Catecholaminergic polymorphic ventricular tachycardia
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- Ylänen, K., Poutanen, T., Hiippala, A. et al. Eur J Pediatr (2010) 169: 535. doi:10.1007/s00431-010-1154-2
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Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that causes syncopal episodes related with stress or emotion and even sudden cardiac deaths. Signs and symptoms usually begin in childhood. A suspicion of CPVT should be kept in mind when a child or an adolescent suddenly loses consciousness, particularly if this happens upon physical exercise or sudden mental stress. During the past decade, the knowledge of CPVT genetics and physiology has increased. Exercise testing is essential when suspecting arrhythmogenic origin of syncope, and in the case of CPVT, it may be even more sensitive than Holter monitoring. Beta-antiadrenergic medication can substantially decrease the mortality associated with CPVT. Asymptomatic patients with known CPVT gene defects should also be treated because sudden cardiac death may be the first manifestation of the disease. An implantable cardioverter-defibrillator may also be required in the most severe CPVT cases. In this review, we summarise the current knowledge on the clinical characteristics, diagnostic, genetic and prognostic features of CPVT in children. In all, 133 publications covering 60 years were checked, and those written in English and containing ten or more, mainly paediatric CPVT cases, were included. In addition, a CPVT family with three members and delayed diagnoses until late childhood and adulthood is presented.
KeywordsArrhythmia Catecholaminergic polymorphic ventricular tachycardia Childhood Syncope
Syncopal spell is a common symptom in children. When evaluating its cause, a detailed event history and the observations by the eyewitnesses are often useful. Often, the preceding events and symptoms are compatible with a harmless vasovagal collapse. However, a syncopal spell associated with physical effort should raise a suspicion of a cardiac disorder. If the loss of consciousness is associated with convulsions, it may be misdiagnosed as epilepsy if a prolonged circulatory arrest resulted in brain ischaemia. Most structural heart diseases can be diagnosed or ruled out with echocardiography. A 12-lead electrocardiography (ECG) can reveal an underlying arrhythmogenic disorder such as long QT syndrome (LQTS) or Brugada syndrome [3, 4, 14]. However, a syncopal spell associated with physical exercise or emotional stress may be of arrhythmogenic origin despite normal findings in physical examination, ECG and echocardiography .
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but highly malignant inherited arrhythmia disorder. It is characterised by ventricular tachycardia (VT) which is polymorphic or bidirectional and induced by catecholamines triggered by physical exercise or emotional stress, typically in the absence of a structural heart disease [1, 2, 6, 8, 9, 11, 12, 16, 19]. Sudden cardiac death may be the first manifestation of CPVT [1, 19]. A standard resting ECG is usually normal [2, 6, 9, 11, 16]. An exercise stress test is essential if CPVT is suspected by symptom history.
For this review, we searched the Ovid Medline database for presumptive CPVT cases using the keyword “catecholaminergic polymorphic ventricular tachycardia”, covering the 60-year time period from 1950 to March 2009. In all, 133 hits were obtained. All abstracts were checked, and a total of seven original articles written in English with ten or more CPVT cases, consisting mainly of paediatric patients, were included in the review [1, 2, 6, 9, 11, 12, 16].
Summary of the studies published on catecholaminergic polymorphic ventricular tachycardia in children
Number of patients (female/male)
Age at onset (years)a
Age at diagnosis (years)a
Follow-up time (years)a
Heart rate at rest (bpm)a
Threshold frequency (bpm)a
Mortality among the probands
Onset of ventricular premature complexes
Onset of ventricular tachycardia
Leenhardt et al. 1995
Lahat et al. 2001
Chromosome 1p13-21 (recessive)b
Priori et al. 2002c
RyR2 gene mutations
Sumitomo et al. 2003
Allouis et al. 2005
RyR2 gene mutation
Postma et al. 2005c
RyR2 gene mutations
Celiker et al. 2009
RyR2 gene mutationd
Diagnostic studies and differential diagnosis
Symptoms and findings in catecholaminergic polymorphic ventricular tachycardia
Exercise- or emotion-related syncope or sudden death
Cardiac imaging studies:
The structure of the heart is normal
The corrected QT interval <470 ms
Sinus bradycardia is possible
24-h Holter recording and exercise stress test:
The highly reproducible progressive worsening of arrhythmias during exercise consisting of PVCs, ventricular bigeminy, salvoes of polymorphic PVCs, polymorphic or bidirectional ventricular tachycardia
Atrial arrhythmias may precede ventricular arrhythmias during exercise
Arrhythmias are seldom inducible by programmed electrical stimulation
Progressive ventricular arrhythmias may be induced in some cases by intravenous infusion of catecholamines
RyR2 gene mutations
CASQ2 gene mutations
Other possible yet unknown gene defects
Inherited arrhythmogenic cardiac disorders causing malignant ventricular tachyarrhythmias
Typical findings in the resting ECG
Catecholaminergic polymorphic ventricular tachycardia (CPVT)
Multifocal premature ventricular complexes and polymorphic ventricular tachycardia during exercise or emotional stress
Long QT syndrome (LQTS)
Prolongation of the OTc interval (>460 ms)
Arrhythmias associated with physical or emotional stress, sudden arousal or sleep
Abnormal T-wave morphology
ST elevation in the right precordial leads
Arrhythmias occurring at rest or during sleep
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)
T-wave inversion in the right precordial leads
Arrhytmias during exercise LBBB pattern during tachycardia
Structural abnormalities of the right ventricle
Short QT syndrome
Short QTc interval (<320 ms)
Outflow tract murmur due to hypertrophy of the left ventricle
Cardiac insufficiency due to dilatation of the left ventricle
CPVT can be inherited either in an autosomal dominant (CPVT1) or recessive (CPVT2) way. The more common type 1 CPVT (MIM#604772) is caused by mutations in the cardiac ryanodine receptor gene RyR2 on chromosome 1q42-q43 and is a consequence of a defective calcium release from sarcoplasmic reticulum [8, 13, 19]. In the autosomal recessive variant, type 2 CPVT (MIM#611938), the causative gene, is the cardiac calsequestrin gene CASQ2 located on chromosome 1p13-21 [6, 7]. CASQ2 is a calcium buffering protein that has an active role in the control of calcium release from sarcoplasmic reticulum to cytosol. To date, there are over 70 known mutations in RyR2 gene and seven known mutations in CASQ2 gene associated with CPVT (more information is available online at http//www.fsm.it/cardmoc/). Mutations in the RyR2 gene have been identified in around 50% and those in the CASQ2 gene in <2% of patients with CPVT [5, 12]. Other yet unknown CPVT genes are likely to exist. In the study of Priori et al. , 90% of patients with non-genotyped CPVT were women and they became symptomatic in adulthood, at 20 (mean) ± 12 (SD) years of age, whereas the respective age was 8 (mean) ± 2 (SD) years in the RyR2-associated CPVT cases.
Therapy and prognosis
The cumulative mortality of the untreated CPVT cases is 30–50% by the age of 20–30 years [8, 9, 19]. Because of the poor prognosis of untreated CPVT, drug therapy is indicated for all clinically diagnosed patients and usually also for all silent carriers of a RyR2 mutation . According to the current knowledge, beta-antiadrenergic medication is the drug of choice [2, 9, 16], and a maximal tolerated dose should be used. An implantable cardioverter-defibrillator is indicated for those patients who experience cardiac arrest, sustained VT or syncopal spell despite an adequate beta-blocker therapy . Regular medication is of uttermost importance because missing even a single dose may lead to arrhythmias and increase the risk of sudden death . Exercise stress test and Holter monitoring may help in finding the adequate dosage of the beta-antiadrenergic medication to control arrhythmias. It should be noted, though, that the absence of exercise-provoked arrhythmias does not completely exclude the risk of more severe arrhythmias. The aim of the medication is to avoid the heart rate exceeding the threshold heart rate for CPVT, and some studies have reported an almost complete prevention of cardiac events during beta-antiadrenergic medication [6, 11, 19]. However, other studies have reported a high recurrence rate of symptoms and even sudden death despite medication [2, 12, 16]. Calcium channel antagonists in combination with beta-antiadrenergic medication have been shown to significantly reduce the exercise-provoked ventricular arrhythmias in CPVT patients , but their impact in prognosis is not known.
A previously healthy 13-year-old boy fell unconscious whilst playing baseball at school. The onset was sudden, not associated with any preceding symptoms but evidently associated with a short intensive running. Unconsciousness lasted about a minute, and some convulsive movements were observed in the legs. The boy recovered spontaneously and completely. There was no known preceding trauma, infection or intoxication. A few years earlier, the boy had experienced a near-drowning situation whilst swimming, but had managed to get up from the water. He had also felt occasional chest palpitations. In the emergency room, the patient was in good general condition. The clinical neurologic and cardiologic status was normal. The blood pressure was 116/70 mmHg, and the transcutaneous oxygen saturation was 98%. The basic laboratory tests as well as the chest X-ray and the electroencephalogram were all normal. The patient was monitored at an acute paediatric ward for 2 days, and no syncope, convulsions or arrhythmias occurred. The 12-lead ECG showed sinus rhythm with 56 bpm, and the corrected QT interval was normal (380 ms). The 24-h Holter recording revealed sinus rhythm between 40 and 113 bpm, and there were neither ectopic beats nor arrhythmias. The structure and the function of the heart were found to be normal on echocardiography.
The index patient was treated with a beta-blocker, bisoprolol, at a dosage of 0.2 mg kg−1 day−1. The aim of the medication was to prevent the heart rate from exceeding 130 bpm. The efficacy of beta-blocker therapy was confirmed by serial exercise stress tests and 24-h Holter recordings. In the Holter recordings, the mean heart rate stayed between 55 and 73 bpm also during physical activities. In the exercise stress tests, the maximal heart rate decreased from 184 bpm before medication to 122 bpm during medication, showing a good response to beta-blocker therapy. Competitive sports demanding vigorous physical exercise were prohibited. During a 2-year follow-up on medication, no syncopal episodes have occurred. Clustering of CPVT in the family suggests a dominant inheritance. The RyR2 gene analysis is in progress
CPVT is an inherited cardiac arrhythmic disorder showing a malignant clinical course in the absence of structural defects in the heart. The mortality rate is high and a sudden death may occur in an otherwise healthy child or adolescent. The patients experience ventricular arrhythmias with modest exercise, emotional stress or exposure to catecholamines. In addition to the typical clinical picture, there are also reports of atypical CPVT cases with paroxysmal atrial fibrillation  or sudden deaths during sleep .
Diagnosing CPVT can be difficult especially in young children. When presumptive symptoms are encountered, an exercise ECG and Holter monitoring should be performed since CPVT cannot be diagnosed by a resting ECG or other cardiologic studies. Sometimes, the exercise-provoked arrhythmias can be demonstrated only after a delay of months or more after the first syncopal episode has occurred, emphasising the necessity of repeated exercise stress tests when there is a high suspicion of CPVT. In the case of a new CPVT diagnosis, it is essential to expand the evaluation to the rest of the family too to find other potential CPVT patients. Screening of family members by genetic testing is possible in the case of a known gene mutation. In most CPVT cases, symptoms can be prevented with beta-antiadrenergic medication. Drug treatment is indicated in all CPVT cases, including non-symptomatic patients diagnosed with a CPVT gene defect.
Conflict of interest
There is no conflict of interest.