Brugada syndrome clinical update.

Brugada syndrome (BrS) was initially described in southeast Asians with a structurally normal heart presenting with polymorphic ventricular tachycardia and fibrillation. This condition is marked by J-point elevation ≥ 2 mm with coved-type ST segment elevation followed by negative T wave inversions in at least one precordial lead (V1 or V2) when other etiologies have been excluded. These changes on electrocardiogram (EKG) can either be spontaneous or manifest after sodium channel blockade. The worldwide prevalence of BrS is about 0.4%; however, it is higher in the Asian population at 0.9%. This article will review the current hypotheses regarding the pathophysiology, spectrum of clinical presentation, strategies for prevention of sudden cardiac death and the treatment for recurrent arrhythmias in BrS.

Ethnic differences in patients with Brugada syndrome and arrhythmic events: New insights from Survey on Arrhythmic Events in Brugada Syndrome.

BACKGROUND: There is limited information on ethnic differences between patients with Brugada syndrome (BrS) and arrhythmic events (AEs). OBJECTIVE: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between white and Asian patients with BrS and AEs. METHODS: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter survey from Western and Asian countries, gathering 678 patients with BrS and first documented AE. After excluding patients with other (n = 14 [2.1%]) or unknown (n = 30 [4.4%]) ethnicity, 364 (53.7%) whites and 270 (39.8%) Asians comprised the study group. RESULTS: There was no difference in AE age onset (41.3 ± 16.1 years in whites vs 43.3 ± 12.3 years in Asians; P = .285). Higher proportions of whites were observed in pediatric and elderly populations. Asians were predominantly men (98.1% vs 85.7% in whites; P < .001) and frequently presented with aborted cardiac arrest (71.1% vs 56%; P < .001). Asians tended to display more spontaneous type 1 BrS-ECG pattern (71.5% vs 64.3%; P = .068). A family history of sudden cardiac death was noted more in whites (29.1% vs 11.5%; P < .001), with a higher rate of SCN5A mutation carriers (40.1% vs 13.2% in Asians; P < .001), as well as more fever-related AEs (8.5% vs 2.9%; P = .011). No difference was observed between the 2 groups regarding history of syncope and ventricular arrhythmia inducibility. CONCLUSION: There are important differences between Asian and white patients with BrS. Asian patients present almost exclusively as male adults, more often with aborted cardiac arrest and spontaneous type 1 BrS-ECG. However, they have less family history of sudden cardiac death and markedly lower SCN5A mutation rates. The striking difference in SCN5A mutation rates should be tested in future studies.

SCN5A mutation status increases the risk of major arrhythmic events in Asian populations with Brugada syndrome: systematic review and meta-analysis.

BACKGROUND: Brugada syndrome (BrS) is an inherited arrhythmic disease linked to SCN5A mutations. It is controversial whether SCN5A mutation carriers possess a greater risk of major arrhythmic events (MAE). We examined the association of SCN5A mutations and MAE in BrS patients. METHODS: We comprehensively searched the databases of MEDLINE and EMBASE from inception to September 2017. Included studies were published cohort and case-control studies that compared MAE in BrS patients with and without SCN5A mutations. Data from each study were combined using the random-effects model. Generic inverse variance method of DerSimonian and Laird was employed to calculate the risk ratios (RR) and 95% confidence intervals (CI). RESULTS: Seven studies from March 2002 to October 2017 were included (1,049 BrS subjects). SCN5A mutations were associated with MAE in Asian populations (RR = 2.03, 95% CI: 1.37-3.00, p = 0.0004, I2  = 0.0%), patients who were symptomatic (RR = 2.66, 95% CI: 1.62-4.36, p = 0.0001, I2  = 23.0%), and individuals with spontaneous type-1 Brugada pattern (RR = 1.84, 95% CI: 1.05-3.23, p = 0.03, I2  = 0.0%). CONCLUSIONS: SCN5A mutations in BrS increase the risk of MAE in Asian populations, symptomatic BrS patients, and individuals with spontaneous type-1 Brugada pattern. Our study suggests that SCN5A mutation status should be an important tool for risk assessment in BrS patients.

An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation.

Calcium regulation plays a central role in cardiac function. Several variants in the calcium channel Cav1.2 have been implicated in arrhythmic syndromes. We screened patients with Brugada syndrome, short QT syndrome, early repolarisation syndrome, and idiopathic ventricular fibrillation to determine the frequency and pathogenicity of Cav1.2 variants. Cav1.2 related genes, CACNA1C, CACNB2 and CACNA2D1, were screened in 65 probands. Missense variants were introduced in the Cav1.2 alpha subunit plasmid by mutagenesis to assess their pathogenicity using patch clamp approaches. Six missense variants were identified in CACNA1C in five individuals. Five of them, A1648T, A1689T, G1795R, R1973Q, C1992F, showed no major alterations of the channel function. The sixth C-terminal variant, Cavα1c-T1787M, present mostly in the African population, was identified in two patients with resuscitated cardiac arrest. The first patient originated from Cameroon and the second was an inhabitant of La Reunion Island with idiopathic ventricular fibrillation originating from Purkinje tissues. Patch-clamp analysis revealed that Cavα1c-T1787M reduces the calcium and barium currents by increasing the auto-inhibition mediated by the C-terminal part and increases the voltage-dependent inhibition. We identified a loss-of-function variant, Cavα1c-T1787M, present in 0.8% of the African population, as a new risk factor for ventricular arrhythmia.

Critical Roles of Xirp Proteins in Cardiac Conduction and Their Rare Variants Identified in Sudden Unexplained Nocturnal Death Syndrome and Brugada Syndrome in Chinese Han Population.

BACKGROUND: Sudden unexplained nocturnal death syndrome (SUNDS) remains an autopsy negative entity with unclear etiology. Arrhythmia has been implicated in SUNDS. Mutations/deficiencies in intercalated disc components have been shown to cause arrhythmias. Human cardiomyopathy-associated 1 (XIRP1) and 3 (XIRP2) are intercalated disc-associated, Xin repeats-containing proteins. Mouse Xirp1 is necessary for the integrity of intercalated disc and for the surface expression of transient outward and delayed rectifier K+ channels, whereas mouse Xirp2 is required for Xirp1 intercalated disc localization. Thus, XIRP1 and XIRP2 may be potentially causal genes for SUNDS. METHODS AND RESULTS: We genetically screened XIRP genes in 134 sporadic SUNDS victims and 22 Brugada syndrome (BrS) cases in a Chinese Han population. We identified 16 rare variants (6 were in silico predicted as deleterious) in SUNDS victims, including a novel variant, XIRP2-E215K. There were also four rare variants (2 were in silico predicted as deleterious) detected in BrS cases, including a novel variant, XIRP2-L2718P. Interestingly, among these 20 variants, we detected 2 likely pathogenic variants: a nonsense variant (XIRP2-Q2875*) and a frameshift variant (XIRP2-T2238QfsX7). Analyzing available Xirp2 knockout mice, we further found that mouse hearts without Xirp2 exhibited prolonged PR and QT intervals, slow conduction velocity, atrioventricular conduction block, and an abnormal infranodal ventricular conduction system. Whole-cell patch-clamp detected altered ionic currents in Xirp2-/- cardiomyocytes, consistent with the observed association between Xirp2 and Nav1.5/Kv1.5 in co-immunoprecipitation. CONCLUSIONS: This is the first report identifying likely pathogenic XIRP rare variants in arrhythmogenic disorders such as SUNDS and Brugada syndrome, and showing critical roles of Xirp2 in cardiac conduction.

An East Asian Common Variant Vinculin P.Asp841His Was Associated With Sudden Unexplained Nocturnal Death Syndrome in the Chinese Han Population.

BACKGROUND: We have identified the cardiomyopathy-susceptibility gene vinculin (VCL) mutation M94I may account for a sudden unexplained nocturnal death syndrome (SUNDS) case. We addressed whether VCL common variant D841H is associated with SUNDS. METHODS AND RESULTS: In 8 of 120 SUNDS cases, we detected an East Asian common VCL variant p.Asp841His (D841H). Comparing the H841 allele frequency of the general population in the local database (15 of 1818) with SUNDS victims (10 of 240) gives an odds ratio for SUNDS of 5.226 (95% CI, 2.321, 11.769). The VCL-D841H variant was engineered and either coexpressed with cardiac sodium channel (SCN5A) in HEK293 cells or overexpressed in human induced pluripotent stem-cell-derived cardiomyocytes to examine its effects on sodium channel function using the whole-cell patch-clamp method. In HEK293 cells, under physiological pH conditions (pH 7.4), D841H caused a 29% decrease in peak INa amplitude compared to wild type (WT), whereas under acidotic conditions (pH 7.0), D841H decreased further to 43% along with significant negative shift in inactivation compared to WT at pH 7.4. In induced pluripotent stem-cell-derived cardiomyocytes, similar effects of D841H on INa were observed. VCL colocalized with SCN5A at the intercalated disk in human cardiomyocytes. VCL was also confirmed to directly interact with SCN5A, and VCL-D841H did not disrupt the association of VCL and SCN5A. CONCLUSIONS: A VCL common variant was genetically and biophysically associated with Chinese SUNDS. The aggravation of loss of function of SCN5A caused by VCL-D841H under acidosis supports that nocturnal sleep respiratory disorders with acidosis may play a key role in the pathogenesis of SUNDS.

Characteristics of syncope in Japan and the Pacific rim.

As is true in the Western world, syncope of cardiac and non-cardiac origin is one of the common clinical presentations in daily medical practice in Japan and Asia. However, the underlying disorders and social backgrounds associated with syncope may differ, from those encountered in Western countries, particularly in Japan. While non-cardiac causes, neurally-mediated reflex faints in particular, are highly prevalent, out-of-hospital deaths by drowning due to syncope occurring during bathing at home are not rare in Japan, particularly in the elderly. Other underlying cardiac or non-cardiac disorders are also noteworthy, particularly Brugada syndrome and coronary vasospasm, which may present as isolated syncope. In addition, the characteristic clinical presentation of micturition and defecation syncope is not uncommon. This review is focused on these specific underlying diseases in the light of the guidelines issued by the Japanese Circulation Society regarding the diagnosis and treatment of syncope.

Prevalence of the type 1 Brugada electrocardiogram in Caucasian patients with suspected coronary spasm.

AIMS: Sporadic cases have reported the coexistence of coronary spasm and Brugada syndrome. However, the prevalence of the Brugada phenotype in coronary spasm is unknown, particularly in non-Japanese populations. In this study, we sought to examine the prevalence of the type 1 Brugada electrocardiogram (ECG) in a large European patient population undergoing intracoronary provocation testing for suspected coronary spasm. METHODS AND RESULTS: We retrospectively evaluated ECG data for the presence of type 1, 2, and 3 Brugada ECGs from 955 consecutive German patients without obstructive coronary artery disease undergoing intracoronary acetylcholine (ACH) provocation (ACH-test). Eight hundred and twenty-seven patients (age 63 ± 12 years; 42% male) with complete ECG data were eligible for further analysis. The ACH-test revealed coronary spasm in 325 patients (39.3%). A Brugada ECG of any type was found in six patients (0.7%) at baseline and eight patients (0.9%) at any time. There was no difference in the prevalence of coronary spasm in patients with (37.5%) and without (39.3%) Brugada-type ECGs. The type 1 Brugada ECG was not seen at baseline, but two type 1 Brugada ECGs were observed during ACH-administration into the right coronary artery (RCA; 0.2%), one with simultaneous RCA spasm and one without. Ajmaline provocation testing reproduced the type-1 Brugada ECG in the patient without coronary spasm but she had no other features of the Brugada syndrome. CONCLUSIONS: This study reports a low prevalence of the type 1 Brugada ECG in the largest known European collection of intracoronary ACH provocation. In these patients, we found no evidence for the coexistence of Brugada syndrome and coronary spasm. This is in contrast to available Japanese data.

Incidence and prognostic value of early repolarization pattern in the 12-lead electrocardiogram.

BACKGROUND: Early repolarization pattern is a common ECG finding characterized by J-point elevation and QRS notching or slurring in the inferior and/or lateral leads, yet little is known about its incidence and long-term prognosis in Asian populations. METHODS AND RESULTS: We reviewed all the ECG records of the 5976 atomic-bomb survivors who were examined at least once during our biennial health examination in Nagasaki, Japan, between July 1958 and December 2004. We defined early repolarization pattern as ≥0.1-mV elevation of the J point or ST segment, with notching or slurring in at least 2 inferior and/or lateral leads. We assessed unexpected, cardiac, and all-cause death risk by Cox analysis. We identified 1429 early repolarization pattern cases (779 incident cases) during follow-up, yielding a positive rate of 23.9% and an incidence rate of 715 per 100 000 person-years. Early repolarization pattern had an elevated risk of unexpected death (hazard ratio, 1.83; 95% confidence interval, 1.12 to 2.97; P=0.02) and a decreased risk of cardiac (hazard ratio, 0.75; 95% confidence interval, 0.60 to 0.93; P<0.01) and all-cause (hazard ratio, 0.85; 95% confidence interval, 0.78 to 0.93; P<0.01) death. In addition, both slurring and notching were related to higher risk of unexpected death (hazard ratio, 2.09; 95% confidence interval, 1.06 to 4.12; P=0.03), as was early repolarization pattern manifestation in both inferior and lateral leads (hazard ratio, 2.50; 95% confidence interval, 1.29 to 4.83; P<0.01). CONCLUSIONS: Early repolarization pattern is associated with an elevated risk of unexpected death and a decreased risk of cardiac and all-cause death. Specific early repolarization pattern morphologies and location are associated with an adverse prognosis.

Frequency of cardiac events at four years among initially asymptomatic filipinos with the Brugada type 1 electrocardiographic pattern.

Brugada type 1 electrocardiographic (ECG) pattern occurs in 0.2% of Filipinos. A knowledge gap exists on the natural course of asymptomatic patients with Brugada type 1 ECG pattern. Most studies that reported cohort event rates were taken from hospitals or referral centers. This is the first cohort from an entire country where the subjects were selected randomly. The objective of this study was to describe the frequency of cardiac events at 4 and 6 years of 7 patients with Brugada type 1 ECG pattern of 3,907 patients previously screened from the general population of the Philippines during the National Nutrition and Health Survey. Personal interviews at year 4 using a structured questionnaire were conducted by 1 of the investigators. Occurrences of major (syncope, seizure, unexplained accidents, sudden death) and minor events in subjects and their first- and second-degree relatives were elicited. Six-year follow-up by text messaging was conducted to ascertain vital status and occurrence of cardiac events. All 7 patients with Brugada type 1 ECG pattern were men. Three of the 7 initially asymptomatic subjects (43%, 95 confidence interval 6 to 80) developed a major cardiac event by the fourth year. Those with events were younger than those without events. All 7 were alive by the sixth year. No additional events were noted between the fourth and sixth years. In conclusion, cardiac events are considerable in initially asymptomatic Filipinos with Brugada type 1 ECG pattern.

Brugada syndrome in pure black Africans.

AIMS: Although all races are concerned with the Brugada syndrome, no case has ever been reported among black Africans. We describe five different cases in this specific group of populations. METHODS AND RESULTS: In all patients, Brugada syndrome was identified after detailed noninvasive and invasive evaluations. Sex ratio was four males for one female. Convulsive syncope was noticed in 1 patient with a family history of sudden death. Diagnostic coved-type pattern was observed spontaneously in the normal position of right precordial leads in 3 patients and in a higher position of leads in 3 patients. Sixty percent had first-degree atrioventricular block. An ajmaline test was performed in 4 patients and was positive either in normal position of leads or in superior position in all of them. Sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) was inducible during programmed ventricular stimulation in 3 patients. Right ventricular cineangiography found localized apical hypokinesia with preserved systolic function in 1 patient. Automatic cardioverter defibrillator was implanted in 2 patients. SCN5A was not found in any of the patients. CONCLUSION: These observations demonstrate that Brugada syndrome is also present in black African populations, and increasingly reported cases of apparent sudden death in the sub-Saharan part of the world need to rule out cardiac electrical disturbance such as Brugada syndrome.

Mechanism and new findings in Brugada syndrome.

Brugada syndrome is a clinical entity characterized by coved type ST-segment elevation in the right precordial electrocardiographic leads (V(1-3)) and an episode of ventricular fibrillation in the absence of structural heart disease. Although a number of clinical and experimental reports have elucidated the electrocardiographic, electrophysiologic, cellular, and molecular aspects, several problems remain unsolved. Recently developed high-resolution optical mapping techniques in arterially-perfused wedge preparations enable recording of transmembrane action potentials from 256 sites simultaneously at the epicardial surface, thus providing further advances in the understanding of the cellular mechanism of the specific ST-segment elevation and subsequent ventricular arrhythmias. In this review article, new findings relating to several unresolved problems such as gender difference (male predominance) and ethnic difference (higher incidence in Asian population) are also presented.

Brugada syndrome in Japan.

The incidence of Brugada syndrome (BS) is relatively high in Japan compared with the rest of the world, ranging between 0.1% and 0.2% in the general population. BS in Japan, as in other countries, is most prevalent in middle-aged men, and has characteristics ECG changes, a high recurrence rate in symptomatic patients, and relatively low incidence of SCN5A mutations. In contrast, both the incidence of a family history of BS and/or sudden cardiac death and the rate of developing cardiac events in asymptomatic patients are less in Japan than in other countries. Increased vagal tone and/or decreased sympathetic activity are suggested as provoking cardiac events. Several factors should be evaluated in risk stratification for recurrence of life-threatening arrhythmias, because there appears to be no single determinant for risk stratification: spontaneous ST elevation of coved-type (Type 1), family history of sudden cardiac death, inducible ventricular tachycardia/ventricular fibrillation and positive late potentials. An implantable cardioverter defibrillator is recommended for patients with aborted sudden cardiac death.

[A survey of Brugada-type electrocardiogram recorded from high right precordial spaces in healthy Chinese].

OBJECTIVE: To investigate the prevalence and the significance of the Brugada-type electrocardiogram (ECG) recorded from higher intercostal space in healthy Chinese. METHODS: The population of the present study consisted of 1005 subjects receiving a health examination. All subjects underwent history inquiry, physical examination and chest X-ray survey. ECGs were taken from the 4th and the 2nd intercostal spaces and examined for Brugada-type ECG according to the diagnostic criteria recommended by European Society of Cardiology. RESULTS: Four patients with cardiovascular disorders were excluded and a total of 1001 healthy subjects [age 17 - 75 years, mean (28.3 +/- 14.8) years, 877 males and 124 females] were included in the study. Five males of the 1001 subjects (0.50%) had Brugada-type 2 pattern on routine 12-lead ECGs. Forty-seven males of all the subjects (4.70%) had Brugada-type ECGs recorded from the 2nd intercostal space and Brugada-type 2 and type 3 patterns were found in 40 and 7 respectively. All these males had no unaccountable syncope, presyncope or a family history of sudden death. CONCLUSIONS: It should be careful to diagnose of Brugada syndrome according to Brugada-type 2 or type 3 ECGs recorded from either the 4th or higher intercostal spaces when typical symptoms are absent.

Risk stratification of individuals with the Brugada electrocardiogram: a meta-analysis.

OBJECTIVES: We performed a meta-analysis of prognostic studies of patients with a Brugada ECG to assess predictors of events. BACKGROUND: The Brugada syndrome is an increasingly recognized cause of idiopathic ventricular fibrillation; however, there is wide variation in the prognosis of patients with the Brugada ECG. METHODS AND RESULTS: We retrieved 30 prospective studies of patients with the Brugada ECG, accumulating data on 1,545 patients. Summary estimates of the relative risk (RR) of events (sudden cardiac death [SCD], syncope, or internal defibrillator shock) for a variety of potential predictors were made using a random-effects model. The overall event rate at an average of 32 months follow-up was 10.0% (95% CI 8.5%, 11.5%). The RR of an event was increased (P < 0.001) among patients with a history of syncope or SCD (RR 3.24 [95% CI 2.13, 4.93]), men compared with women (RR 3.47 [95% CI 1.58, 7.63]), and patients with a spontaneous compared with sodium-channel blocker induced Type I Brugada ECG (RR 4.65 [95% CI 2.25, 9.58]). The RR of events was not significantly increased in patients with a family history of SCD (P = 0.97) or a mutation of the SCN5A gene (P = 0.18). The RR of events was also not significantly increased in patients inducible compared with noninducible by electrophysiologic study (EPS) (RR 1.88 [95% CI 0.62, 5.73], P = 0.27); however, there was significant heterogeneity of the studies included. CONCLUSIONS: Our findings suggest that a history of syncope or SCD, the presence of a spontaneous Type I Brugada ECG, and male gender predict a more malignant natural history. Our findings do not support the use of a family history of SCD, the presence of an SCN5A gene mutation, or EPS to guide the management of patients with a Brugada ECG.