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Challenging the phenotype is key: the example of Catecholaminergic Polymorphic Ventricular Tachycardia

Silvia Castelletti  ; Istituto Auxologico Italiano IRCCS  ; SportsCardiology Unit; Milan, Italy 

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) is an inherited cardiac disorder characterized by adrenergically-induced life-threatening arrhythmias. It usually manifests in childhood or early adolescence, with a mortality rate in severely untreated patients up to 50% before the age of 20 (1, 2). The prevalence is estimated to be 1:10000 and the typical symptoms are syncopal episodes triggered by exercise or acute emotion due to ventricular tachycardia. The basal ECG is normal. As the heart is structurally normal, also the echocardiogram is normal. As such, the patients may report just dizziness or palpitations during exercise or emotion because the non-sustained ventricular (NSVT) are well tolerated. Ventricular arrhythmias are typically polymorphic: a bidirectional VT is considered the hallmark of the disease. The diagnosis is performed with an exercise stress test. Typically, premature ventricular contractions (PVCs) appear at a heart rate around 100-110 bpm. They increase in frequency and complexity with the increase in workload and quickly disappear when the exercise is interrupted. Genetic testing has a high yield in patients with a typical phenotype (around 60%) (1, 3). The genetic substrate includes mutations in genes involved in calcium handling, causing an excess calcium leak from the sarcoplasmic reticulum and electrical instability. Among all, mutations in the RyR2 gene encounter approximately 60-70% (3). The main differential diagnosis is represented by the Andersen-Tawil Syndrome (ATS, LQT7) characterized by the triad of bidirectional ventricular arrhythmias, dysmorphic features and periodic paralysis. However, only one or none of the classic triad may be present (1, 3). To guide the clinical diagnosis and the genetic variants classification, a score has been created and validated: according to this score, in patients without a genetic test with a score ≥ 3.5 the likelihood of CPVT1 (i.e. RYR2-mediated CPVT) is at least 60% (4). As lifestyle changes (ie from competitive sports and strenuous exercise) and therapy are highly efficient, the correct diagnosis is crucial. 

As such, the paper by Peltenburg et al underlies the need for multiple exercise stress test (EST) for both the diagnosis and prognosis of patients with CPVT (5). They studied 349 EST performed within 18 months, on the same protocol and without or on the exact same treatment, from 104 CPVT patients under stable treatment. The authors assessed the occurrence and severity of ventricular arrhythmias, defined as the maximum ventricular arrhythmia score (VAS) (0= no PVC, 1= isolated PVCs, 2= bigeminal PVCs, 3= couplets, 4= NSVT), the heart rate at the first PVC (HR-PVC) and the heart rate at 1 minute in the recovery phase (HR-recovery) and the delta-VAS (ΔVAS), defined as the absolute difference in VAS between the paired ESTs. They found that 42% of EST1 and 39% of EST2 had VAS 0 (no PVC), whilst only 4.3% of EST1 and 3.7% of EST2 had VAS4 . The authors reported 51 of ΔVAS= 0 (reflecting the same VAS on both ESTs), and 31% of ΔVAS= 1 (change of 1 VAS category between the paired ESTs). The proportion ΔVAS<2 was highest in the EST-pairs performed without treatment Of the EST-pairs with a VAS above 0, substantial repeatability and almost perfect repeatability were noted for the HR-PVC and the HR-recovery, respectively (5).  

Despite the limitations of the retrospective design, this study underlies how, even though the intra-patient variability is low, it is important not to exclude the CPVT diagnosis based on a single EST. 

It also suggests that the risk for arrhythmic events is low in those patients who don’t show any ventricular ectopy. On the other hand, a sudden increase in VAS of at least two categories compared with the previous EST under identical circumstances should guide a prompt scaling-up of the patient therapy. 

An open question remains the best exercise stress test protocol, nevertheless, this study provides a simple and valuable tool to guide the clinician in the diagnosis and treatment of CPVT patients, which may also be used as a surrogate endpoint to test the effect of potential new medications or treatments. 



Zeppenfeld K et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Developed by the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC) Endorsed by the Association for European Paediatric and Congenital Cardiology (AEPC). Eur Heart J. 2022;43(40):3997–4126. 

Leinonen JT et al. The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia? Intern J Cardiol. 2018;250: 139-145.  

Wilde AA et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases Europace. 2022;24(8):1307-1367. doi:10.1093/europace/euac030. 

Giudicessi JR et al Assessment and Validation of a Phenotype-Enhanced Variant Classification Framework to Promote or Demote RYR2 Missense Variants of Uncertain Significance. Circ Genom Precis Med. 2019;12(5):e002510. doi:10.1161/CIRCGEN.119.002510. 

Peltenburg PJ et al. Repeatability of ventricular arrhythmia characteristics on the exercise-stress test in RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Europace. 2022 Nov 12;euac177. doi: 10.1093/europace/euac177. Online ahead of print. 

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.