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Backgrounds Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but lethal cardiac ion channelopathy. Delayed diagnosis and misdiagnosis remain a matter of concern due to its rarity and insufficient recognition of this disorder, particularly in developing countries like China. Aims and methods We reported six catecholaminergic polymorphic ventricular tachycardia (CPVT) children diagnosed in our center along with a comprehensive review of Chinese pediatric CPVT patients reported in domestic and overseas literature between January 2013 and December 2021 to provide an essential reference for physicians to deepen their understanding of pediatric CPVT. Results A total of 95 children with CPVT, including our six patients from 21 medical centers were identified. The median age of symptom onset is 8.7 ± 3.0 years. Diagnosis occurred at a median age of 12.9 ± 6.8 years with a delay of 4.3 ± 6.6 years. Selective beta-blockers (Metoprolol and Bisoprolol) were prescribed for 38 patients (56.7%) and 29 (43.3%) patients received non-selective beta-blocker (Propranolol and Nadolol) treatment. Six patients accepted LCSD and seven received ICD implantation at the subsequent therapy. A total of 13 patients died during the disease course. Of the 67 patients with positive gene test results, variants in RYR2 were 47 (70.1%), CASQ2 were 11 (16.4%), and RYR2 accompanied SCN5A were 7 (10.4%). Patients with CASQ2 gene mutations presented with younger symptom onset age, higher positive family history rate and better prognosis than those with RYR2 mutations. Conclusion Chinese pediatric patients with CPVT had a poorer prognosis than other cohorts, probably due to delayed/missed diagnosis, non-standard usage of beta-blockers, unavailability of flecainide, and a lower rate of LCSD and ICD implantation.

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited ion channelopathy characterized by a structurally normal heart sensitive to catecholamines. It primarily presents as Bidirectional ventricular tachycardia (BiVT) and is a significant cause of sudden cardiac death in children. Case presentation We report our experience with central Extracorporeal Membrane Oxygenation (ECMO) therapy in a 4-year-old boy with CPVT. Despite these measures, his CPVT was refractory to standard medical treatment and mechanical ventilatory support, with symptom progression. Consequently, ECMO support was initiated in addition to existing treatment. The patient was successfully weaned off ECMO on the 10th day of therapy and was discharged in a good condition. Follow-up after discharge showed favorable outcomes. Conclusions The successful outcome in this case was attributed to the application of ECMO, which helped maintain the patient’s circulatory status and address progressively worsening cardiogenic shock and uncontrolled ventricular arrhythmia. In such situations, the early use of ECMO can provide essential circulatory support and stability for patients, as demonstrated in this case.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly arrhythmogenic syndrome triggered by stress, primarily linked to gain-of-function point mutations in the cardiac ryanodine receptor (RyR2). Flecainide, as an effective therapy for CPVT, is a known blocker of the surface-membrane Na channel, also affecting the intracellular RyR2 channel. The therapeutic relevance of the flecainide-RyR2 interaction remains controversial, as flecainide blocks only the RyR2 current flowing in the opposite direction to the physiological Ca release from the sarcoplasmic reticulum (SR). However, it has been proposed that charge-compensating countercurrent from the cytosol to SR lumen plays a critical role, and its reduction may indeed suppress excessive diastolic SR Ca release through RyR2 channels in CPVT. Monitoring single-channel properties, we examined whether flecainide can target intracellular pathways for charge-balancing currents carried by RyR2 and SR Cl channels under cell-like conditions. Particularly, the Tris countercurrent flowed through the RyR2 channel simultaneously with a dominant reverse Ca /Ba current. We demonstrate that flecainide blocked the RyR2-mediated countercurrent without affecting channel activity. In contrast, the SR Cl channel was completely resistant to flecainide. Based on these findings, it is reasonable to propose that the primary intracellular target of flecainide in vivo is the RyR2-mediated countercurrent.

Orthosteric beta blockers represent the leading pharmacological intervention for managing heart diseases owing to their ability to competitively antagonize β-adrenergic receptors (βARs). However, their use is often limited by adverse effects such as fatigue, hypotension, and reduced exercise capacity, due in part to nonselective inhibition of multiple βAR subtypes. These challenges are particularly problematic in treating catecholaminergic polymorphic ventricular tachycardia (CPVT), a disease characterized by lethal tachyarrhythmias directly triggered by cardiac β1AR activation. To identify small-molecule allosteric modulators of the β1AR with enhanced subtype specificity and robust functional antagonism of β1AR-mediated signaling, we conducted a DNA-encoded small-molecule library screen and discovered Compound 11 (C11). C11 selectively potentiates the binding affinity of orthosteric agonists to the β1AR while potently inhibiting downstream signaling after β1AR activation. C11 prevents agonist-induced spontaneous contractile activity, Ca2+ release events, and exercise-induced ventricular tachycardia in the CSQ2-/- murine model of CPVT. Our studies demonstrate that C11 belongs to an emerging class of allosteric modulators termed positive allosteric modulator antagonists that positively modulate agonist binding but block downstream function. Its pharmacological properties and selective functional antagonism of β1AR-mediated signaling make C11 a promising therapeutic candidate for the treatment of CPVT and other forms of cardiac disease associated with excessive β1AR activation.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a highly arrhythmogenic syndrome triggered by stress, primarily linked to gain-of-function point mutations in the cardiac ryanodine receptor (RyR2). Flecainide, as an effective therapy for CPVT, is a known blocker of the surface-membrane Na[sup.+] channel, also affecting the intracellular RyR2 channel. The therapeutic relevance of the flecainide-RyR2 interaction remains controversial, as flecainide blocks only the RyR2 current flowing in the opposite direction to the physiological Ca[sup.2+] release from the sarcoplasmic reticulum (SR). However, it has been proposed that charge-compensating countercurrent from the cytosol to SR lumen plays a critical role, and its reduction may indeed suppress excessive diastolic SR Ca[sup.2+] release through RyR2 channels in CPVT. Monitoring single-channel properties, we examined whether flecainide can target intracellular pathways for charge-balancing currents carried by RyR2 and SR Cl[sup.−] channels under cell-like conditions. Particularly, the Tris[sup.+] countercurrent flowed through the RyR2 channel simultaneously with a dominant reverse Ca[sup.2+]/Ba[sup.2+] current. We demonstrate that flecainide blocked the RyR2-mediated countercurrent without affecting channel activity. In contrast, the SR Cl[sup.−] channel was completely resistant to flecainide. Based on these findings, it is reasonable to propose that the primary intracellular target of flecainide in vivo is the RyR2-mediated countercurrent.

Cardiac disease is associated with deleterious emission of mitochondrial reactive oxygen species (mito-ROS), as well as enhanced oxidation and activity of the sarcoplasmic reticulum (SR) Ca2+ release channel, the ryanodine receptor (RyR2). The transfer of Ca2+ from the SR via RyR2 to mitochondria is thought to play a key role in matching increased metabolic demand during stress. In this study, we investigated whether augmented RyR2 activity results in self-imposed exacerbation of SR Ca2+ leak, via altered SR-mitochondrial Ca2+ transfer and elevated mito-ROS emission. Fluorescent indicators and spatially restricted genetic ROS probes revealed that both pharmacologically and genetically enhanced RyR2 activity, in ventricular myocytes from rats and catecholaminergic polymorphic ventricular tachycardia (CPVT) mice, respectively, resulted in increased ROS emission under β-adrenergic stimulation. Expression of mitochondrial Ca2+ probe mtRCamp1h revealed diminished net mitochondrial [Ca2+] with enhanced SR Ca2+ leak, accompanied by depolarization of the mitochondrial matrix. While this may serve as a protective mechanism to prevent mitochondrial Ca2+ overload, protection is not complete and enhanced mito-ROS emission resulted in oxidation of RyR2, further amplifying proarrhythmic SR Ca2+ release. Importantly, the effects of augmented RyR2 activity could be attenuated by mitochondrial ROS scavenging, and experiments with dominant-negative paralogs of the mitochondrial Ca2+ uniporter (MCU) supported the hypothesis that SR-mitochondria Ca2+ transfer is essential for the increase in mito-ROS. We conclude that in a process whereby leak begets leak, augmented RyR2 activity modulates mitochondrial Ca2+ handling, promoting mito-ROS emission and driving further channel activity in a proarrhythmic feedback cycle in the diseased heart.

IntroductionCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare cardiac ion channelopathy. The aim of this study is to examine the clinical characteristics, genetic basis and arrhythmic outcomes in CPVT patients from the Hong Kong city of China.MethodsThis analysis was based on a wider study on ventricular arrhythmias that received approval from the local research ethics committee. Patients diagnosed with CPVT at public hospitals or clinics were included. The primary outcome was spontaneous ventricular tachycardia/ventricular fibrillation (VT/VF).ResultsA total of 16 (mean presentation age=11±4 years old) patients were included. All patients presented at or before 19 years of age. Fifteen patients (93.8%) were initially symptomatic. Ten patients had both premature ventricular complexes (PVCs) and VT/VF, whereas one patient had PVCs without VT/VF. Genetic tests were performed in 14 patients (87.5%). Eight (57.1%) tested positive for the RyR2 gene. Seven variants have been described else-where (c.14848G>A, c.12475C>A, c.7420A>G, c.11836G>A, c.14159T>C, c.10046C>T and c.7202G>A). c.14861C>G is a novel RyR2 variant that has not been reported outside this cohort. All patients were treated with beta-blockers, three patients received amiodarone and two received verapamil. Sympathectomy (n=8) and implantable-cardioverter defibrillator implantation (n=3) were performed. Over a median follow-up of 127 (IQR: 97–143) months, six patients suffered from incident VT/VF. No significant predictors were identified on Cox regression.Abstract 104 Table 1Baseline clinical and demographic characteristics. Categorical and continuous variables were compared between groups using Fisher’s exact test or t-test, respectively. Bolded text indicates P<0.05 Variable All CPVT patients (n=16) CPVT patients with incident VT/VF on follow-up (n=6) CPVT patients without incident VT/VF on follow-up (n=10) P-value Female 8 (50.0) 4 (66.7) 4 (40.0) 0.302 Presentation Age (years) 10.8±4.4 10.7±4.1 10.8±4.9 0.478 Diagnosis Age (years) 11.4±4.4 11.3±3.8 11.4±5.0 0.489 Presentation to Diagnosis (months) 7.7±10.4 7.5±6.8 7.8±12.4 0.479 Family History of CPVT/SCD 3 (18.8) 3 (50.0) 0 (0) 0.137 Initial syncope 14 (87.5) 5 (83.3) 9 (90.0) 0.696 Initial VT/VF/SCD 5 (31.3) 1 (16.7) 4 (40.0) 0.330 Initial palpitations 4 (25.0) 3 (50.0) 1 (10.0) 0.074 Initial seizure 6 (37.5) 3 (50.0) 3 (30.0) 0.424 Follow-Up Duration (months) 116.3±35.9 131.7±17.5 107.0±41.5 0.904 Abstract 104 Table 2Baseline electrocardiographic data. Categorical and continuous variables were compared between groups using Fisher’s exact test or t-test, respectively. Bolded text indicates P<0.05 Variable All CPVT patients (n=16) CPVT patients with incident VT/VF on follow-up (n=6) CPVT patients without incident VT/VF on follow-up (n=10) P-value Heart Rate 81±24 77±19 83±27 0.323 P-Wave Duration 94±18 106±8 85±18 0.881 PR Interval 163±53 191±77 144±14 0.955 QRS Interval 90±25 95±36 85±15 0.757 QT Interval 369±59 391±43 354±66 0.874 QTc Interval 424±34 435±34 417±33 0.836 P Axis 40±35 35±46 44±26 0.338 QRS Axis 67±29 59±32 73±28 0.203 T axis 43±45 62±52 26±32 0.919 Abstract 104 Figure 1Kaplan-Meier survival curve for catecholaminergic polymorphic ventricular tachycardia (CPVT) patientsConclusionAll CPVT patients from Hong Kong presented at or before 19 years of age. Genetic variants in RyR2 were identified.DeclarationA Preprint of this study has been published on Medrxiv.Conflict of InterestNone

ObjectiveTo establish a birth rate for catecholaminergic polymorphic ventricular tachycardia (CPVT) diagnosed in childhood and observe trends in presentation and management.DesignRetrospective cohort study.SettingThe Inherited Arrhythmia Clinic at The Sydney Children’s Hospitals Network, a paediatric tertiary referral network, New South Wales (NSW), Australia (2002–2021), where there are 86 000–97 000 live births/year.PatientsChildren diagnosed with CPVT aged 0–16 years.InterventionsClinical data were extracted and evaluated for trends. Using birth year data, the birth rate of CPVT detected in childhood was calculated.Main outcome measuresBirth rate of CPVT detected in childhood in NSW (with post hoc comparison to New Zealand), trends in diagnosis and management, and outcome at last follow-up.Results32 children in NSW were diagnosed with CPVT between 2002 and 2021 (0–16 years, median 9 years, 14 (54%) female). Of these, 28 (88%) presented with symptoms (cardiac arrest 20/32, 62.5%) and four (12%) were identified through family screening. Relevant genetic variants were identified in 25/31 (78%). During follow-up (median 4.5 years), symptomatic cardiac events (death n=1) occurred in 10 (33%), largely related to suboptimal adherence or monotherapy beta blocker. In NSW, CPVT was diagnosed during childhood following 1 in 65 000 live births (95% CI 1 in 91 000 to 1 in 46 000). In New Zealand, the corresponding figure was 1 in 84 000 live births (95% CI 1 in 138 000 to 1 in 52 000).ConclusionsThe rate of infants born who are later diagnosed with CPVT in childhood is approximately 1 in 65 000 live births. Suboptimal adherence and beta blocker therapy without flecainide appeared related to recurrent cardiac events.

Long QT syndrome, short QT syndrome, Brugada syndrome and catecholaminergic polymorphic ventricular tachycardia are inherited primary electrical disorders that predispose to sudden cardiac death in the absence of structural heart disease. Also known as cardiac channelopathies, primary electrical disorders respond to mutations in genes encoding cardiac ion channels and/or their regulatory proteins, which result in modifications in the cardiac action potential or in the intracellular calcium handling that lead to electrical instability and life-threatening ventricular arrhythmias. These disorders may have low penetrance and expressivity, making clinical diagnosis often challenging. However, because sudden cardiac death might be the first presenting symptom of the disease, early diagnosis becomes essential. Genetic testing might be helpful in this regard, providing a definite diagnosis in some patients. Yet important limitations still exist, with a significant proportion of patients remaining with no causative mutation identifiable after genetic testing. This review aims to provide the latest knowledge on the genetic basis of cardiac channelopathies and discuss the role of the affected proteins in the pathophysiology of each one of these diseases.

Cardiac diseases are the leading causes of death, with a growing number of cases worldwide, posing a challenge for both healthcare and research. Therefore, the most relevant aim of cardiac research is to unravel the molecular pathomechanisms and identify new therapeutic targets. Cardiac ryanodine receptor (RyR2), the Ca2+ release channel of the sarcoplasmic reticulum, is believed to be a good therapeutic target in a group of certain heart diseases, collectively called cardiac ryanopathies. Ryanopathies are associated with the impaired function of the RyR, leading to heart diseases such as congestive heart failure (CHF), catecholaminergic polymorphic ventricular tachycardia (CPVT), arrhythmogenic right ventricular dysplasia type 2 (ARVD2), and calcium release deficiency syndrome (CRDS). The aim of the current review is to provide a short insight into the pathological mechanisms of ryanopathies and discuss the pharmacological approaches targeting RyR2.