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

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

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

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

8 Roston Circulation Arrhythmia, EP 2015

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

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

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

heartbeat@cw.bc.ca

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

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

•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

• 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

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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