10-genetic channelopathies, aziz - akron children's hospital · furst ml, aziz pf trends cv...
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Genetic Channelopathies: Long QT, Brugada Syndrome and CPVTFebruary 7, 2020Peter Aziz, MDDirector, Pediatric Electrophysiology
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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
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Ion Channels
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Defective Ion Channels
Ackerman MJ, Current Prob Card 2013
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A Molecular Problem
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Patient Presentation #1
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13 yo Evaluated for Chest Pain• No other symptoms• Otherwise healthy• No medications• Pain is at rest
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Family History
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13 yo Evaluated for Chest Pain
QTc = 505 ms
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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:
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Epidemiology of LQTS• Equally present in all races and ethnic
groups
•
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• Italian Ministry of Health screening program• Neonatal ECGs performed on the 15th and 25th
day of life• 44,596 neonates from 2001-2006
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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%)
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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
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Furst ML, Aziz PF Trends CV Medicine 2016
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Furst ML, Aziz PF Trends CV Medicine 2016
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Furst ML, Aziz PF Trends CV Medicine 2016
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QTc Adaptation
• Recovery ∆QTc (7 min – 1 min)− ∆QTc > 30 ms predicts LQT1 vs
LQT2
Aziz PF, Circulation AE 2009
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Clinical Diagnosis Schwartz Score
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Cornerstones of TherapyTrigger Modification
Schwartz, JACC 2013
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Ancient Guidelines
Mitchell et al, Bethesda 36th Conference, JACC 2005
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Cornerstone of Therapy
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Medication Avoidancewww.crediblemeds.org
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13 yo Evaluated for Chest Pain
Now What?
• Cascade screening for family• Placed on Nadolol• Asymptomatic since• Allowed to continue sports participation
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Patient Presentation #2
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10yo with Syncope at Rest
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Brugada SyndromeBench to Bedside
Wilde Circulation, 2002Zhang, Circulation 2015
Chen and Priori, JACC 2008
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Risk/TreatmentTreatment• Quinidine• ICD− Unexplained syncope− Spontaneous type 1
Risk Stratification• ?EP study• Provocative Testing
- Procainamide/Ajmaline- Fevers- High lead placement
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Patient Presentation #3
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• Syncope while coming down water slide• Normal ECG• Normal echocardiogram• Negative family history• Seen in ED in Atlanta
11yo with syncope
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Just Before Discharge
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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
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Exercise Stress Test• Polymorphic VT
• Bidirectional VT
Mohamed JCE Cardiology 2007
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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
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CPVT Treatment
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Key Takeaways
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Primary Prevention
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“Screening”AAP Guidelines
History
PhysicalExamination
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The Italian ExperiencePre-participation Sports Screening
• Implemented in 1982• Routine:
- Cardiac exam- Family history- ECG
• Outcome$43,000 per life year saved
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Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)
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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
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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
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18 yo Presenting After Aborted Cardiac Arrest
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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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• 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