Lead II ECG (dog) Hypothermia (24.5 C) Yan and Antzelevitch. - - PowerPoint PPT Presentation

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California Heart Rhythm Symposium

San Francisco, CA September 8, 2012

“ J Wave Syndromes. Mechanisms”

Charles Antzelevitch

Masonic Medical Research Laboratory Utica, NY 13501 Gilead Sciences

• Research Support and Consultantship

AstraZeneca

• Research Support and Consultantship

Cardiome

• Research Support

Merck

• Research Support

Population Council - Research Support Buchang Group

• Research Support

NIH

• Research Support

NYSTEM

• Research Support

AHA

• Research Support

New York State &Florida Masons - Research Support

Disclosures & Acknowledgments

Action Potential Studies

Silvio Litovsky Anton Lukas

• S. Krishnan

Action Potential Studies

Silvio Litovsky Anton Lukas

• S. Krishnan

Voltage Clamp Studies

Andrew Zygmunt Jonathan Cordeiro Helen Diana (Dan Hu) Hector Barajas-Martinez Janire Urrutia Yoshiyasu Aizawa

Voltage Clamp Studies

Andrew Zygmunt Jonathan Cordeiro Helen Diana (Dan Hu) Hector Barajas-Martinez Janire Urrutia Yoshiyasu Aizawa

Perfused Wedge Studies

Gan-Xin Yan Serge Sicouri Wataru Shimizu Jose Di Diego

• A. Burashnikov

Jeffrey Fish Gi-Byoung Nam Tetsuro Emori Masahiko Kondo Masato Tsuboi Fabrice Extramiana Chinmay Patel Eyal Nof Yoshino Minoura István Koncz

Perfused Wedge Studies

Gan-Xin Yan Serge Sicouri Wataru Shimizu Jose Di Diego

• A. Burashnikov

Jeffrey Fish Gi-Byoung Nam Tetsuro Emori Masahiko Kondo Masato Tsuboi Fabrice Extramiana Chinmay Patel Eyal Nof Yoshino Minoura István Koncz

In Vivo and Modeling Studies

Vladislav V. Nesterenko

In Vivo and Modeling Studies

Vladislav V. Nesterenko

Stem Cell & Molecular Biology

Xavier Michael Jesudoss Bobby Cherian Kallukalam Yuesheng Wu Mayurika Desai Jackie Treat

Stem Cell & Molecular Biology

Xavier Michael Jesudoss Bobby Cherian Kallukalam Yuesheng Wu Mayurika Desai Jackie Treat

Collaborators

Sami 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

Collaborators

Sami 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 Genetics

Guido Pollevick Alejandra Guerchicoff Ryan Pfeiffer Elena Burashnikov Gabriel Caceres

Colleen Puleo

Molecular Genetics

Guido Pollevick Alejandra Guerchicoff Ryan Pfeiffer Elena Burashnikov Gabriel Caceres

Colleen Puleo

Characteristics of the J Wave

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

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Lead II ECG (dog) Hypothermia (24.5 C)

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

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Restitution of J wave parallels that of action potential notch

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

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

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

Early Repolarization Patterns

Modified from Antzelevitch et al, JACC, 2011

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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 Syndrome

Causative Genes Locus Ion Channel Gene/Protein % of Probands

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15q24-q25 If HCN4 7q35 IKr KCNH2, HERG Xq22.3 Ito KCNE5 (KCNE1-like)

Genetic Basis for Brugada Syndrome

Modulatory 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) Lithium Anticonvulsants (clonazepam) Antipsychotics (Trifluoperazine, Loxapine)

• IV. Other drugs

Histaminic H1 receptor antagonists Dimenhydrinate Diphenhydramine Cocaine intoxication Alcohol 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 Heterogeneity Intrinsic Heterogeneity

Accentuate Notch & Cause Loss of APD Dome in Epicardium Accentuate Notch & Cause Loss of APD Dome in Epicardium

Dispersion of Repolarization

Transmural Epicardial

QT interval

Phase 2 reentry

Dispersion of Repolarization

Transmural Epicardial

QT interval

Phase 2 reentry

ST Segment

(Vulnerable Window)

ST Segment

(Vulnerable Window)

Extrasystole Extrasystole

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

Brugada Syndrome

INa, ICa INa, ICa

Ito, IKr, IKs, IK-ATP, ICl(Ca) Ito, IKr, IKs, IK-ATP, ICl(Ca) Transmural Dispersion

• f Repolarization

Transmural Dispersion

• f 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 50 mV 50 mV 0.5 mV

50 mV 200 msec

4 3 2 1

200 msec

50 mV

Epi M Endo

4 3 2 1

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

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

Therapy - Brugada Syndrome

Devices or Ablative

• ICD

? Pacemaker ? Ablation or Cryosurgery Pharmacologic Χ 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 - contraindicated Χ 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
• Ito Blocker - cardioselective and ion channel specific

?

Late INa agonist – dmLSB (Danshen derivative) Devices or Ablative

• ICD

? Pacemaker ? Ablation or Cryosurgery Pharmacologic Χ 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 - contraindicated Χ 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
• Ito Blocker - cardioselective and ion channel specific

?

Late INa agonist – dmLSB (Danshen derivative)

↑ ICa ↓ Ito

Early Repolarization Pattern Predisposes to Development of Polymorphic VT/VF via a Brugada Syndrome-like Mechanism

Yan an Antzelevitch, Circulation, 1999 Gussak 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 Pattern and SCD 31% of IVF vs. 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, 2008 Nam…Antzelevitch. Eur Heart J. 31:330-9, 2010

Early Repolarization Pattern and SCD

60% of IVF vs. 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

• ccurrences. 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

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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

• f the KCNJ8-S422L

mutant KATP channels to ATP

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

ERS Type 3

SCN5A (NaV1.5) -G1297G FSX22 + ABCC9 (SUR2A)-V734I

Gain of Function in IK-ATP due to reduced sensitivity of the ABCC9 (SUR2A)- V734I mutant KATP channels 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, 1999 Gussak 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

INa, ICa INa, ICa Ito Ito IK-ATP IK-ATP IK-ACh IK-ACh IK-ATP IK-ATP

?

INa, ICa INa, ICa

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 42 Dynamicity 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 ICa and indirect effect to increase Ito (due to slowing of heart rate)

Features Common to Brugada and Early Repolarization Syndromes and 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

Therapy Early 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 ?

• Ito Blocker - cardioselective and ion channel specific
• Anti-androgen therapy ?

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 ?

• Ito Blocker - cardioselective and ion channel specific
• Anti-androgen therapy ?

↑ ICa ↓ Ito

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Modified from Antzelevitch and Yan. Heart Rhythm 7:549-58. 2010

J Wave Syndromes

Inherited Acquired

ER in Lateral Leads ERS Type 1 ER in inferior or infero-lateral leads ERS Type 2 Global ER ERS Type 3 Brugada Syndrome Ischemia-mediated VT/VF Hypothermia- mediated VT/VF Anatomic Location Antero-lateral left ventricle Inferior left ventricle Left and right ventricles Right ventricle Left and right ventricles Left 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/VF Rare ER pattern is common in healthy athletes11,31,51 Yes21,23 Yes Electrical Storms7,27 Yes Yes Yes Response to Quinidine : Limited data J wave/ST Elevation VT/VF

59

Response to Isoproterenol : 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., P ACE, 2003

Case 2 V1 V2 V1 V2 Age 57 59 61 63 65 67 68 71 74 75 77 79 80 81 Age

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 (Ito) 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)

Therapy Early 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 ?

• Ito Blocker - cardioselective and ion channel specific
• Anti-androgen therapy ?

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 ?

• Ito Blocker - cardioselective and ion channel specific
• Anti-androgen therapy ?

↑ ICa ↓ Ito

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.

SLIDE 12

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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 extrasystoles 5) 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 segment 7) Association of ER pattern with SCD, Unexplained syncope, or unexplained family history of SCD.

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 extrasystoles 5) 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 segment 7) 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

ca@mmrl.edu WWW.MMRL.EDU

Molecular Genetics Wing

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 extrasystoles 5) 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 segment 7) Association of ER pattern with SCD, Unexplained syncope, or unexplained family history of SCD.

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 extrasystoles 5) 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 segment 7) Association of ER pattern with SCD, Unexplained syncope, or unexplained family history of SCD.

Action Potential Studies

Silvio Litovsky Anton Lukas

• S. Krishnan

Action Potential Studies

Silvio Litovsky Anton Lukas

• S. Krishnan

Voltage Clamp Studies

Andrew Zygmunt Jonathan Cordeiro Helen Diana (Dan Hu) Hector Barajas-Martinez Janire Urrutia Yoshiyasu Aizawa

Voltage Clamp Studies

Andrew Zygmunt Jonathan Cordeiro Helen Diana (Dan Hu) Hector Barajas-Martinez Janire Urrutia Yoshiyasu Aizawa

Perfused Wedge Studies

Gan-Xin Yan Serge Sicouri Wataru Shimizu Jose Di Diego

• A. Burashnikov

Jeffrey Fish Gi-Byoung Nam Tetsuro Emori Masahiko Kondo Masato Tsuboi Fabrice Extramiana Chinmay Patel Eyal Nof Yoshino Minoura István Koncz

Perfused Wedge Studies

Gan-Xin Yan Serge Sicouri Wataru Shimizu Jose Di Diego

• A. Burashnikov

Jeffrey Fish Gi-Byoung Nam Tetsuro Emori Masahiko Kondo Masato Tsuboi Fabrice Extramiana Chinmay Patel Eyal Nof Yoshino Minoura István Koncz

In Vivo and Modeling Studies

Vladislav V. Nesterenko

In Vivo and Modeling Studies

Vladislav V. Nesterenko

Stem Cell & Molecular Biology

Xavier Michael Jesudoss Bobby Cherian Kallukalam Yuesheng Wu Mayurika Desai Jackie Treat

Stem Cell & Molecular Biology

Xavier Michael Jesudoss Bobby Cherian Kallukalam Yuesheng Wu Mayurika Desai Jackie Treat

Collaborators

Sami 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

Collaborators

Sami 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

Molecular Genetics

Guido Pollevick Alejandra Guerchicoff Ryan Pfeiffer Elena Burashnikov Gabriel Caceres

Colleen Puleo

Molecular Genetics

Guido Pollevick Alejandra Guerchicoff Ryan Pfeiffer Elena Burashnikov Gabriel Caceres

Colleen Puleo