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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., (Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: There is limited information on gender differences in patients with Brugada syndrome (BrS) who experienced arrhythmic events (AEs)., Objective: The purpose of this study was to compare clinical, electrocardiographic (ECG), electrophysiological, and genetic characteristics between males and females in patients with BrS with their first AE., Methods: The multicenter Survey on Arrhythmic Events in BRUgada Syndrome collected data on the first AE in 678 patients with BrS including 619 males (91.3%) and 59 females (8.7%) aged 0.27-84 years (mean age 42.5 ± 14.1 years) at the time of AE occurrence., Results: After excluding pediatric patients, it was found that females were older than males (49.5 ± 14.4 years vs 43 ± 12.7 years, respectively; P = .001). Higher proportions of females were observed in the pediatric and elderly populations. In Asians, the male to female ratio for AEs was ≈9-fold higher than that in White. Spontaneous type 1 BrS ECG was associated with an earlier onset of AEs in pediatric females. A similar prevalence (≈65%) of spontaneous type 1 BrS ECG was present in males and females above the age of 60 years. Females less frequently showed spontaneous type 1 BrS ECG (41% vs 69%; P < .001) or arrhythmia inducibility at electrophysiology study (36% vs 66%; P < .001). An SCN5A mutation was more frequently found in females (48% vs 28% in males; P = .007)., Conclusion: This study confirms that female patients with BrS are much rarer, display less type 1 Brugada ECG, and exhibit lower inducibility rates than do males. It shows for the first time that female patients with BrS with AE have higher SCN5A mutation rates as well as the relationship between gender vs age at the onset of AEs and ethnicity., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The literature on fever-related arrhythmic events (AEs) in Brugada syndrome (BrS) is currently limited to few case reports and small series., Objective: The present study aimed to describe the characteristics of fever-related AE in a large cohort of patients with BrS., Methods: The Survey on Arrhythmic Events in Brugada Syndrome is a multicenter study on 678 patients with BrS with first AE documented at the time of aborted cardiac arrest (n = 426) or after prophylactic implantable cardioverter-defibrillator implantation (n = 252)., Results: In 35 of 588 patients (6%) with available information, the AE occurred during a febrile illness. Most of the 35 patients were male (80%), Caucasian (83%), and proband (70%). The mean age at the time of AE was 29 ± 24 years (range 0.3-76 years). Most patients (80%) presented with aborted cardiac arrest and 6 (17%) with arrhythmic storm. Family history of sudden death, history of syncope, and spontaneous type 1 Brugada electrocardiogram were noted in 17%, 40%, and 71% of patients, respectively. Ventricular fibrillation was induced at electrophysiology study in 9 of 19 patients (47%). An SCN5A mutation was found in 14 of 28 patients (50%). The highest proportion of fever-related AE was observed in the pediatric population (age <16 years), with a disproportionally higher event rate in the very young (age 0-5 years) (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., Conclusion: The risk of fever-related AE in BrS markedly varies according to age group, sex, and ethnicity. Taking these factors into account could help the clinical management of patients with BrS with fever., (Copyright © 2018 Heart Rhythm Society. All rights reserved.)

Background: Detailed information on the profile of patients with Brugada syndrome (BrS) presenting their first arrhythmic event (AE) after prophylactic implantation of an implantable cardioverter-defibrillator (ICD) is limited., Objectives: The objectives of this study were (1) to compare clinical, electrocardiographic, electrophysiologic, and genetic profiles of patients who exhibited their first documented AE as aborted cardiac arrest (group A) with profiles of those in whom the AE was documented after prophylactic ICD implantation (group B) and (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 patients with BrS who exhibited their AE (group A, n = 426; group B, n = 252)., Results: The first AE occurred in group B patients 6.7 years later than in group A (mean age 46.1 ± 13.3 years vs 39.4 ± 15.1 years; P < .001). Group B patients had a higher incidence of family history of sudden cardiac death 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: Patients with BrS with the first AE documented after prophylactic ICD implantation exhibited their AE at a later age with a higher incidence of positive family history of sudden cardiac death and SCN5A mutations as compared with those presenting with aborted cardiac arrest. Only 75% of patients who exhibited an AE after receiving a prophylactic ICD complied with the 2013 class II indications, suggesting that efforts are still required for improving risk stratification., (Copyright © 2018 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Frailty has been identified as a risk factor for mortality. However, whether frailty increases mortality risk in patients undergoing percutaneous coronary intervention (PCI) has been controversial. Therefore, we conducted a systematic review and meta-analysis of the frailty measures and mortality outcomes in this setting., Methods: PubMed and EMBASE were searched until July 23, 2017 for studies evaluating the association between frailty measures and mortality in individuals who have undergone PCI., Results: A total of 141 entries were retrieved from our search strategy. A total of 8 studies involving 2332 patients were included in the final meta-analysis (mean age: 69 years; 68% male, follow-up duration was 30 ± 28 months). Frailty was a significant predictor of all-cause mortality after PCI, with a hazard ratio (HR) of 2.97 [95% confidence interval (CI) 1.56-5.66, P = .001]. This was substantial heterogeneity present (I 2 : 79%). Subgroup analysis using the Fried score reduced I 2 to 68% without altering the pooled HR (2.78, 95% CI 1.02-7.76; P < .05). Using the Canadian Study of Health and Aging Clinical Frailty Scale reduced I 2 to 0% while preserving the pooled HR (5.99, 95% CI 2.77-12.95, P < .001)., Conclusions: Frailty leads to significantly higher mortality rates in patients who have undergone PCI. Both the Fried score and Canadian Study of Health and Aging Clinical Frailty Scale are powerful predictors of mortality. These findings may support the notion that an alternative to invasive strategy should be considered in frail patients who are indicated for revascularization., (Copyright © 2017. Published by Elsevier Inc.)

Background: The T peak - T end interval (the interval from the peak to the end of the T wave), an electrocardiographic marker reflecting transmural dispersion of repolarization, has been used to predict ventricular tachycardia/fibrillation (VT/VF) and sudden cardiac death in different clinical settings., Objective: This systematic review and meta-analysis evaluated the significance of the T peak - T end interval in predicting arrhythmic and/or mortality end points., Methods: PubMed, Embase, Cochrane Library, and CINAHL Plus databases were searched through November 30, 2016., Results: Of the 854 studies identified initially, 33 observational studies involving 155,856 patients were included in our meta-analysis. T peak - T end interval prolongation (mean cutoff value 103.3 ± 17.4 ms) was a significant predictor of the arrhythmic or mortality outcomes (odds ratio [OR] 1.14; 95% confidence interval [CI] 1.11-1.17; P < .001). When different end points were analyzed, the ORs were as follows: VT/VF, 1.10 (95% CI 1.06-1.13; P < .0001); sudden cardiac death, 1.27 (95% CI 1.17-1.39; P < .0001); cardiovascular death, 1.40 (95% CI 1.19-1.64; P < .0001); and all-cause mortality, 4.56 (95% CI 0.62-33.68; P < .0001). Subgroup analysis for each disease revealed that the risk of VT/VF or death was highest for Brugada syndrome (OR 5.68; 95% CI 1.57-20.53; P < .01), followed by hypertension (OR 1.52; 95% CI 1.26-1.85; P < .0001), heart failure (OR 1.07; 95% CI 1.04-1.11; P < .0001), and ischemic heart disease (OR 1.06; 95% CI 1.02-1.10; P = 0.001)., Conclusion: The T peak - T end interval is a useful risk stratification tool in different diseases and in the general population., (Copyright © 2017 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Randomized controlled trials (RCTs) on the use of ranolazine (RN) for prevention and cardioversion of atrial fibrillation (AF) have yielded conflicting results., Objective: The purpose of this study was to conduct a meta-analysis of RCTs to examine the potential role of RN in the prevention and cardioversion of AF., Methods: PubMed and EMBASE were searched until June 2016. Of 484 initially identified studies, 8 RCTs were finally analyzed., Results: The analysis of RCTs showed that RN significantly reduced the incidence of AF compared to the control group in various clinical settings, such as after cardiac surgery, in acute coronary syndromes, and post-electrical cardioversion of AF (relative risk [RR] 0.67, 95% confidence interval [CI] 0.52-0.87, Z = 3.06, P = .002). Furthermore, a higher conversion rate of AF from the combined use of RN and amiodarone compared to amiodarone alone (RR 1.23, 95% CI 1.08-1.40, Z = 3.07, P = .002) was clear, with conversion time significantly shorter in RN plus amiodarone compared to the amiodarone group (weighted mean difference [WMD] = -10.38 hours, 95% CI -18.18 to -2.57, Z = 2.61, P = .009)., Conclusion: Our meta-analysis suggests that RN may be effective in AF prevention, whereas it potentiates and accelerates the conversion effect of amiodarone of recent-onset AF. Larger RCTs with long-term follow-up in diverse clinical settings are needed to further clarify the impact of RN on AF therapy., (Copyright © 2016 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: The rabbit left ventricular wedge (RLVW) has been demonstrated as a highly sensitive and specific preclinical model in assessing drug-induced QT prolongation and proarrhythmias. However, there is a need to determine drugs' cardiac ion channel profiles beyond QT measurement. In this study, we present an approach to determine cardiac ion channels targeted by drugs with analyzing a few key ECG parameters plus a contractility parameter obtained from the RLVW., Methods: The RLVW assay was used for testing 18 drugs with well-known ion channel profiles. A transmural ECG and isometric contractility were recorded. Five parameters including QRS, QT, Tp-e/QT ratio, QT-BCL slope and the positive staircase response of contractility were analyzed., Results: There were distinguished drug-induced ECG and contractility changes from which targeted cardiac ion channels by drugs could be determined. Inhibition of sodium channel resulted in rate-dependent QRS widening, QT and Tp-e shortening and a reduced QT-BCL slope. Although both IKr and IKs blockers prolonged QT interval, IKr blockers but not IKs increased Tp-e/QT ratio. Both potassium channel openers and calcium channel blockers markedly shortened QT and Tp-e intervals, but only calcium channel blockers could reverse the positive staircase response of contractility., Discussion: The results in the present study are correlated closely to the drugs' well-known clinical profiles. This indicates that the RLVW assay with an adequate experimental protocol plus analysis of 5 key parameters is highly valuable in preclinical assessment of drug candidates for their detailed ion channel activities, proarrhythmic risks and other adverse effects. The limitations of the RLVW assay are also addressed., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In the present study, we investigated an impact of the stimulation rate on the detection of the proarrhythmic potential of 10 reference compounds with effects on different cardiac ion channels in the isolated arterially-perfused rabbit left ventricular wedge preparation. The compounds were tested in the wedge model using two distinct protocols; including baseline stimulation at 1-Hz followed by a brief period at 0.5-Hz, either without an additional brief period of 2-Hz stimulation (i.e. Protocol 1) or with 2-Hz stimulation (i.e. Protocol 2). As expected, QT-prolonging drugs (ibutilide and quinidine) prolonged the QT interval, similarly increased the Torsades de Pointes (TdP) score, and elicited early afterdepolarizations (EADs) in both protocols. HMR1556 and JNJ-303 (IKs blockers) also prolonged the QT interval up to 1μM similarly in both protocols. Nifedipine (Ca(2+) antagonist) shortened the QT interval, and reduced force of contraction similarly in both protocols. However, Na(+) channel blockers (Ia, Ib, Ic) widened the QRS duration more in Protocol 2 than in Protocol 1. Furthermore, it was only possible to detect non-TdP-like ventricular tachycardia/fibrillation (VT/VF) induced by Na(+) blockers and by QT-shortening drugs (levcromakalim and mallotoxin) using the 2-Hz stimulation (Protocol 2). Our data suggest that the inclusion of a brief period of fast stimulation at 2Hz is critical for detecting drug-induced slowing of conduction (QRS widening), QT shortening and associated (non-TdP-like) VT/VF, which are distinct from the QT prolongation/TdP proarrhythmia in isolated, arterially-perfused rabbit left ventricular wedges., (Copyright © 2016 Elsevier Inc. All rights reserved.)

A prominent J wave is encountered in a number of life-threatening cardiac arrhythmia syndromes, including the Brugada syndrome and early repolarization syndromes. Brugada syndrome and early repolarization syndromes differ with respect to the magnitude and lead location of abnormal J waves and are thought to represent a continuous spectrum of phenotypic expression termed J-wave syndromes. Despite two decades of intensive research, risk stratification and the approach to therapy of these 2 inherited cardiac arrhythmia syndromes are still undergoing rapid evolution. Our objective in this review is to provide an integrated synopsis of the clinical characteristics, risk stratifiers, and molecular, ionic, cellular, and genetic mechanisms underlying these 2 fascinating syndromes that have captured the interest and attention of the cardiology community in recent years., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: The QT interval, an index of ventricular repolarization, is rate dependent. Exaggerated rate dependence of repolarization is arrhythmogenic. Whether there are differences in rate-dependent repolarization among different heart chambers is unknown., Objective: The purpose of this study was to test our hypothesis that heterogeneous distribution in late sodium current (INa-L) is responsible for interregional differences in rate adaptation of repolarization., Methods: Action potential duration (APD), QT intervals, and their rate adaptation were studied in isolated arterially perfused ventricular and atrial wedge preparations. APD and INa-L were recorded in isolated rabbit myocytes using the microelectrode and the whole-cell patch clamp technique, respectively., Results: There were distinct interregional differences in repolarization and its rate adaptations among different cardiac chambers: the left ventricle exhibited the longest QT and APD with the greatest rate dependence, followed by the right ventricle, whereas the atria had the shortest APD without significant rate dependence. Interestingly, INa-L densities distributed heterogeneously and matched to interregional APDs and rate dependences as follows: left ventricle > right ventricle > left/right atria. Both dofetilide (an IKr blocker) and anemone toxin (a specific INa-L enhancer) amplified QT/APD rate adaptation preferentially in the left ventricle and therefore exacerbated interregional dispersion of repolarization. On the other hand, the atria exhibited blunted responses to both QT-prolonging agents. Mexiletine with an INa-L blockade effect blunted QT/APD rate adaptation preferentially in the ventricles and significantly reduced bradycardia-dependent interregional dispersion of repolarization., Conclusion: Our results demonstrate that heterogeneous distribution of INa-L contributes importantly to the interregional heterogeneity of repolarization in response to rate changes and APD/QT-prolonging agents., (Copyright © 2015 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Introduction: In the present study, we investigated whether a new biomarker - index of cardiac electrophysiological balance (iCEB=QT/QRS) - could predict drug-induced cardiac arrhythmias (CAs), including ventricular tachycardia/ventricular fibrillation (VT/VF) and Torsades de Pointes (TdPs)., Methods: The rabbit left ventricular arterially-perfused-wedge was used to investigate whether the simple iCEB measured from the ECG is reflective of the more difficult measurement of λ (effective refractory period×conduction velocity) for predicting CAs induced by a number of drugs., Results: Dofetilide concentration-dependently increased iCEB and λ, predicting potential risk of drug-induced incidence of early afterdepolarizations (EADs) starting at 0.01μM. Digoxin (1 and 5μM), encainide (5 and 20μM) and propoxyphene (10 and 100μM) markedly reduced both iCEB and λ, predicting their ability to induce non-TdP-like VT/VF. At 10μM, both NS1643 and levcromakalim significantly decreased λ and iCEB, which was preceded with presence of non-TdP-like VT/VF. Isoprenaline (0.05 to 0.5μM) significantly reduced both λ and iCEB, which was associated with a high incidence of non-TdP-like VT/VF in most preparations. Other biomarkers (i.e. transmural dispersion of T-wave and instability of the QT interval) predicted only dofetilide-induced long QT and EADs, but did not predict drug-induced risk of non-TdP-like VT/VF., Discussion: Our data from 7 reference drugs of known pro-arrhythmic effects suggests that 1) this non-invasive iCEB predicts potential risk of drug-induced CAs beyond long QT and TdP; 2) iCEB is more useful than the current biomarkers (i.e. transmural dispersion and instability) in predicting potential risks for drug-induced non-TdP-like VT/VF., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The ventricular components (QRS and QT) on the electrocardiogram (ECG) depend on the properties of ventricular action potentials that can be modulated by drugs via specific ion channels. However, the correlation of ECG ventricular waveforms with underlying ion actions is not well established and has been extensively debated., Objective: To conduct a blinded in vitro assessment of the ionic mechanisms for drug-induced ECG changes., Methods and Results: Fourteen cardiac and noncardiac drugs with known effects on cardiac ion channels were selected by the study sponsor, and were tested in the rabbit left ventricular wedge preparation with recording of the ECG and contractility. The investigators who performed the experiments and analyzed the data were blinded to names, concentrations, and molecular weights of the drugs. The compounds were prepared by the sponsor and sent to the investigators as 56 stock solutions. The effects of I(Kr), I(Ks), I(Ca,L), I(Na) blocker, and I(KATP) opener on QRS, QT, and T(p-e), were evaluated. Disclosure of the names and concentrations after completion of the study revealed that there were highly correlated ECG changes with underlying ionic mechanisms and proarrhythmic potential of drugs that, respectively, target I(Kr), I(Ks), I(Ca,L), I(Na), and I(KATP). Among ECG parameters, T(p-e) was more useful in differentiating drugs' actions., Conclusions: Specific electrophysiological action and the consequent proarrhythmic potential of a drug can be accurately determined by analysis of drug-induced changes in ECG in the rabbit left ventricular wedge preparation. Change in T(p-e) provides the most relevant information., (Copyright © 2012 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Abnormal rate adaptation of ventricular repolarization is arrhythmogenic. There is controversy on the underlying ionic mechanisms for rate-dependent change in repolarization., Objective: The purpose of this study was to examine the role of the late sodium current (I(Na-L)) in normal rate-dependence of ventricular repolarization and reverse use-dependence of QT-prolonging agents., Methods: The effects of I(Na-L) blockade, I(Na-L) enhancement, I(Kr) blockade, and changes in extracellular potassium concentration ([K(+)](o)) on rate adaptation of the QT interval and action potential duration (APD) were examined in isolated rabbit ventricular wedges and single myocytes. Rate dependence of I(Na-L), delayed rectifier potassium current (I(K)), and L-type calcium current (I(Ca)) was determined using a whole-cell, voltage clamp technique., Results: At control, APD exhibited rate-dependent changes in the multicellular preparations as well as in the isolated single ventricular myocytes when [K(+)](o) remained constant. The rate dependence of APD was significantly enhanced by reduction of [K(+)](o) from 4 to 1 mM or by I(Na-L) enhancement but was markedly blunted by the selective sodium channel blocker tetrodotoxin. The I(Kr) blocker dofetilide (3 nM) amplified the QT to basic cycle length slope (71.2 ± 13.1 ms/s vs 35.1 ± 8.8 ms/s in control, n = 4, P <.05). This reverse use-dependence was abolished by tetrodotoxin at 5 μM (11.4 ± 4.3 ms/s, n = 4, P <.01). There were no significant differences in I(Ca) or I(K) over the range of basic cycle lengths from 2,000 to 500 ms. However, I(Na-L) exhibited a significant rate-dependent reduction., Conclusion: I(Na-L) is sensitive to rate change due to its slow inactivation and recovery kinetics and plays a central role in the rate dependence of APD/QT and in the reverse use-dependence of select APD/QT-prolonging agents., (Copyright © 2011 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Atrial fibrillation (AF) is the most common cardiac arrhythmia encountered in clinical practice. Although once considered a nuisance arrhythmia, recent clinical trial evidence suggests that the presence of AF is an important independent predictor of mortality and morbidity. The primary goals of AF treatment are relief of symptoms and prevention of stroke. The value of anticoagulation with warfarin has been proven unequivocally. Control of ventricular rate with atrioventricular nodal blocking agents-the so-called rate control strategy-is least cumbersome and sometimes the best approach. By contrast, efforts to restore and maintain sinus rhythm using antiarrhythmic drugs-the rhythm control approach-although tedious, may be ideal in patients who are young or highly symptomatic and in those with new-onset AF. The relative merits of both treatment strategies are discussed in this article, emphasizing the excellent clinical trial data that support each., (Copyright © 2011 Mosby, Inc. All rights reserved.)

The J wave, also referred to as an Osborn wave, is a deflection immediately following the QRS complex of the surface ECG. When partially buried in the R wave, the J wave appears as J-point elevation or ST-segment elevation. Several lines of evidence have suggested that arrhythmias associated with an early repolarization pattern in the inferior or mid to lateral precordial leads, Brugada syndrome, or arrhythmias associated with hypothermia and the acute phase of ST-segment elevation myocardial infarction are mechanistically linked to abnormalities in the manifestation of the transient outward current (I(to))-mediated J wave. Although Brugada syndrome and early repolarization syndrome differ with respect to the magnitude and lead location of abnormal J-wave manifestation, they can be considered to represent a continuous spectrum of phenotypic expression that we propose be termed J-wave syndromes. This review summarizes our current state of knowledge concerning J-wave syndromes, bridging basic and clinical aspects. We propose to divide early repolarization syndrome into three subtypes: type 1, which displays an early repolarization pattern predominantly in the lateral precordial leads, is prevalent among healthy male athletes and is rarely seen in ventricular fibrillation survivors; type 2, which displays an early repolarization pattern predominantly in the inferior or inferolateral leads, is associated with a higher level of risk; and type 3, which displays an early repolarization pattern globally in the inferior, lateral, and right precordial leads, is associated with the highest level of risk for development of malignant arrhythmias and is often associated with ventricular fibrillation storms., (Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.)

Background: Arrhythmic risk stratification in patients with Brugada syndrome remains controversial. Several recent reports have highlighted the possible role of late potential (LP) on the signal-averaged electrocardiogram (SAECG) as a noninvasive risk stratification tool in Brugada syndrome, but further prospective study is required before its general applicability., Objective: The purpose of this study was to investigate the role of LP in arrhythmic risk stratification of Brugada syndrome patients., Methods: Forty-three patients with Brugada syndrome were enrolled and divided into a symptomatic group (group A, n = 24) and an asymptomatic group (group B, n = 19). SAECG was performed to analyze the characteristics of LP in all subjects. The prospective study was conducted to observe the occurrence of arrhythmic events., Results: LP was positive in 22 (91.7%) of 24 patients in the symptomatic group and in 7 (36.8%) of 19 patients in the asymptomatic group. During mean follow-up of 33.8 +/- 9.0 months, the incidence rate of arrhythmic events was 72.4% (21/29) in LP-positive [LP(+)] patients compared with 14.3% (2/14) in LP-negative [LP(-)] patients. Multivariate Cox proportional hazard analyses revealed that the presence of LP had the most significant hazard ratio of 10.9 (95% confidence interval 1.1-104.3, P = .038), with sensitivity of 95.7%, specificity 65.0%, positive predictive value 75.9%, negative predictive value 92.9%, and predictive accuracy 81.4%. Kaplan-Meier curves plotted for event-free survival according to LP showed a significant difference between LP(+) and LP(-) patients (log rank, P = .003)., Conclusion: The results of this study support the role of LP detected by SAECG in arrhythmic risk stratification of Brugada syndrome patients.

Background: Quinidine is used to treat atrial fibrillation and ventricular arrhythmias. However, at low concentrations, it can induce torsade de pointes (TdP)., Objective: The purpose of this study was to examine the role of late sodium current (I(Na)) as a modulator of the arrhythmogenicity of quinidine in female rabbit isolated hearts and cardiomyocytes., Methods: Epicardial and endocardial monophasic action potentials (MAPs), ECG signals, and ion channel currents were measured. The sea anemone toxin ATX-II was used to increase late I(Na)., Results: Quinidine had concentration-dependent and often biphasic effects on measures of arrhythmogenicity. Quinidine increased the duration of epicardial MAP (MAPD(90)), QT interval, transmural dispersion of repolarization (TDR), and ventricular effective refractory period. Beat-to-beat variability of MAPD(90) (BVR), the interval from peak to end of the T wave (Tpeak-Tend) and index of Tpeak-Tend/QT interval were greater at 0.1 to 3 micromol/L than at 10-30 micromol/L quinidine. In the presence of 1 nmol/L ATX-II, quinidine caused significantly greater concentration-dependent and biphasic changes of Tpeak-Tend, TDR, BVR, and index of Tpeak-Tend/QT interval. Quinidine (1 micromol/L) induced TdP in 2 and 13 of 14 hearts in the absence and presence of ATX-II, respectively. Increases of BVR, index of Tpeak-Tend/QT interval, and Tpeak-Tend were associated with quinidine-induced TdP. Quinidine inhibited I(Kr), peak I(Na), and late I(Na) with IC(50)s of 4.5 +/- 0.3 micromol/L, 11.0 +/- 0.7 micromol/L, and 12.0 +/- 0.7 micromol/L., Conclusion: Quinidine had biphasic proarrhythmic effects in the presence of ATX-II, suggesting that late I(Na) is a modulator of the arrhythmogenicity of quinidine. Enhancement of late I(Na) increased proarrhythmia caused by low but not high concentrations of quinidine.

Background: Long QT syndrome is associated with early after-depolarization (EAD) that may result in torsade de pointes (TdP). Interestingly, the corrected QT interval seems to be proportional to body mass across species under physiologic conditions., Objective: The purpose of this study was to test whether recovery of L-type calcium current (I(Ca,L)), the primary charge carrier for EADs, from its inactivated state matches ventricular repolarization time and whether impairment of this relationship leads to development of EAD and TdP., Methods: Transmembrane action potentials from the epicardium, endocardium, or subendocardium were recorded simultaneously with a transmural ECG in arterially perfused left ventricular wedges isolated from cow, dog, rabbit, and guinea pig hearts. I(Ca,L) recovery was examined using action potential stimulation in isolated left ventricular myocytes., Results: The ventricular repolarization time (action potential duration at 90% repolarization [APD(90)]), ranging from 194.7 +/- 1.8 ms in guinea pig to 370.2 +/- 9.9 ms in cows, was linearly related to the thickness of the left ventricular wall among the species studied. The time constants (tau) of I(Ca,L) recovery were proportional to APD(90), making the ratios of tau to APD(90) fall into a relatively narrow range among these species despite markedly different ventricular repolarization time. Drugs with risk for TdP in humans were shown to impair this intrinsic balance by either prolongation of the repolarization time and/or acceleration of I(Ca,L) recovery, leading to the appearance of EADs capable of initiating TdP., Conclusion: An adequate balance between I(Ca,L) recovery and ventricular repolarization serves as a "physiologic stabilizer" of ventricular action potentials in repolarization phases.

Background: The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP., Methods and Results: Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max)., Conclusions: Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.