Genetic Channelopathies: Long QT, Brugada Syndrome and CPVTFebruary 7, 2020Peter Aziz, MDDirector, Pediatric Electrophysiology

Objectives• Identify the channelopathies that cause sudden cardiac death• Compose comprehensive cardiovascular history to screen for risk factors• Understand diagnostic testing and interpretation• Define treatment modalities to prevent sudden cardiac death

Ion Channels

Defective Ion Channels

Ackerman MJ, Current Prob Card 2013

A Molecular Problem

Patient Presentation #1

13 yo Evaluated for Chest Pain• No other symptoms• Otherwise healthy• No medications• Pain is at rest

Family History

13 yo Evaluated for Chest Pain

QTc = 505 ms

Long QT Syndrome• Leading cause of autopsy-negative sudden

death− 1000/year in the US− Mostly young children

• Hallmark presentation:− Syncope – NO prodrome

• Hallmark arrhythmia:

Epidemiology of LQTS• Equally present in all races and ethnic

groups

•

• Italian Ministry of Health screening program• Neonatal ECGs performed on the 15th and 25th

day of life• 44,596 neonates from 2001-2006

Prevalence of Long QT Syndrome

Schwartz, Circulation 2009Schwartz, Circulation 2009

0.07%

0.06%

0.41%

2.00%

97.46%

470 ms

460 ms

450 ms

440 ms

N=31

N=28

N=177

N=41,986

N=858

LQTS mutationsIn 12/28 (43%)

LQTS mutationsIn 4/14 29%)

Estimated Prevalence of LQTS

• 16 gene + patients• 1 patient with clinical LQTS• Prevalence among white patients− 17/43,080 = 1:2534

• Data does not include the genotype negative patients − prevalence is likely higher

Furst ML, Aziz PF Trends CV Medicine 2016

Furst ML, Aziz PF Trends CV Medicine 2016

Furst ML, Aziz PF Trends CV Medicine 2016

QTc Adaptation

• Recovery ∆QTc (7 min – 1 min)− ∆QTc > 30 ms predicts LQT1 vs

LQT2

Aziz PF, Circulation AE 2009

Clinical Diagnosis Schwartz Score

Cornerstones of TherapyTrigger Modification

Schwartz, JACC 2013

Ancient Guidelines

Mitchell et al, Bethesda 36th Conference, JACC 2005

Cornerstone of Therapy

Medication Avoidancewww.crediblemeds.org

13 yo Evaluated for Chest Pain

Now What?

• Cascade screening for family• Placed on Nadolol• Asymptomatic since• Allowed to continue sports participation

Patient Presentation #2

10yo with Syncope at Rest

Brugada SyndromeBench to Bedside

Wilde Circulation, 2002Zhang, Circulation 2015

Chen and Priori, JACC 2008

Risk/TreatmentTreatment• Quinidine• ICD− Unexplained syncope− Spontaneous type 1

Risk Stratification• ?EP study• Provocative Testing

- Procainamide/Ajmaline- Fevers- High lead placement

Patient Presentation #3

• Syncope while coming down water slide• Normal ECG• Normal echocardiogram• Negative family history• Seen in ED in Atlanta

11yo with syncope

Just Before Discharge

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

• SCD in the setting of emotional or physical stress• Exercise stress test is the key

− Complex ectopy− Bidirectional VT

• 30% will have at least 1 cardiac arrest• 80% will have at least 1 syncopal event• Estimated prevalence

− 1:10000

Exercise Stress Test• Polymorphic VT

• Bidirectional VT

Mohamed JCE Cardiology 2007

CPVT ClassificationGene Protein Proportion of

CPVT (%)Inheritance Pattern

RYR2 Ryanodine 50-55 AD

CASQ2 Calsequestrin 2-5 AR

CALM1 Calmodulin <1 AD

TRDN Triadin Unknown AR

CPVT Treatment

Key Takeaways

Primary Prevention

“Screening”AAP Guidelines

History

PhysicalExamination

The Italian ExperiencePre-participation Sports Screening

• Implemented in 1982• Routine:

- Cardiac exam- Family history- ECG

• Outcome$43,000 per life year saved

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)

The United States• ECG screening

- $91,000 to $214,000 per patient year life saved

- $50,000 to $100,000 is considered cost-effective

• Compared to Italy- High health care costs- Lower incidence of SCD

ECG Screening• “Pre-participation ECG screening is

probably impractical and would require considerable resources that do not currently exist”

Maron, AHA Consensus Statement, Circulation 2007

18 yo Presenting After Aborted Cardiac Arrest

Can ECG Screening Reconcile This?

Normal examination, normal ECGCPVT

Aborted Sudden Death

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• Font – Arial, grey, 40pt• Bullets – round, white, sized at 100% of text• Line Spacing – single, 7.2pt space before,

0pt space after, left aligned− 2nd level bullets – hyphen-minus, 36pt

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Bulleted Slide – full corner logo

• Font – Arial, grey, 40pt• Bullets – round, white, sized at 100% of text• Line Spacing – single, 7.2pt space before,

0pt space after, left aligned− 2nd level bullets – hyphen-minus, 36pt

• 3rd level bullets – round, 32pt

Bulleted Slide – full corner logo