7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Catecholaminergic polymorphic ventricular tachycardia : Alfred Buxton, MD : Peter J Zimetbaum, MD : Nisha Parikh, MD, MPH All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 14, 2022. INTRODUCTION Polymorphic (or polymorphous) ventricular tachycardia (VT) is defined as a ventricular rhythm at a rate greater than 100 beats per minute (bpm) with a continuously varying QRS complex morphology in any recorded electrocardiographic (ECG) lead. The simultaneous recording of more than one ECG lead is often necessary to detect these changes. Most polymorphic VTs are rapid (often >200 bpm), but an absolute rate has not been established, and VT at a slower rate can manifest changing QRS morphology [1]. Some episodes of polymorphic VT cause hemodynamic collapse, and some degenerate into ventricular fibrillation (VF); however, many episodes terminate spontaneously. Polymorphic VTs are classified based upon their association with a normal or prolonged QT interval. Spontaneous polymorphic VT in the presence of a normal QT interval usually occurs in the setting of coronary heart disease or nonischemic cardiomyopathy. However, some patients have no structural heart disease or may have a familial syndrome. Catecholaminergic polymorphic VT (CPVT) will be reviewed here. Polymorphic VT associated with a prolonged QT interval, which has a different etiology and mechanism, is known as torsades de pointes ("twisting of points") and is discussed separately. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations", section on 'Polymorphic VT/torsades de pointes' and "Acquired long QT syndrome: Definitions, pathophysiology, and causes".) EPIDEMIOLOGY https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 1/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate CPVT, also known as familial CPVT, occurs in the absence of structural heart disease or known associated syndromes [2-11]. This disorder typically begins in childhood or adolescence, although cases have been reported with initial presentation in the fourth decade of life [5]. Affected patients may have a family history of juvenile sudden death or stress-induced syncope [3,5]. CPVT may also present sporadically as a de novo mutation in individuals with no family history [5,12]. CPVT occurs with similar frequency in males and females, but males are more likely to present at an earlier age (in childhood or adolescence), while females are more likely to present at an older age (20 years, mean) [5]. GENETICS Pathogenic variants in several genes have been identified in patients with CPVT. The most common variants are in the cardiac ryanodine receptor gene (an autosomal dominant form) and the calsequestrin 2 gene (autosomal recessive). Both mutations appear to act by inducing diastolic calcium release from the sarcoplasmic reticulum. The resulting intracellular calcium overload leads to delayed afterdepolarizations and triggered activity, which can induce ventricular tachycardia and fibrillation. Mutations in these two genes have been recognized in only 70 percent of patients with CPVT, implying that other genes play a role [13]. More recently, an analysis of published studies found other pathogenic variants that are associated with CPVT; these variants are much less common than RyR2 and CASQ2 and are described in more detail below [14]. Cardiac ryanodine receptor An autosomal dominant form of CPVT was initially linked to chromosome 1q42-q43 [6]. Subsequent studies identified mutations in the gene for the human cardiac ryanodine receptor (RyR2), which is also called the cardiac sarcoplasmic calcium release channel [5,7,8,15,16]. One report suggested that abnormal RyR2 channels may account for at least one in every seven cases of sudden unexplained death [17]. RyR2 mediates the release of calcium from the sarcoplasmic reticulum that is required for myocardial contraction. The FK506 binding protein (FKBP12.6) stabilizes RyR2, preventing aberrant activation. In familial polymorphic VT, mutations in RYR2 change RyR2's protein structure, which prevents regulation by FKBP12.6 and results in increased RyR2 channel activity during adrenergic stimulation (eg, simulated exercise, beta adrenergic stimulation) [15,18]. In these settings, the "leaky" RyR2 channels increase diastolic calcium release and can trigger life-threatening ventricular arrhythmias, probably via delayed afterdepolarizations [15,18,19]. https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 2/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Two other types of RYR2 mutations differ from those associated with familial polymorphic VT in structurally normal hearts. A large genomic deletion in RYR2 that leads to polymorphic VT and extended phenotypes (including sinoatrial node and atrioventricular node dysfunction, atrial fibrillation, atrial standstill, and dilated left ventricular cardiomyopathy) has been identified in 16 members of two separate families [20]. Another mutation in RYR2 is responsible for exercise-induced familial polymorphic VT occurring in arrhythmogenic right ventricular cardiomyopathy [21-23]. (See "Arrhythmogenic right ventricular cardiomyopathy: Pathogenesis and genetics".) The frequency with which RyR2 mutations occur in patients with CPVT was assessed in a series of 30 probands and 118 family members [5]. RyR2 mutations were detected in 14 of the 30 probands (47 percent) and in nine family members, four of whom were silent carriers. The patients with RyR2 mutations, compared with those without such mutations, had events at a younger age (age at first syncope 8 versus 20 years), and male sex was an important risk factor for syncope. Calsequestrin 2 The calsequestrin 2 protein is the major calcium reservoir within the sarcoplasmic reticulum of cardiac myocytes. This protein is bound physically and functionally to the ryanodine receptor, where it binds large amounts of calcium [24]. The mechanism by which the reported mutation causes ventricular arrhythmias is not clearly established. A second genetic form of CPVT, with autosomal recessive inheritance, involves the calsequestrin 2 gene (CASQ2) [9,25,26]. This form was first identified in seven related Bedouin families [9]. These families included nine children who died suddenly at an average age of seven years and 12 others with a history of recurrent syncope or seizures beginning at six years of age. The 12 symptomatic patients had a relative resting bradycardia and polymorphic VT induced by exercise or isoproterenol infusion. Other genetic variants Other genes that are strongly associated with CPVT and display autosomal recessive inheritance patterns encode the following proteins [14]: Triadin This protein is associated with the release of calcium ions from the sarcoplasmic reticulum and the triggering of muscular contraction. Specific pathogenic variants in the triadin gene (TRDN) are associated with CPVT. Trans-2,3-enoyl-CoA reductase-like This protein is in the steroid 5-alpha reductase family and is located in the endoplasmic reticulum of cardiomyocytes. Mutations in the gene for this protein (TECRL) are associated with CPVT. Calmodulin This protein is expressed in all eukaryotic cells and has many functions; one is to activate smooth muscle contraction. Pathogenic variants in calmodulin may https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 3/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate contribute to CPVT (CALM1, CALM2, CALM3), although the evidence for this is less robust than for variants in TRDN and TERCL. CLINICAL PRESENTATION Signs and symptoms The clinical presentation of CPVT is variable, including some patients who are asymptomatic and identified as part of familial screening. Symptomatic affected patients typically present with syncope or cardiac arrest due to VT or ventricular fibrillation (VF) precipitated by emotional or physical stress [5,11,27]. The VT morphology may vary continuously, from beat to beat, or may appear as a bidirectional VT [5,10]. Presentation with VF is less common, but sudden death may be the initial manifestation [5]. When VT develops, the type and intensity of symptoms will vary depending upon the rate and duration of VT along with the presence or absence of significant comorbid conditions. Patients with CPVT and symptoms typically present with one or more of the following: Sudden cardiac arrest Syncope or presyncope "Seizure-like" activity Palpitations Bidirectional VT has been considered virtually pathognomonic for digitalis intoxication. However, it may also occur in patients with CPVT [5,10]. Of note, in both cases, the arrhythmia is thought to result from intracellular calcium overload, leading to delayed afterdepolarizations, causing triggered activity. (See "Cardiac arrhythmias due to digoxin toxicity", section on 'Bidirectional ventricular tachycardia'.) RyR2 mutations have also been associated with neurodevelopmental disorders. Among a cohort of 421 patients with CPVT and RyR2 mutations, 34 patients (8 percent) were found to have intellectual disabilities, a rate significantly higher than the expected rate of 1 percent in the general population [28]. Risk of cardiac events The clinical features of familial polymorphic VT were evaluated in two unrelated families with 24 members who had experienced exercise-induced VT or syncope or had an episode of cardiac arrest [6]. Some of the family members had delayed clinical manifestations, which necessitated continued observation and repeated evaluation. The cumulative incidence of sudden cardiac death by the age of 30 was 31 percent. Only one heterozygous carrier was clinically unaffected, suggesting high disease penetrance by adulthood. https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 4/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate There are few studies of predictors of cardiac events in CPVT. One study of 133 children with CPVT showed that probands had a higher rate of cardiac events compared with relatives (38 versus 15 percent; hazard ratio 4.4; 95% CI 1.46-13.30) [29]. Neither age at diagnoses nor sex were associated with cardiac events. ECG characteristics All patients with suspected CPVT should have a 12-lead ECG performed. The ECG during sinus rhythm is generally normal. Two types of polymorphic VTs have been described in patients with CPVT [30]: "Typical" polymorphic VT with continuously varying QRS morphology, similar to that seen in patients with acute ischemia or nonischemic cardiomyopathies Bidirectional tachycardia, demonstrating alternans of the QRS complexes in the limb leads Patients with CPVT may also develop supraventricular tachycardias (primarily atrial tachycardias) [31,32]. DIAGNOSTIC TESTING AND DIAGNOSIS The primary diagnostic test and means of making the diagnosis of CPVT is the exercise stress test. An alternative for patients who are unable to exercise is infusion of epinephrine. The protocols for testing and the protocol-specific criteria for the diagnosis of CPVT are as follows: Exercise testing In patients with suspected CPVT (symptomatic patients and asymptomatic family members), we obtain an exercise test to provoke rhythms diagnostic of CPVT. The finding of an increased frequency of nonsustained or sustained VT during exercise or recovery confirms the diagnosis of CPVT ( waveform 1). However, exercise- induced VT is not specific for CPVT, as other ventricular arrhythmias may be induced by exercise, such as idiopathic outflow tract VT. Stress testing is performed in an appropriately monitored setting and typically employs a standard Bruce protocol. The exercise test is terminated upon identification of an increasing frequency of premature ventricular complexes (PVCs) with increasing exercise load or at maximal exertion as defined by the patient. Both nonsustained and sustained VT may also occur during the stress or recovery phase. In our experience, exercise stress testing is more sensitive than other forms of provocative testing. If a standard exercise study does not show exercise-induced ventricular arrhythmias and clinical suspicion for CPVT remains high, an exercise test using a "burst" protocol may reveal arrhythmias diagnostic of CPVT [33]. https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 5/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Exercise testing can also be used to risk-stratify patients for arrhythmic events [34-36] or to assess whether chronic beta-blocker therapy suppresses heart rate to levels below those associated with previous arrhythmias. (See 'Initial therapy' below.) Epinephrine infusion Epinephrine infusion is an alternative for patients who are unable to exercise. The test is conducted in the electrophysiology suite with continuous multilead ECG monitoring and resuscitation equipment at the bedside. The initial dose of epinephrine is 0.05 to 0.1 mcg/kg/min, which is increased by 0.05 mcg/kg/min to a maximum of 0.20 mcg/kg/min. CPVT is diagnosed if epinephrine infusion causes nonsustained or sustained polymorphic VT with more than 10 PVCs/minute or new T-wave alternans. Epinephrine appears quite specific for provoking arrhythmia in CPVT patients but is not as sensitive as the exercise test. Ambulatory ECG In children or others unable to perform an exercise stress test and who may have CPVT, we obtain annual ambulatory ECG monitoring. If ambulatory monitoring shows arrhythmias suspicious for CPVT, we pursue exercise testing or epinephrine infusion. Electrophysiology testing We do not use programmed electrical stimulation (electrophysiologic testing) to test for CPVT; exercise testing is a more sensitive test. Studies of CPVT patients suggest that atrial pacing does not readily induce ventricular arrythmias and that exercise provocation is more likely to reveal diagnostic rhythms [5,32,37]. Genetic testing In patients with clinical presentation or pedigree that is suggestive for CPVT, a genetic screening panel may help support the diagnosis. The genetic panel should include the following genes: RYR2, CASQ2, TRDN, TECRL, CALM1, CALM2, and CALM3 [14]. (See 'Genetics' above.) If a patient is found to have a pathogenic variant for CPVT, we perform genetic screening in all of their first-degree relatives. TREATMENT Treatment goals The goals of treatment are to: Stop an acute polymorphic VT episode Prevent cardiac arrest and sustained VT with implantable cardioverter-defibrillator (ICD) plus antiadrenergic medications https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 6/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Minimize VT recurrence Acute management Acute initial management focuses on rapid termination of polymorphic VT. Treatment decisions are often made in the absence of a detailed knowledge of underlying cardiac disease, thus our recommendations do not make clear distinctions based upon the presence of coronary heart disease or primary electrical disease. Patients with polymorphic VT who are hemodynamically unstable or become pulseless require prompt treatment with electrical cardioversion/defibrillation. (See "Overview of the acute management of tachyarrhythmias", section on 'Wide QRS complex tachyarrhythmias'.) We use propranolol (40 mg oral doses [or appropriate weight-based dosing in children] every six hours for the first 48 hours, with additional intravenous doses as needed for recurrent breakthrough ventricular arrhythmias) for acute suppression of recurrent polymorphic VT. For long-term preventive therapy, nadolol (1 to 2 mg/kg) is preferred (because of its long duration of action) [3,5]. (See "Electrical storm and incessant ventricular tachycardia", section on 'Initial management' and 'Beta blockers' below.) This guidance agrees with the suggested acute treatment of CPVT as provided in the 2013 HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and Management of Patients with Inherited Primary Arrhythmia Syndromes (endorsed by the American College of Cardiology and the American Heart Association) [38]. Avoidance of strenuous exercise Participation in competitive athletics and strenuous exercise increases the risk of ventricular arrhythmias in patients with CPVT due to the rise in catecholamines associated with exertion. Thus, we counsel all patients with CPVT to avoid competitive sports. However, some patients may reasonably choose to continue to participate with appropriate cautionary measures, including an emergency action plan with an automated external defibrillator immediately available. (See "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Inherited arrhythmia syndromes'.) Despite our recommendation, limited data suggest that sports participation may be safe for selected patients with CPVT. In a cohort study of 63 patients with CPVT, including 21 active competitive athletes, continuing participation in sports did not elevate rates of life-threatening arrhythmias or death [39]. We await additional data replicating the findings from this small, nonrandomized observational study prior to changing our recommendation against competitive sports for patients with CPVT. https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 7/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate High-risk patients High-risk patients are survivors of cardiac arrest (SCA), syncope, sustained VT or ventricular fibrillation (VF), as well as those who have recurrent arrhythmia despite treatment with beta blockers. Initial therapy Implantable cardioverter-defibrillators For patients with CPVT who have survived sudden cardiac arrest (SCA) or who experience syncope due to sustained VT or VF despite therapy with beta blockers, we recommend ICD implantation in addition to beta blocker therapy. Several unique considerations in ICD implantation for CPVT are outlined below: ICDs should not be used alone without pharmacologic therapy [40]. Patients with CPVT who have survived SCA due to sustained VT or VF usually receive an ICD in addition to beta blocker therapy [41]. (See 'Beta blockers' below.) The younger average age of patients with CPVT referred for ICD necessitates a thorough discussion emphasizing the impact of potential complications and repeated procedures on quality of life. In particular, ICD shocks in patients with CPVT can trigger electrical storm, which lowers quality of life. (See "Electrical storm and incessant ventricular tachycardia" and "Cardiac implantable electronic devices: Long-term complications", section on 'Quality of life'.) When ICDs are implanted, they should be programmed with long detection times and high detection rates to minimize the chance of shocks for nonsustained VT or other arrhythmias not requiring such therapy. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Our approach'.) Data from a recent meta-analysis of 53 studies of CPVT emphasizes the efficacy of ICDs in preventing life-threatening arrhythmias but also the high prevalence of device complications and shocks [40]. Among 503 patients with CPVT (median age 15 years) treated with an ICD plus anti-adrenergic therapy (medication and/or sympathetic denervation), 40 percent of patients had at least one appropriate shock, and 21 percent had at least one inappropriate shock. A device-related complication occurred in nearly one-third of ICD recipients during the available follow-up. (See "Cardiac implantable electronic devices: Long-term complications" and "Cardiac implantable electronic devices: Periprocedural complications".) Beta blockers We recommend beta blocker treatment for all patients with spontaneous or documented stress-induced ventricular arrhythmias. We suggest the following treatment approaches: https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 8/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Use of long-acting, nonselective beta blockers (we use nadolol 1 to 2 mg/kg). The long duration of action aides with compliance. Given that most affected individuals are young, repeated education regarding the importance of medication compliance is warranted (see "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy", section on 'Beta blockers'). In some families, beta blocker therapy completely prevents recurrent arrhythmias [4,9]. Thus, it is important to advise patients on the need to be compulsive (not to miss any doses) when taking pharmacologic therapy for CPVT. A systematic review and meta-analysis of 11 observational studies including 403 patients with CPVT revealed that 88 percent of patients were prescribed a beta blocker at some point [42]. There were no control groups for comparison. However, the event rates at four and eight years were as follows: Arrhythmic events (syncope, aborted cardiac arrest, sudden cardiac death [SCD]) 18.6 and 37.2 percent at four and eight years, respectively Near fatal events (aborted cardiac arrest, SCD) 7.7 and 15.3 percent Fatal events (SCD) 3.2 and 6.4 percent Some studies suggest that nonselective beta blockers (eg, nadolol, propranolol) are more effective than beta-1 selective beta blockers at preventing exercise-induced arrhythmias. In a study of 34 patients with CPVT who underwent three exercise stress tests, the maximum heart rate achieved during exercise was significantly lower following nadolol treatment (122 versus 139 beats per minute [bpm]), with a significant reduction in exercise-induced arrhythmias with nadolol compared with beta-1 selective beta blockers and no treatment [43]. Severity of arrhythmias was scored as 1 point for no arrhythmias or only single ventricular extrasystoles, 2 points for >10 ventricular extrasystoles per minute or bigeminy, 3 points for couplets, and 4 points for nonsustained ventricular tachycardia or sustained ventricular tachycardia. Arrhythmias during exercise stress testing were less severe during treatment with nadolol compared with beta-1 selective beta blockers (arrhythmic score 1.6 0.9 versus 2.5 0.8) and before the initiation of beta blocker treatment (arrhythmic score 1.6 0.9 versus 2.7 0.9); however, no differences were observed during additional treatment with beta-1 selective beta blockers (arrhythmic score 2.5 0.8 versus 2.7 0.9). Monitoring for recurrent ventricular arrythmias After initiating therapy, it is important to regularly monitor for significant spontaneous and stress-induced VT: Regular ICD device checks that can capture a history of ventricular arrythmias. (See "Cardiac implantable electronic devices: Patient follow-up".) https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 9/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate At least annual follow-up exercise test and/or Holter monitor testing while on beta blocker/antiarrhythmic CPVT therapy to confirm that heart rate response to exercise is sufficiently and persistently blunted. The persistence of ventricular premature beats on a Holter monitor is not necessarily an indication of treatment failure. However, recurrent VT despite compliant therapy with beta- adrenergic blocking agents is an indication to add other therapy. Second-line therapy Flecainide For patients with an ICD who continue to have stress-induced ventricular arrhythmias despite beta blocker therapy, we suggest the addition of flecainide for further arrhythmia suppression. For patients who cannot tolerate beta blockers, flecainide may be used as monotherapy. If a patient has a contraindication to flecainide such as coronary disease or a medication intolerance, then verapamil can also be used in its place. Flecainide blocks cardiac sodium channels and inhibits the cardiac ryanodine receptor (RyR2). These combined effects make it an attractive potential therapy for CPVT. Data from animal models have shown the potent inhibitor effect of flecainide on RyR2 channels and suppression of catecholamine-induced polymorphic VT [44]. (See 'Genetics' above.) When added to baseline therapy with a beta blocker, calcium channel blocker, or both, flecainide has been shown to significantly reduce ventricular arrhythmias during exercise [44-49]. Supporting evidence is somewhat limited by studies with small sample sizes: Flecainide as a second agent is efficacious. In one study, flecainide (median daily dose of 150 mg), in addition to either a beta blocker or calcium channel blocker, suppressed exercise-induced ventricular arrhythmias in 76 percent of patients given this regimen [45]. All patients had recognized mutations associated with CPVT. Flecainide may also be effective as a third agent along with both a beta blocker and a calcium channel blocker [44,46-48]. In a series of 10 patients with CPVT who had recurrent VT in spite of therapy with beta-adrenergic blocking agents (all patients) and calcium channel blockers (in 6 of 10 cases), flecainide was effective in suppressing exercise-induced ventricular tachyarrhythmia when given in addition to beta blockers [48]. Flecainide monotherapy may be an option for patients who are unable to tolerate beta blockers due to side effects. In one nonrandomized study of eight patients with CPVT, including seven who were intolerant of beta blockers, no instances of arrhythmic presyncope, syncope, or SCA were seen during the median follow-up of 37 months [50]. In a separate crossover study, 13 patients with CPVT randomized to flecainide versus placebo https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 10/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate for three months had a reduction in exercise-induced arrhythmias and complete suppression of induced arrhythmias in 85 percent of patients [49]. Calcium channel blockers We suggest that verapamil be used as an adjunctive therapy for CPVT patients with ongoing ventricular arrhythmias despite beta blockers and/or flecainide. The addition of a calcium channel blocker, specifically verapamil, appears to provide some additional benefit in patients with ongoing symptomatic arrhythmias. Two small nonrandomized studies have shown a reduction in the amount of ventricular arrhythmias following the addition of verapamil to beta blocker therapy [51,52]. In a crossover study of exercise testing in six CPVT patients on beta blocker therapy, verapamil reduced the number of isolated and successive premature ventricular complexes (PVCs) during exercise by an average of 76 percent [51]. PVCs appeared later and at higher heart rate during verapamil than at baseline (119 versus 127 bpm). In a study of five patients with CPVT and one with hypertrophic cardiomyopathy/exercise- induced ventricular ectopy, verapamil in addition to beta blocker therapy was studied on exercise stress testing. The number of average ventricular ectopic beats decreased from 78 to 6 beats [52]. Sympathetic denervation For patients with CPVT who remain symptomatic after maximal tolerated medical therapy, we suggest left cardiac sympathetic denervation (LCSD). Side effects from sympathetic denervation are common, although overall patient satisfaction following surgery is high. The rationale for and description of LCSD are described separately. (See "Congenital long QT syndrome: Treatment", section on 'Left cardiac sympathetic denervation'.) Data from several observational studies suggest a role for PCSD in patients with refractory CPVT [12,53-55]. Among 63 patients with CPVT who had LCSD for either secondary or primary prevention, the one- and two-year cumulative event-free survival rates were 87 and 81 percent [55]. Additional findings included: The nine primary prevention patients remained free of major cardiac events. Of the 54 secondary prevention patients, 13 had at least one recurrence, no patients had aborted cardiac arrest, two patients had syncope, 10 patients had 1 appropriate ICD discharges, and one patient died suddenly. The percentage of patients with major cardiac events despite optimal medical therapy was reduced from 100 to 32. Among 29 patients with an ICD, the rate of shocks dropped from 3.6 to 0.6 shocks per person per year. https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 11/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Patients with an incomplete LCSD were more likely to experience major cardiac events after LCSD (71 versus 17 percent) compared with those with a complete LCSD. While sympathetic denervation can successfully treat CPVT, side effects following the procedure are common. Among 44 patients who underwent LCSD (including patients with CPVT and long QT syndrome), 42 (95 percent) reported postoperative side effects including left-sided dryness, unilateral facial flushing, contralateral hyperhidrosis, and differential hand temperatures [56]. In spite of the side effects, the vast majority of patients were satisfied and felt safer following the procedure. Low-risk patients For CPVT patients who have not had a cardiac arrest, syncope, or sustained VT or VF, we recommend starting beta blocker therapy. (See 'Beta blockers' above.) After starting a beta blocker, patients must be closely followed for any recurrent spontaneous or stress-induced ventricular arrythmias after several weeks of therapy. If there are no recurrent ventricular arrythmias, we recommend continuing medical therapy and periodic outpatient follow-up. (See 'Monitoring for recurrent ventricular arrythmias' above.) If there is any recurrent ventricular arrythmia in low-risk patients once beta blockers have been started, we believe this now places them in a high-risk category, and thus we recommend ICD placement and initiation of flecainide. Specific subsequent treatment steps are outlined above (see 'High-risk patients' above) and in the algorithm ( algorithm 1). Management considerations in patients with COVID-19 Patients with severe COVID-19 disease may require circulatory support with catecholamines. Such therapy may provoke arrhythmias in patients with CPVT or among previously undiagnosed patients. In this situation, use of agents with alpha- and beta-stimulating properties, including epinephrine, should be avoided or used only when the potential benefits outweigh the risks [57]. (See "COVID-19: Arrhythmias and conduction system disease" and "COVID-19: Management of the intubated adult".) Management of genotype positive, phenotype negative patients For patients without clinical manifestations who are diagnosed in childhood based upon genetic analysis, we suggest the use of beta blockers. There are minimal data available to guide the long-term management of genotype-positive, phenotype-negative patients who are diagnosed solely based upon genetic screening. Expert opinion differs slightly on the long-term role of beta blocker therapy, based upon the age at diagnosis: https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 12/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Expert opinion supports the use of beta blockers in patients without clinical manifestations who are diagnosed in childhood based upon genetic analysis [38]. The usefulness and/or efficacy of beta blockers is less well established in patients without clinical evidence of arrhythmias who are diagnosed in adulthood based upon genetic analysis [38]. SOCIETY GUIDELINE LINKS Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Inherited arrhythmia syndromes" and "Society guideline links: Ventricular arrhythmias" and "Society guideline links: Cardiac implantable electronic devices".) SUMMARY AND RECOMMENDATIONS Definition Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic disorder that presents as familial as well as sporadic cases. Genetics Pathogenic variants in the ryanodine receptor and calsequestrin 2 protein are found in 70 percent of people with CPVT. Other pathogenic variants can cause CPVT, but they are less common. (See 'Genetics' above.) Clinical presentation and risk factors CPVT occurs in the absence of structural heart disease and typically presents in adolescence. The clinical presentation of CPVT is variable; some patients are asymptomatic and identified as part of family screening. Symptomatic patients typically present with syncope or cardiac arrest due to ventricular tachycardia (VT) or ventricular fibrillation (VF) precipitated by emotional or physical stress. (See 'Clinical presentation' above.) Risk factors for sudden death include documented VF, a family history of sudden death, and onset of symptoms in childhood. (See 'Epidemiology' above.) Diagnosis CPVT is diagnosed by an exercise stress test that shows increased frequency of nonsustained or sustained VT during exercise or recovery. In patients with a suspicious clinical presentation or pedigree, appropriate genetic testing can provide additional diagnostic support. (See 'Diagnostic testing and diagnosis' above.) https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 13/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate Acute management The acute management of patients with CPVT (or suspected CPVT) includes: Patients with polymorphic VT who are hemodynamically unstable or become pulseless require prompt treatment with electrical cardioversion/defibrillation. (See "Overview of the acute management of tachyarrhythmias", section on 'Wide QRS complex tachyarrhythmias'.) Propranolol is used for acute suppression of recurrent polymorphic VT. Propranolol is given as 40 mg oral doses (or appropriate weight-based dosing in children) every six hours for the first 48 hours, with additional intravenous doses as needed for recurrent breakthrough ventricular arrhythmias. (See "Electrical storm and incessant ventricular tachycardia", section on 'Initial management' and 'Beta blockers' above.) Subsequent management Management of CPVT is summarized in the algorithm ( algorithm 1). All patients - For all patients with CPVT (high and low risk), we recommend initiation of beta blocker therapy (Grade 1B). We suggest the use of long-acting nonselective beta blockers (such as nadolol) rather than short-acting or beta-1 selective beta blockers (Grade 2B). (See 'Beta blockers' above.) We advise that patients avoid strenuous exercise; however, some patients may reasonably choose to continue to participate. Appropriate cautionary measures include an emergency action plan with an automated external defibrillator immediately available. (See 'Avoidance of strenuous exercise' above and "Athletes: Overview of sudden cardiac death risk and sport participation", section on 'Inherited arrhythmia syndromes'.) Monitoring for recurrent ventricular arrythmias is done by regular device checks, exercise testing, and 24-hour Holter monitoring to confirm suppression of exercise- induced heart rate. High-risk patients are survivors of cardiac arrest (SCA), syncope, or sustained VT or VF. Others are low risk unless they have recurrent arrhythmia despite treatment with beta blockers. High-risk patients require an implantable cardioverter-defibrillator (ICD) in addition to beta blocker therapy. ICDs should not be used alone without pharmacologic therapy. https://www.uptodate.com/contents/catecholaminergic-polymorphic-ventricular-tachycardia/print 14/23 7/6/23, 3:39 PM Catecholaminergic polymorphic ventricular tachycardia - UpToDate (See 'Implantable cardioverter-defibrillators' above and "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".) For patients with continued arrythmia despite beta blocker therapy, we suggest the addition of flecainide (Grade 2C). (See 'Flecainide' above.) Therapy for refractory arrythmia or spontaneous cardiac arrest Additional treatment options for patients with refractory arrhythmias include verapamil and left sympathetic denervation. Side effects from sympathetic denervation are common, although overall patient satisfaction following surgery is high. (See 'Sympathetic denervation' above.) Genotype-positive, phenotype-negative patients For patients without clinical manifestations who are diagnosed in childhood based upon genetic analysis, we suggest the use of beta blockers (Grade 2C). (See 'Management of genotype positive, phenotype negative patients' above.) Use of UpToDate is subject to the Terms of Use. REFERENCES 1. Nguyen PT, Scheinman MM, Seger J. Polymorphous ventricular tachycardia: clinical characterization, therapy, and the QT interval. Circulation 1986; 74:340. 2. Wren C, Rowland E, Burn J, Campbell RW. Familial ventricular tachycardia: a report of four families. Br Heart J 1990; 63:169. 3. 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