J-wave Syndromes Research Articles

Acacetin is a Promising Drug Candidate for Cardiovascular Diseases.

Phytochemical flavonoids have been proven to be effective in treating various disorders, including cardiovascular diseases. Acacetin is a natural flavone with diverse pharmacological effects, uniquely including atrial-selective anti-atrial fibrillation (AF) via the inhibition of the atrial specific potassium channel currents [Formula: see text] (ultra-rapidly delayed rectifier potassium current), [Formula: see text] (acetylcholine-activated potassium current), [Formula: see text] (calcium-activated small conductance potassium current), and [Formula: see text] (transient outward potassium current). [Formula: see text] inhibition by acacetin, notably, suppresses experimental J-wave syndromes. In addition, acacetin provides extensive cardiovascular protection against ischemia/reperfusion injury, cardiomyopathies/heart failure, autoimmune myocarditis, pulmonary artery hypertension, vascular remodeling, and atherosclerosis by restoring the downregulated intracellular signaling pathway of Sirt1/AMPK/PGC-1[Formula: see text] followed by increasing Nrf2/HO-1/SOD thereby inhibiting oxidation, inflammation, and apoptosis. This review provides an integrated insight into the capabilities of acacetin as a drug candidate for treating cardiovascular diseases, especially atrial fibrillation and cardiomyopathies/heart failure.

Distinct Electrogram Features and Ventricular Arrhythmia Induction Modes Between Repolarization and Conduction Heterogeneities

BackgroundRecent clinical studies have indicated the presence of localized electrical abnormalities in idiopathic ventricular fibrillation and J-wave syndrome patients. ObjectivesThis study aims to characterize the specific electrical signatures of localized repolarization and conduction heterogeneities and their respective role in vulnerability to arrhythmias. MethodsOptical mapping was performed in porcine right ventricles with local: 1) repolarization shortening; 2) conduction slowing; or 3) structural heterogeneity induced by locally perfusing: 1) pinacidil (20 μmol/L, n = 13); or 2) flecainide (2 μmol/L, n = 13) via an epicardial catheter; or 3) by local epicardial tissue destruction (9 radiofrequency lesions n = 12). Electrograms were recorded (n = 5 in each group) and spontaneous and induced arrhythmias were quantified and optically mapped. ResultsElectrograms were normal in (1) but showed local fragmentation in 40% of preparations in (2) with greater effects observed at high pacing frequencies dependent on the wavefront direction. In (3), the structural substrate alone increased the width and number of peaks in the electrograms, and addition of flecainide induced pronounced fragmentation (≥3 peaks and ≥70 ms) in all cases. Occurrence of spontaneous arrhythmias was significantly increased in (1) and (2) (P < 0.0001 and 0.05, respectively, vs baseline) and were triggered by ectopies. Vulnerability to arrhythmias at high pacing frequencies (≥2 Hz) was the lowest in (1) and greatest in (2). ConclusionsMicrostructural substrates have the most pronounced impact on electrograms, especially when combined with sodium channel blockers, whereas local action potential duration shortening does not lead to electrogram fragmentation even though it is associated with the highest prevalence of spontaneous arrhythmias.

Abstract 11956: Arumenamide-787 Suppresses Arrhythmogenesis Associated With the J Wave Syndrome as Well as Hypothermia

Background: The J-wave syndromes (JWS), comprised of Brugada (BrS) and early repolarization syndromes (ERS), increase the risk of life-threatening ventricular arrhythmias in patients resulting in sudden cardiac death. There are limited therapeutic strategies to treat these life-threatening conditions. Present management is via an implantable cardioverter defibrillator and/or medication, including quinidine. However, these treatments may have serious side-effects. Thus, novel therapies are needed to treat JWS. In this study, we investigate the effects of ARumenamide-787 (AR-787) in suppressing the electrocardiographic and arrhythmic manifestations of JWS and hypothermia. Methods: We studied the effects of AR-787 on sodium current (I Na ) and the delayed-rectifier potassium current (I Kr ) in HEK-293 cells stably expressing the α- and β1-subunits of the cardiac (Na V 1.5) sodium channel or the hERG channel. In addition, we studied its effect on the transient outward potassium current (I to ) and calcium current (I Ca ) from dissociated canine ventricular myocytes, along with action potentials and ECG from coronary-perfused right (RV) and left (LV) ventricular wedge preparations. The I to agonist, NS5806, I Ca blocker, verapamil, and sodium current (I Na ) blocker, ajmaline, to induce the electrocardiographic and arrhythmic manifestations of JWS (prominent J waves/ST segment elevation, phase 2 reentry, and polymorphic VT/VF) in right and left canine ventricular wedge preparations. Results: AR-787 exerted pleiotropic effects on the cardiac ion channels. The predominant effect was an inhibition of I to and enhancement of I Na , with subtle effects to inhibit the I Kr and augment I Ca . AR-787 diminished the electrocardiographic J wave and prevented and/or suppressed all arrhythmic activity in canine RV and LV experimental models of BrS, ERS and hypothermia. We observed no arrhythmogenic effects of AR-787 on I Kr . Conclusions: Our findings point to AR-787 as a promising candidate for the pharmacologic treatment of JWS and hypothermia. AR-787 suppresses the electrocardiographic and arrhythmic manifestations of JWS and hypothermia without significant prolongation of the QT interval, as with the classic BrS drug, quinidine.

Triggers of Ventricular Fibrillation in Patients With Inferolateral J-Wave Syndrome

BackgroundThere are few data on ventricular fibrillation (VF) initiation in patients with inferolateral J waves. ObjectivesThis multicenter study investigated the characteristics of triggers initiating spontaneous VF in inferolateral J-wave syndrome. MethodsA total of 31 patients (age 37 ± 14 years, 24 male) with spontaneous VF episodes associated with inferolateral J waves were evaluated to determine the origin and characteristics of triggers. The J-wave pattern was recorded in inferior leads in 11 patients, lateral leads in 3, and inferolateral leads in 17. ResultsThe VF triggers (n = 37) exhibited varying QRS durations (176 ± 21 milliseconds, range 119-219 milliseconds) and coupling intervals (339 ± 46 milliseconds, range 250-508 milliseconds) with a right (70%) or left (30%) bundle branch block (BBB) pattern. Trigger patterns were associated with J-wave location: left BBB triggers with inferior J waves and right BBB triggers with lateral J waves. Electrophysiologic study was performed for 22 VF triggers in 19 patients. They originated from the left or right Purkinje system in 6 and from the ventricular myocardium in 10 and were undetermined in 6. Purkinje vs myocardial triggers showed distinct electrocardiographic characteristics in coupling interval and QRS-complex duration and morphology. Abnormal epicardial substrate associated with fragmented electrograms was identified in 9 patients, with triggers originating from the same region in 7 patients. Catheter ablation resulted in VF suppression in 15 patients (79%). ConclusionsVF initiation in inferolateral J-wave syndrome is associated with significant individual heterogeneity in trigger characteristics. Myocardial triggers have electrocardiographic features distinct from Purkinje triggers, and their origin often colocalizes with an abnormal epicardial substrate.

Significance of left posterior extension of early repolarization in patients with J-wave syndrome

J waves in the inferior or lateral leads are characteristic electrocardiographic (ECG) changes in patients with early repolarizationsyndrome (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 V7-V9 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 V7-V9 and an 87-lead BSM. Additionally, we assessed the arrhythmogenicity of the posterior regions based on the morphology ofthe premature ventricular complexes (PVCs) associated with ventricularfibrillation (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 V7-V9 and the BSM system and may be associated with arrhythmogenesis.

Trigger and Substrate Mapping and Ablation for Ventricular Fibrillation in the Structurally Normal Heart.

Sudden cardiac death (SCD) represents approximately 50% of all cardiovascular mortality in the United States. The majority of SCD occurs in individuals with structural heart disease; however, around 5% of individuals have no identifiable cause on autopsy. This proportion is even higher in those <40 years old, where SCD is particularly devastating. Ventricular fibrillation (VF) is often the terminal rhythm leading to SCD. Catheter ablation for VF has emerged as an effective tool to alter the natural history of this disease among high-risk individuals. Important advances have been made in the identification of several mechanisms involved in the initiation and maintenance of VF. Targeting the triggers of VF as well as the underlying substrate that perpetuates these lethal arrhythmias has the potential to eliminate further episodes. Although important gaps remain in our understanding of VF, catheter ablation has become an important option for individuals with refractory arrhythmias. This review outlines a contemporary approach to the mapping and ablation of VF in the structurally normal heart, specifically focusing on the following major conditions: idiopathic ventricular fibrillation, short-coupled ventricular fibrillation, and the J-wave syndromes-Brugada syndrome and early-repolarization syndrome.

Functional identification of hot-spot mutations in cardiac calcium channel genes associated with the J wave syndromes.

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'.

Role of localized repolarization and conduction heterogeneities in ventricular arrhythmias and sudden cardiac death

Recent clinical studies have indicated the presence of localized tissue abnormalities in sudden cardiac death (SCD) survivors without apparent structural heart disease, including idiopathic ventricular fibrillation (VF) and J-wave Syndromes. The origin of these abnormalities, showing distinct electrical features on contact mapping, and mechanisms of associated arrhythmias are still a matter of debate. To determine the respective role of localized repolarization and conduction heterogeneities in vulnerability to arrhythmias and SCD, and to characterize their specific electrical signatures. Optical mapping was performed on porcine right ventricular models of either local (i) repolarization shortening, (ii) conduction slowing, or (iii) micro-structural heterogeneity which were created by locally perfusing (i) pinacidil (20 μM n = 13) or (ii) flecainide (2 μM n = 13) via an epicardial catheter (branch of right coronary artery), or (iii) by local epicardial tissue destruction through radiofrequency application (9 micro lesions 30W 1 sec n = 13). Pseudo-ECG were assessed and the number of induced and spontaneous arrhythmias were quantified and mapped in each preparation. An HD grid mapping catheter was used to record bipolar electrograms (n = 5 in each group). Electrograms were normal in model (i), but showed local fragmentation in 40% of preparations in model (ii) with greater effects observed at high pacing frequencies (3 Hz). In model (iii), the structural substrate alone increased the width and number of peaks in the electrograms, and addition of flecainide (2 μM) in this model induced pronounced fragmentation (≥ 3 peaks and ≥ 70ms duration) in 100% of the cases. Arrhythmogenicity was significantly increased in models (i) and (ii) which presented 82% and 45% more spontaneous arrhythmias (P < 0.0001 and 0.05 vs. baseline) and a reduced pacing frequency threshold to induce arrhythmias (−69% and −50%, P < 0.001 vs. baseline). In these models, the frequency of spontaneous activity was increased (+411% P < 0.01 and +181% P < 0.05 vs. baseline) and originated near the heterogeneous area. Microstructural substrates have the most pronounced impact on electrograms, especially when combined with sodium channel blockers, while repolarization heterogeneities do not lead to electrogram fragmentation but are associated with the highest prevalence of spontaneous arrhythmias. Both heterogeneities show increased ectopic activity.

PO-04-053 OUT-OF-HOSPITAL CARDIAC ARREST ASSOCIATED WITH EARLY REPOLARIZATION

Early repolarization syndrome (ERS) is characterized by J-point elevation presenting as slurring or notching of the terminal part of the QRS complex. Of the several congenital and acquired disorders that encompass J-wave syndromes, ERS has been linked to increased risk of developing polymorphic VT and idiopathic VF that can lead to sudden cardiac death. To describe a patient who presented after a cardiac arrest with initial ECG criteria consistent with Type III ERS who recieved a dual-chamber ICD. n/a We present a case of a 42-year-old man without any prior history that presented to the emergency room after successful resuscitation from out-of-hospital cardiac arrest due to VF. After noticing agonal respiration during early morning hours, his wife called emergency medical services (EMS) and promptly performed cardiopulmonary resuscitation. Upon arrival, EMS found the patient to be in VF. He was shocked once by an automatic external defibrillation leading to ROSC with restoration of sinus rhythm. In the ED, his initial vitals were 122/93 mmHg, 104 bpm, 95% oxygen saturation on room air, and temperature of 36.4 °C. He denied any family history of sudden cardiac death. Wife reported prior history of nocturnal agonal respirations. Initial diagnostic work-up was significant for a leukocytosis of 19,000 and serial high-sensitivity cardiac troponins of 130, 305, and 364 with a 0/3-hour delta change of 234. A12-lead ECG upon presentation is shown in Figure 1 without previous ECGs available for comparison. An emergent coronary angiography was performed which revealed no significant coronary obstruction or anomaly. With both his ECG findings and a Shanghai Score of 7, a diagnosis of Type III ERS was highly suspected. Further diagnostic testing included a TTE showing left ventricular dysfunction with an ejection fraction of 40-45%. CMR showed no delayed gadolinium enhancement. Ultimately, a dual-chamber ICD was implanted during the admission. Follow-up ECGs revealed resolution of slurred terminal QRS complexes. He was discharged on beta blocker and low-dose losartan with close outpatient follow-up with electrophysiology. ECG changes of ERS can be dynamic and may sometimes be concealed, particularly in the setting of an out-of-hospital cardiac arrest. It is important to identify early repolarization patterns due to the adverse prognostic significance especially of Type III ERS which is associated with the highest level of risk for development of malignant arrhythmia.

Electrocardiographic features in SCN5A mutation-positive patients with Brugada and early repolarization syndromes: a systematic review and meta-analysis

BackgroundEarly repolarization syndrome (ERS) and Brugada syndrome (BrS) are both J-wave syndromes. Both can involve mutations in the SCN5A gene but may exhibit distinct electrocardiographic (ECG) differences. The aim of this systematic review and meta-analysis is to investigate possible differences in ECG markers between SCN5A-positive patients with ERS and BrS.MethodsPubMed and Embase were searched from their inception to 20 October 2021 for human studies containing the search terms “SCN5A” and “variant” and “early repolarization” or “Brugada”, with no language restrictions. Continuous variables were expressed as mean±standard deviation. PR interval, QRS duration, QTc and heart rate from the included studies were pooled to calculate a mean for each variable amongst BrS and ERS patients. A two-tailed Student’s t test was then performed to for comparisons.ResultsA total of 328 studies were identified. After full-text screening, 12 studies met our inclusion criteria and were included in this present study. One hundred and four ERS patients (mean age 30.86±14.45) and 2000 BrS patients (mean age 36.17±11.39) were studied. Our meta-analysis found that ERS patients had shorter QRS duration (90.40±9.97 vs. 114.79±20.10, P = 0.0001) and shorter corrected QT intervals (QTc) with borderline significance (393.63±40.04 vs. 416.82±37.43, P = 0.052). By contrast, no significant differences in baseline heart rate (65.15±18.78 vs. 76.06±18.78, P = 0.068) or PR intervals (197.40±34.69 vs. 191.88±35.08, P = 0.621) were observed between ERS and BrS patients.ConclusionBrS patients with positive SCN5A mutations exhibited prolonged QRS, indicating conduction abnormalities, whereas ERS patients with positive SCN5A mutations showed normal QRS. By contrast, whilst QTc intervals were longer in BrS than in ERS SCN5A positive patients, they were within normal limits. Further studies are needed to examine the implications of these findings for arrhythmic risk stratification.

PO-615-05 ACACETIN, A POTENT TRANSIENT OUTWARD CURRENT BLOCKER, MAY BE A NOVEL THERAPEUTIC FOR KCND3-ENCODED KV4.3 GAIN-OF-FUNCTION-ASSOCIATED J-WAVE SYNDROMES

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 (BrS) and early repolarization syndrome (ERS), as well as autopsy-negative sudden unexplained death (SUD). Acacetin, a natural flavone, is a potent Ito current blocker. We hypothesize that Acacetin may be a novel therapeutic for KCND3-mediated JWS. KCND3-V392I was identified in an 18-year-old male with JWS/ERS, and a history of cardiac arrest including ventricular tachycardia/fibrillation and atrial fibrillation/flutter. KCND3-V392I was engineered by site directed mutagenesis and expressed in TSA201 cells. Gene-edited/variant-corrected isogenic control and patient-specific pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) from the KCND3-V392I-positive patient were generated. Ito currents and action potentials (APs) were recorded before and after treatment with Acacetin using the whole cell patch-clamp and multielectrode array (MEA) technique. Western blot and immunocytochemistry were performed to investigate KCND3 expression. KCND3-V392I demonstrated a marked gain-of-function phenotype, increasing peak Ito current density by 92% (p<0.05 vs. KCND3-WT) in TSA201 cells and by 61% in Kv4.3-V392I iPSC-CM (p<0.05 vs. isogenic control). KCND3 transcript and translate expression was increased significantly in KCND3-V392I-derived iPSC-CMs (p<0.05 vs. isogenic control). While KCND3-WT revealed an IC50 of 7.2±1.0 μM for Acacetin effect, 30 μM Acacetin dramatically inhibited KCND3-V392I peak Ito current density by 96% (p<0.05 vs. before Acacetin). 10 μM Acacetin, a concentration approaching its IC50 value, inhibited Ito by 54% (P<0.05 vs. before Acacetin) in patient-derived iPSC-CMs and reduced the accentuated AP notch displayed in KCND3-V392I-derived iPSC-CMs. This pre-clinical study provides pharmacological and functional evidence to suggest that Acacetin may be a novel therapeutic for patients with KCND3 gain-of-function-associated JWS by inhibiting Ito and abolishing the accentuated AP notch in patient-derived iPSC-CMs.

Contribution of the vectorcardiogram in the differential diagnosis of Brugada electrocardiographic pattern

BackgroundThe electrocardiogram (ECG) is a powerful tool for differential diagnosis among a group of pathologies with different therapeutic approaches/prognoses, the so-called J-wave syndrome. The vectorcardiogram (VCG) can be used as a complementary method to the ECG in several dubious electrocardiographic alterations. ObjectiveWe carried out a VCG analysis after conceiving and measuring a novel parameter (JT-distance) that allows diagnosis of the Brugada ECG pattern. MethodsA retrospective cohort study selected ninety-six ECGs with J-point elevation in V1/V2, ECG superior leads and VCGs, all performed on the same day. A new VCG measurement by Frank method (JT-distance) was conceived and designed in transverse and right sagittal planes by 3 lines drawn 1) at the final third of the QRS loop, comprehending the J-point; 2) at the initial portion of the T loop; 3) a parallel of the J-point line at the beginning of the T loop. JT measure was determined by the distance between parallels. A validation cohort was established in a new sample of thirty-five patients. ResultsJT-distance ≥1.5 mm (tranverse plane) and JT-distance >1.25 mm, in the sagittal plane, differentiated Brugada type-1 from Brugada type-2, early repolarization and others, with 95% sensitivity and 68% specificity. JT-distance <1.5 mm (transverse plane) and JT >1.25 mm (sagittal plane) had 100% sensitivity and 85% specificity for Brugada type-1 diagnosis. A validation cohort showed very similar Cohen's kappa levels (0.65 and 0.77, test and validation cohorts, respectively), with overlapping 95% confidence intervals. ConclusionsThe novel vectorcardiogram measurement (JT-distance) presented a new diagnostic criterion to identify Brugada pattern. Nevertheless, prospective studies should be performed by other centers to confirm these findings.

Brugada syndrome and early repolarization syndrome: various clinical forms of J-wave syndrome in one family

Brugada syndrome and early repolarization syndrome: various clinical forms of J-wave syndrome in one family

C40. Early Repolarization Syndrome: The Dangerous One

Abstract Background Early repolarization pattern (ERP) in electrocardiogram (ECG) was thought to be benign in nature. However, for the last 2 decades, several cases reported sudden cardiac deaths (SCD) in patient with ERP. Case Summary A 40-year-old male with a history of several syncope episodes. The latest episode in 2019 at 5 am, a brief convulsion happened before the patient went unconscious. In emergency room, he had another convulsion with a witnessed ventricular fibrillation. After resuscitation and defibrillation, the patient awoke, and ECG was recorded showing ST-segment elevation at V2-3 which suspected to be a Brugada syndrome (BrS). Patient then referred to Sardjito hospital for echocardiography and treadmill test, and the results were within normal limit. Coronary CT Scan showed a non-significant lesion at LAD. Holter examination showed during sleeping, J-wave elevation appeared at the rate of 50 bpm. Meanwhile, during exercise, J-wave disappeared at the rate of 135 bpm. The patient was diagnosed as early repolarization syndrome (ERS) and managed with implantable cardioverter-defibrillator (ICD) implantation. Discussion Patient with ERP who suffers syncope/cardiac arrest is classified as an ERS. Particular clinical findings such as history of cardiac arrest, convulsion, apnea, and ECG findings such as short coupled premature ventricular contraction, dynamic J-wave changes, widespread J-wave are associated with a higher chance for ventricular arrhythmia. Due to its similar nature in ECG morphology and its pathophysiology, ERS and BrS are classified into J-wave syndrome.

C40. Early Repolarization Syndrome: The Dangerous One

Abstract Background Early repolarization pattern (ERP) in electrocardiogram (ECG) was thought to be benign in nature. However, for the last 2 decades, several cases reported sudden cardiac deaths (SCD) in patient with ERP. Case Summary A 40-year-old male with a history of several syncope episodes. The latest episode in 2019 at 5 am, a brief convulsion happened before the patient went unconscious. In emergency room, he had another convulsion with a witnessed ventricular fibrillation. After resuscitation and defibrillation, the patient awoke, and ECG was recorded showing ST-segment elevation at V2-3 which suspected to be a Brugada syndrome (BrS). Patient then referred to Sardjito hospital for echocardiography and treadmill test, and the results were within normal limit. Coronary CT Scan showed a non-significant lesion at LAD. Holter examination showed during sleeping, J-wave elevation appeared at the rate of 50 bpm. Meanwhile, during exercise, J-wave disappeared at the rate of 135 bpm. The patient was diagnosed as early repolarization syndrome (ERS) and managed with implantable cardioverter-defibrillator (ICD) implantation. Discussion Patient with ERP who suffers syncope/cardiac arrest is classified as an ERS. Particular clinical findings such as history of cardiac arrest, convulsion, apnea, and ECG findings such as short coupled premature ventricular contraction, dynamic J-wave changes, widespread J-wave are associated with a higher chance for ventricular arrhythmia. Due to its similar nature in ECG morphology and its pathophysiology, ERS and BrS are classified into J-wave syndrome.

Delta QRS distinguishes Ito -mediated J waves from pseudo J waves produced by conduction delay on body surface electrocardiographic.

On surface electrocardiographic (ECGs), it is difficult to differentiate Ito -mediated J waves, a repolarization phenomenon seen in J wave syndromes (JWS) from terminal QRS deflections that mimic J waves (pseudo J waves) in intraventricular conduction delay (IVCD), an abnormality in depolarization. We hypothesize that the difference between the "maximum QRS duration" inclusive of J point or terminal QRS deflections and the minimum QRS duration identified across a 12-lead ECG is significantly larger in Ito -mediated J waves, and can serve as a marker to make this distinction. A retrospective analysis was performed on adults with ECGs consisting of one of the four following manifestations: J waves associated with hypothermia and early repolarization, and pseudo J waves associated with right bundle branch block (RBBB) and non-specific intraventricular conduction delay (NS-IVCD). All ECGs were assessed individually and the maximum and minimum discrete QRS deflections on 12-lead tracings, defined as "QRSmax " and QRSmin , were identified. The difference between "QRSmax " and QRSmin , designated as ∆QRS, was calculated and compared across the studied populations. A total of 60 patients consisting of 15 patients in each arm were included in the study. ΔQRS was significantly larger in the hypothermia and early repolarization groups, compared to RBBB and NS-IVCD (p<.0001), with the following mean ∆QRS: hypothermia 54.3±13.7ms, early repolarization pattern 47.3±15.3ms, RBBB 19.3±6.5ms, and NS-IVCD 16.0±6.6ms. ∆QRS may serve as a reliable ECG parameter for distinguishing Ito -mediated J waves from pseudo J waves produced by delayed intraventricular conduction.

Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants

BackgroundTwo major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS). ObjectivesThis study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A. MethodsClinical evaluation and next-generation sequencing were performed in 262 probands with BrS and 104 with ERS. Nav1.5 and Kv4.3 channels were studied with the use of patch-clamp techniques. A computational model was used to investigate the protein structure. ResultsThe SCN5A+ yield in ERS was significantly lower than in BrS (9.62% vs 22.90%; P = 0.004). Patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS. More than 2 pathogenic SCN5A variants were found in 5 probands. These patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant. SCN5A-L1412F, detected in a fever-induced ERS patient, led to total loss of function, destabilized the Nav1.5 structure, and showed a dominant-negative effect, which was accentuated during a febrile state. ERS-related SCN5A-G452C did not alter the inward sodium current (INa) when SCN5A was expressed alone, but when coexpressed with KCND3 it reduced peak INa by 44.52% and increased the transient outward potassium current (Ito) by 106.81%. ConclusionsThese findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5A+ ratio in ERS indicates the difference in underlying electrophysiology. These findings also identify the first case of fever-induced ERS and demonstrate a critical role of Ito in JWS and a higher risk for MAE in JWS probands carrying multiple pathogenic variants in SCN5A.

Advances in Mapping and Ablation of Ventricular Fibrillation

Catheter ablation of ventricular fibrillation (VF) is challenging due to the difficulty in interpreting fibrillatory electrograms and the complete hemodynamic collapse with VF precluding detailed mapping. Successful ablation can be performed by eliminating triggers of VF. We review the contemporary advances in VF ablation, especially targeting the substrate for VF. Strategies to map and eliminate the substrate for VF can be applied generally, even in the absence of a reliable trigger. VF substrate can be mapped during sinus rhythm with signature low-voltage, fractionated, and late electrograms. Such substrate can be harbored within regions of scar in structural heart disease, or localized as epicardial microstructural abnormality in Brugada syndrome, inferolateral J-wave syndrome, and unexplained VF. Ablation of such substrate is an effective antiarrhythmic strategy. Furthermore, innovations in expeditious panoramic mapping techniques have generated interest in directly mapping and ablating drivers that sustain VF. Advances in understanding of ablation targets and innovations in mapping techniques are enabling successful ablation of VF in the electrophysiology laboratory. Beyond ablation of VF triggers in a subset of patients, progress is being made in ablating the substrate for VF in patients afflicted by this lethal arrhythmia.

Fibrosis and Conduction Abnormalities as Basis for Overlap of Brugada Syndrome and Early Repolarization Syndrome.

Brugada syndrome and early repolarization syndrome are both classified as J-wave syndromes, with a similar mechanism of arrhythmogenesis and with the same basis for genesis of the characteristic electrocardiographic features. The Brugada syndrome is now considered a conduction disorder based on subtle structural abnormalities in the right ventricular outflow tract. Recent evidence suggests structural substrate in patients with the early repolarization syndrome as well. We propose a unifying mechanism based on these structural abnormalities explaining both arrhythmogenesis and the electrocardiographic changes. In addition, we speculate that, with increasing technical advances in imaging techniques and their spatial resolution, these syndromes will be reclassified as structural heart diseases or cardiomyopathies.

Predictive effect of J waves on cardiac compression and clinical prognosis of esophageal tumors: a retrospective study.

The J wave syndromes (JWS) could be observed in patients with mediastinal tumors, though few studies have verified the statistical correlation between J waves and cardiac compression by tumors. This study aimed to investigate the relationship between J waves and cardiac compression by esophageal tumor and to compare the prediction of J waves on clinical prognosis with that of cardiac compression by esophageal tumor. We enrolled 273 patients (228 males, 45 females; mean 63.8±7.5 years) with esophageal tumors admitted to Shanghai Chest Hospital between August 2016 and November 2020. The J wave was defined as a J-point elevation of ≥0.1 mV in a 12-lead electrocardiogram (ECG) and classified into multiple types. Chest computed tomography (CT) was reviewed to clarify the anatomical relationship between the heart and the esophageal tumor. The prognosis of severe cardiac events and survival status were followed up through medical history, examination records and telephone records. J waves were present in 141 patients among all 273 cases. The sensitivity and specificity of cardiac compression by the tumor for J waves were 78.1% and 67.3%, respectively. The odds ratio (OR) of cardiac compression by the tumor to J waves was 7.33 [95% confidence interval (CI): 4.21-12.74; P<0.001]. The Kappa coefficient between J waves and cardiac compression was 0.44±0.05. The significance association between J waves and cardiac compression was independent from other clinical variables (P<0.001). Decreased J wave amplitude was correlated with the disappearance of cardiac compression during follow-up (P=0.03). Patients with J waves had a higher risk of severe cardiac events than those without J waves (OR =2.84, 95% CI: 1.22-6.63; P=0.01). During the follow-up period, we found that the presence of J waves [hazard ratio (HR) =2.28; 95% CI: 1.35-3.84; P=0.002] and cardiac compression by the tumor (HR =2.51; 95% CI: 1.51-4.17; P<0.001) were both negatively correlated with the survival time of patients. The presence of J waves could be used as an effective mean to predict the mechanical impact of esophageal tumor on the heart, and played an important role in predicting the survival of patients.