Treatment Outcomes in Children With Catecholaminergic Polymorphic Ventricular Tachycardia: A Single Institutional Experience

Author's summary

Studies on neuropsychiatric manifestations and treatment outcomes in children with catecholaminergic polymorphic ventricular tachycardia in Korea were scarce. Neuropsychiatric disorders, such as intellectual disability and attention deficit hyperactivity disorder, were common. Combined with beta-blocker therapy, flecainide reduced cardiac events and left cardiac sympathetic denervation reduced ventricular arrhythmia burden. These medical advances improved recent outcomes. However, patients with a history of near-fatal cardiac events after diagnosis had a significantly increased risk of death, highlighting the need for additional proactive management and further studies.

Abstract

Background and Objectives

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening inherited arrhythmogenic disorder. Recently, RYR2, the major CPVT-causative gene, was associated with neuropsychiatric manifestations. We aimed to analyze the clinical presentations, neuropsychiatric manifestations, and treatment outcomes of children with CPVT.

Methods

We retrospectively reviewed 23 patients diagnosed with CPVT before 19 years of age. Genetic analysis, history of neuropsychiatric manifestations, changes in ventricular arrhythmia burden before and after treatment, occurrence of cardiac events, and overall survival (OS) were investigated.

Results

RYR2 variants were identified in 17 patients, and 14 were classified as pathogenic or likely pathogenic. Neuropsychiatric manifestations, including intellectual disability and attention deficit hyperactivity disorder, were identified in 10 patients (43.5%). The 5-year cardiac event-free survival rate was 31.2%, and the 10-year OS rate was 73.1%. Patients diagnosed since 2009 had a higher cardiac event-free survival rate than those diagnosed before 2009 (p=0.0028). Combined beta-blocker and flecainide therapy demonstrated a lower risk of cardiac events than beta-blocker monotherapy (hazard ratio [HR], 0.08; 95% confidence interval [CI], 0.02–0.38; p=0.002). Left cardiac sympathetic denervation (LCSD) reduced the ventricular arrhythmia burden in Holter monitoring. Occurrence of near-fatal cardiac events after diagnosis was an independent predictor of death (HR, 33.40; 95% CI, 6.23–179.95; p<0.001).

Conclusions

Neuropsychiatric manifestations are common in children with CPVT. Flecainide and/or LCSD, when added to beta-blocker therapy, reduce the ventricular arrhythmia burden and cardiac events, thereby improving treatment outcomes in recent years.

Graphical Abstract

INTRODUCTION

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by polymorphic ventricular tachyarrhythmias, which are triggered by physical or emotional stress in the absence of structural heart disease.¹⁾ It has a highly malignant clinical course and is associated with a risk of sudden cardiac death despite proactive medical treatment, including the use of non-selective beta-blockers, flecainide, and left cardiac sympathetic denervation (LCSD).²⁾,³⁾ Genetic alterations in RYR2, CASQ2, TRDN, TECRL, and CALM1–3 have been identified that contribute to inappropriate release of calcium from the sarcoplasmic reticulum, ultimately leading to the development of CPVT.⁴⁾

The cardiac ryanodine receptor (RYR2), in which gain-of-function variants are identified in 60–70% of patients with CPVT, is abundantly expressed not only in the heart but also in the brain.⁴⁾,⁵⁾ Specifically, it is found in regions such as the hippocampus and neocortex, which are crucial for learning, memory, and cognition. Recent experimental and clinical studies have demonstrated that RYR2 variants are linked to intellectual disability, seizures, and other neurodevelopmental disorders, irrespective of their impact on cardiac arrhythmias.⁶⁾,⁷⁾,⁸⁾,⁹⁾

Since our center reported a case series in 2000, there have been no subsequent studies on pediatric patients with CPVT in Korea.¹⁰⁾ This study aimed to analyze the clinical presentations, neuropsychiatric manifestations, and treatment outcomes in pediatric patients with CPVT, with a specific focus on identifying the factors associated with the outcomes and survival after CPVT diagnosis.

METHODS

Ethical statement

Ethical approval for this study was obtained from the Institutional Review Board of Seoul National University Hospital and the requirement for informed consent was waived (approval number: 2204-160-1320).

Study population

This retrospective observational cohort study investigated patients diagnosed with CPVT before 19 years of age at Seoul National University Children’s Hospital between January 1984 and December 2021. CPVT was diagnosed in accordance with the international recommendations, specifically those regarding exertion-induced polymorphic or bidirectional ventricular tachycardia (VT).¹⁾ A total of 23 patients were included in the study (Figure 1).

Figure 1. Flowchart of the study population and treatment.

BB = beta-blocker; CPVT = catechoaminergic polymorphic ventricular tachycardia; FCN = flecainde; LCSD = left cardaic sympathetic denervation.

Genetic analysis

Genomic DNA was extracted from white blood cells in the peripheral blood. The molecular testing methods varied depending on the year of analysis. Before the second half of 2015, variant screening of the open reading frame focused on codons 77–466 (N-terminus), codons 3778–4201 (Ca2+-binding domain), and transmembrane domains including codons 4497–4959 (C-terminus) through the amplification of critical domains of RYR2 using polymerase chain reaction and Sanger sequencing. Variants identified during this period were re-evaluated using VarSome (https://varsome.com; accessed February 28, 2023) with the integration of established clinical data. In the latter half of 2015, we initiated the application of a next generation sequencing-based gene panel test comprising RYR2 and other arrhythmia-associated genes. The gene panel initially comprised RYR2, AKAP9, ANK2, CACNA1C, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, and SNTA1. In September 2017, it was expanded to include 16 additional genes: CACNB2, CASQ2, DES, DSC2, DSG2, DSP, GPD1L, HCN4, JUP, KCNE3, PKP2, SCN1B, SCN3B, SLMAP, TGFB3, and TMEM43. All pathogenic or likely pathogenic variants identified by the gene panel sequencing were validated by Sanger sequencing. The clinical significance of each variant was classified according to the American College of Medical Genetics and Genomics recommendations.¹¹⁾

Data collection

Comprehensive medical histories were collected by reviewing the patients' medical records, along with findings from 12-lead electrocardiogram, 24-hour Holter monitoring, treadmill test, and echocardiogram. The causes and dates of death of the patients were accurately obtained from Statistics Korea.

Intellectual disabilities are characterized by notable impairments in both the intellectual capability (with an intelligence quotient of approximately 70 or lower) and adaptive behavior. To identify intellectual disabilities and other neurodevelopmental disorders, we confirmed whether the patient had undergone assessments at the psychiatry department of our institution or whether there was any mention of evaluations conducted at other psychiatric clinics in the medical records. Patients who had not experienced an aborted cardiac arrest (ACA) and those who were suspected of having an intellectual disability prior to the occurrence of an ACA were evaluated. The outcomes of the Korean Wechsler Intelligence Scale for Children and additional neurocognitive function assessments were assessed. Brain computed tomography and magnetic resonance imaging scans were also reviewed. The presence of epilepsy treated with antiepileptic drugs before the CPVT diagnosis was also assessed.

Outcomes

To assess the impact of flecainide and LCSD on the burden of ventricular arrhythmia, we conducted comparisons between Holter monitoring and treadmill test results conducted within three months before initiating flecainide or LCSD and within six months after implementing flecainide or LCSD. In the Holter monitoring, we examined the frequency of premature ventricular contractions (PVCs). In the treadmill test, we used the quantified ventricular arrhythmia score for comparison: 1) absent or isolated PVC, 2) bigeminal PVCs, 3) couplets, and 4) non-sustained VT.

The treatment outcomes were assessed based on the first occurrence of a cardiac event or death during the course of treatment. A cardiac event was defined as a composite of presumed cardiac death, ACA, appropriate implantable cardioverter-defibrillator (ICD) shock, or syncope of (probable) cardiac origin. A near-fatal cardiac event was defined as either an ACA or appropriate ICD shock. ACA was specified as requiring cardiopulmonary resuscitation, with or without external defibrillation. The follow-up period was defined as the interval from the initial clinical diagnosis of CPVT to the most recent outpatient follow-up or date of death.

Statistical analysis

Categorical variables are presented as frequencies and percentages, while continuous variables are presented as means with standard deviation for normally distributed data and medians with interquartile range (IQR) for non-normally distributed data. The paired Wilcoxon signed-rank test was used to compare ordinal and continuous variables, whereas the McNemar’s test was applied for binary variables. The visual representation of cardiac event-free survival and overall survival (OS) is presented using Kaplan–Meier curves. We used the log-rank test to compare the survival curves of patients diagnosed with CPVT before and since 2009, reflecting the implementation of LCSD for patients with CPVT at our center from that year. The predictors of cardiac event-free survival and OS were identified using the Cox proportional hazards model. The analyzed variables included sex, age at diagnosis, use of flecainide, and LCSD. Near-fatal cardiac events during treatment were incorporated as an additional variable in the analysis of OS. The use of flecainide, LCSD, and near-fatal cardiac events during treatment were considered as time-dependent covariates in this analysis. Initially, a univariable analysis was performed, followed by a multivariable analysis that incorporated the variables with a p value <0.20 in the univariable analysis. A p value <0.05 was considered statistically significant. All analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, USA) and R software version 3.6.1 (R Project for Statistical Computing, Vienna, Austria).

RESULTS

Patient characteristics

A total of 23 patients clinically diagnosed with CPVT were included in this study. Baseline characteristics of the study population are summarized in Table 1. All patients were probands. Five patients (21.7%) survived after a cardiac arrest before the diagnosis of CPVT. Through family history assessment, a history of sudden cardiac death or ACA was found in a first-degree relative in 2 patients, a second-degree relative in one patient, and a third-degree relative in 1 patient.

Table 1. Clinical characteristics of the study population.

Characteristics			Values
Male sex			16 (69.6)
Proband			23 (100.0)
Age at first symptom (year)			7.2±3.0
Age at diagnosis (year)			10.5±3.3
First symptom
	Syncope		19 (82.6)
	ACA		3 (13.0)
	Other		1 (4.3)
Family history of ACA or sudden cardiac death			4 (17.4)
Genetic test
	RYR2 mutation		17 (73.9)
		Pathogenic	6 (26.1)
		Likely pathogenic	8 (34.8)
		Uncertain significance	3 (13.0)
	Not identified		1 (4.3)
	Not performed		5 (21.7)
Treatment at last follow-up
	Beta blocker		23 (100.0)
	Flecainide		17 (73.9)
	Implantable cardioverter-defibrillator		2 (8.7)
	Left cardiac sympathetic denervation		15 (65.2)
Treatment outcomes
	Syncope		16 (69.6)
	ACA		10 (43.5)
	Appropriate implantable cardioverter-defibrillator shock		2 (8.7)
	Death		5 (21.7)

Values are presented as mean ± standard deviation or number (%).

ACA = aborted cardiac arrest.

Genetic analysis was conducted in 18 patients, of whom 17 underwent the analysis at our institution and one at another. RYR2 variants were identified in 17 patients, of which seven were discovered through the gene panel sequencing and 10 through Sanger sequencing of focused regions in the RYR2 gene. Among these variants, 14 were classified as pathogenic or likely pathogenic. Parental screening in five families yielded negative results, indicating that these variants were de novo. Five patients had six additional gene variants associated with genetic arrhythmias. None of these genes, except TRDN, have been directly associated with CPVT. Considering that TRDN-related CPVT is inherited in an autosomal recessive manner, the identified heterozygous TRDN variant, c.1620A>G, p.Ile540Met, is also not the cause of CPVT. Furthermore, these six additional variants were all classified as variants of unknown significance, and there were no pathogenic or likely pathogenic variants. Detailed information about these variants, other than the RYR2 variants, is provided in Supplementary Table 1.

The treatment flow is illustrated in Figure 1. Seven patients were already receiving beta-blocker treatment at the time of CPVT diagnosis, while the remaining patients commenced the therapy within one month of the diagnosis. Three patients were prescribed non-selective beta-blockers, such as propranolol and nadolol, while 19 were prescribed selective beta-blockers, such as atenolol. One patient was taking non-selective and selective beta-blockers concurrently. In addition to beta-blockers, 17 patients received flecainide. Oral verapamil was administered for a period of time in three patients before the introduction of flecainide for CPVT therapy; currently, none of the patients are continuing this treatment. Among the 15 patients who underwent LCSD, sympathicotomy at various levels, primarily T2–T5, was performed in 12 patients, while stellate ganglion (T1) resection was performed in only two patients because of concerns regarding adverse events, including compensatory hyperhidrosis. An ICD was implanted in two patients, one of whom frequently experienced syncope despite beta-blocker therapy and the other who had ACAs despite receiving LCSD along with beta-blocker and flecainide therapy. Appropriate ICD shock was administered twice to one of these patients and once to the other. Additionally, one of the patients suffered an electrical storm due to inappropriate shock therapy for polymorphic VT (Figure 2). Both patients are currently treated with LCSD, beta-blockers, and flecainide, and the ICD is programmed with a sufficient detection period and specific shock therapy for ventricular fibrillation.

Figure 2. Typical bidirectional polymorphic VT was observed during Holter monitoring, and subsequently, implantable cardioverter-defibrillator shock therapy (blue arrow) was delivered. However, the VT was not terminated; instead, it accelerated.

pVT = polymorphic ventricular tachycardia; VE = ventricular ectopy; VT = ventricular tachycardia.

Neuropsychiatric manifestations

Intellectual disability or attention deficit hyperactivity disorder (ADHD) were identified in 10 patients, with seven individuals having intellectual disability and eight individuals exhibiting ADHD (Table 2). Two patients with a history of ACA underwent psychiatric evaluation. One had pre-existing intellectual impairment and attended special classes, and the other struggled with academic focus, was identified as needing special education, and attended supportive classes alongside regular classes prior to the cardiac event. Five patients were considered to have epilepsy and received antiepileptic drugs before the diagnosis of CPVT. Among these, 2 had intellectual disabilities, 1 had both intellectual disability and ADHD, and the remaining 2 did not exhibit any neuropsychiatric manifestations. Following the diagnosis and treatment of CPVT, 4 patients discontinued antiepileptic drugs, while 1 patient continued antiepileptic medication due to persistent electroencephalogram abnormalities.

Table 2. Neuropsychiatric manifestations in patients with CPVT.

Case	Sex	Age at CPVT diagnosis (year)	RYR2 variant	ACA before psychiatric evaluation	Neuropsychiatric manifestation	Degree of ID	Brain imaging
1	M	17.2	c.11995A>G	Yes	Intellectual disability	Mild	Normal MRI
2	M	8.8	c.508T>C	No	ADHD		Not performed
3	M	6.3	c.14569A>G	No	Intellectual disability, ADHD	Mild	Normal MRI
4	M	10.0	c.7420A>G	Yes	Intellectual disability, ADHD	Mild	Normal CT
5	F	8.1	c.14284C>T	No	ADHD		Normal CT
6	M	16.4	c.12533A>G	No	Intellectual disability, ADHD	Mild	Normal MRI
7	F	11.7	c.14162A>C	No	Intellectual disability, ADHD	No record	Normal MRI
8	M	6.6	Not performed	No	Intellectual disability	Mild	Not performed
9	F	10.7	c.12401G>T	No	ADHD		Normal MRI
10	F	13.9	c.12313C>T	No	Intellectual disability, ADHD	Mild → severe	Normal MRI

ACA = aborted cardiac arrest; ADHD = attention deficit hyperactivity disorder; CPVT = catecholaminergic polymorphic ventricular tachycardia; CT = computed tomography; F = female; ID = intellectual disability; M = male; MRI = magnetic resonance imaging.

Therapeutic effect of additional flecainide or left cardiac sympathetic denervation on ventricular arrhythmia

In the treadmill test, there were no statistically significant changes in ventricular arrhythmia scores between baseline and additional flecainide therapy among the 4 patients (2.50 [IQR, 1.25–3.75] vs. 2.00 [IQR, 1.25–3.50]; p=0.317); similarly, there were no significant changes in ventricular arrhythmia scores between baseline and after LCSD among the six patients (3.50 [IQR, 2.00–4.00] vs. 2.50 [IQR, 1.75–3.25]; p=0.180). However, in Holter monitoring, the reduction in PVC burden as a result of flecainide therapy was not statistically significant among the four patients (0.8082% [IQR, 0.1320–3.5124] vs. 0.6759% [IQR, 0.0808–2.2116]; p=0.144). Among the two patients who showed VT at baseline, one did not exhibit VT, and the other demonstrated reduced VT burden after flecainide therapy. Moreover, there was a statistically significant reduction in PVC burden attributed to LCSD in Holter monitoring among the eight patients (0.7994% [IQR, 0.0479–1.1938] vs. 0.0103% [IQR, 0.0005–0.5544]; p=0.018). Among the four patients who had VT at baseline, three did not exhibit VT, and one demonstrated reduced VT burden after LCSD.

Factors for cardiac event-free survival and overall survival

Among the 23 patients included in this study, one patient was lost to follow-up, while the remaining patients continued to attend regular outpatient clinic visits throughout the study period. During a follow-up period of 9.4±6.5 years, 17 patients (73.9%) developed cardiac events and 10 patients (43.5%) experienced an ACA. Five patients (21.7%) died within 8.1±3.9 years after CPVT diagnosis, and the median age at death was 20.1 years (IQR, 13.6–20.1). Three patients died while on beta-blocker therapy, 1 died while receiving beta-blockers along with LCSD, and 1 died while undergoing treatment with beta-blockers and flecainide in addition to LCSD (Supplementary Table 2). Four patients experienced near-fatal cardiac events before their deaths, and 2 of these patients suffered from hypoxic-ischemic encephalopathy following these events. In three patients, poor medication compliance was documented at least once in the medical records, or they demonstrated irregular attendance at outpatient visits; however, the exact adherence to medication at the time of death is not fully known. Additionally, three patients lived in regions far from our institution, which may have affected their medical adherence.

The 5-year and 10-year cardiac event-free survival rates were 31.2% and 9.4%, respectively (Figure 3). The 10-year OS rate was 73.1%. Patients diagnosed before 2009 and since 2009 had a 5-year cardiac event-free survival rate of 10.0% and 50.1%, respectively (p=0.0028 by log-rank test) (Figure 4). Patients diagnosed before 2009 had a 10-year OS rate of 60.0%, whereas there was no mortality among patients diagnosed since 2009, although this was not statistically significant (p=0.11 by log-rank test). The predictors of cardiac events and death, determined using Cox proportional hazards analysis, are presented in Table 3. The results of the multivariable analysis indicated that combination therapy with beta-blocker and flecainide was associated with a significantly lower risk of cardiac events than beta-blocker monotherapy (hazard ratio [HR], 0.08; 95% confidence interval [CI], 0.02–0.38; p=0.002). A history of near-fatal cardiac events during treatment was identified as an independent predictor of death (HR, 33.40; 95% CI, 6.23–179.95; p<0.001).

Figure 3. Cardiac event-free survival and overall survival. Kaplan–Meier estimates of (A) cumulative cardiac event-free survival and (B) OS in patients with catecholaminergic polymorphic ventricular tachycardia after diagnosis.

Figure 4. Cardiac event-free survival and overall survival according to year of diagnosis. Kaplan–Meier estimates of (A) cumulative cardiac event-free survival and (B) OS according to year of diagnosis in patients with catecholaminergic polymorphic ventricular tachycardia after diagnosis.

Table 3. Time-dependent Cox proportional hazards analysis results for predictors of cardiac events and mortality after CPVT diagnosis.

Variable	Cardiac event				Mortality
	Univariable analysis		Multivariable analysis		Univariable analysis		Multivariable analysis
	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value	HR (95% CI)	p value
Sex	1.37 (0.47–3.98)	0.568			1.61 (0.31–8.34)	0.570
Age at diagnosis	0.93 (0.79–1.10)	0.411			0.86 (0.70–1.06)	0.163	0.79 (0.61–1.01)	0.055
Flecainide	0.06 (0.01–0.30)	<0.001	0.08 (0.02–0.38)	0.002	0.21 (0.03–1.59)	0.130	0.27 (0.04–2.12)	0.214
LCSD	0.26 (0.07–1.03)	0.055	0.38 (0.09–1.54)	0.174	0.52 (0.10–2.74)	0.444
Near-fatal cardiac event after diagnosis					13.97 (2.55–76.39)	0.002	33.40 (6.23–179.95)	<0.001

CI = confidence interval; CPVT = catecholaminergic polymorphic ventricular tachycardia; HR = hazard ratio; LCSD = left cardiac sympathetic denervation.

DISCUSSION

The key findings of this study are as follows. First, RYR2 variants were detected in a substantial proportion of pediatric patients diagnosed with CPVT. Second, a significant proportion of patients with CPVT exhibit a high frequency of neuropsychiatric manifestations. Third, when combined with beta-blocker therapy, flecainide reduced cardiac events and LCSD reduced the ventricular arrhythmia burden. Fourth, a high mortality rate was observed in patients with CPVT; however, those diagnosed in recent years demonstrated an improvement in treatment outcomes. Lastly, patients with a history of near-fatal cardiac events after CPVT diagnosis had a higher risk of death.

This study found a high prevalence of RYR2 variants, with 14 patients having pathogenic or likely pathogenic variants, which is consistent with the findings of previous studies.¹²⁾,¹³⁾ Additionally, three patients with a definite CPVT phenotype were found to have variants of uncertain significance (VUS). The cardiac ryanodine receptor, a large protein comprising 4967 amino acids with a molecular weight of 565 kDa, has a background rare variant rate in the general population ranging from 3% to 6%.¹⁴⁾,¹⁵⁾ A significant number of rare RYR2 variants, including those detected in patients with definite CPVT phenotypes, still fall under the category of VUS. Recently, a clinical CPVT score system was employed through a phenotype-enhanced variant readjudication approach, reducing the number of VUS by reclassifying these variants.⁴⁾,¹⁶⁾

The prevalence of neuropsychiatric manifestations in patients with CPVT was observed to be substantial, which aligns with the findings of previous studies.⁷⁾,¹⁷⁾ A recent retrospective multicenter observational cohort study demonstrated that the prevalence of intellectual disability in patients with RYR2-associated CPVT was 8%, which exceeds the prevalence in the general population.⁷⁾ Furthermore, an animal study using a murine model showed that the heterozygous RyR2 R4496C^+/− variant increased neuronal excitability of hippocampal CA1 neurons and impaired hippocampal long-term potentiation, resulting in deficits in learning and memory.⁹⁾ Another experimental study revealed that mice carrying the RyR2 R2474S^+/− variant exhibited tonic-clonic seizures regardless of the presence of arrhythmia.⁶⁾ Additionally, Yap et al.⁸⁾ reported a 32-year-old woman with the RYR2 A77T^+/− variant who presented with a generalized epilepsy without any prior cardiac symptoms. The association of neuropsychiatric manifestations with CPVT underscores the need for early neuropsychiatric evaluation of patients and timely intervention. Providing comprehensive information on these potential neuropsychiatric issues to parents, families, and social support networks is essential to facilitate patients’ adaptation to social and educational environments. This approach should ensure access to specialized educational resources when required and promote sustained medical adherence, supported by family involvement, extending into adulthood.

In this study, flecainide did not significantly reduce the ventricular arrhythmia burden in Holter monitoring or treadmill tests, but was effective in reducing the occurrence of cardiac events. Previous studies have demonstrated that the addition of flecainide to beta-blocker therapy successfully reduced ventricular arrhythmia during exercise and prevented arrhythmia events in both genotype-positive and genotype-negative patients with CPVT.¹⁸⁾,¹⁹⁾ A multicenter randomized clinical crossover trial also showed that combination therapy with flecainide and beta-blockers significantly reduced the incidence of ventricular arrhythmia during exercise compared to beta-blockers alone.²⁰⁾ Flecainide directly blocks the cardiac ryanodine receptor.²¹⁾ It also has sodium channel-blocking properties and enhances Na+/Ca2+ exchanger activity, as demonstrated in vitro studies; flecainide was shown to dramatically reduce ventricular arrhythmia in a Casq2^−/− murine model of CPVT.²²⁾ Unlike patients included in previous studies, some patients in this study had already undergone LCSD before commencing flecainide therapy, which seemed to mitigate the effect of flecainide on changes in the ventricular arrhythmia burden. This study found that flecainide therapy was an independent factor for reducing the occurrence of cardiac events, thus supporting the currently adopted recommendation of flecainide as an additional treatment option for patients with CPVT.²³⁾

In this study, LCSD significantly reduced the ventricular arrhythmia burden in Holter monitoring but was not effective in reducing cardiac events. Several studies have demonstrated that LCSD decreases the occurrence of major cardiac events among symptomatic patients with CPVT.²⁴⁾,²⁵⁾ De Ferrari et al.²⁴⁾ revealed that the percentage of patients with major cardiac events decreased from 86% to 21% after LCSD (p<0.001). In a group of 29 patients with ICDs, LCSD led to a significant 93% reduction in the average shock rate and a notable decrease in the proportion of patients experiencing electrical storms from 38% to 14%. In the present study, there was a relatively low frequency of stellate ganglion (T1) lower part resections, which might have contributed to the inability of LCSD to significantly reduce cardiac events in patients with CPVT.²⁴⁾,²⁶⁾

The mortality rate among patients with CPVT was higher than that reported in previous studies.²⁾,³⁾,¹⁷⁾ However, treatment outcomes showed an improvement in patients diagnosed since 2009, which may be attributed to more active recommendations regarding lifestyle changes, including the avoidance of strenuous physical activity and stressful environments, as well as the introduction of combination therapies, such as LCSD in 2009 and flecainide in 2011. Importantly, a history of near-fatal cardiac events after CPVT diagnosis was found to be an independent predictor of death in patients with CPVT. Moreover, three patients who received LCSD along with beta-blocker and flecainide therapy still experienced near-fatal or fatal events. This finding may support the current recommendation, which advocates the implantation of an ICD in patients with CPVT who have experienced an ACA while being on a combination of beta-blockers and flecainide.²³⁾ However, the pain and anxiety resulting from an ICD shock can further stimulate the release of catecholamines, possibly leading to the occurrence of electrical storms. An ICD shock is also ineffective in terminating VT, although it is usually effective in restoring sinus rhythm from ventricular fibrillation.²⁷⁾,²⁸⁾ Previous studies have also reported fatalities among patients who had an ICD, which were attributable to electrical storms, along with a substantial incidence of inappropriate shocks and device-related complications.²⁷⁾,²⁹⁾ Therefore, it is essential to program ICDs meticulously, incorporating long delays and high heart rates before shock delivery.

This study has some limitations, as it was retrospective and conducted in a single institution with a small number of patients and events, which resulted in low statistical power. Additionally, genetic testing was not uniformly performed in all patients, with some only undergoing testing for genes other than RYR2. Family testing was also limited. The analysis using treadmill tests and Holter monitoring to evaluate the effects of flecainide and LCSD is limited due to the small number of patients with complete data available for both before and after treatment. Treatment strategies were dependent on the era of diagnosis, such as the introduction of LCSD in 2009 and flecainide in 2011, the physician’s clinical judgment, and the status of the patient's arrhythmia control, which might have caused cause selection bias. While recent findings suggest that non-selective beta-blockers, such as nadolol, may be more effective than selective beta-blockers, they were unavailable for a part of the study period, leading to the predominant use of selective beta-blockers.³⁰⁾ Finally, medication adherence is an important factor that influences cardiac events and mortality associated with channelopathy; however, this was not evaluated in this study.

Neuropsychiatric manifestations such as intellectual disability and ADHD are relatively common in children with CPVT. Combining beta-blockers with flecainide and/or LCSD is effective in reducing the burden of ventricular arrhythmias and cardiac events and has led to improved treatment outcomes in recent years. However, patients with a history of near-fatal cardiac events after diagnosis remain at a significant risk of death, underscoring the need for additional proactive management and further studies.

SUPPLEMENTARY MATERIALS

Supplementary Table 1

Variants other than those of RYR2 identified through gene panel sequencing in patients with catecholaminergic polymorphic ventricular tachycardia

Supplementary Table 2

Clinical characteristics of deceased patients with catecholaminergic polymorphic ventricular tachycardia