Plan? Susan P. Etheridge, MD 1 What is CPVT? Potentially lethal - - PowerPoint PPT Presentation

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Plan? Susan P. Etheridge, MD 1 What is CPVT? Potentially lethal - - PowerPoint PPT Presentation

Aug 16, 2022 234 likes •708 views

You Have Been Diagnosed with CPVT: What is the Plan? Susan P. Etheridge, MD 1 What is CPVT? Potentially lethal genetic arrhythmia syndrome Rare (1:10,000*) but important cause of sudden death in young 15% autopsy (-) sudden death

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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

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*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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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 heartbeat@cw.bc.ca

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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

  • r 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 medic

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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 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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