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 < age 40 • 1/3 sudden death 1st symptom • Untreated 30% mortality < age 40 *minimal evidence 2
Differential Diagnosis Digoxin toxicity Andersen Tawil Syndrome Bidirectional VT Beat-to-beat 180 degree QRS rotation HIGHLY suggestive of CPVT Not always observed 3
patients may tolerate BiVT well because of normal heart but… BiVT can quickly degenerate into VF 4
Some have primary polymorphic VT Some have supraventricular arrhythmias including atrial fibrillation, flutter, AET especially younger children DiPino Heart Rhythm 2014 5
Structurally normal heart and a normal ECG 6
Bradycardia and U waves Uncertain clinical relevance possibly a function of altered calcium metabolism 7
Roston Circulation Arrhythmia, EP 2015 8
So, how can we identify these patients with a normal ECG and echo? 9
• High rate of life-threatening symptoms, treatment failure in probands 226 patients Diagnosed 2 years after 1st symptom • Delay in diagnosis Patients exposed to RISK • Universal use of BB 10 10
Early diagnosis important Sylvia Priori Invitae Lecture 2017 Early onset of symptoms > 80% with events by age 40 years More symptoms than BrS and LQTS 11
Exercise testing: The most important tool 12
Exercise Testing 116 bpm 142 bpm 153 bpm • Heart rate reaches critical rate - arrhythmias occur • Atrial arrhythmias can occur and may precede ventricular arrhythmias • Reproducible: can use to assess efficacy of therapy 13
What is the Plan? Do an exercise test 14
Holter/Event Monitor • Less sensitive • Patient too small or unable to perform exercise test • Trigger is something other than exercise 15
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 16
L-type calcium channels release calcium Trigger calcium release from sarcoplasmic reticulum 17
18
Ryanodine Large ion channel sits in membrane of sarcoplasmic reticulum Receptor (RyR2) 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 Ca2+ Ca2+ Ca2+ 19
Sodium depolarizes the cell and creates DAD Na+ Na+ Na+ + stress Ca2+ Ca2+ Cell tries to get rid of excess calcium Exchanges it for sodium RyR2 Ca2+ Calcium release in diastole Na+ Na+ Na+ Important when considering therapy 20
What is the Plan? Understand the disease 21 21
Average age at symptoms onset 10.5 years syncope 43% cardiac arrest 19% palpitations 5% asymptomatic 22% M=F heartbeat@cw.bc.ca 22
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 23
CPVT: Genetic disease of dysregulation in intracellular calcium handling CALM 1 and 2 encoding calmodulin Unknown 35- rare 1-2% 45% 55-65% 2-5% 24
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 25
What is the Plan? Test the family 26 26 26
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 27
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 28
• High rate of life-threatening symptoms, treatment failure in probands • Delay in diagnosis Mainstay of therapy BUT…. • Universal use of BB • noncompliance • intolerance • subtherapeutic dosing 29 29 29
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 30
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 31
What is the Plan? Treat with beta blockers preferably nadolol 32 32 32
• Events despite BB • Fail to sufficiently suppress arrhythmias on exercise testing • Noncompliance and intolerance 33
• 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 Watanabe Nat Med . 2009, Liu Circ Res . 2011, van der Werf J Am Coll Cardiol . 2011, Hayashi Circulation . 2009 34
• 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 Watanabe Nat Med 2013, Padfield Heart Rhythm 2016 35
Single-blind, multicenter, placebo controlled, clinical crossover study Placebo vs Flecainide + Maximally-tolerated BB 36
Flecainide added to β -blocker - superior to maximally tolerated β -blocker alone in reducing exercise-induced ventricular arrhythmias in patients with CPVT Change in arrhythmia score with flecainide 37
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 38
Circulation. 2015;131:2185-2193. LCSD is an effective antifibrillatory intervention in CPVT • 63 patients LCSD as secondary (n=54) or primary (n=9) prevention Syncope despite optimal medical therapy LCSD could be considered next rather than an ICD • LCSD or as a complement to ICD in patients with recurrent shocks • 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) Event-free survival before LCSD Event-free survival after LCSD 1 year event-free survival 87% 2 year event-free survival 81% 39
What is the Plan? Consider dual/triple therapy for severe disease 40 40 40
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 41
ICD after cardiac arrest recurrent syncope, arrhythmias despite medic 42
“rhythms” associated with shocks ectopy 4% Proarrhythmic noise • 54% appropriate shocks VF 12% • 46% inappropriate shocks 33% • 24% electrical storm atrial tach • 36% induction of more malignant arrhythmias 16% polymorph ICD Problematic VT BiVT 31% 4% CPVT patients are young and have a lifetime of exposure to ICD risks 85% CPVT patients with ICD related complications Circ Arrhythm Electrophysiol. 2013;6:579-587, Roses-Noguer Heart Rhythm 2014, Olde Nordkamp Heart Rhythm 2016 43
What is the Plan? Try to avoid an ICD 44 44 44
Shared decision making Well-informed patient and family Maximally-treated patient AED no time-dependent difference in outcome between athletes and non-athletes 45
What is the Plan? Find a balance between exercise and safety 46 46 46
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