Human induced pluripotent stem cell (iPSC) lines were generated from peripheral blood mononuclear cells (PBMCs) isolated from two related patients diagnosed with either idiopathic ventricular fibrillation or catecholaminergic polymorphic ventricular tachycardia, carrying an unknown variant in the RYR2 gene, c.14201A>G (p.Y4734C) and one healthy related individual. Reprogramming was done using a commercially available Epi5 Reprogramming Kit. The pluripotency of the iPSC lines was verified by the expression of pluripotency markers and by their capacity to differentiate into all three embryonic germ layers in vitro. These iPSC lines are available for functional analysis and in vitro studies of RYR2 channelopathy.

• MeSH
• Cell Differentiation MeSH
• Cell Line MeSH
• Adult MeSH
• Ventricular Fibrillation * genetics   MeSH
• Induced Pluripotent Stem Cells * metabolism   MeSH
• Polymorphic Catecholaminergic Ventricular Tachycardia MeSH
• Tachycardia, Ventricular * genetics   metabolism   MeSH
• Humans MeSH
• Ryanodine Receptor Calcium Release Channel * genetics   metabolism   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) may cause sudden cardiac death (SCD) despite medical therapy. Therefore, implantable cardioverter-defibrillators (ICDs) are commonly advised. However, there is limited data on the outcomes of ICD use in children. OBJECTIVE: The purpose of this study was to compare the risk of arrhythmic events in pediatric patients with CPVT with and without an ICD. METHODS: We compared the risk of SCD in patients with RYR2 (ryanodine receptor 2) variants and phenotype-positive symptomatic CPVT patients with and without an ICD who were younger than 19 years and had no history of sudden cardiac arrest at phenotype diagnosis. The primary outcome was SCD; secondary outcomes were composite end points of SCD, sudden cardiac arrest, or appropriate ICD shocks with or without arrhythmic syncope. RESULTS: The study included 235 patients, 73 with an ICD (31.1%) and 162 without an ICD (68.9%). Over a median follow-up of 8.0 years (interquartile range 4.3-13.4 years), SCD occurred in 7 patients (3.0%), of whom 4 (57.1%) were noncompliant with medications and none had an ICD. Patients with ICD had a higher risk of both secondary composite outcomes (without syncope: hazard ratio 5.85; 95% confidence interval 3.40-10.09; P < .0001; with syncope: hazard ratio 2.55; 95% confidence interval 1.50-4.34; P = .0005). Thirty-one patients with ICD (42.5%) experienced appropriate shocks, 18 (24.7%) inappropriate shocks, and 21 (28.8%) device-related complications. CONCLUSION: SCD events occurred only in patients without an ICD and mostly in those not on optimal medical therapy. Patients with an ICD had a high risk of appropriate and inappropriate shocks, which may be reduced with appropriate device programming. Severe ICD complications were common, and risks vs benefits of ICDs need to be considered.

• MeSH
• Defibrillators, Implantable * MeSH
• Child MeSH
• Polymorphic Catecholaminergic Ventricular Tachycardia MeSH
• Tachycardia, Ventricular * therapy   physiopathology   MeSH
• Humans MeSH
• Adolescent MeSH
• Death, Sudden, Cardiac * prevention & control   etiology   MeSH
• Follow-Up Studies MeSH
• Child, Preschool MeSH
• Retrospective Studies MeSH
• Ryanodine Receptor Calcium Release Channel genetics   MeSH
• Treatment Outcome MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

BACKGROUND: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT. METHODS: From 2 international registries of patients with CPVT, RYR2 variant-carrying symptomatic children (defined as syncope or sudden cardiac arrest before β-blocker initiation and age at start of β-blocker therapy <18 years), treated with a β-blocker were included. Cox regression analyses with time-dependent covariates for β-blockers 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 outcome 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 nonselective β-blocker (predominantly nadolol [n=140] or propranolol [n=70]) and 111 (33.7%) used a β1-selective β-blocker (predominantly atenolol [n=51], metoprolol [n=33], or bisoprolol [n=19]) as initial β-blocker. Baseline characteristics did not differ. The HRs for both the primary and secondary outcomes were higher for β1-selective compared with nonselective β-blockers (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: β1-selective β-blockers were associated with a significantly higher risk for arrhythmic events in symptomatic children with CPVT compared with nonselective β-blockers, specifically nadolol. Nadolol, or propranolol if nadolol is unavailable, should be the preferred β-blocker for treating symptomatic children with CPVT.

• MeSH
• Adrenergic beta-Antagonists pharmacology   therapeutic use   MeSH
• Child MeSH
• Cohort Studies MeSH
• Tachycardia, Ventricular drug therapy   MeSH
• Humans MeSH
• Adolescent MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: Children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for sudden death, and a risk stratification tool does not exist. OBJECTIVE: The purpose of this study was to determine whether proband status, age at symptom onset, and/or sex are independent predictors of cardiac events. METHODS: A multicenter, ambispective, cohort of pediatric CPVT patients was categorized by sex, proband status, and age at symptom onset (D1: first decade of life [symptom onset <10 years] or D2: second decade of life [symptom onset 10-18 years, inclusive]). Demographics, therapy, genetics, and outcomes were compared between groups. RESULTS: A total of 133 patients were included and stratified into 58 D1 and 75 D2 patients (68 female and 65 male; 106 probands and 27 relatives). Localization of RYR2 variants to hotspots differed based on proband status and age at symptom onset. The cardiac event rate was 33% (n = 44/133), inclusive of a 3% (n = 4/133) mortality rate, over a median of 6 years (interquartile range 3-11) after time of symptom onset. Proband status, rather than age at of symptom onset or sex, was an independent predictor of time to first cardiac event (P = .008; hazard ratio = 4.4). The 5-, 10- and 15-year event-free survival rates for probands were 77%, 56%, and 46%, respectively, and for relatives were 96%, 91%, and 86%, respectively. Event risk after diagnosis was 48% (32/67) in patients on β-blocker or flecainide alone vs 10% (5/48) in patients on β-blocker plus flecainide and/or left cardiac sympathetic denervation (P <.001). CONCLUSION: Proband status, but not age at symptom onset or male sex, independently predicted an earlier onset of cardiac events. A larger sample size would enable a comprehensive investigation of other risk factors.

• MeSH
• Child MeSH
• Tachycardia, Ventricular epidemiology   therapy   MeSH
• Humans MeSH
• Adolescent MeSH
• Risk Factors MeSH
• Sex Factors MeSH
• Severity of Illness Index MeSH
• Age of Onset MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Canada MeSH
• United States MeSH

Komorové extrasystoly (KES) mohou být benigní, nicméně mohou značit i závažné onemocnění. Při vyšetřování příčin četné komorové ektopie se po vyloučení nekardiální příčiny zaměřujeme na vyloučení strukturálního onemocnění srdce, kdy systolická funkce levé komory slouží jako jeden z markerů stratifikace rizika náhlé srdeční smrti. Výskyt četných komorových extrasystol bez organického poškození srdce je považován za benigní. nicméně je známo, že více než deset tisíc KES za 24 hodin již může vést k arytmiemi navozené kardiomyopatii. Je tedy namístě provést kvantifikaci KES a zhodnotit jejich morfologii. Polymorfní komorové arytmie totiž mohou signalizovat nejen významnou aterosklerotickou nemoc koronárních tepen, ale i výskyt vzácného hereditárního arytmického onemocnění, např. katecholaminergní polymorfní komorové tachykardie (CPVT), a to i ve vyšším věku. na následující kazuistice popisujeme primozáchyt CPVT až v sedmém decenniu života.

Premature ventricular complexes (PVCs) are often considered benign, nevertheless they can be a sign of serious disease. In the assessment of frequent PVCs the first step is to rule out structural heart disease while left ventricular systolic dysfunction is one of the risk factors for sudden cardiac death. In the absence of a serious structural heart disease, PVCs are considered benign. however, more than 10.000 PVCs in 24 hours can lead to PVC-induced cardiomyopathy. It is therefore important to quantify PVCs and evaluate their morphology. Polymorphic ventricular arrhythmias can point towards coronary artery disease. They can also be a sign of a rare hereditary arrhythmic disease – catecholaminergic polymorphic ventricular tachycardia (CPVT). This case report describes a new diagnosis of CPVT in a patient in the seventh decennium, with emphasis on the importance of exercise stress testing in the diagnostic algorithm of PVCs.

Primární dědičné arytmické syndromy patří do skupiny onemocnění, které způsobují poruchy elektrické aktivace srdečních buněk a tím predisponují ke vzniku život ohrožujících arytmií. Mezi dědičné arytmické syndromy patří syndrom dlouhého QT intervalu, krátkého QT intervalu, katecholaminergní polymorfní komorová tachykardie, či onemocnění sodíkového kanálu (gen SCN5A), která zahrnují např. syndrom bratří Brugadových, progresivní převodní poruchy, familiární sick sinus syndrom apod. Volně je k nim řazena i arytmogenní kardiomyopatie, která je však způsobena poruchou desmosomálních proteinů.Abnormality elektrické aktivace srdečních buněk jsou dány ve většině případů geneticky podmíněnou poruchou funkce iontových kanálů kardiomyocytů, proto se někdy označují i jako kanálopatie a jejich dědičnost je nejčastěji autosomálně dominantní. Prvním příznakem těchto syndromů můžou být palpitace, synkopy, křeče, ale i náhlá srdečná smrt. Jejich příčinou je shodně u všech uvedených onemocnění maligní komorová tachyarytmie vedoucí k mozkové hypoxii. Diagnostika těchto syndromů je založena na symptomech, typickém EKG obrazu a genetické stratifikaci, která přispívá k volbě terapie včetně specifických doporučení úpravy životního stylu. Nutná je úzká vzájemná mezioborová spolupráce pediatra, dětského kardiologa, dospělého kardiologa, klinického genetika, sportovního lékaře a v neposlední řadě i soudního lékaře a psychologa.

IInherited arrhythmic syndromes, also known as cardiac channelopathies, are group of cardiac electrophysiological disorders characterized by a specific pattern on electrocardiogram and a disease specific risk for malignant ventricular arrhythmias. This group includes long QT syndrome (LQT), short QT syndrome (SQT), catecholaminerg polymorphic ventricular tachycardia (CPVT) and a sodium channelopathies (SCN5A) like Brugada syndrome, progressive cardiac conduction disease (PCCD) etc. Channelopathies manifest mostly in form of syncopes, epileptic seizures or sudden cardiac death. Most types of cardiac channelopathies are inherited in autosomal dominant pattern, autosomal recessive variants are rare and associated with a severe course of the disease. In some cases arrhythmic syndromes overlap arrhythmic cardiomyopathies, which are mainly caused by disorders in desmosomal proteins. The genetic stratification allows in many cases installation of individualized therapy and presymptomatic treatment of mutation carriers, who are at risk of malignant arrhythmias. The proper clinical diagnosis, genetic analysis and long-term treatment demand multidisciplinary approach and close cooperation among pediatric and adult cardiologists, geneticist, molecular geneticist, psychologists, sport and forensic medicine professionals.

• Keywords
• genetická analýza,
• MeSH
• Child MeSH
• Genetic Diseases, Inborn MeSH
• Humans MeSH
• Arrhythmias, Cardiac * diagnosis   genetics   pathology   therapy   MeSH
• Tachycardia diagnosis   genetics   pathology   therapy   MeSH
• Heart Defects, Congenital MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Review MeSH

BACKGROUND: Sarcoplasmic reticulum Ca2+ leak and post-translational modifications under stress have been implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT), a highly lethal inherited arrhythmogenic disorder. Human induced pluripotent stem cells (hiPSCs) offer a unique opportunity for disease modeling. OBJECTIVE: The aims were to obtain functional hiPSC-derived cardiomyocytes from a CPVT patient harboring a novel ryanodine receptor (RyR2) mutation and model the syndrome, drug responses and investigate the molecular mechanisms associated to the CPVT syndrome. METHODS: Patient-specific cardiomyocytes were generated from a young athletic female diagnosed with CPVT. The contractile, intracellular Ca2+ handling and electrophysiological properties as well as the RyR2 macromolecular remodeling were studied. RESULTS: Exercise stress electrocardiography revealed polymorphic ventricular tachycardia when treated with metoprolol and marked improvement with flecainide alone. We found abnormal stress-induced contractile and electrophysiological properties associated with sarcoplasmic reticulum Ca2+ leak in CPVT hiPSC-derived cardiomyocytes. We found inadequate response to metoprolol and a potent response of flecainide. Stabilizing RyR2 with a Rycal compound prevents those abnormalities specifically in CPVT hiPSC-derived cardiomyocytes. The RyR2-D3638A mutation is located in the conformational change inducing-central core domain and leads to RyR2 macromolecular remodeling including depletion of PP2A and Calstabin2. CONCLUSION: We identified a novel RyR2-D3638A mutation causing 3D conformational defects and aberrant biophysical properties associated to RyR2 macromolecular complex post-translational remodeling. The molecular remodeling is for the first time revealed using patient-specific hiPSC-derived cardiomyocytes which may explain the CPVT proband's resistance. Our study promotes hiPSC-derived cardiomyocytes as a suitable model for disease modeling, testing new therapeutic compounds, personalized medicine and deciphering underlying molecular mechanisms.

• Publication type
• Journal Article MeSH

Aims: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an ion channelopathy characterized by ventricular arrhythmia during exertion or stress. Mutations in RYR2-coded Ryanodine Receptor-2 (RyR2) and CASQ2-coded Calsequestrin-2 (CASQ2) genes underlie CPVT1 and CPVT2, respectively. However, prognostic markers are scarce. We sought to better characterize the phenotypic and genotypic spectrum of CPVT, and utilize molecular modelling to help account for clinical phenotypes. Methods and results: This is a Pediatric and Congenital Electrophysiology Society multicentre, retrospective cohort study of CPVT patients diagnosed at <19 years of age and their first-degree relatives. Genetic testing was undertaken in 194 of 236 subjects (82%) during 3.5 (1.4-5.3) years of follow-up. The majority (60%) had RyR2-associated CPVT1. Variant locations were predicted based on a 3D structural model of RyR2. Specific residues appear to have key structural importance, supported by an association between cardiac arrest and mutations in the intersubunit interface of the N-terminus, and the S4-S5 linker and helices S5 and S6 of the RyR2 C-terminus. In approximately one quarter of symptomatic patients, cardiac events were precipitated by only normal wakeful activities. Conclusion: This large, multicentre study identifies contemporary challenges related to the diagnosis and prognostication of CPVT patients. Structural modelling of RyR2 can improve our understanding severe CPVT phenotypes. Wakeful rest, rather than exertion, often precipitated life-threatening cardiac events.

• MeSH
• Heredity MeSH
• Child MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Markers MeSH
• Calsequestrin genetics   MeSH
• Tachycardia, Ventricular diagnosis   genetics   mortality   physiopathology   MeSH
• Protein Conformation MeSH
• Humans MeSH
• Adolescent MeSH
• Models, Molecular MeSH
• Mutation * MeSH
• DNA Mutational Analysis MeSH
• Death, Sudden, Cardiac epidemiology   MeSH
• Prognosis MeSH
• Registries MeSH
• Retrospective Studies MeSH
• Risk Factors MeSH
• Pedigree MeSH
• Ryanodine Receptor Calcium Release Channel chemistry   genetics   metabolism   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare hereditary arrhythmia. The onset of clinical symptoms usually occurs during childhood, and is typically related to exercise. The aim of our study was to describe the clinical characteristics of seven Czech families with CPVT and the results of mutational analysis of the RyR2 gene in these families. METHODS: The subjects and their relatives were investigated at the participating departments. They underwent basic clinical investigation, and history was focused on possible CPVT symptoms, that is, syncopes during exercise. Bicycle ergometry was performed to obtain electrocardiogram recording during adrenergic stimulation. In all the investigated individuals, blood samples were taken for mutation analysis of the RyR2 gene. RESULTS: To date, seven families have been investigated, comprising 11 adults and 13 children. In seven CPVT patients, the indication for examination was syncope during exercise. Diagnosis was confirmed by bicycle ergometry-induced polymorphic ventricular tachycardia. In one relative, polymorphic ventricular tachycardia was also induced. All eight affected individuals were treated with β-blockers and in two, a cardioverter-defibrillator was implanted due to recurrent syncopi. Coding variants of the RyR2 gene were found in four probands. CONCLUSIONS: This is a systematic description of CPVT families in the Czech Republic. Our data support the importance of exercise testing for the diagnosis of CPVT. In addition, RyR2 gene coding variants were found in 50% of affected individuals.

• MeSH
• Child MeSH
• Adult MeSH
• Genetic Predisposition to Disease genetics   MeSH
• Heterozygote MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Tachycardia, Ventricular diagnosis   genetics   MeSH
• Humans MeSH
• Young Adult MeSH
• Mutation genetics   MeSH
• Pedigree MeSH
• Ryanodine Receptor Calcium Release Channel genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Czech Republic MeSH

Cíl: Katecholaminergní polymorfní komorová tachykardie (CPVT) je vzácná dědičná arytmie, která se manifestuje nejčastěji už v dětském věku, typicky při zátěži. Cílem naší práce je klinický popis tří českých rodin s výskytem CPVT a pilotní výsledky mutační analýzy genu RyR2. Metodika: Na zúčastněných pracovištích jsou vyšetřováni probandi a jejich nejbližší příbuzní. Absolvují základní klinické vyšetření, anamnéza je cílena na možné projevy CPVT – synkopy při zátěži. Dále podstupují bicyklovou ergometrii za účelem získání EKG křivek při adrenergní stimulaci. U všech vyšetřených jedinců je proveden odběr krve na izolaci DNA. U probandů byla zahájena analýza genu RyR2. Výsledky: Celkem byly vyšetřeny tři rodiny – jedenáct dospělých, pět dětí, ve kterých se v každé u jednoho z dětí vyskytla synkopa. Indikací k vyšetření byla ve všech třech případech synkopa při zátěži. Diagnóza byla stanovena pomocí ergometrie provokací polymorfní komorové tachykardie. U dalších příbuzných arytmie nebyla vyvolána. Všichni tři postižení byli léčeni beta-blokátorem, u jednoho z nich musel být pro recidivy synkop implantován kardioverter-defi brilátor. U jednoho z probandů byla detekována sekvenční změna c.14101-6A>G a 14101-21A>G blízko 3´-konce intronu 94-95 a 14231+12A>C blízko 5´-konce intronu 95-96. Detekované sekvenční změny nejsou zařazeny do databáze mutací CPVT a dosud nebyly publikovány. Závěry: CPVT je vzácné onemocnění s velmi vysokým rizikem náhlé smrti. Na tuto diagnózu je třeba vždy myslet v případě synkop při zátěži. Klidový elektrokardiogram je zcela normální, k potvrzení diagnózy je nutný zátěžový test. Mutační analýza souvisejících genů umožní identifi kovat asymptomatické jedince, u nichž je pak indikována léčba beta-blokátorem.

Aim: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare hereditary arrhythmia. The onset of clinical symptoms usually occurs during childhood, and is typically related to stress. The aim of our study is to provide clinical characteristics of three Czech families with CPVT and pilot results of mutation analysis of the RyR2 gene. Methods: The subjects and their relatives are investigated at the participating departments. They undergo basic clinical investigation, with their history-taking focused on possible CPVT symptoms, i.e. syncopes during stress. Bicycle ergometry is performed to obtain ECG recordings during adrenergic stimulation. In all the investigated individuals, blood samples are taken for DNA isolation, with mutation analysis of the RyR2 gene started in subjects. Results: To date, three families (11 adults and fi ve children) have been investigated. In three CPVT patients, the indication for examination was syncope during stress. The diagnosis was confi rmed with bicycle ergometry-induced polymorphic ventricular tachycardia. The arrhythmia was not induced in any other relatives. All three aff ected individuals were treated with a beta-blocker, with one having a cardioverter-defi brillator implanted because of recurrent syncopes. Sequence changes c.14101-6A>G and 14101-21A>G close to 3´-end of intron 94-95, and in 14231+12A>C close to 5´-end of intron 95-96 were detected in one subject. The detected sequence changes have not been included in the CPVT mutation database and published yet. Conclusions: CPVT is a rare disease with a high risk of sudden death. This diagnosis must be considered in all cases of exercise-related syncope. A resting electrocardiogram is completely unremarkable. For the confi rmation of the diagnosis an exercise test is necessary. Mutation analysis of related genes may reveal asymptomatic individuals in whom beta-blocker therapy is recommended.

• MeSH
• Calcium Channel Blockers therapeutic use   MeSH
• Defibrillators, Implantable utilization   MeSH
• Child MeSH
• Adult MeSH
• Electrocardiography utilization   MeSH
• Financing, Organized MeSH
• Tachycardia, Ventricular diagnosis   genetics   MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Ryanodine Receptor Calcium Release Channel genetics   MeSH
• Syncope diagnosis   etiology   MeSH
• Exercise Test instrumentation   utilization   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH