Search

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.

The cover image is based on the Original Article Continuous multi‐day tracking of post‐myocardial infarction recovery of cardiac electrical stability and autonomic tone using electrocardiogram patch monitors by Richard L. Verrier et al., https://doi.org/10.1111/anec.13035. Image Credit: Richard L. Verrier and Bruce D. Nearing. [Image: see text]

Prevention of premature death in patients with chronic epilepsy remains a major challenge. Multiple pathophysiologic factors have been implicated, with intense investigation of cardiorespiratory mechanisms. Up to four in five patients with chronic epilepsy exhibit cardiovascular comorbidities. These findings led us to propose the concept of an "epileptic heart," defined as "a heart and coronary vasculature damaged by chronic epilepsy as a result of repeated surges in catecholamines and hypoxemia leading to electrical and mechanical dysfunction." Among the most prominent changes documented in the literature are high incidence of myocardial infarction and arrhythmia, altered autonomic tone, diastolic dysfunction, hyperlipidemia, and accelerated atherosclerosis. This suite of pathologic changes prompted us to propose for the first time in this review a syndromic approach for improved clinical detection of the epileptic heart condition. In this review, we discuss the key pathophysiologic mechanisms underlying the candidate criteria along with standard and novel techniques that permit evaluation of each of these factors. Specifically, we present evidence of the utility of standard 12-lead, ambulatory, and multiday patch-based electrocardiograms, along with measures of cardiac electrical instability, including T-wave alternans, heart rate variability to detect altered autonomic tone, echocardiography to detect diastolic dysfunction, and plasma biomarkers for assessing hyperlipidemia and accelerated atherosclerosis. Ultimately, the proposed clinical syndromic approach is intended to improve monitoring and evaluation of cardiac risk in patients with chronic epilepsy to foster improved therapeutic strategies to reduce premature cardiac death.

Purpose Disturbed autonomic function is implicated in high mortality rates in heart failure patients. High-intensity vagus nerve stimulation therapy was shown to improve intrinsic heart rate recovery and left ventricular ejection fraction over a period of 1 year. Whether these beneficial effects are sustained across multiple years and are related to improved baroreceptor response was unknown. Methods All patients (n = 21) enrolled in the ANTHEM-HF clinical trial (NCT01823887, registered 4/3/2013) with 24 h ambulatory electrocardiograms at all time points and 54 normal subjects (PhysioNet database) were included. Intrinsic heart rate recovery, based on ~ 2000 spontaneous daily activity-induced heart rate acceleration/deceleration events per patient, was analyzed at screening and after 12, 24, and 36 months of chronic vagus nerve stimulation therapy (10 or 5 Hz, 250 μs pulse width, 18% duty cycle, maximum tolerable current amplitude). Results In response to chronic high-intensity vagus nerve stimulation (≥ 2.0 mA), intrinsic heart rate recovery (all time points, p p ≤ 0.02), and left ventricular ejection fraction (all, p ≤ 0.04) were improved over screening at 12, 24, and 36 months. Intrinsic heart rate recovery and heart rate turbulence slope were inversely correlated at both screening (r = 0.67, p r = 0.78, p Conclusion This non-randomized study provides evidence of an association between improvement in intrinsic heart rate recovery and left ventricular ejection fraction during high-intensity vagus nerve stimulation for a period of ≥ 3 years. Correlated favorable effects on heart rate turbulence slope implicate enhanced baroreceptor function in response to chronic, continuously cyclic vagus nerve stimulation as a physiologic mechanism.

Patients with heart failure with reduced left ventricular ejection fraction (LVEF) (HFrEF) experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased mortality risk. The Autonomic Neural Regulation Therapy to Enhance Myocardial Function in Heart Failure (ANTHEM-HF) trial reported improved heart rate variability (HRV) and heart rate turbulence (HRT) and reduced T-wave alternans (TWA) after 12 months of vagus nerve stimulation (VNS). We investigated whether the benefits of chronic VNS persist in the long term.Effects of chronic VNS on heart rate, HRV, HRT, TWA, R-wave and T-wave heterogeneity (RWH, TWH), and nonsustained ventricular tachycardia (NSVT) incidence were evaluated in all ANTHEM-HF patients with ambulatory ECG data at 24 and 36 months (n = 25). Autonomic markers improved significantly at 24 and 36 months compared to baseline [heart rate, square root of the mean squared differences of successive normal-to-normal intervals (rMSSD), standard deviation of the normal-to-normal intervals (SDNN), HF-HRV, HRT slope, P0.05]. Peak TWA levels remained reduced at 24 and 36 months (P0.0001). Reductions in RWH and TWH at 6 and 12 months persisted at 24 and 36 months (P0.01). NSVT decreased at 12, 24, and 36 months (P0.025). No sudden cardiac deaths, ventricular fibrillation, or sustained ventricular tachycardia occurred.In symptomatic patients with HFrEF, chronic VNS appears to confer wide-ranging, persistent improvements in autonomic tone (HRV), baroreceptor sensitivity (HRT), and cardiac electrical stability (TWA, RWH, TWH).

Pharmacologic management of atrial fibrillation (AF) is a pressing problem. This arrhythmia afflicts >5 million individuals in the United States and prevalence is estimated to rise to 12 million by 2050. Although the pill-in-the-pocket regimen for self-administered AF cardioversion introduced over a decade ago has proven useful, significant drawbacks exist. Among these are the relatively long latency of effects in the range of hours along with potential for hypotension and other adverse effects. This experience prompted development of a new strategy for increasing plasma concentrations of antiarrhythmic drugs rapidly and for a limited time, namely, pulmonary delivery. In preclinical studies in Yorkshire pigs, intratracheal administration of flecainide was shown to cause a rapid, reproducible increase in plasma drug levels. Moreover, pulmonary delivery of flecainide converted AF to normal sinus rhythm by prolonging atrial depolarization, which slows intra-atrial conduction and seems to be directly correlated with efficacy in converting AF. The rapid rise in plasma flecainide levels optimizes its anti-AF effects while minimizing adverse influences on ventricular depolarization and contractility. A more concentrated and soluble formulation of flecainide using a novel cyclodextrin complex excipient reduced net drug delivery for AF conversion when compared to the acetate formulation. Inhalation of the beta-adrenergic blocking agent metoprolol slows ventricular rate and can also terminate AF. In human subjects, oral inhalation of flecainide acetate with a hand-held, breath-actuated nebulizer results in signature prolongation of the QRS complex without serious adverse events. Thus, pulmonary delivery is a promising advance in pharmacologic approach to management of AF.

BACKGROUND: Refractory epilepsy confers a considerable lifetime risk of sudden unexplained death (SUDEP). Mechanisms may overlap with sudden cardiac death (SCD), particularly regarding QTc prolongation. Guidelines in the US do not mandate the use of ECG in diagnostic evaluation of seizures or epilepsy. OBJECTIVE: We aimed to determine the frequency of ECG use, QT prolongation and whether it predicts mortality in patients with seizures. METHODS: We performed a retrospective cohort study including all patients seen at Mayo Clinic in Rochester, MN from January 1(st) 2000 to July 31(st) 2015 with index evaluation for seizure or epilepsy. Patients with an ECG were categorized by presence of a prolonged QT interval with a primary endpoint of all-cause mortality after the 15-year observation period. RESULTS: Optimal cut-off QT intervals most predictive of mortality were identified. Median age was 40.0 years. An ECG was obtained in 18,222 (57.4%) patients. After excluding patients with confounding ECG findings, primary prolonged QT intervals were seen in 223 (1.4%) cases, similar to general population. Kaplan-Meier analysis demonstrated a significant increase in mortality (Cox HR 1.90; 95%CI: 1.76, 2.05) for prolonged optimal cut-off QT, maintained after adjustments for age, Charlson Comorbidity Index and sex (HR 1.48; 95%CI: 1.37, 1.59). CONCLUSIONS: Use of ECG in diagnostic workup of patients with seizures is poor. A prolonged optimal cut-off QTc interval predicts all-cause mortality in patients evaluated for seizure and those diagnosed with epilepsy. We advocate the routine use of a 12-lead ECG at index evaluation in patients with seizure or epilepsy.

The cover image is based on the Review Article Spectrum of clinical applications of interlead ECG heterogeneity assessment: From myocardial ischemia detection to sudden cardiac death risk stratification by Richard L. Verrier, Bruce D. Nearing, and Andre D'Avila., https://doi.org/10.1111/anec.12894. [Image: see text]

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.

ObjectiveWe hypothesized that cardiac electrical instability and abnormal autonomic tone result from cumulative cardiac injury sustained in recurrent seizures. We tested this hypothesis by comparing T-wave alternans (TWA) and heart rate variability (HRV), both established markers of sudden cardiac death (SCD) risk, in patients with chronic as compared to newly diagnosed epilepsy.MethodsIn this prospective, observational cohort study, patients (newly diagnosed epilepsy, n = 6, age 41.8 ± 6.8 years; chronic epilepsy, n = 6, age 40.2 ± 5.6 years [p = 0.85]) were monitored either with Holter recorder alone or simultaneously with 14-day Zio XT extended continuous ECG patch monitor. TWA was assessed by Food and Drug Administration–cleared Modified Moving Average analysis; HRV was calculated by rMSSD.ResultsTWA levels in chronic epilepsy were significantly higher than in newly diagnosed epilepsy (62 ± 5.4 vs 35 ± 1.3 μV, p < 0.002); the latter did not differ from healthy control adults. In all patients with chronic epilepsy, TWA exceeded the established ≥47-μV TWA cutpoint and rMSSD HRV was inversely related to TWA levels. Patients with chronic epilepsy exhibited elevated TWA levels equivalently on Holter and ECG patch recordings (p = 0.38) with a high correlation (r2 = 0.99, p < 0.01) across 24 hours.ConclusionBased on the limited number of patients studied, it appears that chronic epilepsy, the common use of sodium channel antagonists, or other factors are associated with higher TWA levels and simultaneously with lower rMSSD HRV, which is suggestive of autonomic dysfunction or higher sympathetic tone. The ECG patch monitor used has equivalent accuracy to Holter monitoring for TWA and HRV and permits longer-term ECG sampling.

Improved electrocardiographic (EKG) markers and monitoring platforms for sudden cardiac death risk are urgently needed. Wearable wireless EKG patches offer a patient-friendly novel approach to long-term monitoring, in the range of two weeks, extending traditional Holter monitoring, which is typically limited to 24–48 h. The capacity to transmit recordings via telemetry to health care providers offers a further benefit for real-time detection and analysis of cardiac events. Until recently, the primary application of EKG patches has been evaluation of syncope and atrial and ventricular rhythm abnormalities. Used in combination with highly accurate algorithms for monitoring QT intervals and T-wave alternans, a beat-to-beat fluctuation in ST-segment and T-wave morphology linked to sudden cardiac death risk, the applications of EKG monitoring can be significantly expanded.

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.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.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.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."

Background The negative inotropic effect of Class IC antiarrhythmic drugs limits their use for acute cardioversion of atrial fibrillation (AF). Objective The purpose of this study was to examine, in an intact porcine model, the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility and QRS complex width at doses that are effective in converting new-onset AF to sinus rhythm. Methods Flecainide (1.5 mg/kg bolus) was delivered by intratracheal administration and compared to 2.0 mg/kg 10-minute IV administration (European Society of Cardiology guideline) and to 0.5 and 1.0 mg/kg 2-minute IV doses in 40 closed-chest, anesthetized Yorkshire pigs. Catheters were fluoroscopically positioned in the LV to monitor QRS complex width and contractility and at the bifurcation of the main bronchi to deliver intratracheal flecainide. Results Peak flecainide plasma concentrations (Cmax) were similar, but the 30-minute area under the curve (AUC) of plasma levels was 1.4- to 2.8-fold greater for 2.0 mg/kg 10-minute IV infusion than for the lower, more rapidly delivered intratracheal and IV doses. AUC for LV contractility (ie, negative inotropic burden) was 2.2- to 3.6-fold greater for 2.0 mg/kg 10-minute IV dose than for the lower, more rapidly delivered doses. QRS complex widening by flecainide was highly correlated with the decrease in LV contractility (r2 = 0.890, P Conclusion QRS complex widening in response to flecainide is strongly correlated with decrease in LV contractility. Rapid pulmonary or IV flecainide delivery reduces the negative inotropic burden while quickly achieving Cmax levels associated with conversion of AF.

Background We investigated whether T‐wave heterogeneity (TWH) can identify patients who are at risk for near‐term cardiac mortality. Methods A nested case–control analysis was performed in the 888 patients admitted to the Emergency Department (ED) of our medical center in July through September 2018 who had ≥2 serial troponin measurement tests within 6 hr for acute coronary syndrome evaluation to rule‐in or rule‐out the presence of acute myocardial infarction. Patients who died from cardiac causes during 90 days after ED admission were considered cases (n = 20; 10 women) and were matched 1:4 on sex and age with patients who survived during this period (n = 80, 40 women). TWH, that is, interlead splay of T waves, was automatically assessed from precordial leads by second central moment analysis. Results TWHV4‐6 was significantly elevated at ED admission in 12‐lead resting ECGs of female patients who died of cardiac causes during the following 90 days compared to female survivors (100 ± 14.9 vs. 40 ± 3.6 µV, p

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.

Background Reliable quantitative predictors of response to cardiac resynchronization therapy (CRT) are needed. We compared the utility of pre-implantation R-wave and T-wave heterogeneity (RWH, TWH) to standard QRS complex duration for determination of mechanical super-response and mortality risk. Methods Of patients who received CRT devices between 2006 and 2018 at our institution, we retrospectively analyzed resting 12-lead ECG recordings from all 155 who met class I and IIA ACC/AHA/HRS guideline-based indications and had echocardiograms before and after implantation. Super-responders (n=35) (patients with ≥20% increase in LVEF and/or ≥20% decrease in LVESD) were compared to non super-responders (n=120), who did not. RWH and TWH, i.e., interlead splay, were measured by second central moment analysis. QRS complex duration was computed from the longest interval in a representative non-premature beat. Results Pre-implantation RWHV1–3 (p=0.01) and TWH in all lead sets tested (p=0.004 to 0.04) were significantly lower in super-responders than in non super-responders with corresponding significance for area under the curve (AUC) (p=0.002 to 0.03). Preimplantation QRS complex duration did not differ between super-responders and non super-responders (166±3 vs. 167±2 ms, p=0.8); the AUC for QRS complex duration (0.48, p=0.74) was not significant. RWHV1–3LILII at >420 μV predicted 3-year all-cause mortality (p=0.037) with a hazard ratio of 7.440 (95% CI: 1.015–54.527, p=0.048) but QRS complex duration >150 ms did not predict mortality (p=0.27). Conclusion Pre-implantation interlead EKG heterogeneity is superior to QRS complex duration in predicting mechanical super-response to CRT and survival. Bortolotto ESC graph Funding Acknowledgement Type of funding source: None

Background/Introduction The negative inotropic effect of certain antiarrhythmic drugs limits their use for acute cardioversion of new-onset paroxysmal atrial fibrillation (AF). Purpose In an intact porcine model of AF, we examined the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility, i.e., LV dP/dt max, at doses that are effective in converting AF to sinus rhythm. The magnitude of the decrease in LV dP/dt max and time that it remained below baseline, measured by the area under the curve (AUC), is referred to as negative inotropic burden. Methods Flecainide was delivered via intratracheal administration at 1.5 mg/kg bolus and compared to IV infusion at 1.0 mg/kg over 2 min (lower-dose, rapid) and 2.0 mg/kg over 10 min (ESC guideline) in 11 closed-chest, anesthetized Yorkshire pigs. These doses of flecainide have been shown effective in converting AF to sinus rhythm. Catheters were fluoroscopically positioned in the right atrium for pacing at 140 beats/min and in the LV to measure QRS complex duration and contractility (LV dP/dt). Intratracheal flecainide was delivered via a catheter positioned at the bifurcation of the main bronchi. Results The peak plasma levels (Cmax values) were similar but the AUC of plasma concentrations over time was greater for the higher-dose, slow IV infusion of flecainide than for either intratracheal instillation (by 32%) or lower-dose, rapid IV infusion (by 88%). Based on AUCs of LV dP/dt max (figure, left panel), the negative inotropic burden is 3.1- to 3.8-fold greater for the higher IV (1006% • min) than for the lower IV (323%·min) or the intratracheal doses (263% • min). There was a corresponding inverse increase in the AUC of QRS complex prolongation. The decrease in LV dP/dt max (Δ%) was correlated with the prolongation of the QRS complex (Δms) (y = −1.4337x + 3.6613, r2=0.69, p Conclusion Rapid delivery of pulmonary or IV flecainide reduces the dose of drug required to achieve Cmax levels associated with conversion of AF. The attendant decrease across time in exposure of the ventricles to flecainide reduces QRS complex prolongation and the accompanying negative inotropic burden. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): InCarda Therapeutics, Inc.

BACKGROUND Pulmonary delivery of flecainide results in the rapid conversion of atrial fibrillation (AF) to normal sinus rhythm in large-animal models and is safe and well-tolerated by normal human volunteers. OBJECTIVE We investigated the effects of pulmonary delivery of flecainide on atrial and ventricular depolarization and repolarization duration. METHODS Intratracheal instillation (1.5 mg/kg, rapid push) of flecainide or sterile water (placebo) was performed in 12 closed-chest, anesthetized Yorkshire pigs with a catheter positioned at the bifurcation of the main bronchi. High-resolution electrograms obtained from catheters fluoroscopically positioned in the right atrium and left ventricle circumvented measurement errors due to the fusion of P and T waves in surface leads when rapid heart rates shortened the TP interval. Pacing was achieved using electrical stimuli delivered via right atrial catheter electrodes. RESULTS During sinus rhythm (98 ± 4.7 beats/min), intratracheal flecainide caused comparable (P = 0.56) increases in atrial depolarization (P a ) duration by 22% (39.8 ± 3.2 to 48.7 ± 3.3 milliseconds) and left ventricular (LV) QRS complex duration by 20% (47.9 ± 1.6 to 57.3 ± 1.8 milliseconds) at peak effect at 2 minutes post-dosing. During right atrial pacing at 180 beats/min, Pa duration increased by 55% (37.0 ± 2.0 to 57.2 ± 1.6 milliseconds; P

We compared the pharmacokinetic (PK) profile and electrocardiographic (ECG) changes in response to intratracheal instillation of flecainide acetate into the left atrium and ventricle with intravenous (IV) flecainide acetate administration. In 12 closed-chest anesthetized Yorkshire pigs, we monitored the QRS complex and PR, JTc, and QTc intervals during sinus rhythm and correlated changes with venous plasma drug concentrations before and at 2, 5, 10, 15, and 30 minutes after drug administration. Intratracheal instillation of flecainide (0.75 and 1.5 mg/kg, rapid bolus) caused dose/concentration-dependent increases in the QRS complex duration of 10% and 19%, respectively, at 2 minutes, coinciding with peak venous plasma levels (1688 ± 177 and 2808 ± 217 ng/mL, respectively). IV infusion of flecainide (2 mg/kg) over 2 or 10 minutes similarly prolonged QRS complexes and PR intervals (both, P < 0.001). Intratracheal flecainide instillation increased PR interval briefly at 5 minutes. Neither intratracheal nor IV flecainide affected JTc or QTc intervals. Thus, the PK pattern of intratracheal instillation of flecainide is comparable to IV administration, although the absolute plasma concentrations were higher with IV infusion. Both modes of delivery elicited ECG changes that were consistent with the expected pharmacological activity of flecainide.

ObjectiveTranscatheter aortic valve replacement (TAVR) complications include left bundle branch block (LBBB) and right ventricular paced rhythm (RVP). We hypothesised that changes in electrocardiographic heterogeneity would correlate better with speckle tracking strain measures than with left ventricular ejection fraction (LVEF) on transthoracic echocardiogram (TTE) among patients with TAVR-induced conduction abnormalities.MethodsWe reviewed medical records of 446 consecutive patients who underwent TAVR at our institution. Of the 238 patients with 12-lead electrocardiograms (ECGs) that met our inclusion criteria, 58 had pre-TAVR and post-TAVR TTEs adequate for strain assessment. We compared patients who did not have an LBBB or RVP pre-TAVR and post-TAVR (controls, n=11) with patients who developed LBBBs (n=11) and who required RVPs (n=10) post-TAVR. In our study population (n=32, 41% female, mean age 85.8 years), we evaluated QRS complex duration, R-wave heterogeneity (RWH), T-wave heterogeneity (TWH), LVEF, global longitudinal strain (GLS) and mechanical dispersion (MD).ResultsTAVR-induced changes on ECG did not correlate with LVEF. TAVR-induced changes in MD and QRS complex duration correlated among all patients (r=0.4, p=0.04). GLS and RWH correlated among RVP patients (r=0.7, p=0.00003). MD and TWH correlated among LBBB patients (r=0.7, p=0.00004).ConclusionsIn this convenience sample of patients with TAVR-induced conduction abnormalities, RWH and TWH correlated with strain measures but not with LVEF. Strain measures, RWH and TWH may offer additional insights for pre-TAVR evaluation and post-TAVR clinical management.

Introduction Nonuniformities in depolarization and repolarization morphology are critical factors in ventricular arrhythmogenesis. Methods and results We assessed interlead R-wave and T-wave heterogeneity (RWH, TWH) in standard 12-lead electrocardiograms using second central moment analysis. This technique quantifies variance about the mean morphology of beats in adjoining precordial leads, V4, V5, and V6. The study was conducted in 120 consecutive patients without an apparent reversible trigger for VT, recent myocardial infarction, or active ischemia, who presented for electrophysiologic study, implantable cardioverter defibrillator (ICD) placement, or generator change at our institution from 2008 to 2011. Primary outcome was sustained VT/VF or appropriate ICD therapies. Secondary outcome was arrhythmic death or resuscitated cardiac arrest. Cutpoints for elevated RWH (>160 μV) and TWH (>80 μV) identified 69% of primary outcome cases and 85% of secondary outcome cases. Cardiomyopathy patients who met the primary outcome (n = 42) had significantly higher TWH than those who did not (n = 28) (TWH: 95±11 vs. 44±9 μV, p

Introduction We examined the effects of the selective late INa inhibitor eleclazine on the 50% probability of successful defibrillation (DFT50) before and after administration of amiodarone to determine its suitability for use in patients with implantable cardioverter defibrillators (ICDs). Methods and results In 20 anesthetized pigs, transvenous active-fixation cardiac defibrillation leads were fluoroscopically positioned into right ventricular apex through jugular vein. ICDs were implanted subcutaneously. Dominant frequency of ventricular fibrillation was analyzed by fast Fourier transform. The measurements were made before drug administration (control), and at 40 minutes after vehicle, eleclazine (2 mg/kg, i.v., bolus over 15 minutes), or subsequent/single amiodarone administration (10 mg/kg, i.v., bolus over 10 minutes). Eleclazine did not alter DFT50, dominant frequency, heart rate, or mean arterial pressure (MAP). Subsequent amiodarone increased DFT50 (P = 0.006), decreased dominant frequency (P = 0.022), and reduced heart rate (P = 0.031) with no change in MAP. Amiodarone alone increased DFT50 (P = 0.005; NS compared to following eleclazine) and decreased dominant frequency (P = 0.003; NS compared to following eleclazine). Conclusion Selective late INa inhibition with eleclazine does not alter DFT50 or dominant frequency of ventricular fibrillation when administered alone or in combination with amiodarone. Accordingly, eleclazine would not be anticipated to affect the margin of defibrillation safety in patients with ICDs.

Identification of individuals at risk for sudden cardiac death (SCD), the primary cause of adult mortality in industrially developed countries, persists as a major challenge. The main contemporary noninvasive marker, left ventricular ejection fraction (LVEF), has not proved adequately reliable, as the majority of individuals who succumb to SCD have relatively preserved LVEF. Monitoring of T-wave alternans (TWA), a beat-to-beat fluctuation in ST-segment or T-wave morphology, on ambulatory electrocardiogram is an attractive approach on both scientific and clinical grounds. Specifically, TWA's capacity to assess risk for life-threatening ventricular arrhythmias has been shown to rest on sound electrophysiologic principles, and TWA monitoring can be carried out during the conduct of routine clinical evaluation. This review (1) summarizes briefly the electrophysiology basis for TWA's predictive capacity and the underlying physiologic factors that influence its level; (2) discusses the contemporary methodologies and clinical evidence supporting TWA's predictive value; and (3) reviews available evidence indicating potential sex-related differences in this phenomenon.

From 95,196 sample adults in the combined 2010, 2013, and 2015 U.S. National Health Interview Survey, we estimated the association between histories of epilepsy and heart disease after accounting for sociodemographic characteristics and behavioral risk factors. Adults 18 years old or older with an epilepsy history reported heart disease (21%) about nine percentage points more often than those without such a history (12%), overall and within levels of characteristics and risk factors. These increases in heart disease history for adults with an epilepsy history compared with adults without such a history were greater in those 45–64 years old or at the lowest family income levels. These increases of heart disease in adults with an epilepsy history highlight two needs—to prevent the occurrence of heart disease and to reduce its consequences. Because comorbidity from heart disease can complicate epilepsy management, physicians caring for those with epilepsy should be aware of these increased risks, identify risk factors for heart disease, and recommend to their patients with epilepsy ways to diminish these risks.

Background Safe, effective pulmonary delivery of cardioactive agents in humans is under development. Objectives We examined whether intratracheal delivery of metoprolol can reduce ventricular rate during atrial fibrillation (AF) and accelerate conversion to sinus rhythm. Methods In 7 closed-chest, anesthetized Yorkshire pigs, AF was induced by intrapericardial infusion of acetylcholine (1 mL of 102.5-mM solution) followed by atrial burst pacing and was allowed to continue for 2 minutes before intratracheal instillation of sterile water or metoprolol (0.2-mg/kg bolus) using a catheter positioned at the bifurcation of the main bronchi. High-resolution electrograms were obtained from catheters fluoroscopically positioned in the right atrium and left ventricle. Results Rapid intratracheal instillation of metoprolol caused a 32-beat/min reduction in ventricular rate during AF (from 272 ± 13.7 to 240 ± 12.6 beats/min, P = 0.008) and a 2.3-minute reduction in AF duration (from 10.3 ± 2.0 to 8.0 ± 1.4 minutes, P = 0.018) compared with sterile water control. Conversion of AF to sinus rhythm was associated with rapid restoration (5-6 minutes) of heart rate and arterial blood pressure toward control values. Intratracheal metoprolol reduced AF dominant frequency by 31% (from 8.7 ± 0.9 to 6.0 ± 1.1 Hz, P = 0.04) compared with control and resulted in a trend toward a 5% increase in PR interval (from 174 ± 11.2 to 182 ± 11.4 ms, P = 0.07). Conclusions Intratracheal delivery of metoprolol effectively reduces ventricular rate during AF and accelerates conversion to normal sinus rhythm in a pig model of acetylcholine-induced AF.

Sudden unexpected death in epilepsy (SUDEP) is generally considered to result from a seizure, typically convulsive and usually but not always occurring during sleep, followed by a sequence of events in the postictal period starting with respiratory distress and progressing to eventual cardiac asystole and death. Yet, recent community-based studies indicate a 3-fold greater incidence of sudden cardiac death in patients with chronic epilepsy than in the general population, and that in 66% of cases, the cardiac arrest occurred during routine daily activity and without a temporal relationship with a typical seizure. To distinguish a primarily cardiac cause of death in patients with epilepsy from the above description of SUDEP, we propose the concept of the "Epileptic Heart" as "a heart and coronary vasculature damaged by chronic epilepsy as a result of repeated surges in catecholamines and hypoxemia leading to electrical and mechanical dysfunction." This review starts with an overview of the pathophysiological and other lines of evidence supporting the biological plausibility of the Epileptic Heart, followed by a description of tools that have been used to generate new electrocardiogram (EKG)-derived data in patients with epilepsy that strongly support the Epileptic Heart concept and its propensity to cause sudden cardiac death in patients with epilepsy independent of an immediately preceding seizure.