Patients’ descriptions in our centerClinical information and diagnosis

Table 1 summarizes six patients with CPVT diagnosed in our center, including five males and one female. They were admitted to our hospital for at least 3 times recurrent syncope, and all their symptoms were triggered by exercise or emotional stress and three patients presented with cardiac arrest during attendance. However, they have no positive family history of sudden cardiac death (SCD), seizure, pregnancy loss, and neonatal death. Two patients first received treatment in neurology and were misdiagnosed with epilepsy, and the other four patients were diagnosed with ventricular arrhythmia and early repolarization syndrome when visiting our department. Diagnosis occurred at a median age of 8.2 ± 3.1 (5.0-11.4) years with a delay to diagnosis of 2.6 ± 2.0 (0.5–4.7) years (Fig. 1c). Sinus bradycardia exists in all patients. In all cases, polymorphic ventricular premature beat (bigeminy and couplets), polymorphic and bidirectional VT with degeneration into ventricular tachycardia was detected during exercise testing. Gene results reported heterozygous mutants of the RYR2 gene in all patients, which is the most frequent variant of CPVT. The classification of RYR2 variant location was based on 4 hotspots: I (amino acids 44–466); II (2246–2534); III(3778–4201); and IV (4497–4959) [5]. RYR2 amino acid was divided into several different domains according to the study by Dhindwal et al. [6] Variant in the NTD domain was found in patient 1 (N-terminal domain, amino acids 1-643), HD1 in patient 2 and patient 4 (amino acids 2110–2679), VSC in patient 3 (amino acids 4594–4719), CTD in patient 5 (C-terminal domain, amino acids 4889–4969), and U-motif in patient 6 (amino acids 4091–4207). Meanwhile, two patients tested more than one potential mutation as SCN5A. Patient 3 and Patient 4 in our cohort were detected with RYR2 mutation accompanied by SCN5A mutation. In Patient 4, a heterozygous mutation of SCN5A, c.677 C > T was reported. Dynamic Electrocardiogram presented multifocal ventricular premature beat, 19 episodes of burst ventricular tachycardia, ventricular bigeminy and QT prolongation but no Brugada pattern in Patient 4. Similarly, a heterozygous mutation of SCN5A, c.3183 A > C emerged in Patient 3. However, pathogenicity analysis reported uncertain in gene result. Prolonged QTc and Brugada patterns were not observed during the therapeutic process.

Table 1 Clinical characteristic of six children with CPVT in our centerFig. 1

(a) Gender distribution of Chinese CPVT patients. Our study included 95 patients with CPVT, 59.4% of them are male. (b) Cases reported in Chinese Hospitals. The patients we included are from 21 Chinese pediatric centers. The hospital of Tsinghua University and Peking University People’s Hospital provided the largest samples of 21 and 20 patients, respectively. (c) Delayed diagnosis in our center. We reported six cases diagnosed in our center and visually displayed the delay in diagnosis time

Treatment and follow up

A summary of the treatment and follow-up is shown in Table 1. In our center, all patients were recommended to avoid strenuous exercise and given long-term beta-blocker (Metoprolol) therapy. No patients received the flecainide treatment due to its unavailability in China. Only patient 3 received ICD therapy and other patients didn’t receive left cardiac sympathetic denervation (LCSD) and ICD implantation due to the refusal by their parents.

In detail, oral Metoprolol was prescribed to Patient 1 (loading dose: 0.5 mg/kg per day; maintenance dose: 1 mg/kg per day). Unfortunately, the patient died suddenly during the morning reading after a 16-months follow-up. The exact dosage of Metoprolol (loading dose: 0.5 mg/kg per day; maintenance dose: 1 mg/kg per day) was prescribed to Patient 2, and he died of emotional stress after discharge for 20 months. For patient 3, oral Propranolol (loading dose: 0.6 mg/kg per day; maintenance dose: 2 mg/kg per day) was taken to him and he received ICD implantation at our center due to recurrent syncope and bVT persisted during the disease course despite on highest tolerated beta-blocker dose. Fortunately, this patient got a successful rescue after the break out of a ventricular arrhythmia because of the ICD placement, and no syncope and/or cardiac arrest was found later. For Patient 4, Metoprolol (loading dose: 0.4 mg/kg per day; maintenance dose: 1 mg/kg per day) was taken under the doctor’s advice. Unfortunately, Patient 4 died from suffocation due to gastric reflux caused by syncope after 33 months of beta-blocker therapy. Patient 5 and Patient 6 were prescribed the same (1 mg/kg/d) Metoprolol dosage in initial medical treatment, and the maintained dosage was 1 mg/kg/d and 1.5 mg/kg/d. Syncope exists with them in occasional attacks after 28- and 18-month follow-ups.

Patients’ description of the Chinese pediatric cohortClinical information and diagnosis

To establish the baseline information of Chinese pediatric patients with CPVT, our study included 95 children (59.4% male) with CPVT (Table 2) from 21 Chinese pediatric centers (Fig. 1a). Tsinghua University and Peking University People’s hospital provided the most extensive samples of 21 and 20 patients, respectively (Fig. 1b). Almost all patients (99.0%) were admitted to the hospital for recurrent syncope triggered by exercise or emotional stress and 13 of 34 (38.2%) available patients came up with a cardiac arrest. 16 patients (25.8%) presented with a positive family history of possible CPVT, such as sudden death after exercise of young relatives and parents as the carrier of mutated variants. The median age of Chinese pediatric CPVT patients is 8.7 ± 3.0 (3.0–20.0) years when they present symptomatically. Diagnosis occurred at a median (range) age of 12.9 ± 6.8 (2.1–45.0) years with a delay of 4.3 ± 6.6 (0.0–36.0) years due to the lack of recognition of CPVT. 13 patients received a misdiagnosis of epilepsy. Sinus bradycardia was detected in 20 of 95 (22.1%) patients during ECG and DCG (Dynamic Electrocardiography). 66 of 67 (98.5%) patients performed exercise testing, and 9 presented pVT (22.4%), 11 bVT (18.4%) and 29 (59.2%) had both. Genetic testing was accepted in 79 of 95 (83.1%) patients (NA = 16). Of the 79 patients with genetic test, “negative” genetic results were observed in 12 cases since they only received the gene screening of 45 high mutation exons of RYR2 and CASQ genes and the remaining 60 exons were not screened. In total, genetic test were positive in 67 patients. In detail, variants were RYR2 in 47 of 67 (70.1%), CASQ2 in 11 (16.4%), and RYR2 accompany accompanied SCN5A in 7 (10.4%). Tecrl and LGTs variants were also found in our cohort, and the proportions were 1.4% and 1.4%, respectively.

Table 2 The summary of clinical features of Chinese pediatric patients with CPVTTreatment and follow up

Beta-blocker was administrated for most Chinese pediatric patients (100%, NA = 28) as the first-line therapy. Selective beta-blocker was prescribed for 38 patients (56.7%) and 29 (43.3%) patients received non-selective beta-blocker treatment. The medications are as follows: patients initially used Metoprolol in 36 (53.7%), Propranolol in 21 (31.3%), nadolol in 8 (11.9%) and 2 in bisoprolol (3.0%). Chinese doctors prescribed Metoprolol to patients from 0.2 mg/kg/d to 1.7 mg/kg/d with different dosages. Propranolol ranges from 1.1 mg/kg/d to 2.5 mg/kg/d. Nadolol from 10 mg/d to 80 mg/d according to different kilograms. Fewer prescribed Bisoprolol dosages from 2.5 to 5 mg/d. 20 (42.5%) patients got clinical remission (lack of syncope and/or cardiac arrest), and 24 (51.1%) patients still experienced recurrent syncope after beta-blocker therapy. 27.3% of patients were prescribed dosage drugs, 30.3% added other drugs, 6 accepted LCSD and 7 received ICD implantation at the subsequent therapy due to the treatment failure events. The follow-up duration of this cohort was 17.3 ± 23.6 months, and 86.7% (n = 75) of patients obtained clinical remission. 3 patients died in first-line therapy, and 10 died in the whole therapy process.

Genetic analysis

Patients’ distribution of RYR2 variant location was 5 in I (17.2%), 7 in II (24.1%),6 in III (20.7%),8 in IV (27.6%) and 3 in non-hotspot (10.3%). 6 patients with the variant in NTD (24.1%), 1 in SPRY1 (amino acids 1084–1217) (3.4%), 7 with HD1 (24.1%), 3 with Central (amino acid 3636–4020) (10.3%), 3 with U-motif (10.3%), 2 with VSC (amino acids 4594–4719) (6.9%), 2 with S6 (amino acids 4836–4888) (2.9%), and 4 with CTD (13.8%). 2 patients died in variant NTD and HD1, respectively. 1 patient died in the variant central domain.

The clinical characteristics of CPVT patients with RYR2 and CASQ2 mutations were compared and the results are shown in Table 3. It was found that the age of symptom onset in patients with RYR2 mutations was older than that in children with CASQ2 mutations (8.3 ± 2.6 years vs. 6.6 ± 1.4 years, p = 0.048). Patients with CASQ2 mutations presented a higher rate of positive family history (45.5% vs. 18.2%, p = 0.035). In addition, despite no statistical significance, patients with CASQ2 mutations appeared to suffer from a lower rate of cardiac arrest and mortality rate compared to those with RYR2 mutations.

Table 3 Clinical comparisons between patients with different gene mutations in pediatric patients with CPVT