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This consensus guideline was prepared on behalf of the International Society for Holter and Noninvasive Electrocardiology and is cosponsored by the Japanese Circulation Society, the Computers in Cardiology Working Group on e-Cardiology of the European Society of Cardiology, and the European Cardiac Arrhythmia Society. It discusses the electrocardiographic phenomenon of T-wave alternans (TWA) (i.e., a beat-to-beat alternation in the morphology and amplitude of the ST-segment or T-wave). This statement focuses on its physiological basis and measurement technologies and its clinical utility in stratifying risk for life-threatening ventricular arrhythmias. Signal processing techniques including the frequency-domain Spectral Method and the time-domain Modified Moving Average method have demonstrated the utility of TWA in arrhythmia risk stratification in prospective studies in >12,000 patients. The majority of exercise-based studies using both methods have reported high relative risks for cardiovascular mortality and for sudden cardiac death in patients with preserved as well as depressed left ventricular ejection fraction. Studies with ambulatory electrocardiogram-based TWA analysis with Modified Moving Average method have yielded significant predictive capacity. However, negative studies with the Spectral Method have also appeared, including 2 interventional studies in patients with implantable defibrillators. Meta-analyses have been performed to gain insights into this issue. Frontiers of TWA research include use in arrhythmia risk stratification of individuals with preserved ejection fraction, improvements in predictivity with quantitative analysis, and utility in guiding medical as well as device-based therapy. Overall, although TWA appears to be a useful marker of risk for arrhythmic and cardiovascular death, there is as yet no definitive evidence that it can guide therapy. [ABSTRACT FROM AUTHOR]

Background: Experimental and observational studies have demonstrated that short-term exposure to ambient particulate matter (PM) exacerbates myocardial ischemia. Objectives: We conducted this study to investigate the effects of concentrated ambient particles (CAPs) on myocardial blood flow during myocardial ischemia in chronically instrumented conscious canines. Methods: Eleven canines were instrumented with a balloon occluder around the left anterior descending coronary artery and catheters for determination of myocardial blood flow using fluorescent microspheres. Telemetric electrocardiographic and blood pressure monitoring was available for four of these animals. After recovery, we exposed animals by inhalation to 5 hr of either filtered air or CAPs (mean concentration ± SD, 349.0 ± 282.6 µg/m3) in a crossover protocol. We determined myocardial blood flow during a 5-min coronary artery occlusion immediately after each exposure. Data were analyzed using mixed models for repeated measures. The primary analysis was based on four canines that completed the protocol. Results: CAPs exposure decreased total myocardial blood flow during coronary artery occlusion by 0.12 mL/min/g (p < 0.001) and was accompanied by a 13% (p < 0.001) increase in coronary vascular resistance. Rate-Spressure product, an index of myocardial oxygen demand, did not differ by exposure (p = 0.90) . CAPs effects on myocardial blood flow were significantly more pronounced in myocardium within or near the ischemic zone versus more remote myocardium (p interaction < 0.001) . Conclusions: These results suggest that PM exacerbates myocardial ischemia by increased coronary vascular resistance and decreased myocardial perfusion. Further studies are needed to elucidate the mechanism of these effects. [ABSTRACT FROM AUTHOR]

Extensive experimental and clinical evidence supports the utility of T-wave alternans (TWA) as a marker of risk for ventricular fibrillation. This entity appears to reflect the fundamental arrhythmogenic property of enhanced dispersion of repolarization. This relationship probably accounts for its relative ubiquity in patients with diverse types of cardiac disease, as has been recognized with the development of analytical tools. A basic premise of this review is that ambulatory ECG monitoring of TWA as patients experience the provocative stimuli of daily activities can expose latent electrical instability in individuals at heightened risk for arrhythmias. We will discuss the literature that supports this concept and summarize the current state of knowledge regarding the use of routine ambulatory ECGs to evaluate TWA for arrhythmia risk stratification. The dynamic, nonspectral modified moving average analysis method for assessing TWA, which is compatible with ambulatory ECG monitoring, is described along with methodological guidelines for its implementation. Finally, the rationale for combined monitoring of autonomic markers along with TWA will be presented. [ABSTRACT FROM AUTHOR]

Concurrent electrocardiogram (ECG) and electroencephalogram (EEG) recording both ictally and interictally has significant value in the comprehensive management of epilepsy. This review highlights the diagnostic utility of simultaneous ECG and EEG monitoring in differentiating between epileptic and cardiac events, detecting cardiac abnormalities, and identifying autonomic dysfunction. The critical role of this combined approach to defining the mechanisms underlying cardiac morbidity and sudden cardiac death in patients with epilepsy and in guiding therapeutic interventions is underscored. The "Epileptic Heart Syndrome" is examined, illustrating how chronic epilepsy can adversely affect cardiac structure and function, leading to increased risk for interictal cardiac arrhythmias, morbidities, and mortality. The findings emphasize the need for standardized protocols for routine concurrent ECG and EEG recording in epilepsy monitoring units both ictally and interictally to ensure comprehensive patient care, improve diagnostic accuracy, and potentially reduce epilepsy-related morbidity and mortality. Future research directions are proposed to address existing gaps and to advance the technology and methodology for concurrent monitoring including wearable and computer-based monitoring systems., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jeremy Slater is CMO of Stratus, Inc., and reports financial support and administrative support provided by Stratus including employment, equity or stocks, and non-financial support. He owns stock in Zeto, Inc., a manufacturer of a dry electrode EEG headset. Selim Benbadis is National Medical Director of Stratus. Richard Verrier is a member of the Medical Advisory Board of Stratus and has received lecture honoraria from Stratus and from UCB., (© 2024 The Authors. Published by Elsevier Inc.)

Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Verrier is a member of the medical advisory board of Stratus, Inc., Irving TX. Dr. Verrier declares that he has no other known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Dr. Schachter declares that he has no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Population studies report elevated incidence of cardiovascular events in patients with chronic epilepsy. Multiple pathophysiologic processes have been implicated, including accelerated atherosclerosis, myocardial infarction, altered autonomic tone, heart failure, atrial and ventricular arrhythmias, and hyperlipidemia. These deleterious influences on the cardiovascular system have been attributed to seizure-induced surges in catecholamines and hypoxemic damage to the heart and coronary vasculature. Certain antiseizure medications can accelerate heart disease through enzyme-inducing increases in plasma lipids and/or increasing risk for life-threatening ventricular arrhythmias as a result of sodium channel blockade. In this review, we propose that this suite of pathophysiologic processes constitutes "The Epileptic Heart Syndrome." We further propose that this condition can be diagnosed using standard electrocardiography, echocardiography, and lipid panels. The ultimate goal of this syndromic approach is to evaluate cardiac risk in patients with chronic epilepsy and to promote improved diagnostic strategies to reduce premature cardiac death., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Verrier is coinventor of United States Patent #10,022,060, which protects analytical methodologies used by Dr. Fialho and colleagues in Reference #60. Dr. Verrier is a member of the Medical Advisory Board of StratusNeuro, Inc. (Houston TX, USA) and has received consulting fees from Union Chimique Belge (UCB) Pharma S.A. (Brussels, Belgium). Dr. Schachter reports no conflicts of interest., (© 2024 The Authors. Published by Elsevier Inc.)

Introduction: Numerous P-wave indices have been explored as biomarkers to assess atrial fibrillation (AF) risk and the impact of therapy with variable success., Objective: We investigated the utility of P-wave alternans (PWA) to track the effects of pulmonary vein isolation (PVI) and to predict atrial arrhythmia recurrence., Methods: This medical records study included patients who underwent PVI for AF ablation at our institution, along with 20 control subjects without AF or overt cardiovascular disease. PWA was assessed using novel artificial intelligence-enabled modified moving average (AI-MMA) algorithms. PWA was monitored from the 12-lead ECG at ~1 h before and ~16 h after PVI (n = 45) and at the 4- to 17-week clinically indicated follow-up visit (n = 30). The arrhythmia follow-up period was 955 ± 112 days., Results: PVI acutely reduced PWA by 48%-63% (p < .05) to control ranges in leads II, III, aVF, the leads with the greatest sensitivity in monitoring PWA. Pre-ablation PWA was ~6 µV and decreased to ~3 µV following ablation. Patients who exhibited a rebound in PWA to pre-ablation levels at 4- to 17-week follow-up (p < .01) experienced recurrent atrial arrhythmias, whereas patients whose PWA remained reduced (p = .85) did not, resulting in a significant difference (p < .001) at follow-up. The AUC for PWA's prediction of first recurrence of atrial arrhythmia was 0.81 (p < .01) with 88% sensitivity and 82% specificity. Kaplan-Meier analysis estimated atrial arrhythmia-free survival (p < .01) with an adjusted hazard ratio of 3.4 (95% CI: 1.47-5.24, p < .02)., Conclusion: A rebound in PWA to pre-ablation levels detected by AI-MMA in the 12-lead ECG at standard clinical follow-up predicts atrial arrhythmia recurrence., (© 2024 Wiley Periodicals LLC.)

Background: The incidence of myocardial infarction (MI) and sudden cardiac death (SCD) is significantly higher in individuals with Type 2 Diabetes Mellitus (T2DM) than in the general population. Strategies for the prevention of fatal arrhythmias are often insufficient, highlighting the need for additional non-invasive diagnostic tools. The T-wave heterogeneity (TWH) index measures variations in ventricular repolarization and has emerged as a promising predictor for severe ventricular arrhythmias. Although the EMPA-REG trial reported reduced cardiovascular mortality with empagliflozin, the underlying mechanisms remain unclear. This study investigates the potential of empagliflozin in mitigating cardiac electrical instability in patients with T2DM and coronary heart disease (CHD) by examining changes in TWH., Methods: Participants were adult outpatients with T2DM and CHD who exhibited TWH > 80 µV at baseline. They received a 25 mg daily dose of empagliflozin and were evaluated clinically including electrocardiogram (ECG) measurements at baseline and after 4 weeks. TWH was computed from leads V4, V5, and V6 using a validated technique. The primary study outcome was a significant (p < 0.05) change in TWH following empagliflozin administration., Results: An initial review of 6,000 medical records pinpointed 800 patients for TWH evaluation. Of these, 412 exhibited TWH above 80 µV, with 97 completing clinical assessments and 90 meeting the criteria for high cardiovascular risk enrollment. Empagliflozin adherence exceeded 80%, resulting in notable reductions in blood pressure without affecting heart rate. Side effects were generally mild, with 13.3% experiencing Level 1 hypoglycemia, alongside infrequent urinary and genital infections. The treatment consistently reduced mean TWH from 116 to 103 µV (p = 0.01)., Conclusions: The EMPATHY-HEART trial preliminarily suggests that empagliflozin decreases heterogeneity in ventricular repolarization among patients with T2DM and CHD. This reduction in TWH may provide insight into the mechanism behind the decreased cardiovascular mortality observed in previous trials, potentially offering a therapeutic pathway to mitigate the risk of severe arrhythmias in this population., Trial Registration: NCT: 04117763., (© 2024. The Author(s).)

Background: T-wave alternans (TWA) analysis was shown in >14,000 individuals studied worldwide over the past two decades to be a useful tool to assess risk for cardiovascular mortality and sudden arrhythmic death. TWA analysis by the modified moving average (MMA) method is FDA-cleared and CMS-reimbursed (CAG-00293R2)., Objective: Because the MMA technique is inherently suitable for dynamic tracking of alternans levels, it was selected for development of artificial intelligence (AI)-enabled algorithms using convolutional neural networks (CNN) to achieve rapid, efficient, and accurate assessment of P-wave alternans (PWA), R-wave alternans (RWA), and TWA., Methods: The novel application of CNN algorithms to enhance MMA analysis generated efficient and powerful pattern-recognition algorithms for highly accurate alternans quantification. Algorithm reliability and accuracy were verified using simulated ECGs achieving R 2  ≥ 0.99 (p < 0.01) in response to noise inputs and artifacts that emulate real-life conditions., Results: Accuracy of the new AI-MMA algorithms in TWA analysis (n = 5) was significantly improved over unsupervised, automated MMA output (p = 0.036) and did not differ from conventional MMA analysis with expert overreading (p = 0.21). Accuracy of AI-MMA in PWA analysis (n = 45) was significantly improved over unsupervised, automated MMA output (p < 0.005) and did not differ from conventional MMA analysis with expert overreading (p = 0.89). TWA and PWA by AI-MMA were correlated with conventional MMA output over-read by an expert reader (R 2  = 0.7765, R 2  = 0.9504, respectively)., Conclusion: This novel technique for AI-MMA analysis could be suitable for use in diverse in-hospital and out-of-hospital monitoring systems, including cardiac implantable electronic devices and smartwatches, for tracking atrial and ventricular arrhythmia risk., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Sudden cardiac death (SCD) resulting from ventricular arrhythmia is the main complication of hypertrophic cardiomyopathy (HCM). Microvolt T-wave alternans (MTWA) is associated with the occurrence of ventricular arrhythmias in several heart diseases, but its role in HCM remains uncertain., Objective: To evaluate the association of MTWA with the occurrence of SCD or potentially fatal ventricular arrhythmias in HCM patients in a long-term follow-up., Methods: Patients diagnosed with HCM and NYHA functional class I-II were consecutively selected. At the beginning of the follow-up, the participants performed the MTWA evaluation using the modified moving average during the stress test. The results were classified as altered or normal. The composite endpoint of SCD, ventricular fibrillation, sustained ventricular tachycardia (SVT) or appropriate implantable cardiac defibrillation (ICD) therapy was assessed. The level of significance was set at 5%., Results: A total of 132 patients (mean age of 39.5 ± 12.6 years) were recruited and followed for a mean of 9.5 years. The MTWA test was altered in 74 (56%) participants and normal in 58 (44%). Nine events (6.8%) occurred during the follow-up, with a prevalence of 1.0%/year - six SCDs, two appropriate ICD shocks and one episode of (SVT). Altered MTWA was associated with non-sustained ventricular tachycardia on Holter (p = 0.016), septal thickness ≥30 mm (p < 0.001) and inadequate blood pressure response to effort (p = 0.046). Five patients with altered MTWA (7%) and four patients with normal MTWA (7%) had the primary outcome [OR = 0.85 (95% CI: 0.21 - 3.35, p=0.83)]. Kaplan-Meir event curves showed no differences between normal and altered MTWA., Conclusion: Altered MTWA was not associated with the occurrence of SCD or potentially fatal ventricular arrhythmias in HCM patients, and the low rate of these events during long-term follow-up suggests the good prognosis of this heart disease.

Objective: Identification of epilepsy patients with elevated risk for atrial fibrillation (AF) is critical given the heightened morbidity and premature mortality associated with this arrhythmia. Epilepsy is a worldwide health problem affecting nearly 3.4 million people in the United States alone. The potential for increased risk for AF in patients with epilepsy is not well appreciated, despite recent evidence from a national survey of 1.4 million hospitalizations indicating that AF is the most common arrhythmia in people with epilepsy., Methods: We analyzed inter-lead heterogeneity of P-wave morphology, a marker reflecting arrhythmogenic nonuniformities of activation/conduction in atrial tissue. The study groups consisted of 96 patients with epilepsy and 44 consecutive patients with AF in sinus rhythm before clinically indicated ablation. Individuals without cardiovascular or neurological conditions (n = 77) were also assessed. We calculated P-wave heterogeneity (PWH) by second central moment analysis of simultaneous beats from leads II, III, and aVR ("atrial dedicated leads") from standard 12-lead electrocardiography (ECG) recordings from admission day to the epilepsy monitoring unit (EMU)., Results: Female patients composed 62.5%, 59.6%, and 57.1% of the epilepsy, AF, and control subjects, respectively. The AF cohort was older (66 ± 1.1 years) than the epilepsy group (44 ± 1.8 years, p < .001). The level of PWH was greater in the epilepsy group than in the control group (67 ± 2.6 vs. 57 ± 2.5 μV, p = .046) and reached levels observed in AF patients (67 ± 2.6 vs. 68 ± 4.9 μV, p = .99). In multiple linear regression analysis, PWH levels in individuals with epilepsy were mainly correlated with the PR interval and could be related to sympathetic tone. Epilepsy remained associated with PWH after adjustments for cardiac risk factors, age, and sex., Significance: Patients with chronic epilepsy have increased PWH comparable to levels observed in patients with AF, while being ~20 years younger, suggesting an acceleration in structural change and/or cardiac electrical instability. These observations are consistent with emerging evidence of an "epileptic heart" condition., (© 2023 International League Against Epilepsy.)

Background: Autonomic regulation therapy (ART) utilizing cervical vagus nerve stimulation (VNS) appeared to be safe and to improve autonomic tone, symptoms, and cardiac mechanical function in patients with symptomatic heart failure and reduced ejection fraction in the ANTHEM-HF Study. The ANTHEM-HFpEF Study is the first investigation to evaluate the safety and feasibility of ART in patients with symptomatic heart failure and preserved or mildly reduced ejection fraction (HFpEF, HFmrEF)., Methods: This open-label interventional study enrolled 52 patients with HFpEF or HFmrEF, NYHA Class II-III, and LVEF ≥40%, who received stable guideline-directed medical therapy. All patients were successfully implanted with LivaNova VNS Therapy® system with an electrical lead surrounding the right cervical vagus nerve., Results: Adverse event incidence was low. At 12 months, NYHA class (p <0.0001), 6-min walk distance (p <0.05), and quality of life (p <0.0001) were improved. Cardiac mechanical function measures were normal at baseline, except for left ventricular mass index in women and E/e' ratio in all patients, which were elevated at baseline, and were unchanged by ART. Autonomic tone and reflexes improved, indicated by 29% decrease in low-frequency/high-frequency heart rate variability to normal levels (p = 0.028) and by increased heart rate turbulence slope (p = 0.047). T-wave alternans (p = 0.001) and T-wave heterogeneity (p = 0.001) were reduced from abnormal to normal ranges. Nonsustained ventricular tachycardia incidence decreased (p = 0.027)., Conclusions: ART appeared well-tolerated and safe in patients with HFpEF or HFmrEF. Chronic ART did not alter mechanical function measures but was associated with improved heart failure symptoms, exercise tolerance, autonomic tone, and cardiac electrical stability., Clinical Trial Registry: Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure with Preserved Ejection Fraction [ClinicalTrials.gov #NCT03163030, registered 05/22/2017]., Competing Interests: Declaration of Competing Interest Drs. Kumar, Mittal, and Premchand were site investigators and Dr. Anand was Principal Investigator of the ANTHEM-HFpEF Study. Drs. Libbus, DiCarlo, and KenKnight and Mr. Amurthur are employees and shareholders in LivaNova USA. Drs. Nearing and Verrier declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: People with epilepsy (PWE) are at increased risk for premature death due to many factors. Sudden unexpected death in epilepsy (SUDEP) is among the most important causes of death in these individuals and possibly, sudden cardiac death (SCD) in epilepsy is also as important. The possibility of concurrent derangement in electrical and mechanical cardiac function, which could be a marker of early cardiac involvement in PWE, has not been investigated in that population., Methods: Electrical dispersion indices (T-wave peak to T-wave end, TpTe; QT dispersion, QTd; QT interval corrected for heart rate, QTc) were analyzed in patients with pharmacoresistant temporal lobe epilepsy and compared to a control group. The electromechanical relationship between those indices and echocardiographic parameters were further assessed in PWE., Results: In 19 PWE and 21 controls, we found greater TpTe and QTd in PWE (TpTe: 91.6 ± 16.4 ms vs. 65.2 ± 12.1 ms, p < 0.0001; and QTd: 45.3 ± 13.1 ms vs. 19 ± 6.2 ms, p < 0.0001, respectively). QTc was similar between PWE and controls (419.2 ± 31.4 ms vs. 435.1 ± 31.4 ms, p = 0.12). In multivariate linear regression, TpTe, QTc, and epilepsy duration were related to left ventricular mass; QTc was associated with left atrial volume; QTc, the number of seizures per month, epilepsy duration and antiseizure medication explained 81% of E/A mitral wave Doppler ratio., Conclusions: This is the first report to demonstrate concurrent electrical dispersion and diastolic dysfunction in PWE. These noninvasive biomarkers could prove useful in early detection of the "Epileptic Heart" condition., Competing Interests: Declaration of Competing Interest None of the authors has any conflict of interest to disclose. No funding was received. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Pulmonary vein isolation (PVI) modulates the intrinsic cardiac autonomic nervous system and reduces atrial fibrillation (AF) recurrence., Methods: In this retrospective analysis, we investigated the impact of PVI on ECG interlead P-wave, R-wave, and T-wave heterogeneity (PWH, RWH, TWH) in 45 patients in sinus rhythm undergoing clinically indicated PVI for AF. We measured PWH as a marker of atrial electrical dispersion and AF susceptibility and RWH and TWH as markers of ventricular arrhythmia risk along with standard ECG measures., Results: PVI acutely (16 ± 8.9 h) reduced PWH by 20.7% (from 31 ± 1.9 to 25 ± 1.6 µV, p < 0.001) and TWH by 27% (from 111 ± 7.8 to 81 ± 6.5 µV, p < 0.001). RWH was unchanged after PVI (p = 0.068). In a subgroup of 20 patients with longer follow-up (mean = 47 ± 3.7 days after PVI), PWH remained low (25 ± 1.7 µV, p = 0.01), but TWH partially returned to the pre-ablation level (to 93 ± 10.2, p = 0.16). In three individuals with early recurrence of atrial arrhythmia in the first 3 months after ablation, PWH increased acutely by 8.5%, while in patients without early recurrence, PWH decreased acutely by 22.3% (p = 0.048). PWH was superior to other contemporary P-wave metrics including P-wave axis, dispersion, and duration in predicting early AF recurrence., Conclusion: The rapid time course of decreased PWH and TWH after PVI suggests a beneficial influence likely mediated via ablation of the intrinsic cardiac nervous system. Acute responses of PWH and TWH to PVI suggest a favorable dual effect on atrial and ventricular electrical stability and could be used to track individual patients' electrical heterogeneity profile., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sudden cardiac death (SCD) risk is elevated following acute myocardial infarction (MI). The time course of SCD susceptibility post-MI requires further investigation., Methods: In this observational cohort study, we employed state-of-the-art noninvasive ECG techniques to track the daily time course of cardiac electrical instability and autonomic function following ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI). Preventice BodyGuardian MINI-EL Holters continuously recorded ECGs for 7 days at hospital discharge and at 40 days for STEMI (N = 5) or at 90 days for NSTEMI patients (N = 5). Cardiac electrical instability was assessed by T-wave alternans (TWA) and T-wave heterogeneity (TWH); autonomic tone was determined by rMSSD-heart rate variability (HRV)., Results: TWA was severely elevated (≥60 μV) in STEMI patients (80 ± 10.3 μV) at discharge and throughout the first recording period but declined by 50% to 40 ± 2.3 μV (p = .03) by Day 40 and remained in the normal range (<47 μV). TWH, a related phenomenon analyzed from 12-lead ECGs, was reduced by 63% in the five STEMI patients from discharge to normal (<80 μV) at follow-up (105 ± 27.3 to 39 ± 3.3 μV, p < .04) but increased by 65% in a STEMI case (89 to 147 μV), who received a wearable defibrillator vest and later implantable cardioverter defibrillator. In NSTEMI patients, TWA was borderline abnormal (47 ± 3.3 μV) at discharge and declined by 19% to normal (38 ± 1.2 μV) by Day 90 (p = .05). An overall reciprocal increase in rMSSD-HRV suggested recovery of vagal tone., Conclusions: This study provides proof-of-principle for tracking post-MI SCD risk in individual patients with implications for personalized therapy., (© 2022 The Authors. Annals of Noninvasive Electrocardiology published by Wiley Periodicals LLC.)

A dire complication associated with chronic epilepsy is abrupt premature death, currently referred to as sudden unexpected death in epilepsy (SUDEP). Although the traditional view has been that SUDEP is due primarily to peri-ictal respiratory failure leading to cardiac asystole, mounting evidence implicates accelerated heart disease, leading to an "epileptic heart" condition, especially after age 40, as another potential cause of abrupt premature death, although cardiac death is specifically excluded by the standard definition of SUDEP. Sudden cardiac death in epilepsy carries a 2.8-fold greater risk than in the general population and is 4.5 times more frequent than SUDEP. This review will discuss the rationale for routine use of electrocardiograms to assess cardiac risk in patients with epilepsy and the impact of epilepsy treatments, namely antiseizure medications and chronic vagus nerve stimulation., Competing Interests: Conflicts of interest None of the authors has a conflict of interest relative to this review. Drs R.L. Verrier and T.D. Pang are members of the medical advisory board of StratusNeuro (Irving TX). Drs R.L. Verrier and B.D. Nearing receive research funding from LivaNova USA (Houston TX), Medtronic (Minneapolis MN), Preventice Solutions/Boston Scientific (Marlborough MA), and StratusNeuro (Irving TX). Dr T.D. Pang receives research funding from Beth Israel Deaconess Medical Center Department of Neurology. Dr S.C. Schachter receives funding from Elsevier and National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health (NIBIB, NIH)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Sudden cardiac arrest results from cardiac electrical instability and is 3-fold more frequent in patients with chronic epilepsy than in the general population. We hypothesized that focal to bilateral tonic-clonic seizures (FTBTCS) would acutely impact T-wave alternans (TWA), a marker of cardiac electrical instability linked to an elevated risk for sudden cardiac death, more than focal seizures (FS) [focal aware seizures (FAS) and focal with impaired awareness seizures (FIAS)], due to their greater sympathetic stimulation of the heart. Since stress has been shown to cause significant TWA elevations in patients with heart disease, we also hypothesized that the early days of an inpatient admission to an epilepsy monitoring unit (EMU) would be associated with higher TWA levels compared to later hospital days in patients with chronic epilepsy, presumably due to stress., Design/methods: We analyzed the acute effects of seizures [FAS, FIAS, FTBTCS, and nonepileptic seizures (NES)] and day of hospital stay on TWA in 18 patients admitted to the EMU using high-resolution wireless electrocardiographic (ECG) patch monitors., Results: A total of 5 patients had FTBTCS, 7 patients had FS (2 FAS, 5 FIAS), and 3 patients had NES only during the index hospital stay. Four patients did not have any electroclinical seizures or NES. FTBTCS resulted in marked acute increases in ictal TWA from baseline (2 ± 0.3 µV) to ictal maximum (70 ± 6.1 µV, p < 0.0001), the latter exceeding the 60 µV cut point defined as severely abnormal. By comparison, while FAS and FIAS also provoked significant increases in TWA (from 2 ± 0.5 µV to 30 ± 3.3 µV, p < 0.0001), maximum ictal TWA levels did not reach the 47 µV cut point defined as abnormal. Heart rate increases during FTBTCS from baseline (62 ± 5.8 beats/min) to ictal maximum (134 ± 8.6 beats/min, an increase of 72 ± 7.2 beats/min, p < 0.02) were also greater (p = 0.014) than heart rate increases during FS (from 70 ± 5.2 beats/min to 118 ± 6.2 beats/min, an increase of 48 ± 2.6 beats/min, p < 0.03). In 3 patients with NES, TWA rose mildly during the patients' typical episodes (from 2 ± 0.6 µV to 14 ± 2.6 µV, p < 0.0004), well below the cut point of abnormality, while heart rate increases were observed (from 75 ± 1.3 to 112 ± 8.7 beats/min, an increase of 37 ± 8.9 beats/min, p = 0.03). Patients with EEG-confirmed electroclinical seizures recorded while in the EMU exhibited significantly elevated interictal TWA maxima (61 ± 3.4 µV) on EMU admission day which were similar in magnitude to ictal maxima seen during FTBTCS (70 ± 6.1 µV, p = 0.21). During subsequent days of hospitalization, daily interictal TWA maxima showed gradual habituation in patients with both FS and FTBTCS but not in patients with NES only., Conclusions: This is the first study to our knowledge demonstrating that FTBTCS acutely provoke highly significant increases in TWA to levels that have been associated with heightened risk for sudden cardiac death in other patient populations. We speculate that mortality temporally associated with FTBTCS may, in some cases, be due to sudden cardiac death rather than respiratory failure. In patients with EEG-confirmed epilepsy, hospital admission is associated with interictal TWA maxima that approach those seen during FTBTCS, presumably related to stress during the early phase of hospitalization compared to later in the hospitalization, indicating cardiac electrical instability and potential vulnerability to sudden cardiac death related to stress independent of temporal relationships to seizures. The elevated heart rates observed acutely with seizures and on hospital Day 1 are consistent with a hyperadrenergic state and the effect of elevated sympathetic output on a vulnerable cardiac substrate, a phenomenon termed "the Epileptic Heart.", Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

We examined whether T-wave heterogeneity (TWH) on the surface electrocardiographic (EKG) could predict epileptic seizure onset. Patients with electroencephalography-confirmed generalized tonic-clonic seizures (GTCS) (n = 6) exhibited abnormal elevations in TWH (>80 µV) at baseline (105 ± 20.4 µV), which increased from 30 min prior to seizure without heart rate increases > 2 beats/min until 10 min pre-seizure. Specifically, TWH on 3-lead surface EKG patch recordings increased from 1-hour baseline to 30 min (<0.05), 20 min (p < 0.002), 10 min (p = 0.01), and 1 min (p = 0.01) before seizure onset. At 10 min following GTCS, TWH returned to 110 ± 20.3 µV, similar to baseline (p = 0.54). This pre-ictal TWH warning pattern was not present in patients with psychogenic nonepileptic seizures (PNES) (n = 3), as TWH did not increase until PNES and returned to baseline within 10 min after PNES. Acute elevations in TWH may predict impending GTCS and may discriminate patients with GTCS from those with behaviorally similar PNES., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Heart failure with reduced left ventricular ejection fraction is a progressive disease that claims > 352,000 lives annually in the United States alone. Despite the development of an extensive array of pharmacologic and device therapies, prognosis remains poor. Disruption in autonomic balance in the form of heightened sympathetic nerve activity and reduced vagal tone have been established as major causes of heart failure progression. Interest in chronic neuromodulation mediated by vagus nerve stimulation (VNS) has intensified in recent years. This review focuses on four main goals: (1) To review the preclinical evidence that supports the concept of a cardioprotective effect of VNS on autonomic function and cardiac electrical stability along with the underlying putative mechanisms. (2) To present the initial clinical experience with chronic VNS in patients with heart failure and highlight the controversial aspects of the findings. (3) To discuss the latest findings of the multifactorial effects of VNS on autonomic tone, baroreceptor sensitivity, and cardiac electrical stability and the state-of-the-art methods employed to monitor these relationships. (4) To discuss the implications of the current findings and the gaps in knowledge that require attention in future investigations., Competing Interests: RV and BN receive research funding from LivaNova USA. BK and IL are employees of LivaNova USA., (Copyright © 2022 Verrier, Libbus, Nearing and KenKnight.)

This virtual workshop was convened by the National Heart, Lung, and Blood Institute, in partnership with the Office of Strategic Coordination of the Office of the National Institutes of Health Director, and held September 2 to 3, 2020. The intent was to assemble a multidisciplinary group of experts in basic, translational, and clinical research in neuroscience and cardiopulmonary disorders to identify knowledge gaps, guide future research efforts, and foster multidisciplinary collaborations pertaining to autonomic neural mechanisms of cardiopulmonary regulation. The group critically evaluated the current state of knowledge of the roles that the autonomic nervous system plays in regulation of cardiopulmonary function in health and in pathophysiology of arrhythmias, heart failure, sleep and circadian dysfunction, and breathing disorders. Opportunities to leverage the Common Fund's SPARC (Stimulating Peripheral Activity to Relieve Conditions) program were characterized as related to nonpharmacologic neuromodulation and device-based therapies. Common themes discussed include knowledge gaps, research priorities, and approaches to develop novel predictive markers of autonomic dysfunction. Approaches to precisely target neural pathophysiological mechanisms to herald new therapies for arrhythmias, heart failure, sleep and circadian rhythm physiology, and breathing disorders were also detailed., Competing Interests: This workshop was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institutes of Health (NIH) Office of the Director. Dr Ajijola is supported by NIH grants DP2 OD024323, OT2 OD028201, and OT2 OD023848, Dr Chen was supported by NIH grants OT2 OD028190, R01 HL139829, and the Burns & Allen Chair in Cardiology Research, Cedars-Sinai Medical Center. Dr Clancy has received research funding from NIH grants OT2 OD026580, OT2 OD026580, R01 HL152681, R01 HL128170, and U01 HL126273, InCarda Therapeutics, and the Department of Physiology and Membrane Biology Research Partnership Fund, Oracle cloud for research allocation. Dr Delisle is supported by NIH grants R01 HL153042, R01 HL141343, and the American Heart Association grant 20IPA35320141. Dr Habecker was supported by NIH grants R01 HL093056 and R01 HL146822. Dr Handoko has received an educational grant from Novartis and Boehringer Ingelheim. Dr Redline has received research funding from NIH grants R35 HL135818, R01 HL133684, U10 HD036801, R01 HL137234, R01 DK118736, R01 AG056331, and U24 HL140412, and Jazz Pharmaceuticals. Dr Ripplinger is supported in part by research funding from NIH grants OT2 OD026580, R01 HL093056, and R01 HL111600. Dr Somers is supported by NIH grants R01 HL065176 and R01 HL134885. Dr Stavrakis was supported by NIH grant R21 AG057879. Dr Taylor-Clark is supported by NIH grants R01 HL152219, U01 NS113868, OT2 OD023854, R21 DK124894, R01 DK110366, and U01 DK110366. Dr Undem is supported by NIH grant R35 HL155671. Dr Zucker has received support from Sorrento Therapeutics, Inc. and from NIH grant R01 HL126796. Dr Shivkumar is supported by NIH grants OT2 OD028201 and OT2 OD023848. Dr Ajijola is a cofounder and equity holder of NeuCures; has served as a consultant for Merck and Biosense-Webster Inc. Dr Gold has received clinical trial research funding from Boston Scientific and Medtronic; and has been a consultant for Boston Scientific, CVRx. and Medtronic. Dr Habecker is a co-inventor of a technology (intracellular sigma peptide) that Oregon Health and Science University has licensed to NervGen Pharma Corp. Dr Handoko has received research funding from Vifor Pharma; and has been a consultant for Novartis, Boehringer Ingelheim, Vifor Pharma, AstraZeneca, Bayer, MSD, Daiichi Sankyo, and Quin. Dr Hummel has been a scientific advisory board member; and holds equity in Nuvaira, Inc. Dr Redline has received consulting fees from Jazz Pharmaceuticals and Apnimed Inc. Dr Redline has received research funding from Jazz Pharmaceuticals. Dr Somers has served as a consultant for Bayer, Respicardia, Baker Tilly, and Jazz Pharmaceuticals; and has served on the scientific advisory board of the Sleep Number Corporation. Dr Shivkumar is a cofounder and equity holder of NeuCures Inc. Dr Simon is supported in part by NIH grant R01 AG058659, serves on a clinical trial steering committee for Janssen, and has consulted for Acceleron and Bial. Dr Mehra is supported by NIH grants U01HL125177, UH3HL140144 and the American Heart Association AHA 18SFRN34170013. Dr Arora is supported by NIH grants R01 HL140061, R01 HL125881, Technology Development Program, NIH Center for Accelerated Innovations at Cleveland Clinic, the American Heart Association Strategically Focused Research Networks Atrial Fibrillation Center, and has ownership interest in Rhythm Therapeutics, Inc. Dr Handoko is supported by the Dutch Heart Foundation (Senior Clinical Scientist grant 2020T058); has received research funding from Vifor Pharma; and has been a consultant for Novartis, Boehringer Ingelheim, Vifor Pharma, AstraZeneca, Bayer, MSD, Daiichi Sankyo, and Quin. The views expressed in this article are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2022 The Authors.)

Heterogeneity in depolarization and repolarization among regions of cardiac cells has long been recognized as a major factor in cardiac arrhythmogenesis. This fundamental principle has motivated development of noninvasive techniques for quantification of heterogeneity using the surface electrocardiogram (ECG). The initial approaches focused on interval analysis such as interlead QT dispersion and T peak -T end difference. However, because of inherent difficulties in measuring the termination point of the T wave and commonly encountered irregularities in the apex of the T wave, additional techniques have been pursued. The newer methods incorporate assessment of the entire morphology of the T wave and in some cases of the R wave as well. This goal has been accomplished using a number of promising vectorial approaches with the resting 12-lead ECG. An important limitation of vectorcardiographic analyses is that they require exquisite stability of the recordings and are not inherently suitable for use in exercise tolerance testing (ETT) and/or ambulatory ECG monitoring for provocative stress testing or evaluation of the influence of daily activities on cardiac electrical instability. The objectives of the present review are to describe a technique that has been under clinical evaluation for nearly a decade, termed "interlead ECG heterogeneity." Preclinical testing data will be briefly reviewed. We will discuss the main clinical findings with regard to sudden cardiac death risk stratification, heart failure evaluation, and myocardial ischemia detection using standard recording platforms including resting 12-lead ECG, ambulatory ECG monitoring, ETT, and pharmacologic stress testing in conjunction with single-photon emission computed tomography myocardial perfusion imaging., (© 2021 Wiley Periodicals, Inc.)

Aims: We analysed whether incorporating electrocardiographic interlead T-wave heterogeneity (TWH) with myocardial perfusion imaging (MPI) during pharmacologic stress improves detection of flow-limiting lesions (FLL)., Methods and Results: Medical records of all 103 patients at our institution who underwent stress testing with regadenoson (0.4 mg IV bolus) within 3 months of coronary angiography from September 2017 to March 2019 were studied. Cases (N = 59) had angiographically significant FLL (≥50% of left main or ≥70% of other epicardial coronary arteries ≥2 mm in diameter); controls (N = 44) were normal or had non-FLL. TWH, i.e., interlead splay of T waves, was assessed from precordial leads V4-6 by second central moment analysis. Maximum TWHV4-6 levels during regadenoson stress were 68% higher in cases than in controls (P < 0.0001). TWHV4-6 generated areas under the receiver-operating characteristic (ROC) curve of 0.79 in men (P < 0.0001) and 0.71 in women (P = 0.007). In men, the ROC-guided 54-µV TWHV4-6 cut-point for FLL produced adjusted odds of 7.3 [95% confidence interval (CI): 1.3-41.5, P = 0.03], 79% sensitivity, and 78% specificity. In women, the ROC-guided 35-µV TWHV4-6 cut-point produced adjusted odds of 4.5 (95% CI: 1.1-18.9, P = 0.04), 84% sensitivity, and 52% specificity. Adding TWHV4-6 to MPI determinations reduced false-positive results by 70%, more than doubled true-negative results, and improved adjusted odds ratio to 6.8 (95% CI: 2.2-21.4, P = 0.001) with specificity of 78% in men and 86% in women., Conclusion: This observational study is the first to demonstrate the benefit of combining TWHV4-6 with MPI to enhance FLL detection during MPI with regadenoson in both men and women., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)