In this post, I link to and excerpt from Catecholaminergic Polymorphic Ventricular Tachycardia Synonym: Catecholamine-Induced Polymorphic Ventricular Tachycardia (CPVT) [PubMed Abstract] [Full-Text HTML]. Initial Posting: October 14, 2004; Last Update: October 13, 2016. From GeneReviews.
All that follows is from the above resource.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by cardiac electrical instability exacerbated by acute activation of the adrenergic nervous system. If untreated the disease is highly lethal, as approximately 30% of those affected experience at least one cardiac arrest and up to 80% one or more syncopal spells.
The main clinical manifestation of CPVT is episodic syncope occurring during exercise or acute emotion. The underlying cause of these episodes is the onset of fast ventricular tachycardia (bidirectional or polymorphic). This may be associated with:
- Spontaneous recovery when these arrhythmias self-terminate,OR
- Ventricular tachycardia may degenerate into ventricular fibrillation and cause sudden death if cardiopulmonary resuscitation is not readily available.
Sudden death may be the first manifestation of the disorder in previously asymptomatic individuals (no history of syncope or dizziness) who die suddenly during exercise or while experiencing acute emotions [Priori et al 2002, Krahn et al 2005, Watanabe et al 2013].
Note: As there is no structural abnormality of the myocardium, several individuals have tolerated the arrhythmias rather well, with only mild symptoms such as dizziness or faintness. If such symptoms reproducibly recur during exercise, further clinical investigations for CPVT may be indicated.
The mean age of onset of CPVT symptoms (usually a syncopal episode) is between age seven and twelve years [Leenhardt et al 1995, Priori et al 2002, Postma et al 2005]; onset as late as the fourth decade of life has been reported.
Instances of SIDS (sudden infant death syndrome) have been associated with pathogenic variants in RYR2 [Tester et al 2007].
Other. A single case report highlighted the possible proarrhythmic effect of an insulin tolerance test (ITT), driven by severe hypokalemia and adrenergic activation secondary to the metabolic imbalance induced by the test [Binder et al 2004]. Of note, RYR2 is expressed in pancreatic beta cells responsible for insulin secretion, suggesting that altered glucose metabolism can represent a manifestation of RYR2-related CPVT [Santulli et al 2015].
CASQ2 and RYR2. Available evidence suggests that the clinical features of CASQ2– and RYR2-related CPVT are virtually identical. Lahat et al  reported a mild QT interval prolongation in their initial paper; however, this was not confirmed in subsequent reports [Postma et al 2002]. CASQ2-CPVT may be more severe and more resistant to beta-blockers; however, comparisons with large series of individuals are not available. Individuals with polymorphic VT without a “stable” QRS vector alternans are more likely to have pathogenic variants in CASQ2.
The mean penetrance of RYR2 pathogenic variants is 83% [Author, unpublished data]. Therefore, asymptomatic individuals with RYR2-related CPVT are a minority. Too few individuals with CASQ2, CALM1, and TRDN have been reported to date to allow a robust estimate of the penetrance. All described individuals do show the clinical phenotype.
CPVT has also been referred to as familial polymorphic ventricular tachycardia (FPVT).
The true prevalence of CPVT in the population is not known. An estimate of CPVT prevalence is 1:10,000.
The high prevalence of simplex cases (i.e., single occurrences in a family) and lethality at a young age suggest that the overall prevalence of CPVT is significantly lower than that of other inherited arrhythmogenic disorders such as long QT syndrome (1:7,000-1:5,000).
Genetically Related (Allelic) Disorders
CALM1 pathogenic variants also cause long QT syndrome (LQTS), epilepsy, and neurodevelopmental disorders [Crotti et al 2013]. This phenotype is compatible with the wide expression pattern of CALM1 and the finding suggests that CALM1 pathogenic variants may cause an atypical form of catecholaminergic polymorphic ventricular tachycardia (CPVT), often with QT prolongation.
CASQ2. No phenotypes other than those discussed in this GeneReview are known to be associated with CASQ2 pathogenic variants.
RYR2. Cardiac ryanodine receptor variants have been associated with “mild” arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) with exercise-induced arrhythmias [Tiso et al 2001]. In a group of 64 individuals with ARVC, RYR2 pathogenic variants were identified in 9% of individuals who did not have a pathogenic variant identified in any of the main desmosomal ARVC-related genes [Roux-Buisson et al 2014].
Large deletions of RYR2 have been linked with left ventricular non-compaction (LVNC) with [Campbell et al 2015] or without [Ohno et al 2014] CPVT. Experimental data suggest that RYR2 pathogenic variants associated with cardiomyopathies and ventricular non-compaction may have different pathophysiologic mechanisms [Tang et al 2012] or specific localization [Amador et al 2013].
TRDN pathogenic variants can cause LQTS. Five TRDN variants have been identified in 33 genetically elusive LQTS families with possible recessive pattern of inheritance [Altmann et al 2015]. Two additional pathogenic variants have been identified in two sibs who experienced recurrent cardiac arrest during exercise and presented with borderline-prolonged QT interval and atypical CPVT [Walsh et al 2016].
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. Most of the genes associated with ARVC code for desmosomal proteins. Individuals with CPVT do not have structural cardiac abnormalities. The evidence of overlapping phenotypes (see Genetically Related Disorders) calls for careful imaging assessment (echocardiogram, MRI) in all individuals with CPVT.
Short-coupled ventricular tachycardia (SC-torsade de pointes [TdP]) is a clinical entity presenting with life-threatening polymorphic ventricular arrhythmias resembling in part the pattern of arrhythmias observed in individuals with CPVT. SC-TdP presents with polymorphic ventricular tachycardia (VT) occurring in the setting of a structurally normal heart and in the absence of any overt baseline electrocardiographic abnormality. However, the onset of SC-TdP is not clearly related to adrenergic stimuli (exercise or emotion) and is not associated with the typical bidirectional pattern of CPVT-related tachycardia. Distinguishing between the two disorders is important as there is no known effective therapy for SC-TdP, whereas CPVT usually responds to beta-blocking agents.
Long QT syndrome (LQTS). Exercise-related syncope is also typically found in the LQT1 variant of LQTS. Since incomplete penetrance is possible in LQT1, some individuals may have a normal QT interval and may present with a clinical history similar to that of CPVT (exercise-related syncope and normal ECG). Unlike CPVT, LQT1 does not present with inducible arrhythmia during graded exercise (exercise stress test). The initial description of CPVT by Philippe Coumel included cases with borderline or mildly prolonged QT interval.
Andersen-Tawil syndrome (ATS, LQTS type 7) is an inherited arrhythmogenic disorder caused by mutation of KCNJ2. ATS is characterized by cardiac (QT prolongation, prominent U waves) and extra-cardiac features (distinctive facial features, periodic paralysis). The present authors and others [Postma et al 2006, Tester et al 2006] have observed that some individuals with ATS may develop bidirectional VT similar to that of CPVT. However, ATS is to be considered a distinct disorder with manifestations that may overlap with CVPT in rare instances. In ATS the presence of extracardiac manifestations, the low or absent risk of sudden death, and the lack of a direct relationship of arrhythmias to adrenergic activation distinguish it from CPVT.
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with catecholaminergic polymorphic ventricular tachycardia (CPVT), the following evaluations are recommended:
- Resting ECG
- Holter monitoring, as arrhythmias develop when heart rate increases
- Exercise stress test both for diagnosis and monitoring of therapy
- Echocardiogram and/or MRI to evaluate for structural defects
- Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations
Management of CPVT is summarized in a specific consensus document from the Heart Rhythm Association (HRS) and the European Heart Rhythm Association (EHRA) [Priori et al 2013b] (full text) and summarized in the recent version of the European Society of Cardiology (ESC) guidelines on ventricular arrhythmias [Priori et al 2015] (full text).