Local dispersion of repolarization in the occurrence of ventricular fibrillation in Brugada syndrome: Possibility of phase 2 reentry?

To date, there have been no reports of recording epicardial electrograms at the onset of spontaneous ventricular fibrillation (VF) in patients with Brugada syndrome (BrS). In the case of BrS, unipolar and bipolar electrogram recording on the right ventricular epicardium revealed that dispersion of repolarization with delayed potential was associated with spontaneous occurrence of VF. Phase 2 reentry associated with shortening and dispersion of action potential could have been recorded for the first time in BrS. Epicardial unipolar mapping can guide accurate and appropriate ablation for the elimination of arrhythmia substrate in J wave syndrome.

A case of early repolarization syndrome in which hyponatremia and coronary vasospasms induced ventricular fibrillation.

A 60-year-old man was referred to our hospital presenting with unconsciousness due to severe hyponatremia. The twelve­lead 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.

Early repolarization syndrome, epilepsy, and atrial fibrillation in a young girl with novel KCND3 mutation managed with quinidine.

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.

Transcranial direct current stimulation in patient with J wave syndrome and implantable cardioverter defibrillator.

J wave syndrome is a spectrum of proarrhythmic disorders including Brugada syndrome and early repolarization syndrome (ERS), that are prone to ventricular fibrillation and sudden cardiac death (SCD). In this case report we present a patient with ERS and aborted SCD complicated with cognitive impairment. We also investigated whether performing transcranial direct current stimulation to target his cognitive impairment, interfered with the function of his implantable cardioverter defibrillator.

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

BACKGROUND: The 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. OBJECTIVE: We carried out a VCG analysis after conceiving and measuring a novel parameter (JT-distance) that allows diagnosis of the Brugada ECG pattern. METHODS: A 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. RESULTS: JT-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. CONCLUSIONS: The 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.

The regulation of the small-conductance calcium-activated potassium current and the mechanisms of sex dimorphism in J wave syndrome.

Apamin-sensitive small-conductance calcium-activated potassium (SK) current (IKAS) plays an important role in cardiac repolarization under a variety of physiological and pathological conditions. The regulation of cardiac IKAS relies on SK channel expression, intracellular Ca2+, and interaction between SK channel and intracellular Ca2+. IKAS activation participates in multiple types of arrhythmias, including atrial fibrillation, ventricular tachyarrhythmias, and automaticity and conduction abnormality. Recently, sex dimorphisms in autonomic control have been noticed in IKAS activation, resulting in sex-differentiated action potential morphology and arrhythmogenesis. This review provides an update on the Ca2+-dependent regulation of cardiac IKAS and the role of IKAS on arrhythmias, with a special focus on sex differences in IKAS activation. We propose that sex dimorphism in autonomic control of IKAS may play a role in J wave syndrome.

Day-to-Day Variation of Early Repolarization Pattern Predicts Life-Threatening Arrhythmias in Patients With Brugada Syndrome.

BACKGROUND: We assessed the relationship between day-to-day variation of the early repolarization (ER) pattern and ventricular tachyarrhythmia (VTA) events in Brugada syndrome (BrS) patients because the clinical implications are unclear.Methods and Results:This retrospective study consisted of 41 patients with BrS who underwent implantable cardioverter-defibrillator (ICD) implantation. BrS was diagnosed by a spontaneous or drug-induced type 1 ECG without structural heart disease. Day-to-day variation of the ER pattern was defined as temporal change in the J-point (≥0.1 mV) on ECG. VTA events were detected via ICD interrogation: 15 patients experienced VTA events during 124±62 months' observation. Day-to-day variation of the ER pattern was positive in 7 patients (17%). In the multivariate Cox proportional hazards model, day-to-day variation of a positive ER pattern (hazard ratio [HR]: 3.475, 95% confidence interval [CI]: 1.105-10.414, P=0.034) and documented history of VTA (HR: 4.802, 95% CI: 1.547-17.995, P=0.006) were independent predictors of VTA events. In patients with electrical storm (ES: n=9), day-to-day variation of the ER pattern was positive in 5 patients (56%). ES events were more frequently observed in patients with a positive day-to-day variation of ER pattern than in those without (P<0.05). CONCLUSIONS: The incidence of day-to-day variation of the ER pattern was higher in patients with arrhythmic events of VTA and/or ES among BrS patients with ICD.

Efficacy of a Subcutaneous Implantable Cardioverter Defibrillator in a Child with Early Repolarization Syndrome.

An early repolarization (ER) pattern or J waves are considered to be a benign finding observed in the healthy population, however, it has been pointed out that the ER pattern seen in the inferolateral leads could be an independent risk factor for fatal arrhythmias. We present a pediatric case in which early repolarization syndrome (ERS) was suspected due to the presence of ER or J waves in the inferior leads, which eventually disappeared after the administration of pilsicainide. During the follow-up period, several fatal ventricular arrhythmias were recorded after implantation of a subcutaneous implantable cardiac defibrillator (S-ICD). This report describes the efficacy of S-ICDs in a child with an ER pattern after aborted sudden cardiac death.

A meta-analysis on the prognostic significance of inferolateral early repolarization pattern in Brugada syndrome.

Aims: The early repolarization (ER) pattern has been linked to an increased risk for arrhythmic death in various clinical settings. There are limited and conflicting data regarding the prognostic significance of ER pattern in Brugada syndrome (BS). The aim of this meta-analysis was to provide a detailed analysis of the currently available studies regarding the arrhythmic risk in patients with BS and ER pattern. Methods and results: Current databases were searched until May 2015. A random-effect meta-analysis of the effect of ER pattern on the incidence of arrhythmic events in patients with BS was performed. Five studies were included comprising a total of 1375 patients with BS. An ER pattern was reported in 177 patients (12.8%). During follow-up (44.9-93 months), 143 patients (10.4%) suffered an arrhythmic event. Overall, BS patients with ER pattern displayed an increased risk of arrhythmic events compared to patients without ER (OR 3.29, 95% CI: 2.06 to 5.26, P < 0.00001; Heterogeneity: P = 0.11, I2 = 48%). Three studies provided data regarding ER pattern location. Inferior, lateral, or inferolateral ER pattern location was observed in 20.3%, 32.2%, and 48%, respectively. An inferolateral ER location conferred the higher arrhythmic risk (OR 4.87, 95% CI: 2.64 to 9.01, P< 0.00001; Heterogeneity: P = 0.85, I2 = 0%). Conclusion: This meta-analysis suggests that the ER pattern is associated with a high risk of arrhythmic events in patients with BS. In particular, BS patients with inferolateral ER (global ER pattern) displayed the highest arrhythmic risk.

Exaggerated Reactivity of Parasympathetic Nerves Is Involved in Ventricular Fibrillation in J-Wave Syndrome.

INTRODUCTION: Brugada syndrome (BrS) and early repolarization syndrome (ERS) are termed the J-wave syndrome. In most cases of J-wave syndrome, ventricular fibrillation (VF) often occurs around midnight or in the early morning when parasympathetic tone is augmented. OBJECTIVE: The purpose of this study was to clarify the relationship between VF and autonomic nervous activity in patients with J-wave syndrome. METHODS AND RESULTS: We enrolled 28 consecutive patients with J-wave syndrome (20 BrS and 8 ERS) in whom implantable cardioverter defibrillators (ICDs) were implanted between January 2002 and December 2014. Eleven patients (39%) experienced ICD shock delivery due to VF recurrence after ICD implantation (recurrent-VF group). We investigated baroreflex sensitivity (BRS) using the phenylephrine method, heart rate variability (HRV) with Holter electrocardiography, plasma levels of norepinephrine, and cardiac 123 I-metaiodobenzylguanidine (MIBG) scintigraphy to estimate autonomic nervous function. Upon measurement of HRV, plasma levels of norepinephrine, and 123 I-MIBG testing, there was no significant difference between recurrent-VF and nonrecurrent-VF groups. However, BRS was significantly higher in the recurrent-VF group than in the nonrecurrent-VF group (P = 0.03). Kaplan-Meier curves suggested that high-BRS patients had higher VF recurrence than those with nonhigh-BRS (P = 0.04). Cox proportional hazards regression analyses showed that high BRS was associated independently with VF recurrence (P = 0.002). CONCLUSIONS: Our results suggest that exaggerated reactivity of parasympathetic nerves, as represented by increased BRS, may underlie VF in patients with J-wave syndrome.

Electrophysiological analyses of transgenic mice overexpressing KCNJ8 with S422L mutation in cardiomyocytes.

Genetic analysis of KCNJ8 has pointed a mutation (S422L) as a susceptible link to J wave syndrome (JWS). In vitro expression study indicated that the ATP-sensitive K+ (KATP) channel with the S422L mutation has the gain-of-function with reduced sensitivity to ATP. However, the electrophysiological impact of KCNJ8 has not been elucidated in vivo. Transgenic mouse strains overexpressing KCNJ8 S422L variant (TGmt) or WT (TGWT) in cardiomyocytes have been created to investigate the influence of KCNJ8 in cardiomyocytes and the JWS-related feature of the S422L variant on the cardiac electrophysiology. These TG strains demonstrated distinct changes in the J-ST segment of ECG with marked QT prolongation, which might be ascribed to the action potential prolongation resulting from the reduction of voltage-dependent K+ currents in ventricular cells. The pinacidil-induced KATP current was decreased in these TG myocytes and no obvious difference between TG and non-TG (WT) myocytes in the ATP sensitivity of the KATP channel was observed although the open probability of the KATP channels was significantly lower in TG myocytes than WT. These transgenic mouse strains with distinct ECG changes suggested that the S422L mutation in KCNJ8 gene is not a direct cause of JWS.

Silent and Malignant Early Repolarization Syndrome Mimicking Hyper-Acute ST Elevation Myocardial Infarction.

A 55-year-old male with underlying type 2 diabetes mellitus and hypertension presented at our emergency department with ventricular fibrillation-related cardiac arrest. Hyper-acute ST elevation myocardial infarction was the preliminary diagnosis by 12-lead electrocardiography, which simultaneously showed J point ST elevation and tall T waves. However, the echocardiography showed concentric left ventricle hypertrophy and preserved left ventricular systolic function with no regional wall motion abnormalities, and coronary angiography did not show any critical coronary artery lesion. Malignant early repolarization syndrome was diagnosed, and an implantable cardioverter defibrillator was implanted. Early repolarization syndrome is associated with J point elevation, and more involved leads and an increased J point elevation amplitude can increase the risk of arrhythmogenicity. In summary, we report a case with asymptomatic type 3 early repolarization syndrome-induced idiopathic ventricular fibrillation mimicking hyper-acute ST elevation myocardial infarction.

Some Controversies about Early Repolarization: The Haïssaguerre Syndrome.

Controversy has followed the groundbreaking and cornerstone paper of Haïssaguerre et al. Much of this controversy has been due to the use of the term "early repolarization pattern" and possible waveform morphologies on the standard 12-lead ECG ( it is 10 second strip) that could predict who will manifest the malignant arrhythmogenic syndrome described by Haïssaguerre et al. The standard ECG definition of early repolarization pattern (ERP) or early repolarization variant (ERV) since then has changed its clinical meaning for a surface electrocardiographic waveform from benign to malignant. The new definition of ERP/ERV contains only J wave but ST-segment elevation is no more obligatory. In the old definition, early repolarization pattern (ERP) or early repolarization variant (ERV) 3 is a well-recognized idiopathic electrocardiographic phenomenon considered to be present when at least two adjacent precordial leads show elevation of the ST segment, with values equal or higher than 1 mm. In the new electrocardiographic ERP concept, the ST segment may or may not be elevated and can be up-sloping, horizontal or down-sloping while in the old ERP/ERV concept it must be elevated at least 1 mm in at least two adjacent leads and the variant is characterized by a diffuse elevation of the ST segment of upper concavity, ending in a positive T wave of V2 to V4 or V5 and prominent J wave and ST-segment elevation predominantly in left precordial leads. The phenomenon constitutes a normal variant; it is almost a rule in athletes (present in 89% of the cases in this universe).

Preoperative Prevalence of J-Wave Syndrome Electrocardiographic Patterns and Their Association With Perioperative Cardiac Events.

OBJECTIVE: To evaluate the preoperative prevalence of each type of J-wave syndrome electrocardiographic pattern and its association with perioperative cardiac events. DESIGN: Retrospective study. SETTING: Single hospital university study. PARTICIPANTS: The study evaluated 930 patients who underwent gynecologic, abdominal, neurosurgical, orthopedic, and urologic surgeries. INTERVENTIONS: Preoperative standard 12-lead electrocardiogram (ECG) monitoring was performed, and each type of J-wave syndrome ECG pattern-types 1, 2, and 3 and Brugada syndrome-type-was evaluated. Incidence of perioperative cardiac events was investigated up to 1 year postoperatively using an electronic medical record system. MEASUREMENTS AND MAIN RESULTS: Data from 789 patients were included in the final study. Of these, 16 patients (2.0%) had J-wave syndrome: 7 patients (0.9%) had type-1 patterns; 5 patients (0.6%) had type-2 patterns; 2 patients (0.3%) had type-3 patterns; and 2 patients (0.3%) had Brugada syndrome-type ECG patterns. A J-point elevation≥0.2 mV, which is considered to be more dangerous, was found in only 2 patients with Brugada syndrome-type ECG patterns, both of whom suffered perioperative lethal arrhythmias. CONCLUSION: Patients with J-wave syndrome ECG patterns, even dangerous patterns, are not necessarily associated with a higher risk of perioperative cardiac events. However, Brugada syndrome type ECG patterns should be carefully monitored.

Mechanisms underlying the development of the electrocardiographic and arrhythmic manifestations of early repolarization syndrome.

Early repolarization pattern in the ECG has been associated with increased risk for ventricular tachycardia/fibrillation (VT/VF), particularly when manifest in inferior leads. This study examines the mechanisms underlying VT/VF in early repolarization syndrome (ERS). Transmembrane action potentials (APs) were simultaneously recorded from 2 epicardial sites and 1 endocardial site of coronary-perfused canine left-ventricular (LV) wedge preparations, together with a pseudo-ECG. Transient outward current (Ito) was recorded from epicardial myocytes isolated from the inferior and lateral LV of the same heart. J wave area (pseudo-ECG), epicardial AP notch magnitude and index were larger in inferior vs. lateral wall preparations at baseline and after exposure to provocative agents (NS5806+verapamil+acetylcholine (ACh)). Ito density was greater in myocytes from inferior vs. lateral wall (18.4 ± 2.3pA/pF vs. 11.6 ± 2.0pA/pF; p<0.05). A combination of NS5806 (7 µM) and verapamil (3 µM) or pinacidil (4 µM), used to pharmacologically model the genetic defects responsible for ERS, resulted in prominent J-point and ST-segment elevation. ACh (3 µM), simulating increased vagal tone, precipitated phase-2-reentry-induced polymorphic VT/VF. Using identical protocols, inducibility of arrhythmias was 3-fold higher in inferior vs. lateral wedges. Quinidine (10 µM) or isoproterenol (1 µM) restored homogeneity and suppressed VT/VF. Our data support the hypothesis that 1) ERS is caused by a preferential accentuation of the AP notch in the LV epicardium; 2) this repolarization defect is accentuated by elevated vagal tone; 3) higher intrinsic levels of Ito account for the greater sensitivity of the inferior LV wall to development of VT/VF; and 4) quinidine and isoproterenol exert ameliorative effects by reversing the repolarization abnormality.

Skin sympathetic nerve activity and ST-segment depression in women.

Background: ST-segment depression (ST depression) on exercise electrocardiogram (ECG) and ambulatory ECG monitoring may occur without myocardial ischemia. The mechanisms of nonischemic ST depression remain poorly understood. Objective: The study sought to test the hypothesis that the magnitudes of skin sympathetic nerve activity (SKNA) correlate negatively with the ST-segment height (ST height) in ambulatory participants. Methods: We used neuECG (simultaneous recording of SKNA and ECG) to measure ambulatory ST height and average SKNA (aSKNA) in 19 healthy women, 6 women with a history of Takotsubo syndrome (TTS), and 4 women with ischemia and no obstructive coronary arteries (INOCA). Results: Baseline aSKNA was similar between healthy women, women with TTS, and women with INOCA (1.098 ± 0.291 µV, 0.980 ± 0.061 µV, and 0.919 ± 0.0397 µV, respectively; P = .22). The healthy women had only asymptomatic upsloping ST depression. All participants had a significant (P < .05) negative correlation between ST height and aSKNA. Ischemic episodes (n = 15) were identified in 2 TTS and 4 INOCA participants. The ischemic ST depression was associated with increased heart rate and elevated aSKNA compared with baseline. An analysis of SKNA burst patterns at similar heart rates revealed that SKNA total burst area was significantly higher during ischemic episodes than nonischemic episodes (0.301 ± 0.380 µV·s and 0.165 ± 0.205 µV·s; P = .023) in both the TTS and INOCA participants. Conclusion: Asymptomatic ST depression in ambulatory women is associated with elevated SKNA. Heightened aSKNA is also noted during ischemic ST depression in women with TTS and INOCA. These findings suggest that ST segment depression is a physiological response to heightened sympathetic tone but may be aggravated by myocardial ischemia.

Demonstration of Arrhythmia Substrate-Associated Dispersion of Repolarization by Epicardial Unipolar Mapping in Brugada Syndrome.

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.

Sinus rhythm electrocardiographic abnormalities, sites of origin, and ablation outcomes of ventricular premature depolarizations initiating ventricular fibrillation.

BACKGROUND: Ventricular fibrillation (VF) can be initiated by ventricular premature depolarizations (VPDs) in the absence of obvious structural abnormalities. OBJECTIVE: The purpose of this study was to determine the prevalence of 12-lead electrocardiographic (ECG) sinus rhythm reduced QRS amplitude, QRS fractionation (QRSf), and early repolarization (ER) pattern, and the outcome of catheter ablation and VPD anatomic distribution in patients with VPDs initiating VF. METHODS: We compared a cohort with no apparent structural heart disease and VPDs initiating VF (group 1; n = 42) to a reference cohort (group 2; n = 61) of patients with no structural heart disease and symptomatic unifocal VPDs. RESULTS: A reduced QRS amplitude (<0.55 mV) in aVF (59% vs 10%; P <.001), QRSf in ≥2 contiguous leads (50% vs 16%; P <.001), and ER pattern (21.4% vs 1.6%; P = .01) were more common in group 1 than in group 2. At least 1 abnormal ECG finding was present in 34 group 1 patients (81%) vs 17 group 2 patients (28%) (P <.001). VPD origin included right ventricular and left ventricular distal Purkinje system and moderator band/papillary muscles in 83% of group 1 patients vs 18% of group 2 patients (P <.001). VF was eliminated with a single ablation procedure in 77% of group 1 patients with at least 2 years of follow-up. CONCLUSION: A reduced QRS amplitude (<0.55 mV) in aVF, QRSf in ≥2 contiguous leads, and/or an ER pattern are frequently observed in patients with VPDs initiating VF. VPDs initiating VF typically originate from the distal Purkinje system and papillary muscles and can be successfully eliminated with catheter ablation.

J wave syndromes in patients with spinal and bulbar muscular atrophy.

BACKGROUND: Males with X-linked recessive spinobulbar muscular atrophy (SBMA) are reported to die suddenly and a Brugada electrocardiography (ECG) pattern may be present. A hallmark of this pattern is the presence of ST segment elevations in right precordial leads associated with an increased risk of sudden cardiac death. OBJECTIVE: We aimed to detect subtle myocardial abnormalities using ECG and cardiovascular magnetic resonance imaging (CMR) in patients with SBMA. METHODS: 30 SBMA patients (55.7 ± 11.9 years) and 11 healthy male controls underwent 12-lead ECGs were recorded using conventional and modified chest leads. CMR included feature-tracking strain analysis, late gadolinium enhancement and native T1 and T2 mapping. RESULTS: Testosterone levels were increased in 6/29 patients. Abnormal ECGs were recorded in 70%, consisting of a Brugada ECG pattern, early repolarization or fragmented QRS. Despite normal left ventricular ejection fraction (66 ± 5%), SBMA patients exhibited more often left ventricular hypertrophy as compared to controls (34.5% vs 20%). End-diastolic volumes were smaller in SBMA patients (left ventricular volume index 61.7 ± 14.7 ml/m2 vs. 79.1 ± 15.5 ml/m2; right ventricular volume index 64.4 ± 16.4 ml/m2 vs. 75.3 ± 17.5 ml/m2). Tissue characterization with T1-mapping revealed diffuse myocardial fibrosis in SBMA patients (73.9% vs. 9.1%, device-specific threshold for T1: 1030 ms). CONCLUSION: SBMA patients show abnormal ECGs and structural abnormalities, which may explain an increased risk of sudden death. These findings underline the importance of ECG screening, measurement of testosterone levels and potentially CMR imaging to assess cardiac risk factors.

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

BACKGROUND: Two major forms of inherited J-wave syndrome (JWS) are recognized: early repolarization syndrome (ERS) and Brugada syndrome (BrS). OBJECTIVES: This study sought to assess the distinct features between patients with ERS and BrS carrying pathogenic variants in SCN5A. METHODS: Clinical 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. RESULTS: The 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%. CONCLUSIONS: These 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.