you have been diagnosed with cpvt: what is the plan?...genes encode for proteins of channel 4...
TRANSCRIPT
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Susan P. Etheridge, MD
You Have Been Diagnosed
with CPVT: What is the
Plan?
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What is CPVT?
•Potentially lethal genetic arrhythmia syndrome
•Rare (1:10,000*) but important cause of sudden death in
young
•15% autopsy (-) sudden death < age 40
•1/3 sudden death 1st symptom
• Untreated 30% mortality < age 40 2 *minimal evidence
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Bidirectional VT
Beat-to-beat 180 degree QRS rotation
HIGHLY suggestive of CPVT
Not always observed
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Differential Diagnosis
Digoxin toxicity
Andersen Tawil Syndrome
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patients may tolerate BiVT well because of normal heart
but… BiVT can quickly degenerate into VF
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Some have primary polymorphic VT
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Some have supraventricular arrhythmias
including atrial fibrillation, flutter, AET especially younger children DiPino Heart Rhythm 2014
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Structurally normal heart and
a normal ECG
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Bradycardia and U waves
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Uncertain clinical relevance
possibly a function of altered calcium metabolism
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8 Roston Circulation Arrhythmia, EP 2015
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So, how can we identify
these patients with a
normal ECG and echo?
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• High rate of life-threatening symptoms, treatment failure in
probands
• Delay in diagnosis
• Universal use of BB
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226 patients
Diagnosed 2 years after 1st symptom
Patients exposed to RISK
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Sylvia Priori Invitae Lecture 2017
Early onset of symptoms
> 80% with events by age 40 years
More symptoms than BrS and LQTS
Early diagnosis important
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Exercise testing: The most important tool
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Exercise Testing
• Heart rate reaches critical rate - arrhythmias occur
• Atrial arrhythmias can occur and may precede
ventricular arrhythmias
• Reproducible: can use to assess efficacy of
therapy
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116 bpm 153 bpm 142 bpm
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What is the Plan?
Do an exercise test
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Holter/Event Monitor
• Less sensitive
• Patient too small or unable to perform exercise test
• Trigger is something other than exercise
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Epinephrine Infusion
• Useful if patient cannot perform an
exercise test (too young, still ill after
an arrest…)
• Generally lower peak heart rates than
exercise test
• Lower sensitivity but high specificity
• ? utility for therapy assessment
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L-type calcium channels release calcium
Trigger calcium release from sarcoplasmic reticulum
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Ryanodine
Receptor (RyR2)
Ca2+
Ca2+
Ca2+
Large ion channel
sits in membrane of sarcoplasmic reticulum
Genes encode for proteins of channel
4 proteins come together to make this structure with a hole in the middle
where the calcium goes through
Mutation channel conformational changes in protein
Channel unable to stay closed
Calcium leaks out
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Ca2+
Na+
Na+ Na+ Sodium depolarizes the cell and creates DAD
RyR2
Ca2+
Ca2+
Calcium release in diastole
Na+
Na+ Na+
Important when considering therapy
Cell tries to get rid of excess calcium
Exchanges it for sodium
+ stress
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What is the Plan?
Understand the disease
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Average age at symptoms onset 10.5 years
syncope 43%
cardiac arrest 19%
palpitations 5%
asymptomatic 22%
M=F
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CPVT is a Genetic Disease
• Penetrance RyR2 CPVT > 80%
•Genetic testing is recommended for
proband with clinical features of CPVT
starting with RyR2 and CASQ
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CPVT: Genetic disease of dysregulation
in intracellular calcium handling
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55-65% 2-5%
1-2% Unknown 35-
45%
CALM 1 and 2
encoding calmodulin
rare
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Cascade Screening • Test early since disease onset young age
(mean age 10 years)
• Genetic testing when “target” exists
• Exercise testing but disease penetrance <
100% so a negative test does not
completely rule out disease
• Presymptomatic treatment important since
sudden death can be 1st symptom
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What is the Plan?
Test the family
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Challenges in CPVT
• Hard to diagnose while patient is
alive, harder after death
• First symptom may be sudden
death and there may be no further
investigation of family or victim
• About 1/3 are gene negative
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Beta Blockers
• 1st line of therapy
• Highest tolerable dose
• Class I - symptomatic patients
• Class IIa - Gene (+) phenotype (-) patients
• Evaluate efficacy/compliance regularly by
exercise testing
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• High rate of life-threatening symptoms, treatment failure
in probands
• Delay in diagnosis
• Universal use of BB
Mainstay of therapy
BUT….
• noncompliance
• intolerance
• subtherapeutic dosing
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Cardiac Event Rates Fatal or Near Fatal Event Rates
• 81 patients on BB
• 62 (77%) no events
• 8-year cardiac (27%) and fatal or near-fatal (11%) event rates on BB
• Event rate not sufficiently low
• Some events associated noncompliance
• BB other than nadolol and younger age at diagnosis independent predictors for events
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Not all BB are equal Nadolol superior
Heart Rhythm
2016
• lower maximal heart rate than B1 selective
• more pronounced chronotropic effect
• once daily dosing, better compliance
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What is the Plan?
Treat with beta blockers
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preferably nadolol
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•Events despite BB
•Fail to sufficiently suppress arrhythmias on exercise
testing
•Noncompliance and intolerance
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Watanabe Nat Med. 2009, Liu Circ Res. 2011, van der Werf J Am Coll Cardiol. 2011, Hayashi Circulation. 2009
•Ic antiarrhythmic
•Sodium channel blocking agent
•Approved for children with life-threatening arrhythmias
•Dose response effect
•Minimal side-effects
•Fail to sufficiently suppress arrhythmias on exercise testing
•Noncompliance and intolerance
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• Decrease arrhythmias in CASQ2 knockout mouse
• Effective in RyR2, CASQ2 and gene (-) CPVT
•Monotherapy in patients intolerance of BB
• Suppresses DADs
•Mechanism
• Na-channel blocking agent
• ?direct effect on RyR2
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Watanabe Nat Med 2013, Padfield Heart Rhythm 2016
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Single-blind, multicenter, placebo controlled, clinical crossover study
Placebo vs Flecainide
+ Maximally-tolerated BB
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Change in arrhythmia score with flecainide
Flecainide added to β-blocker - superior to
maximally tolerated β-blocker alone in reducing
exercise-induced ventricular arrhythmias in
patients with CPVT
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Left Cardiac Sympathetic
Denervation
• Surgical ablation of the lower 2/3 of
stellate ganglion and thoracic
ganglia T2-T4 (complete)
• Interrupt major source of
epinephrine release in the heart
• Partial LSCD ineffective
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•63 patients LCSD as secondary (n=54) or primary (n=9) prevention
•LCSD
•Decreased % cardiac events despite optimal medical therapy from 100% to 32%
(P<0.001)
•Decreased rate of shocks by 93% (3.6 to 0.6 shocks person/year, P<0.001)
•Incomplete LCSD - more events compared to complete (71% vs 17%, P<0.01)
Circulation. 2015;131:2185-2193.
Event-free survival before LCSD
Syncope despite optimal medical therapy
LCSD could be considered next rather than an ICD
or as a complement to ICD in patients with recurrent shocks
LCSD is an effective antifibrillatory intervention in CPVT
1 year event-free survival 87%
2 year event-free survival 81%
Event-free survival after LCSD
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What is the Plan?
Consider dual/triple therapy for severe disease
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Exercise testing in CPVT
• Use exercise test to assess
adequacy of therapy
• Delay in arrhythmia onset (at faster
heart rates)
• Test for disease progression in
children with mild phenotype
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ICD
after cardiac arrest
recurrent syncope, arrhythmias despite medical management
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VF 33%
polymorph VT
31% BiVT 4%
atrial tach 16%
noise 12%
ectopy 4%
Circ Arrhythm Electrophysiol. 2013;6:579-587, Roses-Noguer Heart Rhythm 2014, Olde Nordkamp Heart Rhythm 2016
• 54% appropriate shocks
• 46% inappropriate shocks
• 24% electrical storm
• 36% induction of more malignant arrhythmias
ICD Problematic
Proarrhythmic
CPVT patients are young and have a lifetime of exposure to ICD risks/complications
85% CPVT patients with ICD related complications
“rhythms” associated with shocks
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What is the Plan?
Try to avoid an ICD
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Shared decision making
Well-informed patient and
family
Maximally-treated patient
AED no time-dependent difference in outcome between athletes and non-athletes
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What is the Plan?
Find a balance between exercise and safety
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