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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
• 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
• 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
• 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
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