An autoantibody profile detects Brugada syndrome and identifies abnormally expressed myocardial proteins.

AIMS: Brugada syndrome (BrS) is characterized by a unique electrocardiogram (ECG) pattern and life-threatening arrhythmias. However, the Type 1 Brugada ECG pattern is often transient, and a genetic cause is only identified in <25% of patients. We sought to identify an additional biomarker for this rare condition. As myocardial inflammation may be present in BrS, we evaluated whether myocardial autoantibodies can be detected in these patients. METHODS AND RESULTS: For antibody (Ab) discovery, normal human ventricular myocardial proteins were solubilized and separated by isoelectric focusing (IEF) and molecular weight on two-dimensional (2D) gels and used to discover Abs by plating with sera from patients with BrS and control subjects. Target proteins were identified by mass spectrometry (MS). Brugada syndrome subjects were defined based on a consensus clinical scoring system. We assessed discovery and validation cohorts by 2D gels, western blots, and ELISA. We performed immunohistochemistry on myocardium from BrS subjects (vs. control). All (3/3) 2D gels exposed to sera from BrS patients demonstrated specific Abs to four proteins, confirmed by MS to be α-cardiac actin, α-skeletal actin, keratin, and connexin-43, vs. 0/8 control subjects. All (18/18) BrS subjects from our validation cohorts demonstrated the same Abs, confirmed by western blots, vs. 0/24 additional controls. ELISA optical densities for all Abs were elevated in all BrS subjects compared to controls. In myocardium obtained from BrS subjects, each protein, as well as SCN5A, demonstrated abnormal protein expression in aggregates. CONCLUSION: A biomarker profile of autoantibodies against four cardiac proteins, namely α-cardiac actin, α-skeletal actin, keratin, and connexin-43, can be identified from sera of BrS patients and is highly sensitive and specific, irrespective of genetic cause for BrS. The four involved proteins, along with the SCN5A-encoded Nav1.5 alpha subunit are expressed abnormally in the myocardium of patients with BrS.

Hypertrophic Cardiomyopathy-Related Sudden Cardiac Death in Young People in Ontario.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is considered a leading cause of sudden cardiac death (SCD) in younger people. The incidence of HCM-related SCD and its relationship to exercise have not been well studied in large comprehensive studies outside of tertiary care settings. This study sought to estimate the incidence of HCM-related SCD and its association with exercise in a large unselected population. METHODS: Using the Office of the Chief Coroner of Ontario database encompassing all deaths attended by the coroner, we identified all HCM-related SCDs in individuals 10 to 45 years of age between 2005 and 2016 (70 million person-years). Confirmation of HCM was based on typical macroscopic and microscopic features (definite HCM-related SCD). Sudden deaths with a prior clinical diagnosis of HCM but no autopsy were considered probable HCM-related SCDs. Cases with typical features but no myofiber disarray were considered possible HCM. The completeness of data was verified in a subset of patients in the Toronto area with the use of a registry of all emergency medical services-attended cardiac arrests, with an autopsy rate of 94%. To estimate the number of HCM-related aborted cardiac arrests and lives potentially saved by implantable cardioverter-defibrillators, all de novo implantations for secondary prevention and all implantations and appropriate shocks for primary prevention in patients with HCM 10 to 45 years of age, respectively, were identified with the use of a registry containing data on implantable cardioverter-defibrillator implantations from all implanting sites throughout Ontario. RESULTS: Forty-four, 3, and 6 cases of definite, probable, and possible HCM-related SCDs, respectively, were identified, corresponding to estimated annual incidence rates of 0.31 per 1000 HCM person-years (95% CI, 0.24-0.44) for definite HCM-related SCD, 0.33 per 1000 HCM person-years (95% CI, 0.34-0.62) for definite or probable HCM-related SCD, and 0.39 per 1000 HCM person-years (95% CI, 0.28-0.49) for definite, probable, or possible HCM-related SCD (estimated 140 740 HCM person-years of observation). The estimated annual incidence rate for HCM-related SCD plus aborted cardiac arrest and HCM-related life-threatening arrhythmia (SCD, aborted cardiac arrest, and appropriate implantable cardioverter-defibrillator shocks) was 0.84 per 1000 HCM person-years (95% CI, 0.70-1.0). The majority (70%) of SCDs occurred in previously undiagnosed individuals. Most SCDs occurred during rest (64.8%) or light activity (18.5%). CONCLUSIONS: The incidence of HCM-related SCD in the general population 10 to 45 years of age is substantially lower than previously reported, with most cases occurring in previously undiagnosed individuals. SCDs are infrequently related to exercise.

The relationship between the quantitative extent of late gadolinium enhancement and burden of nonsustained ventricular tachycardia in hypertrophic cardiomyopathy: A delayed contrast-enhanced magnetic resonance study.

OBJECTIVES: To examine the relationship between late gadolinium enhancement (LGE) extent and nonsustained ventricular tachycardia (NSVT) characteristics in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND: NSVT has been shown to be independently associated with sudden cardiac death (SCD) in HCM. Previous studies have found LGE on cardiac magnetic resonance (CMR) to be independently associated with NSVT. METHODS: Seventy-three patients who had 14-day Holter monitoring for either risk stratification for SCD (n = 62) or evaluation of atrial fibrillation (n = 11) on a CMR study were included. Areas of LGE in left ventricle (LV) were visually identified and analyzed quantitatively for both high (≥6 SD above the mean signal intensity of normal myocardium) and intermediate (≥4 but <6 SD) LGE signal intensity. RESULTS: Patients with more extensive LGE had longer (P = 0.0028) and more frequent (P = 0.02) episodes of NSVT. In univariate analyses, frequency of NSVT was associated with LGE extent (rs = 0.43, P = 0.001), LV ejection fraction (rs = -0.38, P < 0.001), LV mass (rs = 0.32, P = 0.005), LV maximal wall thickness (rs = 0.28, P = 0.016), and left atrium diameter (rs = 0.29, P = 0.001); maximal length of NSVT was associated with LGE extent (rs = 0.52, P < 0.001), LV ejection fraction (rs = -0.44, P < 0.001), LV mass (rs = 0.37, P = 0.001), and left atrium diameter (rs = 0.3, P < 0.001). In multivariable analyses, LGE extent remained the sole variable independently associated with frequency (P = 0.001) and maximal length of episodes of NSVT (P = 0.001). No significant association was found between the rate of NSVT and LGE extent. CONCLUSIONS: LGE extent is independently associated with a greater burden and longer episodes of NSVT in HCM. These findings support the association between myocardial fibrosis as represented by LGE and ventricular tachyarrhythmias in HCM.

An autoantibody identifies arrhythmogenic right ventricular cardiomyopathy and participates in its pathogenesis.

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by right ventricular myocardial replacement and life-threatening ventricular arrhythmias. Desmosomal gene mutations are sometimes identified, but clinical and genetic diagnosis remains challenging. Desmosomal skin disorders can be caused by desmosomal gene mutations or autoantibodies. We sought to determine if anti-desmosome antibodies are present in subjects with ARVC. Methods and results: We evaluated ARVC subjects and controls for antibodies to cardiac desmosomal cadherin proteins. Desmoglein-2 (DSG2), desmocollin-2, and N-cadherin proteins on western blots were exposed to sera, in primary and validation cohorts of subjects and controls, as well as the naturally occurring Boxer dog model of ARVC. We identified anti-DSG2 antibodies in 12/12 and 25/25 definite ARVC cohorts and 7/8 borderline subjects. Antibody was absent in 11/12, faint in 1/12, and absent in 20/20 of two control cohorts. Anti-DSG2 antibodies were present in 10/10 Boxer dogs with ARVC, and absent in 18/18 without. In humans, the level of anti-DSG2 antibodies correlated with the burden of premature ventricular contractions (r = 0.70), and antibodies caused gap junction dysfunction, a common feature of ARVC, in vitro. Anti-DSG2 antibodies were present in ARVC subjects regardless of whether an underlying mutation was identified, or which mutation was present. A disease-specific DSG2 epitope was identified. Conclusion: Anti-DSG2 antibodies are a sensitive and specific biomarker for ARVC. The development of autoimmunity as a result of target-related mutations is unique. Anti-DSG2 antibodies likely explain the cardiac inflammation that is frequently identified in ARVC and may represent a new therapeutic target.

Whole exome sequencing identified 1 base pair novel deletion in BCL2-associated athanogene 3 (BAG3) gene associated with severe dilated cardiomyopathy (DCM) requiring heart transplant in multiple family members.

Dilated cardiomyopathy (DCM) is characterized by dilation and impaired contraction of the left ventricle or both ventricles. Among hereditary DCM, the genetic causes are heterogeneous, and include mutations encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium-handling proteins. We report three severely affected males, in a four-generation pedigree, with DCM phenotype who underwent cardiac transplant. Cardiomegaly with marked biventricular dilation and fibrosis were noticeable histopathological findings. The affected males had tested negative on a 46-gene pancardiomyopathy panel. Whole Exome Sequencing (WES) was performed to reveal mutation in the gene responsible in generation of DCM phenotypes. The 1-bp (Chr10:121435979delC; c.913delC) novel heterozygous deletion in exon 4 of BAG3, was identified in three affected males, resulted in frame-shift and a premature termination codon (p.Met306-Stop) producing a truncated BAG3 protein lacking functionally important PXXP and BAG domains. WES data were further utilized to map 10 SNP markers around the discovered mutation to generate shared disease haplotype in all affected individuals encompassing 11 Mb on 10q25.3-26.2 harboring BAG3. Finally genotypes were inferred for the unavailable/deceased individuals in the pedigrees. Here we propose that Chr10:121435979delC in BAG3 is a causal mutation in these subjects. Our and earlier studies indicate that BAG3 mutations are associated with DCM phenotypes. BAG3 should be added to cardiomyopathy gene panels for screening of DCM patients, and patients previously considered gene elusive should undergo sequencing of the BAG3 gene. © 2017 Wiley Periodicals, Inc.

Evaluation of Prolonged QT Interval: Structural Heart Disease Mimicking Long QT Syndrome.

BACKGROUND: In about 20-25% of patients with congenital long QT syndrome (LQTS) a causative pathogenic mutation is not found. The aim of this study was to explore the prevalence of alternative cardiac diagnoses among patients exhibiting prolongation of QT interval with negative genetic testing for LQTS genes. METHODS: We conducted a retrospective analysis of 239 consecutive patients who were evaluated in the inherited arrhythmia clinic at the Toronto General Hospital between July 2013 and December 2015 for possible LQTS. A detailed review of the patients' charts, electrocardiograms, and imaging was carried out. RESULTS: The analysis included 56 gene-negative patients and 61 gene-positive patients. Of the gene-negative group, 25% had structural heart disease compared to only 1.6% of gene-positive patients (P < 0.001). Structural heart disease was more likely if only one abnormal QTc parameter was found in the course of the evaluation (35.2% vs 9.1%, P = 0.01). The most common structural cardiac pathology was bileaflet mitral valve prolapse (8.9%). No gene-positive patient had episodes of nonsustained ventricular tachycardia, compared to seven of the gene-negative patients (0% vs 12.5%, P = 0.005). CONCLUSIONS: Structural pathology was detected in a quarter of gene-negative patients evaluated for possible LQTS. Hence, cardiac imaging and Holter monitoring should be strongly encouraged to rule out structural heart disease in this population.

High-resolution 3D scar imaging using a novel late iodine enhancement multidetector CT protocol to guide ventricular tachycardia catheter ablation.

Scar delineation with late gadolinium-enhanced MRI can direct VT substrate mapping and ablation, but imaging is poor and relatively contraindicated in the majority of patients with ICDs. We present a case of scar definition using late iodine-enhanced multidetector CT in a patient with ischemic cardiomyopathy and multiple ICD shocks for VT. CT images were acquired using a novel intracoronary contrast delivery protocol which provided high-resolution subendocardial scar visualization. The segmented scar images were subsequently imported into an electroanatomic mapping platform to guide successful VT ablation.

Management of tachyarrhythmias in pregnancy - A review.

The most common arrhythmias detected during pregnancy include sinus tachycardia, sinus bradycardia, and sinus arrhythmia, identified in 0.1% of pregnancies. Isolated premature atrial or ventricular arrhythmias are observed in 0.03% of pregnancies. Arrhythmias may become more frequent during pregnancy or may manifest for the first time.

Evaluation of cardiac hypertrophy in the setting of sudden cardiac death.

Ventricular hypertrophy is a common pathological finding at autopsy that can act as a substrate for arrhythmogenesis. Pathologists grapple with the significance of ventricular hypertrophy when assessing the sudden and unexpected deaths of young people and what it could mean for surviving family members. The pathological spectrum of left ventricular hypertrophy (LVH) is reviewed herein. This article is oriented to the practicing autopsy pathologist to help make sense of various patterns of increased heart muscle, particularly those that are not clearly cardiomyopathic, yet present in the setting of sudden cardiac death. The article also reviews factors influencing arrhythmogenesis as well as genetic mutations most commonly associated with ventricular hypertrophy, especially those associated with hypertrophic cardiomyopathy (HCM).

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal ß-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and ß-catenin. A pharmacological activator of the WNT/ß-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and ß-catenin, and evidence for targeted activation of the WNT/ß-catenin pathway as a potential treatment for this disease.

Concurrent maternal and fetal tachyarrhythmia in pregnancy.

The occurrence of a maternal and fetal tachyarrhythmia together in pregnancy is exceedingly rare. We report a case of a persistent fetal atrial ectopic tachycardia occurring in conjunction with a maternal atrial tachycardia with left ventricular systolic dysfunction. Amiodarone was effective in treating both maternal and fetal arrhythmias.

Automated Quantification of Low-Amplitude Abnormal QRS Peaks From High-Resolution ECG Recordings Predicts Arrhythmic Events in Patients With Cardiomyopathy.

BACKGROUND: Cardiomyopathy patients are at risk of sudden death, typically from scar-related abnormalities of electrical activation that promote ventricular tachyarrhythmias. Abnormal intra-QRS peaks may provide a measure of altered activation. We hypothesized that quantification of such QRS peaks (QRSp) in high-resolution ECGs would predict arrhythmic events in implantable cardioverter-defibrillator (ICD)-eligible cardiomyopathy patients. METHODS AND RESULTS: Ninety-nine patients with ischemic or non-ischemic dilated cardiomyopathy undergoing prophylactic ICD implantation were prospectively enrolled (age 62±11 years, left ventricular ejection fraction 27±7%). High-resolution (1024 Hz) digital 12-lead ECGs were recorded during intrinsic rhythm. QRSp was quantified for each precordial lead as the total number of low-amplitude deflections that deviated from their respective naive QRS template. The primary end point of arrhythmic events was defined as appropriate ICD therapy or sustained ventricular tachyarrhythmias. After a median follow-up of 24 (15-43) months, 20 (20%) patients had arrhythmic events. Both QRSp and QRS duration were greater in those with arrhythmic events (both P<0.001) and this was consistent for QRSp for both cardiomyopathy types. In a multivariable Cox regression model that included age, left ventricular ejection fraction, QRS duration, and QRSp, only QRSp was an independent predictor of arrhythmic events (hazard ratio, 2.1; P<0.001). Receiver operating characteristic analysis revealed that a QRSp ≥2.25 identified arrhythmic events with greater sensitivity (100% versus 70%, P<0.05) and negative predictive value (100% versus 89%, P<0.05) than QRS duration ≥120 ms. CONCLUSIONS: QRSp measured from high-resolution digital 12-lead ECGs independently predicts ventricular tachyarrhythmias in ICD-eligible cardiomyopathy patients. This novel QRS morphology index has the potential to improve sudden death risk stratification and patient selection for prophylactic ICD therapy.

T-Wave Morphology Analysis in Congenital Long QT Syndrome Discriminates Patients From Healthy Individuals.

OBJECTIVES: This study aims to assess the capability of T-wave analysis to: 1) identify genotype-positive long QT syndrome (LQTS) patients; 2) identify LQTS patients with borderline or normal QTc interval (≤460 ms); and 3) classify LQTS subtype. BACKGROUND: LQTS often presents with a nondiagnostic electrocardiogram (ECG). T-wave abnormalities may be the only marker of this potentially lethal arrhythmia syndrome. METHODS: ECGs taken at rest in 108 patients (43 with LQTS1, 20 with LQTS2, and 45 control subjects) were evaluated for T-wave flatness, asymmetry, and notching, which produces a morphology combination score (MCS) of the 3 features (MCS = 1.6 × flatness + asymmetry + notch) using QT Guard Plus Software (GE Healthcare, Milwaukee, Wisconsin). To assess for heterogeneity of repolarization, the principal component analysis ratio 2 (PCA-2) was calculated. RESULTS: Mean QTc intervals were 486 ± 50 ms (LQTS1), 479 ± 36 ms (LQTS2), and 418 ± 24 ms (control subjects) (p < 0.05). MCS and PCA-2 differed between LQTS patients and control subjects (MCS: 117.8 ± 57.4 vs. 71.9 ± 16.2; p < 0.001; PCA-2: 20.2 ± 10.4% vs. 14.6 ± 5.5%; p < 0.001), LQTS1 and LQTS2 patients (MCS: 96.3 ± 28.7 vs. 164 ± 75.2; p < 0.001; PCA-2: 17.8 ± 8.3% vs. 25 ± 12.6%; p < 0.001), and between LQTS patients with borderline or normal QTc intervals (n = 17) and control subjects (MCS: 105.7 ± 49.9 vs. 71.9 ± 16.2; p < 0.001; PCA-2: 18.1 ± 7.2% vs. 14.6 ± 5.5%; p < 0.001). T-wave metrics were consistent across multiple ECGs from individual patients based on the average intraclass correlation coefficient (MCS: 0.96; PCA-2: 0.86). CONCLUSIONS: Automated T-wave morphology analysis accurately discriminates patients with pathogenic LQTS mutations from control subjects and between the 2 most common LQTS subtypes. Mutation carriers without baseline QTc prolongation were also identified. This may be a useful tool for screening families of LQTS patients, particularly when the QTc interval is subthreshold and genetic testing is unavailable.

Usefulness of 14-Day Holter for Detection of Nonsustained Ventricular Tachycardia in Patients With Hypertrophic Cardiomyopathy.

Nonsustained ventricular tachycardia (NSVT), defined as ≥3 consecutive ventricular beats at ≥120 beats/min lasting <30 seconds, is an independent predictor of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HC). Current guidelines recommend 24- to 48-hour Holter monitoring as part of SCD risk stratification. We sought to assess the difference in diagnostic yield of 14-day Holter monitoring compared to 24-48 hours for the detection of NSVT and to assess the prevalence and characteristics of NSVT in patients with HC with prolonged monitoring. We retrospectively analyzed the 14-day Holter monitors of 77 patients with HC from May 2014 to March 2016. Number of episodes and maximal length and rate on each day were recorded. NSVT was detected in 75.3% of patients during 14-day Holter monitoring. The median number of runs was 2 (range 0 to 26 runs). The median number of beats of the longest run was 10.5 (range 3 to 68 beats) with a mean maximum rate of 159.5 ± 20.8.4 beats/min (range 102 to 203 beats/min). First episodes of NSVT were detected throughout the 14 days, with only 22.5% and 44.8% of the episodes captured within the first 24 and 48 hours of monitoring, respectively. In conclusion, prolonged Holter monitoring revealed ≥1 episode of NSVT in 75% of patients with HC of which <50% were detected within the first 48 hours. Hence, prolonged Holter monitoring may be superior for SCD risk stratification in HC. However, the high prevalence of NSVT in this population may limit its utility in evaluating the risk for SCD of the individual patient.

Patient Outcomes From a Specialized Inherited Arrhythmia Clinic.

BACKGROUND: Patients with inherited arrhythmia syndromes are at an increased risk of sudden cardiac death (SCD). Specialized inherited arrhythmia clinics were founded to optimize management and prevention of SCD in this population. However, the clinical effectiveness of these clinics has never been evaluated. METHODS AND RESULTS: Clinical outcome data of patients referred to a specialized inherited arrhythmia clinic between 2005 and 2014 for a possible primary electric syndrome or arrhythmogenic right ventricular cardiomyopathy were analyzed. Of 720 patients evaluated, 278 received a definite or probable diagnosis and received long-term management in the inherited arrhythmia clinic. All patients diagnosed with long QT syndrome and catecholaminergic polymorphic ventricular tachycardia received routine ß-blocker therapy and demonstrated >90% long-term compliance. In patients with arrhythmogenic right ventricular cardiomyopathy, those demonstrating an arrhythmia burden on Holter or treadmill testing received ß-blocker therapy (17%). In diagnosed channelopathy or arrhythmogenic right ventricular cardiomyopathy index cases, 44 patients received secondary prevention implantable cardioverter-defibrillators (long QT syndrome, 9; Brugada syndrome, 8; catecholaminergic polymorphic ventricular tachycardia, 3; short QT syndrome, 1; and arrhythmogenic right ventricular cardiomyopathy, 23). Median follow-up was 4.1 years with 43% having a follow-up period of >5 years. SCD occurred in a single patient (annualized risk of SCD, 0.1% per year). In individuals determined to have clinical or genetic disease by cascade screening, no SCD has occurred over a median follow-up of 5.6 years (55%, >5 years). Low event rates occurred despite a low rate (4.0%) of primary prevention implantable cardioverter-defibrillator utilization. CONCLUSIONS: Longitudinal care in a specialized inherited arrhythmia clinic is associated with a low incidence of SCD and a low rate of primary implantable cardioverter-defibrillator utilization in patients with inherited arrhythmia syndromes.

A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation.

Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.

Genetics of inherited primary arrhythmia disorders.

A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening.

Temporal-component analysis of diastolic electrograms in ventricular tachycardia differentiates nonvulnerable regions of the circuit.

BACKGROUND: Successful activation mapping of ventricular tachycardia (VT) is dependent on the identification of a region of diastolic conduction by use of point-by-point sequential mapping. It is important to identify the site of transition from diastolic conduction to systolic activation of healthy myocardium (exit site) and differentiate this from nonvulnerable regions of the circuit. OBJECTIVE: We sought to determine the temporal and component characteristics of exit-site electrograms using simultaneous multielectrode endocardial mapping and to differentiate them from bystander sites during activation mapping. METHODS: Sixteen VTs induced in 12 patients with ischemic cardiomyopathy who underwent multielectrode mapping during VT performed with a custom-made 112-bipolar-electrode endocardial array were analyzed retrospectively. The activation sequence in systole and diastole was annotated, and the timing at exit and bystander sites of the near-field component was characterized in relation to surface electrocardiogram activation and to the far-field component. Spectral content of bipolar electrograms recorded at these sites was additionally analyzed to identify the near-field to far-field interval. RESULTS: The mean activation time at exit sites was 60.0 ± 31.5 ms (range 21-113 ms) ahead of surface QRS but was not significantly different from bystander sites (72.0 ± 55.0 ms, P = .63). However, the time delay from local to far-field activity was significantly lower at exit sites than at bystander sites (24.9 ± 15.6 vs. 86.6 ± 92.0 ms, P = .003), which was confirmed by spectral analysis (10.0 ± 13.1 vs. 89.0 ± 64.5 ms, P = .003). CONCLUSION: Our analysis suggests that temporal-component analysis of diastolic electrograms during activation mapping of VT provides a practical method to differentiate nonvulnerable sites from the exit site without the need for pacing maneuvers.