The role for ambulatory electrocardiogram monitoring in the diagnosis and prognostication of Brugada syndrome: a sub-study of the Rare Arrhythmia Syndrome Evaluation (RASE) Brugada study.

AIMS: Brugada syndrome (BrS) diagnosis and risk stratification rely on the presence of a spontaneous type 1 (spT1) electrocardiogram (ECG) pattern; however, its spontaneous fluctuations may lead to misdiagnosis and risk underestimation. This study aims to assess the role for repeat high precordial lead (HPL) resting and ambulatory ECG monitoring in identifying a spT1, and evaluate its prognostic role. METHODS AND RESULTS: HPL resting and ambulatory monitoring ECGs of BrS subjects were reviewed retrospectively, and the presence of a spT1 associated with ventricular dysrhythmias and sudden cardiac death (SCD). Three-hundred and fifty-eight subjects (77 with spT1 pattern at presentation, Group 1, and 281 without, Group 2) were included. In total, 1651 resting HPL resting and 621 ambulatory monitoring ECGs were available for review, or adequately described. Over a median follow-up of 72 months (interquartile range - IQR - 75), 42/77 (55%) subjects in Group 1 showed a spT1 in at least one ECG. In Group 2, 36/281 subjects (13%) had a newly detected spT1 (1.9 per 100 person-year) and 23 on an HPL ambulatory recording (8%). Seven previously asymptomatic subjects, five of whom had a spT1 (four at presentation and one at follow-up), experienced arrhythmic events; survival analysis indicated that a spT1, either at presentation or during lifetime, was associated with events. Univariate models showed that a spT1 was consistently associated with increased risk [spT1 at presentation: hazard ratio (HR) 6.3, 95% confidence interval (CI) 1.4-28, P = 0.016; spT1 at follow-up: HR 3.1, 95% CI 1.3-7.2, P = 0.008]. CONCLUSION: Repeated ECG evaluation and HPL ambulatory monitoring are vital in identifying transient spT1 Brugada pattern and its associated risk.

Arrhythmia detection using an implantable loop recorder after a negative electrophysiology study in Brugada syndrome: Observations from a multicenter international registry.

BACKGROUND: Risk stratification in Brugada syndrome (BrS) remains controversial. In this respect, the role of the electrophysiology study (EPS) has been a subject of debate. In some centers, it is common practice to use an implantable loop recorder (ILR) after a negative EPS to help in risk stratification. However, the diagnostic value of this approach has never been specifically addressed. OBJECTIVE: The aim of this study was to describe the baseline characteristics and the main findings of a diagnostic workup strategy with an ILR after a negative EPS in BrS. METHODS: We conducted a retrospective international registry including patients with BrS and negative EPS (ie, noninducible ventricular tachycardia or ventricular fibrillation) before ILR monitoring. RESULTS: The study included 65 patients from 8 referral hospitals in The Netherlands, Spain, and the United Kingdom (mean age, 39 ± 16 years; 72% male). The main indication for ILR monitoring was unexplained syncope/presyncope (66.2%). During a median follow-up of 39.0 months (Q1 25.0-Q3 47.6 months), 18 patients (27.7%) experienced 21 arrhythmic events (AEs). None of the patients died during follow-up. Bradyarrhythmias were the most common finding (47.6%), followed by atrial tachyarrhythmias (38.1%). Only 3 patients presented with ventricular arrhythmias. AEs were considered incidental in 12 patients (66.7%). In 11 patients (61.1%), AEs led to specific changes in treatment. CONCLUSION: The use of ILR after a negative EPS in BrS is a safe strategy that reflected the high negative predictive value of EPS for ventricular arrhythmia in this syndrome. In addition, it allowed the detection of AEs in a significant proportion of patients, with therapeutic implications in most of them.

Subepicardial Cardiomyopathy: A Disease Underlying J-Wave Syndromes and Idiopathic Ventricular Fibrillation.

Brugada syndrome (BrS), early repolarization syndrome (ERS), and idiopathic ventricular fibrillation (iVF) have long been considered primary electrical disorders associated with malignant ventricular arrhythmia and sudden cardiac death. However, recent studies have revealed the presence of subtle microstructural abnormalities of the extracellular matrix in some cases of BrS, ERS, and iVF, particularly within right ventricular subepicardial myocardium. Substrate-based ablation within this region has been shown to ameliorate the electrocardiographic phenotype and to reduce arrhythmia frequency in BrS. Patients with ERS and iVF may also exhibit low-voltage and fractionated electrograms in the ventricular subepicardial myocardium, which can be treated with ablation. A significant proportion of patients with BrS and ERS, as well as some iVF survivors, harbor pathogenic variants in the voltage-gated sodium channel gene, SCN5A, but the majority of genetic susceptibility of these disorders is likely to be polygenic. Here, we postulate that BrS, ERS, and iVF may form part of a spectrum of subtle subepicardial cardiomyopathy. We propose that impaired sodium current, along with genetic and environmental susceptibility, precipitates a reduction in epicardial conduction reserve, facilitating current-to-load mismatch at sites of structural discontinuity, giving rise to electrocardiographic changes and the arrhythmogenic substrate.

The Utility of Sodium Channel Provocation in Unexplained Cardiac Arrest Survivors and Electrocardiographic Predictors of Ventricular Fibrillation Recurrence.

BACKGROUND: The implications of a drug-induced type 1 Brugada ECG pattern following sodium channel blocker provocation (SCBP) are not fully understood. METHODS: Baseline clinical and ECG data were obtained from consecutive unexplained cardiac arrest survivors undergoing SCBP at 3 centers. A further 15 SCBP positive (SCBP+) unexplained cardiac arrest survivors were recruited from 3 additional centers to explore ventricular fibrillation recurrence. RESULTS: A total of 121 consecutive unexplained cardiac arrest survivors underwent SCBP. The yield of the drug-induced type 1 Brugada ECG pattern was 17%. A baseline type 2/3 Brugada pattern (T2/3BP) (adjusted odds ratio, 19.36 [2.74-136.61]; P=0.003) and PR interval (odds ratio, 1.03 [1.01-1.05] per ms; P=0.017) were independent predictors of SCBP+ response. A pathogenic SCN5A variant was identified in 36% of the SCBP+ group versus 0% in the SCBP- group (P<0.001). Amongst SCBP+ patients, a spontaneous type 1 Brugada pattern was identified in 19% during follow up and in 24% a type 1 Brugada pattern was identified in a relative. Prior syncope (adjusted hazard ratio, 3.83 [1.36-10.78]; P=0.011) and the presence of global early repolarization (hazard ratio, 7.91 [3.22-19.44]; P<0.001) were independent predictors of 5-year ventricular fibrillation recurrence. There was a nonsignificant trend toward greater 5-year ventricular fibrillation recurrence in the SCBP- group (23/95 [24%] versus 3/34 [9%]; P=0.055). CONCLUSIONS: The yield of the drug-induced type 1 Brugada ECG pattern in consecutive unexplained cardiac arrest survivors undergoing SCBP is 17%. A baseline T2/3BP and PR interval were independent predictors of the drug-induced type 1 Brugada ECG pattern. Greater heritability of BrS phenotype in this group was evidenced by a greater prevalence of pathogenic SCN5A variants and relatives with a type 1 Brugada pattern. A history of prior syncope and the presence of global early repolarization were independent predictors of ventricular fibrillation recurrence.

Role of subcutaneous implantable loop recorder for the diagnosis of arrhythmias in Brugada syndrome: A United Kingdom single-center experience.

BACKGROUND: Experience with implantable loop recorders (ILRs) in Brugada syndrome (BrS) is limited. OBJECTIVE: The purpose of this study was to evaluate the indications and yield of ILR monitoring in a single-center BrS registry. METHODS: Demographic, clinical and follow-up data of BrS patients with ILR were collected. RESULTS: Of 415 BrS patients recruited consecutively, 50 (12%) received an ILR (58% male). Mean age at ILR implantation was 44 ± 15 years. Thirty-one (62%) had experienced syncopal or presyncopal episodes, and 23 (46%) had palpitations. During median follow-up of 28 months (range 1-68), actionable events were detected in 11 subjects (22%); 7 had recurrences of syncope/presyncope, with 4 showing defects in sinus node function or atrioventricular conduction. New supraventricular tachyarrhythmias were recorded in 6 subjects; a run of fast nonsustained ventricular tachycardia was detected in 1 patient. Patients implanted with an ILR were less likely to show a spontaneous type 1 pattern or depolarization electrocardiographic (ECG) abnormalities compared to those receiving a primary prevention implantable-cardioverter defibrillator. Age at implantation, gender, Shanghai score, and ECG parameters did not differ between subjects with and those without actionable events. ILR-related complications occurred in 3 cases (6%). CONCLUSION: In a large cohort of BrS patients, continuous ILR monitoring yielded a diagnosis of tachy- or bradyarrhythmic episodes in 22% of cases. Recurrences of syncope were associated with bradyarrhythmic events. Use of ILR can be helpful in guiding the management of low-/intermediate-risk BrS patients and ascertaining the cause of unexplained syncope.

Investigation on Sudden Unexpected Death in the Young (SUDY) in Europe: results of the European Heart Rhythm Association Survey.

The aims of this centre-based survey, promoted and disseminated by the European Heart Rhythm Association (EHRA) was to investigate the current practice for the investigation of Sudden Unexplained Death in the Young (SUDY) amongst European countries. An online questionnaire composed of 21 questions was submitted to the EHRA Research Network, European Cardiac Arrhythmia Genetics (ECGen) Focus Group members, and European Reference Network GUARD-Heart healthcare partners. There were 81 respondents from 24 European countries. The majority (78%) worked in a dedicated clinic focusing on families with inherited cardiac conditions and/or SUDY or had easy access to a nearby one. On average, an autopsy was performed in 43% of SUDY cases. Macroscopic examination of the body and all organs were completed in 71% of cases undergoing autopsy, and expert cardiac examination in 32%. Post-mortem genetic testing was requested on average in 37% of Sudden Arrhythmic Death Syndrome (SADS) cases, but not at all by 20% of survey respondents. Psychological support and bereavement counselling for SADS/SUDY families were available for ≤50% of participants. Whilst electrocardiogram (ECG) and echocardiography were largely employed to investigate SADS relatives, there was an inconsistent approach to the use of provocative testing with exercise ECG, sodium channel blocking drugs, and/or epinephrine and genetic testing. The survey highlighted a significant heterogeneity of service provision and variable adherence to current recommendations for the investigation of SUDY, partly attributable to the availability of dedicated units and specialist tests, genetic evaluation, and post-mortem examination.

Genetics and genomics of arrhythmic risk: current and future strategies to prevent sudden cardiac death.

A genetic risk of sudden cardiac arrest and sudden death due to an arrhythmic cause, known as sudden cardiac death (SCD), has become apparent from epidemiological studies in the general population and in patients with ischaemic heart disease. However, genetic susceptibility to sudden death is greatest in young people and is associated with uncommon, monogenic forms of heart disease. Despite comprehensive pathology and genetic evaluations, SCD remains unexplained in a proportion of young people and is termed sudden arrhythmic death syndrome, which poses challenges to the identification of relatives from affected families who might be at risk of SCD. In this Review, we assess the current understanding of the epidemiology and causes of SCD and evaluate both the monogenic and the polygenic contributions to the risk of SCD in the young and SCD associated with drug therapy. Finally, we analyse the potential clinical role of genomic testing in the prevention of SCD in the general population.

Familial Evaluation in Idiopathic Ventricular Fibrillation: Diagnostic Yield and Significance of J Wave Syndromes.

[Figure: see text].

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.

New echocardiographic insights in short QT syndrome: More than a channelopathy?

BACKGROUND: Short QT syndrome (SQTS) is a congenital ion channel disease characterized by an increased risk of sudden cardiac death. Little is known about the possibility that accelerated repolarization alters mechanical function in SQTS. OBJECTIVES: The study investigated the presence of left ventricular dysfunction and mechanical dispersion, assessed by tissue Doppler imaging (TDI) and speckle tracking echocardiography (STE), and their correlation with QT interval duration and genetics. METHODS: Fifteen SQTS patients (7 with HERG and 3 with KCNQ1 mutation) were studied. Electrocardiographic and echocardiographic parameters were compared with age- and sex-matched healthy controls. RESULTS: When compared to the control group, SQTS patients showed reduced left ventricular contraction (global longitudinal strain: -16.0% ± 3.4% vs -22.6% ± 1.7%, P < .001; myocardial performance index 0.59 ± 0.17 vs 0.34 ± 0.08, P < .001) and a higher incidence of ejection fraction <55% (odds ratio 11, 95% confidence interval 1.045-374, P = .04). Mechanical dispersion assessed by TDI (P < .01) and STE (P < .001) was higher in the SQTS group than in controls; each parameter showed a significant inverse correlation with QT interval but not with QT dispersion. CONCLUSION: This study showed that in SQTS systolic function may also be affected. SQTS patients presented a significant dispersion of myocardial contraction. TDI and STE could become part of the evaluation of this rare disease.

Usefulness of exercise test in the diagnosis of short QT syndrome.

AIMS: Short QT syndrome (SQTS) is a rare arrhythmogenic inherited heart disease. Diagnosis can be challenging in subjects with slightly shortened QT interval at electrocardiogram. In this study we compared the QT interval behaviour during exercise in a cohort of SQTS patients with a control group, to evaluate the usefulness of exercise test in the diagnosis of SQTS. METHODS AND RESULTS: Twenty-one SQTS patients and 20 matched control subjects underwent an exercise test. QT interval was measured at different heart rates (HRs), at rest and during effort. The relation between QT interval and HR was evaluated by linear regression analysis according to the formula: QT = ß ×HR + α, where ß is the slope of the linear relation, and α is the intercept. Rest and peak exercise HRs were not different in the two groups. Short QT syndrome patients showed lower QT intervals as compared with controls both at rest (276 ± 27 ms vs. 364 ± 25 ms, P < 0.0001) and at peak exercise (228 ± 27 ms vs. 245 ± 26 ms, P = 0.05), with a mean variation from rest to peak effort of 48 ± 14 ms vs. 120 ± 20 ms (P < 0.0001). Regression analysis of QT/HR relationship revealed a less steep slope for SQTS patients compared with the control group, never exceeding the value of -0.90 ms/beat/min (mean value -0.53 ± 0.15 ms/beat/min vs. -1.29 ± 0.30 ms/beat/min, P < 0.0001). CONCLUSION: Short QT syndrome patients show a reduced adaptation of the QT interval to HR. Exercise test can be a useful tool in the diagnosis of SQTS.

Prevalence of type 1 brugada electrocardiographic pattern evaluated by twelve-lead twenty-four-hour holter monitoring.

Patients with drug-induced type 1 Brugada electrocardiograms (BrECGs) are considered to have good prognosis. Spontaneous type 1 is, instead, considered a risk factor; however, it is probably underestimated because of the BrECG fluctuations. The aim of this study was to analyze, in a large population of patients with Br, the real prevalence of type 1 BrECG using 12-lead 24-hour Holter monitoring (12L-Holter) and its correlation with the time of the day. We recorded 303 12L-Holter in 251 patients. Seventy-five (30%) patients exhibited spontaneous type 1 BrECG at 12-lead ECG (group 1) and 176 (70%) had only drug-induced type 1 (group 2). Type 1 BrECG was defined as "persistent" (>85% of the recording), "intermittent" (<85%), or "absent." In group 1, 12% showed persistent type 1 at 12L-Holter, 57% intermittent type 1%, and 31% never had type 1; in group 2, none had persistent type 1, 20% had intermittent type 1%, and 80% never showed type 1. To evaluate the circadian fluctuations of BrECG, 4 periods in the day were considered. Type 1 BrECG was more frequent between 12-noon and 6 p.m. (52%, p <0.001). In conclusion, in patients with drug-induced type 1, spontaneous type 1 BrECG can be detected more frequently with 12L-Holter than with conventional follow-up with periodic ECGs and this has important implications in the risk stratification. 12L-Holter recording might avoid 20% of the pharmacological challenges with sodium channel blockers, which are not without risks, and should thus be considered as the first screening test, particularly in children or in presence of borderline diagnostic basal ECG.

PQ segment depression in patients with short QT syndrome: a novel marker for diagnosing short QT syndrome?

BACKGROUND: Patients with short QT syndrome (SQTS) have an increased risk for atrial tachyarrhythmias, ventricular tachyarrhythmias, and/or sudden cardiac death. PQ segment depression (PQD) is related to atrial fibrillation and carries a poor prognosis in the setting of acute inferior myocardial infarction and is a well-defined electrocardiographic (ECG) marker of acute pericarditis. OBJECTIVE: To evaluate the prevalence of PQD in SQTS and to analyze the association with atrial arrhythmias. METHODS: Digitalized 12-lead ECGs of SQTS patients were evaluated for PQD in all leads and for QT intervals in leads II and V5. PQD was defined as ≥0.05 mV (0.5 mm) depression from the isoelectric line. RESULTS: A total of 760 leads from 64 SQTS patients (mean age 36 ± 18 years; 48 [75%] men) were analyzed. PQD was seen in 265 (35%) leads from 52 (81%) patients and was more frequent in leads II, V3, aVF, V4, and I (n = 43 [67%], n = 30 [47%], n = 27 [42%], n = 25 [39%], and n = 25 [39%], respectively). Nine of 64 (14%) patients presented with atrial tachyarrhythmias, and all of them had PQD. CONCLUSION: Fifty-two of 64 (81%) patients with SQTS reveal PQD. As PQD is rarely observed in healthy individuals, this ECG stigma may constitute a novel marker for SQTS in addition to a short QT interval.