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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.)

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]

Of the monomorphic ventricular tachycardias, there are 4 specific tachycardias related to the Purkinje system: 1) idiopathic verapamil-sensitive fascicular ventricular tachycardia (FVT); 2) non-re-entrant FVT; 3) bundle branch re-entry and interfascicular re-entry; and 4) Purkinje-mediated VT in structural heart disease. Verapamil-sensitive FVT is classified into 4 types according to the location of the circuit: 1) left posterior type; 2) left anterior type; 3) left upper septal type;and 4) reverse type. And, in the left anterior and posterior types, there are septal and papillary muscle subtypes. Although macro-re-entry has been reported to be the mechanism underlying verapamil-sensitive FVT, recording the entire circuit is challenging. One possible reason is that the Purkinje-muscle junction may penetrate the myocardial layer as a part of the circuit. The Purkinje network may thus play an important role in the initiation and maintenance of ventricular fibrillation. Further, it has been reported that the development and the abnormalities of the Purkinje system are associated with the arrhythmogenesis of ventricular fibrillation. Furthermore, it has been reported that catheter ablation of trigger ventricular premature complexes, and/or "de-networking" of the Purkinje system, can be used as electrical bailout therapy. There is a hypothesis that the intramural Purkinje system is involved in the generation of J waves. Nevertheless, as there are still unresolved issues that must be debated and accurately analyzed, this review aims to discuss the solved and unsolved questions related to Purkinje-related arrhythmias., Competing Interests: Funding Support and Author Disclosures Dr Nogami has received honoraria from Abbott and Johnson & Johnson; and has received endowments from Medtronic and DVX. Dr Morishima has received honoraria from Abbott. All other authors have reported that they have no relationships relevant to the content of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Mutations in the SCN5A gene has been recognized as resulting in a series of life-threatening arrhythmias. However, it also causes idiopathic ventricular fibrillation (IVF) with J wave in inferior leads and prolonged S-wave upstroke in precordial leads, which has not been previously reported. The present study aimed to study the mechanisms of a patient with IVF manifested with J wave in inferior leads and prolonged S-wave upstroke in precordial leads. The electrocardiograms (ECG) of the proband were recorded and genetic testing was conducted. Patch-clamp and immunocytochemical studies were performed in heterologously transfected 293 cells. The VF attacks was documented in a 55-year-old male proband with syncope episodes. 12-lead ECG shown the transient J wave in the inferior leads and prolonged S-wave upstroke in precordial V1-V3 leads in the same timeframe. Genetic analysis revealed a novel 1 base deletion (G) at position 839 in exon 2 in SCN5A gene (C280S*fs61), which causes a severe truncation of the sodium channel. The functional study revealed that in 293 cells transfected with mutant channel, no sodium current could be recorded even though the immunocytochemical experiment confirmed the truncated sodium channel existed in cytosol. The kinetics of the wild-type (WT) channel were not altered when co-transfected with C280S*fs61 mutant which suggested a haploinsufficiency effect of sodium channel in the cells. The present study identified a novel C280Sfs*61 mutation that caused the 'loss of function' of the sodium channel by haploinsufficiency mechanism. The reduced sodium channel function in the heart may cause conduction delay that may underlie the manifestation of J wave and prolonged S-wave upstroke associated with IVF. [ABSTRACT FROM AUTHOR]

Globally, cardiac channelopathies leading to electrical disorders are responsible for a significant number of sudden cardiac deaths without structural heart disease. Many genes encoding different ion channels in the heart were identified and their impairment was found to be associated with life-threatening cardiac abnormalities. KCND3, one of the genes expressed both in the heart and brain, is reported to have an association with Brugada syndrome, early-onset atrial fibrillation, early repolarization syndrome, and sudden unexplained death syndrome. KCND3 genetic screening could be a promising tool for functional studies for an understanding of the pathogenesis and genetic determinants of the above-mentioned electrical disorders., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ahammed et al.)

Background: The transient outward current (Ito) that mediates early (phase 1) repolarization is conducted by the KCND3 -encoded Kv4.3 pore-forming α-subunit. KCND3 gain-of-function mutations have been reported previously as a pathogenic substrate for J wave syndromes (JWS), including the Brugada syndrome and early repolarization syndrome, as well as autopsy-negative sudden unexplained death (SUD). Acacetin, a natural flavone, is a potent Ito current blocker. Acacetin may be a novel therapeutic for KCND3 -mediated J wave syndrome., Methods: KCND3-V392I was identified in an 18-year-old male with J wave syndrome/early repolarization syndrome, and a history of cardiac arrest including ventricular tachycardia/ventricular fibrillation and atrial fibrillation/atrial flutter. Pathogenic KCND3 mutation was engineered by site-directed mutagenesis and co-expressed with wild-type KChIP2 in TSA201 cells. Gene-edited/variant-corrected isogenic control and patient-specific pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from the p. Val392Ile-KCND3-positive patient were generated. I to currents and action potentials were recorded before and after treatment with Acacetin using the whole cell patch-clamp and multielectrode array technique. Western blot and immunocytochemistry were performed to investigate KCND3 expression., Results: KCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak I to current density by 92.2% ( P <0.05 versus KCND3-WT). KCND3 expression was significantly increased in KCND3-V392I-derived iPSC-CMs ( P <0.05 versus isogenic control). While KCND3-WT revealed an IC50 of 7.2±1.0 µmol/L for acacetin effect, 30 µmol/L acacetin dramatically inhibited KCND3-V392I peak Ito current density by 96.2% ( P <0.05 versus before Acacetin). Ito was also increased by 60.9% in Kv4.3-V392I iPSC-CM ( P <0.05 versus isogenic control iPSC-CM). Ten micromoles per liter acacetin, a concentration approaching its IC50 value, inhibited Ito by ≈50% in patient-derived iPSC-CMs and reduced the accentuated action potential notch displayed in KCND3-V392I-derived iPSC-CMs., Conclusions: This preclinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated J wave syndrome by inhibiting I to and abolishing the accentuated action potential notch in patient-derived iPSC-CMs.

Among the inherited ion channelopathies associated with potentially life-threatening ventricular arrhythmia syndromes in nominally structurally normal hearts are the J wave syndromes, which include the Brugada (BrS) and early repolarization (ERS) syndromes. These ion channelopathies are responsible for sudden cardiac death (SCD), most often in young adults in the third and fourth decade of life. Our principal goal in this review is to briefly outline the clinical characteristics, as well as the molecular, ionic, cellular, and genetic mechanisms underlying these primary electrical diseases that have challenged the cardiology community over the past two decades. In addition, we discuss our recently developed whole-heart experimental model of BrS, providing compelling evidence in support of the repolarization hypothesis for the BrS phenotype as well as novel findings demonstrating that voltage-gated sodium and transient outward current channels can modulate each other's function via trafficking and gating mechanisms with implications for improved understanding of the genetics of both cardiac and neuronal syndromes., (Copyright © 2021. Published by Elsevier Inc.)

The last two decades have changed the viewpoint on early repolarization syndrome (ERS). The prevalence of the early repolarization pattern is variable and ranges between 3-24% depending upon age, gender, and criteria used for J-point upliftment from baseline (0.05mV vs. 1 mV). While this pattern was previously linked with a benign result, multiple recent investigations have found a link between early repolarization and Sudden Cardiac Death (SCD) by causing life-threatening arrhythmias like Ventricular tachycardia/Ventricular fibrillation, a condition known as early repolarization syndrome. The syndrome falls under a broader bracket of J wave syndromes, which can be caused by early repolarization or depolarization abnormalities. The characteristics of early repolarization that are considered high risk for Sudden Cardiac Death include the amplitude of J-point upliftment from baseline ( > 0.2 mV), Inferior-lateral location of Early Repolarization pattern, and horizontal and downsloping ST-segment. Patients with symptomatic early repolarisation patterns on ECG are more likely to have repeated cardiac episodes. Implantable Cardioverter-Defibrillator (ICD) implantation and isoproterenol are the recommended treatments in symptomatic patients. On the other hand, asymptomatic patients with early repolarization patterns are prevalent and have a better outcome. Risk categorization is still obscure in asymptomatic early repolarization patterns. This traditional review outlines the known knowledge of pathophysiology behind the increased risk of sudden cardiac death, risk stratification of patients with ERS, and the treatment guidelines for patients with ERS. Further prospective studies are recommended to elucidate the exact mechanism for ventricular arrhythmogenesis in ERS patients and to risk stratifying asymptomatic patients with ERS., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Yakkali et al.)

A 54-year-old man with early repolarization syndrome (ERS) implanted with an implantable cardioverter-defibrillator (ICD) developed persistent atrial fibrillation (AF) three years after the implantation. Similarly, the remote monitoring system begun frequently detecting ventricular fibrillation (VF) and polymorphic ventricular tachycardia (PVT). Longer RR intervals were repeatedly observed just before the initiation of PVT/VF. Catheter ablation for AF successfully diminished both the PVT and VF events.