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A 60-year-old man was referred to our hospital presenting with unconsciousness due to severe hyponatremia. The twelve‑lead ECG on admission exhibited prominent J waves in the inferolateral leads. During the treatment for hyponatremia, ventricular fibrillation (VF) occurred and the electrogram (ECG) after the VF incident exhibited marked ST elevation in the inferolateral leads. An Ach provocation test induced vasospasms in the right and left coronary arteries and J wave augmentation, suggesting a high risk for vasospastic angina. Finally, a subcutaneous implantable cardioverter defibrillator was implanted in the patient. We hereby discuss the possible contribution of hyponatremia to VF episodes in early repolarization syndrome based on the present case. [ABSTRACT FROM AUTHOR]

Early repolarization syndrome (ERS) is an idiopathic ventricular fibrillation (VF) associated with inferolateral J waves. While electrical storm (ES) in ERS is not rare, their characteristics and risk factors are not fully understood. This study aimed to clarify the significance of ES in ERS. We evaluated 44 patients with ERS who experienced VF/sudden cardiac death or arrhythmic syncope. We assessed clinical characteristics to identify the risk factors for ES. In total, 13 patients (30%) experienced ES (ES group). Of these, 11 patients (85%) experienced ES during the acute phase of initial VF episodes and 2 patients (2%) experienced ES during follow-up. VF associated with ES occurred during therapeutic hypothermia in 6 of 13 patients (46%). The J-wave voltage during therapeutic hypothermia was higher in the ES group than that in the patients without ES. Isoproterenol was used in 5 patients (38%), which decreased J-wave voltage and relieved ES. Among the clinical markers, shorter QT and QTp intervals (the interval from QRS onset to the peak of T wave), pilsicainide-induced ST elevation, and high scores on the Shanghai Score System were associated with ES. Although pilsicainide induced ST elevation in 6 of 34 patients (18%), spontaneous Brugada electrocardiographic patterns did not appear to be associated with VF. Therapeutic hypothermia was also a risk factor for acute phase ES. Patients with ERS in the ES group frequently had short QT and QTp intervals, pilsicainide-induced ST elevations, and high Shanghai Score System scores. Therapeutic hypothermia was also associated with acute phase ES. [Display omitted] [ABSTRACT FROM AUTHOR]

Primary electrical heart diseases, often considered channelopathies, are inherited genetic abnormalities of cardiomyocyte electrical behavior carrying the risk of malignant arrhythmias leading to sudden cardiac death (SCD). Approximately 54% of sudden, unexpected deaths in individuals under the age of 35 do not exhibit signs of structural heart disease during autopsy, suggesting the potential significance of channelopathies in this group of age. Channelopathies constitute a highly heterogenous group comprising various diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndromes (ERS). Although new advances in the diagnostic process of channelopathies have been made, the link between a disease and sudden cardiac death remains not fully explained. Evolving data in electrophysiology and genetic testing suggest previously described diseases as complex with multiple underlying genes and a high variety of factors associated with SCD in channelopathies. This review summarizes available, well-established information about channelopathy pathogenesis, genetic basics, and molecular aspects relative to principles of the pathophysiology of arrhythmia. In addition, general information about diagnostic approaches and management is presented. Analyzing principles of channelopathies and their underlying causes improves the understanding of genetic and molecular basics that may assist general research and improve SCD prevention. [ABSTRACT FROM AUTHOR]

Ventricular arrhythmias in cardiac channelopathies are linked to autonomic triggers, which are sub-optimally targeted in current management strategies. Improved molecular understanding of cardiac channelopathies and cellular autonomic signalling could refine autonomic therapies to target the specific signalling pathways relevant to the specific aetiologies as well as the central nervous system centres involved in the cardiac autonomic regulation. This review summarizes key anatomical and physiological aspects of the cardiac autonomic nervous system and its impact on ventricular arrhythmias in primary inherited arrhythmia syndromes. Proarrhythmogenic autonomic effects and potential therapeutic targets in defined conditions including the Brugada syndrome, early repolarization syndrome, long QT syndrome, and catecholaminergic polymorphic ventricular tachycardia will be examined. Pharmacological and interventional neuromodulation options for these cardiac channelopathies are discussed. Promising new targets for cardiac neuromodulation include inhibitory and excitatory G-protein coupled receptors, neuropeptides, chemorepellents/attractants as well as the vagal and sympathetic nuclei in the central nervous system. Novel therapeutic strategies utilizing invasive and non-invasive deep brain/brain stem stimulation as well as the rapidly growing field of chemo-, opto-, or sonogenetics allowing cell-specific targeting to reduce ventricular arrhythmias are presented. [ABSTRACT FROM AUTHOR]

Mapping advances have expanded both the feasibility and benefits of ablation as a therapeutic approach, including in the treatment of two heart conditions that contribute to sudden cardiac death in young people: Brugada syndrome (BrS) and early repolarization syndrome (ERS). Although these conditions share a number of similarities, debates persist regarding the underlying pathophysiology and origin of the ventricular arrhythmias associated with them. By synthesizing available data (PubMed), including current recommendations, pathophysiological insights and case reports, patient registries, our aim is to elucidate and establish the nuanced role of radiofrequency ablation (RFA) in therapeutic management. RFA is a particularly promising approach in BrS, with a proven long-term benefit. Concerning ERS, RFA seems to be interesting at the price of more complex procedures with more nuanced results. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) in children is a devastating event, often linked to primary electrical diseases (PED) of the heart. PEDs, often referred to as channelopathies, are a group of genetic disorders that disrupt the normal ion channel function in cardiac cells, leading to arrhythmias and sudden cardiac death. This paper investigates the unique challenges of risk assessment and stratification for channelopathy-related SCD in pediatric patients—Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, idiopathic ventricular fibrillation, long QT syndrome, Anderson–Tawil syndrome, short QT syndrome, and early repolarization syndrome. We explore the intricate interplay of genetic, clinical, and electrophysiological factors that contribute to the complex nature of these conditions. Recognizing the significance of early identification and tailored management, this paper underscores the need for a comprehensive risk stratification approach specifically designed for pediatric populations. By integrating genetic testing, family history, and advanced electrophysiological evaluation, clinicians can enhance their ability to identify children at the highest risk for SCD, ultimately paving the way for more effective preventive strategies and improved outcomes in this vulnerable patient group. [ABSTRACT FROM AUTHOR]

J waves in the inferior or lateral leads are characteristic electrocardiographic (ECG) changes in patients with early repolarization syndrome (ERS). However, the presence of J waves in the left posterior region has not yet been evaluated. The purpose of this study was to clarify the significance of J waves in the posterior left ventricle using leads V 7 –V 9 and a body surface mapping (BSM) system. Forty patients diagnosed with ERS were included. All patients exhibited J waves in either the contiguous inferior, lateral, or posterior leads. We evaluated the incidence of J waves in the inferolateral and posterior leads using a 15-lead ECG with synthesized V 7 –V 9 and an 87-lead BSM. Additionally, we assessed the arrhythmogenicity of the posterior regions based on the morphology of the premature ventricular complexes (PVCs) associated with ventricular fibrillation (VF). J waves were observed in the lateral, inferior, and posterior leads of 26 (65%), 31 (78%), and 39 (97%) patients, respectively. J waves were found only in the posterior leads of 5 patients. BSM was evaluated in 9 patients, all of whom exhibited a positive area on the posterior region. PVCs associated with VF were recorded in 5 patients. Among patients with inferolateral and posterior J waves, all except 1 patient who displayed left bundle branch block morphology showed PVCs originating from the posterior left ventricular region. Posterior J waves are common in ERS patients. This abnormality can be detected using leads V 7 –V 9 and the BSM system and may be associated with arrhythmogenesis. [Display omitted] [ABSTRACT FROM AUTHOR]

J wave syndrome (JWS) is an inherited cardiac channelopathy associated with malignant ventricular arrhythmias and sudden cardiac death (SCD), which comprises early repolarization syndrome and Brugada syndrome. Here, we explore the association between variants in the L-type calcium channel gene subunits, α1C (CACNA1C) and β2b (CACNB2b), and the JWS phenotype. Using next-generation genetic sequencing of 402 JWS probands and their family members, we identified a CACNA1C-G37R (p.Gly37Arg) mutation in five individuals in four families, two of which had a family history of SCD as well as a CACNB2b-S143F (p.Ser143Phe) mutation in seven individuals in three families, two of which had a family history of SCD. The variants were located in exon 2 in CACNA1C and exon 5 in CACNB2b; both were in highly conserved amino acid residues. Whole-cell patch-clamp results showed that compared with the wild-type group, calcium current density of CACNB2b-S143F and CACNA1C-G37R were significantly lower displaying a dominant-negative effect. Our findings provide further support for the hypothesis that variants in CACNA1C and CACNB2b are associated with JWS. The results suggest that mutations in these two genes lead to loss-of-function of the cardiac calcium channel current warranting their inclusion in genetic screening protocols. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'. [ABSTRACT FROM AUTHOR]

Patients with early repolarization syndrome (ERS) and Brugada syndrome (BruS) have comparable clinical symptoms. In both conditions, ventricular fibrillation (VF) is experienced often near midnight or in the early morning hours when the parasympathetic tone is augmented. However, differences between ERS and BruS regarding the risk of VF occurrence have recently been reported. The role of vagal activity remains especially unclear. The goal of this study was to determine the relationship between VF occurrence and autonomic nervous activity in patients with ERS and BruS. We enrolled 50 patients with ERS (n = 16) and BruS (n = 34) who received an implantable cardioverter-defibrillator. Of these, 20 patients (5 ERS and 15 BruS) experienced VF recurrence (recurrent VF group). We investigated baroreflex sensitivity (BaReS) with the phenylephrine method and heart rate variability using Holter electrocardiography in all patients to estimate autonomic nervous function. In both patients with ERS and BruS, there was no significant difference in heart rate variability between the recurrent VF and nonrecurrent VF groups. However, in patients with ERS, BaReS was significantly higher in the recurrent VF group than in the nonrecurrent VF group (P =.03); this difference was not evident in patients with BruS. High BaReS was independently associated with VF recurrence in patients with ERS according to Cox proportional hazards regression analyses (hazard ratio 1.52; 95% confidence interval 1.031–3.061; P =.032). Our findings suggest that in patients with ERS, an exaggerated vagal response, as represented by increased BaReS indices, may be involved in the risk of VF occurrence. [Display omitted] [ABSTRACT FROM AUTHOR]

The presence of J waves in cases of ventricular fibrillation (VF) is known to be a risk for sudden cardiac death. Recently, the effectiveness of radiofrequency catheter ablation (RFCA) for early repolarization syndrome (ERS) has been reported. The patient is a 30-year-old male with elevated J waves of 0.1 mV in the inferior leads, who had previously developed VF and undergone implantable cardioverter defibrillator (ICD) implantation. Because the VF from short coupled premature ventricular contraction (PVC) was presented, the RFCA of the triggered PVC was attempted. But it was unsuccessful due to no inducibility of the triggered PVC. After that, despite anti-arrythmia drug treatment, appropriate ICD shock for VF was observed. Although we decided to do a second ablation and evaluated epicardial arrhythmia substrate, no specific findings of early repolarization syndrome were found in the electrophysiological study. Finally, we considered that the cause of VF was short-coupled variant of Torsade de Pointes, and PVC ablation was performed. VF has not occurred since. We consider that this is a rare case to evaluate the epicardial arrhythmogenic substrate of J wave. Ablation of the epicardial arrhythmogenic substrate in patients with early repolarization syndrome (ERS) has been shown to be effective, but the relationship between abnormal epicardial potentials and the pathophysiology is unclear. In this case, J-wave and epicardial delayed potentials were not considered to represent obvious arrhythmogenic substrates. Ablation of the triggered premature ventricular contraction may be effective in ERS without apparent abnormal potentials. [ABSTRACT FROM AUTHOR]

Primary electrical heart diseases, often considered channelopathies, are inherited genetic abnormalities of cardiomyocyte electrical behavior carrying the risk of malignant arrhythmias leading to sudden cardiac death (SCD). Approximately 54% of sudden, unexpected deaths in individuals under the age of 35 do not exhibit signs of structural heart disease during autopsy, suggesting the potential significance of channelopathies in this group of age. Channelopathies constitute a highly heterogenous group comprising various diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndromes (ERS). Although new advances in the diagnostic process of channelopathies have been made, the link between a disease and sudden cardiac death remains not fully explained. Evolving data in electrophysiology and genetic testing suggest previously described diseases as complex with multiple underlying genes and a high variety of factors associated with SCD in channelopathies. This review summarizes available, well-established information about channelopathy pathogenesis, genetic basics, and molecular aspects relative to principles of the pathophysiology of arrhythmia. In addition, general information about diagnostic approaches and management is presented. Analyzing principles of channelopathies and their underlying causes improves the understanding of genetic and molecular basics that may assist general research and improve SCD prevention.

Despite early repolarization (ER) syndrome being usually considered benign, its association with severe/malignant ventricular arrhythmias (VA) was also reported. Microvolt T‐wave alternans (MTWA) is an electrocardiographic marker for the development of VA, but its role in ER syndrome remains unknown. A 90‐second 6‐lead electrocardiogram from an ER syndrome patient, acquired with the Kardia recorder, was analyzed by the enhanced adaptive matched filter for MTWA quantification. On average, MTWA was 50 μV, higher than what was previously observed on healthy subjects using the same method. In our ER syndrome patient, MTWA plays a potential role in VA development in ER syndrome. [ABSTRACT FROM AUTHOR]

Abstract Despite early repolarization (ER) syndrome being usually considered benign, its association with severe/malignant ventricular arrhythmias (VA) was also reported. Microvolt T‐wave alternans (MTWA) is an electrocardiographic marker for the development of VA, but its role in ER syndrome remains unknown. A 90‐second 6‐lead electrocardiogram from an ER syndrome patient, acquired with the Kardia recorder, was analyzed by the enhanced adaptive matched filter for MTWA quantification. On average, MTWA was 50 μV, higher than what was previously observed on healthy subjects using the same method. In our ER syndrome patient, MTWA plays a potential role in VA development in ER syndrome.

Background: Several signs of malignant early repolarizations have been proposed in patients with early repolarization syndrome (ERS). However, reports have challenged the efficacy of these signs in predicting future ventricular fibrillation (VF) in patients with ERS., Objective: This study aimed to assess the predictive value of various electrocardiogram (ECG) markers for future VF events in patients with ERS., Methods: We retrospectively evaluated the clinical characteristics of 44 patients with ERS to identify risk factors for VF during follow-up., Results: After the initial event, 16 patients experienced VF (VF group), whereas 28 did not (non-VF group). The VF group had a longer QRS interval, more fragmented QRS (fQRS), and a higher T/R voltage ratio than the non-VF group. Wide J waves were more prevalent in the VF group; however, other J-wave markers did not differ between the groups. Positive late potentials recorded on signal-averaged ECGs were more frequent in the VF group. Whereas none of the patients showed spontaneous Brugada syndrome on ECG, the VF group frequently exhibited pilsicainide-induced ST-segment elevation. These ECG markers were significantly associated with the occurrence of VF during follow-up. Patients with multiple ECG factors, including QRS abnormalities (wide QRS or fQRS), wide J waves, and a high T/R ratio, had a worse prognosis than patients without multiple factors, effectively stratifying patient risk., Conclusion: The occurrence of VF in patients with ERS may be associated with conduction abnormalities such as QRS widening, fQRS, high T/R ratio, positive late potentials, and pilsicainide test results. Therefore, ECG factors could be useful in identifying high-risk patients., Competing Interests: Disclosures H.M. and N.N. are affiliated with the endowed department by Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Early repolarization syndrome is rare in children. Mutation of genes encoding ion channels could display mixed electrophysiological phenotype of Kv4.3 including both cardiac phenotype (early repolarization syndrome, atrial fibrillation) and cerebral phenotype (epilepsy, intellectual disability). This situation is rare and was named as cardiocerebral channelopathy. Here, we report a case of an 11-year-old-girl with cardiocerebral channelopathy caused by KCND3 mutation, who was successfully treated with oral quinidine, metoprolol and implantable cardioverter-defibrillator. Clinicians should be vigilant on the risk of cardiogenic syncope and sudden cardiac death in a patient with epilepsy, intellectual disability and early repolarization pattern.

A 6‐year‐old girl presented with a difficult to control epilepsy syndrome. On evaluation, additional presyncope episodes associated with polymorphic ventricular tachycardia were also noted. A diagnosis of early repolarization syndrome (ERS) was made with an early repolarization pattern on electrocardiogram, documented VT episodes, and clinical presyncope (proposed Shanghai score 7). Paroxysmal atrial fibrillation (AF) was also noted on 24‐h Holter recordings. The child was stabilized with isoprenaline infusion and was later discharged with arrhythmia control on quinidine and cilostazol. The genetic evaluation revealed a potassium channel KCND3 gene missense mutation. The case highlights the association of epilepsy syndrome and AF with ERS; the possible association of KCND3 gene mutation with a malignant phenotype; and management issues in a small child. [ABSTRACT FROM AUTHOR]

Background: In patients with Brugada syndrome, myocardial fibrosis can be identified through epicardial biopsy or cardiac magnetic resonance (CMR) imaging with late gadolinium enhancement (LGE). However, the myocardial alterations in patients with early repolarization syndrome (ERS) remain poorly elucidated., Objective: The objective of this study was to investigate the presence of myocardial fibrosis in patients with ERS by LGE in CMR., Methods: We retrospectively evaluated 20 patients with ERS, all of whom exhibited J waves in the contiguous 2 leads. The location of J waves was classified as in the septum (V 1 -V 2 ), anterior (V 3 -V 4 ), lateral (I, aVL, V 5 -V 6 ), inferior (II, III, aVF), or posterior (V 7 -V 9 ) regions. To compare the distribution of LGE on CMR imaging with J waves, sections on short-axis view of the left ventricle (LV) were categorized as located in the septum, anterior, lateral, inferior, and posterior regions., Results: Overall, 85% of ERS patients displayed LGE, which was more prevalent in the septum and posterior regions, followed by the inferior and lateral regions. The presence or absence of J waves and LGE coincided in 61% of LV areas, whereas discordance between the distributions of J waves and LGE was observed in 38%. LGE was most frequent in the septum (75%), where its reflection in J waves may be less robust. The appearance of LGE was not associated with symptoms, electrical storm, or ventricular fibrillation occurrence during follow-up., Conclusion: LGE is common in patients with ERS, and the distribution of J waves and LGE coincides in approximately 60% of LV areas., Competing Interests: Disclosure H.M. and N.N. are affiliated with a department endowed by Japan Medtronic Inc., (Copyright © 2024 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Epicardial unipolar mapping has not been thoroughly investigated in Brugada syndrome (BrS)., Objectives: This study aims to examine the characteristics of epicardial unipolar potentials in BrS and investigate the differences from overt cardiomyopathy., Methods: Epicardial mapping was performed in 8 patients with BrS and 6 patients with cardiomyopathy. We investigated the J-wave amplitudes using unipolar recordings at delayed potential (DP) sites via bipolar recordings. The repolarization time (RT) at and around the DP recording sites was measured, and maximum dispersion of the RT divided by the distance was defined as the RT dispersion index., Results: Epicardial mapping at baseline revealed significantly higher J-wave amplitude with bipolar DP in patients with BrS than in patients with cardiomyopathy. J-wave amplitude ≥0.42 mV had 99.1% sensitivity and 100% specificity for diagnosing BrS. The RT dispersion index was significantly higher in patients with BrS than in patients with cardiomyopathy at baseline. In all patients with BrS, coved-type unipolar electrograms without negative T waves (short RT) appeared close to coved-type electrograms with negative T waves (long RT) at the DP recording sites after pilsicainide administration. Thus, a steep RT dispersion was observed in this region, and ventricular arrhythmias emerged from this shorter RT area in all 3 patients with BrS in whom ventricular arrhythmias were induced., Conclusions: Bipolar DP-related prominent unipolar J waves and steep repolarization gradients may be more specific for characterizing BrS than for overt cardiomyopathy. Ventricular arrhythmias in BrS are associated with a steep repolarization gradient, indicating phase 2 re-entry as a possible cause., Competing Interests: Funding Support and Author Disclosures Drs Nagase and Morita are affiliated with departments that receive grants from Medtronic. Dr Kataoka has received grants from Medtronic; and has received speaker fees from Medtronic, Biosense Webster, and Abbott. Drs Kamakura, Wakamiya , and Nakajima have received speaker fees from Medtronic and Biosense Webster. Dr Ueda has received speaker fees from Medtronic. Dr Ishibashi has received speaker fees from Medtronic, Abbott, and Japan Lifeline. Dr Miyamoto has received grants from Medtronic, Biosense Webster, and Abbott; and has received speaker fees from Medtronic, Biosense Webster, and Abbott. Dr Kusano has received grants from Medtronic, Biosense Webster, and Abbott; and has received speaker fees from Medtronic and Biosense Webster. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Early repolarization syndrome (ERS) is an inherited sudden cardiac death (SCD) syndrome. The present study investigates the role of genetic variants in cardiac calcium-channel genes in the pathogenesis of ERS and probes the underlying mechanisms.Methods: Polymerase chain reaction–based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium-channel variants were evaluated clinically and compared with matched healthy controls. Wild-type (WT) and mutant CACNA1C genes were coexpressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp techniques and confocal fluorescence microscope.Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium-channel genes (32.2 ± 14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (62.5%), and SCD (56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS-susceptible genes. Compared with controls, the heart rate was slower (72.7 ± 8.9 vs. 65.6 ± 16.1 beats/min, *p < 0.05), QTc interval was shorter (408.2 ± 21.4 vs. 386.8 ± 16.9 ms, **p < 0.01), and Tp-e/QT was longer (0.22 ± 0.05 vs. 0.28 ± 0.04, ***p < 0.001) in single calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C-P817S (c.2449C>T), revealed that the density of whole-cell calcium current (ICa) was reduced by ~84.61% compared to WT (−3.17 ± 2.53 vs. −20.59 ± 3.60 pA/pF, n = 11 and 15, respectively, **p < 0.01). Heterozygous expression of mutant channels was associated with a 51.35% reduction of ICa. Steady-state inactivation was shifted to more negative potentials and significantly accelerated as well. Confocal microscopy revealed trafficking impairment of CACNA1C-P817S (peripheral/central intensity: 0.94 ± 0.10 in WT vs. 0.33 ± 0.12 in P817S, n = 10 and 9, respectively, **p < 0.01).Conclusions: ERS associated with loss-of-function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C-P817S, impaired trafficking of the channel to the membrane contributes to the LOF.

This case outlines the dynamic and often concealed electrocardiographic findings associated with Brugada syndrome and explores its important relationship with early repolarization syndrome as part of a spectrum of inherited J-wave syndromes. (Level of Difficulty: Beginner.)

Relevance of the study of early repolarization syndrome is associated with a high degree of its occurrence among the general population, namely among young people and people doing sports. Objective is to generalize the data of experimental and clinical studies which have found that the early repolarization syndrome is an idiopathic electrocardiographic phenomenon, which is considered by various specialists ambiguously; to assess the state of the cardiovascular system in the subjects, both adults and children with early repolarization syndrome, and to propose a diagnostic algorithm for detecting this phenomenon on the ECG when admitting to physical exercise and sports. The history of the development of early repolarization syndrome has been shown since 1936 to present time, which was first described by R. Shipley and W. Halleran. Clinical interest in ERS appeared as a result of a clinically established relationship with lethal arrhythmias in healthy people without structural changes in the heart. According to existing recommendations, the opinions of leading experts, including members of Heart Rhythm Society (HRS), the European Heart Rhythm Association (EHRA), the Asia-Pacific Society for Heart Rhythm (2015), it should be distinguished between the pattern and the syndrome of early ventricular repolarization. The Shanghai scale for the diagnosis of early repolarization syndrome, as well as the etiology, electrophysiology of early repolarization syndrome, its modern classification and electrocardiographic signs are presented. The features of early repolarization syndrome in athletes and in children, as well as the features of its treatment and prevention are shown. Conclusions. Thus, the early repolarization syndrome is an important cardiac problem. Future clinical and experimental studies should focus on finding out the exact causes and mechanisms for the development of the early repolarization syndrome and, ultimately, on developing strategies to prevent premature death from cardiac causes in individuals with this electrocardiogram disorder.

Ablation of sites showing Purkinje activity is antiarrhythmic in some patients with idiopathic ventricular fibrillation (iVF). The mechanism for the therapeutic success of ablation is not fully understood. We propose that deeper penetrance of the Purkinje network allows faster activation of the ventricles and is proarrhythmic in the presence of steep repolarization gradients. Reduction of Purkinje penetrance, or its indirect reducing effect on apparent propagation velocity may be a therapeutic target in patients with iVF.

Ablation of sites showing Purkinje activity is antiarrhythmic in some patients with idiopathic ventricular fibrillation (iVF). The mechanism for the therapeutic success of ablation is not fully understood. We propose that deeper penetrance of the Purkinje network allows faster activation of the ventricles and is proarrhythmic in the presence of steep repolarization gradients. Reduction of Purkinje penetrance, or its indirect reducing effect on apparent propagation velocity may be a therapeutic target in patients with iVF. [ABSTRACT FROM AUTHOR]

Background: Concomitant apamin-sensitive small conductance calcium-activated potassium current (IKAS) activation and sodium current inhibition induce J-wave syndrome (JWS) in rabbit hearts. Sudden death in JWS occurs predominantly in men at night when parasympathetic tone is strong.Objective: The purpose of this study was to test the hypotheses that acetylcholine (ACh), the parasympathetic transmitter, activates IKAS and causes JWS in the presence of ajmaline.Methods: We performed optical mapping in Langendorff-perfused rabbit hearts and whole-cell voltage clamp to determine IKAS in isolated ventricular cardiomyocytes.Results: ACh (1 μM) + ajmaline (2 μM) induced J-point elevations in all (6 male and 6 female) hearts from 0.01± 0.01 to 0.31 ± 0.05 mV (P<.001), which were reduced by apamin (specific IKAS inhibitor, 100 nM) to 0.14 ± 0.02 mV (P<.001). More J-point elevation was noted in male than in female hearts (P=.037). Patch clamp studies showed that ACh significantly (P<.001) activated IKAS in isolated male but not in female ventricular myocytes (n=8). Optical mapping studies showed that ACh induced action potential duration (APD) heterogeneity, which was more significant in right than in left ventricles. Apamin in the presence of ACh prolonged both APD at the level of 25% (P<.001) and APD at the level of 80% (P<.001) and attenuated APD heterogeneity. Ajmaline further increased APD heterogeneity induced by ACh. Ventricular arrhythmias were induced in 6 of 6 male and 1 of 6 female hearts (P=.015) in the presence of ACh and ajmaline, which was significantly suppressed by apamin in the former.Conclusion: ACh activates ventricular IKAS. ACh and ajmaline induce JWS and facilitate the induction of ventricular arrhythmias more in male than in female ventricles. [ABSTRACT FROM AUTHOR]

Background/Aims: Early repolarization syndrome (ERS) has been recently recognized as early repolarization pattern with idiopathic ventricular fibrillation. However, the genetic background of ERS has not been fully understood. Methods: A Chinese family with sudden cardiac death associated with ERS was investigated. Direct sequencing of ERS susceptibility genes was performed on the proband and family members. Whole-cell patch-clamp methods were used to characterize the mutant channel expressed in HEK 293 cells. Results: One missense mutation (p. K801T) was found in the hERG (KCNH2 gene) by the direct sequencing of candidate genes. Whole cell voltage clamp studies of the K801T mutation in HEK 293 cells demonstrated a 1.5-fold increase in maximum steady state current (37.2±7.3 vs 20.3±4.4 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -59.5±1.4 vs K801T -44.3±1.2 mV). Kinetic analysis revealed slower inactivation rates of K801T, but faster rates of activation and deactivation. The hERG channel blockers tested inhibited K801T-hERG channel in concentration response, and the potencies of these drugs can be rank-ordered as follows: quinidine> disopyramide> sotalol> flecainide. Conclusion: Our study indicated that the K801T mutation caused the gain of function of hERG channels that may account for the clinical phenotype of ERS. Quinidine and disopyramide could improve the function of K801T-hERG mutant channel, and may be therapeutic options for patients with the K801T hERG mutation.

Abstract A 23‐year‐old male with manifest Wolff–Parkinson–White syndrome presented with a first occurrence of ventricular fibrillation (VF). Initially, we anticipated the occurrence of atrial fibrillation, causing rapid antegrade conduction over the accessory pathway and, thus, resulting in hemodynamic deterioration. Electrophysiological study revealed that the atrioventricular accessory pathway was located at the mid‐septum. After eliminating the pathway, a J‐point elevation was revealed in the inferior and lateral leads. In addition, program ventricular stimulation induced VF, and the administration of isoproterenol suppressed VF. In our case, VF occurrence can be attributed to early repolarization syndrome and ventricular preexcitation‐modified J‐point elevation.

In the pathological aspect of J wave syndrome, delayed depolarization is defined as the difference in local conduction velocity of the ventricular myocardium. If polymorphic ventricular tachycardia is induced without local conduction velocity heterogeneity, this contradicts the delayed depolarization theory. In the present study, the transmural conduction time at was evaluated at several transmural locations in a canine early repolarization model. The transmural pseudo-electrocardiogram and endocardial/epicardial action potentials were recorded from coronary-perfused canine left ventricular wedge preparations (n=18). The Ito agonist NS5806 (9-10 µM), Ca2+ channel blocker verapamil (2 µM) and acetylcholine (ACh) (2 µM) were used to pharmacologically mimic early repolarization syndrome genotypes. The transmural conduction times were measured at five fixed epicardial unipolar electrodes before and after the perfusion of provocative agents. The transmural conduction time was defined as the time from endocardial stimulation to the maximal negative deflection (dV/dt) of the endocardial electrogram at the unipolar electrode. Polymorphic ventricular tachycardia developed in 14/18 preparations. In the transmembrane action potentials, there was no definite delayed phase 0 upstroke in any induced polymorphic ventricular tachycardia preparations. In all preparations, the transmural conduction time increased significantly after perfusing the Ito agonist NS5806, verapamil and Ach; however, the increase was only 2.6±0.4 msec, and dispersion of the transmural conduction time did not exhibit significant heterogeneity (7.16±0.93 vs. 7.76±1.21 msec; P=0.240). In the early repolarization model, polymorphic ventricular tachycardia was induced without any regional conduction velocity heterogeneity. This finding suggests that local depolarization heterogeneity would not be a major contributor to the generation of ventricular arrhythmia in the early repolarization syndrome wedge preparation model. [ABSTRACT FROM AUTHOR]

Objective To study the relationship between electrocardiogram (ECG) characteristics and prognosis of early repolarizalion syndrome (ERS ) among community physical examination population. Methods A community population of 6612 was enrolled in our study. These research objects were aged between 18 and 75 years old with complete ECG and clinical data in the remote ECG examination in Binhu Hospital of Hefci City. The patients were diagnosed and classified according to the ECG diagnostic criteria of ERS; their biochemical indicators and clinical data were recorded. Results There are 185 cases with ERS (2. 8%) and 6427 cases without ERS; in the ERS group, the average heart rate is significantly lower than that in the non-ERS group while QT interval and QTc arc both significantly prolonged (P < 0. 05). ERS subgroup analysis indicates that QT interval of the population with amaurosis history is significantly longer than that of the population without amaurosis history (P < 0. 05). There is statistically significant differences between the two groups in aspects of sex, history of smoking, history of amaurosis, body mass index, history of coronary heart disease, diabetes and cerebral infarction, and total cholesterol and high density lipoprotein (P < 0. 05). Regression analysis suggests that heart rate, PQ interval, QHS duration, QT interval and QTc arc risk factors for ERS (P < 0. 05 ) ; age, sex, and histories of hypertension, diabetes and coronary heart disease are not risk factors for EHS (P > 0. 05) . Conclusion Among the ERS patients in the community physical examination population, the heart rate is significantly slower, and QT and QTc intervals an: significantly prolonged; the incidence of amaurosis significantly increases which is apparently corrrelated with QT interval. P-wave duration, PQ interval, QRS duration, and QT interval and QTc may be risk factors for ERS [ABSTRACT FROM AUTHOR]

Objectives. Pericarditis, takotsubo cardiomyopathy and early repolarization syndrome (ERS) are well-known to mimic ST elevation myocardial infarction (STEMI). We aimed to study whether ECG findings of reciprocal ST depression, PR depression, ST-segment convexity or terminal QRS distortion can discriminate between ST elevation due to ischemia and non-ischemic conditions. Design. Eighty-five patients with STEMI and 94 patients with non-ischemic ST elevation were included. All patients had acute chest pain and at least 0.1 mV ST elevation. Presence of PR depression, ST-segment convexity, terminal QRS distortion or reciprocal ST depression was assessed in each ECG. Results. In anterior ST elevation, ST depression in lead II (≥0.025 mV) occurred in 40% of patients with STEMI but in none of the non-ischemic cases. In inferior ST elevation, ST depression in lead I (≥0.025 mV) was present in 83% of patients with STEMI but in none of the non-ischemic cases. Chest-lead PR depression was uncommon in STEMI (12%) compared to non-ischemic cases (38%; p < .001). Convex ST elevation occurred in 22% of STEMI cases and in 9% of non-ischemic cases (p = .01). Terminal QRS distortion was more prevalent in STEMI (40%) than in non-ischemic ST elevation (7%). In multivariable analysis, reciprocal ST depression was associated with an ischemic diagnosis, whereas ST depression in aVR and chest-lead PR depression were associated with a non-ischemic diagnosis. Conclusions. Identification of true STEMI among patients with different ST-elevation etiology may be improved by considering reciprocal ST depression, ST depression in aVR and chest-lead PR depression. [ABSTRACT FROM AUTHOR]

Background: Early repolarization syndrome (ERS) is a rare but increasingly recognized cause of malignant ventricular arrhythmias.Objective: The purpose of this study was to characterize the presentations and treatments of ERS at our institution.Methods: We performed a retrospective chart review of all patients presenting to our institution between 2008 and 2019 with ERS. Exclusion criteria included Brugada syndrome, positive provocative testing with class I antiarrhythmic drugs, metabolic disturbances, or structural heart disease.Results: Of 10 patients identified with ERS, 8 were men with a mean age of 30 ± 17 years at diagnosis. Documented arrhythmias included ventricular fibrillation in 7 of 10, polymorphic ventricular tachycardia in 3 of 10, and monomorphic ventricular tachycardia in 3 of 10 patients. Atrial fibrillation was diagnosed in 3 of 10, and atrioventricular block was seen in 2 of 10. J waves and/or electrocardiographic early repolarization patterns were dynamic in 7 of 10. Arrhythmias occurred at rest in 8 of 10 and with exertion in 2 of 10. Only 1 patient had a family history of sudden death, and 4 of 10 patients had variants of uncertain significance on genetic testing. Quinidine effectively suppressed arrhythmias in 5 of 5 patients but required dose escalation to >1 g/d in 3 of 5 patients. Abnormal epicardial electrograms were recorded over the inferolateral left ventricle in 2 patients who underwent mapping and were successfully ablated. Premature ventricular contraction triggers were also targeted for ablation in 3 patients.Conclusion: ERS is a heterogeneous condition and may be associated with both atrial and ventricular arrhythmias, atrioventricular block, dynamic electrocardiographic changes, and variable triggers. In addition to targeting premature ventricular contraction triggers, mapping and ablation of abnormal epicardial electrograms may be a potential future treatment strategy. [ABSTRACT FROM AUTHOR]

Early repolarization syndrome (ERS) is defined as occurring in patients with early repolarization pattern who have survived idiopathic ventricular fibrillation with clinical evaluation unrevealing for other explanations. The pathophysiologic basis of the ERS is currently uncertain. The objective of the present study was to examine the electrophysiological mechanism of ERS utilizing induced pluripotent stem cells (iPSCs) and CRISPR/Cas9 genome editing. Whole genome sequencing was used to identify the DPP6 (c.2561T > C/p.L854P) variant in four families with sudden cardiac arrest induced by ERS. Cardiomyocytes were generated from iPSCs from a 14-year-old boy in the four families with ERS and an unrelated healthy control subject. Patch clamp recordings revealed more significant prolongation of the action potential duration (APD) and increased transient outward potassium current (I to) (103.97 ± 18.73 pA/pF vs 44.36 ± 16.54 pA/pF at +70 mV, P < 0.05) in ERS cardiomyocytes compared with control cardiomyocytes. Of note, the selective correction of the causal variant in iPSC-derived cardiomyocytes using CRISPR/Cas9 gene editing normalized the I to , whereas prolongation of the APD remained unchanged. ERS cardiomyocytes carrying DPP6 mutation increased I to and lengthen APD, which maybe lay the electrophysiological foundation of ERS. [ABSTRACT FROM AUTHOR]

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Acetylcholine is widely used for a diagnostic provocation test of coronary spasm in patients with vasospastic angina. Acetylcholine usually induces coronary vasodilatation mediated by muscarinic receptor activation, but sometimes it evokes vasoconstriction of coronary arteries where the endothelium is damaged. Early repolarization syndrome is characterized by a J wave observed at the end of the QRS complex in a surface electrocardiogram. The J wave is attributed to the transmural voltage gradient at the early repolarization phase across the ventricular wall, which stems mainly from prominent transient outward current in the epicardium, but not in the endocardium. Transient high-dose application of acetylcholine into the epicardial coronary arteries provides a unique opportunity to augment net outward current, selectively, in the ventricular epicardium and unmask the J wave, irrespective of the cardiac ischemia based on coronary spasm. Acetylcholine augments cardiac membrane potassium conductance by enhancing acetylcholine-activated potassium current directly and by activating adenosine triphosphate-sensitive potassium current, in addition to the reduced sodium and calcium currents in the setting of severe ischemia due to vasospasm. However, the role of acetylcholine as an arrhythmogenic probe of the J wave induction in patients with suspected early repolarization syndrome warrants future prospective study.

Most causal genes for inherited arrhythmia syndromes (IASs) encode cardiac ion channel-related proteins. Genotype-phenotype studies and functional analyses of mutant genes, using heterologous expression systems and animal models, have revealed the pathophysiology of IASs and enabled, in part, the establishment of causal gene-specific precision medicine. Additionally, the utilization of induced pluripotent stem cell (iPSC) technology have provided further insights into the pathophysiology of IASs and novel promising therapeutic strategies, especially in long QT syndrome. It is now known that there are atypical clinical phenotypes of IASs associated with specific mutations that have unique electrophysiological properties, which raises a possibility of mutation-specific precision medicine. In particular, patients with Brugada syndrome harboring an SCN5A R1632C mutation exhibit exercise-induced cardiac events, which may be caused by a marked activity-dependent loss of R1632C-Nav1.5 availability due to a marked delay of recovery from inactivation. This suggests that the use of isoproterenol should be avoided. Conversely, the efficacy of β-blocker needs to be examined. Patients harboring a KCND3 V392I mutation exhibit both cardiac (early repolarization syndrome and paroxysmal atrial fibrillation) and cerebral (epilepsy) phenotypes, which may be associated with a unique mixed electrophysiological property of V392I-Kv4.3. Since the epileptic phenotype appears to manifest prior to cardiac events in this mutation carrier, identifying KCND3 mutations in patients with epilepsy and providing optimal therapy will help prevent sudden unexpected death in epilepsy. Further studies using the iPSC technology may provide novel insights into the pathophysiology of atypical clinical phenotypes of IASs and the development of mutation-specific precision medicine.

Background: Early repolarization syndrome (ERS) is characterized by J-point elevation on electrocardiograms and ventricular fibrillation (VF). Early repolarization arises from augmentation of the transmural electrical gradient in the cardiac action potential; therefore, the transient outward potassium current (Ito) has been regarded as a key candidate current for elucidating the mechanism of ERS. KCND3 encoding Kv4.3, an α-subunit of the Ito channel, is considered as one of target genes.Objective: The purpose of this study was to search for novel KCND3 mutations associated with ERS and to clarify the pathogenesis.Methods: We performed genetic screening for 11 unrelated probands with ERS and analyzed the electrophysiological properties of detected mutations by patch-clamp methods.Results: A novel de novo KCND3 heterozygous mutation, Gly306Ala (c.917g>c), was found in 1 proband. The proband was a 12-year-old boy, who suffered VF storm and showed significant J-point elevation in multiple leads. Intravenous isoproterenol and subsequent administration of quinidine were effective in preventing VF recurrence and restored the J-point elevation. In electrophysiological analysis, cultured cells expressing mutant Kv4.3 showed significantly increased current densities, slow inactivation, and slow recovery from inactivation compared to wild type. Extracellular application of quinidine significantly restored the inactivation time course in mutant Kv4.3. A simulation study confirmed the relationship between the novel KCND3 mutation and early repolarization on electrocardiograms.Conclusion: A novel KCND3 heterozygous mutation was found to be associated with ERS. The pathogenesis can be explained by the increased Ito. Genetic screening for KCND3 could be useful for understanding the pathogenesis and selecting effective treatment. [ABSTRACT FROM AUTHOR]