Shortening of the Short Refractory Periods in Short QT Syndrome.

BACKGROUND: Diagnosis of short QT syndrome (SQTS) remains difficult in case of borderline QT values as often found in normal populations. Whether some shortening of refractory periods (RP) may help in differentiating SQTS from normal subjects is unknown. METHODS AND RESULTS: Atrial and right ventricular RP at the apex and right ventricular outflow tract as determined during standard electrophysiological study were compared between 16 SQTS patients (QTc 324±24 ms) and 15 controls with similar clinical characteristics (QTc 417±32 ms). Atrial RP were significantly shorter in SQTS compared with controls at 600- and 500-ms basic cycle lengths. Baseline ventricular RP were significantly shorter in SQTS patients than in controls, both at the apex and right ventricular outflow tract and for any cycle length. Differences remained significant for RP of any subsequent extrastimulus at any cycle length and any pacing site. A cut-off value of baseline RP <200 ms at the right ventricular outflow tract either at 600- or 500-ms cycle length had a sensitivity of 86% and a specificity of 100% for the diagnosis of SQTS. CONCLUSIONS: Patients with SQTS have shorter ventricular RP than controls, both at baseline during various cycle lengths and after premature extrastimuli. A cut-off value of 200 ms at the right ventricular outflow tract during 600- and 500-ms basic cycle length may help in detecting true SQTS from normal subjects with borderline QT values

Etiological diagnosis, prognostic significance and role of electrophysiological study in patients with Brugada ECG and syncope.

BACKGROUND: Syncope is considered a risk factor for life-threatening arrhythmias in Brugada patients. Distinguishing a benign syncope from one due to ventricular arrhythmias is often difficult, unless an ECG is recorded during the episode. Aim of the study was to analyze the characteristics of syncopal episodes in a large population of Brugada patients and evaluate the role of electrophysiological study (EPS) and the prognosis in the different subgroups. METHODS AND RESULTS: One hundred ninety-five Brugada patients with history of syncope were considered. Syncope were classified as neurally mediated (group 1, 61%) or unexplained (group 2, 39%) on the basis of personal and family history, clinical features, triggers, situations, associated signs, concomitant therapy. Most patients underwent EPS; they received ICD or implantable loop-recorder on the basis of the result of investigations and physician's judgment. At 62±45months of mean follow-up, group 1 showed a significantly lower incidence of arrhythmic events (2%) as compared to group 2 (9%, p<0.001). Group 2 patients with positive EPS showed the highest risk of arrhythmic events (27%). No ventricular events occurred in subjects with negative EPS. CONCLUSION: Etiological definition of syncope in Brugada patients is important, as it allows identifying two groups with different outcome. Patients with unexplained syncope and ventricular fibrillation induced at EPS have the highest risk of arrhythmic events. Patients presenting with neurally mediated syncope showed a prognosis similar to that of the asymptomatic and the role of EPS in this group is unproven

In silico investigation of a KCNQ1 mutation associated with short QT syndrome

Short QT syndrome (SQTS) is a rare condition characterized by abnormally ‘short’ QT intervals on the ECG and increased susceptibility to cardiac arrhythmias and sudden death. This simulation study investigated arrhythmia dynamics in multi-scale human ventricle models associated with the SQT2-related V307L KCNQ1 ‘gain-of-function’ mutation, which increases slow-delayed rectifier potassium current (IKs). A Markov chain (MC) model recapitulating wild type (WT) and V307L mutant IKs kinetics was incorporated into a model of the human ventricular action potential (AP) for investigation of QT interval changes and arrhythmia substrates. In addition, the degree of simulated IKs inhibition necessary to normalize the QT interval and terminate re-entry in SQT2 conditions was quantified. The developed MC model accurately reproduced AP shortening and reduced effective refractory period associated with altered IKs kinetics in homozygous (V307L) and heterozygous (WT-V307L) mutation conditions, which increased the lifespan and dominant frequency of re-entry in 3D human ventricle models. IKs reductions of 58% and 65% were sufficient to terminate re-entry in WT-V307L and V307L conditions, respectively. This study further substantiates a causal link between the V307L KCNQ1 mutation and pro-arrhythmia in human ventricles, and establishes partial inhibition of IKs as a potential anti-arrhythmic strategy in SQT2

Profile of Brugada Syndrome Patients Presenting with Their First Documented Arrhythmic Event. Data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

BACKGROUND: Detailed information on the profile of Brugada syndrome (BrS) patients presenting their first arrhythmic event (AE) after prophylactic implantation of a cardioverter defibrillator (ICD) is limited. OBJECTIVES: 1) To compare clinical, electrocardiographic, electrophysiologic and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (CA) (group A) with those in whom the AE was documented after prophylactic ICD implantation (group B); 2) To characterize group B patients' profile using the Class II indications for ICD implantation established by HRS/EHRA/APHRS Expert Consensus Statement in 2013. METHODS: A survey of 23 centers from 10 Western and 4 Asian countries enabled data collection of 678 BrS patients with AE (group A, n=426; group B, n=252). RESULTS: First AE occurred in group B patients 6.7 years later than in group A (46.1+ 13.3 vs. 39.4+15.1, P<0.001). Group B patients had a higher incidence of family history of sudden cardiac death (SCD) and SCN5A mutations. Of the 252 group B patients, 189 (75%) complied with the HRS/EHRA/APHRS indications whereas the remaining 63 (25%) did not. CONCLUSION: BrS patients with first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of SCD and SCN5A mutations compared to those presenting with an aborted CA. Only 75% of patients who suffered an AE after receiving a prophylactic ICD complied with the 2013 Class II indications, suggesting efforts are still required for improving risk stratification

Gender Differences in Patients with Brugada Syndrome and Arrhythmic Events: Data from a Survey on Arrhythmic Events in 678 Patients.

BACKGROUND: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs). OBJECTIVES: To compare clinical, electrocardiographic (ECG), electrophysiologic (EP) and genetic characteristics between males and females in BrS-patients with their first AE. METHODS: The multicenter Survey on AE in BrS (SABRUS) collected data on first AE in 678 BrS-patients including 619 (91.3%) males and 59 (8.7%) females aged 0.27 to 84 (mean 42.5±14.1) years at the time of AE. RESULTS: After excluding pediatric patients, females were older than males (49.5±14.4 vs. 43±12.7 years, respectively, P=0.001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, male/female ratio of AE was ≈9-fold higher compared to Caucasians. Spontaneous type 1 BrS-ECG was associated with earlier onset of AE in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS-ECG was present in males and females above age of 60 years. Females less frequently showed a spontaneous type-1 BrS-ECG (31% vs. 59%, P<0.001) or arrhythmia-inducibility at EP study (34% vs. 64%, P<0.001). An SCN5A mutation was more frequently found in females (47.6% vs. 27.8% in males, P=0.007). CONCLUSIONS: This study confirms that female BrS-patients are much rarer, display less type 1 Brugada-ECG and exhibit lower inducibility rates than males. It shows for the first time that BrS females with AE have higher SCN5A mutation rates as well as the relationship between gender vs. age at onset of AE and ethnicity

Age of First Arrhythmic Event in Brugada Syndrome: Data From the SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) in 678 Patients.

BACKGROUND: Data on the age at first arrhythmic event (AE) in Brugada syndrome are from limited patient cohorts. The aim of this study is 2-fold: (1) to define the age at first AE in a large cohort of patients with Brugada syndrome, and (2) to assess the influence of the mode of AE documentation, sex, and ethnicity on the age at first AE. METHODS AND RESULTS: A survey of 23 centers from 10 Western and 4 Asian countries gathered data from 678 patients with Brugada syndrome (91.3% men) with first AE documented at time of aborted cardiac arrest (group A, n=426) or after prophylactic implantable cardioverter-defibrillator implantation (group B, n=252). The vast majority (94.2%) of the patients were 16 to 70 years old at the time of AE, whereas pediatric (70 years) comprised 4.3% and 1.5%, respectively. Peak AE rate occurred between 38 and 48 years (mean, 41.9±14.8; range, 0.27-84 years). Group A patients were younger than in Group B by a mean of 6.7 years (46.1±13.2 versus 39.4±15.0 years; P<0.001). In adult patients (≥16 years), women experienced AE 6.5 years later than men (P=0.003). Whites and Asians exhibited their AE at the same median age (43 years). CONCLUSIONS: SABRUS (Survey on Arrhythmic Events in Brugada Syndrome) presents the first analysis on the age distribution of AE in Brugada syndrome, suggesting 2 age cutoffs (16 and 70 years) that might be important for decision-making. It also allows gaining insights on the influence of mode of arrhythmia documentation, patient sex, and ethnic origin on the age at AE

Time-to-first appropriate shock in patients implanted prophylactically with an implantable cardioverter-defibrillator: data from the Survey on Arrhythmic Events in BRUgada Syndrome (SABRUS).

Aims: Data on predictors of time-to-first appropriate implantable cardioverter-defibrillator (ICD) therapy in patients with Brugada Syndrome (BrS) and prophylactically implanted ICD's are scarce. Methods and results: SABRUS (Survey on Arrhythmic Events in BRUgada Syndrome) is an international survey on 678 BrS patients who experienced arrhythmic event (AE) including 252 patients in whom AE occurred after prophylactic ICD implantation. Analysis was performed on time-to-first appropriate ICD discharge regarding patients' characteristics. Multivariate logistic regression models were utilized to identify which parameters predicted time to arrhythmia ≤5 years. The median time-to-first appropriate ICD therapy was 24.8 ± 2.8 months. A shorter time was observed in patients from Asian ethnicity (P < 0.05), those with syncope (P = 0.001), and those with Class IIa indication for ICD (P = 0.001). A longer time was associated with a positive family history of sudden cardiac death (P < 0.05). Multivariate Cox regression revealed shorter time-to-ICD therapy in patients with syncope [odds ratio (OR) 1.65, P = 0.001]. In 193 patients (76.6%), therapy was delivered during the first 5 years. Factors associated with this time were syncope (OR 0.36, P = 0.001), spontaneous Type 1 Brugada electrocardiogram (ECG) (OR 0.5, P < 0.05), and Class IIa indication (OR 0.38, P < 0.01) as opposed to Class IIb (OR 2.41, P < 0.01). A near-significant trend for female gender was also noted (OR 0.13, P = 0.052). Two score models for prediction of <5 years to shock were built. Conclusion: First appropriate therapy in BrS patients with prophylactic ICD's occurred during the first 5 years in 76.6% of patients. Syncope and spontaneous Type 1 Brugada ECG correlated with a shorter time to ICD therapy

Fever-related arrhythmic events in the multicenter Survey on Arrhythmic Events in Brugada Syndrome

BACKGROUND: The literature on fever related arrhythmic events (AE) in Brugada syndrome (BrS) is currently limited to few case reports and small series. OBJECTIVE: The current study aims to describe the characteristics of fever-related AE in a large cohort of BrS patients. METHODS: SABRUS is a multicenter study on 678 BrS patients with first AE documented at time of aborted cardiac arrest (ACA) (n=426) or after prophylactic ICD implantation (n=252). RESULTS: In 35(6%) of the 588 patients with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%) and proband (70%). Age at time of AE was 29±24 (range 0.3-76) years. Most patients (80%) presented with ACA and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope and spontaneous type 1 Brugada-ECG were noted in 17%, 40% and 66% of patients, respectively. VF was induced at EPS in 9/19(47%) patients. An SCN5A mutation was found in 14/28(50%) patients. The highest proportion of fever-related AE was observed in the pediatric population (age <16), with disproportionally higher event rate in the very young (0-5 years old) (65%). Males were involved in all age groups and females only in the pediatric and elderly groups. Fever-related AE affected 17 Caucasians aged<24 years, but no Asians aged <24 years. CONCLUSIONS: The risk of fever-related AE in BrS markedly varies according to age group, gender and ethnicity. Taking these factors into account could help the clinical management of BrS patients with fever