Incremental value of the signal-averaged ECG for diagnosing arrhythmogenic cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is currently diagnosed using a combination of clinical features, imaging, electrocardiography, and genetic investigations. An abnormal signal-averaged electrocardiogram (SAECG) is defined as a minor diagnostic criterion by the 2010 Task Force Criteria, but doubts remain about the value of this investigation. OBJECTIVE: We evaluated the utility of the SAECG in diagnosing ARVC using the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry, a population representative registry of probands with ARVC and relatives, less influenced by referral bias. METHODS: Probands with ARVC and family members from the Canadian Arrhythmogenic Right Ventricular Cardiomyopathy Registry underwent phenotype review. SAECG parameters were compared individually and in combination between those with varying degrees of ARVC severity and healthy controls (family members of probands with ARVC and unexplained sudden death, free of evidence of cardiac disease). RESULTS: A total of 196 patients with ARVC and 205 controls were included (mean age 44 ± 15 years; 186 of 401 men [46%]). SAECG abnormalities were seen in 83 of 205 controls (40%), 33 of 68 patients with ARVC and mild disease (51%), and 31 of 42 with severe disease (74%). The SAECG associated strongly with imaging abnormalities (major: odds ratio 3.0, 95% confidence interval 1.3-6.9; minor: odds ratio 3.5, 95% confidence interval 0.7-16.5) but not with other aspects of phenotype. Patients carrying pathogenic variants but with minimal phenotype had similar SAECGs to healthy controls (filtered QRS duration 111.2 ± 11.2 ms vs 111 ± 7.6 ms, P = .93; duration of low amplitude signals < 40 µV 32.3 ± 8.9 ms vs 34.2 ± 7.2 ms, P = .32; root mean square of the terminal 40 ms of the filtered QRS complex 43.1 ± 25.2 ms vs 38.2 ± 20.2 ms, P = .38). CONCLUSION: The SAECG appears to be a surrogate marker for structural abnormalities seen on imaging in those with ARVC. Great caution is required in interpreting SAECG findings in those without other corroborating evidence of an ARVC phenotype.

Evaluation of the efficacy of signal-averaged electrocardiogram testing in the cardiac assessment of beta-thalassemia major patients.

BACKGROUND: More than 70% of thalassemia's major mortality is due to the cardiac complications of this syndrome, mostly consequent to myocardial Iron overload; therefore, evaluation of such complications is of utmost importance. T2*MRI is used to assess hepatic and myocardial Iron load in thalassemia patients, which is not always available. Signal-Averaged Electrocardiography is a rather easy method of evaluating major thalassemia patients regarding their risk for sudden cardiac death. METHODS AND MATERIALS: In this cross-sectional study, 48 patients with thalassemia major underwent evaluation with electrocardiography, signal-averaged electrocardiography, echocardiography, T2*MRI, and ferritin level. The association of the existence of ventricular late potentials in SAECG and other cardiac variables was evaluated. Moreover, the association between myocardial and hepatic Iron load and cardiac characteristics was assessed. RESULTS: 48 patients with a mean age of 30.31 ± 7.22 years old entered the study. 27 (56.3%) of the patients had ventricular late potentials, which were associated with myocardial dry Iron weight (P = 0.011). Nonspecific ST-T changes and premature atrial and ventricular contractions were seen more frequently in patients with late potentials (P = 0.002, 0.031, and 0.031, respectively). Patients with higher myocardial and hepatic Iron loads had longer QTc in their 12-lead surface electrocardiograms. CONCLUSION: Patients with ventricular late potentials assessed by SAECG had a higher myocardial Iron load. Higher myocardial Iron load is associated with higher cardiac complications in patients with beta-thalassemia major; therefore, SAECG can be used as a screening test for cardiac complications in beta-thalassemia major patients.

The clinical utility of procainamide-induced late potentials on the signal averaged ECG.

BACKGROUND: Late potentials (LPs) identified on the signal averaged electrocardiogram (SAECG) are a marker for an increased risk of arrhythmias in Brugada syndrome (BrS). Procainamide is a sodium channel blocker used to diagnose BrS. The effects of Procainamide on the SAECG in those with BrS and the significance of Procainamide-induced LPs are unknown. METHODS: Procainamide provocation was performed for suspected BrS with 12-lead and SAECG pre- and post-infusion. Filtered QRS duration (fQRSd), duration of low amplitude signals <40 µV (LAS40) and root-mean-square voltage in the terminal 40 ms (RMS40) were determined. RESULTS: Data from 150 patients were included in the analysis (mean age 44.5 years, 109 males). Procainamide increased fQRSd (Pre 118.8 ± 10.5 ms, post 121.2 ± 10.2 ms, p < 0.001) and LAS40 (Pre 38.7 ± 9.8 ms, post 40.2 ± 10.5 ms, p = 0.005) and decreased RMS40 (Pre 24.6 ± 12 ms, post 22.8 ± 12 ms, p = 0.002). LPs were present in 68/150 (45%) at baseline. Fifteen patients with negative baseline SAECGs had LPs unmasked by Procainamide, but six patients had LPs at baseline that were no longer present following Procainamide. Comparing those with normal hearts (n = 48) to those with a final diagnosis of BrS (n = 38), Procainamide prolonged fQRSd to a greater extent in those with BrS. Comparing those with Procainamide-induced LPs to those with no LPs at any time did not highlight any aspect of phenotype and did not correlate with a history of ventricular arrhythmias. CONCLUSIONS: Procainamide influences the SAECG, provoking LPs in a small proportion of patients. However, there is no evidence that Procainamide-induced LPs provide additional diagnostic information or aid risk stratification.

Late potentials and their correlation with ventricular structure in patients with ventricular arrhythmias.

INTRODUCTION: The presence of late potentials (LP) may indicate a predisposition to ventricular arrhythmias and sudden cardiac death. We investigated the association between presence of LP and structural cardiac anomalies assessed by magnetic resonance (CMR) in patients presenting with ventricular arrhythmias. METHODS: We included 42 patients admitted with ventricular tachycardia or fibrillation who had undergone both signal-averaged ECG recording and CMR imaging. Clinical data and CMR findings were compared in patients with and without LP. RESULTS: The majority, 26 (62%) patients, were sudden cardiac death survivors and the remaining 16 (38%) were admitted with ventricular tachycardia. After full diagnostic work-up, the most common diagnoses in the cohort were idiopathic ventricular tachycardia/ventricular fibrillation (25 patients, 60%) or cardiomyopathies (11 patients, 26%). LPs were positive in 29 (69%) when using the revised Task Force criteria. When comparing patients with and without late potentials, there were no significant differences in right ventricular size relative to body surface area (102 mL/m2 vs 92 mL/m2 ), right ventricular ejection fraction (55% vs 58%), or positive late gadolinium enhancement (29% vs 24%). CONCLUSIONS: Among patients with malignant arrhythmias, the presence of LP does not distinguish between patients with normal and abnormal RV structure or function on CMR. LP may indicate the presence of an arrhythmic heart disease beyond what can be inferred from CMR. The frequent finding of late potentials indicates that the diagnostic value of LP as an ARVC criteria should be tested in larger studies comparing ARVC patients and controls.

The application of signal average ECG in the prediction of recurrences after catheter ablation of ventricular arrhythmias in arrhythmogenic right ventricular dysplasia/cardiomyopathy.

BACKGROUND: The changes of signal averaged ECG (SAECG) in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) undergoing radiofrequency catheter ablation (RFCA) of ventricular arrhythmias (VAs) remains unknown. METHODS: Between 2010 and 2014, a total of 81 ARVD/C patients underwent endocardial and/or epicardial RFCA for drug-refractory VAs. Seventy patients (mean age 46.2±14.1years, 37 males) achieving acute procedure success (negative inducibility) were enrolled. Baseline characteristics, non-invasive examinations and SAECG (before and 3months after RFCA) were collected retrospectively. RESULTS: After successful RFCA, the electrical parameters of SAECG changed in 39 patients (55.7%), including 28 patients (40%) with electrical regression (group 1), and 11 patients (15.7%) with electrical progression (group 3). Thirty-one patients (44.3%) showed no significant SAECG change (group 2). During a mean follow-up of 17.8±10.7months, 23 patients (32.9%) had VA recurrences, including 4 in group 1, 12 in group 2, and 7 in group 3. In comparisons with groups 2 and 3, group 1 patients had a significantly better VA recurrence-free survival (P=0.02). In multivariable Cox regression analysis, electrical regression was found to be associated with fewer VA recurrences (P=0.02, OR: 0.28, 95% CI: 0.10-0.83). CONCLUSIONS: Electrical regression of SAECG after RFCA in ARVD/C was found to be associated with fewer VA recurrences.

Electrocardiographic methods for diagnosis and risk stratification in the Brugada syndrome.

The Brugada syndrome (BrS) is a malignant, genetically-determined, arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals with structurally normal hearts. The diagnosis of the BrS is mainly based on the presence of a spontaneous or Na + channel blocker induced characteristic, electrocardiographic (ECG) pattern (type 1 or coved Brugada ECG pattern) typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal (i.c.) spaces. This pattern needs to be distinguished from similar ECG changes due to other causes (Brugada ECG phenocopies). This review focuses mainly on the ECG-based methods for diagnosis and arrhythmia risk assessment in the BrS. Presently, the main unresolved clinical problem is the identification of those patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD), which is the only therapy with proven efficacy. Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern, and either history of aborted cardiac arrest or documented sustained VT (class I), or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmic events (up to 10% or more annually for those with aborted cardiac arrest). The majority of BrS patients are asymptomatic when diagnosed and considered to have low risk (around 0.5% annually) and therefore not indicated for ICD. The majority of SCD victims in the BrS, however, had no symptoms prior to the fatal event and therefore were not protected with an ICD. While some ECG markers such as QRS fragmentation, infero-lateral early repolarisation, and abnormal late potentials on signal-averaged ECG are known to be linked to increased arrhythmic risk, they are not sufficiently sensitive or specific. Potential novel ECG-based strategies for risk stratification are discussed based on computerised methods for depolarisation and repolarisation analysis, a composite approach targeting several major components of ventricular arrhythmogenesis, and the collection of large digital ECG databases in genotyped BrS patients and their relatives.

Number of P-wave fragmentations on P-SAECG correlates with infiltrated atrial fat.

BACKGROUND: Although atrial fibrillation (AF) triggers are known, the underlying AF substrate is less well understood. The goal of our study was to explore correlations between electrophysiological and structural characteristics of atria in patients with paroxysmal AF and individuals at AF risk. METHODS: Patients in sinus rhythm (N = 90; age 57 ± 10 year; 55 men [63.2%]) with structural heart disease and paroxysmal AF (n = 12 [13%]), or with AF risk factors and LVEF > 35% (n = 78), underwent SAECG and cardiac magnetic resonance study. Interatrial and epicardial fat was analyzed with a Dark-blood DIR-prepared Fat-Water-separated sequence in the horizontal longitudinal axis. All local P-wave extrema were identified on SAECG leads during sinus rhythm. A P-wave fragmentation (Pf) was defined as an absolute difference between adjacent extrema which was above three standard deviations of noise, and was normalized by the duration of the P wave in the corresponding lead. RESULTS: The Pf was greater on the filtered than on the unfiltered P-SAECG signal (13.1 ± 3.8 vs. 3.4 ± 1.2; P < 0.0001). Pf was the greatest on the Y lead (13.0 ± 3.5 on Y lead vs. 12.1 ± 3.4 on Z lead; P = 0.003. Pf on Z lead correlated with interatrial fat index (r = 0.544; P = 0.001). Epicardial fat significantly correlated with body mass index (BMI; r = 0.302; P = 0.015). After adjustment for BMI, left atrium (LA) size, epicardial fat, and interatrial septum width, interatrial fat independently associated with the Pf on Z lead (ß-coefficient 0.009 [95%CI 0.0003-0.019]; P = 0.043). CONCLUSIONS: Infiltrated atrial fat correlates with discontinuous conduction on posterior LA wall and represents AF early substrate.

Evolution of clinical diagnosis in patients presenting with unexplained cardiac arrest or syncope due to polymorphic ventricular tachycardia.

BACKGROUND: A systematic evaluation of patients with unexplained cardiac arrest (UCA) yields a diagnosis in 50% of the cases. However, evolution of clinical phenotype, identification of new disease-causing mutations, and description of new syndromes may revise the diagnosis. OBJECTIVE: To assess the evolution in diagnosis among patients with initially UCA. METHODS: Diagnoses were reviewed for all patients with UCA recruited from the Cardiac Arrest Survivors with Preserved Ejection Fraction Registry with at least 1 year of follow-up. RESULTS: After comprehensive investigation of 68 patients (age 45.2 ± 14.9 years; 63% men), the initial diagnosis was as follows: idiopathic ventricular fibrillation (n = 34 [50%]), a primary arrhythmic disorder (n = 21 [31%]), and an occult structural cause (n = 13 [19%]). Patients were followed for 30 ± 17 months, during which time the diagnosis changed in 12 (18%) patients. A specific diagnosis emerged for 7 patients (21%) with an initial diagnosis of idiopathic ventricular fibrillation. A structural cardiomyopathy evolved in 2 patients with an initial diagnosis of primary electrical disorder, while the specific structural cardiomyopathy was revised for 1 patient. Two patients with an initial diagnosis of a primary arrhythmic disorder were subsequently considered to have a different primary arrhythmic disorder. A follow-up resting electrocardiogram was the test that most frequently changed the diagnosis (67% of the cases), followed by genetic testing (17%). CONCLUSIONS: The reevaluation of patients presenting with UCA may lead to a change in diagnosis in up to 20%. This emphasizes the need to actively monitor the phenotype and also has implications for the treatment of these patients and the screening of their relatives.

The Connexin40A96S mutation from a patient with atrial fibrillation causes decreased atrial conduction velocities and sustained episodes of induced atrial fibrillation in mice.

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and a major cause of stroke. In the mammalian heart the gap junction proteins connexin40 (Cx40) and connexin43 (Cx43) are strongly expressed in the atrial myocardium mediating effective propagation of electrical impulses. Different heterozygous mutations in the coding region for Cx40 were identified in patients with AF. We have generated transgenic Cx40A96S mice harboring one of these mutations, the loss-of-function Cx40A96S mutation, as a model for atrial fibrillation. Cx40A96S mice were characterized by immunochemical and electrophysiological analyses. Significantly reduced atrial conduction velocities and strongly prolonged episodes of atrial fibrillation were found after induction in Cx40A96S mice. Analyses of the gating properties of Cx40A96S channels in cultured HeLa cells also revealed significantly lower junctional conductance and enhanced sensitivity voltage gating of Cx40A96S in comparison to Cx40 wild-type gap junctions. This is caused by reduced open probabilities of Cx40A96S gap junction channels, while single channel conductance remained the same. Similar to the corresponding patient, heterozygous Cx40A96S mice revealed normal expression levels and localization of the Cx40 protein. We conclude that heterozygous Cx40A96S mice exhibit prolonged episodes of induced atrial fibrillation and severely reduced atrial conduction velocities similar to the corresponding human patient.

Malignant arrhythmogenic right ventricular dysplasia/cardiomyopathy with a normal 12-lead electrocardiogram: a rare but underrecognized clinical entity.

BACKGROUND: In Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C), a normal electrocardiogram (ECG) is considered reassuring. However, some patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG. OBJECTIVES: To estimate how often patients with ARVD/C experiencing ventricular arrhythmias have a normal ECG during sinus rhythm, and to provide a clinical profile of these patients. METHODS: We included 145 patients with ARVD/C experiencing a documented sustained ventricular arrhythmia. Conventional 12-lead sinus rhythm ECGs within 6 months of the event were reviewed for diagnostic Task Force Criteria (TFC). ECGs were classified as abnormal (≥1 TFC), nonspecific (abnormal, no TFC), or normal. Cardiologic investigations within 6 months of the event were evaluated as per TFC in those with a nonspecific or normal ECG. RESULTS: The ECG was nonspecific or normal in 17 of 145 (12%) subjects. Mean age of these patients was 41.3 ± 12.4 years and 14 (82%) were men, comparable to those with an abnormal ECG. Most patients with a nonspecific or normal ECG showed ≥1 TFC on Holter monitoring (n = 9 of 10) and signal-averaged ECG (n = 4 of 5), and all had nonsustained ventricular tachycardia recorded. Among 15 patients who underwent structural evaluation, 11 (73%) showed structural TFC (9 major and 2 minor). CONCLUSIONS: Although most patients with ARVD/C experiencing arrhythmias have an abnormal ECG, a nonspecific or normal ECG does not preclude ARVD/C diagnosis. All patients with a nonspecific or normal ECG had alternative evidence of disease expression. These results alert the physician not to rely exclusively on ECG in ARVD/C, but to assess arrhythmic risk by comprehensive clinical evaluation.

Low noise level unmasks late potentials on signal-averaged electrocardiography.

INTRODUCTION: Identification of late potentials requires the reduction of random noise by signal averaging. The importance of using a very low noise level (NL) as the end point of the averaging process in patients with ventricular tachycardia, the variation of results when a lower than standard NL was used and the modification of the sensitivity of the test when a very low NL was reached were evaluated. METHODS AND RESULTS: Signal-averaged electrocardiograms were recorded in 36 patients with ischemic heart disease and spontaneous or induced sustained or nonsustained ventricular tachycardia. Thirteen patients showed negative or indeterminate results on recordings with an NL of 0.3 µV. Eight patients (group 1) underwent a second recording with an NL of 0.1 µV. Eight normal volunteers constituted the control group (group 2). The total duration of the filtered QRS vector magnitude (QRSd), the root mean square voltage of the terminal 40 ms of the vector magnitude (RMS(40)) and the low amplitude signal duration under 40 µV in the terminal portion of the vector magnitude (LAS) modifications were evaluated. A significant difference (P<0.01) in these parameters was observed in group 1 (15.88%, 48.25% and 68.5%, respectively) when both recordings were compared. Tests were positive in all patients (100%) with NL reduction. In group 2, tests were negative in all patients (100%) at both NLs (0.3 µV and 0.1 µV). QRSd was 1.18% longer, RMS(40) was 1.38% lower and LAS was 3.55% longer with NL reduction. CONCLUSION: Late potentials in patients with ischemic heart disease, ventricular tachycardia, and a negative or indeterminate signal-averaged electrocardiogram may be detected if the NL is reduced to 0.1 µV. Reduction of the NL increased the sensitivity of the test without modifying its specificity.