Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the genetic basis and identify predictive factors for arrhythmic outcomes of CPVT patients from China. Methods: PubMed and MedRxiv were systematically searched for case reports or case series reporting on CPVT patients from China. Clinical characteristics, genetic findings and primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A total of 56 (median presentation age=9 [6-13] years old) patients were included. All patients except for one presented at or before 19 years of age. Fifty-three patients (94.6%) were initially symptomatic. PVCs were present in 40 out of 45 patients (88.9%) and VT in 51 out of 56 patients (91.1%). Genetic tests were performed in 50 patients (89.3%). RyR2, CASQ2 and TERCL mutations were found in 32 (57.1%), 11 (19.6%) and one (0.02%) patients, respectively. Fifty patients were treated with beta-blockers, eight patients received flecainide, four patients received amiodarone, two received verapamil and one received propafenone. Sympathectomy (n=10) and implantable-cardioverter defibrillator implantation (n=7) were performed. On follow-up, 17 patients developed incident VT/VF. Conclusion: This is the first systemic review and meta-analysis of CPVT patients from China. Most patients had symptoms on initial presentation, and around a third had VT as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2 and TERCL mutations. Some of these mutations have not been hitherto reported outside of China. Most patients received β-blocker therapy. Around 18% had sympathectomy and 13% had ICDs implanted.

Clinical features and antiarrhythmic therapy in patients with catecholaminergic polymorphic ventricular tachycardia

Aims. To evaluate the long-term efficacy of antiarrhythmic therapy in patients with catecholaminergic polymorphic ventricular tachycardia (CPVT).Methods. CPVT was diagnosed in 11 patients between the ages of 3-12 years with a minimum follow-up of 10 years. The data analyzed was obtained from existing medical records that included symptoms, family screenings, treadmill tests, electrocardiography, echocardiography, implanted cardioverter-defibrillator data (ICD), and medical treatments.Results. Cardiac events were registered in 75% of patients on beta-blocker therapy. Supraventricular arrhythmias such as atrial and atrioventicular nodal tachycardia, atrial fibrillation and atrial flutter were detected using various ECG diagnostic methods in all patients, which is significantly higher than reported in similar studies. A combination of anti-arrhythmic therapy and beta-blocker treatment reduced the number of cardiac events by 50% as compared to only beta-blocker treatment.Conclusion. Multiple supraventricular arrhythmias have a high prevalence in patients with CPVT and can trigger ventricular arrhythmia. Combined antiarrhythmic therapy is effective because it prevents cardiac events in patients with CPVT. Combined antiarrhythmic therapy improves the prognosis of patients with CPVT and may help to avoid or postpone ICD implantation.

Clinical Characteristics, Genetic Findings and Arrhythmic Outcomes of Patients with Catecholaminergic Polymorphic Ventricular Tachycardia from China

Introduction: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the genetic basis and identify predictive factors for arrhythmic outcomes of CPVT patients from China. Methods: PubMed and MedRxiv were systematically searched for case reports or case series reporting on CPVT patients from China. Clinical characteristics, genetic findings and primary outcome of spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF) were analyzed. Results: A total of 56 (median presentation age=9 [6-13] years old) patients were included. All patients except for one presented at or before 19 years of age. Fifty-three patients (94.6%) were initially symptomatic. PVCs were present in 40 out of 45 patients (88.9%) and VT in 51 out of 56 patients (91.1%). Genetic tests were performed in 50 patients (89.3%). RyR2, CASQ2 and TERCL mutations were found in 32 (57.1%), 11 (19.6%) and one (0.02%) patients, respectively. Fifty patients were treated with beta-blockers, eight patients received flecainide, four patients received amiodarone, two received verapamil and one received propafenone. Sympathectomy (n=10) and implantable-cardioverter defibrillator implantation (n=7) were performed. On follow-up, 17 patients developed incident VT/VF. Conclusion: This is the first systemic review and meta-analysis of CPVT patients from China. Most patients had symptoms on initial presentation, and around a third had VT as the presenting complaint. RyR2 mutation accounts for more than half of the CPVT cases, followed by CASQ2 and TERCL mutations. Some of these mutations have not been hitherto reported outside of China. Most patients received β-blocker therapy. Around 18% had sympathectomy and 13% had ICDs implanted.

An International Multi-Center Cohort Study on β-blockers for the Treatment of Symptomatic Children with Catecholaminergic Polymorphic Ventricular Tachycardia

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. Beta-blockers (BBs) decrease this risk, but studies comparing individual BBs in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of BB in a large cohort of symptomatic children with CPVT. Methods: From two international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest prior to BB initiation and age at start of BB therapy <18 years), treated with a BB were included. Cox-regression analyses with time-dependent covariates for BB and potential confounders were used to assess the hazard ratio (HR). The primary outcome was the first occurrence of sudden cardiac death, sudden cardiac arrest, appropriate implantable cardioverter-defibrillator shock, or syncope. The secondary outcome was the first occurrence of any of the primary outcomes except syncope. Results: We included 329 patients (median age at diagnosis 12 [interquartile range, 7-15] years, 35% females). Ninety-nine (30.1%) patients experienced the primary and 74 (22.5%) experienced the secondary outcome during a median follow-up of 6.7 [interquartile range, 2.8-12.5] years. Two-hundred sixteen patients (66.0%) used a non-selective BB (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective BB (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial BB. Baseline characteristics did not differ. The HR for both the primary and secondary outcomes were higher for β1-selective compared with non-selective BBs (HR, 2.04 95% CI, 1.31-3.17; and HR, 1.99; 95% CI, 1.20-3.30, respectively). When assessed separately, the HR for the primary outcome was higher for atenolol (HR, 2.68; 95% CI, 1.44-4.99), bisoprolol (HR, 3.24; 95% CI, 1.47-7.18), and metoprolol (HR, 2.18; 95% CI, 1.08-4.40) compared with nadolol, but did not differ from propranolol. The HR of the secondary outcome was only higher in atenolol compared with nadolol (HR, 2.68; 95% CI, 1.30-5.55). Conclusions: B1-selective BBs were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with non-selective BBs, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred BB for treating symptomatic children with CPVT.

769 Differential pharmacological modulation of arrhythmic phenotype in catecholaminergic polymorphic ventricular tachycardia: not all betablockers are the same

Aims Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that predisposes patients to develop catecholamine-mediated ventricular arrhythmias (VA), manifesting as exercise- or emotion-induced syncope or cardiac arrest. Due to the catecholaminergic nature of CPVT, exercise stress test (EST) represents the most important diagnostic test. Although widely used in clinical practice to monitor response to therapy, how BBs modulate the occurrence of ventricular arrhythmias during EST in CPVT patients is unclear. To compare the relative efficacy of different classes of betablockers (BBs, β1-selective BBs vs. nadolol) on the arrhythmic manifestations during ESTs performed off-therapy and on-therapy in patients with CPVT. Methods and results We selected 72 patients (45 females) with pathogenic or likely pathogenic variants on RYR2 or CASQ2 from our cohort of 246 genotype-positive CPVT patients, who had at least one EST off-therapy and at least one EST during BB therapy. Overall, 507 ESTs (77 ESTs off-therapy, 29 ESTs during β1-selective BBs, and 401 during nadolol) were prospectively collected over 11.1 ± 6.8 years of follow-up and analysed, with a median of 5 ESTs per patient [interquartile range (IQR): 3–10 ESTs, range: 2–27 ESTs]. In the absence of therapy, VT was documented in 46/77 (60%) cases. BB therapy with nadolol significantly reduced VT at EST to 10% (41/398; P &lt; 0.001). Conversely, β1-selective BBs did not significantly decrease VT incidence at EST (13/29, 45%, P = 0.289) as compared to baseline. Importantly, nadolol was superior in preventing VT both when compared to off-therapy [odds ratio (OR): 33.9, 95% confidence interval (CI): 15.6–73.5, P &lt; 0.001] but also when compared to β1-selective BBs [OR: 18.0, 95% CI: 6.0–53.5, P &lt; 0.001]. Although β1-selective BBs significantly increased the total exercise time free of arrhythmias (median 248 s, IQR: 212–315 s) as compared to baseline (median 83 s, IQR: 12–207 s; P &lt; 0.001), arrhythmia-free exercise time during nadolol (median 381 s, IQR: 251–543 s) was significantly longer as compared to both off-therapy (P &lt; 0.001) and β1-selective BBs (P = 0.020). Multivariate mixed effects logistic regression confirmed that at parity of time of occurrence of first arrhythmia and percentage of maximal heart rate reached, both of which were significantly associated to VT occurrence (P = 0.001 for both), the use of nadolol (OR: 0.23; 95% CI: 0.09–0.60; P = 0.011) was independently associated with decreased incidence of VT. Focusing on the 14 patients (overall 133 ESTs) who had at least one ESTs after the occurrence of VT in nadolol, we dissected the effect of dose increase on the probability of VT reoccurrence. Following the documentation of breakthrough VT, increasing the dose of nadolol by 0.5 mg/kg reduced by 2.5 times the probability of having a recurrence of VT (OR: −2.49, 95% CI: −3.96 to − 1.0; P &lt; 0.001). Conclusions Once CPVT is diagnosed, nadolol at 1 mg/kg/day should be used as preferred therapy as it has been shown to suppress VT in most patients. In rare instances in which VA persist despite an adequate nadolol dose, dose increase to 1.5 mg/kg/day may represent an efficacious antiarrhythmic strategy.

Identification of two variants in AGRN and RPL3L genes in a patient with catecholaminergic polymorphic ventricular tachycardia suggesting new candidate disease genes and digenic inheritance

Catecholaminergic Polymorphic Ventricular Tachycardia is a life-threatening disorder. The clinical diagnosis is challenging owing to the absence of electrocardiogram and overt structural heart abnormalities in the majority of patients. Approximately 35% of cases remain without a genetic etiology. Here, we identified two genes as a novel promising candidate for CPVT.