channelopathies for clinicians · channelopathies in the heart are inherited genetic disorders of...

Channelopathies for Clinicians

2nd Philadelphia Cardiovascular SummitNovember 2-3, 2018

Alexander Burashnikov PhD FHRSLankenau Institute for Medical Research

Sidney Kimmel Medical College of Thomas Jefferson University

Disclosure:

None

Channelopathies in the heart are inherited genetic disorders of cardiac ion channels and/or their regulatory proteins predisposing to arrhythmias in the absence of structural heart disease.

Cardiac channelopathies: definition

Other prominent ion channel diseases: • Epilepsy (sodium channel) • Diabetes mellitus (ATP-sensitive potassium channel) • Systic fibrosis (chloride channel)

George et al, J Clin Invest 2013

Ion channels are pore-forming membrane proteins

Ion channels?

ECG and the cardiac action potential

• Long QT syndrome• Brugada syndrome (BrS)• Early repolarization syndrome (ERS) • Short-QT syndrome (SQTS)• Catecholaminergic polymorphic

ventricular tachycardia (CPVT)* * - not a pure channelapathy

Channelopathies in the heart

1) QTc ≥450-480 msQTc > 500 ms – high risk

2) Confirmed pathogenic LQTS mutation, irrespective QTc

Grilo et al, Front Pharm 2010

Long QT Syndrome (LQTS)

Diagnosis:

Spears et al, Apl Clin Gen 2014

LQTS phenotype positive patients: the yield of genetic testing is ̴ 80%

LQTS genotype-positive patients: ̴ 25% have QTc interval ≤ 440 ms(most commonly patients with LQT1).

AHA/ACC/HRS Guidelines: Ventricular arrhythmias/SCDAl-Khatib et al, JACC, 2018

Congenital Long QT Syndrome (LQTS): genetics

> 90% of all genotype positive patients

Min

or L

QTS

gen

es

Recent development…

NIH’S Clinical Genome Resources (ClinGen; Strande et al, Am J Hum Gen 2017) criteria:

Some ultra-rare variants (ANK2,KCNE2, SCN4B, AKAP9, SNTA1, and KCNJ5) have a limited- or disputed-evidence status (as monogenic causes), i.e., variants of unknown significance (VUSs)

Congenital Long QT Syndrome (LQTS): genetics

VUS

VUS

VUS

VUS

VUSVUS

Min

or L

QTS

gen

esContinuous debates…

Strande et al, Am J Hum Gen, 2017Guidicessi et al, Trend Card Med, 2018

Genetic abnormalities may promote acquired long QT syndrome

Acquired long QT syndrome is caused or promoted by: • drugs• hypokalaemia, • bradycardia, exc.

A third of acquired LQTS patients carry congenital LQTS mutations. Most commonly on KCNH2

Itoh et al Eur Heart J, 2016

ER, event rate; F, female; HR, hazard ratio; M, male; MM, multiple mutations, pt, patient.

Genotype and risk stratification in congenital long QT syndrome

Genotyping in long QT patients is recommended: has therapeutic and prognostic values.

Napolitano et al, Curr Opin Card 2018


The risk of arrhythmias is associated with:• type of LQTS (LQT1, LQT2, or LQT3), • location of mutation (pore, C-loop,

etc.). • Number of mutations

Diagnosis: pathogenic LQTS mutation, irrespective QTc. Patients with mutation and QTc<440 ms have a 10-fold increased VT/VF risk vs. controls

• Prevalence: 1:2000

• The longer QT the greater risk of arrhythmias

• Most patients are asymptomatic

• Experience SCD: up to 13%

• The mean time of the first symptom is ̴ 14 years.

• Pre-puberty: The risk of VT/VF is similar in males and femalesPost-puberty: This risk is reduced in males but not in females

• Arrhythmias commonly occur: LQT1 - Exercise LQT2 - Emotion LQT3 - Sleep/Rest

Congenital long QT syndrome: facts/statistics

Burashnikov et al, PACE, 2006

Electrophysiological mechanisms of Torsade de Pointes

Early afterdepolorization (EAD)

Fermini et al, Nat Rev Drug Dis, 2013

Bradycardia and pause-dependent


Long QT syndrome: therapy

Recommended:

• A β-blocker • Left cardiac

sympathetic denervation or ICD

First described in 1992 Pedro and Joseph BrugadaBrugada&Brugada, JACC 1992.

This arrhythmic entity was named Brugada Syndrome in 1996Yan & Antzelevitch, Circ 1996; Miyazaki et al, JACC 1996

Originally: • ST segment elevation • Structurally normal heart

Currently:• ST segment elevation • Structural alterations (commonly subtle), particularly in RVOT

Still, most investigators consider Brugada Syndrome as a prime electrical disease

Brugada syndrome (BrS)

Type 1 morphology, an ST segment elevation ≥ 2 mm in ≥1 lead among the right precordial reals V1 and V2 positioned in the 2nd, 3rd, or 4th intercostal space occurring spontaneously.

Antzelevitch et al. Heart Rhythm 2016. (J wave syndrome consensus)

Coved type Saddle-backtype

Saddle-backType(Epsilone wave)

Brugada syndrome: diagnosis

Similar ECG pattern:• Arrhythmogenic right ventricular cardiomyopathy • Atypical right bundle branch block• Ventricular hypertrophy• Acute myocardial ischemia (especially in RV)• Etc.


Coved type

Needed to be excluded before diagnosis of Brugadasyndrome

When BrS is suspected (without Type 1 ECG pattern), a sodium channel block test should be performed to unmask the disease


When Type 1 is unmasked, diagnosis of BrS requires 1 of: 1) Documented VT/VF2) Syncope of probable arrhythmic cause3) A family history of SCD with negative

autopsy 4) Type 1 ECG in family member5) Nocturnal agonal respiration


The risk of VT/VF in patients diagnosed with this test is much lower than the risk in patients with spontaneous type 1

Genetic Defects Associated with BrSLocus Gene/Protein Ion Channel % of Probands

BrS1 3p21 SCN5A, Nav1.5 ↓ INa 11-28%BrS2 3p24 GPD1L ↓ INa RareBrS3 12p13.3 CACNA1C, Cav1.2 ↓ ICa 6.6%BrS4 10p12.33 CACNB2b, Cavß2b ↓ ICa 4.8%BrS5 19q13.1 SCN1B, Navß1 ↓ INa 1.1%BrS6 11q13-14 KCNE3, MiRP2 ↑ Ito RareBrS7 11q23.3 SCN3B, Navß3 ↓ INa RareBrS8 12p11.23 KCNJ8, Kir6.1 ↑ IK-ATP 2%BrS9 7q21.11 CACNA2D1, Cav2δ1 ↓ ICa 1.8%BrS10 1p13.2 KCND3, Kv4.3 ↑ Ito RareBrS11 17p13.1 RANGRF, MOG1 ↓ INa RareBrS12 3p21.2-p14.3 SLMAP ↓ INa RareBrS13 12p12.1 ABCC9, SUR2A ↑ IK-ATP RareBrS14 11q23 SCN2B, Navß2 ↓ INa RareBrS15 12p11 PKP2, Plakophillin-2 ↓ INa RareBrS16 3q28 FGF12, FHAF1 ↓ INa RareBrS17 3p22.2 SCN10A, Nav1.8 ↓ INa 5-16.7%BrS18 6q HEY2 (transcriptional factor) ↑ INa RareBrS19 1p36.3 KCNAB2, Kvβ2 ↑ Ito Rare

In phenotype positive patients: the yield of genetic testing is 20% to 30%.

Brugada syndrome: Genetics

Genetic Defects Associated with BrS

Locus Gene/Protein

BrS1 3p21 SCN5A, Nav1.5BrS2 3p24 GPD1LBrS3 12p13.3 CACNA1C, Cav1.2BrS4 10p12.33 CACNB2b, Cavß2bBrS5 19q13.1 SCN1B, Navß1BrS6 11q13-14 KCNE3, MiRP2BrS7 11q23.3 SCN3B, Navß3BrS8 12p11.23 KCNJ8, Kir6.1BrS9 7q21.11 CACNA2D1, Cav2δ1BrS10 1p13.2 KCND3, Kv4.3BrS11 17p13.1 RANGRF, MOG1BrS12 3p21.2-

p14.3SLMAP

BrS13 12p12.1 ABCC9, SUR2ABrS14 11q23 SCN2B, Navß2BrS15 12p11 PKP2, Plakophillin-2BrS16 3q28 FGF12, FHAF1BrS17 3p22.2 SCN10A, Nav1.8BrS18 6q HEY2 (transcriptional

factor)

BrS19 1p36.3 KCNAB2, Kvβ2

Utilizing NIH’S Clinical Genome Resources (ClinGen) criteria:

Only the SCN5A gene is classified as having definitive evidence as a cause for BrS

The other genes: may be causative or contribute.Limited or disputed evidence

Hosseini et al, Circulation, 2018

Le Scouarnec et al, Hum Mol Gen 2015Kapplinger et al, Circ Card Gen 2015

Proven causative gene(s)

Continuous debates…

Genotype status is not correlated with the risk of adverse events


Genotype: risk of VT/VF, prognosis, and treatment in Brugada syndrome

Genotype status does not influence prognosis or treatment

ESC Guidelines: Ventricular arrhythmias/SCDPriori et al, Eur Heart J, 2015

Currently:

In patients with Brugada Syndrome, genetic testing may be useful to facilitate cascade screening of relatives


• Prevalence: 1:1,000 to 1:10,000

• More often in Asian vs. Whites or Blacks ( ̴ 8 : 1)

• Mean age of first arrhythmic event is 41±15 years

• Arrhythmic events: usually at rest or steeping

• Fever promotes arrhythmic events

• More often in male vs. female ( ̴ 10 : 1)

Brugada syndrome: Facts/statistics:

In patients with BrS (n= 678; Males = 91%):An SCN5A mutation: in females = 48%

in males = 28% (P = .007) The history of SCD is similar and inducibility of VT/VF is lower in

females vs. males. Milman et al, Heart Rhythm, 2018

Critical factors other than SCN5A mutation may determine phenotype and VT/VF in BrS

Brugada syndrome: Gender differences

BrS is more often in male vs. female ( ̴ 10 : 1)

Electrophysiological mechanism of VF in Brugada syndrome: Depolarization vs. repolarization hypotheses:

Support “depolarization”:1) Most BrS patients have some

form of conduction abnormalities (due to sodium channel mutation and/or structural alterations).

2) INa blockers unmask BrS

Support “repolarization”:1) VT/VF starts at bradycardia2) ST segment elevation is reduced

with acceleration of heart rate3) Experimental data

Not mutually exclusive

Fish & Antzelevitch, Heart Rhythm, 2004

Canine LV wedge preparation

Imbalance between inward and outward currents during early repolarization: lost of dome

Caused by: Sodium channel blockCalcium channel blockIto or IK(ATP) augmentation

Repolarization hypothesis

Recommended:• ICD in patients with

history of SCA/syncope

• Quinidine or ablation. In addition to ICD or instead of ICD


Brugada syndrome: treatment

“ER” was first described in 1936 Shipley and Hallaran, Am Heart J, 1936

The term “J wave” (or Osborn’s wave) was introduced in 1953.

Osborn, Am J Physiol, 1953

Before 2008: “ER” - benign

ER Pattern can be malignant: First case report in 1984 Otto et al, Ann Intern Med, 1984Predicted in 2000 (largely based on experimental data).Gussak and Anzelevitch, J Electrocardiol, 2000.

Confirmed clinically in 2008.Haissaguerre et al, NEJM 2008Nam et al, NEJM, 2008Rosso et al, JACC, 2008+ many other studies in 2009-2018.

Haissaguerre et al, NEJM 2008

Baseline

Early repolarization (ER) syndrome

• A J-wave: notch and/or slur at the end of QRS• J-peak ≥ 0.1 mV in ≥ 2 contiguous leads of the 12-lead ECG

(excluding V1–V3). • ST segment elevation is not a required criterion

Early repolarization (ER) pattern

J-peak J-peak

Consensus (MacFarlane et al, JACC 2015)

“Horizontal” and “descending” are more likely to be associated with worse prognosis than “ascending”

ER syndrome: ST segment configuration

Tikkanen et al, Circ 2011Rosso et al, Heart Rhythm,2012


High prevalence of ER Pattern!in 2 to 31%; up to 40-90% in athletes

Low risk of VT/VF in ER PatternAbsolute risk difference – 0.0007% per year

Wu et al, JACC 2013

The risk of VT/VF increases when:- Jpoint ≥ 0.2 mV and/or - inferior and lateral leads

Tikkanen et al, NEJM 2009; Rosso et al, JACC 2008

Early repolarization (ER) pattern

ER pattern is not necessarily ER syndrome

ER Syndrome:ER pattern in the inferior and/or lateral leads with history of aborted cardiac arrest, documented VT/VF

J wave syndrome consensus:Antzelevitch et al. Heart Rhythm 2016.

ER pattern and VT/VF: Race differences

• ER pattern is more prevalent in Blacks than Asians and Whites

• But ER pattern is associated with SCD in Asians and Whites but not Blacks

Olson et al Eur Heart J 2011, Perez et al, Heart Rhythm, 2012; Kelly et al Am J Card, 2018.

Why? Unknown

Genetic Defects Associated with ERSLocus Gene/Protein Ion Channel % of

Probands

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

ERS2 12p13.3 CACNA1C, Cav1.2 ↓ ICa 4.1%

ERS3 10p12.33 CACNB2b, Cavß2b ↓ ICa 8.3%

ERS4 7q21.11 CACNA2D1, Cav2δ1 ↓ ICa 4.1%

ERS5 12p12.1 ABCC9, SUR2A ↑ IK-ATP Rare

ERS6 3p21 SCN5A, Nav1.5 ↓ INa Rare

ERS7 3p22.2 SCN10A, Nav1.8 ↓ INa Rare

In phenotype positive patients with history of SCA/Syncope: the yield of genetic testing is ̴ 15%

• Genetic testing has not reliably identified mutation predisposing to ER

• Genetic testing is not recommended

ER syndrome: Genetics

Al-Khatib et al, JACC, 2018, GuidelinesPriori et al. Eur Heart J, 2015, Guidelines

Mechanisms of J wave:1) Transmural difference

in the early repolarization phase (dominant)

2) Conduction abnormalities

Yan&Antzelevitch, Circulation, 1996

Electrophysiological mechanism of ER Pattern

Canine LV wedge preparation.

Early repolarization syndrome: Treatment

Recommended: ICD in patients with ER pattern and history of SCA/VT

AHA/ACC/HRS Guidelines: Ventricular arrhythmias/SCDAL-Khatib et al, JACC, 2018

Poorly defined

Antzelevitch, 2016

First described in Kangaroos in 1986. Kangaroos have short QT interval and a high rate of SCD.

O’Rourke et al Card Res 1986

First documented case of SCD in patients with short QT in 2000. Heritable short QT.

Gussak et al, Cardiology, 2000. Gollob et al, JACC 2011

Short-QT syndrome (SQTS)

1) QTc ≤ 340 ms with or without symptoms

2) QTc ≤ 360 ms if: • History of VT/VF in the absence of other heart diseases• Family history of SQTS, • Family history of unexplained SCD at age ≤ 40; or • A confirmed pathogenic mutation

ESC Guidelines: Ventricular arrhythmias/SCDPriori et al, Eur Heart J, 2015

Short-QT syndrome: Diagnosis


Risk of VT/VF is not associated with the degree of QTc shortening Mezzanti et al, JCE 2018

Short-QT syndrome: Genetics

Genetic Defects Associated with SQTS

Gene Ion Channel % of Probands

SQT1 KCNH2 ↑IKr ̴ 10-15%

SQT1 KCNQ1 ↑IKs <1%

SQT3 KCNJ2 ↑IK1 <1%

SQT4 CACNA1C ↓ ICa <1%

SQT5 CACNB2B ↓ ICa <1%

SQT6 CACNA2D1 ↓ ICa <1%

Only about 200 individuals (50 families) with SQTS worldwide (2017; SQTS + history of SCA/syncope)

• Genotyping may help to confirm SQTS diagnosis • Value of genotyping for the risk of VT/VF and for therapy or

prognosis: Poorly defined

In phenotype positive patients with history of SCA/Syncope: the yield of genetic testing is 10% to 20%.

Mezzanti et al, JCE 2018

Short-QT syndrome (SQTS): treatment

Recommended: 1) ICD in patients history of SCA/VT

2) Quinidine or isoproterenol in patients with history of SCA/VT


Catecholaminergic polymorphic ventricular tachycardia (CPVT)

CPVT was first recognized in 1960

Bidirectional VT

Diagnosis:• Baseline ECG is normal• No structural heart disease • Exercise stress: bidirectional or

polymorphic VT

Priori et al, ESC Guidelines, Eur Heart J 2015

• Genetic testing may be useful to confirm the diagnosis of CPVT • Therapy for CPVT is not guided by genotype status

Gollob, Appl Clin Gen, 2015

CPVT: Genetics

The yield of genetic testing is ̴ 60-65% in CPVT phenotype positive patients


• Prevalence 1: 10,000

• SCA/SCD is reported in 3-13% of CPVT patients

• VT/VF typically occur during exercise or at times of emotional stress

CPVT: Facts/Statistics

Electrophysiological mechanisms of CPVT-induced VT/VF

Canine LV wedge preparation: An experimental model of CPVT

Nam et al Circ, 2005

Intracellular Ca -mediated delay afterdelarization (DAD)

CPVT is caused by intracellular Ca2+

abnormalities –involving sarcoplasmic reticulum

CPVT: treatment

Recommended: • β Blockers• In addition to β-blocker therapy: flecainide, left cardiac

sympathetic denervation, and/or ICD


Cause(s) of VT/VF in patients with Channelopahties

Genetics• Monogenic• Oligogenic• Poligenic

Environment

Epigenetics

Lahrouchi et al JACC 2017

13%

A panel of 77 channelopathy and cardiomyopathy genesMean age = 24 years; 1-65 years; Mostly European ancestry.

Mostly: CPVT - 6%LQTS - 4%

Applying American College of Medical Genetics (ACMG) consensus guidelines (2015):

Current “contribution” of channelopathies in sudden arrhythmic death in population with “normal” heart

Post-mortem

Ischemic heart disease ̴70-80%Genetic heart disease ̴ 2-10% (???)

Contribution of genetic heart diseases (GHD) to sudden cardiac arrest (SCA) in general population

Common genetic variants do not appear to contribute significantly to SCA in the general populationNo common genetic variants were associated with SCAThe largest Genome-Wide Association Study (GWAS) in the genomics of SCA in general population Plus - Candidate gene analysis (54 inherited arrhythmia genes)

Geri et al, Resuscitation, 2017; Napolitano et al, Cur Opin Card, 2018

Ashar et al, Eur Heart J, 2018 (in press)

Rare “private” mutations can cause/contribute to SCA in LQTS, CPVT, BrS, HCM, DCM, etc. (in family-based studies) Most mutations are “private” (i.e., unique to the family)

Conclusions:

• Genetic abnormalities in the cardiac ion channels and their regulatory proteins may cause or contribute to the risk of VT/VF in patients with LQTS, CPVT, BrS, SQTS, and ERS.

• Currently, genotyping has therapeutic and prognostic values for long QTS patients.

• Genotyping may be useful for diagnosis of CPVT, BrS, and SQTS.

Thank you

Private mutation: A rare gene mutation that is usually found only in a single family or a small population. A private mutation occurs and is passed to a few family members, but not to future generations.

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