Matthew Needleman, MD, and Mark Haigney, MD
A 16-year-old boy presents for evaluation after a syncopal episode associated with exercise in gym class. Further questioning reveals that the patient has had two syncopal episodes in the 3 years prior to his current presentation, one during a track meet, and the other during a soccer game. The patient is otherwise healthy, has no medical problems, and is not taking any medications. His family history is significant for a younger brother with a “seizure” disorder. The patient also has a maternal uncle who died after he “lost control” and fell off a bicycle during a cycling race.
Physical examination was normal. The baseline electrocardiogram revealed sinus bradycardia with a normal QT interval and no pathologic changes. Echocardiography revealed a structurally normal heart with no abnormalities. An exercise test was then performed. In early stages of exercise, there were frequent monomorphic PVCs, but in later stages of exercise the patient developed bidirectional VT. The patient became presyncopal during the treadmill test, and the test was stopped.
The patient was started on nadolol after the treadmill test. An implantable loop recorder was placed. Genetic testing was ordered, and the patient was found to have a ryanodine receptor (RyR2) mutation confirming the diagnosis of catecholaminergic polymorphic ventricular tachycardia (CPVT). Despite being on nadolol therapy, the patient experienced another syncopal episode during an episode of emotional stress, which correlated with ventricular tachycardia (Figures 56-1 and 56-2). Given his arrhythmogenic syncope despite β-blocker therapy, it was felt that an implantable cardioverter defibrillator would be appropriate, and this was placed. In addition, the patient was started on flecainide therapy with no recurrent syncopal events in follow-up.
FIGURE 56-1 Implantable loop recorder in early exercise showing monomorphic premature ventricular contractions followed by salvos of polymorphic ventricular tachycardia.
FIGURE 56-2 Implantable loop recorder showing sustained polymorphic ventricular tachycardia as exercise continues. This event was recorded as presyncope by the patient.
Syncope during exercise is always concerning and requires a thorough evaluation. In patients with a structurally normal heart, the differential for a genetic electrical disorder includes the long QT syndromes, the short QT syndrome, Brugada syndrome, the Haissaguerre syndrome (idiopathic ventricular fibrillation associated with early repolarization), and CPVT. Of these syndromes, only CPVT has a normal baseline electrocardiogram with a normal QT interval. In addition to the baseline normal electrocardiogram, hallmarks of this syndrome include polymorphic or bidirectional VT that is reproducible with exercise and a family history of sudden death or syncope in an autosomal-dominant pattern. Based on recent investigations into the genetics of intracellular calcium regulation, the understanding of this disease has expanded, and this chapter will review the molecular genetics and discuss management of this newly described disease.
• The first case report of CPVT was reported in 1975. A case series of four children with bidirectional ventricular tachycardia that was catecholamine-induced was reported in 1978.
• Multiple different cases series have now been reported, and currently it is estimated that the prevalence of the disease in 1:10,000 in Europe.1
• The syndrome is usually diagnosed in children and adolescents, although typically not before 2 years of age.
• The mortality of CPVT is 31% in untreated adults by the age of 30.1
Calcium leakage from the sarcoplasmic reticulum (SR) is the mechanism of cellular cystolic calcium overload, resulting in CPVT. Normal calcium regulation during cardiac muscle contraction occurs in the SR and is controlled by the macromolecule called the calcium release complex (CRC)2 which is composed of the following:
The Cardiac Ryanodine Receptor (RyR2)3
• This is the main calcium release channel present in the SR.
• RyR2 is a large protein with a large cytoplasmic footprint that allows regulatory proteins to modulate its function.
• The channel works though calcium-induced calcium release.
Calcium binds to RyR2 and triggers opening of L-type calcium channel, allowing rapid calcium to efflux from the SR.
• Calsequestrin is a large acidic protein that serves as a calcium buffer within the SR.
• Mechanistically, CASQ2 though interactions with triadin and junction confer RyR2 calcium luminal sensitivity such that CASQ2 inhibits RYR2 calcium release at low luminal calcium levels.4
Triadin and Junctin2
• Trisk 32 is an isoform of triadin found in cardiac muscle.
• Two isoforms of junctin are found in both skeletal muscle and cardiac muscle.
• Knockout mice of both Trisk 32 and junctin have resulted in fatal arrhythmias.
• These proteins anchor CSQ2 to RyR2 and work though a complex mechanism with CASQ2 to regulate SR calcium through the RYR2 membrane channel.
• Mutations in RyR2, CASQ2, and triadin lead to cystolic calcium overload, which generates delayed after depolarizations (DADs), triggered activity, and ventricular arrhythmias.
• Adrenergic stimulation results in an increased open probability of the RYR2 though phosphorylation of regulatory component of the RYR2, leading to higher levels of cytosolic calcium.
• In mouse models of CPVT, it appears that there is Purkinje origin of the ventricular premature beats resulting from calcium overload.5
As our understanding of molecular genetics increases, mutations in the RyR2 membrane channel, calsequestrin, and tritan have been identified.
Mutations in RyR2
• RyR2 mutations are the most frequent mutations identified in CPVT.
• The typical pattern identified was found to be autosomal dominant and was found on chromosome 1q42-43.6
• RyR2 is a 4967-amino acid protein, one of the largest genes in the human genome, with 105 exons.
• At least 50 mutations have been identified in RYR2 that are likely associated with CPVT, although some mutations have been found in arrhythmogenic right ventricular cardiomyopathy.
• Most mutations occur in the N-terminal region, the central zone, or in the c-terminal region and are missense mutations.
• Despite having a disease-associated mutation, relatives carrying an RYR2 mutation have marked phenotypic variability, and no genetic genotype-phenotype correlations have been established.7
Mutations in CASQ2
• Mutations in CASQ2 are less common and have been described to map to chromosome 1p13-21.8
• CASQ2 is a 399 amino acid protein, and over 20 unique disease-causing mutations in this protein have been described.
• Approximately half the mutations are missense mutations, and the other half lead to premature stop codons, leading to a truncated protein.
• Phenotypically, patients with a single CASQ2 mutation have less severe symptoms than CPVT patients with RYR2 mutations, but patients with multiple mutations have been described and are susceptible to ventricular arrhythmias.
Mutations in Triadin2
• Three unique mutations of triadin have been identified in patients with clinical CPVT who do not have mutations in RYR2 or CASQ2. Two of these mutations resulted in a premature stop codon, and another led to a missense mutation.
• As some of these mutations affect all triadin isoforms, skeletal muscle could be affected, and muscle weakness has been observed in at least one patient with a triadin stop codon mutation.
Other Described Mutations
• A mutation on chromosome 7p14-p22 has also been described in an autosomal recessive Arab family with an early onset lethal form of CPVT, but no specific gene or protein in calcium regulation has been identified.9
• Despite the known mutations previously described, a genetic cause is only found in 60% of cases of CPVT.
• Syncope typically occurs during the first or second decade of life.
• Syncope is triggered by emotional stress or exercise.
• In children and young adults, syncope with seizure is often seen, and epilepsy is frequently misdiagnosed. Often, there may be a 2-year delay in the correct diagnosis.
• Depending on the causative mutation, there is usually a family history of syncope, seizure, or sudden death in approximately 30% of patients. An autosomal-dominant pattern suggests a RYR2 mutation whereas an autosomal-recessive pattern suggests a CASQ2 mutation.
• Exercise or emotional syncope with muscle weakness suggests a possible triadin mutation.2
• The baseline resting electrocardiogram is normal with a normal QT interval.
• A low resting heart rate has been described in some patients with a RyR2 mutation. Mechanistically, it appears that increased RyR2 activity decreases sinus node activity by calcium dependent decrease in diastolic calcium, which decreases automaticity.10
• Atrial fibrillation is also seen in patients with CPVT. In a similar mechanism, RyR2 diastolic SR calcium leak appears to be associated with AF development in patients with CPVT.11
• The heart is structurally normal on echocardiogram and cardiac MRI.
• Exercise testing or Holter monitoring during exercise typically reveals monomorphic ventricular premature beats at low heart rates. As the heart rate accelerates, the ventricular ectopy becomes more polymorphic and can become bidirectional (see Figures 56-2 and 56-3).
FIGURE 56-3 Summary of historical and objective findings in CPVT.
• The premature ventricular beats usually have right bundle branch block morphology with a left axis deviation, consistent with a left ventricular source.12
• If exercise continues, salvos of polymorphic ventricular tachycardia can occur and be sustained, leading to syncope.
• There is mixed evidence for the diagnostic benefit of an epinephrine infusion for inducing polymorphic ventricular tachycardia. In one study, the sensitivity of an epinephrine infusion was 28% and should not be considered routinely as a diagnostic alternative to exercise testing.13
• Polymorphic or biventricular tachycardia is usually not induced with programmed stimulation.
• In younger patients who may be noncompliant with exercise testing or Holter monitoring, there may be a diagnostic benefit to placement of an implantable loop recorder.
• The differential diagnosis for bidirectional ventricular tachycardia includes CPVT, Andersen-Tawil syndrome, and digoxin toxicity. Only CPVT should have normal baseline electrocardiogram, whereas Andersen-Tawil syndrome patients typically have a distinct T-U wave morphology that may aid in diagnosis.
• Commercially available genetic testing is currently available for mutations in RyR2 and calsequestrin only. Genetic mutations are found in approximately 60% of patients with CPVT, suggesting that there are other genes and mutations involved that have not been discovered yet.1
MANAGEMENT (FIGURE 56-4)
FIGURE 56-4 Summary of treatment options available in CPVT.
Exercise restriction is required in all patients with CPVT.
• β-Blockers without sympathomimetic activity are the first-line medical therapy.
• Nadolol is the preferred prophylactic therapy, and the dose typically required to reduce symptoms such as syncope is 1.8 mg/kg.1
• Even in patients on adequate dosage of β-blockers, there is a 27% cardiac event rate. In this study, independent predictors of cardiac events were younger age at time of diagnosis and absence of β-blockers.14
• After an appropriate β-blocker titration, repeat exercise testing and/or Holter monitoring should be performed to document appropriate prevention of heart rates that may result in ventricular arrhythmias.
• Couplets and higher degree of ventricular arrhythmias on Holter monitoring suggest a higher cardiac event rate and indicate that medical therapy should be intensified.
• The importance of daily compliance with β-blockers should be stressed with patients and their families.
• Flecainide likely prevents spontaneous calcium release by inhibiting RyR2 and also prevents triggering of action potentials by inhibiting sodium channels. Both properties allow Flecainide to significantly reduce ventricular arrhythmias.
• In a study of 33 patients who had ventricular arrhythmias despite β-blocker therapy, 76% of patients had either partial or complete relief of ventricular arrhythmias when Flecainide was added to a β-blocker.15
• Flecainide has also been shown to be useful in terminating defibrillator-induced storming of ICD discharges resulting from the hyperadrenergic state of the post-shock period.16
• In a small study of 5 patients with CPVT, adding verapamil to a β-blocker reduced ventricular arrhythmias better than β-blockers alone in short-term follow-up.17
• Dantrolene reduces calcium leakage though skeletal muscle RyR1 and has been found to have effect on the RyR2 cardiac channel as well. In a mouse model, dantrolene was shown to have some benefit in reduction of arrhythmias, but human studies are in progress.18
Other Available Therapies
Implantable Cardioverter Defibrillator (ICD) Therapy
• ICD therapy is generally recommended for patients with CPVT and syncope despite β-blocker therapy, or documented sustained VT despite β-blocker therapy.
• ICD therapy is also indicated for secondary prevention of sudden cardiac death in patients with CPVT.
• Because ICD shocks provoke adrenaline release, ICDs can have proarrhythmic effects and induce a dangerous vicious cycle of shocks with additional sympathetic stimulation leading to defibrillator-induced storming.19
• Placement of ICDs in children and adolescents also carries a higher risk than typically described in adults such as multiple interventions for lead complications and revisions for growing.
Left Cardiac Sympathetic Denervation
• In small case series of 13 CPVT patients with refractory arrhythmias, despite β-blocker therapy left cardiac sympathetic denervation has proven beneficial in reducing ventricular arrhythmias.20 Longer term multicenter studies are still needed.
• Successful catheter ablation for bidirectional ventricular tachycardia associated with CPVT in patients with recurrent ventricular ectopy has been described in case reports.12
Figure 56-4 summarizes the treatment options available for CPVT.
FOLLOW-UP AND LONG-TERM COMPLICATIONS
• A family history of syncope, a seizure disorder, or sudden cardiac death is reported in 30% of family members of patients with CPVT.
• Given that RyR2 mutations are inherited in an autosomal dominant pattern, screening of asymptomatic family members is necessary.
• In a large study, the event rates in “asymptomatic” family members with genetic mutations were similar to that of the index case in the family.14
• Despite the phenotypic variability, frequent reevaluation with exercise testing, Holter monitoring, and/or implantable loop recorder and consideration of β-blocker therapy should occur in all genetic mutation patients regardless of initial symptoms.
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