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      Bradycardia Is a Specific Phenotype of Catecholaminergic Polymorphic Ventricular Tachycardia Induced by RYR2 Mutations

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          Abstract

          Objective

          Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a lethal inherited disease characterized by ventricular arrhythmias induced by physical exercise or emotional stress. The major cause of CPVT is mutations in RYR2, which encodes the cardiac ryanodine receptor channel. Recent advances in sequencing technology have yielded incidental findings of RYR2 variants in other cardiac diseases. Analyzing the characteristics of RYR2 variants related to CPVT will be useful for differentiation from those related to other cardiac diseases. We examined the phenotypic characteristics of patients with RYR2 variants.

          Methods

          Seventy-nine probands carrying RYR2 variantswhose diagnoses were either CPVT (n=68) or long QT syndrome (LQTS; n=11) were enrolled. We compared the characteristics of the electrocardiogram (ECG) and the location of the RYR2 mutations-N-terminal (NT), central region (CR) or C-terminal (CT)-between the two patient groups.

          Results

          Using the ECGs available from 53 probands before β-blocker therapies, we analyzed the heart rates (HRs). CPVT probands showed bradycardia more frequently (25/44; 57%) than LQTS probands (1/9; 11%; p=0.024). In CPVT patients, 20 mutations were located in NT, 25 in CR and 23 in CT. In LQTS patients, 5 mutations were located in NT, 2 in CR and 4 in CT. There were no significant differences in the locations of the RYR2 mutations between the phenotypes.

          Conclusion

          Bradycardia was highly correlated with the phenotype of CPVT. When a clinically-diagnosed LQTS patient with bradycardia carries an RYR2 mutation, we should be careful to avoid making a misdiagnosis, as the patient may actually have CPVT.

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          Most cited references11

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          Incidence and risk factors of arrhythmic events in catecholaminergic polymorphic ventricular tachycardia.

          The pathophysiological background of catecholaminergic polymorphic ventricular tachycardia is well understood, but the clinical features of this stress-induced arrhythmic disorder, especially the incidence and risk factors of arrhythmic events, have not been fully ascertained. The outcome in 101 catecholaminergic polymorphic ventricular tachycardia patients, including 50 probands, was analyzed. During a mean follow-up of 7.9 years, cardiac events defined as syncope, aborted cardiac arrest, including appropriate discharges from implantable defibrillators, or sudden cardiac death occurred in 27 patients, including 2 mutation carriers with normal exercise tests. The estimated 8-year event rate was 32% in the total population and 27% and 58% in the patients with and without beta-blockers, respectively. Absence of beta-blockers (hazard ratio [HR], 5.48; 95% CI, 1.80 to 16.68) and younger age at diagnosis (HR, 0.54 per decade; 95% CI, 0.33 to 0.89) were independent predictors. Fatal or near-fatal events defined as aborted cardiac arrest or sudden cardiac death occurred in 13 patients, resulting in an estimated 8-year event rate of 13%. Absence of beta-blockers (HR, 5.54; 95% CI, 1.17 to 26.15) and history of aborted cardiac arrest (HR, 13.01; 95% CI, 2.48 to 68.21) were independent predictors. No difference was observed in cardiac and fatal or near-fatal event rates between probands and family members. Cardiac and fatal or near-fatal events were not rare in both catecholaminergic polymorphic ventricular tachycardia probands and affected family members during the long-term follow-up, even while taking beta-blockers, which was associated with a lower event rate. Further studies evaluating concomitant therapies are necessary to improve outcome in these patients.
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            New normal limits for the paediatric electrocardiogram.

            Previous studies that determined the normal limits for the paediatric ECG had their imperfections: ECGs were recorded at a relatively low sampling rate, ECG measurements were conducted manually, or normal limits were presented for only a limited set of parameters. The aim of this study was to establish an up-to-date and complete set of clinically relevant normal limits for the paediatric ECG. ECGs from 1912 healthy Dutch children (age 11 days to 16 years) were recorded at a sampling rate of 1200 Hz. The digitally stored ECGs were analysed using a well-validated ECG computer program. The normal limits of all clinically relevant ECG measurements were determined for nine age groups. Clinically significant differences were shown to exist, compared with previously established normal limits. Sex differences could be demonstrated for QRS duration and several amplitude measurements. These new normal limits differ substantially from those commonly used and suggest that diagnostic criteria for the paediatric ECG should be adjusted. Copyright 2001 The European Society of Cardiology.
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              Spectrum and frequency of cardiac channel defects in swimming-triggered arrhythmia syndromes.

              Swimming is a relatively genotype-specific arrhythmogenic trigger for type 1 long-QT syndrome (LQT1). We hypothesize that mimickers of concealed LQT1, namely catecholaminergic polymorphic ventricular tachycardia (CPVT), may also underlie swimming-triggered cardiac events. Between August 1997 and May 2003, 388 consecutive, unrelated patients were referred specifically for LQTS genetic testing. The presence of a personal and/or family history of a near-drowning or drowning was determined by review of the medical records and/or phone interviews and was blinded to genetic test results. Comprehensive mutational analysis of the 5 LQTS-causing channel genes, KCNQ1 (LQT1), KCNH2 (LQT2), SCN5A (LQT3), KCNE1 (LQT5), and KCNE2 (LQT6), along with KCNJ2 (Andersen-Tawil syndrome) and targeted analysis of 18 CPVT1-associated exons in RyR2, was performed with the use of denaturing high-performance liquid chromatography and direct DNA sequencing. Approximately 11% (43 of 388) of the index cases had a positive swimming phenotype. Thirty-three of these 43 index cases had a "Schwartz" score (> or =4) suggesting high clinical probability of LQTS. Among this subset, 28 patients (85%) were LQT1, 2 patients (6%) were LQT2, and 3 were genotype negative. Among the 10 cases with low clinical probability for LQTS, 9 had novel, putative CPVT1-causing RyR2 mutations. In contrast to previous studies that suggested universal LQT1 specificity, genetic heterogeneity underlies channelopathies that are suspected chiefly because of a near-drowning or drowning. CPVT1 and strategic genotyping of RyR2 should be considered when LQT1 is excluded in the pathogenesis of a swimming-triggered arrhythmia syndrome.
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                Author and article information

                Journal
                Intern Med
                Intern. Med
                Internal Medicine
                The Japanese Society of Internal Medicine
                0918-2918
                1349-7235
                9 February 2018
                1 July 2018
                : 57
                : 13
                : 1813-1817
                Affiliations
                [1 ]Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Japan
                [2 ]Department of Cardiovascular Medicine, Iga City General Hospital, Japan
                Author notes

                Correspondence to Dr. Seiko Ohno, seikoono@ 123456belle.shiga-med.ac.jp

                Article
                10.2169/internalmedicine.9843-17
                6064684
                29434162
                15c8a39d-da79-49d5-b592-ed88ebb96681
                Copyright © 2018 by The Japanese Society of Internal Medicine

                The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit ( https://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 19 July 2017
                : 6 November 2017
                Categories
                Original Article

                catecholaminergic polymorphic ventricular tachycardia,long qt syndrome,bradycardia,ryr2 mutation

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