolol intoxication)

II. Antianginal drugs Ca2+ channel blockers (Nifedipine, Diltiazem) Nitrates (Isosorbide dinitrate, Nitroglycerine) K+ channel openers (Nicorandil)

III. Psychotropic drugs Tricyclic antidepressants (Amitriptyline, Nortriptyline, Desipramine, Clomipramine) Tetracyclic antidepressants (Maprotiline)Phenothiazine (Perphenazine, Cyamemazine) Selective serotonin reuptake inhibitors (Fluoxetine) LithiumAnticonvulsants (clonazepam)Antipsychotics (Trifluoperazine, Loxapine)

IV. Other drugs Histaminic H1 receptor antagonists DimenhydrinateDiphenhydramineCocaine intoxicationAlcohol Intoxication

Drug-induced Brugada Syndrome

Modified from Antzelevitch. PACE 29:1130-1159, 2006 and Shimizu, J Electrocardiol, 2005

Amitriptyline-induced Brugada Syndrome

Minoura et al.J Cardiovasc Electrophysiol 23:423-32, 2012

Intrinsic HeterogeneityIntrinsic HeterogeneityAccentuate Notch &Cause Loss of APDDome in Epicardium

Accentuate Notch &Cause Loss of APDDome in Epicardium

Dispersion of RepolarizationTransmural Epicardial

QT interval Phase 2 reentry

Dispersion of RepolarizationTransmural Epicardial

QT interval Phase 2 reentry

ST Segment(Vulnerable Window)

ST Segment(Vulnerable Window)

ExtrasystoleExtrasystole

VT/VF (Reentry)VT/VF (Reentry)

Brugada Syndrome

INa, ICaINa, ICaI to, IKr , IKs, IK-ATP , ICl(Ca)

I to, IKr , IKs, IK-ATP , ICl(Ca)

Transmural Dispersion of Repolarization

Transmural Dispersion of Repolarization

Phase 2 Reentry in RV Epicardium

Phase 2 Reentry in RV Epicardium

Phase 2 Reentry-induced VT/VF

Phase 2 Reentry-induced VT/VF

Epi 1

Epi 2

ECG

500 msec

50mV

50mV

0.5mV

50mV

200 msec

0

0

0

0

4 3

21

200 msec

50mV

0 0 0Epi M Endo

4

3

2

1

Antzelevitch. Am J Physiol 293:H2024-38, 2007

6

Journal of Molecular and Cellular Cardiology 49 (2010) 543–553

Therapy - Brugada Syndrome

Devices or Ablative� ICD ? Pacemaker? Ablation or Cryosurgery

PharmacologicΧ Amiodarone - does not protect (Brugada et al. Circulation, 1998)

Χ β Blockers - do not protect (Brugada et al, 1998, Nademanee et al)

� β Adrenergic agonists – Isoproterenol (Miyazaki et al, 1996; Shimizu et al, )

� Phosphodiesterase Inhibitors-cilostazol(Tsuchiya et al., JCE 13: 698, 2002)

Χ Class IC antiarrhythmics – Flecainide, Propafenone - contraindicatedΧ Class IA antiarrhythmics

Χ Procainamide, Disopyramide - contraindicated� Quinidine (Yan and Antzelevitch, 1999; Alings et al, 2001; Belhassan et al, 1999)

? Tedisamil? AVE0118

� Anti-androgen therapy � I to Blocker - cardioselective and ion channel specific? Late INa agonist – dmLSB (Danshen derivative)

Devices or Ablative� ICD ? Pacemaker? Ablation or Cryosurgery

PharmacologicΧ Amiodarone - does not protect (Brugada et al. Circulation, 1998)

Χ β Blockers - do not protect (Brugada et al, 1998, Nademanee et al)

� β Adrenergic agonists – Isoproterenol (Miyazaki et al, 1996; Shimizu et al, )

� Phosphodiesterase Inhibitors-cilostazol(Tsuchiya et al., JCE 13: 698, 2002)

Χ Class IC antiarrhythmics – Flecainide, Propafenone - contraindicatedΧ Class IA antiarrhythmics

Χ Procainamide, Disopyramide - contraindicated� Quinidine (Yan and Antzelevitch, 1999; Alings et al, 2001; Belhassan et al, 1999)

? Tedisamil? AVE0118

� Anti-androgen therapy � I to Blocker - cardioselective and ion channel specific? Late INa agonist – dmLSB (Danshen derivative)

↑ ICa

↓ I to

Early Repolarization Pattern Predisposes to

Development of Polymorphic VT/VF via a Brugada Syndrome-like

Mechanism

Yan an Antzelevitch, Circulation, 1999Gussak and Antzelevitch, J Electrocardiol, 2000

Antzelevitch and Yan, Heart Rhythm7:549-58, 2010 Haïssaguerre et al., N Engl J Med 358:2016-23, 2008

Early Repolarization

Patternand SCD

31% of IVFvs.

5% of Controls

ER was defined as QRS-ST junction elevation of > 0.1 mV manifested as QRS slurring or

notching

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Nam, Kim, Antzelevitch, N Engl J Med 358:2078-79, 2008Nam…Antzelevitch. Eur Heart J. 31:330-9, 2010

Early Repolarization

Patternand SCD

60% of IVFvs.

3.3% of Controls

4 developed electrical storms

Tikannen et al, N Engl J Med 361, 2009.

Kaplan–Meier Curves for Death from Cardiac Causes and from Arrhythmia in Subjects with J-Point Elevation

Early Repolarization Is an Independent Predictor of Occurrences of Ventricular Fibrillation in the Very Early Phase of Acute Myocardial Infarction

Yoshihisa Naruse, MD; Hiroshi Tada, MD; Yoshie Harimura, MD; Mayu Hayashi, MD; Yuichi Noguchi, MD; Akira Sato, MD; Kentaro Yoshida, MD; Yukio Sekiguchi, MD; Kazutaka Aonuma, MD

Background—Recent evidence has linked early repolarization (ER) to idiopathic ventricular fibrillation (VF) in patients without structural heart disease. However, no studies have clarified whether or not there is an association between ER and the VF occurrences after the onset of an acute myocardial infarction (AMI).

Methods and Results—This study retrospectively included 220 consecutive patients with an AMI (57 female; mean age, 69±11 years) in whom the 12-lead ECGs before the AMI onset could be evaluated. The patients were classified on the basis of a VF occurrence within 48 hours after the AMI onset. Early repolarization was defined as an elevation of the QRS-ST junction of >0.1 mV from baseline in at least 2 inferior or lateral leads, manifested as QRS slurring or notching. Twenty-one (10%) patients had a VF occurrence within 48 hours of the AMI onset. A multivariate analysis revealed that ER (odds ratio [OR], 7.31; 95% confidence interval [CI], 2.21–24.14; P<0.01), a time from the onset to admission of <180 minutes (OR, 3.77; 95% CI, 1.13–12.59; P<0.05), and a Killip class greater than I (OR, 13.60; 95% CI, 3.43–53.99; P<0.001) were independent predictors of VF occurrences. As features of the ER pattern, a J-point elevation in the inferior leads, greater magnitude of the J-point elevation, notched morphology of the ER, and ER with a horizontal/descending ST segment, all were significantly associated with a VF occurrence.

Conclusions—The presence of ER increased the risk of VF occurrences within 48 hours after the AMI onset.

Clinical Trial Registration Information—http://www.umin.ac.jp; Identifier: UMIN000005533.

(Circ Arrhythm Electrophysiol. 2012;5:506-513.)

Genetic Basis for Early Repolarization Syndrome

Locus Ion Channel Gene/Protein % of Probands

ERS1 12p11.23 IK-ATP KCNJ8, Kir6.1

ERS2 12p13.3 ICa CACNA1C,CaV1.2 4.1%

ERS3 10p12.33 ICa CACNB2b, Cavβ2b 8.3

ERS4 7q21.11 ICa CACNA2D1, Cavα2d 4.1%

ERS5 12p12.1 IK-ATP ABCC9, SUR2A

ERS6 3p21 INa SCN5A, NaV1.5

8

KCNJ8 mutation (S422L)

Barajas-Martinez et al. Heart Rhythm, Nov. 3, 2011 Epub ahead of print

Gain of Function in IK-ATP due to

reduced sensitivity of the KCNJ8-S422L

mutant KATP

channels to ATP

Barajas-Martinez et al.Heart Rhythm 9:548-55, 2012

ERS Type 3SCN5A (NaV1.5) -G1297G FSX22

+ABCC9 (SUR2A)-V734I

Gain of Function in IK-ATP due to reduced

sensitivity of the ABCC9 (SUR2A)-

V734I mutant KATPchannels to ATP

Hu et al.Unpublished data, 2012

Early Repolarization Pattern Predisposes to

Development of Polymorphic VT/VF via a Brugada Syndrome-like

Mechanism

Yan an Antzelevitch, Circulation, 1999Gussak and Antzelevitch, J Electrocardiol, 2000

Antzelevitch and Yan, Heart Rhythm7:549-58, 2010

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J Wave Syndromes

Brugada Syndrome Early Repolarization

Syndrome

Outward shift of repolarizing current during early phase of the action potential

Phase 2 Reentry

I Na, I CaI Na, I Ca

I toI to

I K-ATPI K-ATPI K-AChI K-ACh

I K-ATPI K-ATP

?

I Na, I CaI Na, I Ca

BrS ERS Possible Mechanism(s)Region Associated with highest arrhythmic risk

RVOT Inferior myocardium

Increased levels of Ito

Male Predominance Yes (75%) Yes (80%) Testosterone modulation of ion currents underlying the epicardial AP notch

Average age of first event ~35-40 42Dynamicity of ECG High High Autonomic modulation of ion channel currents underlying

early phases of the epicardial AP

VT/VF trigger Short-coupled PVC

Short-coupled PVC

Phase 2 reentry

Ameliorative response to quinidine

Yes Yes Inhibition of Ito and possible vagolytic effect

Ameliorative response to Isoproterenol and cilostazol

Yes Yes Increased ICa and faster heart rate

Ameliorative response to pacing

Yes Yes Reduced availability of Ito due to slow recovery from inactivation

Vagally-mediated accentuation of ECG pattern

Yes Yes Direct effect to inhibit ICaand indirect effect to increase Ito (due to slowing of heart rate)

Features Common to Brugada and Early Repolarization Syndromesand Possible Underlying Mechanisms

RVOT=right ventricular outflow tract, AP=action potential; PVC=premature ventricular contraction

Continuous Spectrum Between BrS and ERS

• Brugada (BrS) and Early Repolarization (ERS) Syndromes share similar ECG characteristics, clinical outcomes, risk factors and arrhythmic characteristics.

• BrS and ERS share a common arrhythmic platform related to amplification of Ito-mediated J waves.

• Although BrS and ERS differ with respect to the magnitude and lead location of abnormal J wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression, termed J wave syndromes.

Hypothesis

TherapyEarly Repolarization Syndrome

Devices � ICD

Pharmacologic? Amiodarone - (3 out of 10) (Haïssaguerre et al . JACC 53: 612, 2009)Χ β Blockers - do not protect (Haïssaguerre et al . JACC 53: 612, 2009)Χ Verapamil - does not protect (Haïssaguerre et al . JACC 53: 612, 2009)

� Β Adrenergic agonists –Isoproterenol (Yan and Antzelevitch, 1999; Haïssaguerre et al . 2009)

� Class IA antiarrhythmics� Quinidine (Yan and Antzelevitch, 1999; Haïssaguerre et al . 2009)

Χ Class IB antiarrhythmics – Lidocaine, Mexiletine – do not protect (Haïssaguerre et al . 2009)Χ Class IC antiarrhythmics – Flecainide, Propafenone – contraindicated ?

� I to Blocker - cardioselective and ion channel specific� Anti-androgen therapy ?

Devices � ICD






↑ ICa

↓ I to

10

Modified from Antzelevitch and Yan.

Heart Rhythm 7:549-58. 2010

J Wave SyndromesInherited Acquired

ER in Lateral Leads

ERS Type 1

ER in inferior or infero-lateral leads

ERS Type 2

Global ER

ERS Type 3

BrugadaSyndrome

Ischemia-mediatedVT/VF

Hypothermia-mediatedVT/VF

Anatomic LocationAntero-lateral left

ventricleInferior left ventricle

Left and right ventricles

Right ventricle

Left and right ventriclesLeft and right

ventricles

Leads Displaying J-wave / J-point elevation

I, V4-V6 II, III, aVF Global V1-V3 Any of 12 leads Any of 12 leads

Response of J wave or ST Elevation to:

Bradycardia or pause N/A N/A

Na+ channel blockers N/A N/A

Sex Dominance Male Male Male Male Male70,71 Either gender

VT/VFRare

ER pattern is common inhealthy athletes11,31,51

Yes21,23Yes

ElectricalStorms7,27

Yes Yes Yes

Response toQuinidine :

Limited data

J wave/ST Elevation

VT/VF 59

Response toIsoproterenol :

Limited data N/A N/A

J wave/ST Elevation

VT/VF

EP= electrophysiology; N/A=not available; ERS=early repolarization syndrome; VT=ventricular tachycardia; VF=ventricular fibrillation

Effect of age and gender on ST segment elevation

Ezaki et al, Circ J, 2010

Effect of Androgen-deprivation on ST segment Elevation

Ezaki et al, Circ J, 2010

Disappearance of ST Segment Elevation in Brugada Patient after Orchiectomy

Matsuo K, et al., PACE, 2003

Case 2

V1

V2

V1

V2

Age 57 59 61 63 65 67 68

71 74 75 77 79 80 81Age

1960 1962 1964 1966 1968 1970 1971

1974 1977 1978 1980 1982 1983 1984

Castration

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Chronic exposure to testosterone (4 weeks) increases expression of

Transient Outward Current (I to)

in induced pluripotent stem cell-derived cardiomyocytes

10 µm 20 µm

Barajas-Martinez, Hu et al., Unpublished data

Testosterone 1 uM

Testosterone 1 uM (n=20)

TherapyEarly Repolarization Syndrome

Devices � ICD






Devices � ICD






↑ ICa

↓ I to

Thank You Risk Stratification of Patients with Early Repolarization Pattern

• Available data clearly indicate that incidental discovery of a J wave on routine screening should not be interpreted as a marker of “high risk” for SCD since the odds for this leading to a fatal outcome is relatively low.

• However, mounting evidence suggests that careful attention should be paid to subjects with “high risk” ER.

• Available data clearly indicate that incidental discovery of a J wave on routine screening should not be interpreted as a marker of “high risk” for SCD since the odds for this leading to a fatal outcome is relatively low.

• However, mounting evidence suggests that careful attention should be paid to subjects with “high risk” ER.

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Risk Stratification of Patients with Early Repolarization Pattern

Who is at risk?1) J point or ST segment elevation of 0.2 mV or greater in

inferior and infero-lateral or global leads. 2) Appearance of distinct and prominent J waves.3) Association of ER pattern with abbreviated QT intervals.4) Short-coupled extrasystoles5) Transient J wave augmentation or fluctuation of J wave

portends a high risk for VF in patients with ER.6) Association with Horizontal or Descending ST segment7) Association of ER pattern with SCD, Unexplained

syncope, or unexplained family history of SCD.





Genetic Screening Utica, NY

• Brugada Syndrome• Familial Atrial Fibrillation • Catecholamine-sensitive VT• Non-ischemia VT/VF in young • Post-MI QT prolongation and TdP• Progressive Conduction Disease• Sudden death in infants & children(including SIDS)

• Acquired Long QT Syndrome (or unusual forms of congenital LQTS)

• Short QT syndrome

Inherited Cardiac Arrhythmias and Sudden Cardiac Death

• Molecular Genetics• Molecular Biology• Electrophysiology

[email protected]

Molecular Genetics Wing

Risk Stratification of Patients with Early Repolarization Pattern



















CollaboratorsSami Viskin, Michel Haissaguerre, Mel Scheinman, Arthur Wilde, Andras Varro, Michael

Glickson, Michael Eldar, Liron Miler, Michael Ackerman, Minoru Horie, Jon Steinberg, Pedro, Josep & Ramon Brugada, Wee Nademanee, Fiorenzo Gaita, Carla Giustetto, Martin

Borggrefe,, Peter Schwartz, Lia Crotti, Michael Sanguinetti, Mike Ackerman, Christian Wolpert, Rainer Schimpf, Christian Veltmann, Michael Sanguinetti, Lior Gepstein

CollaboratorsSami Viskin, Michel Haissaguerre, Mel Scheinman, Arthur Wilde, Andras Varro, Michael

Glickson, Michael Eldar, Liron Miler, Michael Ackerman, Minoru Horie, Jon Steinberg, Pedro, Josep & Ramon Brugada, Wee Nademanee, Fiorenzo Gaita, Carla Giustetto, Martin

Borggrefe,, Peter Schwartz, Lia Crotti, Michael Sanguinetti, Mike Ackerman, Christian Wolpert, Rainer Schimpf, Christian Veltmann, Michael Sanguinetti, Lior Gepstein



disclosures & acknowledgments california heart … · fabrice extramiana chinmay patel eyal nof...

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